109
Critical Review,s in Oncology/Hematology. 1991; 11: 109-135 0 1991 Elsevier Science Publishers B.V. 1040-8428/91/$3.50
ONCHEM
00006
Small cell carcinoma of the lung: clinical and biologic aspects Jean Viallet ‘NCI-Navy
and Daniel C. Ihde’
Medical Oncology Branch, National Cancer Institute and National Naval Medical Center, and Uniformed Services University @‘the
Health Sciences1 Bethesda, MD. U.S.A. and 2the Departments
of Medicine and Oncology and the Montreal General Hospital Lung Oncology Group,
McGill University,
Montreal,
Quebec, Canada
Contents 1.
Introduction
II.
..............................................................
..................... Current status of therapeutic approaches to SCLC ............................. A. Combination and single-agent chemotherapy. . .. . Clinical features,
III.
B. Intensity c.
pathology,
staging,
of induction
Cyclic alternating
D. Duration
of chemotherapy
F. Strategies
factors
110 112 112
chemotherapy
non-cross
E. Late intensification
109
and prognostic
113
resistant
chemotherapy
and management
with autologous
for evaluation
regimens.
113
of tumor progression
bone marrow
114
transplantation.
114
.
of new drugs
.
115
G. In vitro drug testing.. H. Combined
116
modality
I.
Prophylactic
J.
Adjuvant
therapy
and therapeutic surgical
K. Biological
response
L. Modification
B. Interruption
of autocrine
growth
tional Cancer
toxin on signal transduction
fessor in the Departments versity,
Montreal,
Research
Council
from Stanford
logy at Memorial tional Cancer
of Canada.
University. Institute,
Deputy
Chief (Clinical)
National Uniformed
Naval
fellowships
Cancer
Bethesda, Cancer
is a Scholar
Center
Services University
Pro-
at McGill
Uni-
an M.D.
degree
in Medical
Onco-
NY and the Na-
MD. Since 1975, he has been on the
Institute,
where
of the Navy Medical
Medical
Center,
at the Na-
Assistant
of the Medical
Daniel Ihde received
Sloan-Kettering
staff of the National
and Oncology
He completed
of Montreal,
Oncology
and a Professor of the Health
until recently
Oncology
he was
Branch
at the
of Medicine
at the
Sciences,
also in Bethes-
da. Correspondenre: Branch, Bethesda,
National
Daniel Naval
MD, 20889-5105.
C.
Ihde,
Medical U.S.A.
NCI-Navy Center,
Medical
Building
Oncology
8, Room
5101.
123 123
signal transduction pathways
pathways and growth
................
125
..............
126 126 127
....... .... ......... .. .......
MD. He is currently
Dr. Viallet
stimulated
SCLC.......................................................
....... .
in Medical
of Medicine
Canada.
121 therapeutics
.....................................................................
. ... .
Bethesda,
121
as a target for developmental
3. Effects of cholera
a fellowship
Institute,
stimulation
peptide
Jean Viallet received an M.D. degree from the University He completed
121
............................................ ...................................................
of SCLC
2. Gastrin-releasing
References
120
treatment.
survivors.
............................................................
C. Genetic lesions in
Canada.
119 119
with adjunctive
in long-term
mechanisms
I. Growthfactors
Conclusions
II8
.
in the biology
A. Drug resistance
117
irradiation.
modifiers
of host environment
Recent advances
V.
cranial
irradiation
resection
M ‘Cure’ and morbidity IV.
with chest and multiple-site
........ . ..
.
128
I. Introduction Small cell lung cancer (SCLC) distinguishes itself from the other types of lung carcinomas by a remarkable propensity for early systemic spread and by substantially greater initial sensitivity to chemotherapy and radiation therapy. The former is exemplified by the fact that nearly all patients present with mediastinal or systemic metastases at the time of initial diagnosis. Indeed, even patients that were surgically resected but died within 1 month of surgery were found at autopsy to have a high incidence of residual cancer, most often distant metastases [l]. The predominant influence of systemic cancer on survival in SCLC is confirmed by the trivial ef-
110
fects of surgery and radiotherapy on the life-span of all but a handful of patients. Systemic chemotherapy, on the other hand, has increased median survival by 45fold since its introduction in the 1960s [2], even though the impact of chemotherapy on survival in other cell types of lung cancer is marginal at best [3]. Since it comprises approx. 25% of all lung cancer, SCLC is the sixth most common malignancy and the fourth leading cause of death from cancer in the United States [4]. It is the most common neoplasm in which a fraction of patients can be cured with chemotherapy. Substantially more successful management of this tumor would therefore clearly have a significant impact on overall cancer mortality. In the early 196Os, the Medical Research Council of Great Britain conducted a clinical trial in operable SCLC patients comparing surgical resection to locoregional irradiation [5]. Although radiotherapy was found to be superior to surgery in prolonging median survival, neither modality provided long-term tumor control in this relatively favorable group of patients without obvious distant metastatic disease. In contrast, single agent chemotherapy with cyclophosphamide resulted in a doubling of the median survival in both limited and extensive stage patients when compared to placebo treatment in a prospective randomized clinical trial published in 1969 [6]. Administration of this drug to patients with other lung cancer cell types yielded neither substantial tumor regression nor any improvement in survival. Since then, a large number of individual drugs have been utilized in the management of SCLC patients. It was rapidly established that combination chemotherapy was superior to single agent therapy. By the end of the 197Os, drug treatments for SCLC, with or without the addition of chest radiotherapy, were reproducibly associated with median survivals of 10-16 months in patients with localized and 611 months in those with overtly disseminated cancers. Two-year survival of 10-25s and O--3%for localized and disseminated tumors, respectively, was often reported by the early 1980s. These survival results are quite impressive compared to the previously observed median survival of 334 and 1.5-2 months, respectively, in untreated patients [3, 71. There is little data from the pre-chemotherapy era on 2-year survival of unselected patients with SCLC, but it was certainly a rare occurrence. However, there has been little further improvement in survival results over the succeeding 10 years. Figs. 1 and 2 show that this therapeutic plateau has not resulted from inactivity on the part of clinical investigators, as the numbers of both individual agents and innovative therapeutic strategies which have been evaluated have continued to increase. Rather, the generally disappoint-
ing results of these continuing efforts might suggest that empirical selection of drug combinations and variations in their mode of delivery using presently available cytotoxic agents may not be the ultimate answer to the successful management of this disease. During the same decade, in contrast, our understanding of the fundamental biology of SCLC has rapidly expanded and reached a point where it may serve as a basis for the development of novel treatment approaches. In this review, it will be our purpose to trace the evolution of the therapy of SCLC to its current state, with emphasis on areas which have not been sufficiently evaluated, as well as to provide an overview of SCLC tumor biology in an effort to identify potential targets for experimental therapeutics.
II. Clinical features, pathology, staging, and prognostic factors
In most cases of SCLC, it is the location and size of the primary tumor and the presence and nature of metastatic deposits which dictate the accompanying signs and symptoms. Because SCLC tends to present centrally and to infiltrate the submucosa [8], bronchial obstruction with consequent cough, dyspnea, wheezing, chest discomfort, hemoptysis or post-obstructive pneumonia is common. Two-thirds of patients will have evidence of distant metastases, most often to the liver, bone, bone marrow, or brain, at the time of original diagnosis. The clinician must also be alert to signs and symptoms which may be manifestations of the many paraneoplastic syndromes associated with SCLC and which may be confused with symptomatic metastases [9]. These syndromes are often due to the elaboration and release by the tumor of various humoral products (adrenocorticotrophic factor (ACTH) causing ectopic Cushing’s syndrome or arginine vasopressin (AVP) and atria1 natriuretie factor (ANF) [lo] causing hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion) or to immune reactions to a tumorassociated antigen, especially in neurologic syndromes such as the Eaton-Lambert myasthenic syndrome, in which the presence of circulating antibodies reacting with voltage-gated calcium channels has been documented [I 11. Visual deficits produced by retinal degeneration and sensory neuronopathy are two other syndromes most commonly found in SCLC in which serum antibodies reacting with both tumor and neuronal tissue are observed [9]. A diagnosis of SCLC can be made from tissue obtained through a variety of techniques, either from the primary site or a nodal or distant metastasis. Special
111
caution is required in pathologic interpretation of needle aspiration biopsies, however, as crush artifact can sometimes be mistaken for SCLC. The tumor consists of cells that are 2-3-times the size of mature lymphocytes. Nuclei are darkly staining with a characteristic ‘salt and pepper’ chromatin distribution [12]. Small, relatively infrequent dense-core granules, which are a manifestation of the peptide secretion that is the hallmark of the ‘neuroendocrine’ properties which are observed in most SCLC but are relatively infrequent in other types of lung carcinomas, can be demonstrated on electron microscopy in most tumor specimens which are diagnosed as SCLC by light microscopy. Whether these neurosecretory granules are present, however, is not associated with response to chemotherapy [ 19. Whereas the classic oat-cell subtype has little cytoplasm and indistinct or absent nucleoli, the intermediate subtype is composed of somewhat larger cells with more distinct cytoplasm. The distinction between these two subtypes provides no prognostic information, as patients with each of these pathologic diagnoses present with similar extents of tumor dissemination and experience no differences in response to therapy, duration of response, or survival [1416]. However, 5514% of patients present with a tumor composed of classical small cell elements admixed with larger cells with more abundant cytoplasm and prominent nucleoli. This small cell/large cell subtype was of prognostic significance at two different institutions which documented a lesser likelihood of response and shorter median survival in this group of patients [16, 11. This finding, however, could not be confirmed in patients entering a cooperative group chemotherapy trial [18]. A much smaller frequency (2% in one series) of SCLC patients have elements of squamous or adenocarcinoma in their diagnostic biopsy specimens. Although the natural history of patients with this ‘combined’ subtype is not well characterized, they may present more often with surgically resectable lesions P91. Essentially all investigators currently employ the twostage system first proposed by the Veterans Administration Lung Group. The distinction between the two stages is based upon whether the known tumor can be encompassed within a tolerable radiation field, thus introducing physiologic as well as anatomic factors into assignment of stage [3]. Limited stage is defined as disease confined to the hemithorax of origin and its regional lymph nodes (including mediastinal, contralateral hilar and, in most definitions, ipsilateral or contralateral supraclavicular), whereas extensive stage is defined as disease extending beyond this area. Since in many institutions patients with limited-stage disease will receive chest irradiation in addition to systemic chemotherapy,
the definition of stage influences the primary management of the patient. The extent of the staging process varies with the specific clinical situation. In usual practice, presenting signs and symptoms guide the choice of diagnostic procedures. If an unequivocal site of distant metastases is identified, eliminating the indication for elective thoracic irradiation, no further procedures need be performed unless the information sought will modify clinical management. In the rare patient with a proven diagnosis of SCLC who may still be a candidate for surgical resection, preoperative mediastinoscopy should be performed since documentation of mediastinal node involvement would preclude thoracotomy, and the tumor should be staged by the recently revised, more detailed TNM staging system [20]. After therapy has been administered, sites of prior involvement should be reevaluated to determine whether complete, partial, or no objective response is present. The response category is strongly associated with ultimate survival, with virtually no patients without a complete response living beyond 2 years. In the context of a clinical trial, where a careful characterization of the patient population under study is necessary to assure optimal interpretation of the observed outcomes, more detailed and rigorous staging evaluations are usually justifiably pursued. Ambulatory or performance status and tumor stage at presentation are the most powerful prognostic factors in SCLC. In large groups of patients who receive combination chemotherapy, additional factors which refine prognosis can often be demonstrated. Some directly relate to total tumor burden, such as the favorable effect of tumors which were completely surgically resected in limited-stage disease [21] and the number of organ systems involved by metastases in extensive stage patients [22-251. In patients whose tumors are surgically removed, hilar and especially mediastinal node involvement are associated with considerably worse prognosis [26]. Some are host characteristics; women [22, 25, 271 and younger patients (below 60 or 70 years of age) [22, 25,281 have a more favorable outcome in some series or patient subgroups. Finally, abnormal serum biochemical values (elevated liver function tests or low albumin or sodium determinations) provide prognostic information independent of documented tumor extent in many reports [23, 25, 28, 291. Abnormalities in serum biochemical tests are strongly correlated with the number of distant metastatic tumor sites in patients who have undergone numerous systematic staging procedures, and both are likely to be surrogates for overall tumor burden [23, 241. As in all other cancers, SCLC patients who have developed tumor progression after receiving chemotherapy have a
112
markedly inferior prognosis, with median survival of only 24 months [3]. Most, if not all, treatment programs for SCLC are adopted only after documentation of their efficacy in a clinical trial is published in the medical literature. Therefore, it is of great interest to know whether there are any marked differences in prognosis between patients who are entered on clinical trials and those who are not. One report which investigated this issue found little difference in outcome in limited-stage patients whether or not they were placed on institutional clinical trials, but much shorter survival in extensive-stage patients who were not placed on trials because of poor performance status or medical problems unrelated to their cancer [30]. This result is not unexpected, since most limited-stage patients are fully ambulatory, but emphasizes that outcome similar to that reported in clinical trials should not necessarily be expected in more acutely or chronically ill patients. III. Current status of therapeutic approaches to SCLC
The current status of SCLC therapy has recently been extensively and comprehensively reviewed [3, 31, 321. Only the salient points will be summarized here. The ability of combination chemotherapy to substantially improve the clinical outcome of SCLC patients was documented relatively quickly after its introduction, certainly by the end of the 1970s. Since then, clinical evaluation of multiple combinations of drugs, selected both empirically and rationally, and variations in duration and intensity of therapy, including autologous bone marrow support, have had only very modest additional impact on survival. This suggests that future investigations might better focus on the biological mechanisms underlying drug resistance or on alternative forms of therapy diverging from the classical cytotoxic chemotherapy paradigm. III-A. Combination and single-agent chemotherapy
When combination chemotherapy programs were first introduced into the management of SCLC, they appeared to yield much higher response rates, especially complete response rates, than had been observed with single-agent treatment. However, there are relatively few prospective randomized trials which specifically confirm this point. Two- [33] or three-drug [34] regimens containing cyclophosphamide were compared to cyclophosphamide alone, with improved response rates and survival found using the combination programs. Another trial compared concurrent administration of four drugs with the sequential administration of the same
agents and found a superior response rate with the use of the combination [35]. All these trials were published before 1980. They are confirmed by a recent British study which randomized 151 patients to receive combination chemotherapy (with chest irradiation in limited disease) or single-agent cyclophosphamide or palliative radiotherapy whenever indicated. Median survival was doubled from 4 to 8 months and l-year survival increased from 8% to 30% with the combination regimen [36]. The optimal number of drugs in a combination program is not established, but two to four are most commonly given. Since most agents used in the treatment of SCLC are myelosuppressive, each addition to a combination usually requires compromising the dose of all the agents, probably accounting for the fact that little or no benefit has been documented from administering more than three drugs simultaneously [3]. It has proven quite difficult to establish the superiority of any specific chemotherapeutic regimen in the treatment of SCLC. For example, etoposide (VP- 16) as a single agent has one of the highest reported response rates against this tumor, but adding this drug to an effective combination program containing other drugs has generally not led to improved outcome in randomized trials [37-391. In one study in which etoposide was substituted for vincristine in the cyclophosphamide/doxorubicin (Adriamycin@)/vincristine (CAV) combination, survival was significantly improved with etoposide, but only in extensive- stage patients [40]. Etoposide when given as a single agent is more effective on a 5-day than on a lday schedule [41], but when etoposide was added to cyclophosphamide and doxorubicin on either a S-day or 1-day schedule, no differences in outcome could be demonstrated [42], probably because the considerable efficacy of the latter two drugs greatly diluted any therapeutic impact which the addition of etoposide in a superior schedule could provide. A two-drug regimen frequently utilized in SCLC after the mid-1980s is cisplatin and etoposide (PE), which is therapeutically synergistic in murine tumors and extremely effective against testicular cancer [3]. It was first shown to have activity in patients who developed progressive tumor following CAV treatment [43] and then found to yield survival results similar to other regimens when used alone as the only form of chemotherapy [44]. In a randomized study PE produced significantly better survival than ifosfamide/etoposide [45]. In another randomized trial in extensive-stage patients, relatively low doses of PE were equally as effective as 67% higher doses, while producing very modest myelosuppression [46], suggesting that this combination has a very favorable therapeutic index compared to most other combination programs which are administered in SCLC.
113
Thus,
numerous
mens currently
combination
chemotherapy
offer approximately
comparable
regiefficacy
in SCLC patients. The two-drug PE combination appears to be as effective as three- and four-drug programs utilizing
various
combinations
doxorubicin, etoposide, cristine, methotrexate,
of cyclophosphamide,
cisplatin and its analogs, vinand nitrosoureas, the agents
therapy
requiring
prolonged
led to any obvious tions utilized phosphamide,
doxorubicin,
and etoposide
binations,
single agent in a randomized
hematologic
once the three-drug
program
easy to add a third drug toxicity
to this program,
has been shown
to have
greater efficacy. At present, the choice of a specific combination regimen can be appropriately tailored to take into account
the expected
tolerance
of an individual
pa-
tient to drug-specific toxicities other than myelosuppression, as well as cost and ease of administration. Although combination chemotherapy is the treatment of choice for SCLC at present, some recent studies, most of them performed in Europe, have administered a single-agent podophyllotoxin derivative, either etoposide or teniposide, as sole therapy for previously untreated, generally elderly patients [47.48]. Response rates of 8& 90% were observed, with median survival of approx. 9 months and very modest toxicity. Whether this result is equivalent to what would have been obtained with combination chemotherapy is unknown, but such therapy may appropriately be considered for elderly or poor performance status patients, particularly with extensivestage disease. Prolonged oral administration of oral etoposide, which can maintain cytotoxic serum concentrations of the drug for protracted periods, has also been investigated in previously untreated patients [49]. III-B.
Intensity
of induction
chemotherapy
With the exception of some programs of PE, most current chemotherapy regimens are designed to produce moderately severe myelosuppression, their dose-limiting toxicity (nadir white blood cell count of lOOO-2000/~1 in the majority of patients). Some early randomized studies utilizing cyclophosphamide-based regimens supported the concept that higher doses of drugs were associated with a modest but significant improvement in survival [50, 511. Extremely high doses of single-agent cyclophosphamide (200 mg/kg) combined with chest irradiation have also yielded an apparently increased fraction of complete responses and survival similar to patients given more usual chemotherapy in limited disease [52]. However, improved survival with higher initial drug doses has not been demonstrated in randomized studies employing the CAV program [53, 541 or PE [46]. Tnuncontrolledstudies,evenhigherinitialdosesofchemo-
not
Combina-
[55-571 or cy-
clophosphamide, cisplatin, and etoposide [58]. The failure of etoposide-containing high-dose programs to yield markedly superior results is consistent with the lack of improvement doubling or tripling
it should be relatively
have
in survival.
in these trials have been based on cyclo-
most commonly utilized in SCLC [3]. Since it is also somewhat less myelosuppressive than most other comwith substantial
hospitalization
improvement
in response rates or survival with of the dose of etoposide given as a
rent SCLC [59]. In summary, vincing more
evidence than
that
moderately
trial in patients presently
treatment
with recur-
there is no con-
designed
to produce
severe myelosuppression
at the
time of induction yields better results, and such therapy should be administered only in the setting of a clinical trial.
III-C.
Cyclic
chemotherapy
alternating
non-cross
resistant
regimens
Goldie et al. have proposed an elegant mathematical model of the emergence of chemotherapy-resistant clones in malignancies [60] which predicts that superior clinical efficacy would be expected with the earliest feasible administration of as many active drugs as possible. Because of the partially overlapping toxicities of most regimens, this goal can be best achieved with the least compromise in doses of individual agents by cyclic alteration of non-cross resistant drug combinations. However, if we accept as a reasonable definition of non-cross resistance the ability to induce complete remissions after tumor progression while receiving primary treatment, no current chemotherapy programs for SCLC can be considered non-cross resistant. It is, therefore, not surprising that most randomized clinical trials comparing this strategy to the standard approach of treating with a single regimen until therapy is completed have generally failed to yield superior survival results [3], although in some studies duration of initial remission was prolonged [61]. A more recent trial conducted by the National Cancer Institute of Canada randomized extensive-stage patients to receive either the CAV combination for six cylces or CAV alternating with PE for the same duration of treatment [62]. Patients given the alternating regimen experienced a 6-week prolongation in median survival which was statistically significant. However, it is not clear whether this modest improvement was due to the alternating strategy or to an inherent superiority of PE, especially since in another randomized trial conducted in limited-stage patients the addition of only two cycles of PE given after completion of six cycles of CAV led
114
to a 7-month improvement in median survival compared to no further therapy [63]. Two more recent, larger studies comparing CAV to PE to alternation of the two programs should help to resolve this issue, although they include relatively few patients with limited disease. Preliminary results indicate no substantial survival differences [64, 651. At present, the use of noncross resistant chemotherapy regimens is an available option in the primary management of SCLC. Its bestestablished virtue at this time is not in offering clearly superior survival but rather in permitting reduction in toxicities dependent upon the cumulative dose of individual agents, such as cardiotoxicity of doxorubicin or neurotoxicity of vincristine and cisplatin. III-D. Duration of chemotherapy tumor progression
and management
of
Early chemotherapeutic programs for SCLC were frequently administered for up to 2 years in the few patients in whom tumor progression had not occurred by that time. However, it has now become clear from both uncontrolled data [66] and most prospective randomized trials [67-69] that prolonged maintenance chemotherapy does not extend survival, although the duration of initial remission may be prolonged [70]. One large trial of 610 patients was able to assess the survival benefit of administering chemotherapy at relapse in a randomized fashion [67]. Survival was prolonged with such ‘salvage’ treatment in patients receiving only four cycles of initial therapy, but not in those given eight cycles. At present, induction chemotherapy lasting 12 to 18 weeks would appear to be optimal. One method to increase delivery of drugs, while still reducing duration of therapy, is weekly administration of myelosuppressive and non-myelosuppressive drugs on an alternating basis. This approach appeared promising in a pilot study [71]. In addition to worsening the morbidity of treatment, maintenance chemotherapy may also reduce the likelihood of palliation from drug regimens given for relapsing tumor. PE chemotherapy produced much lower response rates in one study conducted in patients with recurrent SCLC who had a median ‘drug-free’ interval of less than 1 month since their most recent prior treatment than was observed in other trials of PE in which, due to the policy of avoiding prolonged maintenance therapy, the median time since previous therapy was 3 to 5 months [72]. Much higher response rates in previously treated patients who had not received chemotherapy for at least 10 to 12 weeks were also noted in Phase II studies of teniposide [73] and daily oral etoposide [74].
III-E. Late intensiJication with autologous bone marrow transplantation
Most patients with SCLC who achieve remission with currently available therapies will relapse and die from their disease, indicating the persistence of occult tumor deposits even in clinically complete tumor regression. Given this context, various investigators have proposed the use of high-intensity therapy after induction with conventional doses of agents to take advantage of treating patients at a time when tumor bulk is at its lowest and the physiological status of the patient optimized. At least nine trials have explored this strategy with a variety of high-dose chemotherapy regimens, usually with autologous bone marrow support and sometimes with the addition of regional or total body irradiation [75]. Most included both limited-stage and extensive-stage patients, and some included drugs which had already been administered at more conventional doses during the induction phase in the late intensification regimen. Only 18-38s of patients beginning therapy with the intent of eventually administering late intensification actually received the high-dose treatment. Although some partial responses were converted to complete responses during the late intensification phase, these responses tended to be of short duration. Importantly, relapses at the primary site in the absence of chest irradiation were prevalent even in patients who were in complete remission prior to intensification, suggesting that the late high-dose chemotherapy by itself had very modest ability to eradicate occult tumor. Overall survival in these uncontrolled trials was not obviously different from that of patients receiving conventional therapy [75]. In the only study utilizing a prospectively randomized design, remission duration (though not survival) was prolonged with late intensification, but survival of all patients beginning induction chemotherapy was similar to most reports of treatment without intensification [76]. Late intensification should be administered only in the setting of a clinical trial. Given the very limited benefits of this approach thus far, future studies might best focus on the limited-stage patient who has achieved a complete remission withconventionalchemotherapy and include thoracic irradiation, probably after intensification, to better control the primary site [77]. Care should be taken to utilize autologous marrow support only if necessary, because of the potential risk of reinfusing marrow contaminated with viable tumor cells 1781. Because of unavoidable selection biases in patient entry onto such toxic therapeutic programs, the value of dose-intense approaches in initially responding patients can most likely become established only by randomized clinical studies.
115 2All antibody G-CSF Am&de
Iproplatin RA233 Idambicin GM-CSF Lonidamine y-interferon DFMO Aclarubicin Propionobacterium 6-M-urine Zinostatin BtitlWle Mitoguazone zII a-interferon Mitoxantrone VinbIastine Aziridinylbenzcquinone Pmcart&ne Maytansine DON Chlorozotocin Amsacrine Vindesiie PALA 5-Fu ACNU DianhydrogaIactilol Warfarin TriaziIlate Prednimustine BCG MER High-dose methouexate Thymosin Cisolatin
Dibromodulcitol
Sueptozotocin Mitomycin C Procarbazine
63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
Fig. 1, Perspective
on the evaluation
of single agents in the treatment
of SCLC. Data were abstracted
from the reviews of Cohen and Perevodchikova
[291] and that of Joss et al. [292] as well as from selected primary references [85-87, 148-l 50, 165, 169, 170, 173, 174, 293-2951. have well documented activity as single agents.
III-F.
Strategies for evaluation
of new drugs
At least eleven drugs have been shown to have measurable activity when given as single agents to patients with SCLC (Fig. 1). At a time when therapeutic results have been almost static for the last decade, it is disappointing that most if not all efficacious drugs identified during this period, such as carboplatin and epirubicin, are structural analogs of agents which were already known to be active at the time the newer drugs were introduced.
Drugs in boldface
Patients who progress in the face of or shortly after receiving induction or subsequent chemotherapy programs seldom experience a meaningful response to additional treatment. In this setting, even drugs quite useful as primary therapy, such as etoposide [79] and cisplatin [80] may have minimal or no detectable activity. Because of this, there is justifiable concern that the investigation of new drugs in previously heavily pretreated patients, as was customary until relatively recently, may lead to the inappropriate classification of truly active agents as being inactive [8 11.
116
Since the ultimate value of a new drug can only be determined in the clinic, novel strategies have been proposed to optimize the evaluation of Phase II drugs. These include the study of relapsed patients while lowering the cut-off point for a Phase II study response rate that is considered promising to 10% [82], enrolling only patients who relapse after a certain interval free of treatment [83], and testing novel agents as initial therapy in newly diagnosed patients [84]. The latter strategy is probably the most efficient in terms of estimating the true activity of a novel compound with the fewest patients. However, some uncontrolled studies employing this policy have reported that it may be deleterious to the ultimate survival of the enrolled patients, after observing a compromised response rate to standard therapy following initial exposure to an inactive investigational agent [85]. Recent Phase II trials using more stringent entry criteria have evaluated new drugs, including the active agent epirubicin [86] and the inactive agent amonafide [87], with overall survival comparable to that of patients treated conventionally. Most convincingly, a randomized trial of the Eastern Cooperative Oncology Group (ECOG) compared the ultimately inactive agent menogaril to CAV combination chemotherapy in good performance status extensive-stage patients in no need of immediate palliation of tumorrelated symptoms with strict rules requiring cross-over from the investigational agent to a standard combination regimen whenever clinically indicated, without observing any compromise in survival [88]. Initial therapy of extensive-stage SCLC patients with an investigational single agent appears to be a reasonable approach if there is reason to believe that the agent to be tested may be active and that the patient population is selected in such a way that an initial lack of response is not likely to be associated with immediately life-threatening tumor progression. The detailed criteria of Ettinger et al. [89] and Cullen et al. [84] provide generally adequate guidelines for this trial design. The recent suggestion by the National Cancer Institute of Canada Clinical Trials Group that a trial should be terminated if the initial experience rules out a minimal response rate of 30% is attractive [87]. It would limit the number of patients exposed to ineffective therapy and focus the drug development process on the most acitive agents. At present, such a policy appears to be the most promising way to identify novel active drugs for SCLC, which are sorely needed. III-G. In vitro drug testing
If new, more effective drugs are not immediately forthcoming, it may be possible to optimize an individu-
al patient’s therapy by selecting the currently available agent(s) to which his tumor is the most sensitive. This concept was recently tested by our group in a prospective study of extensive-stage SCLC in which a concerted effort was undertaken to establish a cell line from clinical tumor specimens obtained at the time of initial diagnostic and staging procedures [go]. Because of unavoidable delay in obtaining sufficient cultured tumor cells to perform in vitro sensitivity testing with seven drugs known to be active in SCLC, the 80 patients entered in the study were initially treated with PE chemotherapy for 12 weeks. Patients achieving partial remission or experiencing no response, as well as those patients suffering a relapse after an initial complete remission, were treated with a three-drug combination based on in vitro drug testing of their own tumor, if that information was available, or alternatively with the standard CAV combination. Despite being able to obtain tumor-containing specimens for cell culture in 75% of patients, cell lines could be established and drugs tested in only 33%. Ultimately, 20% of all patients received a regimen based on in vitro sensitivity testing. Of interest, in vitro drug sensitivity was significantly correlated with clinical response to both primary and second-line therapy. However, because SCLC cultures tended to be either generally sensitive or generally resistant to most drugs evaluated, the selection of a second-line regimen with in vitro drug testing did not translate into an obvious therapeutic advantage; 4/ 16 (25%) of patients receiving an ‘in vitro best regimen’ achieved further remission, whereas 3/43 (7%) treated with CAV did so. This modest difference was not statistically significant. In vitro drug testing as performed in this study was of only minimal clinical value. The labor-intensive technology employed and the lack of marked heterogeneity in sensitivity among cell lines to the standard drugs tested currently limit in vitro sensitivity testing to select drugs for individual SCLC patients to investigational studies. However, the correlations observed between in vitro and clinical drug sensitivity, which have now been maintained for a median of 27 months in cell culture [91], suggest that these or similar cell lines taken directly from SCLC patients might be useful for studying mechanisms of drug resistance or in screening for new chemotherapeutic agents. The National Cancer Institute, through its Lung Cancer Drug Discovery Project and other drug screening programs, has reorganized its strategy for the identification of novel active agents [92]. It is hoped that a panel of human lung cancer cell lines of diverse origins, used in an in vitro screening process, will identify compounds with tumor type-specific activity which could more frequently be documented to possess clinical efficacy
117 Growthfacta antagonists In vitro drug testing Hypeaftxtiarated cheat Won “Adjuvant” surgical reacction Bone marrow stimulation with CSFs High intensity induction Hypxalimentation Mainturancecllem~ Autologous bone marrow transplant AnticoagoMon Immimotkaapy Cyclic alternating chemotherapy Prophylactic cranial irradiation Comb&on chemotherapy Chemomdiotheraov for LD Single agent chemotheqy
FvimarY ldialioll themov .SurRery
63 64 65 66 61 68 69 70 71 72 73 74 75 76 II
Fig. 2. Perspective introduction
on the evolution
of the indicated
of treatment
modalities
modalities
was chosen
78 79 80 81 82 83 84 85 86 87 88 89 90
for SCLC.
from among
The publication
available
colony-stimulating
than agents previously identified through initially screening against highly sensitive murine leukemias. III-H. Combined modality therapy with chest and multiple-site irradiation
The refinement of combined modality treatment with chemotherapy and chest irradiation is the area of investigation which appears to show the greatest promise in terms of improving the outcome of limited-stage SCLC patients in the near future. Since radiotherapy can induce regression of thoracic tumor in up to 90% of cases and was the standard treatment for SCLC at the time combination chemotherapy began to be administered for this .disease, initially many programs included chest irradiation as a component of treatment. A review of published literature in 1981 revealed, perhaps not surprisingly, that chest radiotherapy seemed to add little to therapeutic results that could be achieved with chemotherapy alone in patients with extensive stage disease. In limited disease, although there was little difference in reported median survival whether or not irradiation was given in conjunction with chemotherapy, 2-year survival appeared superior with radiotherapy [93]. However, biases in patient selection could have accounted for this result in this uncontrolled data. In the past decade, long-term results of at least seven large randomized trials comparing chemotherapy given with or without thoracic irradiation in limited-stage SCLC have become available and help to clarify this issue. The majority of these studies found that the addition of chest radiotherapy to systemic chemotherapy leads to an improvement in complete response rate, control of the primary tumor, and disease-free survival and overall survival [94-971, although several [98-1001 did
references.
date of the paper Abbreviations
felt to be most representative
used are: LD, limited
disease;
of the
and CSF’s,
factors.
not. Differences in the temporal relationship between radiotherapy and chemotherapy among the trials may account for variations in the effectiveness of irradiation. In general, studies in which chemotherapy and radiotherapy were given either concurrently or in an altemating fashion without any delay in the scheduled administration of chemotherapy were much more likely to document survival benefit from radiation than studies in which the two modalities were given sequentially, with a planned interruption in chemotherapy in order to deliver the irradiation [3]. The survival advantage with radiotherapy in positive studies has been relatively modest, with l- to 4-month improvement in median and 717% absolute increase in 2-year survival. However, advantages of this combined modality approach have been somewhat compromised by the associated increase in toxicities such as myelosuppression, esophagitis, weight loss [3], and in particular severe pulmonary toxicity which in one trial accounted for fatalities in complete remission of 10% of patients [loll. Many trials used chemotherapy regimens which included agents with a potential for lung damage. Unfortunately, the apparently more efficacious concurrent combined modality programs are usually more toxic than sequential ones. Although only a few controlled [96] and uncontrolled [102] studies have been performed, rapidly alternating programs of chemoradiotherapy may have reduced pulmonary toxicity while preserving the probable survival advantage of concurrent combined modality approaches. The basic radiobiological observation that SCLC cell lines had a reduced ability to recover from low doses of radiation when compared to normal cells has led to a novel approach using twice-daily administration of radiation therapy [103]. In pilot trials in combination with
118
PE chemotherapy, this approach appeared both highly effective, with median survival in excess of 2 years, and better tolerated than previous regimens [104, 1051.These experiences from single institutions were recently extended through the ECOG, which treated 40 patients in this fashion; a 95% overall response rate was observed, with 3 1 complete remissions [ 1061.There were four toxic deaths, two of them pulmonary, but 2-year actuarial survival was 36%. A randomized trial designed to assess the contribution of twice-daily radiation therapy compared to a standard once-daily concurrent combined modality approach with PE is currently underway, since it is possible that PE chemotherapy itself is especially well suited for concurrent administration with chest irradiation, being both less toxic and perhaps more effective [ 1071, and accounts for the apparently better results of the twice-daily programs. Some combined modality programs thus appear to produce improved survival in limited-stage SCLC, but these are technically complex in their delivery and require close cooperation between radiation and medical oncologists. Since not all combined modality treatments increase survival, but essentially all increase toxicity, chest irradiation is not mandatory in all patients, especially those with poor pulmonary function or performance status. For other patients not participating in clinical trials, concurrent radiotherapy and PE chemotherapy are at present most often recommended. Irradiation to extrathoracic sites other than brain in conjunction with chemotherapy for SCLC appears to yield no clinical benefits, either prophylactically in limited disease [108] or to the primary tumor and clinically involved extrathoracic sites in extensive disease [ 1091. Thoracic radiotherapy alone given with chemotherapy to extensive-disease patients can reduce the frequency of tumor progression in the chest but appears to have no effect on survival [ 1lo]. III-I. Prophylactic and therapeutic cranial irradiation
Patients receiving chemotherapy for SCLC have a tendency, which progressively increases over time, to develop central nervous system (CNS) metastases, especially in the brain. In one series, the actuarial likelihood of CNS metastases in the absence of specific therapy was approx. 80% at 2 years [l 111. Because these findings were similar to what had previously been observed in childhood acute lymphoblastic leukemia, prophylactic cranial irradiation (PCI) was also proposed as a potentially useful maneuver for SCLC. This topic has recently been comprehensively reviewed [ 1121. A combined analysis of the nine published randomized studies assessing the impact of PC1 in
SCLC shows a definite ability of this intervention to reduce the incidence of clinically detected brain metastases from 23% to 6%, without, however, affecting survival. Retrospective analysis indicates that the benefits of PC1 are principally restricted to patients who attain a complete remission of their cancer [113], a not unexpected result since if extracranial tumor persists after PCI, it would still have the potential to continue metastasizing to the brain. Although little data addresses this point, a survival benefit does not appear to exist for PC1 therapy even if analysis is restricted to patients in complete remission [113, 1141. The obvious value of reducing the development of brain metastases must be balanced, however, against the possibility of late neurological side-effects associated with the administration of PCI. Combining data from eight studies of long-term survivors of SCLC, most of whom (102/123) had received PCI, showed a 45% incidence of symptomatic organic brain syndrome, which was most commonly manifested by memory loss, gait abnormalities, and coordination defects [112]. Most of these patients also had received long-term chemotherapy regimens which included potentially neurotoxic drugs such as methotrexate and nitrosureas. We [115] recently updated our observations in long-term survivors 6-13 years after therapy for SCLC and found that the high incidence of neuropsychological sequelae observed in an earlier evaluation performed 4 years previously had often continued to progress, albeit not dramatically, in some patients. It should be emphasized, however, that most neurologic morbidity observed in long-term survivors does not compromise patients’ ability to care for themselves [116, 1171, and whether all of the neurologic morbidity observed in these patients is directly related to PC1 is by no means established. Whether PC1 in the context of short-term, cisplatinbased chemotherapy is associated with the same longterm sequelae is unknown at present. In the meantime, it seems prudent to limit the administration of PC1 to patients who achieve complete remission of their tumor and consent to receive it after becoming thoroughly aware of benefits and potential risks. Treating with low doses of irradiation per fraction only after all other therapy is completed may be associated with less neurologic toxicity [ 118-J. Most SCLC patients who develop brain metastases during or after chemotherapy do so in the setting of progressive cancer in multiple sites. Therapeutic brain irradiation in the majority of cases is able to relieve or reduce neurologic symptoms for the remainder of the patients’ usually short life expectancy. However, symptomatic recurrent metastases after irradiation are a common problem in patients who survive for several months
119
or longer [119, 1201. Therefore, attempts to achieve more durable control of intracranial tumor should be considered in patients who have brain metastases as their sole site of extensive disease at the time of diagnosis [121, 1221 or those who relapse from complete response solely in the brain. It has recently become apparent that systemic chemotherapy without cranial irradiation may produce regression of brain metastases which are present at the time of diagnosis [123, 1241, presumably because the bloodbrain barrier to penetration of chemotherapeutic agents is disrupted in areas of gross metastases. What effect this knowledge will have on policies for treatment of brain metastases remains to be seen. III-J. Adjuvant surgical resection
The early experience with surgical resection in the treatment of SCLC was disappointing. The Medical Research Council trial, which randomized potentially resectable patients by the standards of the day, which included much less extensive staging procedures, to undergo surgery or radiation therapy had no long-term survivors in the surgery arm [5]. These and other [125] observations led to the abandonment of surgery in the primary management of this disease. However, more recent reports have challenged this attitude by demonstrating favorable long-term survival in patients with localized presentations (Tl-T2, NO or Nl) treated with initial surgery with or without additional chemotherapy and radiotherapy [21, 26, 126, 1271. Whether this relatively good prognosis is related to the therapeutic effects of surgical resection, the smaller overall tumor burden, or the inherent less aggressive biological behavior of what some have suggested to be more differentiated neuroendocrine lung carcinomas [ 1281 remains unclear. However, it is clear that concern about discovering an SCLC histology should not motivate heroic efforts at obtaining a preoperative diagnosis in the case of a patient presenting with a peripheral lung lesion and no contraindications to surgery. Should such a lesion prove to be SCLC, it should be resected if otherwise appropriate provided mediastinal nodes are not involved, and the patient should then receive six cycles of adjuvant chemotherapy, possibly with chest irradiation. If a diagnosis of SCLC is known preoperatively in a patient who appears to be a good surgical candidate, thoracotomy should be considered only after a negative mediastinoscopy or mediastinotomy. A more controversial area is whether surgery should be employed for resection of residual disease after a maximal response is achieved with chemotherapy. The rationale for this approach is based on the observation
that the site of first relapse in patients achieving a complete remission is often the original site of disease in the chest. It is reasoned that surgical resection of the initially involved lung might decrease the incidence of recurrence and improve survival. Many uncontrolled series have been published [ 129-1331, some of which reported a decreased rate of thoracic recurrence in patients undergoing surgical resection [ 129, 132, 1341. Resected patients experience overall survival much better than reported for limited-stage patients in general; however, this would be expected since they have tumor of relatively small extent which can be completely surgically extirpated. The impact of surgery on these favorable outcomes is currently the object of a prospective randomized study conducted by the Lung Cancer Study Group. Uncontrolled data suggest the major benefit of post-chemotherapy surgery is confined to patients without mediastinal lymph node metastases at diagnosis [ 1351. III-K. Biologic response modifiers
Various immune deficits have been observed in patients with SCLC. Initial reports focused on depression of total lymphocytes and T-cell levels [136], as well as a decreased response to DNCB skin testing [137]. Impaired response to delayed hypersensitivity skin testing has been associated with impaired survival in patients receiving chemotherapy, especially those with otherwise favorable prognostic factors [ 1381.More recently, significantly decreased numbers of T-helper and T-suppressor subsets of circulating lymphocytes [ 1391, as well as a decreased proliferative response of peripheral blood lymphocytes to phytohemaglutinin and interleukin-2, have been described [140]. Although some of these findings are likely to be secondary to the generalized debility associated with an advanced malignancy, the coexistence of pulmonary [ 14 1, 1421and extrapulmonary [ 1431small cell carcinomas in cases of the acquired immune deficiency syndrome raises the possibility that these immune deficits might participate in the genesis of SCLC. However, it should be noted that other authors have found an increase in activated T cells in the peripheral blood of SCLC patients [ 1441,and that in two immunotherapy trials, lack of response to a panel of skin test antigens was of no prognostic import [ 145, 1461. The possible contribution of an immune deficit to the pathogenesis or progressive nature of SCLC led to a number of trials using non-specific immunotherapy in this disease. Initial non-randomized studies were inconclusive [ 1471.Since then a number of randomized studies evaluating the addition of different forms of immunotherapy to various combination chemotherapy regimens, often combined with thoracic irradiation, have
120
been reported. Propionobacterium granulosum strain KP-45 [148], bacillus Calmette-Guerin (BCG) [149], and the methanol extractable residue of BCG (MER) in various schedules [145, 146, 1501 have been studied. These trials have included a total of 870 patients; all have shown no significant difference between standard treatment and immunochemotherapy in terms of response rate, duration of response, or survival. However, significantly increased morbidity was observed with the use of MER. In addition, an early randomized trial suggesting survival benefit (but no effect on the response rate) with the addition of thymosin fraction V to chemotherapy [ 15 l] could not be confirmed [152]. These data indicate that non-specific stimulation of the depressed immune function observed in SCLC does not alter the course of this disease or its response to therapy. In an effort to identify targets for specific immunotherapy, various groups of investigators have generated a plethora of murine monoclonal antibodies after immunization of animals with SCLC tumor preparations. The antigenic specificity of most of these reagents remains undefined, but there appears to be overlap among several of them. To try to bring some order to this field, an international workshop was held in 1987 and led to a grouping of most antibodies within five clusters, each of which detected related antigenic characteristics [ 1531. It was concluded that no antibody showed absolute specificity for SCLC, although some appeared to be relatively specific for neuroendocrine tissue. The ultimate usefulness of these reagents as tools in diagnosis, immunodetection, or therapy remains undefined. In vitro studies suggest that some of these monoclonal antibodies might be useful for the eradication of occult cancer cells from bone marrow in preparation for autologous transplantation [154156] or as potentiators of lymphokine-activated killer cell activity against SCLC [ 1571. Perhaps of more interst is the reduced expression of specific antigens on the surface of SCLC cells, namely the class I major histocompatibility antigens. Since these molecules play a crucial role in immune recognition, their lack of expression may be relevant to the escape of SCLC from putative immune surveillance and contribute to its metastatic potential. Doyle et al. [158] found that SCLC cell lines, in contrast to other lung cancer lines, are deficient in the expression of HLA-A, B, and C antigens as well as of µglobulin, but that treatment with leukocyte-A interferon as well as y-interferon could induce the expression of these antigens. However, in a different panel of SCLC cell lines, Ball et al. [159] were able to detect expression of class I and II major histocompatibility antigens but did note increased expression after treatment with y-interferon. In addition, they and others [160] observed decreased pro-
liferation of SCLC in response to y-interferon. More recently, it was shown that y-interferon-induced modulation of class I major histocompatibility antigen expression in SCLC is associated with increased lysis by cytolytic T lymphocytes [161] but decreased sensitivity to natural killer cells in vitro [162, 1631. The various interferons have not been extensively evaluated in the treatment of SCLC. However, thus far no significant tumor regression has been observed with either cr-interferon [ 1641 or y-interferon [165] in small Phase II trials. However, as has been suggested [166], interferons theoretically might be more useful in maintaining response in patients experiencing a complete remission on chemotherapy. Preliminary results of a randomized trial in Finland testing the efficacy of low-dose a-interferon in SCLC patients in complete remission demonstrate modestly but insignificantly better survival with cx-interferon compared to continued chemotherapy or no further treatment [167]. An additional randomized trial evaluating this treatment is underway. III-L. ModiJication of host environment with adjunctive treatment The frequent weight loss observed at diagnosis in SCLC patients is a factor of negative prognostic significance [28]. Because of this, attempts to improve prognosis by administering parenteral hyperalimentation during chemotherapy have been evaluated in randomized trials. These have failed to show improvement in response rates, survival, or chemotherapy-induced morbidity [168], despite improvements in body weight and reversal of anergy to skin test antigens in another study [169]. Another strategy which has generated interest since the initial description of its antimetastatic effects in some animal tumors has been the use of anticoagulation as an adjunct to chemotherapy. An initial trial conducted by the Veterans Administration Lung Group randomized 50 patients with limited, extensive, and undefined disease extent to receive chemotherapy and thoracic irradiation with or without warfarin anticoagulation. The 25 patients randomized to standard treatment experienced a median survival of 24 weeks, whereas those receiving adjunctive anticoagulation had a median survival of 50 weeks. There were no differences in response rates, which were low (28 and 32% overall) in both arms [170, 1711. The Cancer and Leukemia Group B (CALGB) explored this issue within a larger randomized trial in which 86 extensive-stage patients received combination chemotherapy alone and 103 received the same chemotherapy with warfarin. Despite a statistically superior overall response rate in the warfarin arm,
121
there was no significant difference in survival [172]. The results of a similar CALGB trial in limited-stage patients are awaited. In the meantime, warfarin should not be part of therapeutic interventions in SCLC except in clinical trials. In addition, the putative antiplatelet agent mopidamol (RA-233) was not found to improve the results of combination chemotherapy in another randomized study [173]. The availability of recombinant human granulocyte/ macrophage colony-stimulating factor (GM-CSF) has raised the possibility of reducing chemotherapy-induced neutropenia, the cause of much of the iatrogenic morbidity associated with treatment of SCLC. In vitro studies have suggested that SCLC growth could be inhibited by this agent [160]. Preliminary uncontrolled trials supported the notion that GM-CSF can be administered safely to SCLC patients, and that it does in fact ameliorate myelosuppression [174, 1751. An interim analysis of a large randomized study designed to test the effects of granulocyte-CSF (G-CSF) on myelosuppression induced by the combination of cyclophosphamide, doxorubicin and etoposide has been reported. G-CSF administration was associated with a significant reduction of the frequency and severity of neutropenia. The number of days of hospitalization and antibiotic therapy required for febrile neutropenia were reduced by 4&50$, for the chemotherapy cycles including G-CSF, compared to cycles during which patients were receiving a placebo [ 1761. The role of this novel approach remains to be defined. Given the treatment-related death rates from current SCLC therapy of 0-4s in limited and 2-8s in extensive disease [3], the potential for improving survival with the addition of CSFs to standard chemotherapy is negligible. Their efficacy in reducing the frequency of fever and documented infection compared to prophylactic antibiotics should be investigated. It is possible that CSFs will permit escalation to a higher level of dose intensity of chemotherapy, which may allow the attainment of better therapeutic results with at least some drugs [177]. However, it must be noted that some current regimens such as PE achieve therapeutic results at least very similar to those of more myelotoxic programs based on combinations of alkylating agents and doxorubicin.
reports from six institutions or groups describing survival of a total of 2000 SCLC patients followed for a minimum of 5 years from the initiation of chemotherapy revealed that 4% of all patients, including 7% with limitedand 1% with extensive-stage disease, were alive at the 5year point [31]. Since the probability of recurrence of the original tumor is 33% after disease-free survival of 24 months, 26% after 30 months, 14% after 36 months, and rare after 5 or 6 years [178-1801, 5-year survival, as is true in other types of lung cancer, is a reasonable benchmark for ‘cure’ of SCLC. This cancer can therefore be eradictated by current therapy in a small fraction of patients. Whether such patients should be considered to be cured of their disease, however, is dependent upon the definition of cure. Patients who are free of SCLC 18 to 24 months after the beginning of therapy have a IO-fold increased risk of dying over the next 5 years compared to the general population [180] and a 6-fold increased risk of dying of non-neoplastic causes [178]. The major causes of this excess mortality are principally smoking-related, as was the original SCLC, and include cardiopulmonary disease and second malignancies, the most common of which is non-small cell carcinoma of the lung [181]. Chemotherapy-related acute myelogenous leukemia is rarely observed [182], but this complication should become even more uncommon since the customary duration of chemotherapy is being shortened and nitrosoureas and procarbazine, which are highly leukemogenic drugs, are being utilized much less frequently in treatment of SCLC. Neuropsychological deficits noted in some long-term survivors have been discussed in Section III-I. Although these second malignancies and chronic toxicities can be devastating in some individuals, they are clearly outweighed by the several-fold prolongation in median survival for all patients receiving current therapy and the small but real prospect of permanent eradication of their cancer for a few. Despite the major advances made in the management of SCLC in the chemotherapy era, however, it is sobering to reflect that the great majority of patients still die of their cancer.
III-M.
IV-A.
‘Cure’ and morbidity
in long-term survivors
Although the improvement in median survival of SCLC patients given combination chemotherapy was obvious almost immediately after its utilization became widespread in the 1970s the question of whether any patients are ultimately cured of their disease began to be answered only within the past few years. A summary of
IV. Recent advances in the biology of SCLC Drug resistance mechanisms
The empirical chemotherapy of SCLC, despite remarkable early successes, appears to have reached a plateau. One possible approach to breach this impasse is to seek an understanding of the mechanisms by which SCLC cells escape the toxic effects of the diverse classes of agents to which they have been exposed. This knowl-
122
edge might then be applied to novel strategies designed to neutralize or bypass these defense mechanisms. The study of drug resistance of cancer cells has attracted much attention in recent years. The earliest data were obtained on the mechanisms of resistance to the antimetabolite methotrexate. Before reaching its major intracellular target, the enzyme dihydrofolate reductase, methotrexate must enter the cell through an energy-dependent specific carrier, after which its intracellular accumulation is facilitated by polyglutamation. Sensitivity to dihydrofolate reductase inhibition depends in part on the continuous consumption of reduced folates by thymidylate synthesis. As a consequence of these complex events, resistance to methotrexate can result from alterations in many different aspects of the drug’s interactions [183]. In SCLC cell lines, Curt et al. [ 1841were able to correlate relative methotrexate resistance with reduced intracellular drug accumulation due to decreased polyglutamation, as well as decreased thymidylate synthetase activity. In addition, unstable methotrexate resistance in cultured SCLC cell lines was occasionally found to be due to elevated levels of dihydrofolate reductase caused by gene amplification associated with the presence of double-minute chromosomes [ 1851. Although these early observations emphasized the ability of neoplastic cells to develop mechanisms to escape the toxic effects of specific chemotherapeutic agents, they could not address the broader question of concomitant resistance to diverse classes of agents so often observed in the clinic. Variants of the ‘multidrug resistance’ phenotype have been attributed to the highlevel expression of a drug efflux pump, the ~170 glycoprotein encoded by the multi-drug resistance gene MDRl[l86-1891, the expression of efficient drug-detoxifying enzymes such as the placental form of glutathione transferase [190], or an enhanced ability to repair DNA damage [183]. A particularly useful resource to address these issues is the large panel of lung cancer cell lines now in existence. Studies with these lines, derived from both previously treated and untreated patients, should allow the eventual correlation of drug sensitivity patterns with cellular mechanisms of drug resistance. Our group has studied a population of 68 consecutive extensive-stage SCLC patients in whom systematic efforts were made to harvest tumor tissues and establish a cell line from each patient [191] and found no correlation between the ability to establish a cell line in the 23 patients in whom that could be accomplished and their clinical outcome. These findings support the conclusion that, at least in extensive-stage SCLC, established cell lines are not derived from patients whose tumors have an inherently different biology. Thus, the biologic fea-
tures of the cell lines may be representative of SCLC tumors as a whole. In addition, in vitro chemosensitivity testing of human lung cancer lines shows patterns of resistance reminiscent of what is observed in the clinic [192]. Cell lines from untreated SCLC patients were more sensitive to doxorubicin, carmustine, cisplatin, melphalan, vincristine, and etoposide than non-small cell lung carcinoma (NSCLC) cell lines. Cell lines from previously treated SCLC patients had drug sensitivity more similar to NSCLC lines. Consequently, it is reasonable to consider that these cell lines may be appropriate surrogates for primary patient material in the study of drug resistance mechanisms in human lung cancer. Several studies employing both primary tumor tissue and established cell lines have addressed the mechanisms of drug resistance in SCLC. As already mentioned, the phenotype of pleiotropic or multidrug resistance has been associated in some instances with the overexpression of a membrane glycoprotein which is able to actively transport multiple drugs outside the cell and is encoded by the A4DRl gene [186-1891. The role of this gene in lung cancer was explored by quantitating the level of expression of MDRl-specific message in mRNA extracted from a panel of lung cancer cell lines and tumors. The level of expression was found to be elevated in only 4/23 SCLC cell lines and 3/6 SCLC primary tumors studied. In no instances were elevations of MDRl expression to the very high levels sometimes noted in colon cancer found. Furthermore, no correlation was observed in SCLC material between MDRl expression and whether tumor material was derived from previously treated or untreated patients or from untreated patients who did or did not respond to initial chemotherapy. There was also no correlation between mRNA levels and in vitro chemosensitivity [193]. It would thus appear that enhanced drug efflux through ~170 glycoprotein is not a major factor in the clinical drug resistance of SCLC, and that other mechanisms must be operative. A clinical pilot study attempting to pharmacologically modify putative drug resistance resulting from MDRI overexpression in SCLC has already been performed [ 1941. The discovery that the high-level expression of the placental form of the drug metabolizing enzyme glutathione-4transferase correlated with a phenotype of pleiotropic drug resistance distinct from drug accumulation defects induced in the MCF-7 breast cancer cell line in vitro has several important implications [ 1901. Since this enzyme can not only detoxify a wide range of xenobiotics but also has its expression induced by exposure to these compounds, it was predicted that tumors arising in the context of long-term exposure to environmental carcinogens would be likely to have activated this detox-
123
ifying enzyme system. Since many drugs in common use are derivatives of natural products which can be detoxified by this mechanism, this provided a general framework within which many therapeutic failures could be explained. In fact, it has been shown that the level of glutathione-S-transferase enzymatic activity was increased in the lung tissue of smokers and that this was proportional to the cumulative tobacco exposure measured in pack-years [195]. There are several reports indicating the frequent high-level expression of this enzymatic system in NSCLC tumors and cell lines [196 2001. In contrast, SCLC tissues and cell lines consistently express lower levels of glutathione-S-transferase mRNA [ 1961, immunoreactivity [200], and enzymatic activity [197]. In a study of 15 SCLC cell lines, no correlation was found between glutathione-S-transferase enzymatic activity and sensitivity to doxorubicin or melphalan. Furthermore, there were no differences between cell lines derived from untreated patients when compared to those from previously treated patients [197]. In the aggregate, these observations support the view that the glutathione-S-transferase system does not explain the less common de novo or usual acquired resistance to chemotherapy observed in SCLC. Recent evidence points to alternative mechanisms of pleiotropic drug resistance which may be operative in SCLC. An SCLC cell line made resistant in vitro by graded exposure to doxorubicin was found to show collateral resistance to vincristine, vindesine, etoposide, cisplatin and X-irradiation, but not to melphalan, colchicine and actinomycin D. This drug resistance phenotype was explained on the basis of a combination of decreased intracellular levels of doxorubicin, increased DNA repair, and reduced DNA topoisomerase II activity [201, 2021. Since it appears that the repertoire of known drug resistance mechanisms used by SCLC is limited, further definition of these and other as yet unknown mechanisms is indicated in an effort to identify clinically relevant resistance pathways which might be modulated to improve the efficacy of existing chemotherapeutic agents. Examples of in vitro modulation of drug sensitivity in SCLC cell lines with cyclosporine and docosahexaneoic acid have been reported [203, 2041.
biogenic amine synthetic enzyme L-DOPA decarboxylase) [205]. The most striking manifestation of this phenotype is the elaboration of a large number of peptide hormones and growth factors, several of which were first identified as neuropeptides (see Table 1). This list continues to expand, the most recent additions being atria1 natriuretic factor [lo] and multiple opioid peptides [206]. The first peptide to be specifically documented to be produced by SCLC was gastrin-releasing peptide (GRP), the mammalian homologue of the amphibian tetradecapeptide bombesin [207, 2081. The details of this discovery are of historical interest. It had been recognized since the 1940s that the normal human bronchial
TABLE I Some hormones
produced
Product
Hormone
GRP [207,208,279]
+
IGF-1 [224]
+
Transferrin [225]
+
Calcitonin
+
[280]
AVP [28 I]
IV-B.I.
as a
Growth factors
The neuroendocrine nature of SCLC has been long recognized on morphological grounds (presence of neurosecretory granules), as well as biochemical grounds (expression of chromogranin A and the key
expressed
by human
small
produced
Receptor
expressed
+
Opioid peptides:
[206,
2821 /I-endorphin
+
enkephalin
+
dynorphin Neurotensin Glucagon
[280]
+
Substance
P [209]
+ + _
Somatostatin
+ + + +
+ +
[280,283]
[280,284]
CCK [226, 2841 TGFa: [280]
7 ? + +
VIP [28 I, 2841
+ _
ACTH
2811
+
?
GGAP
[285,286]
+
+
+ ?
1
?
+
ANF Galanin
[226]
Bradykinin
[226]
[ 1601
Interferon-y GM-CSF
[I601
+
+
?
+
?
+
Neurokinin
A [287]
?
Neurokinin
B [287]
?
+ +
?
+
?
+ ?
Acetylcholine,
musca-
rinic [288]
IV-B. Interruption of autocrine growth stimulation target for developmental therapeutics
and receptors
cell lung cancer
Acetylcholine,
nicotinic
VW Serotonin Adapted
[210]
+
from Ref. 289. Hormones
be involved in autocrine is assumed
growth
in boldface
regulatory
if shown by direct radioligand
cal effect of the cognate tion of a specific growth.
hormone
signal
have been shown
loops. Receptor
to
expression
binding
assay or if a biologi-
is demonstrated
by virtue of activa-
transduction
pathway
or stimulation
of
124
epithelium exhibited a cellular component whose morphological features were similar to that of a proposed diffuse neuroendocrine system [209]. Carcinoid tumors and SCLC shared many of these features, including the production of the biogenic amine serotonin [210]. However, the demonstration that these cells could also elaborate biologically active peptides remained elusive. The search for biologically active peptides throughout the animal world, particularly in the Bombina family of amphibians by Vittorio Erspamer, had generated a large family of candidate hormones. Using specific antibodies raised against the amphibian peptide bombesin, Wharton et al. demonstrated in 1978 the presence of immunoreactivity in the normal neuroendocrine cells of the human fetal lung [211]. The presence of bombesin-like immunoreactivity was subsequently reported in SCLC by several groups [207, 2081 and was later shown to be due to the expression of the mammalian homologue GRP [212]. GRP acts as a growth factor for normal human bronchial epithelial cells [213] and for SCLC both in vitro [214-2161 and in vivo [217]. The ability of the 2All monoclonal antibody raised against the carboxyl terminus of bombesin to block binding of GRP to its receptor led to the use of this reagent to study the impact of GRP on SCLC biology. It was found both in vitro and in vivo that exposing SCLC cells to this antibody deprived them of the trophic effect of the endogenously produced GRP and resulted in growth inhibition of the tumor cells [214]. These observations were the first demonstration that autocrine growth stimulatory loops might be an important factor in the genesis or maintenance of these malignant cells. Several synthetic peptides with antiGRP activity have been described (see Table 2), the most recent generation of which can block GRP binding at concentrations in the nanomolar range [218, 2191.
TABLE 2 Bombesin antagonists with in vitro activity against small cell lung cancer Structure (D-Argl, D-Pro*, D-TqP, Leu”) substance P (2201 (D-Argl, D-Phe5, D-Trp7.g, Leu”) substance P [220] (Leu’3-Y-CH2NH-Leu14) bombesin [221] n-Acetyl-GRP-20-26OCH2CH3 [218] (D-Phe6, Leu13-Y-CH2NHPhe14)bombesin (614) [219] Adapted from Ref. 289.
KS0 for growth
I& for binding
82 /LM 24 FM 1fiM
80.4 nM 4nM 3.1 nM
Several have been shown to inhibit SCLC growth in vitro [220,221]. This developmental work has generated novel compounds which hold promise as clinically useful anti-GRP drugs, and the original 2All antibody is currently undergoing human trial [222,223]. However, as is graphically documented by Table 1, GRP is only one of a multitude of peptides with potential growth-regulatory roles in SCLC. Both insulin-like growth factor I and transferrin-like growth factor participate in autocrine growth regulatory loops [224, 2251. In addition, individual SCLC ceil lines can be shown to be responsive to a number of distinct hormones. By monitoring the response of the intracellular calcium concentration, Woll and Rozengurt [226] showed that the SCLC cell line NCI-H345 could respond to eight different individual hormones (acetylcholine, ACTH, bradykinin, cholecystokinin, galanin, GRP, neurotensin, and vasopressin). If one also considers the factors known to be produced by SCLC which do not elicit a rise in intracellular calcium concentration, it becomes obvious that the stimulatory effects on the growth of SCLC cells by themselves (autocrine) or neighboring cells (paracrine) may be extremely varied and complex. In this setting, it would appear unlikely that a therapeutic strategy aimed at any one growth factor would have much clinical impact and that any serious attempt at interrupting these trophic effects must take into account this heterogeneity. Such strategies could be based on the use of combination of antibodies and peptide antagonists (each with their individual specificity) or on the use of peptide antagonists with broader specificities such as the substance P analogues reported to block the mitogenie effects of GRP, vasopressin, and bradykinin in Swiss 3T3 cells [227]. Alternatively, strategies based on interrupting intracellular signal-transducing events shared by these many hormones might be viable. For instance, enzyme effecters such as phospholipase C (PLC), protein kinase C (PKC), G-proteins coupling several receptors to their effecters, and membrane calcium channels are all actually or potentially amenable to pharmacologic manipulation. It is provocative that certain compounds already in common use in medical oncology have pleiotropic mechanisms of action which include modifications of signal transduction pathways. For example, the antiestrogen tamoxifen can block calcium channels [228], and the anti-tumor antibiotic doxorubicin is also an inhibitor of PKC 12291. In addition, the only known animal model for pulmonary neuroendocrine neoplasia appears to be sensitive to such manipulations. Schuller et al. have recently described a protocol wherein hamsters receive repeated injections of the carcinogen N-nitrosodiethylamine [230]. Under standard laboraty conditions, the animals develop peripheral
125
pulmonary adenocarcinomas within 20 weeks. However, when kept in a hyperoxic atmosphere of 60% oxygen, they develop pulmonary neuroendocrine tumors within 8 weeks. Remarkably, the administration of a calcium/ calmodulin inhibitor prevents the appearance of the neuroendocrine tumors but not the adenocarcinomas [23 11. IV-B.2. Gastrin-releasing peptide stimulated signal transduction pathways
The above observations suggest that the manipulation of signal transduction pathways may prove to be a fertile ground for the developmental therapeutics of lung cancer. To better define potential targets, efforts to map the intracellular events following exposure of SCLC to the mitogen GRP are underway. GRP stimulation of SCLC is associated with the activation of a major signal transduction system centered on the enzyme PLC. In recent years, receptors activating PLC have been found to be coupled to it through the action of other membrane-associated proteins characterized by the ability to bind guanine nucleotides in a reversible manner [232] (see Fig. 3). These guanine-nucleotide binding proteins or G-proteins are molecular switches which transmit and amplify the signal initiated by the ligand-bound receptor to an effector, in this case PLC. The ligand-bound receptor adopts a conformational state which causes the binding of GTP to the G-protein. The GTP-bound G-protein is then able to stimulate the effector. The system can revert to baseline because of the intrinsic ability of the G-protein to hydrolyze the bound GTP and thus return to an inactive state. The function
of some G-proteins can be modulated through phosphorylation by the enzyme PKC [233] or through a posttranslational modification (ADP-ribosylation) catalyzed by certain bacterial toxins (cholera and pertussis toxins) which have been used as probes for the detection of Gprotein involvement in biological responses. A hallmark of receptor-effector coupling by a G-protein is the ability of non-hydrolyzable GTP analogs, which cause an irreversible activation of the G-protein, to modulate the affinity of receptor binding and the intensity of the transduced signal such as PLC activity. Bacterial toxins induce the same modifications when the involved G-protein is a substrate for their action (reviewed by Spiegel, Ref. 234). PLC activation results in the hydrolysis of an integral membrane phospholipid, phosphatidylinositol bisphosphate (PIP$ to form two products, inositol trisphosphate (IPs) and diacylglycerol (DAG). IPs in turn binds to a receptor on the endoplasmic reticulum, stimulating the release of endogenous calcium stores and transiently increasing the intracellular concentration of free calcium ([Ca*+]ir,) [235]. DAG activates the calcium and phospholipid-dependent protein kinase PKC. PKC activation can be followed by the activation of other pathways, such as the membrane Na+/H+ ‘antiporter’, causing an elevation of intracellular pH, or the transcriptional activation of certain genes such as the protooncogenes c-fos, c-&n and c-myc [236, 2371. After stimulation by a PLC-activating ligand, cells are often transiently refractory to a repeat stimulation by the same (homologous desensitization) or other (heterologous desensitization) ligands. PKC has been implicated in some of these regulatory events. Fig. 4 summarizes work which has shown that GRP
PMA
Q+y+y c-fos
c-myc
Fig. 3. Intracellular of phospholipase nucleotide ylinositol
binding
pathways protein;
bisphosphate;
lular concentration
involved in receptor
C. Abbreviations
PLC, phospholipase
IP3, inositol
of free calcium;
mediated
used are: R, receptor;
C; PIPZ, phosphatid-
trisphosphate; DAG,
tein kinase C.
activation G, guanine-
[Ca2+]i, intracel-
diacylglycerol;
PKC,
pro-
Fig. 4. Intracellular
pathways
small cell lung cancer with the addition
activated
by gas&in-releasing
cell lines. Abbreviations
of CT, cholera
toxin; and PMA.
istate 13-acetate.
peptide in
used are as in Fig. 3. phorbol
12-myr-
126
stimulation activates PLC in SCLC, both in metabolically labeled whole cell and membrane preparations [238, 2391. This activation is accompanied by an elevation of [Ca2+]irree [240], but PKC response has not yet been characterized. However, GRP stimulation of IP3 formation and increase in [Ca2+]irree were inhibited by prior treatment with the PKC activator phorbol 12myristate 13-acetate (PMA), suggesting that PKC might exert negative feedback regulation on this response.
a complete inhibition of the growth of three SCLC cell lines bearing the GM 1 ganglioside receptor for CT. The effects on signal transduction preceded the effects on cellular metabolic activity, suggesting that CT may be acting principally by depriving the cell of the trophic effects of multiple growth factors [241] and providing a model as well as a potential target for the therapeutic manipulation of growth-associated signal transduction pathways in SCLC.
IV-B.3. Efects of cholera toxin on signal transduction pathways andgrowth Because non-hydrolyzable GTP analogues could modulate PLC activation in response to GRP, it was concluded that the GRP receptor in SCLC was coupled to PLC by a G-protein [239]. The nature of this putative G-protein was investigated further by studying the effects of G-protein modifying bacterial toxins on GRPmediated signals in SCLC. Cholera toxin (CT) is a multimeric bacterial protein composed of five jI subunits, which bind to a specific receptor, the cell surface glycolipid GM1 ganglioside, and one CIsubunit which enters the cell. The a subunit is an enzyme which catalyzes the transfer of ADP-ribose from NADP to certain G-proteins, thus modifying their function by abolishing their intrinsic GTPase activity. CT was found to inhibit GRP-stimulated generation of IP3 and increase of [Ca2+]ir, in the SCLC cell line NCI-H345 [238]. The best characterized action of CT is to modify the G-protein coupled to adenylate cyclase and stimulate the formation of intracellular cyclic AMP (CAMP). CAMP is itself an important second messenger able to activate a family of CAMP-dependent protein kinases mediating pleiotropic cellular effects. Because of this, the possibility that the effects of CT on GRP responses might be indirectly caused by an elevation of CAMP was considered. However, preincubation of SCLC with cyclic AMP analogues had no effect on the generation of GRP-stimulated signals [238]. These observations initially suggested that the GRP receptor of SCLC might be coupled to PLC by a CT-sensitive G-protein. The effects of CT on the signal transduction pathways and biology of SCLC have recently been studied in more detail [241]. CT pretreatment led to an inhibition of signal transduction generated not only by GRP but also by vasopressin and fetal calf serum. This was accompanied by a loss of cell surface membrane ruffling and a decrease in GRP-stimulated PLC activity in membranes prelabeled with [3H]inositol, but with no change in GRP receptor number or affinity. This indicated that CT could perturb membrane function related to PLC activity but not through an effect on the G-protein coupling the GRP receptor to PLC. More importantly, CT led to
IV-C. Genetic lesions in SCLC We now appreciate that established SCLC harbors a wide range of somatic genetic abnormalities, including activation of dominant oncogenes as well as inactivation of several newly recognized tumor suppressor genes. These data have been extensively reviewed recently [242] and will be only summarized here. The appreciation of the range of genetic lesions present in human SCLC followed from a number of serendipitous observations, as well as from specific studies of a panel of SCLC cell lines in the context of the historical development of the field of oncogene research. It was clear early on that SCLC tumors had suffered a number of genetic events. Early cytogenetic studies revealed abnormalities of virtually every chromosome, with the most consistent change being that of a deletion of the
TABLE Major
3 dominant
oncogenes
and tumor
suppressor
genes altered
in
small cell lung cancer Gene
Frequency*
Function
Dominant ras family
O/42 cell lines [272]
~21 membrane-associated protein.
Signal transduc-
tion? Activated
by point
mutations.
myc family
Nuclear
Amplified
phosphoproteins.
Function expression
unknown.
c-myc
coupled
to cell
11-24s
increased Tumor
of and
[262,
Overex-
pressed in 89% of cell
with IYJSin transforming cells. Activated
of tumors
264,267,268].
cycle. All can cooperate primary
in 30-50s
cell lines [264,268]
by
lines and 83% of tumors [268].
expression.
sup-
pressor 3P
Putative
rb
genes not yet identified. Nuclear phosphoprotein.
tumor
P53
cell cycle regulation. Nuclear protein. ? function.
92-100% [250]
suppressor ?
Inactivated
[253]. a Reference
numbers
are in parentheses.
in > 90%
[252, 254, 2901. Inactivated in > 50%
127
short arm of chromosome 3 [243,244]. Further cytogenetic studies as well as restriction fragment length polymorphism analysis confinned the presence of multiple areas of loss of genetic information, particularly at 3p (in 92-100s of SCLC) [245-2501, 1lp (the locus of the Wilm’s tumor gene) [251], 13q (the locus of the retinoblastoma gene), and 17p (the locus of the ~53 gene) [249]. The retinoblastoma gene and ~53 have functional characteristics of tumor suppressor genes, and both have been shown to be inactivated in a high proportion of SCLC by diverse mechanisms including deletions, lack of expression and point mutations [252-2561. It is in this context that it is anticipated that at least one more tumor suppressor gene is localized on 3p; its identification and molecular cloning is the focus of intense efforts in several laboratories. In addition, the recent cloning of a candidate for the Wilm’s tumor gene [257] will allow the study of its expression in SCLC and other tumors which show losses at 1lp. The recent observation that mutant forms of the ~53 protein are more stable and can be detected by standard immunohistochemical techniques [258J is bound to facilitate the analysis of their clinical and biological significance. In contrast to the above genes whose involvement in carcinogenesis is through loss of their normal function in the restrictive control of cellular growth, several other genes manifest themselves by an inappropriate and deregulated functional activation. A paradigm for these dominant oncogenes in SCLC has been the myc family of genes. The genes c-myc, N-myc and L-myc all encode nuclear phosphoproteins whose precise functions remain to be defined. Because they can all cooperate to varying degrees in transforming primary rodent cells, they are thought to stimulate or enhance cellular growth [2592611. All three genes have been shown to be overexpressed in some SCLC tumors and cell lines by virtue of genomic amplification (in 10-20s of primary tumors) or deregulated transcription [262-2691. Overexpression of a myc family gene appears to confer more aggressive biologic properties to SCLC, as tumors with this property are more tumorigenic in nude mice [266] and the patients from whom they are derived have a worse prognosis [263, 2641. There is a relative paucity of information on the expression and function of the scores of other dominant oncogenes that have been described. In particular, the ras family of oncogenes, which can be activated by well characterized point mutations, has been shown to be activated in about 20% of NSCLC, seemingly uniquely at codon 12 of c-ki-rus [270,271]. We have recently studied rus mutations in a panel of SCLC and NSCLC cell lines and have found that 23/63 NSCLC cell lines had rus
gene mutations, most frequently involving codon 12 of c-k&as but also other codons of two other ras family genes. In contrast, none of 42 SCLC cell lines had mutations of any ras gene at any of the three codons studied [272]. These observations suggest that rus mutations do not play an active role in the pathogenesis of SCLC. However, the introduction of an activated rus gene into SCLC cell lines has been associated with the loss of neuroendocrine features, morphological transformation towards an NSCLC histology, and the appearance of growth factors and growth-factor receptors more commonly associated with NSCLC [273,274]. It is not clear whether these provocative observations are relevant to the natural history of lung cancer. As knowledge of the genetic lesions present in SCLC expands, a number of themes are emerging. Any given tumor usually exhibits multiple abnormalities in both the tumor suppressor genes and the dominant-acting oficogenes. In fact, several cell lines harbor abnormalities of all three defined or putative tumor suppressor genes recognized to be involved in SCLC (3p, rb, and p53), as well as lesions at other chromosomal loci combined with a deregulated myc gene [253]. This knowledge may eventually be exploitable in the clinic. Analysis of the cumulative effect of similar genetic abnormalities (termed an allelotype by Vogelstein et al., Ref. 275) is of prognostic value in colon cancer and may be useful in SCLC in terms of targeting therapy to biologically defined subsets of patients. In addition, one can envision strategies designed to deprive tumor cells of the function of a constitutively activated oncogene [276], to replace a critically missing function through gene therapy, or to target novel treatments at mutated genes or their products [277,278].
V. Conelusions
The development of more effective therapeutic approaches to SCLC is at a crossroads. In no other area of oncology is the dialogue between clinicians and molecular and cellular biologists more important and likely to bear fruit. The plateau in our recent therapeutic achievements must not discourage continuing to address the incrementally progressive but important issues of determining the optimal dose and schedule of the agents, including radiation therapy, currently available. It is hoped that the drug screening program utilizing panels of human lung cancer cell lines will identify useful new drugs. However, we must not be timid in exploring the new possibilities identified by our rapidly expanding knowledge of the basic biology of SCLC.
128
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Critical Review,s in Oncology/Hematology. 1991; 11: 109-135 0 1991 Elsevier Science Publishers B.V. 1040-8428/91/$3.50
ONCHEM
00006
Small cell carcinoma of the lung: clinical and biologic aspects Jean Viallet ‘NCI-Navy
and Daniel C. Ihde’
Medical Oncology Branch, National Cancer Institute and National Naval Medical Center, and Uniformed Services University @‘the
Health Sciences1 Bethesda, MD. U.S.A. and 2the Departments
of Medicine and Oncology and the Montreal General Hospital Lung Oncology Group,
McGill University,
Montreal,
Quebec, Canada
Contents 1.
Introduction
II.
..............................................................
..................... Current status of therapeutic approaches to SCLC ............................. A. Combination and single-agent chemotherapy. . .. . Clinical features,
III.
B. Intensity c.
pathology,
staging,
of induction
Cyclic alternating
D. Duration
of chemotherapy
F. Strategies
factors
110 112 112
chemotherapy
non-cross
E. Late intensification
109
and prognostic
113
resistant
chemotherapy
and management
with autologous
for evaluation
regimens.
113
of tumor progression
bone marrow
114
transplantation.
114
.
of new drugs
.
115
G. In vitro drug testing.. H. Combined
116
modality
I.
Prophylactic
J.
Adjuvant
therapy
and therapeutic surgical
K. Biological
response
L. Modification
B. Interruption
of autocrine
growth
tional Cancer
toxin on signal transduction
fessor in the Departments versity,
Montreal,
Research
Council
from Stanford
logy at Memorial tional Cancer
of Canada.
University. Institute,
Deputy
Chief (Clinical)
National Uniformed
Naval
fellowships
Cancer
Bethesda, Cancer
is a Scholar
Center
Services University
Pro-
at McGill
Uni-
an M.D.
degree
in Medical
Onco-
NY and the Na-
MD. Since 1975, he has been on the
Institute,
where
of the Navy Medical
Medical
Center,
at the Na-
Assistant
of the Medical
Daniel Ihde received
Sloan-Kettering
staff of the National
and Oncology
He completed
of Montreal,
Oncology
and a Professor of the Health
until recently
Oncology
he was
Branch
at the
of Medicine
at the
Sciences,
also in Bethes-
da. Correspondenre: Branch, Bethesda,
National
Daniel Naval
MD, 20889-5105.
C.
Ihde,
Medical U.S.A.
NCI-Navy Center,
Medical
Building
Oncology
8, Room
5101.
123 123
signal transduction pathways
pathways and growth
................
125
..............
126 126 127
....... .... ......... .. .......
MD. He is currently
Dr. Viallet
stimulated
SCLC.......................................................
....... .
in Medical
of Medicine
Canada.
121 therapeutics
.....................................................................
. ... .
Bethesda,
121
as a target for developmental
3. Effects of cholera
a fellowship
Institute,
stimulation
peptide
Jean Viallet received an M.D. degree from the University He completed
121
............................................ ...................................................
of SCLC
2. Gastrin-releasing
References
120
treatment.
survivors.
............................................................
C. Genetic lesions in
Canada.
119 119
with adjunctive
in long-term
mechanisms
I. Growthfactors
Conclusions
II8
.
in the biology
A. Drug resistance
117
irradiation.
modifiers
of host environment
Recent advances
V.
cranial
irradiation
resection
M ‘Cure’ and morbidity IV.
with chest and multiple-site
........ . ..
.
128
I. Introduction Small cell lung cancer (SCLC) distinguishes itself from the other types of lung carcinomas by a remarkable propensity for early systemic spread and by substantially greater initial sensitivity to chemotherapy and radiation therapy. The former is exemplified by the fact that nearly all patients present with mediastinal or systemic metastases at the time of initial diagnosis. Indeed, even patients that were surgically resected but died within 1 month of surgery were found at autopsy to have a high incidence of residual cancer, most often distant metastases [l]. The predominant influence of systemic cancer on survival in SCLC is confirmed by the trivial ef-
110
fects of surgery and radiotherapy on the life-span of all but a handful of patients. Systemic chemotherapy, on the other hand, has increased median survival by 45fold since its introduction in the 1960s [2], even though the impact of chemotherapy on survival in other cell types of lung cancer is marginal at best [3]. Since it comprises approx. 25% of all lung cancer, SCLC is the sixth most common malignancy and the fourth leading cause of death from cancer in the United States [4]. It is the most common neoplasm in which a fraction of patients can be cured with chemotherapy. Substantially more successful management of this tumor would therefore clearly have a significant impact on overall cancer mortality. In the early 196Os, the Medical Research Council of Great Britain conducted a clinical trial in operable SCLC patients comparing surgical resection to locoregional irradiation [5]. Although radiotherapy was found to be superior to surgery in prolonging median survival, neither modality provided long-term tumor control in this relatively favorable group of patients without obvious distant metastatic disease. In contrast, single agent chemotherapy with cyclophosphamide resulted in a doubling of the median survival in both limited and extensive stage patients when compared to placebo treatment in a prospective randomized clinical trial published in 1969 [6]. Administration of this drug to patients with other lung cancer cell types yielded neither substantial tumor regression nor any improvement in survival. Since then, a large number of individual drugs have been utilized in the management of SCLC patients. It was rapidly established that combination chemotherapy was superior to single agent therapy. By the end of the 197Os, drug treatments for SCLC, with or without the addition of chest radiotherapy, were reproducibly associated with median survivals of 10-16 months in patients with localized and 611 months in those with overtly disseminated cancers. Two-year survival of 10-25s and O--3%for localized and disseminated tumors, respectively, was often reported by the early 1980s. These survival results are quite impressive compared to the previously observed median survival of 334 and 1.5-2 months, respectively, in untreated patients [3, 71. There is little data from the pre-chemotherapy era on 2-year survival of unselected patients with SCLC, but it was certainly a rare occurrence. However, there has been little further improvement in survival results over the succeeding 10 years. Figs. 1 and 2 show that this therapeutic plateau has not resulted from inactivity on the part of clinical investigators, as the numbers of both individual agents and innovative therapeutic strategies which have been evaluated have continued to increase. Rather, the generally disappoint-
ing results of these continuing efforts might suggest that empirical selection of drug combinations and variations in their mode of delivery using presently available cytotoxic agents may not be the ultimate answer to the successful management of this disease. During the same decade, in contrast, our understanding of the fundamental biology of SCLC has rapidly expanded and reached a point where it may serve as a basis for the development of novel treatment approaches. In this review, it will be our purpose to trace the evolution of the therapy of SCLC to its current state, with emphasis on areas which have not been sufficiently evaluated, as well as to provide an overview of SCLC tumor biology in an effort to identify potential targets for experimental therapeutics.
II. Clinical features, pathology, staging, and prognostic factors
In most cases of SCLC, it is the location and size of the primary tumor and the presence and nature of metastatic deposits which dictate the accompanying signs and symptoms. Because SCLC tends to present centrally and to infiltrate the submucosa [8], bronchial obstruction with consequent cough, dyspnea, wheezing, chest discomfort, hemoptysis or post-obstructive pneumonia is common. Two-thirds of patients will have evidence of distant metastases, most often to the liver, bone, bone marrow, or brain, at the time of original diagnosis. The clinician must also be alert to signs and symptoms which may be manifestations of the many paraneoplastic syndromes associated with SCLC and which may be confused with symptomatic metastases [9]. These syndromes are often due to the elaboration and release by the tumor of various humoral products (adrenocorticotrophic factor (ACTH) causing ectopic Cushing’s syndrome or arginine vasopressin (AVP) and atria1 natriuretie factor (ANF) [lo] causing hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion) or to immune reactions to a tumorassociated antigen, especially in neurologic syndromes such as the Eaton-Lambert myasthenic syndrome, in which the presence of circulating antibodies reacting with voltage-gated calcium channels has been documented [I 11. Visual deficits produced by retinal degeneration and sensory neuronopathy are two other syndromes most commonly found in SCLC in which serum antibodies reacting with both tumor and neuronal tissue are observed [9]. A diagnosis of SCLC can be made from tissue obtained through a variety of techniques, either from the primary site or a nodal or distant metastasis. Special
111
caution is required in pathologic interpretation of needle aspiration biopsies, however, as crush artifact can sometimes be mistaken for SCLC. The tumor consists of cells that are 2-3-times the size of mature lymphocytes. Nuclei are darkly staining with a characteristic ‘salt and pepper’ chromatin distribution [12]. Small, relatively infrequent dense-core granules, which are a manifestation of the peptide secretion that is the hallmark of the ‘neuroendocrine’ properties which are observed in most SCLC but are relatively infrequent in other types of lung carcinomas, can be demonstrated on electron microscopy in most tumor specimens which are diagnosed as SCLC by light microscopy. Whether these neurosecretory granules are present, however, is not associated with response to chemotherapy [ 19. Whereas the classic oat-cell subtype has little cytoplasm and indistinct or absent nucleoli, the intermediate subtype is composed of somewhat larger cells with more distinct cytoplasm. The distinction between these two subtypes provides no prognostic information, as patients with each of these pathologic diagnoses present with similar extents of tumor dissemination and experience no differences in response to therapy, duration of response, or survival [1416]. However, 5514% of patients present with a tumor composed of classical small cell elements admixed with larger cells with more abundant cytoplasm and prominent nucleoli. This small cell/large cell subtype was of prognostic significance at two different institutions which documented a lesser likelihood of response and shorter median survival in this group of patients [16, 11. This finding, however, could not be confirmed in patients entering a cooperative group chemotherapy trial [18]. A much smaller frequency (2% in one series) of SCLC patients have elements of squamous or adenocarcinoma in their diagnostic biopsy specimens. Although the natural history of patients with this ‘combined’ subtype is not well characterized, they may present more often with surgically resectable lesions P91. Essentially all investigators currently employ the twostage system first proposed by the Veterans Administration Lung Group. The distinction between the two stages is based upon whether the known tumor can be encompassed within a tolerable radiation field, thus introducing physiologic as well as anatomic factors into assignment of stage [3]. Limited stage is defined as disease confined to the hemithorax of origin and its regional lymph nodes (including mediastinal, contralateral hilar and, in most definitions, ipsilateral or contralateral supraclavicular), whereas extensive stage is defined as disease extending beyond this area. Since in many institutions patients with limited-stage disease will receive chest irradiation in addition to systemic chemotherapy,
the definition of stage influences the primary management of the patient. The extent of the staging process varies with the specific clinical situation. In usual practice, presenting signs and symptoms guide the choice of diagnostic procedures. If an unequivocal site of distant metastases is identified, eliminating the indication for elective thoracic irradiation, no further procedures need be performed unless the information sought will modify clinical management. In the rare patient with a proven diagnosis of SCLC who may still be a candidate for surgical resection, preoperative mediastinoscopy should be performed since documentation of mediastinal node involvement would preclude thoracotomy, and the tumor should be staged by the recently revised, more detailed TNM staging system [20]. After therapy has been administered, sites of prior involvement should be reevaluated to determine whether complete, partial, or no objective response is present. The response category is strongly associated with ultimate survival, with virtually no patients without a complete response living beyond 2 years. In the context of a clinical trial, where a careful characterization of the patient population under study is necessary to assure optimal interpretation of the observed outcomes, more detailed and rigorous staging evaluations are usually justifiably pursued. Ambulatory or performance status and tumor stage at presentation are the most powerful prognostic factors in SCLC. In large groups of patients who receive combination chemotherapy, additional factors which refine prognosis can often be demonstrated. Some directly relate to total tumor burden, such as the favorable effect of tumors which were completely surgically resected in limited-stage disease [21] and the number of organ systems involved by metastases in extensive stage patients [22-251. In patients whose tumors are surgically removed, hilar and especially mediastinal node involvement are associated with considerably worse prognosis [26]. Some are host characteristics; women [22, 25, 271 and younger patients (below 60 or 70 years of age) [22, 25,281 have a more favorable outcome in some series or patient subgroups. Finally, abnormal serum biochemical values (elevated liver function tests or low albumin or sodium determinations) provide prognostic information independent of documented tumor extent in many reports [23, 25, 28, 291. Abnormalities in serum biochemical tests are strongly correlated with the number of distant metastatic tumor sites in patients who have undergone numerous systematic staging procedures, and both are likely to be surrogates for overall tumor burden [23, 241. As in all other cancers, SCLC patients who have developed tumor progression after receiving chemotherapy have a
112
markedly inferior prognosis, with median survival of only 24 months [3]. Most, if not all, treatment programs for SCLC are adopted only after documentation of their efficacy in a clinical trial is published in the medical literature. Therefore, it is of great interest to know whether there are any marked differences in prognosis between patients who are entered on clinical trials and those who are not. One report which investigated this issue found little difference in outcome in limited-stage patients whether or not they were placed on institutional clinical trials, but much shorter survival in extensive-stage patients who were not placed on trials because of poor performance status or medical problems unrelated to their cancer [30]. This result is not unexpected, since most limited-stage patients are fully ambulatory, but emphasizes that outcome similar to that reported in clinical trials should not necessarily be expected in more acutely or chronically ill patients. III. Current status of therapeutic approaches to SCLC
The current status of SCLC therapy has recently been extensively and comprehensively reviewed [3, 31, 321. Only the salient points will be summarized here. The ability of combination chemotherapy to substantially improve the clinical outcome of SCLC patients was documented relatively quickly after its introduction, certainly by the end of the 1970s. Since then, clinical evaluation of multiple combinations of drugs, selected both empirically and rationally, and variations in duration and intensity of therapy, including autologous bone marrow support, have had only very modest additional impact on survival. This suggests that future investigations might better focus on the biological mechanisms underlying drug resistance or on alternative forms of therapy diverging from the classical cytotoxic chemotherapy paradigm. III-A. Combination and single-agent chemotherapy
When combination chemotherapy programs were first introduced into the management of SCLC, they appeared to yield much higher response rates, especially complete response rates, than had been observed with single-agent treatment. However, there are relatively few prospective randomized trials which specifically confirm this point. Two- [33] or three-drug [34] regimens containing cyclophosphamide were compared to cyclophosphamide alone, with improved response rates and survival found using the combination programs. Another trial compared concurrent administration of four drugs with the sequential administration of the same
agents and found a superior response rate with the use of the combination [35]. All these trials were published before 1980. They are confirmed by a recent British study which randomized 151 patients to receive combination chemotherapy (with chest irradiation in limited disease) or single-agent cyclophosphamide or palliative radiotherapy whenever indicated. Median survival was doubled from 4 to 8 months and l-year survival increased from 8% to 30% with the combination regimen [36]. The optimal number of drugs in a combination program is not established, but two to four are most commonly given. Since most agents used in the treatment of SCLC are myelosuppressive, each addition to a combination usually requires compromising the dose of all the agents, probably accounting for the fact that little or no benefit has been documented from administering more than three drugs simultaneously [3]. It has proven quite difficult to establish the superiority of any specific chemotherapeutic regimen in the treatment of SCLC. For example, etoposide (VP- 16) as a single agent has one of the highest reported response rates against this tumor, but adding this drug to an effective combination program containing other drugs has generally not led to improved outcome in randomized trials [37-391. In one study in which etoposide was substituted for vincristine in the cyclophosphamide/doxorubicin (Adriamycin@)/vincristine (CAV) combination, survival was significantly improved with etoposide, but only in extensive- stage patients [40]. Etoposide when given as a single agent is more effective on a 5-day than on a lday schedule [41], but when etoposide was added to cyclophosphamide and doxorubicin on either a S-day or 1-day schedule, no differences in outcome could be demonstrated [42], probably because the considerable efficacy of the latter two drugs greatly diluted any therapeutic impact which the addition of etoposide in a superior schedule could provide. A two-drug regimen frequently utilized in SCLC after the mid-1980s is cisplatin and etoposide (PE), which is therapeutically synergistic in murine tumors and extremely effective against testicular cancer [3]. It was first shown to have activity in patients who developed progressive tumor following CAV treatment [43] and then found to yield survival results similar to other regimens when used alone as the only form of chemotherapy [44]. In a randomized study PE produced significantly better survival than ifosfamide/etoposide [45]. In another randomized trial in extensive-stage patients, relatively low doses of PE were equally as effective as 67% higher doses, while producing very modest myelosuppression [46], suggesting that this combination has a very favorable therapeutic index compared to most other combination programs which are administered in SCLC.
113
Thus,
numerous
mens currently
combination
chemotherapy
offer approximately
comparable
regiefficacy
in SCLC patients. The two-drug PE combination appears to be as effective as three- and four-drug programs utilizing
various
combinations
doxorubicin, etoposide, cristine, methotrexate,
of cyclophosphamide,
cisplatin and its analogs, vinand nitrosoureas, the agents
therapy
requiring
prolonged
led to any obvious tions utilized phosphamide,
doxorubicin,
and etoposide
binations,
single agent in a randomized
hematologic
once the three-drug
program
easy to add a third drug toxicity
to this program,
has been shown
to have
greater efficacy. At present, the choice of a specific combination regimen can be appropriately tailored to take into account
the expected
tolerance
of an individual
pa-
tient to drug-specific toxicities other than myelosuppression, as well as cost and ease of administration. Although combination chemotherapy is the treatment of choice for SCLC at present, some recent studies, most of them performed in Europe, have administered a single-agent podophyllotoxin derivative, either etoposide or teniposide, as sole therapy for previously untreated, generally elderly patients [47.48]. Response rates of 8& 90% were observed, with median survival of approx. 9 months and very modest toxicity. Whether this result is equivalent to what would have been obtained with combination chemotherapy is unknown, but such therapy may appropriately be considered for elderly or poor performance status patients, particularly with extensivestage disease. Prolonged oral administration of oral etoposide, which can maintain cytotoxic serum concentrations of the drug for protracted periods, has also been investigated in previously untreated patients [49]. III-B.
Intensity
of induction
chemotherapy
With the exception of some programs of PE, most current chemotherapy regimens are designed to produce moderately severe myelosuppression, their dose-limiting toxicity (nadir white blood cell count of lOOO-2000/~1 in the majority of patients). Some early randomized studies utilizing cyclophosphamide-based regimens supported the concept that higher doses of drugs were associated with a modest but significant improvement in survival [50, 511. Extremely high doses of single-agent cyclophosphamide (200 mg/kg) combined with chest irradiation have also yielded an apparently increased fraction of complete responses and survival similar to patients given more usual chemotherapy in limited disease [52]. However, improved survival with higher initial drug doses has not been demonstrated in randomized studies employing the CAV program [53, 541 or PE [46]. Tnuncontrolledstudies,evenhigherinitialdosesofchemo-
not
Combina-
[55-571 or cy-
clophosphamide, cisplatin, and etoposide [58]. The failure of etoposide-containing high-dose programs to yield markedly superior results is consistent with the lack of improvement doubling or tripling
it should be relatively
have
in survival.
in these trials have been based on cyclo-
most commonly utilized in SCLC [3]. Since it is also somewhat less myelosuppressive than most other comwith substantial
hospitalization
improvement
in response rates or survival with of the dose of etoposide given as a
rent SCLC [59]. In summary, vincing more
evidence than
that
moderately
trial in patients presently
treatment
with recur-
there is no con-
designed
to produce
severe myelosuppression
at the
time of induction yields better results, and such therapy should be administered only in the setting of a clinical trial.
III-C.
Cyclic
chemotherapy
alternating
non-cross
resistant
regimens
Goldie et al. have proposed an elegant mathematical model of the emergence of chemotherapy-resistant clones in malignancies [60] which predicts that superior clinical efficacy would be expected with the earliest feasible administration of as many active drugs as possible. Because of the partially overlapping toxicities of most regimens, this goal can be best achieved with the least compromise in doses of individual agents by cyclic alteration of non-cross resistant drug combinations. However, if we accept as a reasonable definition of non-cross resistance the ability to induce complete remissions after tumor progression while receiving primary treatment, no current chemotherapy programs for SCLC can be considered non-cross resistant. It is, therefore, not surprising that most randomized clinical trials comparing this strategy to the standard approach of treating with a single regimen until therapy is completed have generally failed to yield superior survival results [3], although in some studies duration of initial remission was prolonged [61]. A more recent trial conducted by the National Cancer Institute of Canada randomized extensive-stage patients to receive either the CAV combination for six cylces or CAV alternating with PE for the same duration of treatment [62]. Patients given the alternating regimen experienced a 6-week prolongation in median survival which was statistically significant. However, it is not clear whether this modest improvement was due to the alternating strategy or to an inherent superiority of PE, especially since in another randomized trial conducted in limited-stage patients the addition of only two cycles of PE given after completion of six cycles of CAV led
114
to a 7-month improvement in median survival compared to no further therapy [63]. Two more recent, larger studies comparing CAV to PE to alternation of the two programs should help to resolve this issue, although they include relatively few patients with limited disease. Preliminary results indicate no substantial survival differences [64, 651. At present, the use of noncross resistant chemotherapy regimens is an available option in the primary management of SCLC. Its bestestablished virtue at this time is not in offering clearly superior survival but rather in permitting reduction in toxicities dependent upon the cumulative dose of individual agents, such as cardiotoxicity of doxorubicin or neurotoxicity of vincristine and cisplatin. III-D. Duration of chemotherapy tumor progression
and management
of
Early chemotherapeutic programs for SCLC were frequently administered for up to 2 years in the few patients in whom tumor progression had not occurred by that time. However, it has now become clear from both uncontrolled data [66] and most prospective randomized trials [67-69] that prolonged maintenance chemotherapy does not extend survival, although the duration of initial remission may be prolonged [70]. One large trial of 610 patients was able to assess the survival benefit of administering chemotherapy at relapse in a randomized fashion [67]. Survival was prolonged with such ‘salvage’ treatment in patients receiving only four cycles of initial therapy, but not in those given eight cycles. At present, induction chemotherapy lasting 12 to 18 weeks would appear to be optimal. One method to increase delivery of drugs, while still reducing duration of therapy, is weekly administration of myelosuppressive and non-myelosuppressive drugs on an alternating basis. This approach appeared promising in a pilot study [71]. In addition to worsening the morbidity of treatment, maintenance chemotherapy may also reduce the likelihood of palliation from drug regimens given for relapsing tumor. PE chemotherapy produced much lower response rates in one study conducted in patients with recurrent SCLC who had a median ‘drug-free’ interval of less than 1 month since their most recent prior treatment than was observed in other trials of PE in which, due to the policy of avoiding prolonged maintenance therapy, the median time since previous therapy was 3 to 5 months [72]. Much higher response rates in previously treated patients who had not received chemotherapy for at least 10 to 12 weeks were also noted in Phase II studies of teniposide [73] and daily oral etoposide [74].
III-E. Late intensiJication with autologous bone marrow transplantation
Most patients with SCLC who achieve remission with currently available therapies will relapse and die from their disease, indicating the persistence of occult tumor deposits even in clinically complete tumor regression. Given this context, various investigators have proposed the use of high-intensity therapy after induction with conventional doses of agents to take advantage of treating patients at a time when tumor bulk is at its lowest and the physiological status of the patient optimized. At least nine trials have explored this strategy with a variety of high-dose chemotherapy regimens, usually with autologous bone marrow support and sometimes with the addition of regional or total body irradiation [75]. Most included both limited-stage and extensive-stage patients, and some included drugs which had already been administered at more conventional doses during the induction phase in the late intensification regimen. Only 18-38s of patients beginning therapy with the intent of eventually administering late intensification actually received the high-dose treatment. Although some partial responses were converted to complete responses during the late intensification phase, these responses tended to be of short duration. Importantly, relapses at the primary site in the absence of chest irradiation were prevalent even in patients who were in complete remission prior to intensification, suggesting that the late high-dose chemotherapy by itself had very modest ability to eradicate occult tumor. Overall survival in these uncontrolled trials was not obviously different from that of patients receiving conventional therapy [75]. In the only study utilizing a prospectively randomized design, remission duration (though not survival) was prolonged with late intensification, but survival of all patients beginning induction chemotherapy was similar to most reports of treatment without intensification [76]. Late intensification should be administered only in the setting of a clinical trial. Given the very limited benefits of this approach thus far, future studies might best focus on the limited-stage patient who has achieved a complete remission withconventionalchemotherapy and include thoracic irradiation, probably after intensification, to better control the primary site [77]. Care should be taken to utilize autologous marrow support only if necessary, because of the potential risk of reinfusing marrow contaminated with viable tumor cells 1781. Because of unavoidable selection biases in patient entry onto such toxic therapeutic programs, the value of dose-intense approaches in initially responding patients can most likely become established only by randomized clinical studies.
115 2All antibody G-CSF Am&de
Iproplatin RA233 Idambicin GM-CSF Lonidamine y-interferon DFMO Aclarubicin Propionobacterium 6-M-urine Zinostatin BtitlWle Mitoguazone zII a-interferon Mitoxantrone VinbIastine Aziridinylbenzcquinone Pmcart&ne Maytansine DON Chlorozotocin Amsacrine Vindesiie PALA 5-Fu ACNU DianhydrogaIactilol Warfarin TriaziIlate Prednimustine BCG MER High-dose methouexate Thymosin Cisolatin
Dibromodulcitol
Sueptozotocin Mitomycin C Procarbazine
63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
Fig. 1, Perspective
on the evaluation
of single agents in the treatment
of SCLC. Data were abstracted
from the reviews of Cohen and Perevodchikova
[291] and that of Joss et al. [292] as well as from selected primary references [85-87, 148-l 50, 165, 169, 170, 173, 174, 293-2951. have well documented activity as single agents.
III-F.
Strategies for evaluation
of new drugs
At least eleven drugs have been shown to have measurable activity when given as single agents to patients with SCLC (Fig. 1). At a time when therapeutic results have been almost static for the last decade, it is disappointing that most if not all efficacious drugs identified during this period, such as carboplatin and epirubicin, are structural analogs of agents which were already known to be active at the time the newer drugs were introduced.
Drugs in boldface
Patients who progress in the face of or shortly after receiving induction or subsequent chemotherapy programs seldom experience a meaningful response to additional treatment. In this setting, even drugs quite useful as primary therapy, such as etoposide [79] and cisplatin [80] may have minimal or no detectable activity. Because of this, there is justifiable concern that the investigation of new drugs in previously heavily pretreated patients, as was customary until relatively recently, may lead to the inappropriate classification of truly active agents as being inactive [8 11.
116
Since the ultimate value of a new drug can only be determined in the clinic, novel strategies have been proposed to optimize the evaluation of Phase II drugs. These include the study of relapsed patients while lowering the cut-off point for a Phase II study response rate that is considered promising to 10% [82], enrolling only patients who relapse after a certain interval free of treatment [83], and testing novel agents as initial therapy in newly diagnosed patients [84]. The latter strategy is probably the most efficient in terms of estimating the true activity of a novel compound with the fewest patients. However, some uncontrolled studies employing this policy have reported that it may be deleterious to the ultimate survival of the enrolled patients, after observing a compromised response rate to standard therapy following initial exposure to an inactive investigational agent [85]. Recent Phase II trials using more stringent entry criteria have evaluated new drugs, including the active agent epirubicin [86] and the inactive agent amonafide [87], with overall survival comparable to that of patients treated conventionally. Most convincingly, a randomized trial of the Eastern Cooperative Oncology Group (ECOG) compared the ultimately inactive agent menogaril to CAV combination chemotherapy in good performance status extensive-stage patients in no need of immediate palliation of tumorrelated symptoms with strict rules requiring cross-over from the investigational agent to a standard combination regimen whenever clinically indicated, without observing any compromise in survival [88]. Initial therapy of extensive-stage SCLC patients with an investigational single agent appears to be a reasonable approach if there is reason to believe that the agent to be tested may be active and that the patient population is selected in such a way that an initial lack of response is not likely to be associated with immediately life-threatening tumor progression. The detailed criteria of Ettinger et al. [89] and Cullen et al. [84] provide generally adequate guidelines for this trial design. The recent suggestion by the National Cancer Institute of Canada Clinical Trials Group that a trial should be terminated if the initial experience rules out a minimal response rate of 30% is attractive [87]. It would limit the number of patients exposed to ineffective therapy and focus the drug development process on the most acitive agents. At present, such a policy appears to be the most promising way to identify novel active drugs for SCLC, which are sorely needed. III-G. In vitro drug testing
If new, more effective drugs are not immediately forthcoming, it may be possible to optimize an individu-
al patient’s therapy by selecting the currently available agent(s) to which his tumor is the most sensitive. This concept was recently tested by our group in a prospective study of extensive-stage SCLC in which a concerted effort was undertaken to establish a cell line from clinical tumor specimens obtained at the time of initial diagnostic and staging procedures [go]. Because of unavoidable delay in obtaining sufficient cultured tumor cells to perform in vitro sensitivity testing with seven drugs known to be active in SCLC, the 80 patients entered in the study were initially treated with PE chemotherapy for 12 weeks. Patients achieving partial remission or experiencing no response, as well as those patients suffering a relapse after an initial complete remission, were treated with a three-drug combination based on in vitro drug testing of their own tumor, if that information was available, or alternatively with the standard CAV combination. Despite being able to obtain tumor-containing specimens for cell culture in 75% of patients, cell lines could be established and drugs tested in only 33%. Ultimately, 20% of all patients received a regimen based on in vitro sensitivity testing. Of interest, in vitro drug sensitivity was significantly correlated with clinical response to both primary and second-line therapy. However, because SCLC cultures tended to be either generally sensitive or generally resistant to most drugs evaluated, the selection of a second-line regimen with in vitro drug testing did not translate into an obvious therapeutic advantage; 4/ 16 (25%) of patients receiving an ‘in vitro best regimen’ achieved further remission, whereas 3/43 (7%) treated with CAV did so. This modest difference was not statistically significant. In vitro drug testing as performed in this study was of only minimal clinical value. The labor-intensive technology employed and the lack of marked heterogeneity in sensitivity among cell lines to the standard drugs tested currently limit in vitro sensitivity testing to select drugs for individual SCLC patients to investigational studies. However, the correlations observed between in vitro and clinical drug sensitivity, which have now been maintained for a median of 27 months in cell culture [91], suggest that these or similar cell lines taken directly from SCLC patients might be useful for studying mechanisms of drug resistance or in screening for new chemotherapeutic agents. The National Cancer Institute, through its Lung Cancer Drug Discovery Project and other drug screening programs, has reorganized its strategy for the identification of novel active agents [92]. It is hoped that a panel of human lung cancer cell lines of diverse origins, used in an in vitro screening process, will identify compounds with tumor type-specific activity which could more frequently be documented to possess clinical efficacy
117 Growthfacta antagonists In vitro drug testing Hypeaftxtiarated cheat Won “Adjuvant” surgical reacction Bone marrow stimulation with CSFs High intensity induction Hypxalimentation Mainturancecllem~ Autologous bone marrow transplant AnticoagoMon Immimotkaapy Cyclic alternating chemotherapy Prophylactic cranial irradiation Comb&on chemotherapy Chemomdiotheraov for LD Single agent chemotheqy
FvimarY ldialioll themov .SurRery
63 64 65 66 61 68 69 70 71 72 73 74 75 76 II
Fig. 2. Perspective introduction
on the evolution
of the indicated
of treatment
modalities
modalities
was chosen
78 79 80 81 82 83 84 85 86 87 88 89 90
for SCLC.
from among
The publication
available
colony-stimulating
than agents previously identified through initially screening against highly sensitive murine leukemias. III-H. Combined modality therapy with chest and multiple-site irradiation
The refinement of combined modality treatment with chemotherapy and chest irradiation is the area of investigation which appears to show the greatest promise in terms of improving the outcome of limited-stage SCLC patients in the near future. Since radiotherapy can induce regression of thoracic tumor in up to 90% of cases and was the standard treatment for SCLC at the time combination chemotherapy began to be administered for this .disease, initially many programs included chest irradiation as a component of treatment. A review of published literature in 1981 revealed, perhaps not surprisingly, that chest radiotherapy seemed to add little to therapeutic results that could be achieved with chemotherapy alone in patients with extensive stage disease. In limited disease, although there was little difference in reported median survival whether or not irradiation was given in conjunction with chemotherapy, 2-year survival appeared superior with radiotherapy [93]. However, biases in patient selection could have accounted for this result in this uncontrolled data. In the past decade, long-term results of at least seven large randomized trials comparing chemotherapy given with or without thoracic irradiation in limited-stage SCLC have become available and help to clarify this issue. The majority of these studies found that the addition of chest radiotherapy to systemic chemotherapy leads to an improvement in complete response rate, control of the primary tumor, and disease-free survival and overall survival [94-971, although several [98-1001 did
references.
date of the paper Abbreviations
felt to be most representative
used are: LD, limited
disease;
of the
and CSF’s,
factors.
not. Differences in the temporal relationship between radiotherapy and chemotherapy among the trials may account for variations in the effectiveness of irradiation. In general, studies in which chemotherapy and radiotherapy were given either concurrently or in an altemating fashion without any delay in the scheduled administration of chemotherapy were much more likely to document survival benefit from radiation than studies in which the two modalities were given sequentially, with a planned interruption in chemotherapy in order to deliver the irradiation [3]. The survival advantage with radiotherapy in positive studies has been relatively modest, with l- to 4-month improvement in median and 717% absolute increase in 2-year survival. However, advantages of this combined modality approach have been somewhat compromised by the associated increase in toxicities such as myelosuppression, esophagitis, weight loss [3], and in particular severe pulmonary toxicity which in one trial accounted for fatalities in complete remission of 10% of patients [loll. Many trials used chemotherapy regimens which included agents with a potential for lung damage. Unfortunately, the apparently more efficacious concurrent combined modality programs are usually more toxic than sequential ones. Although only a few controlled [96] and uncontrolled [102] studies have been performed, rapidly alternating programs of chemoradiotherapy may have reduced pulmonary toxicity while preserving the probable survival advantage of concurrent combined modality approaches. The basic radiobiological observation that SCLC cell lines had a reduced ability to recover from low doses of radiation when compared to normal cells has led to a novel approach using twice-daily administration of radiation therapy [103]. In pilot trials in combination with
118
PE chemotherapy, this approach appeared both highly effective, with median survival in excess of 2 years, and better tolerated than previous regimens [104, 1051.These experiences from single institutions were recently extended through the ECOG, which treated 40 patients in this fashion; a 95% overall response rate was observed, with 3 1 complete remissions [ 1061.There were four toxic deaths, two of them pulmonary, but 2-year actuarial survival was 36%. A randomized trial designed to assess the contribution of twice-daily radiation therapy compared to a standard once-daily concurrent combined modality approach with PE is currently underway, since it is possible that PE chemotherapy itself is especially well suited for concurrent administration with chest irradiation, being both less toxic and perhaps more effective [ 1071, and accounts for the apparently better results of the twice-daily programs. Some combined modality programs thus appear to produce improved survival in limited-stage SCLC, but these are technically complex in their delivery and require close cooperation between radiation and medical oncologists. Since not all combined modality treatments increase survival, but essentially all increase toxicity, chest irradiation is not mandatory in all patients, especially those with poor pulmonary function or performance status. For other patients not participating in clinical trials, concurrent radiotherapy and PE chemotherapy are at present most often recommended. Irradiation to extrathoracic sites other than brain in conjunction with chemotherapy for SCLC appears to yield no clinical benefits, either prophylactically in limited disease [108] or to the primary tumor and clinically involved extrathoracic sites in extensive disease [ 1091. Thoracic radiotherapy alone given with chemotherapy to extensive-disease patients can reduce the frequency of tumor progression in the chest but appears to have no effect on survival [ 1lo]. III-I. Prophylactic and therapeutic cranial irradiation
Patients receiving chemotherapy for SCLC have a tendency, which progressively increases over time, to develop central nervous system (CNS) metastases, especially in the brain. In one series, the actuarial likelihood of CNS metastases in the absence of specific therapy was approx. 80% at 2 years [l 111. Because these findings were similar to what had previously been observed in childhood acute lymphoblastic leukemia, prophylactic cranial irradiation (PCI) was also proposed as a potentially useful maneuver for SCLC. This topic has recently been comprehensively reviewed [ 1121. A combined analysis of the nine published randomized studies assessing the impact of PC1 in
SCLC shows a definite ability of this intervention to reduce the incidence of clinically detected brain metastases from 23% to 6%, without, however, affecting survival. Retrospective analysis indicates that the benefits of PC1 are principally restricted to patients who attain a complete remission of their cancer [113], a not unexpected result since if extracranial tumor persists after PCI, it would still have the potential to continue metastasizing to the brain. Although little data addresses this point, a survival benefit does not appear to exist for PC1 therapy even if analysis is restricted to patients in complete remission [113, 1141. The obvious value of reducing the development of brain metastases must be balanced, however, against the possibility of late neurological side-effects associated with the administration of PCI. Combining data from eight studies of long-term survivors of SCLC, most of whom (102/123) had received PCI, showed a 45% incidence of symptomatic organic brain syndrome, which was most commonly manifested by memory loss, gait abnormalities, and coordination defects [112]. Most of these patients also had received long-term chemotherapy regimens which included potentially neurotoxic drugs such as methotrexate and nitrosureas. We [115] recently updated our observations in long-term survivors 6-13 years after therapy for SCLC and found that the high incidence of neuropsychological sequelae observed in an earlier evaluation performed 4 years previously had often continued to progress, albeit not dramatically, in some patients. It should be emphasized, however, that most neurologic morbidity observed in long-term survivors does not compromise patients’ ability to care for themselves [116, 1171, and whether all of the neurologic morbidity observed in these patients is directly related to PC1 is by no means established. Whether PC1 in the context of short-term, cisplatinbased chemotherapy is associated with the same longterm sequelae is unknown at present. In the meantime, it seems prudent to limit the administration of PC1 to patients who achieve complete remission of their tumor and consent to receive it after becoming thoroughly aware of benefits and potential risks. Treating with low doses of irradiation per fraction only after all other therapy is completed may be associated with less neurologic toxicity [ 118-J. Most SCLC patients who develop brain metastases during or after chemotherapy do so in the setting of progressive cancer in multiple sites. Therapeutic brain irradiation in the majority of cases is able to relieve or reduce neurologic symptoms for the remainder of the patients’ usually short life expectancy. However, symptomatic recurrent metastases after irradiation are a common problem in patients who survive for several months
119
or longer [119, 1201. Therefore, attempts to achieve more durable control of intracranial tumor should be considered in patients who have brain metastases as their sole site of extensive disease at the time of diagnosis [121, 1221 or those who relapse from complete response solely in the brain. It has recently become apparent that systemic chemotherapy without cranial irradiation may produce regression of brain metastases which are present at the time of diagnosis [123, 1241, presumably because the bloodbrain barrier to penetration of chemotherapeutic agents is disrupted in areas of gross metastases. What effect this knowledge will have on policies for treatment of brain metastases remains to be seen. III-J. Adjuvant surgical resection
The early experience with surgical resection in the treatment of SCLC was disappointing. The Medical Research Council trial, which randomized potentially resectable patients by the standards of the day, which included much less extensive staging procedures, to undergo surgery or radiation therapy had no long-term survivors in the surgery arm [5]. These and other [125] observations led to the abandonment of surgery in the primary management of this disease. However, more recent reports have challenged this attitude by demonstrating favorable long-term survival in patients with localized presentations (Tl-T2, NO or Nl) treated with initial surgery with or without additional chemotherapy and radiotherapy [21, 26, 126, 1271. Whether this relatively good prognosis is related to the therapeutic effects of surgical resection, the smaller overall tumor burden, or the inherent less aggressive biological behavior of what some have suggested to be more differentiated neuroendocrine lung carcinomas [ 1281 remains unclear. However, it is clear that concern about discovering an SCLC histology should not motivate heroic efforts at obtaining a preoperative diagnosis in the case of a patient presenting with a peripheral lung lesion and no contraindications to surgery. Should such a lesion prove to be SCLC, it should be resected if otherwise appropriate provided mediastinal nodes are not involved, and the patient should then receive six cycles of adjuvant chemotherapy, possibly with chest irradiation. If a diagnosis of SCLC is known preoperatively in a patient who appears to be a good surgical candidate, thoracotomy should be considered only after a negative mediastinoscopy or mediastinotomy. A more controversial area is whether surgery should be employed for resection of residual disease after a maximal response is achieved with chemotherapy. The rationale for this approach is based on the observation
that the site of first relapse in patients achieving a complete remission is often the original site of disease in the chest. It is reasoned that surgical resection of the initially involved lung might decrease the incidence of recurrence and improve survival. Many uncontrolled series have been published [ 129-1331, some of which reported a decreased rate of thoracic recurrence in patients undergoing surgical resection [ 129, 132, 1341. Resected patients experience overall survival much better than reported for limited-stage patients in general; however, this would be expected since they have tumor of relatively small extent which can be completely surgically extirpated. The impact of surgery on these favorable outcomes is currently the object of a prospective randomized study conducted by the Lung Cancer Study Group. Uncontrolled data suggest the major benefit of post-chemotherapy surgery is confined to patients without mediastinal lymph node metastases at diagnosis [ 1351. III-K. Biologic response modifiers
Various immune deficits have been observed in patients with SCLC. Initial reports focused on depression of total lymphocytes and T-cell levels [136], as well as a decreased response to DNCB skin testing [137]. Impaired response to delayed hypersensitivity skin testing has been associated with impaired survival in patients receiving chemotherapy, especially those with otherwise favorable prognostic factors [ 1381.More recently, significantly decreased numbers of T-helper and T-suppressor subsets of circulating lymphocytes [ 1391, as well as a decreased proliferative response of peripheral blood lymphocytes to phytohemaglutinin and interleukin-2, have been described [140]. Although some of these findings are likely to be secondary to the generalized debility associated with an advanced malignancy, the coexistence of pulmonary [ 14 1, 1421and extrapulmonary [ 1431small cell carcinomas in cases of the acquired immune deficiency syndrome raises the possibility that these immune deficits might participate in the genesis of SCLC. However, it should be noted that other authors have found an increase in activated T cells in the peripheral blood of SCLC patients [ 1441,and that in two immunotherapy trials, lack of response to a panel of skin test antigens was of no prognostic import [ 145, 1461. The possible contribution of an immune deficit to the pathogenesis or progressive nature of SCLC led to a number of trials using non-specific immunotherapy in this disease. Initial non-randomized studies were inconclusive [ 1471.Since then a number of randomized studies evaluating the addition of different forms of immunotherapy to various combination chemotherapy regimens, often combined with thoracic irradiation, have
120
been reported. Propionobacterium granulosum strain KP-45 [148], bacillus Calmette-Guerin (BCG) [149], and the methanol extractable residue of BCG (MER) in various schedules [145, 146, 1501 have been studied. These trials have included a total of 870 patients; all have shown no significant difference between standard treatment and immunochemotherapy in terms of response rate, duration of response, or survival. However, significantly increased morbidity was observed with the use of MER. In addition, an early randomized trial suggesting survival benefit (but no effect on the response rate) with the addition of thymosin fraction V to chemotherapy [ 15 l] could not be confirmed [152]. These data indicate that non-specific stimulation of the depressed immune function observed in SCLC does not alter the course of this disease or its response to therapy. In an effort to identify targets for specific immunotherapy, various groups of investigators have generated a plethora of murine monoclonal antibodies after immunization of animals with SCLC tumor preparations. The antigenic specificity of most of these reagents remains undefined, but there appears to be overlap among several of them. To try to bring some order to this field, an international workshop was held in 1987 and led to a grouping of most antibodies within five clusters, each of which detected related antigenic characteristics [ 1531. It was concluded that no antibody showed absolute specificity for SCLC, although some appeared to be relatively specific for neuroendocrine tissue. The ultimate usefulness of these reagents as tools in diagnosis, immunodetection, or therapy remains undefined. In vitro studies suggest that some of these monoclonal antibodies might be useful for the eradication of occult cancer cells from bone marrow in preparation for autologous transplantation [154156] or as potentiators of lymphokine-activated killer cell activity against SCLC [ 1571. Perhaps of more interst is the reduced expression of specific antigens on the surface of SCLC cells, namely the class I major histocompatibility antigens. Since these molecules play a crucial role in immune recognition, their lack of expression may be relevant to the escape of SCLC from putative immune surveillance and contribute to its metastatic potential. Doyle et al. [158] found that SCLC cell lines, in contrast to other lung cancer lines, are deficient in the expression of HLA-A, B, and C antigens as well as of µglobulin, but that treatment with leukocyte-A interferon as well as y-interferon could induce the expression of these antigens. However, in a different panel of SCLC cell lines, Ball et al. [159] were able to detect expression of class I and II major histocompatibility antigens but did note increased expression after treatment with y-interferon. In addition, they and others [160] observed decreased pro-
liferation of SCLC in response to y-interferon. More recently, it was shown that y-interferon-induced modulation of class I major histocompatibility antigen expression in SCLC is associated with increased lysis by cytolytic T lymphocytes [161] but decreased sensitivity to natural killer cells in vitro [162, 1631. The various interferons have not been extensively evaluated in the treatment of SCLC. However, thus far no significant tumor regression has been observed with either cr-interferon [ 1641 or y-interferon [165] in small Phase II trials. However, as has been suggested [166], interferons theoretically might be more useful in maintaining response in patients experiencing a complete remission on chemotherapy. Preliminary results of a randomized trial in Finland testing the efficacy of low-dose a-interferon in SCLC patients in complete remission demonstrate modestly but insignificantly better survival with cx-interferon compared to continued chemotherapy or no further treatment [167]. An additional randomized trial evaluating this treatment is underway. III-L. ModiJication of host environment with adjunctive treatment The frequent weight loss observed at diagnosis in SCLC patients is a factor of negative prognostic significance [28]. Because of this, attempts to improve prognosis by administering parenteral hyperalimentation during chemotherapy have been evaluated in randomized trials. These have failed to show improvement in response rates, survival, or chemotherapy-induced morbidity [168], despite improvements in body weight and reversal of anergy to skin test antigens in another study [169]. Another strategy which has generated interest since the initial description of its antimetastatic effects in some animal tumors has been the use of anticoagulation as an adjunct to chemotherapy. An initial trial conducted by the Veterans Administration Lung Group randomized 50 patients with limited, extensive, and undefined disease extent to receive chemotherapy and thoracic irradiation with or without warfarin anticoagulation. The 25 patients randomized to standard treatment experienced a median survival of 24 weeks, whereas those receiving adjunctive anticoagulation had a median survival of 50 weeks. There were no differences in response rates, which were low (28 and 32% overall) in both arms [170, 1711. The Cancer and Leukemia Group B (CALGB) explored this issue within a larger randomized trial in which 86 extensive-stage patients received combination chemotherapy alone and 103 received the same chemotherapy with warfarin. Despite a statistically superior overall response rate in the warfarin arm,
121
there was no significant difference in survival [172]. The results of a similar CALGB trial in limited-stage patients are awaited. In the meantime, warfarin should not be part of therapeutic interventions in SCLC except in clinical trials. In addition, the putative antiplatelet agent mopidamol (RA-233) was not found to improve the results of combination chemotherapy in another randomized study [173]. The availability of recombinant human granulocyte/ macrophage colony-stimulating factor (GM-CSF) has raised the possibility of reducing chemotherapy-induced neutropenia, the cause of much of the iatrogenic morbidity associated with treatment of SCLC. In vitro studies have suggested that SCLC growth could be inhibited by this agent [160]. Preliminary uncontrolled trials supported the notion that GM-CSF can be administered safely to SCLC patients, and that it does in fact ameliorate myelosuppression [174, 1751. An interim analysis of a large randomized study designed to test the effects of granulocyte-CSF (G-CSF) on myelosuppression induced by the combination of cyclophosphamide, doxorubicin and etoposide has been reported. G-CSF administration was associated with a significant reduction of the frequency and severity of neutropenia. The number of days of hospitalization and antibiotic therapy required for febrile neutropenia were reduced by 4&50$, for the chemotherapy cycles including G-CSF, compared to cycles during which patients were receiving a placebo [ 1761. The role of this novel approach remains to be defined. Given the treatment-related death rates from current SCLC therapy of 0-4s in limited and 2-8s in extensive disease [3], the potential for improving survival with the addition of CSFs to standard chemotherapy is negligible. Their efficacy in reducing the frequency of fever and documented infection compared to prophylactic antibiotics should be investigated. It is possible that CSFs will permit escalation to a higher level of dose intensity of chemotherapy, which may allow the attainment of better therapeutic results with at least some drugs [177]. However, it must be noted that some current regimens such as PE achieve therapeutic results at least very similar to those of more myelotoxic programs based on combinations of alkylating agents and doxorubicin.
reports from six institutions or groups describing survival of a total of 2000 SCLC patients followed for a minimum of 5 years from the initiation of chemotherapy revealed that 4% of all patients, including 7% with limitedand 1% with extensive-stage disease, were alive at the 5year point [31]. Since the probability of recurrence of the original tumor is 33% after disease-free survival of 24 months, 26% after 30 months, 14% after 36 months, and rare after 5 or 6 years [178-1801, 5-year survival, as is true in other types of lung cancer, is a reasonable benchmark for ‘cure’ of SCLC. This cancer can therefore be eradictated by current therapy in a small fraction of patients. Whether such patients should be considered to be cured of their disease, however, is dependent upon the definition of cure. Patients who are free of SCLC 18 to 24 months after the beginning of therapy have a IO-fold increased risk of dying over the next 5 years compared to the general population [180] and a 6-fold increased risk of dying of non-neoplastic causes [178]. The major causes of this excess mortality are principally smoking-related, as was the original SCLC, and include cardiopulmonary disease and second malignancies, the most common of which is non-small cell carcinoma of the lung [181]. Chemotherapy-related acute myelogenous leukemia is rarely observed [182], but this complication should become even more uncommon since the customary duration of chemotherapy is being shortened and nitrosoureas and procarbazine, which are highly leukemogenic drugs, are being utilized much less frequently in treatment of SCLC. Neuropsychological deficits noted in some long-term survivors have been discussed in Section III-I. Although these second malignancies and chronic toxicities can be devastating in some individuals, they are clearly outweighed by the several-fold prolongation in median survival for all patients receiving current therapy and the small but real prospect of permanent eradication of their cancer for a few. Despite the major advances made in the management of SCLC in the chemotherapy era, however, it is sobering to reflect that the great majority of patients still die of their cancer.
III-M.
IV-A.
‘Cure’ and morbidity
in long-term survivors
Although the improvement in median survival of SCLC patients given combination chemotherapy was obvious almost immediately after its utilization became widespread in the 1970s the question of whether any patients are ultimately cured of their disease began to be answered only within the past few years. A summary of
IV. Recent advances in the biology of SCLC Drug resistance mechanisms
The empirical chemotherapy of SCLC, despite remarkable early successes, appears to have reached a plateau. One possible approach to breach this impasse is to seek an understanding of the mechanisms by which SCLC cells escape the toxic effects of the diverse classes of agents to which they have been exposed. This knowl-
122
edge might then be applied to novel strategies designed to neutralize or bypass these defense mechanisms. The study of drug resistance of cancer cells has attracted much attention in recent years. The earliest data were obtained on the mechanisms of resistance to the antimetabolite methotrexate. Before reaching its major intracellular target, the enzyme dihydrofolate reductase, methotrexate must enter the cell through an energy-dependent specific carrier, after which its intracellular accumulation is facilitated by polyglutamation. Sensitivity to dihydrofolate reductase inhibition depends in part on the continuous consumption of reduced folates by thymidylate synthesis. As a consequence of these complex events, resistance to methotrexate can result from alterations in many different aspects of the drug’s interactions [183]. In SCLC cell lines, Curt et al. [ 1841were able to correlate relative methotrexate resistance with reduced intracellular drug accumulation due to decreased polyglutamation, as well as decreased thymidylate synthetase activity. In addition, unstable methotrexate resistance in cultured SCLC cell lines was occasionally found to be due to elevated levels of dihydrofolate reductase caused by gene amplification associated with the presence of double-minute chromosomes [ 1851. Although these early observations emphasized the ability of neoplastic cells to develop mechanisms to escape the toxic effects of specific chemotherapeutic agents, they could not address the broader question of concomitant resistance to diverse classes of agents so often observed in the clinic. Variants of the ‘multidrug resistance’ phenotype have been attributed to the highlevel expression of a drug efflux pump, the ~170 glycoprotein encoded by the multi-drug resistance gene MDRl[l86-1891, the expression of efficient drug-detoxifying enzymes such as the placental form of glutathione transferase [190], or an enhanced ability to repair DNA damage [183]. A particularly useful resource to address these issues is the large panel of lung cancer cell lines now in existence. Studies with these lines, derived from both previously treated and untreated patients, should allow the eventual correlation of drug sensitivity patterns with cellular mechanisms of drug resistance. Our group has studied a population of 68 consecutive extensive-stage SCLC patients in whom systematic efforts were made to harvest tumor tissues and establish a cell line from each patient [191] and found no correlation between the ability to establish a cell line in the 23 patients in whom that could be accomplished and their clinical outcome. These findings support the conclusion that, at least in extensive-stage SCLC, established cell lines are not derived from patients whose tumors have an inherently different biology. Thus, the biologic fea-
tures of the cell lines may be representative of SCLC tumors as a whole. In addition, in vitro chemosensitivity testing of human lung cancer lines shows patterns of resistance reminiscent of what is observed in the clinic [192]. Cell lines from untreated SCLC patients were more sensitive to doxorubicin, carmustine, cisplatin, melphalan, vincristine, and etoposide than non-small cell lung carcinoma (NSCLC) cell lines. Cell lines from previously treated SCLC patients had drug sensitivity more similar to NSCLC lines. Consequently, it is reasonable to consider that these cell lines may be appropriate surrogates for primary patient material in the study of drug resistance mechanisms in human lung cancer. Several studies employing both primary tumor tissue and established cell lines have addressed the mechanisms of drug resistance in SCLC. As already mentioned, the phenotype of pleiotropic or multidrug resistance has been associated in some instances with the overexpression of a membrane glycoprotein which is able to actively transport multiple drugs outside the cell and is encoded by the A4DRl gene [186-1891. The role of this gene in lung cancer was explored by quantitating the level of expression of MDRl-specific message in mRNA extracted from a panel of lung cancer cell lines and tumors. The level of expression was found to be elevated in only 4/23 SCLC cell lines and 3/6 SCLC primary tumors studied. In no instances were elevations of MDRl expression to the very high levels sometimes noted in colon cancer found. Furthermore, no correlation was observed in SCLC material between MDRl expression and whether tumor material was derived from previously treated or untreated patients or from untreated patients who did or did not respond to initial chemotherapy. There was also no correlation between mRNA levels and in vitro chemosensitivity [193]. It would thus appear that enhanced drug efflux through ~170 glycoprotein is not a major factor in the clinical drug resistance of SCLC, and that other mechanisms must be operative. A clinical pilot study attempting to pharmacologically modify putative drug resistance resulting from MDRI overexpression in SCLC has already been performed [ 1941. The discovery that the high-level expression of the placental form of the drug metabolizing enzyme glutathione-4transferase correlated with a phenotype of pleiotropic drug resistance distinct from drug accumulation defects induced in the MCF-7 breast cancer cell line in vitro has several important implications [ 1901. Since this enzyme can not only detoxify a wide range of xenobiotics but also has its expression induced by exposure to these compounds, it was predicted that tumors arising in the context of long-term exposure to environmental carcinogens would be likely to have activated this detox-
123
ifying enzyme system. Since many drugs in common use are derivatives of natural products which can be detoxified by this mechanism, this provided a general framework within which many therapeutic failures could be explained. In fact, it has been shown that the level of glutathione-S-transferase enzymatic activity was increased in the lung tissue of smokers and that this was proportional to the cumulative tobacco exposure measured in pack-years [195]. There are several reports indicating the frequent high-level expression of this enzymatic system in NSCLC tumors and cell lines [196 2001. In contrast, SCLC tissues and cell lines consistently express lower levels of glutathione-S-transferase mRNA [ 1961, immunoreactivity [200], and enzymatic activity [197]. In a study of 15 SCLC cell lines, no correlation was found between glutathione-S-transferase enzymatic activity and sensitivity to doxorubicin or melphalan. Furthermore, there were no differences between cell lines derived from untreated patients when compared to those from previously treated patients [197]. In the aggregate, these observations support the view that the glutathione-S-transferase system does not explain the less common de novo or usual acquired resistance to chemotherapy observed in SCLC. Recent evidence points to alternative mechanisms of pleiotropic drug resistance which may be operative in SCLC. An SCLC cell line made resistant in vitro by graded exposure to doxorubicin was found to show collateral resistance to vincristine, vindesine, etoposide, cisplatin and X-irradiation, but not to melphalan, colchicine and actinomycin D. This drug resistance phenotype was explained on the basis of a combination of decreased intracellular levels of doxorubicin, increased DNA repair, and reduced DNA topoisomerase II activity [201, 2021. Since it appears that the repertoire of known drug resistance mechanisms used by SCLC is limited, further definition of these and other as yet unknown mechanisms is indicated in an effort to identify clinically relevant resistance pathways which might be modulated to improve the efficacy of existing chemotherapeutic agents. Examples of in vitro modulation of drug sensitivity in SCLC cell lines with cyclosporine and docosahexaneoic acid have been reported [203, 2041.
biogenic amine synthetic enzyme L-DOPA decarboxylase) [205]. The most striking manifestation of this phenotype is the elaboration of a large number of peptide hormones and growth factors, several of which were first identified as neuropeptides (see Table 1). This list continues to expand, the most recent additions being atria1 natriuretic factor [lo] and multiple opioid peptides [206]. The first peptide to be specifically documented to be produced by SCLC was gastrin-releasing peptide (GRP), the mammalian homologue of the amphibian tetradecapeptide bombesin [207, 2081. The details of this discovery are of historical interest. It had been recognized since the 1940s that the normal human bronchial
TABLE I Some hormones
produced
Product
Hormone
GRP [207,208,279]
+
IGF-1 [224]
+
Transferrin [225]
+
Calcitonin
+
[280]
AVP [28 I]
IV-B.I.
as a
Growth factors
The neuroendocrine nature of SCLC has been long recognized on morphological grounds (presence of neurosecretory granules), as well as biochemical grounds (expression of chromogranin A and the key
expressed
by human
small
produced
Receptor
expressed
+
Opioid peptides:
[206,
2821 /I-endorphin
+
enkephalin
+
dynorphin Neurotensin Glucagon
[280]
+
Substance
P [209]
+ + _
Somatostatin
+ + + +
+ +
[280,283]
[280,284]
CCK [226, 2841 TGFa: [280]
7 ? + +
VIP [28 I, 2841
+ _
ACTH
2811
+
?
GGAP
[285,286]
+
+
+ ?
1
?
+
ANF Galanin
[226]
Bradykinin
[226]
[ 1601
Interferon-y GM-CSF
[I601
+
+
?
+
?
+
Neurokinin
A [287]
?
Neurokinin
B [287]
?
+ +
?
+
?
+ ?
Acetylcholine,
musca-
rinic [288]
IV-B. Interruption of autocrine growth stimulation target for developmental therapeutics
and receptors
cell lung cancer
Acetylcholine,
nicotinic
VW Serotonin Adapted
[210]
+
from Ref. 289. Hormones
be involved in autocrine is assumed
growth
in boldface
regulatory
if shown by direct radioligand
cal effect of the cognate tion of a specific growth.
hormone
signal
have been shown
loops. Receptor
to
expression
binding
assay or if a biologi-
is demonstrated
by virtue of activa-
transduction
pathway
or stimulation
of
124
epithelium exhibited a cellular component whose morphological features were similar to that of a proposed diffuse neuroendocrine system [209]. Carcinoid tumors and SCLC shared many of these features, including the production of the biogenic amine serotonin [210]. However, the demonstration that these cells could also elaborate biologically active peptides remained elusive. The search for biologically active peptides throughout the animal world, particularly in the Bombina family of amphibians by Vittorio Erspamer, had generated a large family of candidate hormones. Using specific antibodies raised against the amphibian peptide bombesin, Wharton et al. demonstrated in 1978 the presence of immunoreactivity in the normal neuroendocrine cells of the human fetal lung [211]. The presence of bombesin-like immunoreactivity was subsequently reported in SCLC by several groups [207, 2081 and was later shown to be due to the expression of the mammalian homologue GRP [212]. GRP acts as a growth factor for normal human bronchial epithelial cells [213] and for SCLC both in vitro [214-2161 and in vivo [217]. The ability of the 2All monoclonal antibody raised against the carboxyl terminus of bombesin to block binding of GRP to its receptor led to the use of this reagent to study the impact of GRP on SCLC biology. It was found both in vitro and in vivo that exposing SCLC cells to this antibody deprived them of the trophic effect of the endogenously produced GRP and resulted in growth inhibition of the tumor cells [214]. These observations were the first demonstration that autocrine growth stimulatory loops might be an important factor in the genesis or maintenance of these malignant cells. Several synthetic peptides with antiGRP activity have been described (see Table 2), the most recent generation of which can block GRP binding at concentrations in the nanomolar range [218, 2191.
TABLE 2 Bombesin antagonists with in vitro activity against small cell lung cancer Structure (D-Argl, D-Pro*, D-TqP, Leu”) substance P (2201 (D-Argl, D-Phe5, D-Trp7.g, Leu”) substance P [220] (Leu’3-Y-CH2NH-Leu14) bombesin [221] n-Acetyl-GRP-20-26OCH2CH3 [218] (D-Phe6, Leu13-Y-CH2NHPhe14)bombesin (614) [219] Adapted from Ref. 289.
KS0 for growth
I& for binding
82 /LM 24 FM 1fiM
80.4 nM 4nM 3.1 nM
Several have been shown to inhibit SCLC growth in vitro [220,221]. This developmental work has generated novel compounds which hold promise as clinically useful anti-GRP drugs, and the original 2All antibody is currently undergoing human trial [222,223]. However, as is graphically documented by Table 1, GRP is only one of a multitude of peptides with potential growth-regulatory roles in SCLC. Both insulin-like growth factor I and transferrin-like growth factor participate in autocrine growth regulatory loops [224, 2251. In addition, individual SCLC ceil lines can be shown to be responsive to a number of distinct hormones. By monitoring the response of the intracellular calcium concentration, Woll and Rozengurt [226] showed that the SCLC cell line NCI-H345 could respond to eight different individual hormones (acetylcholine, ACTH, bradykinin, cholecystokinin, galanin, GRP, neurotensin, and vasopressin). If one also considers the factors known to be produced by SCLC which do not elicit a rise in intracellular calcium concentration, it becomes obvious that the stimulatory effects on the growth of SCLC cells by themselves (autocrine) or neighboring cells (paracrine) may be extremely varied and complex. In this setting, it would appear unlikely that a therapeutic strategy aimed at any one growth factor would have much clinical impact and that any serious attempt at interrupting these trophic effects must take into account this heterogeneity. Such strategies could be based on the use of combination of antibodies and peptide antagonists (each with their individual specificity) or on the use of peptide antagonists with broader specificities such as the substance P analogues reported to block the mitogenie effects of GRP, vasopressin, and bradykinin in Swiss 3T3 cells [227]. Alternatively, strategies based on interrupting intracellular signal-transducing events shared by these many hormones might be viable. For instance, enzyme effecters such as phospholipase C (PLC), protein kinase C (PKC), G-proteins coupling several receptors to their effecters, and membrane calcium channels are all actually or potentially amenable to pharmacologic manipulation. It is provocative that certain compounds already in common use in medical oncology have pleiotropic mechanisms of action which include modifications of signal transduction pathways. For example, the antiestrogen tamoxifen can block calcium channels [228], and the anti-tumor antibiotic doxorubicin is also an inhibitor of PKC 12291. In addition, the only known animal model for pulmonary neuroendocrine neoplasia appears to be sensitive to such manipulations. Schuller et al. have recently described a protocol wherein hamsters receive repeated injections of the carcinogen N-nitrosodiethylamine [230]. Under standard laboraty conditions, the animals develop peripheral
125
pulmonary adenocarcinomas within 20 weeks. However, when kept in a hyperoxic atmosphere of 60% oxygen, they develop pulmonary neuroendocrine tumors within 8 weeks. Remarkably, the administration of a calcium/ calmodulin inhibitor prevents the appearance of the neuroendocrine tumors but not the adenocarcinomas [23 11. IV-B.2. Gastrin-releasing peptide stimulated signal transduction pathways
The above observations suggest that the manipulation of signal transduction pathways may prove to be a fertile ground for the developmental therapeutics of lung cancer. To better define potential targets, efforts to map the intracellular events following exposure of SCLC to the mitogen GRP are underway. GRP stimulation of SCLC is associated with the activation of a major signal transduction system centered on the enzyme PLC. In recent years, receptors activating PLC have been found to be coupled to it through the action of other membrane-associated proteins characterized by the ability to bind guanine nucleotides in a reversible manner [232] (see Fig. 3). These guanine-nucleotide binding proteins or G-proteins are molecular switches which transmit and amplify the signal initiated by the ligand-bound receptor to an effector, in this case PLC. The ligand-bound receptor adopts a conformational state which causes the binding of GTP to the G-protein. The GTP-bound G-protein is then able to stimulate the effector. The system can revert to baseline because of the intrinsic ability of the G-protein to hydrolyze the bound GTP and thus return to an inactive state. The function
of some G-proteins can be modulated through phosphorylation by the enzyme PKC [233] or through a posttranslational modification (ADP-ribosylation) catalyzed by certain bacterial toxins (cholera and pertussis toxins) which have been used as probes for the detection of Gprotein involvement in biological responses. A hallmark of receptor-effector coupling by a G-protein is the ability of non-hydrolyzable GTP analogs, which cause an irreversible activation of the G-protein, to modulate the affinity of receptor binding and the intensity of the transduced signal such as PLC activity. Bacterial toxins induce the same modifications when the involved G-protein is a substrate for their action (reviewed by Spiegel, Ref. 234). PLC activation results in the hydrolysis of an integral membrane phospholipid, phosphatidylinositol bisphosphate (PIP$ to form two products, inositol trisphosphate (IPs) and diacylglycerol (DAG). IPs in turn binds to a receptor on the endoplasmic reticulum, stimulating the release of endogenous calcium stores and transiently increasing the intracellular concentration of free calcium ([Ca*+]ir,) [235]. DAG activates the calcium and phospholipid-dependent protein kinase PKC. PKC activation can be followed by the activation of other pathways, such as the membrane Na+/H+ ‘antiporter’, causing an elevation of intracellular pH, or the transcriptional activation of certain genes such as the protooncogenes c-fos, c-&n and c-myc [236, 2371. After stimulation by a PLC-activating ligand, cells are often transiently refractory to a repeat stimulation by the same (homologous desensitization) or other (heterologous desensitization) ligands. PKC has been implicated in some of these regulatory events. Fig. 4 summarizes work which has shown that GRP
PMA
Q+y+y c-fos
c-myc
Fig. 3. Intracellular of phospholipase nucleotide ylinositol
binding
pathways protein;
bisphosphate;
lular concentration
involved in receptor
C. Abbreviations
PLC, phospholipase
IP3, inositol
of free calcium;
mediated
used are: R, receptor;
C; PIPZ, phosphatid-
trisphosphate; DAG,
tein kinase C.
activation G, guanine-
[Ca2+]i, intracel-
diacylglycerol;
PKC,
pro-
Fig. 4. Intracellular
pathways
small cell lung cancer with the addition
activated
by gas&in-releasing
cell lines. Abbreviations
of CT, cholera
toxin; and PMA.
istate 13-acetate.
peptide in
used are as in Fig. 3. phorbol
12-myr-
126
stimulation activates PLC in SCLC, both in metabolically labeled whole cell and membrane preparations [238, 2391. This activation is accompanied by an elevation of [Ca2+]irree [240], but PKC response has not yet been characterized. However, GRP stimulation of IP3 formation and increase in [Ca2+]irree were inhibited by prior treatment with the PKC activator phorbol 12myristate 13-acetate (PMA), suggesting that PKC might exert negative feedback regulation on this response.
a complete inhibition of the growth of three SCLC cell lines bearing the GM 1 ganglioside receptor for CT. The effects on signal transduction preceded the effects on cellular metabolic activity, suggesting that CT may be acting principally by depriving the cell of the trophic effects of multiple growth factors [241] and providing a model as well as a potential target for the therapeutic manipulation of growth-associated signal transduction pathways in SCLC.
IV-B.3. Efects of cholera toxin on signal transduction pathways andgrowth Because non-hydrolyzable GTP analogues could modulate PLC activation in response to GRP, it was concluded that the GRP receptor in SCLC was coupled to PLC by a G-protein [239]. The nature of this putative G-protein was investigated further by studying the effects of G-protein modifying bacterial toxins on GRPmediated signals in SCLC. Cholera toxin (CT) is a multimeric bacterial protein composed of five jI subunits, which bind to a specific receptor, the cell surface glycolipid GM1 ganglioside, and one CIsubunit which enters the cell. The a subunit is an enzyme which catalyzes the transfer of ADP-ribose from NADP to certain G-proteins, thus modifying their function by abolishing their intrinsic GTPase activity. CT was found to inhibit GRP-stimulated generation of IP3 and increase of [Ca2+]ir, in the SCLC cell line NCI-H345 [238]. The best characterized action of CT is to modify the G-protein coupled to adenylate cyclase and stimulate the formation of intracellular cyclic AMP (CAMP). CAMP is itself an important second messenger able to activate a family of CAMP-dependent protein kinases mediating pleiotropic cellular effects. Because of this, the possibility that the effects of CT on GRP responses might be indirectly caused by an elevation of CAMP was considered. However, preincubation of SCLC with cyclic AMP analogues had no effect on the generation of GRP-stimulated signals [238]. These observations initially suggested that the GRP receptor of SCLC might be coupled to PLC by a CT-sensitive G-protein. The effects of CT on the signal transduction pathways and biology of SCLC have recently been studied in more detail [241]. CT pretreatment led to an inhibition of signal transduction generated not only by GRP but also by vasopressin and fetal calf serum. This was accompanied by a loss of cell surface membrane ruffling and a decrease in GRP-stimulated PLC activity in membranes prelabeled with [3H]inositol, but with no change in GRP receptor number or affinity. This indicated that CT could perturb membrane function related to PLC activity but not through an effect on the G-protein coupling the GRP receptor to PLC. More importantly, CT led to
IV-C. Genetic lesions in SCLC We now appreciate that established SCLC harbors a wide range of somatic genetic abnormalities, including activation of dominant oncogenes as well as inactivation of several newly recognized tumor suppressor genes. These data have been extensively reviewed recently [242] and will be only summarized here. The appreciation of the range of genetic lesions present in human SCLC followed from a number of serendipitous observations, as well as from specific studies of a panel of SCLC cell lines in the context of the historical development of the field of oncogene research. It was clear early on that SCLC tumors had suffered a number of genetic events. Early cytogenetic studies revealed abnormalities of virtually every chromosome, with the most consistent change being that of a deletion of the
TABLE Major
3 dominant
oncogenes
and tumor
suppressor
genes altered
in
small cell lung cancer Gene
Frequency*
Function
Dominant ras family
O/42 cell lines [272]
~21 membrane-associated protein.
Signal transduc-
tion? Activated
by point
mutations.
myc family
Nuclear
Amplified
phosphoproteins.
Function expression
unknown.
c-myc
coupled
to cell
11-24s
increased Tumor
of and
[262,
Overex-
pressed in 89% of cell
with IYJSin transforming cells. Activated
of tumors
264,267,268].
cycle. All can cooperate primary
in 30-50s
cell lines [264,268]
by
lines and 83% of tumors [268].
expression.
sup-
pressor 3P
Putative
rb
genes not yet identified. Nuclear phosphoprotein.
tumor
P53
cell cycle regulation. Nuclear protein. ? function.
92-100% [250]
suppressor ?
Inactivated
[253]. a Reference
numbers
are in parentheses.
in > 90%
[252, 254, 2901. Inactivated in > 50%
127
short arm of chromosome 3 [243,244]. Further cytogenetic studies as well as restriction fragment length polymorphism analysis confinned the presence of multiple areas of loss of genetic information, particularly at 3p (in 92-100s of SCLC) [245-2501, 1lp (the locus of the Wilm’s tumor gene) [251], 13q (the locus of the retinoblastoma gene), and 17p (the locus of the ~53 gene) [249]. The retinoblastoma gene and ~53 have functional characteristics of tumor suppressor genes, and both have been shown to be inactivated in a high proportion of SCLC by diverse mechanisms including deletions, lack of expression and point mutations [252-2561. It is in this context that it is anticipated that at least one more tumor suppressor gene is localized on 3p; its identification and molecular cloning is the focus of intense efforts in several laboratories. In addition, the recent cloning of a candidate for the Wilm’s tumor gene [257] will allow the study of its expression in SCLC and other tumors which show losses at 1lp. The recent observation that mutant forms of the ~53 protein are more stable and can be detected by standard immunohistochemical techniques [258J is bound to facilitate the analysis of their clinical and biological significance. In contrast to the above genes whose involvement in carcinogenesis is through loss of their normal function in the restrictive control of cellular growth, several other genes manifest themselves by an inappropriate and deregulated functional activation. A paradigm for these dominant oncogenes in SCLC has been the myc family of genes. The genes c-myc, N-myc and L-myc all encode nuclear phosphoproteins whose precise functions remain to be defined. Because they can all cooperate to varying degrees in transforming primary rodent cells, they are thought to stimulate or enhance cellular growth [2592611. All three genes have been shown to be overexpressed in some SCLC tumors and cell lines by virtue of genomic amplification (in 10-20s of primary tumors) or deregulated transcription [262-2691. Overexpression of a myc family gene appears to confer more aggressive biologic properties to SCLC, as tumors with this property are more tumorigenic in nude mice [266] and the patients from whom they are derived have a worse prognosis [263, 2641. There is a relative paucity of information on the expression and function of the scores of other dominant oncogenes that have been described. In particular, the ras family of oncogenes, which can be activated by well characterized point mutations, has been shown to be activated in about 20% of NSCLC, seemingly uniquely at codon 12 of c-ki-rus [270,271]. We have recently studied rus mutations in a panel of SCLC and NSCLC cell lines and have found that 23/63 NSCLC cell lines had rus
gene mutations, most frequently involving codon 12 of c-k&as but also other codons of two other ras family genes. In contrast, none of 42 SCLC cell lines had mutations of any ras gene at any of the three codons studied [272]. These observations suggest that rus mutations do not play an active role in the pathogenesis of SCLC. However, the introduction of an activated rus gene into SCLC cell lines has been associated with the loss of neuroendocrine features, morphological transformation towards an NSCLC histology, and the appearance of growth factors and growth-factor receptors more commonly associated with NSCLC [273,274]. It is not clear whether these provocative observations are relevant to the natural history of lung cancer. As knowledge of the genetic lesions present in SCLC expands, a number of themes are emerging. Any given tumor usually exhibits multiple abnormalities in both the tumor suppressor genes and the dominant-acting oficogenes. In fact, several cell lines harbor abnormalities of all three defined or putative tumor suppressor genes recognized to be involved in SCLC (3p, rb, and p53), as well as lesions at other chromosomal loci combined with a deregulated myc gene [253]. This knowledge may eventually be exploitable in the clinic. Analysis of the cumulative effect of similar genetic abnormalities (termed an allelotype by Vogelstein et al., Ref. 275) is of prognostic value in colon cancer and may be useful in SCLC in terms of targeting therapy to biologically defined subsets of patients. In addition, one can envision strategies designed to deprive tumor cells of the function of a constitutively activated oncogene [276], to replace a critically missing function through gene therapy, or to target novel treatments at mutated genes or their products [277,278].
V. Conelusions
The development of more effective therapeutic approaches to SCLC is at a crossroads. In no other area of oncology is the dialogue between clinicians and molecular and cellular biologists more important and likely to bear fruit. The plateau in our recent therapeutic achievements must not discourage continuing to address the incrementally progressive but important issues of determining the optimal dose and schedule of the agents, including radiation therapy, currently available. It is hoped that the drug screening program utilizing panels of human lung cancer cell lines will identify useful new drugs. However, we must not be timid in exploring the new possibilities identified by our rapidly expanding knowledge of the basic biology of SCLC.
128
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