Second Primary Malignancies Following Diagnosis of Small-Cell Lung Cancer By U. Sagman, M. Lishner, E. Maki, F.A. Shepherd, R. Haddad, W.K. Evans, G. DeBoer, D. Payne, J.F. Pringle, J.L Yeoh, R. Ginsberg, and R. Feld Purpose and Methods: The records of 800 patients with small-cell carcinoma of the lung (SCLC) treated between 1971 and 1985 at University of Toronto-affiliated hospitals were reviewed for the occurrence and relative risk of second primary malignancies (SPMs). Almost all patients who developed a SPM were treated previously with chemotherapy and radiation therapy. Results: Nineteen metachronous SPMs (MSPMs) and 11 synchronous SPMs (SSPMs) were identified. SSPMs were detected between I and 12 months after the diagnosis of SCLC. The MSPMs were identified between 1 and 10 years after the diagnosis of SCLC. MSPMs included nonsmall-cell lung cancer (NSCLC) (four patients), hematologic malignancies (HM) (three patients), and 12 with
HISTORICALLY,
treatment with surgery and subsequently with radiotherapy (RT) had a limited impact on the survival of patients with small-cell lung cancer (SCLC). 1 The introduction of combination chemotherapy in the 1970s and current multimodality approaches to the management of patients with SCLC improved the overall 2- and 5-year survival rates in most reported studies to approximately 10% and 5%, respectively. 2-4 With an improved potential for cure and the accrual of long-term survivors of SCLC, the adverse complications of chemotherapy and therapeutic RT have become apparent. Reported chronic sequela of 5 7 therapy have included effects on the nervous, - cardiac,
8
91
hematologic, - 1 and respiratory systems,"-15 as well as infectious disease complications. 16,17 The toxicity of treatment has also been postulated to bear on the higher incidence of both synchronous and metachronous primary and secondary malignancies in long-term survivors of SCLC.6-18 In addition to the plausible effects of treatment, compelling new evidence implicates common genomic abberations in the pathogenesis of SCLC and metachronous second primary malignancies (SPM).19 20 2 6 Identification of SPMs of the lung, - other solid
other solid tumors (OST). The median survival times after the diagnosis of MSPM was 33 months, 10 months, and 1 month, respectively, for those with NSCLC, OST, and HM. Expected cancer incidence rates were used to compute a relative risk rate for developing a MSPM in a subset of 392 patients on whom accurate follow-up information was available. The calculated relative risk for all tumors was 3.73. The relative risk for the development of secondary NSCLC was 6.83. Conclusion: We suggest that increased predisposition to SPM may relate to secondary effects of multimodality treatment and biologic considerations. J Clin Oncol 10: 1525-1533. © 1992 by American Society of Clinical Oncology. the Toronto General Hospital, Toronto, Canada, from 1971 to 1985 were reviewed for the occurrence of SPMs. Before 1976, patients were treated according to their physicians' discretion. Most patients diagnosed between 1976 and 1985 participated in five consecutive study protocols. During this study period, patients were treated on different treatment protocols; most patients received induction chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV) that was alternated with or followed by combinations with etoposide (VP 16), cisplatin, lomustine (CCNU), or methotrexate. Most were also subjected to thoracic and/or prophylactic cranial irradiation. The outline of these studies and their respective outcomes have been reported elsewhere in detail and are summarized in Table 1.43-47 Patients were followed-up at regular intervals, and history and physical examination findings were recorded at each visit. Routine follow-up after the completion of treatment included clinical assessment at least once every 2 months for the first year, every 3 months for the second year, and every 6 months for the third to fifth years. Subsequently, patients returned for routine examinations at least annually. Thirty patients with second primary cancers were identified in total. Diagnosis of second cancers were confirmed by a review of pathology reports. For the purposes of analysis, patients were divided into two categories based on the time of identification of a SPM. The first group included patients in which an SPM was documented a year after the diagnosis of SCLC (synchronous malignancies); the second group included those in which the SPM
tumors,2 7,28 and hematologic malignancies that include 28 4 acute leukemia19, -
2
all have
been documented
in
long-term survivors of SCLC. In this study, we reviewed the records of 800 patients with SCLC observed at University of Toronto-affiliated hospitals between 1971 and 1985 for the occurrence and relative risk of SPMs after the diagnosis and treatment of SCLC. METHODS The records of all 800 patients with histologic and cytologic diagnosis of SCLC treated at the Princess Margaret Hospital and
From the Departments of Medicine, Biostatistics, and Radiation Oncology, Princess MargaretHospital;Departmentof Medical Oncology, Toronto General Hospital; Department of Surgery, Mt Sinai Hospital, Toronto; and Department of Medical Oncology, Ontario Cancer Treatment and Research Foundation,Ottawa, Canada. Submitted December 16, 1991; acceptedJune 22, 1992. Address reprint requests to R. Feld, MD, Department of Medicine, Princess Margaret Hospital, 500 Sherbourne St, Toronto, Ontario, CanadaM4X 1K9. ©1992 by American Society of ClinicalOncology. 0732-183X/92/1010-0005$3.001/0
Journalof Clinical Oncology, Vol 10, No 10 (October), 1992: pp 1525-1533
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1525
1526
SAGMAN ET AL Table 1. Trials of Chemotherapy and Radiotherapy for Patients With SCLC (Toronto 1976 to 1985) Median Median LD ED
No. of Patients
Trial
Reference
Regimen
CAV-1 *
43
CAV-2*
44
BRt
45
TPNJ
46
NOS
47
Cyclophosphamide (750 mg/m ), doxorubicin (50 mg/m2), vincristine (2 mg) + irradiation (25 Gy) in 2 weeks in 10 fractions to primary tumor + 2 mediastinum followed by lomustine (50 mg/m ) + procarbazine (100 2 2 mg/m ) + methotrexate (10 mg/m ) 2 Cyclophosphamide (900 mg/m ), doxorubicin (50 mg/m2), vincristine (2 mg) + irradiation (20 Gy per 1 week in 5 fractions to cranium) Cyclophosphamide (1,000 mg/m2), doxorubicin (50 mg/m2), vincristine (2 mg) + irradiation RT (20 Gy per 1 week in 5 fractions to cranium) + alternoting agents, VP 16 (100 mg/m2) + cisplatin (25 mg/m 2 ) 2 2 Cyclophosphamide (1,000 mg/m ), doxorubicin (50 mg/m ), vincristine (2 2 mg) + irradiation cyclophosphamide (1,200 mg/m ) + Adriamycin (70 2 mg/m2) + vincristine (2 mg) followed byVP 16 (100 mg/m ) + MTX (10 2 mg/m ) + 1-1.5 g protein/kg + 40 kcal/kg body weight Modified CAV-2
2
Survival Overall
148
48
39
43
197
49
34
40
64
63
35
57
43
68
63
66
62
42
32
37
Abbreviations: VP 16, etoposide; MTX, methotrexate. *Sequential study. tRandomized study.
was diagnosed subsequent to that interval (metachronous malignancies). Eleven patients were identified in the former and 19 in the latter category. Identification of a SPM at autopsy was excluded from analysis in this study.
Statistic Considerations The observed incidence of SPMs was obtained in a subset of 392 patients treated at the Princess Margaret Hospital between 1976 and 1985. Patients from other institutions were not included in this analysis because information was not available on all patients observed during this period. The expected number of SPMs was calculated by applying the average of 1981 and 1982 age- and sex-specific incidence rates for the province of Ontario48 to the 2 person-years at risk from 1 year after the date of diagnosis. A X test was used to determine the statistical significance of differences between observed and expected numbers of expected malignancies. The relative risk (observed-to-expected ratio) was also computed. Confidence intervals for the relative risk were calculated under the assumption that the number of primary tumors has a Poisson distribution.
RESULTS Overall, 30 patients who were diagnosed with SCLC developed a SPM, which included 19 metachronous
tumors and 11 synchronous tumors. The characteristics and treatment of patients in the metachronous group are outlined in Table 2. There were 14 men and five
women. The average age was 59 years. Eleven patients presented with limited disease (LD), and eight presented with extensive disease (ED). Seven of 17 patients who were treated with chemotherapy received cyclophos-
phamide, Adriamycin (doxorubicin; Adria Laboratories, Mississauga, Canada), and vincristine alone, whereas
the 10 patients who remained were treated with additional drugs. Two patients did not receive any chemother-
apy. All patients were subjected to local RT. Addition-
ally, 11 patients received prophylactic cranial RT. Fifteen patients achieved a complete response (CR), and four achieved a partial response (PR). The average survival among those observed to have had a SPM was 39 Table 2. Characteristics of Patients With Metachronous SPMs After the First Year From Diagnosis of SCLC Patient Attributes Patient Sex/Age No. (years) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
F/54 M/59 F/59 M/62 M/61 M/62 F/54 F/65 F/57 M/63 M/58 M/58 M/58 M/65 M/59 M/53 M/61 M/62 M/65
Treatment
Extent of Disease
Chemotherapy
Duration
Radiotherapy
Response
ED LD ED LD ED LD LD LD ED LD LD ED LD ED LD ED ED LD LD
CAVPT CAVM CAV CAVPT CAV None CAVBM CAVPT CAVPT CAVMN CAVPT CAV CAV None CAV CAVPT CAV CAVPT CAV
11 7 6 6 6 NA 8 8 12 8 6 6 6 NA 6 6 6 6 6
Local/cranial Local Local/cranial Local Local/cronial Local Local Local/cranial Local Local/cranial Local/cranial Local/cranial Local Local Local/cranial Local/cranial Local Local/cranial Local/cranial
CR CR CR CR CR CR CR PR CR CR CR PR CR PR CR PR CR CR CR
Abbreviations: C, cyclophosphamide; A, Adriamycin; V, vincristine; F, female; M, male; P, VP 16, etoposide; T, cisplatin; B, bleomycin; M, methotrexate; N, lomustine; Local, thoracic; CR, complete response; PR, partial response; NA, not applicable; ED, extensive disease; LD, limited disease.
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1527
SECOND PRIMARY MALIGNANCIES AND SCLC
months. The type and consequence of the secondary malignancy is outlined in Table 3. Three patients developed acute leukemia, and all died within a month of diagnosis regardless of treatment. Four patients developed a SPM in the lung; all were of the squamous cell type. In the first patient (no. 4; Table 3), non-small-cell lung cancer (NSCLC) was identified in the same lobe as the primary SCLC (the right upper lobe). The second patient (no. 5; Table 3) manifested SCLC in the left mediastinum, whereas the NSCLC was identified in the left upper lobe (posterior segment). The third (no. 6, Table 3) patient had SCLC in the left upper lobe (LUL), with a subsequent NSCLC identified in the opposite lung (right upper lobe). The fourth patient had SCLC diagnosed in the left mediastinum (no. 7; Table 3), with subsequent identification of a second NSCLC in the lingula of the left lung. One patient who was treated by lobectomy and one who was treated by local chest RT and surgery for breast cancer were alive at last follow-up at 36 and 8 months, respectively. Two of three patients with breast cancer died at 11 and 33 months of followup; the third patient with a third primary was alive at 8 months of follow-up. Of the two patients with prostatic carcinoma, one was free of detectable disease at 16 months of follow-up, whereas the other died of recurrent SCLC. All three patients with gastrointestinal malignancies died as a result of their second malignancy.
Those with cancer of the pancreas and cholangiocarcinoma died 1 month after diagnosis, and a patient with gastric adenocarcinoma died 5 months later. Two patients treated for synovial carcinoma and epiglottic epidermoid carcinoma did not respond to aggressive surgery and RT and died 3 and 7 months, respectively, after the detection of their second malignancy. One of three patients with basal cell carcinoma of the skin died after disease progression, and the remaining two were alive at 16 and 48 months after the surgical removal of their dermatologic tumors. The category of 11 patients with synchronous SPMs is summarized in Table 4. There were 10 men and one woman with an average age of 62 years at the diagnosis of SCLC. Six presented with ED, and five presented with LD. Treatment included the CAV regimen in six, with additional drugs in two, other drug combinations in two patients, and no chemotherapy in one. Four patients received local (thoracic) RT, three received cranial irradiation, and four were treated with irradiation to both sites. Overall, five patients achieved a CR and two achieved a PR, whereas four manifested disease progression. The average duration of survival for those who had a SPM was 5 months. Table 5 shows the type of synchronous SPM, the treatment, and follow-up of patients in this category. This group included one patient with chronic myelogenous leukemia, two pa-
Table 3. Metachronaus SPM After the First Year of SCLC Follow-Up
Management Patient No.
Months From SCLC to SPM
1 2 3 4 5 6 7
24 45 45 20 29 24 120
8 9 10 11 12 13 14 15 16 17 18 19
17 27 16 66 13 62 36 43 14 68 20 55
Type of SPM
Treatment*
Leukemia (AML) Leukemia (AML) Leukemia (AML) Lung (squamous) Lung (squamous) Lung (squamous) Lung (squamous) Breast (adenocarcinoma) Breast (adenocarcinoma) Breast (adenocarcinoma) Prostate (adenocarcinoma) Prostate (adenocarcinoma) Pancreas (adenocarcinoma) Cholangiocarcinoma Gastric (adenocarcinoma) Synovium (sarcoma) Epiglotis (epidermoid) Skin (basal CA) Skin (basal CA) Skin (basal CA)
Chemotherapy Chemotherapy None Surgery RT RT RT Surgery Surgery Surgery/RT Surgery Surgery/RT Surgery None RT Surgery Surgery/RT Surgery Surgery Surgery/RT
Months From SPM/Status
Cause of Death
PG PG PG CR PR PR PR
1/dead 1/dead 1/dead 36+/alive 6/dead
SPM SPM SPM NA ND
7/dead
SPM
8+/alive
NA
PG PG ND CR PG PG PG PG PG CR CR PG
11/dead 33/dead
ND SPM SCLC NA SPM SPM SPM SPM SPM NA NA SPM
Response
5/dead 16+/alive 1/dead 1/dead 5/dead 3/dead 7/dead 16+/alive 48+/alive 7/dead
Abbreviations: RT, radiotherapy; CR, complete response; PR, partial response; PG, progression; NA, not applicable; ND, not determined; CA, carcinoma. *Chemotherapy, surgery, or radiotherapy.
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1528
SAGMAN ET AL
(patients no. 9 and 10, respectively) from the diagnosis of SCLC. Although autopsy identified SPMs were not a focus in our study, we were able to document six such malignancies in the series of 392 patients between 1976 and 1985. They included three cases of carcinoma of the prostate, one case of breast cancer, one case of renal cell carcinoma, and one case of primary hepatocellular carcinoma. Of the 392 assessable SCLC patients observed at Princess Margaret Hospital between 1976 and 1985, nine developed subsequent malignant primaries. The average of 1981 and 1982 age- and sex-specific incidence rates for the province of Ontario were applied to the years at risk for this patient population to yield an expected number of new primary cancers. The observed incidence of nine new malignancies was significant statistically (X2 = 18.31; degrees of freedom (df) = 1; P < .0001) relative to the average 1981 and 1982 incidence rates in the province of Ontario. The relative risk (observed-to-expected ratio) was calculated as 3.73 for this group. Assuming that the number of new primary cancers has a Poisson distribution and the expected number would be known, a 95% confidence interval was calculated to be 1.71 to 7.09. Three of the nine patients with SPM developed NSCLC. Similarly, the observed incidence of three new lung primaries was significant statistically (X2 = 14.96; df = 1; P = .0001) relative to the average 1981 and 1982 incidence rates in the province of Ontario. The relative risk (observed-toexpected ratio) was calculated as 6.83 for this group of patients, with a 95% confidence interval calculated to be 1.41 to 19.95.
Table 4. Characteristics of Patients With Synchronous SPMs 1 Year After the Diagnosis of SCLC Treatment
Patient Attributes Sex/Age (years)
Disease
Chemotherapy
Duration (months)
1
M/60
ED
CAV
3
2 3 4 5 6 7 8 9 10 11
M/54 F/75 M/67 M/64 M/61 M/39 M/74 M/74 M/57 M/60
ED ED LD ED ED LD ED LD LD LD
CAV CAVPT CAV CAB CB CAVPT CAV CAV CAV
Patient No.
6 11 6 4 1 9 NA 6 6 6
Radiotherapy
Response
Local
PG
Local/cranial Cranial Local/cranial Local Local/cranial Local Local Cranial Cranial Local/cranial
PR CR CR PG PR NG PG CR CR CR
Abbreviations: C, cyclophosphamide; A, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH); V, vincristine; P, VP 16 (etoposide); T, cisplatin; B, bleomycin; M, methotrexate; NA, not applicable; LD, limited disease; ED, extensive disease; M, male; F, female.
tients with secondary lung tumors (anaplastic and multicentric SCLC), two patients with prostatic adenocarcinoma, two patients with gastrointestinal malignancies that included the rectum (patient no. 3 with third primary malignancy) and adenocarcinoma of the pancreas, one patient each with anaplastic testicular carcinoma and Kaposi's sarcoma, and three patients with basal cell carcinoma. In total seven patients died as a result of the primary SCLC, one because of the second malignancy (patient no. 6, adenocarcinoma of the pancreas), and one because of other medical complications (patient no. 4, gastrointestinal bleeding). Two patients with basal cell carcinoma were alive at 4 and 29 months
Table 5. SPMs During the First Year After the Diagnosis of SCLC Follow-Up
Management Patient No.
Months From SCLC to SPM
Type of SPM
Treatment
Response
Chemotherapy Chemotherapy Chemotherapy Surgery Surgery
PG PG PG PG PG
None None Surgery None Surgery RT RT
PG PG PG PG PG PG
1 2 3
1 1 3
4
7
Leukemia (CML) Lung (anaplastic) Lung (SCLC) Rectum (adenocarcinoma) Prostate (adenocarcinoma)
5 6 7 8 9 10 11
3 7 9 2 1 10 11
Prostate (adenocarcinoma) Pancreas (adenocarcinoma) Testis (anaplastic) Sarcoma (Kaposi's) Skin (basal CA) Skin (basal CA) Skin (basal CA)
Months From SPM/Stotus 4/dead 24/dead 22/dead 2/dead 5/dead 1/dead 4/dead 2/dead 4+/alive 29+/alive 3/dead
Cause of Death SCLC SCLC SCLC Gastrointestinal bleeding SCLC SPM SCLC SCLC SCLC NA SCLC
Abbreviations: RT, radiotherapy; CR, complete response; PR, partial response; PG, progression; NA, not applicable; CA, carcinoma.
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1529
SECOND PRIMARY MALIGNANCIES AND SCLC DISCUSSION
SPMs that included second primary cancers of the lung, hematologic malignancies, and other solid tumors were identified in our survey of patients with SCLC. Based on a subset of this group, we found a significantly higher cumulative risk of developing a second malignancy in patients with SCLC that was comparable to a sample from the normal population at risk. Most patients who developed a SPM within 1 year (synchronous tumor) of diagnosis of SCLC died of SCLC, whereas the cause of death in most of those who developed a second primary tumor subsequently (metachronous tumor) was related to that malignancy. The prognosis of patients with a SPM was related to the specific type of malignancy; cases of secondary leukemia were uniformly fatal regardless of treatment. Extrapulmonary solid malignancies entailed a similar grave prognosis. The highest probability of survival after diagnosis of a SPM (excluding skin tumors) was demonstrated in patients who developed a SPM in the lung. A variety of extrapulmonary solid SPMs have been described previously at intervals that ranged from 1 to 10 years after the treatment of SCLC. 27,28 The group
included cancers of the head and neck, gastrointestinal tumors, breast cancer, and renal cell carcinoma. In our review, we have also encountered sarcoma and prostate cancer as SPMs in long-term survivors of SCLC. With some exceptions, most patients died of the SPMs shortly after diagnosis. Several factors may contribute to the emergence of these SPMs. A priori, it is conceivable that similar carcinogenic insults, ie, smoking, may contribute to the emergence of other cancers in patients with SCLC, particularly head and neck tumors. A consensus deletion on the short arm of chromosome 3 described in both renal cell carcinoma and SCLC may support the view that similar genetic defects may operate in the genesis of SCLC and other tumors. 49 Also, familial cancer syndromes 50 may be applicable specifically to patients with SCLC. Finally, the latent sequelae of treatment, either chemotherapy, RT, or combined modality treatment, may be a predisposing factor to several types of cancers, and as such, SPMs may be regarded as a possible complication of therapy. An increased risk of developing metachronous SPMs of the lung in our series was consistent with some20-25 but not all 26 of the reported series in the literature. Both practical and theoretic factors may demonstrate this dichotomy, and, in turn, these should be considered in the computation of the true incidence of SPMs of the lung. Patients with an initial diagnosis of SCLC in
whom initial induction regimens fail may present with apparent NSCLC on rebiopsy. Therefore, it is conceivable that these tumors either failed early detection or originally were misdiagnosed.51 Alternatively, metachronous SPMs of the lung may have evolved as a result of therapy-induced differentiation events. This idea is in fact consistent with a current hypothesis that implicates a common stem cell for all forms of lung cancer. 52 A further problem when considering the incidence of metachronous SPMs of the lung arises with the appearance of new SCLC lesions in the lung. It is difficult to distinguish whether these represent true SPMs or whether they reflect a late metastatic recurrence that results from the original primary lesion. Ideally, we suggest that true SPMs of the lung should be regarded as having a different histology than the primary malignancies and a different site from that of the original tumor. All histologic types of second primary bronchial tumors have been reported.20- 26 Table 6 lists the frequency of these metachronous lung malignancies. As with the other reported cases, the predominant type detected in our survey was squamous cell carcinoma of the lung. In all cases, the second malignancy occurred at a different site from the original SCLC and developed subsequent to the combined modality treatment. Of a total of four patients in our report with metachronous SPM of the lung, two (50%) were alive at 14 and 42 months, respectively, after surgical intervention. The possibility for long-term control in the management of patients with secondary tumors of the lung, therefore, should be pursued. We suggest that the nature of new lesions in the lung, which were detected as early as 1 year after diagnosis of SCLC, or those lesions not responding to standard treatment for SCLC should possibly be investigated further as they may represent metachronous SPMs of the lung and not metastasis and, hence, potentially may be curable. A gradient of abnormalities of the hematopoetic system has been reported in long-term survivors of SCLC with acute leukemia, which represents the extreme of the spectrum. Accumulating evidence confirms Table 6. Second Primary NSCLC After Initial Diagnosis of SCLC Cases Type of Lung Carcinoma 2
Squamous -4,22.39,40 3
Adenocarcinoma-3,39, 23 Large cell , 1 Bronchoalveolar Mucoepidermoid'
No.
%
16
67
4 2 1 1
17 8 4 4
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1530
SAGMAN ET AL were staged as having LD, and 11 were staged as having ED. The average interval from diagnosis of SCLC to detection of acute leukemia was 36 months (range, 15 to 67 months), and the average survival after the diagnosis of leukemia was 3 months (range, 1 to 10 months); 11 of the patients survived less than 1 month. Most reported cases (including all three patients in our study) demonstrated features that commonly were encountered with therapy-associated leukemia, ie, a preleukemic phase, karyotypic abnormalities, and prolonged exposure to leukemogenic agents. These attributes of secondary leukemia in patients with SCLC were consistent with the attributes described for secondary leukemia that were encountered in other cancers. Secondary leukemia, particularly acute nonlymphocytic leukemia, has been described in a variety of malignancies including malignant lymphoma, 55 62 multiple myelo66 67 64 65 ma,63 ovarian carcinoma, , gastrointestinal cancer, ,
the suspicion for therapy-induced chronic myelosuppression determined by the reduction of hematopoetic colony-forming units in the peripheral blood of patients.9 Furthermore, in several long-term survivors, persistent peripheral-blood aneuploidy has been observed with increasing frequency, 53 -54 which is a trend that may precede the development of acute leukemia. More recently, deletion of chromosome 3 (p 1 4 p23) has been described in secondary leukemia that developed in long-term survivors of SCLC. 17 This observation is perhaps the most direct evidence to date for a shared genetic predisposition to these two malignancies. As listed in Table 7, at least 29 cases of secondary leukemia have been reported in patients who were treated for SCLC. The general characteristics of the patients show that the average age was 61 years (range, 42 to 74) at the time of diagnosis of leukemia. No specific sex predilection was noted in the series. Fifteen patients originally
Table 7. Acute Leukemia Following Treatment for SCLC SCLC
Authors Shimp et a129 Newcomer et al"3 Vogelzang et ap13 32 Bradley et al Markman et aP133 Mukerji et a134 Jackson et aPs Rose et 0136 37 Volk et a1 Chak et a138
Pederson-Bjergoard et a128
Gramont et oP Yu et all' Johnson ata142
9
1
Whang-Peng et a '9 Present study
Age (years)/Sex
Stage
Chemotherapy
RT
Duration (months)
59/M 59/F 56/M 65/M 63/F 58/F 47/F 52/M 68/M 63/M 56/M 42/M 52/M 56/M 69/F 71/F 49/F 57/F 74/M 58/F 48/M 64/M 44/F 40/M 68/F 64/F 54/F 59/M 59/F
ED LD LD ED ED LD LD LD ED LD LD ED LD LD ED LD LD LD ED ED LD ED LD ED LD ED
CCnMx CAVMxT CnAVPr CAVMxCnPr CAVEPrBn CAVMxEPrBn CAVMxCnPR CAVE CAVEMx CAVMx CACnMxEPr CAVCnMxEPr CAVCnMxEPr CAVCnMxEPr CnCVE CnAVCMxE CnVCE CnAVCMxE CnAVCMxE CnVCE FMxVC C* CAVMxEHm CAVMxEHm CMxCnAVPr CAECnVMxPr CAVEPt CAVMx CAV
T NS T L T TC NS TC TC TC TC TC C TC NS NS NS NS NS NS T L TC TC L CL TC T TC
23 16 22 27 26 25 13 10 11 24 19 16 18 12 11 13 18 18 18 18 22 12 13 11 7 6
Interval (from SCLC diagnosis to leukemia) (months)
Type of Leukemia
Survivaol (months)
36 24 57 34 38 29 20 10 29 44 40 32 28 39 11 15 19 21 30 43 54 42 22 81 27 36 24 45 45
AML AMML AML ER AML ER AML AMOL AMML AML AML AML AML AMML AML AML AML AML AML AML AMML ER AMML AML ER ER AML AML AML
< 1 10 6 7 9 < 1 < 1 < 1 I 1 < 1 2 < 1 4 3 2 9 7 1 < 1 1 < 1 < 1 < 1 1 < 1 1
Abbreviations: LD, limited disease; ED, extensive disease; M, male; F, female; CYC, cyclophosphamide; CCNU, lomustine; MTX, methotrexate; ADR, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH); VCR, vincristine; ETO, etoposide; PRO, procarbazine; PLT, cisplatin; MIT-C, mitomycin; 5-FU, fluorouracil; AML, acute myelocytic leukemia; AMML, acute myelomonocytic leukemia; ER, erythroleukemia; NS, not stated.
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1531
SECOND PRIMARY MALIGNANCIES AND SCLC
and breast cancer.6 8,69 Secondary leukemia in patients with SCLC was similar to secondary leukemia that manifested subsequent to other malignancies that developed after intensive treatment with chemotherapy, with or without irradiation. The clinical features of patients included a long latent period between the completion of successful induction therapy and the diagnosis of leukemia, the use of intensive induction regimens, which included alkylating agents, and a uniformly poor prognosis after the development of leukemia. These observations may be consistent with the claim that acute nonlymphocytic leukemia represents a late complication of therapy in patients with SCLC. The actuarial risk for the development of secondary leukemia in patients with SCLC has been reported by several investigators.2 8 This risk was unequivocally elevated in all of the reported studies. However, the absolute risk was variable, and ranged between 3% and 40% in the different reports.35,4 142 Several explanations for this discrepancy are possible. First, the population sizes were different, and therefore size sample bias may have been introduced. Second, differences between chemotherapy regimens may contribute to the variable risk. Earlier approaches to the treatment of SCLC with chemotherapy entailed the predominant use of alkylating agents (cyclophosphamide, nitrosoureas), with longer induction durations that included maintenance therapy and, hence, higher cumulative doses. Current approaches used different agents (VP 16, cisplatin), alone or in combination with older regimens and, more recently, for shorter periods. Hence, the type of treatment regimen, the dose of chemotherapy, and the overall duration of treatment may dictate the risk of secondary leukemia. Table 8 enumerates the specific chemotherapeutic agents including exposure to RT administered to the reported cohort of SCLC patients before the development of secondary leukemia. The preponderant use of alkylating agents was demonstrated amply in this group in congruence with the leukemogenic potential of these drugs in other malignancies. It remains to be seen whether agents used more recently in the treatment of SCLC will result in a similar risk for secondary leukemia. Some of these agents have been suspected to contribute 69 to secondary leukemia in other malignancies.6"" As previously mentioned, the increased susceptibility to metachronous SPMs in long-term survivors of SCLC, in part, may be related to the secondary effects of multimodality treatments, By implication, the risk in patients with synchronous tumors in whom the longterm effects of treatment were not substantially incurred
Table 8. Prior Treatment for SCLC in 25 Patients With Secondary
Leukemia No.
RT Yes No Not stated Chemotherapy Average no of agents Range Cyclophosphamide Adrimycin Vincristine Methotrexate CCNU (lomustine) Procarbazine Etoposide Cisplatin Mitomycin 5-FU
7 7 11
6 3-8 24 21 21 19 15 10 8 2 1 1
may be governed by other factors. Indeed it is possible that genetic epigenetic and environmental factors may contribute to multiple synchronous malignancies in patients with SCLC. For example, the long-held familial association between respiratory and gastrointestinal malignancies may be specifically applicable in patients with SCLC.-" Therefore, it is conceivable that genetic or other intrinsic factors may be sufficient to contribute to the emergence of synchronous tumors, whereas the metachronous malignancies may require the contribution of treatment toxicity. In conclusion, we described a series of patients who developed SPMs after the diagnosis of SCLC. We concur with other reports when we suggest that the increased predisposition to metachronous SPMs may relate to the secondary effects of multimodality treatment. The risk of a SPM, therefore, must be considered as a late complication of treatment for SCLC, and should be balanced against the benefits of the current treatment regimens. This risk also must be viewed in the context of recent studies that suggest a genetic basis for the occurrence of second primary cancers in patients with SCLC. In the final analysis, it is particularly devastating to encounter a second malignancy in those few patients who are deemed long-term survivors of SCLC. Nevertheless, the vigilant documentation and study of these second malignancies must continue with vigor because they increase our understanding of the basic biology of the disease and ultimately may have an impact on patients.
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1532
SAGMAN ET AL REFERENCES
1. Miller AB, Fox W, Tall R: Five-year follow-up of the Medical Research Council comparative trial of surgery and radiotherapy for the primary treatment of small or oat-cell carcinoma of the bronchus. Lancet 2:501-505, 1969 2. Minna JD, Higgins GA, Glatstein EI, et al: Cancer of the lung, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology. Philadelphia, PA, J Lippincott, 1989, pp 591-705 3. Morstyn G, Ihde DC, Lichter AS, et al: Small cell lung cancer 1973-1983: Early progress and recent obstacles. Int J Radiat Oncol Biol Phys 10:515-539, 1984 4. Feld R, Ginsberg RJ, Payne DG: Treatment of small cell lung cancer, in Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, PA, Saunders, 1989, pp 229-262 5. Feld R: Complications of the treatment of small cell carcinoma of the lung. Cancer Treat Rev 8:5-25, 1981 6. Feld R: Long-term complications in small cell lung cancer, in Hansen HH (ed): Basic and Clinical Concepts of Lung Cancer. Boston, Kluwer, 1989, pp 301-324. 7. Lishner M, Feld R, Payne DG, et al: Late neurological complications after prophylactic cranial irradiation in patients with small cell lung cancer: The Toronto experience. J Clin Oncol 8:215-221, 1990 8. Lawson RAM, Ross WM, Gold RG: Post irradiation pericarditis: Report on four more cases with special reference to bronchogenic carcinoma. J Thorac Cardiov Surg 63:841-847, 1972 9. Seydel HG, Creech RH, Mietlowski W, et al: Radiation therapy in small cell lung cancer. Semin Oncol 5:288-298, 1978 10. Abrams RA, Lichter A, Johnston-Early A, et al: Enhanced Suppression of peripheral blood CFU, white blood cell and platelet counts by regional radiotherapy in adult patients with nonhematologic malignancy. Proc Am Soc Clin Oncol 20:114, 1979 (abstr) 11. Glode LM, Hartman D, Robinson WA: The acute and cumulative marrow toxicity of chemotherapy in small cell carcinoma of the lung with and without bone marrow support. Proc AACR-ASCO 21:448, 1980 (abstr) 12. Ginsberg SJ, Comis RL: The pulmonary toxicity of antineoplastic agents. Semin Oncol 9:34-51, 1982 13. Gross NJ: Pulmonary effects of radiation therapy. Ann Intern Med 86:81-92, 1977 14. Brooks BJ Jr, Seifier ES, Walsh TE, et al: Pulmonary toxicity with combined modality therapy for limited stage small cell lung cancer. J Clin Oncol 4:200-209, 1986 15. Trask CWL, Joannides T, Harper PG, et al: Radiationinduced lung fibrosis after treatment of small cell carcinoma of the lung with very high-dose cyclophosphamide. Cancer 55:57-60, 1988 16. Feld R, Evans WK, DeBoer G: Herpes zoster in patients with small cell carcinoma of the lung receiving combined modality treatment. Ann Intern Med 93:282-283, 1980 17. Feld R, Evans WK, DeBoer G: Herpes zoster in patients with carcinoma of the lung. AM J Med 73:795-801, 1982 18. Abeloff MD, Klastersky J, Prings PO, et al: Complications of treatment of small cell carcinoma of the lung. Cancer Treat Rev 8:5-25, 1983 19. Whang-Peng J, Lee EC, Minna JD: Deletion of 3 (pl4p23) in secondary erythroleukemia arising in long-term survivors of small cell lung cancer. J Natl Can Inst 80:1253-1255, 1988 20. Beal J: Second primary lung tumours. Illinois Med J 148:603605, 1975
21. Mobley D, Martinez J: Two histologically different primary carcinomas of the lung. Cancer 22:287-292, 1968 22. Struve-Christensen E: Diagnosis and treatment of bilateral primary bronchogenic carcinoma. J Thorac Cardiovasc Surg 61:501512, 1971 23. Billroth T, von Winiwarter A: General surgical pathology and therapeutics, ed 10 (translated from 4th German ed). New York, NY, Appleton, 1883, p 765 24. Craig J, Powel B, Muss HB, et al: Second primary bronchogenic carcinomas after small cell carcinoma. Report of two cases and review of literature. Am J Med 76:1013-1020, 1984 25. Johnson BE, Ihde DC, Mathews MJ, et al: Non-small cell lung cancer, major cause of late mortality in patients with small cell lung cancer. Am J Med 80:1103-1110, 1986 26. Osterlind K, Hansen HH, Hansen M, et al: Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small cell lung cancer. J Clin Oncol 4:1044-1052, 1986 27. Volk SA, Mansour RF, Gandara DR, et al: Morbidity in long-term survivors of small cell carcinoma of the lung. Cancer 54:25-27, 1984 28. Pedersen-Bjergaard J, Osterlind K, Hansen M, et al: Acute non-lymphocytic leukemia, preleukemias and solid tumors following intensive chemotherapy of small cell carcinoma of the lung. Blood 66:1393-1397, 1985 29. Shrimp W, Belzer MB: Acute leukemia after treatment of small cell carcinoma of the lung. N Engl J Med 304:845-846, 1981 30. Newcomer LW, Farber LR: Acute myelogenous leukemia after successful treatment of small cell carcinoma of the lung. South Med J 75:80-81, 1982 31. Vogelzang NJ, Arther D, Kennedy BJ: Leukemia occurring after treatment of small cell lung cancer. Cancer Treat Rep 66:1683-1684, 1982 32. Bradley EC, Schechter GP, Mathews MJ, et al: Erythroleukemia and other hematologic complications of intensive therapy in long-term survivors of small cell lung cancer. Cancer 49:221-223, 1982 33. Markman M, Pary MD, Abeloff MD: Acute leukemia following intensive therapy for small cell carcinoma of the lung. Cancer 50:672-675, 1982 34. Mukherji B, Yamase HT: Acute leukemia developing after intensive chemotherapy for small cell cancer of the lung. Cancer Treat Rep 61:100-101, 1983 35. Jackson DV, Cruz JM, Woodruff RL: Small cell carcinoma of the lung: Rapid development of acute leukemia. NC Med J 44:475-476, 1983 36. Rose VL, Kepper MD, Eichner ER, et al: Acute leukemia after successful chemotherapy for oat cell carcinoma. Am J Clin Pathol79:122-124, 1983 37. Volk SA, Mansour RF, Ganders DR, et al: Morbidity in long term survivors of small cell carcinoma of the lung. Cancer 54:25-27, 1984 38. Chak LY, Sikic BI, Tucker MA, et al: Increased incidence of acute non-lymphocytic leukemia following therapy in patients with small cell carcinoma of the lung. J Clin Oncol 2:385-390, 1984 39. de Gramont A, Rioux E, Fortin P, et al: Acute leukemia secondary to lung cancer. Oncology 42:107-111, 1985 40. Johnson BE, Ihde DC, Bunn PA, et al: Patients with small cell lung cancer treated with combination chemotherapy with or without irradiation. Ann Intern Med 103:430-438, 1985
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SECOND PRIMARY MALIGNANCIES AND SCLC 41. Yu PP, Waxman JS, Chahinian AP, et al: Acute myelogenous leukemias following complete remission of small cell carcinomas of the lung. Med Pediatri Oncol 14:100-103, 1986 42. Johnson DM, Porter LL, Gist AF, et al: Acute nonlymphocytic leukemia after treatment of small cell lung cancer. Am J Med 81:962-968, 1986 43. Feld R, Pringle JF, Evans WK, et al: Combined modality treatment of small cell carcinoma of the lung. Arch Int Med 141:469-473, 1981 44. Feld R, Evans WK, DeBoer G, et al: Combined modality induction therapy without maintenance chemotherapy for smallcell carcinoma of the lung. J Clin Oncol 2:294-304, 1984 45. Dang SP, Liberman BA, Shepherd FA, et al: Therapyrelated leukemia and myelodysplasia in small cell lung cancer. Arch Intern Med 146:1689-1694, 1986 46. Feld R, Evans WK, Coy P, et al: Canadian multicentre randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol 5:1401-1409, 1987 47. Evans WK, Feld R, Murray N, et al: Superiority of alternating non-cross-resistant chemotherapy in extensive small-cell lung cancer: The results of a multicenter randomized National Cancer Institute of Canada Clinical Trial. Ann Intern Med 107:451-458, 1987 48. Statistics Canada. Health and Welfare Division, Public Health Section. New Primary Sites of Malignant Neoplasms in Canada. Catalogue 82-207 49. Birrer MJ, Minna JD: Molecular genetics of lung cancer. Semin Oncol 15:226-235, 1988 50. Berg JW, Schottenfeld D, Ritter F: Incidence of multiple primary cancers: III. Cancers of the respiratory and upper digestive system as multiple primary cancers. J Nat Cancer Inst 44:263-274, 1970 51. Doris S, Wright PW, Schulman SF, et al: Long-term survival in small-cell carcinoma of the lung: A population experience. J Clin Oncol 3:80-91, 1985 52. Gazdar AF, Cavney DN, Guccion JG, et al: Small cell carcinoma of the lung: Cellular origin and relationship to other pulmonary tumors, in Greco FA, Oldham RK, Brunn PA Jr (eds): Small Cell Lung Cancer. New York, NY, Grune and Stratton, 1981, pp 145-177 53. Adelstein DJ, Hines JD: Bone marrow morphologic changes after combination chemotherapy including VP-16. Cancer 56:467471, 1985 54. Tominaga K, Shinkai T, Suijo N, et al: Cytogenetic effects of multiagent chemotherapy on the peripheral lymphocytes of patients with small cell lung cancer. Jpn J Cancer Res 77:1241-1248, 1986 55. Gomez GA, Agarwal KK, Tin H: Post-therapeutic acute malignant myeloproliferative syndrome and acute nonlymphocytic
leukemia in non-Hodgkins lymphoma: Correlation with intensity of treatment. Cancer 50:2285-2288, 1982 56. Glicksman AS, Pajak TF, Gottlieb A, et al: Second malignant neoplasms in patients successfully treated for Hodgkin's disease: A cancer and leukemia group B study. Cancer Treat Rep 66:1035-1044, 1982 57. Valagussa P, Santoro A, Kenda R, et al: Second malignancies in Hodgkin's disease: A complication of certain forms of treatment. Br Med J 280:216-219, 1980 58. Pedersen-Bjergaard J, Larsen SO: Incidence of acute nonlymphocytic leukemia, preleukemia and acute myeloproliferative syndrome up to 10 years after treatment of Hodgkin's disease. N Engl J Med 307:965-971, 1982 59. Aisenberg AC: Acute nonlymphocytic leukemia after treatment for Hodgkin's disease. Am J Med 75:449-454, 1983 60. Greene MH, Young RC, Merrill JM, et al: Evidence of a treatment dose response in acute nonlymphocytic leukemias which occur after therapy of non-Hodgkin's lymphoma. Cancer Res 43:1891-1898, 1983 61. Pedersen-Bjergaard J, Ersboll J, Sorensen HM, et al: Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin's lymphomas. Comparison with results obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating agents. Ann Intern Med 103:195-200, 1985 62. Tucker MA, Coleman CN, Cox RS: Risk of second cancers after treatment for Hodgkin's disease. N Engl J Med 318:76-81, 1988 63. Bergsagel DE, Bailey AJ, Langley GR, et al: The chemotherapy of plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med 301:743-748, 1979 64. Greene MH, Boice JD, Greer BE, et al: Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer. N Engl J Med 307:1416-1421, 1982 65. Pederson-Bjegaard J, Nissen NI, Sorenson HM, et al: Acute non-lymphocytic leukemia in patients with ovarian carcinoma following long-term treatment with treasulfan. Cancer 45:19-29, 1980 66. Boice JD, Greene MH, Killen JY, et al: Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with semustine (methyl-CCNU). N Engl J Med 309:1079-1084, 1983 67. Rosner F, Grunwald HW, Zarrabi HM: Cancer after the use of alkylating and non-alkylating cytotoxic agents in man. Cancer Surveys 1:599-612, 1982 68. Henderson JC, Gelman R: Second malignancies from adjuvant chemotherapy? Too soon to tell. J Clin Oncol 5:1135-1137, 1987 69. Ratain MJ, Kaminer LS, Bitran DJ, et al: Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small cell carcinoma of the lung. Blood 70:1412-1417, 1987
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HISTORICALLY,
treatment with surgery and subsequently with radiotherapy (RT) had a limited impact on the survival of patients with small-cell lung cancer (SCLC). 1 The introduction of combination chemotherapy in the 1970s and current multimodality approaches to the management of patients with SCLC improved the overall 2- and 5-year survival rates in most reported studies to approximately 10% and 5%, respectively. 2-4 With an improved potential for cure and the accrual of long-term survivors of SCLC, the adverse complications of chemotherapy and therapeutic RT have become apparent. Reported chronic sequela of 5 7 therapy have included effects on the nervous, - cardiac,
8
91
hematologic, - 1 and respiratory systems,"-15 as well as infectious disease complications. 16,17 The toxicity of treatment has also been postulated to bear on the higher incidence of both synchronous and metachronous primary and secondary malignancies in long-term survivors of SCLC.6-18 In addition to the plausible effects of treatment, compelling new evidence implicates common genomic abberations in the pathogenesis of SCLC and metachronous second primary malignancies (SPM).19 20 2 6 Identification of SPMs of the lung, - other solid
other solid tumors (OST). The median survival times after the diagnosis of MSPM was 33 months, 10 months, and 1 month, respectively, for those with NSCLC, OST, and HM. Expected cancer incidence rates were used to compute a relative risk rate for developing a MSPM in a subset of 392 patients on whom accurate follow-up information was available. The calculated relative risk for all tumors was 3.73. The relative risk for the development of secondary NSCLC was 6.83. Conclusion: We suggest that increased predisposition to SPM may relate to secondary effects of multimodality treatment and biologic considerations. J Clin Oncol 10: 1525-1533. © 1992 by American Society of Clinical Oncology. the Toronto General Hospital, Toronto, Canada, from 1971 to 1985 were reviewed for the occurrence of SPMs. Before 1976, patients were treated according to their physicians' discretion. Most patients diagnosed between 1976 and 1985 participated in five consecutive study protocols. During this study period, patients were treated on different treatment protocols; most patients received induction chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV) that was alternated with or followed by combinations with etoposide (VP 16), cisplatin, lomustine (CCNU), or methotrexate. Most were also subjected to thoracic and/or prophylactic cranial irradiation. The outline of these studies and their respective outcomes have been reported elsewhere in detail and are summarized in Table 1.43-47 Patients were followed-up at regular intervals, and history and physical examination findings were recorded at each visit. Routine follow-up after the completion of treatment included clinical assessment at least once every 2 months for the first year, every 3 months for the second year, and every 6 months for the third to fifth years. Subsequently, patients returned for routine examinations at least annually. Thirty patients with second primary cancers were identified in total. Diagnosis of second cancers were confirmed by a review of pathology reports. For the purposes of analysis, patients were divided into two categories based on the time of identification of a SPM. The first group included patients in which an SPM was documented a year after the diagnosis of SCLC (synchronous malignancies); the second group included those in which the SPM
tumors,2 7,28 and hematologic malignancies that include 28 4 acute leukemia19, -
2
all have
been documented
in
long-term survivors of SCLC. In this study, we reviewed the records of 800 patients with SCLC observed at University of Toronto-affiliated hospitals between 1971 and 1985 for the occurrence and relative risk of SPMs after the diagnosis and treatment of SCLC. METHODS The records of all 800 patients with histologic and cytologic diagnosis of SCLC treated at the Princess Margaret Hospital and
From the Departments of Medicine, Biostatistics, and Radiation Oncology, Princess MargaretHospital;Departmentof Medical Oncology, Toronto General Hospital; Department of Surgery, Mt Sinai Hospital, Toronto; and Department of Medical Oncology, Ontario Cancer Treatment and Research Foundation,Ottawa, Canada. Submitted December 16, 1991; acceptedJune 22, 1992. Address reprint requests to R. Feld, MD, Department of Medicine, Princess Margaret Hospital, 500 Sherbourne St, Toronto, Ontario, CanadaM4X 1K9. ©1992 by American Society of ClinicalOncology. 0732-183X/92/1010-0005$3.001/0
Journalof Clinical Oncology, Vol 10, No 10 (October), 1992: pp 1525-1533
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1525
1526
SAGMAN ET AL Table 1. Trials of Chemotherapy and Radiotherapy for Patients With SCLC (Toronto 1976 to 1985) Median Median LD ED
No. of Patients
Trial
Reference
Regimen
CAV-1 *
43
CAV-2*
44
BRt
45
TPNJ
46
NOS
47
Cyclophosphamide (750 mg/m ), doxorubicin (50 mg/m2), vincristine (2 mg) + irradiation (25 Gy) in 2 weeks in 10 fractions to primary tumor + 2 mediastinum followed by lomustine (50 mg/m ) + procarbazine (100 2 2 mg/m ) + methotrexate (10 mg/m ) 2 Cyclophosphamide (900 mg/m ), doxorubicin (50 mg/m2), vincristine (2 mg) + irradiation (20 Gy per 1 week in 5 fractions to cranium) Cyclophosphamide (1,000 mg/m2), doxorubicin (50 mg/m2), vincristine (2 mg) + irradiation RT (20 Gy per 1 week in 5 fractions to cranium) + alternoting agents, VP 16 (100 mg/m2) + cisplatin (25 mg/m 2 ) 2 2 Cyclophosphamide (1,000 mg/m ), doxorubicin (50 mg/m ), vincristine (2 2 mg) + irradiation cyclophosphamide (1,200 mg/m ) + Adriamycin (70 2 mg/m2) + vincristine (2 mg) followed byVP 16 (100 mg/m ) + MTX (10 2 mg/m ) + 1-1.5 g protein/kg + 40 kcal/kg body weight Modified CAV-2
2
Survival Overall
148
48
39
43
197
49
34
40
64
63
35
57
43
68
63
66
62
42
32
37
Abbreviations: VP 16, etoposide; MTX, methotrexate. *Sequential study. tRandomized study.
was diagnosed subsequent to that interval (metachronous malignancies). Eleven patients were identified in the former and 19 in the latter category. Identification of a SPM at autopsy was excluded from analysis in this study.
Statistic Considerations The observed incidence of SPMs was obtained in a subset of 392 patients treated at the Princess Margaret Hospital between 1976 and 1985. Patients from other institutions were not included in this analysis because information was not available on all patients observed during this period. The expected number of SPMs was calculated by applying the average of 1981 and 1982 age- and sex-specific incidence rates for the province of Ontario48 to the 2 person-years at risk from 1 year after the date of diagnosis. A X test was used to determine the statistical significance of differences between observed and expected numbers of expected malignancies. The relative risk (observed-to-expected ratio) was also computed. Confidence intervals for the relative risk were calculated under the assumption that the number of primary tumors has a Poisson distribution.
RESULTS Overall, 30 patients who were diagnosed with SCLC developed a SPM, which included 19 metachronous
tumors and 11 synchronous tumors. The characteristics and treatment of patients in the metachronous group are outlined in Table 2. There were 14 men and five
women. The average age was 59 years. Eleven patients presented with limited disease (LD), and eight presented with extensive disease (ED). Seven of 17 patients who were treated with chemotherapy received cyclophos-
phamide, Adriamycin (doxorubicin; Adria Laboratories, Mississauga, Canada), and vincristine alone, whereas
the 10 patients who remained were treated with additional drugs. Two patients did not receive any chemother-
apy. All patients were subjected to local RT. Addition-
ally, 11 patients received prophylactic cranial RT. Fifteen patients achieved a complete response (CR), and four achieved a partial response (PR). The average survival among those observed to have had a SPM was 39 Table 2. Characteristics of Patients With Metachronous SPMs After the First Year From Diagnosis of SCLC Patient Attributes Patient Sex/Age No. (years) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
F/54 M/59 F/59 M/62 M/61 M/62 F/54 F/65 F/57 M/63 M/58 M/58 M/58 M/65 M/59 M/53 M/61 M/62 M/65
Treatment
Extent of Disease
Chemotherapy
Duration
Radiotherapy
Response
ED LD ED LD ED LD LD LD ED LD LD ED LD ED LD ED ED LD LD
CAVPT CAVM CAV CAVPT CAV None CAVBM CAVPT CAVPT CAVMN CAVPT CAV CAV None CAV CAVPT CAV CAVPT CAV
11 7 6 6 6 NA 8 8 12 8 6 6 6 NA 6 6 6 6 6
Local/cranial Local Local/cranial Local Local/cronial Local Local Local/cranial Local Local/cranial Local/cranial Local/cranial Local Local Local/cranial Local/cranial Local Local/cranial Local/cranial
CR CR CR CR CR CR CR PR CR CR CR PR CR PR CR PR CR CR CR
Abbreviations: C, cyclophosphamide; A, Adriamycin; V, vincristine; F, female; M, male; P, VP 16, etoposide; T, cisplatin; B, bleomycin; M, methotrexate; N, lomustine; Local, thoracic; CR, complete response; PR, partial response; NA, not applicable; ED, extensive disease; LD, limited disease.
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1527
SECOND PRIMARY MALIGNANCIES AND SCLC
months. The type and consequence of the secondary malignancy is outlined in Table 3. Three patients developed acute leukemia, and all died within a month of diagnosis regardless of treatment. Four patients developed a SPM in the lung; all were of the squamous cell type. In the first patient (no. 4; Table 3), non-small-cell lung cancer (NSCLC) was identified in the same lobe as the primary SCLC (the right upper lobe). The second patient (no. 5; Table 3) manifested SCLC in the left mediastinum, whereas the NSCLC was identified in the left upper lobe (posterior segment). The third (no. 6, Table 3) patient had SCLC in the left upper lobe (LUL), with a subsequent NSCLC identified in the opposite lung (right upper lobe). The fourth patient had SCLC diagnosed in the left mediastinum (no. 7; Table 3), with subsequent identification of a second NSCLC in the lingula of the left lung. One patient who was treated by lobectomy and one who was treated by local chest RT and surgery for breast cancer were alive at last follow-up at 36 and 8 months, respectively. Two of three patients with breast cancer died at 11 and 33 months of followup; the third patient with a third primary was alive at 8 months of follow-up. Of the two patients with prostatic carcinoma, one was free of detectable disease at 16 months of follow-up, whereas the other died of recurrent SCLC. All three patients with gastrointestinal malignancies died as a result of their second malignancy.
Those with cancer of the pancreas and cholangiocarcinoma died 1 month after diagnosis, and a patient with gastric adenocarcinoma died 5 months later. Two patients treated for synovial carcinoma and epiglottic epidermoid carcinoma did not respond to aggressive surgery and RT and died 3 and 7 months, respectively, after the detection of their second malignancy. One of three patients with basal cell carcinoma of the skin died after disease progression, and the remaining two were alive at 16 and 48 months after the surgical removal of their dermatologic tumors. The category of 11 patients with synchronous SPMs is summarized in Table 4. There were 10 men and one woman with an average age of 62 years at the diagnosis of SCLC. Six presented with ED, and five presented with LD. Treatment included the CAV regimen in six, with additional drugs in two, other drug combinations in two patients, and no chemotherapy in one. Four patients received local (thoracic) RT, three received cranial irradiation, and four were treated with irradiation to both sites. Overall, five patients achieved a CR and two achieved a PR, whereas four manifested disease progression. The average duration of survival for those who had a SPM was 5 months. Table 5 shows the type of synchronous SPM, the treatment, and follow-up of patients in this category. This group included one patient with chronic myelogenous leukemia, two pa-
Table 3. Metachronaus SPM After the First Year of SCLC Follow-Up
Management Patient No.
Months From SCLC to SPM
1 2 3 4 5 6 7
24 45 45 20 29 24 120
8 9 10 11 12 13 14 15 16 17 18 19
17 27 16 66 13 62 36 43 14 68 20 55
Type of SPM
Treatment*
Leukemia (AML) Leukemia (AML) Leukemia (AML) Lung (squamous) Lung (squamous) Lung (squamous) Lung (squamous) Breast (adenocarcinoma) Breast (adenocarcinoma) Breast (adenocarcinoma) Prostate (adenocarcinoma) Prostate (adenocarcinoma) Pancreas (adenocarcinoma) Cholangiocarcinoma Gastric (adenocarcinoma) Synovium (sarcoma) Epiglotis (epidermoid) Skin (basal CA) Skin (basal CA) Skin (basal CA)
Chemotherapy Chemotherapy None Surgery RT RT RT Surgery Surgery Surgery/RT Surgery Surgery/RT Surgery None RT Surgery Surgery/RT Surgery Surgery Surgery/RT
Months From SPM/Status
Cause of Death
PG PG PG CR PR PR PR
1/dead 1/dead 1/dead 36+/alive 6/dead
SPM SPM SPM NA ND
7/dead
SPM
8+/alive
NA
PG PG ND CR PG PG PG PG PG CR CR PG
11/dead 33/dead
ND SPM SCLC NA SPM SPM SPM SPM SPM NA NA SPM
Response
5/dead 16+/alive 1/dead 1/dead 5/dead 3/dead 7/dead 16+/alive 48+/alive 7/dead
Abbreviations: RT, radiotherapy; CR, complete response; PR, partial response; PG, progression; NA, not applicable; ND, not determined; CA, carcinoma. *Chemotherapy, surgery, or radiotherapy.
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1528
SAGMAN ET AL
(patients no. 9 and 10, respectively) from the diagnosis of SCLC. Although autopsy identified SPMs were not a focus in our study, we were able to document six such malignancies in the series of 392 patients between 1976 and 1985. They included three cases of carcinoma of the prostate, one case of breast cancer, one case of renal cell carcinoma, and one case of primary hepatocellular carcinoma. Of the 392 assessable SCLC patients observed at Princess Margaret Hospital between 1976 and 1985, nine developed subsequent malignant primaries. The average of 1981 and 1982 age- and sex-specific incidence rates for the province of Ontario were applied to the years at risk for this patient population to yield an expected number of new primary cancers. The observed incidence of nine new malignancies was significant statistically (X2 = 18.31; degrees of freedom (df) = 1; P < .0001) relative to the average 1981 and 1982 incidence rates in the province of Ontario. The relative risk (observed-to-expected ratio) was calculated as 3.73 for this group. Assuming that the number of new primary cancers has a Poisson distribution and the expected number would be known, a 95% confidence interval was calculated to be 1.71 to 7.09. Three of the nine patients with SPM developed NSCLC. Similarly, the observed incidence of three new lung primaries was significant statistically (X2 = 14.96; df = 1; P = .0001) relative to the average 1981 and 1982 incidence rates in the province of Ontario. The relative risk (observed-toexpected ratio) was calculated as 6.83 for this group of patients, with a 95% confidence interval calculated to be 1.41 to 19.95.
Table 4. Characteristics of Patients With Synchronous SPMs 1 Year After the Diagnosis of SCLC Treatment
Patient Attributes Sex/Age (years)
Disease
Chemotherapy
Duration (months)
1
M/60
ED
CAV
3
2 3 4 5 6 7 8 9 10 11
M/54 F/75 M/67 M/64 M/61 M/39 M/74 M/74 M/57 M/60
ED ED LD ED ED LD ED LD LD LD
CAV CAVPT CAV CAB CB CAVPT CAV CAV CAV
Patient No.
6 11 6 4 1 9 NA 6 6 6
Radiotherapy
Response
Local
PG
Local/cranial Cranial Local/cranial Local Local/cranial Local Local Cranial Cranial Local/cranial
PR CR CR PG PR NG PG CR CR CR
Abbreviations: C, cyclophosphamide; A, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH); V, vincristine; P, VP 16 (etoposide); T, cisplatin; B, bleomycin; M, methotrexate; NA, not applicable; LD, limited disease; ED, extensive disease; M, male; F, female.
tients with secondary lung tumors (anaplastic and multicentric SCLC), two patients with prostatic adenocarcinoma, two patients with gastrointestinal malignancies that included the rectum (patient no. 3 with third primary malignancy) and adenocarcinoma of the pancreas, one patient each with anaplastic testicular carcinoma and Kaposi's sarcoma, and three patients with basal cell carcinoma. In total seven patients died as a result of the primary SCLC, one because of the second malignancy (patient no. 6, adenocarcinoma of the pancreas), and one because of other medical complications (patient no. 4, gastrointestinal bleeding). Two patients with basal cell carcinoma were alive at 4 and 29 months
Table 5. SPMs During the First Year After the Diagnosis of SCLC Follow-Up
Management Patient No.
Months From SCLC to SPM
Type of SPM
Treatment
Response
Chemotherapy Chemotherapy Chemotherapy Surgery Surgery
PG PG PG PG PG
None None Surgery None Surgery RT RT
PG PG PG PG PG PG
1 2 3
1 1 3
4
7
Leukemia (CML) Lung (anaplastic) Lung (SCLC) Rectum (adenocarcinoma) Prostate (adenocarcinoma)
5 6 7 8 9 10 11
3 7 9 2 1 10 11
Prostate (adenocarcinoma) Pancreas (adenocarcinoma) Testis (anaplastic) Sarcoma (Kaposi's) Skin (basal CA) Skin (basal CA) Skin (basal CA)
Months From SPM/Stotus 4/dead 24/dead 22/dead 2/dead 5/dead 1/dead 4/dead 2/dead 4+/alive 29+/alive 3/dead
Cause of Death SCLC SCLC SCLC Gastrointestinal bleeding SCLC SPM SCLC SCLC SCLC NA SCLC
Abbreviations: RT, radiotherapy; CR, complete response; PR, partial response; PG, progression; NA, not applicable; CA, carcinoma.
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1529
SECOND PRIMARY MALIGNANCIES AND SCLC DISCUSSION
SPMs that included second primary cancers of the lung, hematologic malignancies, and other solid tumors were identified in our survey of patients with SCLC. Based on a subset of this group, we found a significantly higher cumulative risk of developing a second malignancy in patients with SCLC that was comparable to a sample from the normal population at risk. Most patients who developed a SPM within 1 year (synchronous tumor) of diagnosis of SCLC died of SCLC, whereas the cause of death in most of those who developed a second primary tumor subsequently (metachronous tumor) was related to that malignancy. The prognosis of patients with a SPM was related to the specific type of malignancy; cases of secondary leukemia were uniformly fatal regardless of treatment. Extrapulmonary solid malignancies entailed a similar grave prognosis. The highest probability of survival after diagnosis of a SPM (excluding skin tumors) was demonstrated in patients who developed a SPM in the lung. A variety of extrapulmonary solid SPMs have been described previously at intervals that ranged from 1 to 10 years after the treatment of SCLC. 27,28 The group
included cancers of the head and neck, gastrointestinal tumors, breast cancer, and renal cell carcinoma. In our review, we have also encountered sarcoma and prostate cancer as SPMs in long-term survivors of SCLC. With some exceptions, most patients died of the SPMs shortly after diagnosis. Several factors may contribute to the emergence of these SPMs. A priori, it is conceivable that similar carcinogenic insults, ie, smoking, may contribute to the emergence of other cancers in patients with SCLC, particularly head and neck tumors. A consensus deletion on the short arm of chromosome 3 described in both renal cell carcinoma and SCLC may support the view that similar genetic defects may operate in the genesis of SCLC and other tumors. 49 Also, familial cancer syndromes 50 may be applicable specifically to patients with SCLC. Finally, the latent sequelae of treatment, either chemotherapy, RT, or combined modality treatment, may be a predisposing factor to several types of cancers, and as such, SPMs may be regarded as a possible complication of therapy. An increased risk of developing metachronous SPMs of the lung in our series was consistent with some20-25 but not all 26 of the reported series in the literature. Both practical and theoretic factors may demonstrate this dichotomy, and, in turn, these should be considered in the computation of the true incidence of SPMs of the lung. Patients with an initial diagnosis of SCLC in
whom initial induction regimens fail may present with apparent NSCLC on rebiopsy. Therefore, it is conceivable that these tumors either failed early detection or originally were misdiagnosed.51 Alternatively, metachronous SPMs of the lung may have evolved as a result of therapy-induced differentiation events. This idea is in fact consistent with a current hypothesis that implicates a common stem cell for all forms of lung cancer. 52 A further problem when considering the incidence of metachronous SPMs of the lung arises with the appearance of new SCLC lesions in the lung. It is difficult to distinguish whether these represent true SPMs or whether they reflect a late metastatic recurrence that results from the original primary lesion. Ideally, we suggest that true SPMs of the lung should be regarded as having a different histology than the primary malignancies and a different site from that of the original tumor. All histologic types of second primary bronchial tumors have been reported.20- 26 Table 6 lists the frequency of these metachronous lung malignancies. As with the other reported cases, the predominant type detected in our survey was squamous cell carcinoma of the lung. In all cases, the second malignancy occurred at a different site from the original SCLC and developed subsequent to the combined modality treatment. Of a total of four patients in our report with metachronous SPM of the lung, two (50%) were alive at 14 and 42 months, respectively, after surgical intervention. The possibility for long-term control in the management of patients with secondary tumors of the lung, therefore, should be pursued. We suggest that the nature of new lesions in the lung, which were detected as early as 1 year after diagnosis of SCLC, or those lesions not responding to standard treatment for SCLC should possibly be investigated further as they may represent metachronous SPMs of the lung and not metastasis and, hence, potentially may be curable. A gradient of abnormalities of the hematopoetic system has been reported in long-term survivors of SCLC with acute leukemia, which represents the extreme of the spectrum. Accumulating evidence confirms Table 6. Second Primary NSCLC After Initial Diagnosis of SCLC Cases Type of Lung Carcinoma 2
Squamous -4,22.39,40 3
Adenocarcinoma-3,39, 23 Large cell , 1 Bronchoalveolar Mucoepidermoid'
No.
%
16
67
4 2 1 1
17 8 4 4
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1530
SAGMAN ET AL were staged as having LD, and 11 were staged as having ED. The average interval from diagnosis of SCLC to detection of acute leukemia was 36 months (range, 15 to 67 months), and the average survival after the diagnosis of leukemia was 3 months (range, 1 to 10 months); 11 of the patients survived less than 1 month. Most reported cases (including all three patients in our study) demonstrated features that commonly were encountered with therapy-associated leukemia, ie, a preleukemic phase, karyotypic abnormalities, and prolonged exposure to leukemogenic agents. These attributes of secondary leukemia in patients with SCLC were consistent with the attributes described for secondary leukemia that were encountered in other cancers. Secondary leukemia, particularly acute nonlymphocytic leukemia, has been described in a variety of malignancies including malignant lymphoma, 55 62 multiple myelo66 67 64 65 ma,63 ovarian carcinoma, , gastrointestinal cancer, ,
the suspicion for therapy-induced chronic myelosuppression determined by the reduction of hematopoetic colony-forming units in the peripheral blood of patients.9 Furthermore, in several long-term survivors, persistent peripheral-blood aneuploidy has been observed with increasing frequency, 53 -54 which is a trend that may precede the development of acute leukemia. More recently, deletion of chromosome 3 (p 1 4 p23) has been described in secondary leukemia that developed in long-term survivors of SCLC. 17 This observation is perhaps the most direct evidence to date for a shared genetic predisposition to these two malignancies. As listed in Table 7, at least 29 cases of secondary leukemia have been reported in patients who were treated for SCLC. The general characteristics of the patients show that the average age was 61 years (range, 42 to 74) at the time of diagnosis of leukemia. No specific sex predilection was noted in the series. Fifteen patients originally
Table 7. Acute Leukemia Following Treatment for SCLC SCLC
Authors Shimp et a129 Newcomer et al"3 Vogelzang et ap13 32 Bradley et al Markman et aP133 Mukerji et a134 Jackson et aPs Rose et 0136 37 Volk et a1 Chak et a138
Pederson-Bjergoard et a128
Gramont et oP Yu et all' Johnson ata142
9
1
Whang-Peng et a '9 Present study
Age (years)/Sex
Stage
Chemotherapy
RT
Duration (months)
59/M 59/F 56/M 65/M 63/F 58/F 47/F 52/M 68/M 63/M 56/M 42/M 52/M 56/M 69/F 71/F 49/F 57/F 74/M 58/F 48/M 64/M 44/F 40/M 68/F 64/F 54/F 59/M 59/F
ED LD LD ED ED LD LD LD ED LD LD ED LD LD ED LD LD LD ED ED LD ED LD ED LD ED
CCnMx CAVMxT CnAVPr CAVMxCnPr CAVEPrBn CAVMxEPrBn CAVMxCnPR CAVE CAVEMx CAVMx CACnMxEPr CAVCnMxEPr CAVCnMxEPr CAVCnMxEPr CnCVE CnAVCMxE CnVCE CnAVCMxE CnAVCMxE CnVCE FMxVC C* CAVMxEHm CAVMxEHm CMxCnAVPr CAECnVMxPr CAVEPt CAVMx CAV
T NS T L T TC NS TC TC TC TC TC C TC NS NS NS NS NS NS T L TC TC L CL TC T TC
23 16 22 27 26 25 13 10 11 24 19 16 18 12 11 13 18 18 18 18 22 12 13 11 7 6
Interval (from SCLC diagnosis to leukemia) (months)
Type of Leukemia
Survivaol (months)
36 24 57 34 38 29 20 10 29 44 40 32 28 39 11 15 19 21 30 43 54 42 22 81 27 36 24 45 45
AML AMML AML ER AML ER AML AMOL AMML AML AML AML AML AMML AML AML AML AML AML AML AMML ER AMML AML ER ER AML AML AML
< 1 10 6 7 9 < 1 < 1 < 1 I 1 < 1 2 < 1 4 3 2 9 7 1 < 1 1 < 1 < 1 < 1 1 < 1 1
Abbreviations: LD, limited disease; ED, extensive disease; M, male; F, female; CYC, cyclophosphamide; CCNU, lomustine; MTX, methotrexate; ADR, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH); VCR, vincristine; ETO, etoposide; PRO, procarbazine; PLT, cisplatin; MIT-C, mitomycin; 5-FU, fluorouracil; AML, acute myelocytic leukemia; AMML, acute myelomonocytic leukemia; ER, erythroleukemia; NS, not stated.
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SECOND PRIMARY MALIGNANCIES AND SCLC
and breast cancer.6 8,69 Secondary leukemia in patients with SCLC was similar to secondary leukemia that manifested subsequent to other malignancies that developed after intensive treatment with chemotherapy, with or without irradiation. The clinical features of patients included a long latent period between the completion of successful induction therapy and the diagnosis of leukemia, the use of intensive induction regimens, which included alkylating agents, and a uniformly poor prognosis after the development of leukemia. These observations may be consistent with the claim that acute nonlymphocytic leukemia represents a late complication of therapy in patients with SCLC. The actuarial risk for the development of secondary leukemia in patients with SCLC has been reported by several investigators.2 8 This risk was unequivocally elevated in all of the reported studies. However, the absolute risk was variable, and ranged between 3% and 40% in the different reports.35,4 142 Several explanations for this discrepancy are possible. First, the population sizes were different, and therefore size sample bias may have been introduced. Second, differences between chemotherapy regimens may contribute to the variable risk. Earlier approaches to the treatment of SCLC with chemotherapy entailed the predominant use of alkylating agents (cyclophosphamide, nitrosoureas), with longer induction durations that included maintenance therapy and, hence, higher cumulative doses. Current approaches used different agents (VP 16, cisplatin), alone or in combination with older regimens and, more recently, for shorter periods. Hence, the type of treatment regimen, the dose of chemotherapy, and the overall duration of treatment may dictate the risk of secondary leukemia. Table 8 enumerates the specific chemotherapeutic agents including exposure to RT administered to the reported cohort of SCLC patients before the development of secondary leukemia. The preponderant use of alkylating agents was demonstrated amply in this group in congruence with the leukemogenic potential of these drugs in other malignancies. It remains to be seen whether agents used more recently in the treatment of SCLC will result in a similar risk for secondary leukemia. Some of these agents have been suspected to contribute 69 to secondary leukemia in other malignancies.6"" As previously mentioned, the increased susceptibility to metachronous SPMs in long-term survivors of SCLC, in part, may be related to the secondary effects of multimodality treatments, By implication, the risk in patients with synchronous tumors in whom the longterm effects of treatment were not substantially incurred
Table 8. Prior Treatment for SCLC in 25 Patients With Secondary
Leukemia No.
RT Yes No Not stated Chemotherapy Average no of agents Range Cyclophosphamide Adrimycin Vincristine Methotrexate CCNU (lomustine) Procarbazine Etoposide Cisplatin Mitomycin 5-FU
7 7 11
6 3-8 24 21 21 19 15 10 8 2 1 1
may be governed by other factors. Indeed it is possible that genetic epigenetic and environmental factors may contribute to multiple synchronous malignancies in patients with SCLC. For example, the long-held familial association between respiratory and gastrointestinal malignancies may be specifically applicable in patients with SCLC.-" Therefore, it is conceivable that genetic or other intrinsic factors may be sufficient to contribute to the emergence of synchronous tumors, whereas the metachronous malignancies may require the contribution of treatment toxicity. In conclusion, we described a series of patients who developed SPMs after the diagnosis of SCLC. We concur with other reports when we suggest that the increased predisposition to metachronous SPMs may relate to the secondary effects of multimodality treatment. The risk of a SPM, therefore, must be considered as a late complication of treatment for SCLC, and should be balanced against the benefits of the current treatment regimens. This risk also must be viewed in the context of recent studies that suggest a genetic basis for the occurrence of second primary cancers in patients with SCLC. In the final analysis, it is particularly devastating to encounter a second malignancy in those few patients who are deemed long-term survivors of SCLC. Nevertheless, the vigilant documentation and study of these second malignancies must continue with vigor because they increase our understanding of the basic biology of the disease and ultimately may have an impact on patients.
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1532
SAGMAN ET AL REFERENCES
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