Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation

We evaluated the 10- to 15-year outcome of 252 patients with small-cell lung cancer entered into therapeutic clinical trials with or without chest and cranial irradiation. Thirty-two patients (13%) survived free of cancer for 2 or more years. Twelve patients (5%) survived at least 10 years free of cancer, and 10 patients are currently alive and free of cancer beyond 10 years. Six of these 10 patients currently function at a level comparable with that before diagnosis. The other 22 patients who were cancer-free at 2 years have died. Nine patients died from recurrent small-cell lung cancer 2 to 6.2 years after initiation of chemotherapy. Five died from non-small-cell lung cancer, three died of other malignancies, and five died of causes other than cancer. A small fraction of patients with small-cell lung cancer are cured of their original malignancy, but these patients remain at high risk for second cancers and death from other causes.     

The role of chest irradiation in limited small cell carcinoma of the lung treated with combination chemotherapy

Between October 1974 and December 1980, 123 patients with limited small cell carcinoma were treated in the Indiana University Medical Center Department of Radiation Oncology. Of these, 115 were treated with preplanned combined modality therapy using irradiation and polychemotherapy (Adriamycin, Cytoxan and Oncovin). All patients received whole brain prophylactic irradiation and were followed a minimum of 2 years. Sixty-six patients were given chest irradiation with all but two receiving 3500–40110 rad while 49 did not receive this treatment. Sixty-five percent of those patients receiving chest irradiation had a complete response to therapy, as opposed to 33% who did not (p < 0.02). The median and overall survivals were significantly different between the 2 groups (423 days vs. 307 days). The overall and long-term survivals were higher in those receiving chest irradiation or resective surgery. Serial chest X rays (and port films, where applicable) were reviewed on all patients to determine sites of failure. Of relapsing patients who did not receive chest irradiation, failure always included the primary site. Of those who had chest irradiation, only 15% of evaluable patients did not relapse in the chest prior to death. This study demonstrates an increased response rate, median survival, and overall survival in patients receiving chest irradiation. The high rate of relapse in the chest suggests the need for more effective control of the primary. This may be accomplished by increasing the dose of chest irradiation or surgical removal when feasible.     

Brain metastases from small cell lung cancer treated with combination chemotherapy

Ten patients with metastatic small cell lung cancer (SCLC) in the brain, shown by CT scan at time of diagnosis, were treated with systemic combination chemotherapy. Repeated CT scans were performed every 4 weeks. Seven patients were evaluable, since three patients died during the first 2–3 weeks. Significant responses on CT scans as well as neurologic improvement were demonstrated in all evaluable patients. Four of seven patients obtained a complete response in the brain, while three had partial remissions. The impact of this observation on the overall treatment strategies in SCLC has further to be defined.     

Prognostic factors in small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with or without irradiation

The relationships between prognostic factors and duration of survival in small cell lung cancer were investigated in a consecutive series of 874 patients treated with combination chemotherapy with or without irradiation. The series included 443 patients with limited and 431 patients with extensive stage disease based on staging including bone marrow examination and peritoneoscopy with liver biopsy but no routine scans. The median durations of survival for the two disease categories were 48 and 30 weeks, respectively. The influence on survival of various pretreatment factors was investigated by use of univariate methods and Cox's multivariate regression model. Patients in each stage were treated according to one of three controlled trials. Variations among the applied treatment regimens did not result in significant differences in duration of survival among patients with limited disease. An alternating regimen was superior to continuous therapy in patients with extensive disease and raised serum lactate dehydrogenase. Prognosis was correlated with disease extent. Surgical resection as well as limited stage disease thus both contributed to survival. Poor performance status, reduced hemoglobin concentration, and raised values for serum lactate dehydrogenase were significantly associated with a reduced duration of survival in both stages. Females with limited disease lived significantly longer than males while advanced age was a negative prognostic factor in extensive disease. Plasma sodium and serum urate were both predictive of survival in limited disease. Proved metastatic disease affecting specific sites or total number of metastatic sites did not carry significant prognostic information in a model including a general variable characterizing stage of disease. Fifty of the 778 patients, on whom the multiple regression model was based, were alive and disease free 2 years after the start of the treatment. Two-year survival rates were strongly correlated to groupings based on prognostic factors, and information about disease extent was not mandatory for predicting the probability of long term disease-free survival.     

Determinants of complete remission induction and maintenance in chemotherapy with or without irradiation of small cell lung cancer

The possible influence of pretreatment patient characteristics upon the probabilities of complete remission (CR) induction and maintenance was investigated in a series of 815 nonresected patients with small cell lung cancer. All patients underwent pretreatment staging which enabled allocation of 391 patients to trials for limited stage disease and 424 patients to trials for extensive disease. Three controlled trials for each disease stage were conducted between 1973 and 1981. All therapeutic regimens consisted of combinations of between three and six agents (lomustine, cyclophosphamide, methotrexate, vincristine, doxorubicin, etoposide) with or without irradiation. Thirty-five % of the limited stage patients and 18% of the extensive stage patients were alive and had achieved a complete remission 16 weeks after initiation of the treatment, i.e., after four cycles of chemotherapy. Relationships between pretreatment characteristics and the probability to pass this benchmark were examined by logistic regression analysis. The probability of CR was negatively related to increased serum lactate dehydrogenase and male sex in both disease stages. Pretreatment anemia (less than 12 g/liter) and poor performance status were associated with a reduced CR rate in limited and extensive stage disease, respectively. Factors related to the maintenance of complete remission were subsequently examined in the 211 complete responders by use of Cox's regression analysis. Complete responders with extensive disease prior to treatment had greater cumulative risk of relapse than those with limited disease (P less than 0.01). Hyponatremia had a significant negative influence on the remission duration in limited disease while age greater than 60 years and bone marrow metastases had significantly negative influence in extensive disease. Using the models it was possible to identify subgroups of patients with CR rates ranging from 5 to 55% and to stratify complete responders according to estimated risks of subsequent relapse.     

Neuropsychological evaluation of patients with inoperable non-small cell lung cancer treated with combination chemotherapy or radiotherapy

Neuropsychological tests were used to evaluate possible central nervous system dysfunction in patients treated with chemotherapy. Ninety-five patients with non-small cell lung cancer limited disease were randomized to either radiotherapy (2.8 Gy × 15) or combination chemotherapy with cisplatin and etoposide. In order to evaluate cognitive functions three neuropsychological tests were applied: Trail Making, Benton Visual Retention Test and Verbal Learning. Changes in the patients' test scores before and after treatment were compared. The chemotherapy patients showed reduced performance on some of the neuropsychological tests compared to the radiotherapy group. This indicates a treatment related effect on the central nervous system, possibly caused by the combination chemotherapy.     

Intensive alternating combination chemotherapy and high dose chest radiotherapy in small cell lung cancer.

Sixty-nine patients, 32 with limited and 37 with extensive small cell lung cancer (SCLC), were admitted to the present study. Patients with limited disease underwent alternating combination chemotherapy consisting of CAV (cyclophosphamide, adriamycin, vincristine) and PE (cisplatin and etoposide) regimens and concurrent high dose thoracic radiotherapy (6,000 cGy); prophylactic brain irradiation (3,000 cGy) was administered to complete responders. Patients with extensive disease received the same alternating chemotherapy but not radiotherapy. In the 25 evaluable patients with limited disease we obtained an objective response (OR) in 80% with a complete response (CR) in 54% and partial response (PR) in 24%, stable disease (SD) in 4% and progressive disease (PD) in 16%. Median duration of response was 9.5 months for CR and 8.5 months for PR. Median survival was 14 months for all patients with 12% long-term survivors. Toxicity was acceptable. In the 32 evaluable patients with extensive disease we observed 65.6% OR with 18.7% CR and 46.8% PR, 9.3% minimal response and 25% PD. Median duration of response was 7 months for CR and 8 months for PR. Median survival was 10 months for all patients. The treatment was well tolerated. Our study did not show a therapeutic advantage for alternating combination chemotherapy in SCLC and failed to show the use of high dose chest radiotherapy in combined modality for limited disease.     

Cyclic alternating combination chemotherapy for small cell lung cancer

Summary Sixty-two patients with small cell carcinoma of lung received cyclic alternating non-cross-resistant combination chemotherapy. Radiation to the chest was given to all the patients. Patients were given a course of VP16, adriamycin and vicristine (VAV) followed by radiation (3,000 rads) to the chest and then a second course of VAV. Three weeks later, a course of cytoxan, CCNU, and methotrexate (CCM) was given (6 weeks). Subsequently, the treatment was cycled between two courses of VAV (6 weeks) and one course of CCM (6 weeks). Overall objective response rate of 73%, with 45% complete response, was noted. Overall median survival was 50 weeks, with 83 weeks for complete responders. Median survival for patients with regional disease was 58 weeks compared to 40 weeks for extensive disease. All the patients headed for complete response did so prior to receiving CCM. These results were not superior to conventional combination chemotherapy regimens.     

Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small-cell lung cancer

Mortality and morbidity was investigated in a consecutive series of 72 patients with small-cell lung cancer (SCLC) who were found to be disease-free at restaging after 18 months of treatment. These patients were all the long-term survivors among 874 patients included in one of six trials between 1973 and 1981. All studies used combination chemotherapy with or without irradiation. Follow-up of the patients varied between 4 and 11 years. The estimated 5-year survival rate subsequent to discontinuation of therapy was 0.24, corresponding to a death rate of 0.25 per year or ten times greater than the expected mortality for persons of the same age group. This high mortality was primarily related to recurrent SCLC, the estimated cumulative risk of relapse reaching 46% at the time of the latest recurrence 5 years from diagnosis. The risk of relapse was generally independent of the pretreatment disease stage although it was reduced in patients with resectable disease and was greater in those with pretreatment liver or bone marrow metastases. Equal risks of relapse were related to the use of regimens with and without radiotherapy. The cumulative risk of relapse in patients surviving 3 years from initiation of the treatment was less than 15% and accordingly, 3 years of follow-up seems sufficient for comparison of long-term results obtained in different trials. The second factor resulting in death or disease was second cancer, for which the cumulated risk increased to 32%, the latest occurring 5.4 years from the diagnosis of SCLC. Five of these cases were non-small-cell lung cancers and three were secondary leukemias. The estimated mortality related to non-neoplastic conditions was just significantly greater than expected. In spite of the increased mortality in this series, 38 of 54 2-year disease-free survivors and 20 of 22 5-year survivors resumed a lifestyle similar to that before diagnosis of SCLC.     

Limited small cell lung cancer of the lung treated with combination chemotherapy and radiotherapy: a retrospective analysis.

We assessed the outcome in 65 patients with limited small cell lung cancer (SCLC) treated from 1980 through 1989 with combination chemotherapy and chest and cranial irradiation. Of the 65 patients, 32.3% (21/65) achieved a complete remission (CR) prior to radiation therapy; six additional cases achieved a CR after radiotherapy with an improvement of 10% in the incidence of CR. In our group, 8 patients were alive and free of disease at 30 months (12.3%). We think that a combination of local thoracic irradiation in SCLC limited disease plus chemotherapy yields more CR and improves survival, especially in the group of patients who obtained the CR after initial induction chemotherapy.     

Use of hemibody irradiation as a non-cross-resistant agent in combination with systematic chemotherapy in small cell lung cancer

Previously, investigators at this institute have studied the use of upper hemibody irradiation as a consolidation agent following combination chemotherapy for small cell lung cancer. There was no improvement in survival compared to that in the group treated with chemotherapy alone. In our present pilot study, we are investigating the toxicity and efficacy of using hemibody irradiation (HBI) as a non-cross-resistant agent early in a program of alternating chemotherapy consisting of six treatment cycles. Toxicity due to the combined effects of chemotherapy (cisplatin and etoposide plus cyclophosphamide, doxorubicin, and vincristine) plus HBI is reported. The HBI was given at a dose of 1,000 cGy in four fractions for limited disease or as a single 800-cGy dose for extensive disease. Bone marrow suppression following HBI necessitated a subsequent delay in the chemotherapy cycle or dose reduction in 55% of the 33 patients. Six patients developed diffuse interstitial pneumonitis following chemotherapy and HBI; 3 have died, and in 2 of these, the etiology was opportunistic infection. In our previous studies utilizing HBI either alone or as consolidation therapy after induction chemotherapy, a low incidence of lung toxicity occurred. This increased incidence suggests a possible drug-radiation interaction when HBI is used as an alternating agent with doxorubicin and cisplatin.     

Accelerated chemotherapy with or without GM-CSF for small cell lung cancer: a non-randomised pilot study

Two series of five consecutive patients with small cell lung cancer were treated with an “accelerated” chemotherapy regimen of cyclophosphamide-doxorubicin-vincristine (CAV) and cisplatin-etoposide (PE) alternated possibly every week. In the first group of patients (median age 49 years, range 46–52) recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) was given as soon as grade IV leukopenia occurred, while in the second group (median age 59 years, 55–68) no growth factor was administered. The mean interval between chemotherapy courses and the mean duration of chemotherapy were 10 and 57 days, respectively, in the patients supported with GM-CSF compared with 13 and 72 days in the control group. One GM-CSF treated patient was withdrawn after the third cycle because of severe toxicity. The mean white blood cell and platelet nadirs were 600 and 46 000/μl in the first group vs. 840 and 105 000/sml in the controls. Overall chemotherapy dose-intensity was increased by two fold in the patients given GM-CSF compared with a 1.5 fold increase in the control patients. In all cases, irrespective of their treatment, there was an impaired colony forming capacity of circulating and marrow haemopoietic progenitor cells when grade IV leukopenia occurred, with recovery after the end of leukopenia. This pilot study suggests that accelerated CAV/PE chemotherapy is feasible both with and without GM-CSF. Different GM-CSF schedules as well as combinations of different haemopoietic growth factors may further improve dose-intensity.     

化疗联合CIK细胞免疫治疗治疗小细胞肺癌

目的:观察化疗联合CIK细胞治疗小细胞肺癌的疗效、生活质量及毒副反应。方法:68例小细胞肺癌患者随机分为研究组（CIK细胞免疫+EP方案）和对照组（EP方案）各34例,评价两组的疗效、治疗前后患者生活质量评分变化和毒副反应。结果:研究组和对照组有效率分别是76.5%和61.8%（P>0.05）,疾病控制率分别是94.1%和70.6%（P<0.05）;治疗后,研究组和对照组生活质量评分分别是57.61±5.48和49.55±9.38（P<0.05）;两组之间毒副反应无统计学差异（P>0.05）。结论:化疗联合CIK细胞免疫治疗能够提高小细胞肺癌患者的近期疗效,改善患者的生活质量。     

Pilot study of teniposide in combination chemotherapy for small cell lung cancer

Teniposide is one of the most active agents in small cell lung cancer (SCLC). Because of the experimental evidence of synergistic activity between teniposide and methotrexate and between vincristine and methotrexate, 34 SCLC patients were treated with a combination of teniposide, vincristine, methotrexate and cyclophosphamide. Chest radiotherapy was given to responding patients with limited disease and prophylactic cranial irradiation was given to complete responders only. Most patients had extensive disease and good performance status. The main side-effects were myelosuppression, mucositis and peripheral neuropathy, which were all common and often severe. A response rate of 78% with 22% complete responses was obtained in 32 evaluable patients. Median durations of responses and survival were 252 and 311 days, respectively. Patients with limited disease had a median survival of 556 days while extensive disease patients had a median survival of 240 days. 2 patients with limited disease have been in continuous complete remission for more than 2 years from start of treatment.     

A combination chemotherapy of cisplatin and etoposide in small cell lung cancer

Fourteen patients with small cell lung cancer were treated with cisplatin (80 mg/m2 i.v.) and etoposide (300, 400, 500 mg/m2 i.v.). This combination chemotherapy was administered over a three- or four-week period. Eleven of 13 evaluable patients showed a greater than 50% tumor reduction, but there were 3 complete responses and 5 partial responses, giving a response rate of 61%. Four patients who were initially treated achieved major responses. In 9 patients who had received prior chemotherapy, 4 achieved a major response. Of 3 complete responders, 2 patients had previously received etoposide treatment alone. The renal toxicity of this regimen was minimal and no patients developed any clinical symptoms. Nausea and vomiting were well controlled by high-dose metoclopramide and methylprednisolone. All patients, however, experienced appetite loss after treatment. The dose-limiting toxic effect of this regimen was hematologic toxicity. We therefore concluded that the combination of etoposide (300 mg/m2 i.v.) and cisplatin (80 mg/m2 i.v.) is repeatable at 3 or 4 week intervals and effective in patients with small cell lung cancer.