COMMENTARY Management of Small Cell Lung Cancer: A Summary of the Third International Association for the Study of Lung Cancer Workshop on Small Cell Lung Cancer
The Third Workshop on Small Cell Lung Cancer (SCLC), arranged by the International Association for the Study of Lung Cancer, was held in June 1989 in Elsinore, Denmark. The aim of the workshop sponsors and participants was to reevaluate the management of SCLC and to reach a consensus on each of six key clinical topics. They also hoped to define strategies that will lead to further therapeutic improvements in the 1990s. To meet these goals, 65 colleagues, all of whom are involved in clinical research on SCLC, representing 17 nations and four continents, were invited. The consensus reports, summarized here, are published both as a comprehensive SCLC review by invited participants in a separate issue of Lung Cancer (7) and as a book (2).
Staging and Prognostic Factors Anatomical staging (2) is necessary in clinical practice only if it influences choice of therapy, including local modalities such as chest irradiation or surgery. Staging remains the recommended choice in clinical trials because of the prognostic impact of extent of disease and its influence on interpretation of results. Staging Systems Two systems are available for the staging of SCLC patients, the classical Veterans Administration Lung Cancer Study Group system of "limited" or "extensive" disease and the recently revised TNM system. With regard to the former system, the classification of patients with contralateral mediastinal or supraclavicular nodes and of those with ipsilateral pleural effusions has not been uniformly handled by different investigators. The committee recommends that the limited disease category include patients with disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and/or supraclavicular nodes. In addition, patients with ipsilateral Vol. 82, No. 4, February 21, 1990
pleural effusion are included, independent of whether the cytology is positive or negative. Participants included the contralateral nodes in the mediastinum and the supraclavicular region because the prognostic influence of these metastatic sites is less than that of distant metastases, and also because the revised TNM system groups these patients in stage in and not in stage IV. The extensive disease classification includes all patients with disease sites not eligible for the limited stage. By this definition, the extensive stage is equivalent to stage IV, whereas limited disease is equivalent to stages I—III of the revised TNM system. The revised TNM system should be used for future clinical trials involving local modalities for validation of its use prospectively. Stage IV should also be subdivided into stage IVa with a single extrathoracic organ system afflicted and IVb with disease in more than one extrathoracic organ system. Staging Procedures Detailed recommendations are provided in the consensus report (7). The bone scan is more sensitive than radiographic bone surveys, but positive findings should be confirmed with at least a skeletal x ray to exclude benign foci. Bone marrow biopsy and aspirate are maintained because these procedures, when positive, are unequivocal and do not require further pathologic confirmation. The committee recognizes that this site is rarely the sole metastatic site and that bone marrow involvement has an important negative prognostic impact.
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Paul E. G. Kristjansen,* Heine H. Hansen
Received November 7, 1989; revised December 7, 1989; accepted December 8, 1989. Supported by Asta-Werke AG-Chemische Fabrik, Brackwede, Federal Republic of Germany; Bristol-Myers Squibb Co., New York, NY; and the Danish Medical Research Council. Department of Oncology, Rigshospitalet, Finsen Institute, Copenhagen, Denmark. *Correspondence to: Paul E. G. Kristjansen, M.D., Department of Oncology, Rigshospitalet, Fmsen Institute, DK-2100, Copenhagen, Denmark.
COMMENTARY
263
Prognostic Factors Multivariate analyses on large patient populations have demonstrated that determination of such routine biochemical values as lactate dehydrogenase, albumin, or alkaline phosphatase allow identification of prognostic subgroups. These might be useful for stratification of patients in large trials, but they cannot presently replace anatomical staging as the selection parameter for local treatment modalities.
Chemotherapy Phase II Studies Because of the observed differences in activity of the same agents in previously treated and untreated patients, it is the opinion of the committee that if new agents result in responses from more than 10% of previously treated patients, they should be considered as possibly active and as warranting further investigation. The design and monitoring of phase II trials should be aimed at minimizing two consequences: highly active drugs may not be identified when tested in previously treated patients. Also, untreated patients, who may be given an inactive phase II agent and no further therapy, may have a poor survival. Previously treated patients may still be included, even when the threshold for further study is more than 10% activity, although such a study would require a considerable number of patients to establish that an agent is inactive. Investigators must report what agents have been administered, the duration of and best response to prior treatment, and the time elapsed since therapy was discontinued. In addition, it is important that they state whether the patient was refractory to initial therapy, refractory to secondary therapy, or progressing without receiving initial therapy. Study protocols in untreated patients must include strict eligibility criteria and cross-over or termination criteria. These include definition of the active regimen to be used in nonresponders, evaluation of response after each cycle, and immediate
264
cross-over criteria for patients with progressive disease after any cycle or for stable disease after two cycles; for those with stable disease and decline in performance status or weight, one cycle would suffice. Responding patients need not necessarily switch to another regimen. Patient survival must be reported. The committee believed that no single combination should be regarded as "the standard" regimen. Several current outpatient regimens provide equally acceptable results. The studies reported since 1983 show no advantage for adding agents to established two- to four-drug regimens. The committee noted that the substitution of etoposide for other drugs in existing combinations often is associated with small survival gains, particularly in extensive disease. Alternating Chemotherapy The published randomized phase III trials, during which alternating combination chemotherapy regimens are evaluated, provide no major advantage for existing regimens, although some of the studies showed a small, statistically significant difference in favor of alternating regimens. The committee believed that many of the studies had serious flaws in trial design. The ideal study design would include comparisons of each combination given alone, with cross-over to the other combinations at progression, and the alternating regimens. The lack of true non-crossresistant regimens could explain the lack of major advantages. Maintenance Therapy Different trial designs are applied in studies on maintenance therapy. In some, patients completing their induction chemotherapy received no further treatment, even when the disease was progressing in those who were responding. These trials sometimes demonstrated a small survival advantage for the maintenance arm. In most, investigators have used a reinduction chemotherapy at the time of disease progression, either with the original regimen or with some other combination. In this group of trials, no survival benefit for maintenance chemotherapy was observed. The committee agreed that six cycles of most active regimens are an acceptable standard. Dose Intensity Studies of high-dose chemotherapy, during which patients were supported by autologous bone marrow infusion, have reported considerable toxic effects but no therapeutic advantage, both when given as part of the initial therapy and as late intensification therapy. Further research on dose intensification should not focus on the alkylating agents, etoposide, or methotrexate. However, a further evaluation of high-dose carboplatin was considered reasonable. The data on short-course weekly chemotherapy are still inconclusive, but some phase II studies do appear promising; this strategy should be evaluated in prospective randomized trials. Future Studies and Recommendations Investigators at research institutes are urged to continue to search for new agents and to emphasize agents with new mechanisms rather than analogues of existing ones. Research on time of administration, especially on daily oral etoposide (and teniposide), is warranted. Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Abdominal ultrasound or computerized tomography scan should be applied in the evaluation of abdominal metastasis. Ultrasound-guided fine needle aspiration or biopsy of suspected liver lesions is considered as sensitive as peritoneoscopy with biopsy and should be preferred. Restaging is important not only for the evaluation of response to therapy, but also when the administration of additional treatment, such as prophylactic cranial irradiation, depends on response. It should include a reevaluation of all abnormal pretreatment findings. The use of magnetic resonance imaging in conventional staging and positron emission tomography scan for the detection of brain metastases is under investigation. With regard to bone marrow, several new procedures have detected metastasis in patients who showed no evidence of marrow involvement by conventional pathology, including culture techniques, discontinuous gradient sedimentation, monoclonal antibody staining, and nuclear magnetic resonance imaging. The impact of these findings on the staging and prognosis of patients remains to be defined. The determination of biologic markers in serum such as neutron-specific enolase is still an investigational procedure.
Thoracic Radiation Therapy
Surgery
Treatment of Brain Metastases Recent reports on chemotherapy of brain metastases have raised several new aspects for further investigation. In previously untreated patients with brain metastases, chemotherapy in conventional dosage has produced response rates in the brain comparable to those of other metastatic sites. High-dose chemotherapy to patients with brain relapses has yielded some responses but with considerable adverse effects. Evaluation of current treatment modalities is complicated because of the retrospective nature of most studies. Several factors, relevant to an evaluation of treatment effects, should be clarified. These are: What is the best measure of treatment effects? Which end points should be used? Is the definition of brain relapse based on clinical, radiologic, or autopsy data? What are the extent and potential influence of diagnostic and therapeutic delay and of selection of the patients? Prospective randomized trials are recommended in which chemotherapy alone or chemotherapy plus cranial irradiation would be compared in patients with newly diagnosed SCLC and brain metastases. Treatment of leptomeningeal carcinomatosis is still disappointing. Intrathecal methotrexate remains the most widely used treatment, but information on the use of other cytostatic agents is sparse. High-dose chemotherapy has been used with modest benefit and again with considerable toxic effects. Radiotherapy can be used for bulky disease sites, whereas irradiation to the whole neuroaxis is rarely indicated. No new data on the treatment of spinal cord compression were available for discussion. Sequelae of Central Nervous System Treatment
Patients with very limited small cell lung cancer (TNM stages I and II) have been effectively managed by initial surgery and postoperative chemotherapy. If all were staged according to a TNM system, the small subgroup of patients who might benefit from surgery would be more easily identified. Because information on the results of chemotherapy alone for patients in the lower TNM stages is lacking, the accumulation of such data is warranted.
Information on the quality of life in general and neuropsychologic functions in particular is needed from prospective studies, with adequate pretherapeutic evaluation. Predominantly retrospective reports on patients who received various treatments have raised concern for possible adverse effects following cranial irradiation. Contributions that can be attributed to the various treatment components have not been delineated.
Central Nervous System Metastases
Biological Response Modifiers
Elective Cranial Irradiation
The clinical evaluation of biological response modifiers in SCLC is still in an early phase. Because many uncertainties arise with regard to their biologic effects, clinical trials of these agents should be designed on the basis of in vitro data and xenografts of panels of well-characterized SCLC cell lines.
The available information suggests (a) the fraction of patients in complete response who develop brain metastases as the sole site of recurrent disease, when cranial irradiation is not given, is 10%; {b) cranial irradiation prolongs the period before occult brain metastases become symptomatic but does not prevent their occurrence; and (c) patients receiving it apparently are at greater risk of developing late neuropsychologic complications. Currently, the benefit of cranial irradiation to complete responders is under prospective evaluation in two large multicenter trials. Additional randomized trials may be needed because information on the proper timing and optimal dosage is lacking. Our present knowledge indicates that its clinical use in complete responders is considered optional. For patients who do not obtain Vol. 82, No. 4, February 21, 1990
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Based on the refined biologic hypotheses and new clinical data available to them, participants at an earlier workshop on combined modalities in Le Havre in 1987 (3) agreed that (a) in limited disease, a small but definite benefit of 5%-15% in disease-free survival at 2 years is observed with the addition of thoracic radiation therapy to combination chemotherapy; (b) a dose-response relationship exists up to 45-50 Gy with conventional 2-Gy daily fractions; and (c) acute and late toxicity is increased when thoracic radiation therapy and chemotherapy are given. It was the opinion of the committee that, without the updated data on toxicity and survival from the recent trials, a definitive recommendation for irradiation of the thorax in combined modality regimens cannot be made. Studies of hyperfractionation of irradiation and rapid alternation of combined modality treatments suggest improvements that require confirmation in randomized trials. Further research is needed before investigators can decide whether the target volume should be based on prechemotherapy or postchemotherapy and radiographic findings and how the limits of a patient's tumor should be assigned, given the current imaging techniques. Radiotherapy is generally not indicated for patients with extensive disease. The three principal end points should be long-term localregional control, long-term survival rate, and acute and late toxic effects. Early reports should contain at least an actuarial 2-year survival rate and a quantitative estimate of acute morbidity of the treatment. Subsequent reports should have crude 2-year survival and local-regional control rates, as well as late critical toxic effects in tissue that are also estimated on an actuarial basis.
a complete response, there is little evidence to support the use of cranial irradiation.
Interferons The therapeutic activity of interferons in SCLC has yet to be established in clinical trials. The optimal doses in vivo are difficult for physicians to define, but it is suggested that low-dose intermittent treatment is more likely to be effective. Also, many believe that interferons may be more active when the tumor volume is low. Accordingly, in future trials, investigators should focus on the potential efficacy of interferon in patients who have COMMENTARY
265
achieved a complete remission, so that they can determine whether interferon influences the duration of remissions. Colony-Stimulating Factors
Early and Late Toxicity All therapeutic actions directed against early adverse effects should be precisely recorded in protocols and study reports. Physicians can reduce acute and chronic toxic reactions today by limiting induction chemotherapy to four to six cycles, substituting less toxic agents for patients with underlying medical problems, and avoiding doxorubicin and alkylating agents in simultaneous combination with radiotherapy. Second primary tumors, including "non-small cell" lung cancers, should be sought and histologically confirmed because they are potentially curable by surgery. According to available data, the frequency of acute leukemia is probably increased in SCLC patients, who should be monitored for this complication during long-term follow-up.
Growth Factors This area needs further assessment in the in vitro and xenograft models. Phase I trials should be encouraged in institutions where investigators conducting basic biologic research could include detailed pharmacokinetic studies. Monoclonal Antibodies The current studies include tumor detection in bone marrow specimens, characterization of the endocrine phenotype of tumors that may be of prognostic value, radioimaging, radioimmunotherapy of tumors, and various phase I trials of antibodies. All studies are preliminary and need expansion before further consideration of their role in SCLC therapy is possible.
Toxicity and Supportive Care It is essential that evaluation of toxicity associated with both old and new treatments be done. The committee concluded that
Supportive Care Adequate antibiotic therapy during febrile neutropenic episodes should include aminoglycosides or, alternatively, should consist of third-generation cephalosporins as single agents. Further causative and clinical research into weight loss in SCLC patients is encouraged; at present, no data support any adjuvant therapy directed at this malevolent condition.
References (/) HANSEN HH, KRISTJANSEN PEG, EDS: Third Workshop on Small Cell Lung Cancer. Lung Cancer 5(No. 4-6):l 19-328, 1989 (2) HANSEN HH, KRISTJANSEN PEG, EDS: Management of Small Cell Lung Cancer. Amsterdam, New York: Elsevier, 1990. In press (3) ARRIAGADA R, LE CHEVALIER T: IASLC Workshop on Combined Modalities. Lung Cancer 5:15-17, 1989
NEW!
CHEW OR SNUFF IS REAL BAD STUFF This free four color brochure informs adolescents about the adverse health and social effects of using chewing tobacco and snuff The brochure, with a foldout poster, is available in quantities for schools, health professionals, and community organizations To order, write the National Cancer Institute, Building 31, Room 10A24, Bethesda, MD 20892, or call the Cancer Information Service toll free at 1 800 4 CANCER
266
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Preliminary clinical trials in SCLC have indicated the following results when colony-stimulating factors (CSFs) are given in conjunction with combination chemotherapy: (a) Impairment of white cell counts is less, (b) recovery of white cell nadir appears quicker, (c) CSFs might eliminate treatment delays, and {d) the use of CSFs can avoid a reduction of the drug dose in some patients. The committee stressed that additional information is essential before CSFs are integrated into SCLC trials. First, a doseresponse relationship with chemotherapy in SCLC must be defined, and second, end points of trials, e.g., white cell counts, infective episodes, chemotherapy dose modification, etc., must also be defined. A comparison of the use of CSFs with best supportive care, including prophylactic oral antibiotics, is important. Future trials should also help oncologists define the acute, subacute, and long-term toxicity of CSFs. Finally, the effect CSFs may have on SCLC growth in vivo needs clarification.
fatal toxicity rates of greater than 5% are unacceptable in new treatments unless they are associated with a dramatically greater survival benefit. Quality-of-life data should be included whenever possible in studies in which different treatments are compared.
The Third Workshop on Small Cell Lung Cancer (SCLC), arranged by the International Association for the Study of Lung Cancer, was held in June 1989 in Elsinore, Denmark. The aim of the workshop sponsors and participants was to reevaluate the management of SCLC and to reach a consensus on each of six key clinical topics. They also hoped to define strategies that will lead to further therapeutic improvements in the 1990s. To meet these goals, 65 colleagues, all of whom are involved in clinical research on SCLC, representing 17 nations and four continents, were invited. The consensus reports, summarized here, are published both as a comprehensive SCLC review by invited participants in a separate issue of Lung Cancer (7) and as a book (2).
Staging and Prognostic Factors Anatomical staging (2) is necessary in clinical practice only if it influences choice of therapy, including local modalities such as chest irradiation or surgery. Staging remains the recommended choice in clinical trials because of the prognostic impact of extent of disease and its influence on interpretation of results. Staging Systems Two systems are available for the staging of SCLC patients, the classical Veterans Administration Lung Cancer Study Group system of "limited" or "extensive" disease and the recently revised TNM system. With regard to the former system, the classification of patients with contralateral mediastinal or supraclavicular nodes and of those with ipsilateral pleural effusions has not been uniformly handled by different investigators. The committee recommends that the limited disease category include patients with disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and/or supraclavicular nodes. In addition, patients with ipsilateral Vol. 82, No. 4, February 21, 1990
pleural effusion are included, independent of whether the cytology is positive or negative. Participants included the contralateral nodes in the mediastinum and the supraclavicular region because the prognostic influence of these metastatic sites is less than that of distant metastases, and also because the revised TNM system groups these patients in stage in and not in stage IV. The extensive disease classification includes all patients with disease sites not eligible for the limited stage. By this definition, the extensive stage is equivalent to stage IV, whereas limited disease is equivalent to stages I—III of the revised TNM system. The revised TNM system should be used for future clinical trials involving local modalities for validation of its use prospectively. Stage IV should also be subdivided into stage IVa with a single extrathoracic organ system afflicted and IVb with disease in more than one extrathoracic organ system. Staging Procedures Detailed recommendations are provided in the consensus report (7). The bone scan is more sensitive than radiographic bone surveys, but positive findings should be confirmed with at least a skeletal x ray to exclude benign foci. Bone marrow biopsy and aspirate are maintained because these procedures, when positive, are unequivocal and do not require further pathologic confirmation. The committee recognizes that this site is rarely the sole metastatic site and that bone marrow involvement has an important negative prognostic impact.
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Paul E. G. Kristjansen,* Heine H. Hansen
Received November 7, 1989; revised December 7, 1989; accepted December 8, 1989. Supported by Asta-Werke AG-Chemische Fabrik, Brackwede, Federal Republic of Germany; Bristol-Myers Squibb Co., New York, NY; and the Danish Medical Research Council. Department of Oncology, Rigshospitalet, Finsen Institute, Copenhagen, Denmark. *Correspondence to: Paul E. G. Kristjansen, M.D., Department of Oncology, Rigshospitalet, Fmsen Institute, DK-2100, Copenhagen, Denmark.
COMMENTARY
263
Prognostic Factors Multivariate analyses on large patient populations have demonstrated that determination of such routine biochemical values as lactate dehydrogenase, albumin, or alkaline phosphatase allow identification of prognostic subgroups. These might be useful for stratification of patients in large trials, but they cannot presently replace anatomical staging as the selection parameter for local treatment modalities.
Chemotherapy Phase II Studies Because of the observed differences in activity of the same agents in previously treated and untreated patients, it is the opinion of the committee that if new agents result in responses from more than 10% of previously treated patients, they should be considered as possibly active and as warranting further investigation. The design and monitoring of phase II trials should be aimed at minimizing two consequences: highly active drugs may not be identified when tested in previously treated patients. Also, untreated patients, who may be given an inactive phase II agent and no further therapy, may have a poor survival. Previously treated patients may still be included, even when the threshold for further study is more than 10% activity, although such a study would require a considerable number of patients to establish that an agent is inactive. Investigators must report what agents have been administered, the duration of and best response to prior treatment, and the time elapsed since therapy was discontinued. In addition, it is important that they state whether the patient was refractory to initial therapy, refractory to secondary therapy, or progressing without receiving initial therapy. Study protocols in untreated patients must include strict eligibility criteria and cross-over or termination criteria. These include definition of the active regimen to be used in nonresponders, evaluation of response after each cycle, and immediate
264
cross-over criteria for patients with progressive disease after any cycle or for stable disease after two cycles; for those with stable disease and decline in performance status or weight, one cycle would suffice. Responding patients need not necessarily switch to another regimen. Patient survival must be reported. The committee believed that no single combination should be regarded as "the standard" regimen. Several current outpatient regimens provide equally acceptable results. The studies reported since 1983 show no advantage for adding agents to established two- to four-drug regimens. The committee noted that the substitution of etoposide for other drugs in existing combinations often is associated with small survival gains, particularly in extensive disease. Alternating Chemotherapy The published randomized phase III trials, during which alternating combination chemotherapy regimens are evaluated, provide no major advantage for existing regimens, although some of the studies showed a small, statistically significant difference in favor of alternating regimens. The committee believed that many of the studies had serious flaws in trial design. The ideal study design would include comparisons of each combination given alone, with cross-over to the other combinations at progression, and the alternating regimens. The lack of true non-crossresistant regimens could explain the lack of major advantages. Maintenance Therapy Different trial designs are applied in studies on maintenance therapy. In some, patients completing their induction chemotherapy received no further treatment, even when the disease was progressing in those who were responding. These trials sometimes demonstrated a small survival advantage for the maintenance arm. In most, investigators have used a reinduction chemotherapy at the time of disease progression, either with the original regimen or with some other combination. In this group of trials, no survival benefit for maintenance chemotherapy was observed. The committee agreed that six cycles of most active regimens are an acceptable standard. Dose Intensity Studies of high-dose chemotherapy, during which patients were supported by autologous bone marrow infusion, have reported considerable toxic effects but no therapeutic advantage, both when given as part of the initial therapy and as late intensification therapy. Further research on dose intensification should not focus on the alkylating agents, etoposide, or methotrexate. However, a further evaluation of high-dose carboplatin was considered reasonable. The data on short-course weekly chemotherapy are still inconclusive, but some phase II studies do appear promising; this strategy should be evaluated in prospective randomized trials. Future Studies and Recommendations Investigators at research institutes are urged to continue to search for new agents and to emphasize agents with new mechanisms rather than analogues of existing ones. Research on time of administration, especially on daily oral etoposide (and teniposide), is warranted. Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Abdominal ultrasound or computerized tomography scan should be applied in the evaluation of abdominal metastasis. Ultrasound-guided fine needle aspiration or biopsy of suspected liver lesions is considered as sensitive as peritoneoscopy with biopsy and should be preferred. Restaging is important not only for the evaluation of response to therapy, but also when the administration of additional treatment, such as prophylactic cranial irradiation, depends on response. It should include a reevaluation of all abnormal pretreatment findings. The use of magnetic resonance imaging in conventional staging and positron emission tomography scan for the detection of brain metastases is under investigation. With regard to bone marrow, several new procedures have detected metastasis in patients who showed no evidence of marrow involvement by conventional pathology, including culture techniques, discontinuous gradient sedimentation, monoclonal antibody staining, and nuclear magnetic resonance imaging. The impact of these findings on the staging and prognosis of patients remains to be defined. The determination of biologic markers in serum such as neutron-specific enolase is still an investigational procedure.
Thoracic Radiation Therapy
Surgery
Treatment of Brain Metastases Recent reports on chemotherapy of brain metastases have raised several new aspects for further investigation. In previously untreated patients with brain metastases, chemotherapy in conventional dosage has produced response rates in the brain comparable to those of other metastatic sites. High-dose chemotherapy to patients with brain relapses has yielded some responses but with considerable adverse effects. Evaluation of current treatment modalities is complicated because of the retrospective nature of most studies. Several factors, relevant to an evaluation of treatment effects, should be clarified. These are: What is the best measure of treatment effects? Which end points should be used? Is the definition of brain relapse based on clinical, radiologic, or autopsy data? What are the extent and potential influence of diagnostic and therapeutic delay and of selection of the patients? Prospective randomized trials are recommended in which chemotherapy alone or chemotherapy plus cranial irradiation would be compared in patients with newly diagnosed SCLC and brain metastases. Treatment of leptomeningeal carcinomatosis is still disappointing. Intrathecal methotrexate remains the most widely used treatment, but information on the use of other cytostatic agents is sparse. High-dose chemotherapy has been used with modest benefit and again with considerable toxic effects. Radiotherapy can be used for bulky disease sites, whereas irradiation to the whole neuroaxis is rarely indicated. No new data on the treatment of spinal cord compression were available for discussion. Sequelae of Central Nervous System Treatment
Patients with very limited small cell lung cancer (TNM stages I and II) have been effectively managed by initial surgery and postoperative chemotherapy. If all were staged according to a TNM system, the small subgroup of patients who might benefit from surgery would be more easily identified. Because information on the results of chemotherapy alone for patients in the lower TNM stages is lacking, the accumulation of such data is warranted.
Information on the quality of life in general and neuropsychologic functions in particular is needed from prospective studies, with adequate pretherapeutic evaluation. Predominantly retrospective reports on patients who received various treatments have raised concern for possible adverse effects following cranial irradiation. Contributions that can be attributed to the various treatment components have not been delineated.
Central Nervous System Metastases
Biological Response Modifiers
Elective Cranial Irradiation
The clinical evaluation of biological response modifiers in SCLC is still in an early phase. Because many uncertainties arise with regard to their biologic effects, clinical trials of these agents should be designed on the basis of in vitro data and xenografts of panels of well-characterized SCLC cell lines.
The available information suggests (a) the fraction of patients in complete response who develop brain metastases as the sole site of recurrent disease, when cranial irradiation is not given, is 10%; {b) cranial irradiation prolongs the period before occult brain metastases become symptomatic but does not prevent their occurrence; and (c) patients receiving it apparently are at greater risk of developing late neuropsychologic complications. Currently, the benefit of cranial irradiation to complete responders is under prospective evaluation in two large multicenter trials. Additional randomized trials may be needed because information on the proper timing and optimal dosage is lacking. Our present knowledge indicates that its clinical use in complete responders is considered optional. For patients who do not obtain Vol. 82, No. 4, February 21, 1990
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Based on the refined biologic hypotheses and new clinical data available to them, participants at an earlier workshop on combined modalities in Le Havre in 1987 (3) agreed that (a) in limited disease, a small but definite benefit of 5%-15% in disease-free survival at 2 years is observed with the addition of thoracic radiation therapy to combination chemotherapy; (b) a dose-response relationship exists up to 45-50 Gy with conventional 2-Gy daily fractions; and (c) acute and late toxicity is increased when thoracic radiation therapy and chemotherapy are given. It was the opinion of the committee that, without the updated data on toxicity and survival from the recent trials, a definitive recommendation for irradiation of the thorax in combined modality regimens cannot be made. Studies of hyperfractionation of irradiation and rapid alternation of combined modality treatments suggest improvements that require confirmation in randomized trials. Further research is needed before investigators can decide whether the target volume should be based on prechemotherapy or postchemotherapy and radiographic findings and how the limits of a patient's tumor should be assigned, given the current imaging techniques. Radiotherapy is generally not indicated for patients with extensive disease. The three principal end points should be long-term localregional control, long-term survival rate, and acute and late toxic effects. Early reports should contain at least an actuarial 2-year survival rate and a quantitative estimate of acute morbidity of the treatment. Subsequent reports should have crude 2-year survival and local-regional control rates, as well as late critical toxic effects in tissue that are also estimated on an actuarial basis.
a complete response, there is little evidence to support the use of cranial irradiation.
Interferons The therapeutic activity of interferons in SCLC has yet to be established in clinical trials. The optimal doses in vivo are difficult for physicians to define, but it is suggested that low-dose intermittent treatment is more likely to be effective. Also, many believe that interferons may be more active when the tumor volume is low. Accordingly, in future trials, investigators should focus on the potential efficacy of interferon in patients who have COMMENTARY
265
achieved a complete remission, so that they can determine whether interferon influences the duration of remissions. Colony-Stimulating Factors
Early and Late Toxicity All therapeutic actions directed against early adverse effects should be precisely recorded in protocols and study reports. Physicians can reduce acute and chronic toxic reactions today by limiting induction chemotherapy to four to six cycles, substituting less toxic agents for patients with underlying medical problems, and avoiding doxorubicin and alkylating agents in simultaneous combination with radiotherapy. Second primary tumors, including "non-small cell" lung cancers, should be sought and histologically confirmed because they are potentially curable by surgery. According to available data, the frequency of acute leukemia is probably increased in SCLC patients, who should be monitored for this complication during long-term follow-up.
Growth Factors This area needs further assessment in the in vitro and xenograft models. Phase I trials should be encouraged in institutions where investigators conducting basic biologic research could include detailed pharmacokinetic studies. Monoclonal Antibodies The current studies include tumor detection in bone marrow specimens, characterization of the endocrine phenotype of tumors that may be of prognostic value, radioimaging, radioimmunotherapy of tumors, and various phase I trials of antibodies. All studies are preliminary and need expansion before further consideration of their role in SCLC therapy is possible.
Toxicity and Supportive Care It is essential that evaluation of toxicity associated with both old and new treatments be done. The committee concluded that
Supportive Care Adequate antibiotic therapy during febrile neutropenic episodes should include aminoglycosides or, alternatively, should consist of third-generation cephalosporins as single agents. Further causative and clinical research into weight loss in SCLC patients is encouraged; at present, no data support any adjuvant therapy directed at this malevolent condition.
References (/) HANSEN HH, KRISTJANSEN PEG, EDS: Third Workshop on Small Cell Lung Cancer. Lung Cancer 5(No. 4-6):l 19-328, 1989 (2) HANSEN HH, KRISTJANSEN PEG, EDS: Management of Small Cell Lung Cancer. Amsterdam, New York: Elsevier, 1990. In press (3) ARRIAGADA R, LE CHEVALIER T: IASLC Workshop on Combined Modalities. Lung Cancer 5:15-17, 1989
NEW!
CHEW OR SNUFF IS REAL BAD STUFF This free four color brochure informs adolescents about the adverse health and social effects of using chewing tobacco and snuff The brochure, with a foldout poster, is available in quantities for schools, health professionals, and community organizations To order, write the National Cancer Institute, Building 31, Room 10A24, Bethesda, MD 20892, or call the Cancer Information Service toll free at 1 800 4 CANCER
266
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of New South Wales on July 10, 2015
Preliminary clinical trials in SCLC have indicated the following results when colony-stimulating factors (CSFs) are given in conjunction with combination chemotherapy: (a) Impairment of white cell counts is less, (b) recovery of white cell nadir appears quicker, (c) CSFs might eliminate treatment delays, and {d) the use of CSFs can avoid a reduction of the drug dose in some patients. The committee stressed that additional information is essential before CSFs are integrated into SCLC trials. First, a doseresponse relationship with chemotherapy in SCLC must be defined, and second, end points of trials, e.g., white cell counts, infective episodes, chemotherapy dose modification, etc., must also be defined. A comparison of the use of CSFs with best supportive care, including prophylactic oral antibiotics, is important. Future trials should also help oncologists define the acute, subacute, and long-term toxicity of CSFs. Finally, the effect CSFs may have on SCLC growth in vivo needs clarification.
fatal toxicity rates of greater than 5% are unacceptable in new treatments unless they are associated with a dramatically greater survival benefit. Quality-of-life data should be included whenever possible in studies in which different treatments are compared.
