Search

Many studies in small cell carcinoma of the lung (SCCL) have demonstrated a high response rate and a potential for cure in a subset of patients. Combination chemotherapy, the cornerstone of all treatment for SCCL, can produce up to 10% long-term, disease-free survival among all patients with SCCL and greater than or equal to 20% survival among patients who present with limited disease. Significant improvements in survival have occurred in all stages of disease, and further investigative efforts are necessary to improve the complete remission rate, the duration of response, and the percentage of long-term, disease-free survivors. The current report, based on the workshop on SCCL held in Ireland under the auspices of the International Association for the Study of Lung Cancer, reviews the current state of the art for chemotherapy and presents potential future directions.

Thirty-two patients with small cell carcinoma of the lung were given chest radiotherapy to progressive intrathoracic tumor after failing chemotherapy. Two-thirds of these patients received split-course treatment at a dose of 4000 rad in 10 fractions. Sixteen of 25 evaluable patients (64%) had an objective response, but only five responders did not progress within the port during life. Median time to local progression was 16 weeks. Two patients, one of whom was given concurrent chemotherapy, survived greater than 18 months, and one is free of disease at 31+ months. Short-term palliation of chest disease and occasional long-term survival are possible with this regimen, although most patients will die with systemic disease within several months. Small cell carcinoma of the lung is less responsive to irradiation as second-line therapy than as initial therapy, but doses of greater than or equal to 4000 rad can offer symptomatic relief in many cases and, rarely, survival beyond 18 months.

Prophylactic brain irradiation significantly reduces the proportion of patients with small cell carcinoma of the lung (SCCL) who develop brain metastases. Therapeutic brain irradiation could be used instead of prophylactic irradiation if it could be delivered promptly after diagnosis of intracranial spread and if it were highly effective. Forty of 188 patients with SCCL seen in the Medical College of Wisconsin Affiliated Hospitals had brain metastases either at initial diagnosis (23 patients) or after treatment (17 patients). Irradiation was administered to the whole brain at doses ranging from 3000 rads in 2 weeks to 4000 rads in 3 weeks. Neurologic function was the same for those patients with initial and delayed metastases and did not correlate with survival. Response to irradiation affected survival. After the diagnosis of brain metastases, survival was the same whether metastases were initially present or were delayed. Eighteen (45%) of the patients died from brain metastases and two (5%) are alive following disease recurrence in the brain. Increasing survival with SCCL due to effective chemotherapy is associated with an increasing failure rate in the brain which may eventually reach the 50% rate found at autopsy. Therapeutic brain irradiation is not sufficiently effective to preclude prophylactic irradiation.

The optimal use of "prophylactic" cranial irradiation (PCI) in patients with small cell lung cancer remains undetermined. This study reviews the impact of PCI, given at complete remission (CR), on neurologic relapse in 172 consecutive patients with small cell lung cancer treated in three sequential chemotherapy protocols at the University of Maryland Cancer Center. In the first study of 38 patients, none received PCI. In the second study of 109 patients, the first 28 achieving CR were randomized to 3000 rad of PCI in ten fractions (PCI+) or to observation (PCI-). Thereafter, based on interim analysis, all patients achieving CR received PCI. In the third study, to date, 25 patients achieving CR have received PCI. Overall, 169 patients were evaluable for neurologic relapse, and 30 of 90 patients achieving CR received PCI. Among all patients with CR, with adjustment for disease extent, there was a significant delay to any neurologic relapse (P = 0.01) and cerebral metastases (P = 0.02) for PCI+ compared to PCI- patients. Among PCI- patients with CR, cerebral metastases alone occurred in 28% as the sole site and in 33% as the initial site, whereas cerebral relapse occurred prior to systemic relapse in only one PCI+ patient with CR. Patient survival however, was not significantly altered by PCI. PCI at CR confers effective and worthwhile local control in the CNS, especially during periods of systemic response, and a small percentage of patients may benefit. Systemic drug resistance still determines overall survival.

Fifty-six patients with small cell carcinoma of the lung were treated with a two-cyclic induction course of hexamethylmelamine, vincristine, doxorubicin, and cyclophosphamide. Patients with limited disease (LD) who responded and patients with extensive disease (ED) who had a complete response received prophylactic whole-brain radiotherapy, as well as radiotherapy to thoracic and abdominal sites of disease. Concurrently with radiotherapy, consolidation chemotherapy was given with doxorubicin, cyclophosphamide, methotrexate, and etoposide. The complete response rate was 35% for ED patients and 68% for LD patients. The median survival time for complete responders was 54 weeks for ED patients and 65 weeks for LD patients. The toxicity of the program was moderate, and the effectiveness was comparable to that of other reported combined-modality treatment programs.

From March 1982, 31 patients with stage IV non-oat cell lung cancer have been treated. Radiotherapy was given as three 2.00-Gy fractions on Days 1 and 2, 8 and 9, 22 and 23, and 29 and 30, for a total dose of 48 Gy over a 30-32-day treatment period. A three-drug combination of cyclophosphamide (400 mg/m2), doxorubicin (17 mg/m2), and methotrexate (15 mg/m2) was given on Days 3 and 24 and repeated thereafter every 21 days. Three of 31 evaluable patients (10%) achieved objective complete response and 18 of 31 (58%) achieved partial response (ie, regression of 50%-90%), while no change or disease progression was observed in ten of 31 (32%). The overall response rate in our study was 68%, which is a response much higher than other results in extensive disease. However, controlled trials will be necessary to definitively establish the superiority of this regimen to conventional trials. There was a significant shift of performance status towards higher values after treatment: 12 of the 27 patients classified in the 70-80 Karnofsky category before treatment moved to the higher category, 13 remained in the same status, and only two shifted to the worst category, indicating that the treatment had been effective in giving patients a better quality of life during their survival. The median survival was 35 weeks for the entire group of patients and 44 and 15 weeks for the responders and nonresponders, respectively. One of the primary findings of this pilot study was the ability to give one course of 12 Gy of radiation as multiple fractions per day during each of the first 2 weeks of treatment alternated with one course of chemotherapy, with most patients having very mild or no side effects. Giving multiple daily fractions greater than or equal to 4 hours apart permits the delivery of a large amount of irradiation over a short time period (ie, 1-2 days) within the limits of normal tissue toxicity. Increasing the recovery time of radiotherapy by alternation with chemotherapy offers the possibility of increasing the total radiation dose beyond the upper limits now considered feasible by conventional radiation schedules for induction therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

The Southwest Oncology Group performed a study for patients with extensive small cell lung cancer in which two hypotheses were tested: that combined alkylating agents for induction might improve the initial response rate; and that multiple-site, involved-field consolidation with irradiation in patients with response to chemotherapy might further improve response quality and duration. A regimen of combined alkylating agents plus vincristine [carmustine, thiotepa, vincristine, and cyclophosphamide (BTOC)] was compared to our standard program of cyclophosphamide, doxorubicin, and vincristine (CAV). Patients with bone marrow metastases and/or disseminated bone metastases were randomized to BTOC or CAV as initial induction therapy, but received no multiple-field irradiation afterward. Among 189 such patients, the overall response rates were similar (48% to BTOC and 61% to CAV, with complete remission in 5% and 15%, respectively). Toxic effects were also comparative, with 23% sustaining life-threatening or fatal complications on BTOC and 16% on CAV. Median survival (5.9 and 7 months for BTOC and CAV, respectively) and overall survival were not different, and are superimposable upon our previously reported results with CAV alone. For patients with no evidence of bone marrow involvement and no metastases identified beyond the confines of ipsilateral hemithorax, liver, and brain, the plan of therapy consisted of induction chemotherapy (BTOC or CAV) every 3 weeks for three cycles, followed by multiple-field irradiation consolidation to sites of prior involvement. Among 239 such patients, response rates to therapy initiated with BTOC and CAV were also similar: 54% for BTOC and 62% for CAV, with complete response in 16% and 13%, respectively. However, the program of BTOC followed by multiple-site irradiation was associated with a higher incidence of severe or life-threatening thrombocytopenia (23% versus 8% for CAV), accounted for almost entirely by patients receiving hepatic irradiation after chemotherapy, among whom the incidence of this complication (grade 3 or 4) was 76% and 14%, respectively. Other toxic effects, including granulocytopenia, were comparable. With the exception of thrombocytopenia in the cited subgroup, multiple-field irradiation consolidation proved feasible and tolerable, with improved quality of response evident after its initiation in 24% of 135 patients. However, a similar proportion developed disease progression during or shortly after radiation therapy, and the median survival of patients who received irradiation was only 9 months (7 months from the start of consolidation).(ABSTRACT TRUNCATED AT 400 WORDS)

Encouraging results of the combination of upper hemibody irradiation (UHBI) and local chest irradiation (LCI) combined withh standard-dose chemotherapy in patients with extensive small cell bronchogenic carcinoma led us to a second pilot study utilizing the same radiation program combined wit high-dose induction chemotherapy. Fourteen patients with small cell bronchogenic carcinoma, five with extensive disease and nine with localized disease, were treated with cyclophosphamide (1.5 g/m2 iv, Days 1 and 22), lomustine (70 mg/m2 orally, Day 1), and methotrexate (15 mg/m2 twice weekly during Weeks 2, 3, 5, and 6). UHBI (600 rads) was given during Week 6 in a single dose and LCI was given during Week 7 (2000 rads/five fractions) to the tumor and mediastinum. Maintenance chemotherapy began in Week 12 with cyclophosphamide (700 mg/m2 iv every 3 weeks) and lomustine (70 mg/m2 orally every 6 weeks). Twelve patients were evaluable for response and toxicity (eight with limited disease). There were three complete response and seven partial responses after induction chemotherapy. After completion of the consolidation radiation therapy, all 12 patients had a response: six complete responses and six partial responses. Acute toxic effects included nausea and vomiting in eight patients, fever in five, and hypotension and angina in one. Subacute toxic effects included nausea, vomiting, and dehydration in two patients who required hospitalization, prolonged aplasia in one, reversible radiation esophagitis in three. Three patients had radiation pneumonitis including one with bilateral diffuse disease that led to death from respiratory failure. Only two of 12 patients received their maintenance therapy on schedule. Treatment failures occurred within the LCI field in seven patients and in distant metastatic sites in six. The median time to first relapse was 7 months and the median survival was 9 months. Because of toxicity, treatment delays, and poor survival in this group of patients, we cannot recommend this combined modality approach.

Twenty-three patients with oat cell cancer of the lung were randomized to receive chemotherapy with POCC (procarbazine, 100 mg/m2/day orally, Days 1-14; vincristine, 2 mg iv, Days 1 and 8; cyclophosphamide, 600 mg/m2 iv, Days 1 and 8; and CCNU, 60 mg/m2 orally, Day 1) or COM (cyclophosphamide, 2000 mg/m2 iv, Day 1; vincristine, 2 mg iv, Day 1; and methotrexate, 30 mg/m2 iv, Day 15). After two to three cycles of chemotherapy, all patients were to receive radiotherapy to initially involved sites and then have chemotherapy continued. Patients treated with POCC had a median survival of 14 months vs 10 months for those treated with COM (P = 0.055). Eight of 15 first sites of relapse were intrathoracic and five of these eight had received radiotherapy to that site. Six central nervous system (CNS) failures were evenly divided between the two chemotherapy programs. Thus, the CNS penetration of procarbazine and CCNU in the POCC combination did not prevent CNS relapse. All future patients will receive prophylactic brain radiotherapy.

Prognostic factors were studied in 224 patients with small cell carcinoma of the lung entered in a Cancer and Leukemia Group B protocol. Extent of disease was the major predictor of complete remission (CR) frequency and survival greater than 2 years, with CR rates being 40% for patients with limited disease (LD) and 10% for those with extensive disease. Patients who were classified as having extensive disease on the basis of isotope scan evidence of a single bone metastasis had survival characteristics and response rates similar to those of patient with LD. A multivariate analysis of various factors, which may influence overall survival, reveals a good-risk population to be defined as having LD and an initial performance status less than or equal to 2, with or without a single metastatic focus on bone scan. Furthermore, this risk definition fairly successfully predicted which patients had the greatest chance of achieving a CR (45%). Age less than 70 years was shown to be a significantly adverse factor on survival in these multivariate analyses after adjusting for risk. When long-term survivors (less than 24 months) were investigated by multivariate analyses, the new risk system was found to be the only significant pretreatment factor. Interestingly, sex was the next marginally influential factor on long-term survival. Future stratification by these risk categories should lead to more homogeneous subgroups for comparison of different therapeutic approaches and should provide some indication as to how much better the newer treatment program is within each risk group.

The previously established roles of radiotherapy in the management of small cell anaplastic carcinoma of the lung have changed with the development of improved chemotherapy. A group of the International Association for the Study of Lung Cancer has concluded that while there is established evidence that the addition of chemotherapy improves the results of radiation therapy, the value of the addition of loco-regional radiation therapy to chemotherapy is uncertain and more difficult to assess. No advantage in short-term (median) survival has been shown in randomized studies, but current data suggest a possible advantage in long-term control of loco-regional disease. Further results of prospective trials are needed to resolve this question. Prophylactic cranial irradiation reduces the incidence of cerebral metastases but so far has not resulted in improved survival. Pending the results of further randomized studies, its routine use in all patients is not advocated. The palliative role of radiation therapy is valuable in symptomatic treatment. Various current modifications of technique to improve the results of conventional radiation treatments with an altered fractionation schedule and use of sensitizers and large fields are not believed to show major advantages. The clear documentation of treatment details and the definition of the criteria for the assessment of results are important if further comparisons of results are to be made possible. In particular, the need for reporting long-term survival at 2 years in contrast to the more usual median survival time is stressed.

Methotrexate (MTX) is an active agent in both non-small cell and small cell anaplastic lung cancer. A 26% partial response rate was obtained in 27 previously untreated patients with squamous cell bronchogenic tumors treated with 24-hour infusions of MTX at 400 mg/m2. Responses were seen predominantly in extrathoracic sites. In 38 evaluable patients with small cell carcinomas, 24-hour infusions of MTX at 200 mg/m2 in combination with cyclophosphamide and CCNU produced a 43% complete remission (CR) rate for a median survival of 62 weeks. Fifty-six percent of the CR's were seen in patients with extensive disease.

A total of 116 patients with small cell lung cancer were randomized to receive either: cyclophosphamide, 750 mg/m2, doxorubicin, 50 mg/m2, and vincristine, 2 mg iv (Regimen A), or the same drugs plus etoposide, 100 mg/m2 iv daily for 2 days (Regimen B) every 3 weeks. Complete responders received whole-brain radiation therapy. The overall response rates were 50% for Regimen A and 65% for Regimen B (P less than 0.05). The complete response rates were 18% for Regimen A and 44% for Regimen B (P less than 0.01). For patients with limited disease, the complete responders were 35% on Regimen A and 52% on Regimen B (P = 0.26); for those with extensive disease, the complete responders were 0% on Regimen A and 35% on Regimen B (P = 0.002). The median survival for complete responders was 17 months on Regimen A and 20 months on Regimen B. The difference is not statistically significant. Toxicity was tolerable for both groups; however, it was greater for the etoposide arm. We conclude that although etoposide improves the overall response rates in patients with small cell lung cancer, especially those with extensive disease, the addition of this drug does not lead to improved survival.

External irradiation with the greatest technical sophistication available is indicated in all patients with inoperable non-small cell carcinoma of the lung confined to the primary site and to regional lymph nodes including the ipsilateral supraclavicular nodes. Irradiation with moderately high doses results in responses in 40%-65% of all patients. With irradiation to a level of at least 6000 rad in 30 fractions in 6 weeks, greater than 60% of patients never fail in the chest. Some of these patients become long-term, disease-free survivors. Until it is possible clearly to predict those patients who do not respond and thereby to justify an approach other than thoracic irradiation, it is necessary to offer radiation therapy to all of these patients. Since local control is far from satisfactory, one can certainly justify investigating new approaches, including further increases of the total dose, altered fractionation schemes, addition of radiosensitizers, and high linear energy transfer radiations. Since distant metastases frequently appear in spite of thorough pretreatment evaluations, one can also justify investigating the addition of systemic agents, both cytotoxic drugs and biologic response modifiers. Benefit from these systemic approaches may be completely masked, even in patients with disseminated disease, by failure to prevent complications and death due to the intrathoracic tumor.

Fifty-five patients with small cell carcinoma of the lung (SCCL) were treated with alternating courses of CAV (cyclophosphamide, doxorubicin, and vincristine) and VHM (etoposide, hexamethylmelamine, and methotrexate) at 21-day intervals. One regimen contained high-dose cyclophosphamide (2400 mg/m2 iv), while the second contained an increased dose of etoposide (250 mg/m2 iv on Days 1-3). Patients achieving a complete response (CR) received a minimum of six cycles of therapy or two cycles beyond the achievement of CR. These patients as well as those with partial response with disease limited to the lung then received radiotherapy to the lung primary (5100 rads in 300-rad fractions) as well as prophylactic cranial radiotherapy (3000 rads in 300-rad fractions). All therapy was subsequently stopped until relapse. There were no deaths during the aplastic periods induced by the intensive chemotherapy. CR was achieved in 57% of the patients and partial response was achieved in 38%. The actuarial median survival for the 27 patients with extensive disease was 13.5 months and for the 28 patients with limited disease was 13 months. Survival at this point appears comparable to less intensive regimens in which maintenance therapy was given. We conclude that prolonged intensive induction chemotherapy in SCCL is well-tolerated. Studies are needed to examine in a randomized trial the role of alternating combinations and maintenance therapy in SCCL.

Forty-seven patients with squamous cell or small cell lung cancer (28 [60%] of whom had cardiac disease too severe to permit the use of doxorubicin) were treated with cyclophosphamide and VP-16-213 with or without cisplatin. Four of 11 patients with squamous cell (36%) and 19 of 24 patients with small cell (79%) cancers had tumor regressions (eight complete regressions) on the three-drug regimen. Median survival times for the 31 patients with small cell lung cancer were 9 months for those with extensive disease and 12.2 months for those with limited disease. The data suggest that the roles of VP-16-213 and cisplatin need further evaluation in these cell types and that doxorubicin may not be mandatory for successful treatment of squamous cell and small cell lung cancers.

Twenty-seven patients with small cell carcinoma of the lung were treated sequentially with induction chemotherapy (adriamycin and cyclophosphamide), radiation therapy (chest and whole-brain), and then maintenance chemotherapy for 2 years. Twenty responding patients were followed to relapse and patterns of recurrence were observed. This combined treatment resulted in a complete remission rate of 80% and a median survival of 565 days in limited-disease patients. Relapse overwhelmingly occurred in the chest, but patients receiving higher-dose radiation (4000-4500 rads in split-course) had a significant prolongation of time to recurrence compared to patients receiving 3000 rads in a single course of radiation (540 versus 270 days). Despite a long mean survival, only one limited-disease patient relapsed outside of the brain or chest, suggesting that chemotherapy had a good protective effect against micrometastatic disease. Three patients relapsed in the brain at 330, 450, and 520 days, suggesting that in future studies the prophylactic whole-brain radiation (3000 rads) should be intensified.

The problem of brain metastasis from small cell carcinoma (SCC) of the lung has been appreciated for many years, but the magnitude of the problem has been underestimated. Recent studies have shown that the risk of brain metastasis increase as survival is prolonged. Although prophylactic cranial irradiation (PCI) has reduced the frequency of brain metastases, the effect on risk estimates of differences in the periods of observation was not evaluated. From 1974 through 1979, 131 patients with SCC of the lung who had no evidence of brain metastasis by radionuclide or computerized tomographic scan were treated in the Division of Therapeutic Radiology at the Medical College of Wisconsin Affiliated Hospitals. PCI was started in 1977; 57 patients received it and 74 did not. To correct for the differing periods of observation for the two groups, an actuarial calculation of the probability of brain metastasis was used. The calculated rate of clinical failure in the brain for patients who did not receive PCI was 28% at 12 months and 58% at 24 months. The calculated failure rate of the brain for patients who received PCI was 11% at 12 and 24 months. The difference in the probability of brain metastasis between the patients who did or did not receive PCI is highly significant (P less than 0.01). The true benefit of PCI becomes apparent only when the risk of intracranial metastasis is evaluated by methods that correct for incomplete followup. PCI eliminates the progressive increase in the risk of brain metastasis that accompanies increased survival and is important to maximize the probability for cure of patients with SCC.

Improvements in therapy for small cell carcinoma of the lung have been achieved with treatment regimens that result in significant toxicity. The workshop of the International Association for the Study of Lung Cancer focused on the following complications of chemotherapy and radiotherapy: leukopenia and resultant infections, esophagitis, pneumonitis and pulmonary fibrosis, cardiac toxicity, second malignancies, neurologic complications, and psychosocial effects. The data regarding the incidence and management of these complications are briefly reviewed, and recommendations for further studies are noted.

Thirty-nine of 225 patients with small cell lung cancer developed brain metastases after the initiation of chemotherapy. Treatment with high-dose dexamethasone in all 39 patients and cranial irradiation in 32 patients resulted in a complete neurological recovery in only eight of 39 patients (20%). Twenty-one of 39 patients (53%) failed to derive lasting benefit from their palliative treatment. Thirteen of 24 patients with limited disease with cranial relapse had no clinical evidence of other distant metastases prior to death and in these patients the CNS disease was an important cause of morbidity. On the basis of this study, it appears that palliative treatment of overt cranial metastases is relatively unsuccessful and that patients with limited disease represent a group with much to gain from effective prophylactic cranial irradiation.

A trial of "neoadjuvant" cisplatin-etoposide and radiation therapy was conducted by the Radiation Therapy Oncology Group for non-small cell carcinoma of the lung limited to the thorax. Thirty evaluable patients were studied: two achieved complete response and four achieved partial response after chemotherapy. All patients underwent radiation therapy as planned, with no unusual acute reactions. Sixteen patients had local failure, and 13 had distant metastasis. Twenty-seven patients are dead, two are alive with cancer, and one is clinically free of cancer at 145 weeks. Five of six patients who survived greater than or equal to 2 years after treatment had adenocarcinomas. There was no unexpected late toxicity. This combination of chemotherapy and radiotherapy is unlikely to improve results in the treatment of inoperable non-small cell carcinoma of the lung over those with radiotherapy alone.