A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. Fifteen-year follow-up of all patients in a study of post-operative chemotherapy for bronchial carcinoma. Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer. Limited squamous cell carcinoma of the lung: a Southwest Oncology Group randomized study of radiation with or without doxorubicin chemotherapy and with or without levamisole immunotherapy. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. Cyclophosphamide (NSC-26271) as adjuvant to radiotherapy in the treatment of unresectable bronchogenic carcinoma. Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. A randomized, phase III trial. Is adjuvant treatment with vinblastine effective in reducing the occurrence of distant metastasis in limited squamous cell lung cancer? A randomized study. Comparison of radiotherapy alone and radiotherapy with chemotherapy using adriamycin and 5-fluorouracil in bronchogenic carcinoma. Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma. A randomized study. Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer. Does chemotherapy make a difference? A randomized study of high-dose split course radiotherapy preceded by high-dose chemotherapy versus high-dose radiotherapy only in locally advanced non-small-cell lung cancer. An EORTC Lung Cancer Cooperative Group trial. Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer. Results of a randomized prospective study. The Japan Clinical Oncology Group. Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer. Adjuvant cancer chemotherapy after resection of carcinoma of the lung. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. The Lung Cancer Study Group. Radical radiotherapy and chemotherapy in localized inoperable non-small-cell lung cancer: a randomized trial. A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer. A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study). The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan). Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung. A randomised trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer.
For patients with locally or regionally advanced non-small-cell lung cancer radiation is the standard treatment, but survival remains poor. We therefore conducted a randomized trial to determine whether induction chemotherapy before irradiation improves survival.
                All the patients had documented non-small-cell cancer of the lung with Stage III disease established by clinical or surgical staging. Eligibility requirements included excellent performance status, minimal weight loss, and visible disease on radiography. Patients randomly assigned to group 1 received cisplatin (100 mg per square meter of body-surface area given intravenously on days 1 and 29) and vinblastine (5 mg per square meter given intravenously on days 1, 8, 15, 22, and 29) and then began radiation therapy on day 50 (60 Gy over a 6-week period). Patients assigned to group 2 received the same radiation therapy but began it immediately and received no chemotherapy.
                The eligible patients in group 1 (n = 78) and group 2 (n = 77) were comparable in terms of age (median, 60 years), sex, performance status, histologic features, stage of disease, and completeness of radiation therapy. The median survival was greater for those in group 1-13.8 versus 9.7 months (P = 0.0066 by log-rank test). Rates of survival in group 1 were 55 percent after one year, 26 percent after two years, and 23 percent after three years, as compared with 40, 13, and 11 percent, respectively, in group 2. Those in group 1 had a higher incidence of serious infections requiring hospitalization (7 percent, vs. 3 percent in group 2) and severe weight loss (14 percent vs. 6 percent), but there were no treatment-related deaths.
                In patients with Stage III non-small-cell lung cancer, induction chemotherapy with cisplatin and vinblastine before radiation significantly improves median survival (by about four months) and doubles the number of long-term survivors, as compared with radiation therapy alone. Since three quarters of the patients still die within three years, however, further improvements in systemic and local therapy are needed. The 15-year findings are presented of a double-blind, randomised study planned in 1964 in which cytotoxic chemotherapy with either busulphan or cyclophosphamide prescribed to be given daily for 2 years as an adjuvant to surgery was compared with placebo in the treatment of 726 patients with carcinoma of the bronchus. The two cytotoxic agents administered in this way did not influence survival. At 15y, 8% of the 243 patients allocated busulphan, 9% of the 234 cyclophosphamide, and 10% of the 249 placebo were alive, these being 10% of the patients who had had epidermoid cancers, 12% large-cell, 5% small-cell, 5% adenocarcinomas, and 8% other histological types. The study provides data on long-term results in a large group of patients who were, in effect, treated by surgery alone. Survival was significantly shorter in patients with histological involvement of the resected intrathoracic nodes (log-rank test P much less than 0.001). A finding of particular interest is that the histological type of the tumour did not influence survival in the 390 patients whose nodes were not involved, although, as expected, it did in the 336 whose nodes were involved, the 226 with epidermoid cancers surviving longer than the 57 with small cell carcinoma, the 31 with adenocarcinoma and all 110 with non-epidermoid carcinomas (P much less than 0.001 in each comparison). The aims of this study were to assess the effect of adjuvant chemotherapy on overall survival, disease-free survival, and relapse pattern, as well as its toxicity in patients who underwent radical surgery for non-small-cell lung cancer (NSCLC).
                One hundred ten patients with T1-3N0 (World Health Organization [WHO] 1981) NSCLC underwent radical surgery during the period of 1982 through 1987. After surgery, the patients were randomized to receive adjuvant chemotherapy (n = 54) (cyclophosphamide 400 mg/m2, doxorubicin 40 mg/m2, and cisplatin 40 mg/m2 [CAP] for six cycles) or no active treatment (n = 56).
                After 10 years from the start of the study, 61% of patients were alive in the chemotherapy group and 48% were alive in the control group (P = .050). Seventeen patients (31%) in the CAP group and 27 patients (48%) in the control group had a recurrence during the follow-up period (P = .01). The 5-year survival rate was 67% in the chemotherapy group and was 56% in the control group (P = .050). The patients in the chemotherapy group who completed the planned treatment had a slightly better 5-year survival than those whose chemotherapy was discontinued (72.5% v 50.3%; P = .15). Chemotherapy-related gastrointestinal toxicity grade 3 to 4 (WHO) occurred in 63% and was the main reason why patients refused further planned therapy.
                Our results suggest that patients with NSCLC at pathologic stage I who have undergone radical surgery benefit from adjuvant chemotherapy. To compare the survival of patients with locally advanced non-small cell lung cancer treated with single-agent vindesine, thoracic radiotherapy, or both treatment modalities.
                Randomized, prospective, phase III trial.
                Multi-institutional, university-based national cooperative oncology group.
                The study included 319 patients with locally advanced, unresectable non-small cell lung cancer who had no evidence of extrathoracic metastases. All patients were ambulatory and had measurable disease. Some patients could not have surgery because of coexisting medical conditions.
                Patients were randomly assigned to receive vindesine, 3 mg/m2 body surface area weekly; standard thoracic radiotherapy, 60 Gy over 6 weeks; or both vindesine and thoracic radiotherapy. Vindesine was administered for 6 weeks and then every other week to patients who had no disease progression. Patients who developed progressive disease while receiving vindesine or radiotherapy alone were crossed over to radiotherapy or vindesine, respectively. Response assessment took place at week 6.
                The overall response rate was superior in the radiotherapy arms (radiotherapy alone, 30%; radiotherapy plus vindesine, 34%; vindesine alone, 10%; P = 0.001). However, with a minimum follow-up of 42 months, no improvement in survival has been seen with radiotherapy. The median survival was 8.6 months for patients receiving radiotherapy alone, 9.4 months for those receiving radiotherapy plus vindesine, and 10.1 months for those receiving vindesine (P = 0.58). Radiotherapy also failed to improve long-term survival. The 5-year survivals were 3%, 3%, and 1%, respectively (P = 0.56).
                Patients with non-small cell lung cancer who have inoperable, nonmetastatic disease gain no clinically meaningful survival advantage with immediate thoracic irradiation, even when modern megavoltage radiation therapy techniques and equipment are used. Patients with TNM stage IV non-small-cell lung cancer have short survival times. Previous controlled studies comparing chemotherapy and supportive care for the treatment of this type of cancer have not given consistent results, have included patients with different disease stages, and have rarely reported drug dose intensity.
                The present trial was designed to assess the safety and the effect on survival of supportive care alone versus chemotherapy with cisplatin, cyclophosphamide, and mitomycin combined with appropriate supportive care in patients with stage IV non-small-cell lung cancer.
                Patients (n = 102) with stage IV non-small-cell lung cancer were randomly assigned to one of two treatment regimens. The combined modality group (52 patients) received supportive care along with cisplatin (75 mg/m2), cyclophosphamide (400 mg/m2), and mitomycin (10 mg/m2) given intravenously at 3-week intervals. The supportive care group (50 patients) received supportive care alone. Randomization was stratified on the basis of histology (squamous versus nonsquamous cell carcinoma), performance status (Karnofsky), and weight loss (during the 6 months preceding randomization). The two groups were well matched for age and sex. Survival analysis was performed after the last patient died.
                The median number of chemotherapy cycles was 3.5 per patient. Mean weekly delivered doses of drugs were as follows: cisplatin, 22.1 mg/m2; cyclophosphamide, 118 mg/m2; and mitomycin, 2.9 mg/m2. Toxic effects due to chemotherapy were generally mild, but peripheral neuropathy and hematologic and renal toxic effects were observed. In the supportive care group, mean survival was 6.1 months (median, 4.0 months); six patients lived at least 12 months and two lived at least 18 months. In the combined modality group, mean survival was 11.3 months (median, 8.5 months); 20 patients lived at least 12 months, 13 lived at least 18 months, and five lived at least 24 months. Difference in survival was statistically significant (P < .0001). Survival was directly related to initial performance status in both groups (P < .01) and was significantly (P < .01) longer for patients with squamous cell carcinoma than for those with nonsquamous cell carcinoma.
                The combination of supportive care and cisplatin-cyclophosphamide-mitomycin therapy offers a survival advantage over supportive care alone in patients with advanced non-small-cell lung cancer.
                Metastatic non-small-cell lung cancer, generally considered to be unresponsive or marginally responsive to chemotherapy, can be treated with chemotherapy, with an expectation of prolonging patient survival. Although the results of the present study are encouraging, clinical research should continue to be directed toward developing more effective treatments for this disease. In 1976, the Southwest Oncology Group activated a four-arm randomized study of limited squamous cell carcinoma of the lung. The purpose of this study was to determine if doxorubicin and/or levamisole added to radiation therapy improved the local control rate and survival in patients with limited squamous cell carcinoma of the lung. Of the 107 eligible patients, 15 (14%) had complete responses and 20 (19%) had partial responses. When compared by chemotherapy, immunotherapy, and performance status, no statistically significant difference was found in response rates or in survival. Although not statistically significant, the survival and response rates of patients in the combined levamisole arms were shorter than those of patients in the combined arms not containing levamisole. Patients receiving radiation therapy alone had the best survival. The irradiated field was the site of failure in 68 (88%) of the 77 patients in whom the site of failure was specified. Fifty (65%) of the patients failed in the radiation therapy field only. Chemotherapy and/or immunotherapy as employed in this protocol were of no benefit. We report the results observed in a large, randomized study that compared the effects of radiotherapy alone (the standard therapy) with those of a combination of radiotherapy and chemotherapy in nonresectable squamous cell and large-cell lung carcinoma. The radiation dose was 65 Gy in each group, and chemotherapy included vindesine, cyclophosphamide, cisplatin, and lomustine. In this study, 177 patients received radiotherapy alone (group A), and 176 patients received the combined treatment (group B). The 2-year survival rate was 14% in group A and 21% in group B (P = .08). The distant metastasis rate was significantly lower in group B (P less than .001). Local control was poor in both groups (17% and 15%, respectively) and remained the major problem. nan High-dose radiation therapy is generally recommended as standard treatment in regionally advanced unresectable non-small-cell lung cancer (NSCLC), but median- and long-term survival remain poor. Some reports have recently shown an improvement of results in advanced NSCLC when cisplatin was included in the chemotherapy regimens. Therefore, we designed a randomized trial to determine whether induction chemotherapy before high-dose radiotherapy improves response rate and survival in stage III NSCLC over that achieved with radiotherapy alone.
                From March, 1984 to December, 1988, 66 consecutive patients with stage III unresectable NSCLC were randomized to one of two treatment arms; 61 were evaluable for survival and 58 for response and toxicity. Patients randomly assigned to arm A received cisplatin (CDDP 100 mg/m2 on day 1) and etoposide (VP 16 120 mg/m2 on days 1, 2, 3) every 3 wks for 3 courses followed by radiotherapy 56 Gy on pre-treatment tumor volume and 40 Gy on mediastinum and bilateral supraclavicular nodes. Patients assigned to arm B received only the same radiotherapy. The 61 eligible patients were comparable in terms of age, performance status, histology and treatment.
                Response rate was 53% in arm A and 32% in arm B. The median survival was 52 wks for the combined treatment arm and 36 wks for the radiation therapy arm. At six years of follow-up all the patients were dead. Toxicity was mild and no treatment-related deaths were recorded.
                Induction chemotherapy produced a better response rate and a trend of improved survival (4 months) but a significant survival advantage was not achieved (p < 0.11), probably because of the small number of patients enrolled in the trial. The survival benefit of combination chemotherapy to patients with advanced non-small-cell carcinoma of the lung (NSCLC) is controversial. To study this question, the National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a prospective randomized trial comparing best supportive care (BSC) to two chemotherapy regimens, vindesine and cisplatin (VP), and cyclophosphamide, doxorubicin, and cisplatin (CAP). Between February 1983 and January 1986, 23 centers across Canada entered 251 patients on study. Eighteen centers participated in the three-arm schema (150 patients); centers choosing not to participate in a study with a no-chemotherapy arm followed a two-arm schema comparing VP with CAP (101 additional patients). Altogether, 233 patients were eligible. Patients had measurable or evaluable disease, with either distant metastases (82.5%) or bulky limited disease considered inoperable or unsuitable for radical radiotherapy. The treatment groups were comparable in terms of age, sex, performance status, histology, disease extent, and weight loss. The overall response rates (complete response [CR] plus partial response [PR]) on the chemotherapy arms were CAP, 15.3%, and VP, 25.3% (P = .06). Patients on the three-arm portion of the trial had a median survival of 32.6 weeks when treated with VP, 24.7 weeks with CAP, and 17 weeks with BSC. The significance of the differences in survival, adjusted for prognostic factors, is as follows: chemotherapy v BSC, P = .02; VP v BSC, P = .01; and CAP v BSC, P = .05. Toxicity on the chemotherapy arms was significant, with leukopenia of severe or greater degree occurring in 37.8% (CAP) and 40.0% (VP), severe vomiting in 12.2% (CAP) and 23.3% (VP), and severe neurotoxicity in 15.6% (VP). To compare the survival of patients with medically inoperable or unresectable stage III non-small cell lung cancer treated with thoracic radiotherapy alone or in combination with chemotherapy.
                Randomized, prospective phase III trial.
                Multi-institutional cooperative oncology group.
                A total of 121 patients were enrolled in the study, of whom 7 (5.8%) were ineligible. All patients were ambulatory and had measurable or evaluable disease. Before they were randomized, patients were stratified by ECOG performance score, histologic type, maximum tumor diameter, and NCCTG institution.
                Radiotherapy consisted of a total of 5000 cGy in 5 weeks with a 1000 cGy boost in 5 fractions to a small tumor field. Combined modality therapy was MACC which is intravenous methotrexate, intravenous doxorubicin, intravenous cyclophosphamide, and oral lomustine (CCNU), on day 1 and 28. Chemotherapy was followed by identical thoracic radiotherapy 4 weeks after the second cycle of chemotherapy. Four weeks after thoracic radiotherapy was completed, patients received another two cycles of identical chemotherapy. Patients who had progression of disease after chest irradiation only were treated with MACC chemotherapy.
                Major clinical responses were observed in 31 of 56 (55%; 95% Cl, 42% to 68%) patients treated with combination therapy and 37 of 58 (64%; Cl, 51% to 76%) treated with radiation only (P greater than 0.2). The median time to progression was 192 days with radiotherapy only compared with 199 days for combined modality therapy (P greater than 0.2). The median survival time was 313 days compared with 317 days, respectively (P greater than 0.2). The 1-, 2-, and 5-year survival rates after thoracic radiation only were 45% (Cl, 32% to 58%), 16% (Cl, 6% to 25%), and 7%. With chemoradiotherapy, the survival rates were 46% (Cl, 33% to 60%), 21% (Cl, 11% to 32%), and 5%, respectively. Myelosuppression was significantly greater for the combined modality therapy arm (P = 0.002).
                Chemotherapy with MACC, in combination with thoracic radiotherapy, did not result in significant survival advantage compared with radiation alone (P greater than 0.2) in patients with medically inoperable or unresectable stage III non-small cell lung cancer. In order to study the usefulness of treatment with vinblastine (VLB) in the prevention of cancer metastasis in squamous cell lung cancer, 50 patients with locoregional disease were randomized to receive either locoregional RT alone (group A) or a weekly intravenous bolus injection of VLB (6 mg/m2) concurrently with and after locoregional radiotherapy (RT) (55 Gy in 6 weeks) until the appearance of metastases (group B). Neither the incidence of death with metastases, metastasis-free survival (MFS) nor overall survival (S) were significantly affected by treatment with the drug. However, due to the limited number of patients in each group, the power of the statistical test was such to allow only the detection of differences in MFS and S to or more than 80 per cent at the P = 0.05 level. Local tumor response was significantly superior in group B (P less than 0.05). Acute toxicity (dysphagia, myelosuppression) during RT was significantly worse in group B. During long-term therapy with VLB, mild polyneuropathy developed in the majority of patients in group B. Furthermore, seven patients discontinued treatment with VLB during maintenance due to compliance (4) and excessive neurotoxicity (3). This treatment schedule with VLB is not recommended for patients with locoregional squamous cell lung cancer as significant toxicity is present during and after RT and significant increase in MFS and S is lacking. Because of an apparent increase in local response, the combination of VLB and RT merits further investigation in those tumors where local tumor control is crucial. Eighty-two patients with histologically confirmed lung cancer were randomly allocated to receive either radiotherapy alone (2400-3200 rads, depending upon cell type) or the same dose of radiotherapy followed by four cycles of adriamycin and 5-fluorouracil. Eighty-one patients were evaluated and for the group as a whole survival was better in the undifferentiated group assigned to receive adjuvant chemotherapy but survival in the patients with squamous tumours was not significantly prolonged. The chemotherapy was not unduly toxic. Between June 1980 and December 1983, 111 patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were entered into a randomized trial comparing radiotherapy alone versus radiotherapy and combination chemotherapy with cyclophosphamide, Adriamycin (doxorubicin), methotrexate, and procarbazine. Thirty-five of 62 (56.4%) patients treated with 4500 rad in 15 fractions in 3 weeks and 19 of 49 (38.8%) patients treated with the same radiation treatment and chemotherapy had an objective response. The difference in response rate was not significant (P = 0.900). Median time to progression was 5.9 and 7.02 months, respectively, for the radiation treatment and the combined treatment. Median survival was 11.74 and 10.03 months, respectively, without statistically significant differences between the two groups of patients. The toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant superiority of combined radiotherapy and chemotherapy treatment over radiation therapy alone was evidenced. Whether different chemotherapy regimens may prove more effective in this context should be clarified by further studies. Current chemotherapy treatment of metastatic non-small cell lung cancer has demonstrated some objective responses, but is still largely palliative. This report reviews the results of a randomized trial in patients with advanced metastatic non-small cell lung cancer which compared treatment with supportive care (treatment with palliative radiation, psychosocial support, analgesics, nutritional support) to supportive care plus combination chemotherapy with cisplatin and vinblastine. Although the patients receiving combination chemotherapy had a slightly longer median survival (20.43 weeks versus 13.57 weeks), it was not statistically significant (P = 0.09). In addition, the patients receiving chemotherapy experienced serious toxicity, and showed no significant benefit in terms of quality of life as measured by Karnofsky performance status score. The authors conclude that contemporary combination chemotherapy provides only modest survival benefit to patients with advanced metastatic non-small cell lung cancer and should not be considered standard therapy. Future investigations of chemotherapy in patients with unresectable non-small cell lung cancer should continue to utilize control arms which provide high-quality supportive care. The treatment results of radiotherapy in stage III non-small-cell lung cancer are very poor. Several phase II studies showed that neoadjuvant chemotherapy followed by radiotherapy was feasible in this patient group and suggested that treatment outcome might improve. A randomized phase II study was performed addressing the response rate and morbidity of high-dose split course radiotherapy (RT) versus the same radiotherapy preceded by high-dose chemotherapy (CT) in patients with stage III non-small-cell lung cancer.
                Seventy eligible patients were randomized in this study. CT consisted of cisplatin 100 mg/m2 days 1 and 22, and vindesine 3 mg/m2 on days 1, 8, 22 and 29. Radiotherapy started on day 43 in the combined arm and immediately in the RT-only arm. The primary tumour and the regional nodes were treated by 30 Gy/10 fractions/2 weeks and after the split by a second course of 25 Gy/10 fractions/2 weeks. In the combined arm a third CT cycle was planned during the split between RT courses.
                In the CT + RT arm 34 patients were evaluable for response and toxicity and 30 patients in the RT only arm. After completion of treatment 7 patients had a complete response (2 in the CT plus RT arm, 5 in the RT alone arm) and 26 patients a partial response (13 in the CT plus RT arm, 13 in the RT alone arm) for an overall response rate of 52% (95% CI 39%-65%). Acute toxicity was worse in the combined treatment arm with grade 4 leucocytopenia in 8 patients and thrombocytopenia grade 4 in one patient. Three patients had reversible renal toxicity grade 2. There was one toxic death in the RT plus CT arm. There was no enhancement of acute or late radiation pulmonary or oesophageal toxicity. Time to progressive disease (median 30 vs. 35 weeks) and overall survival time (median 12 months) were equal in both treatment arms.
                High-dose radiotherapy preceded by high-dose chemotherapy was more toxic than radiotherapy alone and did not result in this study in any benefit in terms of response rate, time to progressive disease and overall survival. Two hundred nine patients with completely resected stage III non-small-cell lung cancer were randomized to receive postoperative cisplatin and vindesine chemotherapy or no further treatment. Before randomization, patients were stratified by the histologic characteristics of their tumors (squamous versus nonsquamous cell carcinoma). Prognostic variables such as histology, performance status, extent of operation, and tumor and nodal status of the eligible patients in chemotherapy (n = 90) and control groups (n = 91) were equally distributed. There was no statistically significant difference in disease-free and overall survival between the two groups. The 3-year disease-free survivals of the chemotherapy and control groups were 37% and 42%, respectively. The median survival times (5-year survival) were 31 months (35%) in the chemotherapy group and 37 months (41%) in the control group. These was no different pattern in the first site of recurrence (local versus systemic) between the two groups. This study failed to demonstrate the therapeutic benefits of postoperative cisplatin and vindesine chemotherapy. In a randomized clinical trial, 87 patients with inoperable, extensive non-small cell lung cancer (NSCLC) were randomized to receive either combination chemotherapy (cisplatin at 70 mg/m2 intravenously [i.v.] on day 1 and etoposide at 100 mg/m2 i.v. on day 1 and 200 mg/m2 orally on days 2 and 3) or symptomatic treatment. No statistically significant differences in survival time were found between the two treatment techniques. A major problem in the interpretation of the results was the use of semicurative radiation therapy (3000 to 4200 cGy) to the primary tumor and mediastinum, which was given with symptomatic intent. Three long-term survivors were seen in the latter group. A prospective randomized trial was conducted by the Veterans Administration Surgical Adjuvant Group in an attempt to discern the value of prolonged intermittent courses of adjuvant cancer chemotherapy after a successful curative resection of a carcinoma of the lung in men. Four hundred and seventeen patients were randomized into three groups; 132 patients received cyclophosphamide (Cytoxan), regimen A; 142 patients received cyclophosphamide alternating with methotrexate, regimen b; and 143 patients received no additional therapy, the controls. The patients in the two treatment groups received an average of 7.1 drug courses. No drug mortality was noted, but toxic symptoms of varying severity were seen after 43.6% of the drug courses. Five-year survival in the two treatment groups was 24.9% (regiment A) and 25.7% (regimen B), respectively, and 23.5% in the control group. No treatment benefit was associated with adjuvant chemotherapy in this trial. Most studies of adjuvant chemotherapy, radiotherapy, or immunotherapy in non-small-cell lung cancer patients with complete surgical resection of disease have shown negative results. However, two studies of stage II and III disease by our Lung Cancer Study Group suggested an advantage to adjuvant therapy with cyclophosphamide, doxorubicin, and cisplatin (CAP).
                Since neither of those studies had an untreated control, the Lung Cancer Study Group undertook a trial that included a control group and also offered the potential benefit of adjuvant therapy with CAP to patients with T1, N1 or T2, N0 (stage I) non-small-cell lung cancer.
                After complete resection, eligible patients with stage I disease were classified by known prognostic factors and randomly assigned to receive or not to receive four courses of CAP at 3-week intervals beginning on day 30 after surgery. The CAP regimen consisted of 400 mg/m2 cyclophosphamide, 40 mg/m2 doxorubicin, and 60 mg/m2 cisplatin. Stratification by prognostic factors was as follows: histology (squamous versus nonsquamous), white blood cell count before surgery (> or = 9100/mm3 versus < 9100/mm3), and Karnofsky performance status before surgery (< or = 90% versus 100%).
                Of the 269 patients entered in the study, 101 had recurrence and 127 have died. Mean time since randomization is 6.4 years; mean follow-up is 3.8 years. There were no differences in time to recurrence or overall survival (not stratified by histology) between the two groups, even when analyses were adjusted for prognostic variables. There was one treatment-related death on the CAP arm due to infection during neutropenia. Only 53% of the eligible patients received all four courses of CAP, and only 57% of such patients received all four cycles on time. In 74% of the patients, the site of initial recurrence was distant.
                The most likely explanations for the lack of efficacy of CAP are poor compliance to the protocol and relative inactivity of the regimen, compared with the activity of drug combinations used in more recent studies. On the basis of this trial, adjuvant therapy with CAP should not be recommended for patients with resected stage I lung cancer.
                Further trials to test adjuvant therapy are indicated, but investigators should use better antiemetics to improve patient compliance as well as more active chemotherapy regimens. nan From April 1985 to September 1988, 128 patients with advanced non-small-cell lung cancer (NSCLC) were enrolled in a prospective randomized trial evaluating chemotherapy (arm A) versus best supportive care (arm B). Chemotherapy consisted of cyclophosphamide 500 mg/m2 intravenously (IV) day 1, epirubicin 50 mg/m2 IV day 1, and cisplatin 80 mg/m2 IV day 1 (CE'P regimen) alternating every 4 weeks with methotrexate 30 mg/m2 IV day 1, etoposide 200 mg/m2 IV day 1, and lomustine (CCNU) 70 mg/m2 orally day 1 (MEC' regimen) until progression. Of the 123 patients (62 treated and 61 controls) eligible for survival, 115 were fully evaluable for response (58 treated and 57 controls). Response rates were 21% partial response, 53% stable disease, and 26% progressive disease in arm A, and 47% stable disease and 53% progressive disease in arm B. Median survival was 34.3 weeks (range, 4.3 to 218.6+ weeks) in arm A versus 21.1 weeks (range, 4.3 to 188.6 weeks) in arm B; the difference was not significant at P = .153 (Mantel-Cox). Subgroups of patients retrospectively analyzed by age, performance status, stage M0/M1, and weight loss or not showed no significant difference in survival. Poor-risk patients (at least two of the following: poor performance status, stage M1, weight loss) of arm A survived significantly longer than poor-risk patients of arm B (23.6 weeks v 12.4 weeks, Mantel-Cox P = .008); a significant difference in survival was also observed between nonsquamous cell patients of arm A and those of arm B (median survival, 38.6 weeks v 16.7 weeks; Mantel-Cox P = .041). Toxicity on the chemotherapy arm was hematologic (World Health Organization [WHO] grade greater than 3) in 12% of CE'P and in 13% of MEC' courses and gastroenteric (WHO grade greater than 3) in 24% of CE'P courses and in 8% of MEC' courses. Our alternating treatment was not significantly superior to supportive care. It is likely that certain subgroups of the NSCLC category may have an advantage with chemotherapy. A prospective randomized trial (the second cooperative study) was conducted from July 1985 to December 1987 to investigate the benefits of postoperative adjuvant chemotherapy in patients for whom non-small cell lung cancer had been resected completely. Patients were randomly assigned either to a chemotherapy group (group A) treated postoperatively with CDDP (66 mg/m2 x 1), ADM (26 mg/m2 x 1) and UFT (8 mg/kg/day) during 6 months, or to a control group (group B) which had undergone surgery only. Three hundred and thirty-three resected cases were registered. Among them, 24 cases (7.2%) were excluded, because of incomplete resection (15), pathologically benign tumour (3), small cell lung cancer (2) and other factors (4). Three hundred and nine cases were eligible: 155 cases in group A (p-Stage I 93, II 19, III 43) and 154 in group B (I 109, II 10, III 35). The 5-year survival rate in group A was 61.8%, and that in group B 58.1%. The 5-year disease-free survival rate for each group was 61.8% and 57.4%, respectively. There were no significant differences in the 5-year survival between the two groups. However, since a significant difference was observed between the two groups regarding pathological lymph node metastasis (pN), the prognostic factors were adjusted using Cox's proportional hazard model. Thereafter the adjusted survival rate and disease-free survival rate for group A became significantly higher than for group B (P = 0.044 and P = 0.036, respectively). Thus, from these results, it is concluded that the role of surgery for non-small cell lung cancer still remains of primary importance, and postoperative adjuvant chemotherapy is effective to improve the results of surgery and prolong life of patients with non-small cell lung cancer. Eight hundred sixty-five patients with a microscopically curative resection for carcinoma of the lung were accepted for study, none of whom were excluded from analysis. Adjuvant therapy was randomly assigned about the tenth to 14th postoperative day; 432 patients (treated) were to receive CCNU and hydroxyurea for one year, while 433 patients (controls) were to receive no adjuvant therapy. Toxic reactions to therapy were reported, but only 1% were severe enough to require stopping therapy. No evidence of improved survival or delayed recurrence of disease was seen in treated patients as a whole or when examined by cell type and by postsurgical TNM category. On the contrary, survival beyond the second year of follow-up may have been impaired by the drugs when administered to patients without evidence of tumor spread to the lymph nodes. The value of chemotherapy in advanced non-small cell lung cancer (NSCLC) remains contentious. Because of this two separate but very similar trials were set up in Australia and Southampton (UK). Two hundred and one patients with stage IIIb or IV NSCLC were randomly assigned to cisplatin 120 mg m-2 on days 1 and 29 and vindesine 3 mg m-2 weekly x 6 or to no chemotherapy. Both groups were eligible to receive radiotherapy or other palliative treatment as required. Of 188 evaluable patients, 97 received chemotherapy and 91 were in the control arm. Response was assessed between days 42 and 49. Responders continued chemotherapy at the same doses though cisplatin being given 6 weekly x 4 and the vindesine 2 weekly x 12. The overall response rate to chemotherapy was 28%; there were no significant differences according to major prognostic criteria. Although the overall survival of the chemotherapy group (median 27 weeks) was longer than that of the no chemotherapy group (median 17 weeks) this was not statistically significant (log rank P = 0.33). For patients without dissemination (IIIb), median survival was 45 weeks in the chemotherapy arm and 26 weeks in the non-chemotherapy (log rank P = 0.075). Toxicity was universal and frequently severe: of 17 patients discontinuing chemotherapy after one cycle, 13 did so because of unacceptable toxicity. This chemotherapy cannot be recommended as routine treatment. Further phase III studies of chemotherapy in advanced NSCLC should continue to use a no chemotherapy control and should also attempt to measure quality of life, an issue not addressed effectively in this or other recent trials.