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A randomized prospective study of cisplatin and vinblastine versus cisplatin, vinblastine and mitomycin in advanced non-small cell lung cancer
Annals ofOncology 3: 127-130, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.
Original article A randomized prospective study of cisplatin and vinblastine versus cisplatin, vinblastine and mitomycin in advanced non-small cell lung cancer N. Mylonakis, N. Tsavaris, C. Bacoyiannis, N. Karvounis, S. Kakolyris, A. Karabelis, M. Beer1 & P. Kosmidis 2nd Department of Medical Oncology, Meloxa Cancer Hospital, Piraeus, and 'Hellenic Cooperative Oncology Group Data Center, Athens, Greece Summary. From June 1986 to February 1989, 103 patients with advanced non-small cell lung cancer, with no previous chemotherapy, were randomized to receive either a combination of cisplatin and vinblastine (group A) or the same combination with the addition of mitomycin (group B). In group A, 15/48 evaluable patients had objective responses, as did 8/45 in group B. The median survivals were 35 and 32 weeks, respectively. The median survival of patients with response or stable disease was 43 weeks. Response and sur-
vival did not differ significantly between treatment groups. The addition of mitomycin to the two-drug combination showed no major therapeutic benefit, while bone marrow toxicity was increased. Three patients in group B died of sepsis. Among the different patient characteristics, disease stage, performance status and response had influence on survival.
Introduction
age less than 75 years, normal renal, liver and cardiac function, and all had given informed consent. No previous chemotherapy was allowed, except in 2 patients treated with one course of cyclophosphamide; evaluated lesions had not been irradiated. Patients were randomized to receive either Regimen A, consisting of cisplatin, 120 mg/m2 on day 1 given by intravenous infusion over 1 h with pre- and post-hydration and mannitol diuresis, and vinblastine, 6 mg/m2 i.v. on days 1 and 8 of each course. Regimen B consisted of the addition to the former of mitomycin, 8 mg/m2 on day 1 of each cycle. Treatment courses were repeated every 4 weeks. A treatment delay of 3 weeks or less was allowed for the recovery of white blood cell and platelet counts. No dosage modifications were permitted. Chemotherapy was continued until either disease progression or completion of 6 courses of treatment. Patients were staged and response assessed by clinical examination, chest x-ray and computerized tomography, and, as indicated, abdominal computerized tomography or liver or adrenal ultrasound and bone scan. Disease parameters were measured every 8 weeks; chest x-rays were repeated monthly. Histopathology slides were reviewed by the same pathologist for classification and definition of the differentiation grade. Complete remission (CR) was defined as disappearance of all signs and symptoms of disease, and partial response (PR) as a decrease by 50% or more of measurable disease in the absence of any new disease during 4 weeks or longer. Stable disease was defined as the absence of either remission or progressive disease during 3 months or longer. Time to progression (TTP) was defined as the time elapsed from the start of treatment to renewed progression, and survival from initiation of chemotherapy until death. Toxicity was evaluated according to the WHO grading system. Results were compared by the t-test or, for proportions, the chisquare test; correlations were tested by regression analysis 118|. Survival curves were drawn with the life-table method and compared using z and logrank tests |20-22|.
Chemotherapy has limited activity in non-small cell lung cancer (NSCLC). Cisplatin, vinblastine, vindesine and mitomycin are among the active single agents in this disease [1-6]. The combination of cisplatin and vindesine was reported to yield improved response rates when compared to single-agent treatment [7, 8|. Response and survival figures in a randomized trial comparing cisplatin plus vindesine to cisplatin plus vinblastine showed no difference between the regimens [9[. Combination chemotherapy with cisplatin and vindesine or vinblastine elicited response rates of over 25% [10-12]. The addition of mitomycin to the cisplatin plus vindesine or vinblastine combinations has yielded controversial results, and this addition seems very likely to enhance the treatment toxicity [ 13-18). We felt that a spectacular improvement in response rate or survival would be needed to justify a major increase in toxicity, and we undertook to randomize patients to receive either a combination of cisplatin and vinblastine, or all three drugs.
Patients and methods From June 1986 to February 1989, 103 patients with advanced (stage 1MB or IV) non-small cell lung cancer, confirmed by biopsy or cytology, were entered into the study. All patients had measurable or evaluable disease, a performance status (ECOG) inferior to 3,
Key words: non-small cell lung cancer, cisplatin, vinblastine, mitomycin, sepsis, survival
128 Table 2. Response, time to progression and survival.
Table I. Patient characteristics.
Number entered
PV
PVM
PV
PVM
52
51
N Weeks Median
N Weeks Median
34-75 56
34-75 55.5
46
43
48 1 0 3
45 0 2 4
3 39-73 35 12 22-78 41 15 9-39 20 18 3-113 35
2 35-60 50 6 19-45 24 23 12-103 20 16 3-134 32
Age
range median Sex
male female Performance status (WHO) 0 1 2 3
Previous treatment radical surgery irradiation Weight loss > 10% Smoking index" range median Tumor, histologic type squamous cell adenocarcinoma large cell/undiffer. Stage 1MB IV
Dominant site lung nodes liver bone
6 7 23 15 7
4 26 12
10 10 18
5 18 15
9
45
0-132 50
18 26 8
16 29 6
26 26
24 27
26 14 2 10
22 15
0-175
1 13
" Smoking index - packs of cigarettes per day x years of smoking.
Results The characteristics of the 103 patients entered into the trial are shown in Table 1. Ninety-three patients were evaluable for response (Table 2). Three patients died within 4 weeks after the start of chemotherapy (one died of initially progressive disease, and two of sepsis); in 7 patients, who were given only one course of treatment, progression was not documented by the end of the first cycle. The
Evaluable early death (tu) early toxic death <2 courses Responses complete partial Stable disease Progressive disease Survival
median rate of complete and partial responses of all entered patients is 29% in group A (95% confidence limits 16%-41%) and 16% in group B (3.4%-28%); the median time which elapsed from the start of treatment to renewed progression (time to progression) is 40.8 and 32.8 weeks, respectively, for patients with complete and partial response. No statistically significant difference was found between the two regimens when response rates, time to progression and survival were compared. The survival curves for both groups are depicted in Fig. 1. All but 10 patients were observed until death; none were lost to follow-up. Regression analysis showed no statistically significant influence on survival of age, initial lactic dehydrogenase serum levels, the total number of cigarettes smoked or previous radiation treatment. There was no difference in the survival curves for the different histologic cancer types, the presence or absence of weight loss or the metastasis pattern. The survival curves of tumor stage NIB compared to stage IV shown in Fig. 2, as well as those of patients with an initial performance status of 0 or 1, compared to 3, revealed a statistically significant difference in survival. The survival of the patients who had either an objective response or stable disease was 12-134 weeks (median 43.7) and that of patients refractory to treatment 9.760 weeks (median 23), with no significant differences between the treatment groups.
months survival I1IB
Fig. I. Treatment regimen and survival; (logrank) no difference.
t
IV
Fig. 2. Tumor stage and survival; (logrank) p < 0.05.
129 Table 3. Treatment toxicity. PV
PVM
WHO grade, % patients
1-2
3-4
1-2
3-4
Leukopenia Thrombocytopenia Nephrotoxicity Nausea/vomiting Neurotoxicity Alopecia
16 10 29 72 30 49
34 0 2 6 0 -
17 10 23 75 26 70
32 13 2 6 2 -
A total of 198 treatment courses were administered in group A and 143 in group B; in both groups patients received 1-6 treatments (median: 4 in group A and 3 in group B). Ninety-six patients were evaluable for toxicity, 49 in group A and 47 in group B (Table 3). Myelotoxicity was more prevalent in group B, due mainly to thrombocytopenia and to leukopenia; there were three treatment-related deaths in this group, all secondary to sepsis during severe leukopenia.
Discussion Combination chemotherapy in non-small cell lung cancer remains a controversial issue; studies generally fail to show a survival advantage for treated patients, even though some authors report a prolonged survival [11, 12]. The result of adding mitomycin to cisplatin and vinblastine has been inconclusive. Our phase HI trial was initiated to determine if this addition would increase response rates and survival enough to justify the possibly increased toxicity of the three-drug regimen. Patients were equally divided with regard to age, sex, performance status, stage, histologic type and prior weight loss into the two groups. More patients in group A had been irradiated in the primary tumor and fewer had undergone radical surgery than in group B. More patients in group A achieved complete or partial response (29% versus 16%) and more of those in group B achieved stable disease (39% versus 29%). Similarly, there was no difference in survival between the two groups, the medians being 35 and 32 weeks (Table 2). The tests for significance in these comparisons should be considered with reservations, as their power, with a one-sided 5% alpha error, is not above 50%. A statistically significant difference in survival according to disease stage (Fig. 2) or performance status was revealed. Also, patients with progressive disease had a significantly shorter survival than those who either achieved a response or had stable disease. Leukopenia and thrombocytopenia were more pronounced and cumulative in group B, in which three treatment-related deaths occurred due to sepsis in severe neutropenia. Renal and neuromuscular toxicity as well as nausea and vomiting were comparable in the two groups. Our question was whether the increased toxicity to be expected with the addition of mitomycin
would be counterbalanced by a major improvement in response rate (30% responders versus a 15% lower rate with the two-drug treatment). At the observed response rate of 16%, a test with a 5% one-sided alpha error can exclude such a difference with 70% power [22, 23]. In conclusion, the low probability of substantially enhancing the activity of the cisplatin and vinblastine combination by the addition of mitomycin does not justify the increase in toxicity. Disease stage, performance status and response to treatment all had prognostic value in our patient population.
References 1. Vogl S, Berenzweig M, Camacho F, Greenwald E, Kaplan BH. Efficacy study of intensive cis-platin therapy in advanced nonsmall cell bronchogenic carcinoma. Cancer 1982; 50: 24-6. 2. Panettiere FJ, Vance RB, Stuckey WJ, Coltman CA, Costanzi JJ, Chen II. Evaluation of single agent cisplatin in the management of non-small cell carcinoma of the lung: A Southwest Oncology Group Study. Cancer Treat Rep 1983; 66: 305. 3. Schulman P, Budman DR, Vinciguerra V et al. Phase II study of divided dose vinblastine in non-small cell bronchogenic carcinoma. Cancer Treat Rep 1982; 66: 171. 4. Sorensen JB. Chemotherapy for advanced adenocarcinoma of the lung: The Copenhagen study and review of the literature. Semin Oncology 1988; 15 (suppl. 7): 56-7. 5. Osterlind K, Horbov S, Dombernowsky P, Rorth M, Hansen HH. Vindesine in the treatment of squamous cell carcinoma, adenocarcinoma and large cell carcinoma of the lung. Cancer Treat Rep 1982; 66: 305. 6. Samson MK, Comis RL, Baker LH et al. Mitomycin C in advanced adenocarcinoma and large cell carcinoma of the lung. Cancer Treat Rep 1978; 62: 163. 7. Einhorn LH, Loehrer PJ, Williams SD et al. A random prospective study of vindesine versus vindesine plus cisplatin versus vindesine plus cisplatin plus mitomycin C in advanced non-small-cell lung cancer. J Clin Oncol 1986; 4: 1037-43. 8. Elliot JA, Ahmezdai S, Hole D et al. Vindesine and cisplatin combination chemotherapy compared with vindesine as a single agent in the management of non-small cell lung cancer: A randomized study. Eur J Cancer Clin Oncol 1984; 20: 1025-32. 9. Kris M, Gralla R, Kalman L et al. Randomized trial comparing vindesine plus cisplatin with vinblastine plus cisplatin in patients with non-small cell lung cancer, with an analysis of methods of response assessment. Cancer Treat Rep 1985; 69:4. 10. Williams CJ, Woods R, Lebi J, Page J. Chemotherapy for nonsmall cell lung cancer A randomized trial of cisplatin/vindesine versus no chemotherapy. Semin Oncol 1988; 15:6. 11. Cellerino R, Tummarello D, Piga A. Chemotherapy or not in advanced non-small cell lung cancer? Lung Cancer 1990; 6: 99-109. 12. Evans WK. Combination chemotherapy confers modest survival advantage in patients with advanced non-small cell lung cancer: Report of a Canadian multicenter randomized trial. Semin Oncol 1988; 15:5. 13. Schulman P, Budman DR, Weiselberg L, Vinciguerra V, Degnan T. Phase II trial of mitomycin, vinblastine, and cisplatin (MVP) in non-small cell bronchogenic carcinoma. Cancer Treat Rep 1983; 67: 943. 14. Neill HB, Griffin JP. Combination chemotherapy with mitomycin-C cisplatin and vinblastine in the treatment of non-small cell lung cancer. Med Ped Oncol 1985; 13: 341. 15. Miller TP, Vance RB, Ahmann FR, Rodney SR Extensive nonsmall cell lung cancer treated with mitomycin, cisplatin, and
130
16.
17.
18.
19. 20.
vindesine (MiPE): A Southwest Oncology Group Study. Cancer Treat Rep 1986,70: 1101. Kris MG, Gralla RJ, Wertheim MS et al. Trial of the combination of mitomycin, vindesine and cisplatin in patients with advanced non-small cell lung cancer. Cancer Treat Rep 1986; 70: 1091. Ruckdeschel JC, Finkelstein DM, Mason BA, Creech RH. Chemotherapy for metastatic non-small-cell bronchogenic carcinoma: EST 2575, generation V - a randomized comparison of four cisplatin-containing regimens. J Clin Oncol 1985; 3: 72-9. GraJla RJ, Kris MG, Burke MT et al. The influence of the addition of mitomycin (M) to vindesine (V) plus cisplatin (P) in a random-assignment trial in 120 patients with non-small cell lung cancer. Proc Am Soc Clin Oncol 1986; 5: 182. Kramer MS. Clinical Epidemiology and Biostatistics. Springer, Berlin 1988, pp 146-98. Peto J. The calculation and interpretation of survival curves. In Buyse ME, Staquet MJ and Sylvester RJ (eds): Cancer Clinical Trials. Methods and Practice. Oxford University Press 1984; 361.
21. Breslow N. Comparison of survival curves. In Buyse ME, Staquet MJ and Sylvester RJ (eds): Cancer Clinical Trials. Methods and Practice. Oxford University Press 1984; 381. 22. Machin D, Campbell MJ. Statistical tables for the design of clinical trials. Blackwell Scientific Publications, Oxford 1987; 10-97. 23. Bennett JE, Dismukes WE, Duma RJ et al. A comparison of amphotericin B alone and combined with fluocytosine in the treatment of cryptococcal meningitis. New Engl J Med 1979; 301:126-31. Received 20 November 1990; accepted 21 August 1991. Correspondence to: Paris A. Kosmidis, M.D. Head, 2nd Department of Medical Oncology Metaxa Cancer Hospital Botassi 51 Piraeus, Greece
Original article A randomized prospective study of cisplatin and vinblastine versus cisplatin, vinblastine and mitomycin in advanced non-small cell lung cancer N. Mylonakis, N. Tsavaris, C. Bacoyiannis, N. Karvounis, S. Kakolyris, A. Karabelis, M. Beer1 & P. Kosmidis 2nd Department of Medical Oncology, Meloxa Cancer Hospital, Piraeus, and 'Hellenic Cooperative Oncology Group Data Center, Athens, Greece Summary. From June 1986 to February 1989, 103 patients with advanced non-small cell lung cancer, with no previous chemotherapy, were randomized to receive either a combination of cisplatin and vinblastine (group A) or the same combination with the addition of mitomycin (group B). In group A, 15/48 evaluable patients had objective responses, as did 8/45 in group B. The median survivals were 35 and 32 weeks, respectively. The median survival of patients with response or stable disease was 43 weeks. Response and sur-
vival did not differ significantly between treatment groups. The addition of mitomycin to the two-drug combination showed no major therapeutic benefit, while bone marrow toxicity was increased. Three patients in group B died of sepsis. Among the different patient characteristics, disease stage, performance status and response had influence on survival.
Introduction
age less than 75 years, normal renal, liver and cardiac function, and all had given informed consent. No previous chemotherapy was allowed, except in 2 patients treated with one course of cyclophosphamide; evaluated lesions had not been irradiated. Patients were randomized to receive either Regimen A, consisting of cisplatin, 120 mg/m2 on day 1 given by intravenous infusion over 1 h with pre- and post-hydration and mannitol diuresis, and vinblastine, 6 mg/m2 i.v. on days 1 and 8 of each course. Regimen B consisted of the addition to the former of mitomycin, 8 mg/m2 on day 1 of each cycle. Treatment courses were repeated every 4 weeks. A treatment delay of 3 weeks or less was allowed for the recovery of white blood cell and platelet counts. No dosage modifications were permitted. Chemotherapy was continued until either disease progression or completion of 6 courses of treatment. Patients were staged and response assessed by clinical examination, chest x-ray and computerized tomography, and, as indicated, abdominal computerized tomography or liver or adrenal ultrasound and bone scan. Disease parameters were measured every 8 weeks; chest x-rays were repeated monthly. Histopathology slides were reviewed by the same pathologist for classification and definition of the differentiation grade. Complete remission (CR) was defined as disappearance of all signs and symptoms of disease, and partial response (PR) as a decrease by 50% or more of measurable disease in the absence of any new disease during 4 weeks or longer. Stable disease was defined as the absence of either remission or progressive disease during 3 months or longer. Time to progression (TTP) was defined as the time elapsed from the start of treatment to renewed progression, and survival from initiation of chemotherapy until death. Toxicity was evaluated according to the WHO grading system. Results were compared by the t-test or, for proportions, the chisquare test; correlations were tested by regression analysis 118|. Survival curves were drawn with the life-table method and compared using z and logrank tests |20-22|.
Chemotherapy has limited activity in non-small cell lung cancer (NSCLC). Cisplatin, vinblastine, vindesine and mitomycin are among the active single agents in this disease [1-6]. The combination of cisplatin and vindesine was reported to yield improved response rates when compared to single-agent treatment [7, 8|. Response and survival figures in a randomized trial comparing cisplatin plus vindesine to cisplatin plus vinblastine showed no difference between the regimens [9[. Combination chemotherapy with cisplatin and vindesine or vinblastine elicited response rates of over 25% [10-12]. The addition of mitomycin to the cisplatin plus vindesine or vinblastine combinations has yielded controversial results, and this addition seems very likely to enhance the treatment toxicity [ 13-18). We felt that a spectacular improvement in response rate or survival would be needed to justify a major increase in toxicity, and we undertook to randomize patients to receive either a combination of cisplatin and vinblastine, or all three drugs.
Patients and methods From June 1986 to February 1989, 103 patients with advanced (stage 1MB or IV) non-small cell lung cancer, confirmed by biopsy or cytology, were entered into the study. All patients had measurable or evaluable disease, a performance status (ECOG) inferior to 3,
Key words: non-small cell lung cancer, cisplatin, vinblastine, mitomycin, sepsis, survival
128 Table 2. Response, time to progression and survival.
Table I. Patient characteristics.
Number entered
PV
PVM
PV
PVM
52
51
N Weeks Median
N Weeks Median
34-75 56
34-75 55.5
46
43
48 1 0 3
45 0 2 4
3 39-73 35 12 22-78 41 15 9-39 20 18 3-113 35
2 35-60 50 6 19-45 24 23 12-103 20 16 3-134 32
Age
range median Sex
male female Performance status (WHO) 0 1 2 3
Previous treatment radical surgery irradiation Weight loss > 10% Smoking index" range median Tumor, histologic type squamous cell adenocarcinoma large cell/undiffer. Stage 1MB IV
Dominant site lung nodes liver bone
6 7 23 15 7
4 26 12
10 10 18
5 18 15
9
45
0-132 50
18 26 8
16 29 6
26 26
24 27
26 14 2 10
22 15
0-175
1 13
" Smoking index - packs of cigarettes per day x years of smoking.
Results The characteristics of the 103 patients entered into the trial are shown in Table 1. Ninety-three patients were evaluable for response (Table 2). Three patients died within 4 weeks after the start of chemotherapy (one died of initially progressive disease, and two of sepsis); in 7 patients, who were given only one course of treatment, progression was not documented by the end of the first cycle. The
Evaluable early death (tu) early toxic death <2 courses Responses complete partial Stable disease Progressive disease Survival
median rate of complete and partial responses of all entered patients is 29% in group A (95% confidence limits 16%-41%) and 16% in group B (3.4%-28%); the median time which elapsed from the start of treatment to renewed progression (time to progression) is 40.8 and 32.8 weeks, respectively, for patients with complete and partial response. No statistically significant difference was found between the two regimens when response rates, time to progression and survival were compared. The survival curves for both groups are depicted in Fig. 1. All but 10 patients were observed until death; none were lost to follow-up. Regression analysis showed no statistically significant influence on survival of age, initial lactic dehydrogenase serum levels, the total number of cigarettes smoked or previous radiation treatment. There was no difference in the survival curves for the different histologic cancer types, the presence or absence of weight loss or the metastasis pattern. The survival curves of tumor stage NIB compared to stage IV shown in Fig. 2, as well as those of patients with an initial performance status of 0 or 1, compared to 3, revealed a statistically significant difference in survival. The survival of the patients who had either an objective response or stable disease was 12-134 weeks (median 43.7) and that of patients refractory to treatment 9.760 weeks (median 23), with no significant differences between the treatment groups.
months survival I1IB
Fig. I. Treatment regimen and survival; (logrank) no difference.
t
IV
Fig. 2. Tumor stage and survival; (logrank) p < 0.05.
129 Table 3. Treatment toxicity. PV
PVM
WHO grade, % patients
1-2
3-4
1-2
3-4
Leukopenia Thrombocytopenia Nephrotoxicity Nausea/vomiting Neurotoxicity Alopecia
16 10 29 72 30 49
34 0 2 6 0 -
17 10 23 75 26 70
32 13 2 6 2 -
A total of 198 treatment courses were administered in group A and 143 in group B; in both groups patients received 1-6 treatments (median: 4 in group A and 3 in group B). Ninety-six patients were evaluable for toxicity, 49 in group A and 47 in group B (Table 3). Myelotoxicity was more prevalent in group B, due mainly to thrombocytopenia and to leukopenia; there were three treatment-related deaths in this group, all secondary to sepsis during severe leukopenia.
Discussion Combination chemotherapy in non-small cell lung cancer remains a controversial issue; studies generally fail to show a survival advantage for treated patients, even though some authors report a prolonged survival [11, 12]. The result of adding mitomycin to cisplatin and vinblastine has been inconclusive. Our phase HI trial was initiated to determine if this addition would increase response rates and survival enough to justify the possibly increased toxicity of the three-drug regimen. Patients were equally divided with regard to age, sex, performance status, stage, histologic type and prior weight loss into the two groups. More patients in group A had been irradiated in the primary tumor and fewer had undergone radical surgery than in group B. More patients in group A achieved complete or partial response (29% versus 16%) and more of those in group B achieved stable disease (39% versus 29%). Similarly, there was no difference in survival between the two groups, the medians being 35 and 32 weeks (Table 2). The tests for significance in these comparisons should be considered with reservations, as their power, with a one-sided 5% alpha error, is not above 50%. A statistically significant difference in survival according to disease stage (Fig. 2) or performance status was revealed. Also, patients with progressive disease had a significantly shorter survival than those who either achieved a response or had stable disease. Leukopenia and thrombocytopenia were more pronounced and cumulative in group B, in which three treatment-related deaths occurred due to sepsis in severe neutropenia. Renal and neuromuscular toxicity as well as nausea and vomiting were comparable in the two groups. Our question was whether the increased toxicity to be expected with the addition of mitomycin
would be counterbalanced by a major improvement in response rate (30% responders versus a 15% lower rate with the two-drug treatment). At the observed response rate of 16%, a test with a 5% one-sided alpha error can exclude such a difference with 70% power [22, 23]. In conclusion, the low probability of substantially enhancing the activity of the cisplatin and vinblastine combination by the addition of mitomycin does not justify the increase in toxicity. Disease stage, performance status and response to treatment all had prognostic value in our patient population.
References 1. Vogl S, Berenzweig M, Camacho F, Greenwald E, Kaplan BH. Efficacy study of intensive cis-platin therapy in advanced nonsmall cell bronchogenic carcinoma. Cancer 1982; 50: 24-6. 2. Panettiere FJ, Vance RB, Stuckey WJ, Coltman CA, Costanzi JJ, Chen II. Evaluation of single agent cisplatin in the management of non-small cell carcinoma of the lung: A Southwest Oncology Group Study. Cancer Treat Rep 1983; 66: 305. 3. Schulman P, Budman DR, Vinciguerra V et al. Phase II study of divided dose vinblastine in non-small cell bronchogenic carcinoma. Cancer Treat Rep 1982; 66: 171. 4. Sorensen JB. Chemotherapy for advanced adenocarcinoma of the lung: The Copenhagen study and review of the literature. Semin Oncology 1988; 15 (suppl. 7): 56-7. 5. Osterlind K, Horbov S, Dombernowsky P, Rorth M, Hansen HH. Vindesine in the treatment of squamous cell carcinoma, adenocarcinoma and large cell carcinoma of the lung. Cancer Treat Rep 1982; 66: 305. 6. Samson MK, Comis RL, Baker LH et al. Mitomycin C in advanced adenocarcinoma and large cell carcinoma of the lung. Cancer Treat Rep 1978; 62: 163. 7. Einhorn LH, Loehrer PJ, Williams SD et al. A random prospective study of vindesine versus vindesine plus cisplatin versus vindesine plus cisplatin plus mitomycin C in advanced non-small-cell lung cancer. J Clin Oncol 1986; 4: 1037-43. 8. Elliot JA, Ahmezdai S, Hole D et al. Vindesine and cisplatin combination chemotherapy compared with vindesine as a single agent in the management of non-small cell lung cancer: A randomized study. Eur J Cancer Clin Oncol 1984; 20: 1025-32. 9. Kris M, Gralla R, Kalman L et al. Randomized trial comparing vindesine plus cisplatin with vinblastine plus cisplatin in patients with non-small cell lung cancer, with an analysis of methods of response assessment. Cancer Treat Rep 1985; 69:4. 10. Williams CJ, Woods R, Lebi J, Page J. Chemotherapy for nonsmall cell lung cancer A randomized trial of cisplatin/vindesine versus no chemotherapy. Semin Oncol 1988; 15:6. 11. Cellerino R, Tummarello D, Piga A. Chemotherapy or not in advanced non-small cell lung cancer? Lung Cancer 1990; 6: 99-109. 12. Evans WK. Combination chemotherapy confers modest survival advantage in patients with advanced non-small cell lung cancer: Report of a Canadian multicenter randomized trial. Semin Oncol 1988; 15:5. 13. Schulman P, Budman DR, Weiselberg L, Vinciguerra V, Degnan T. Phase II trial of mitomycin, vinblastine, and cisplatin (MVP) in non-small cell bronchogenic carcinoma. Cancer Treat Rep 1983; 67: 943. 14. Neill HB, Griffin JP. Combination chemotherapy with mitomycin-C cisplatin and vinblastine in the treatment of non-small cell lung cancer. Med Ped Oncol 1985; 13: 341. 15. Miller TP, Vance RB, Ahmann FR, Rodney SR Extensive nonsmall cell lung cancer treated with mitomycin, cisplatin, and
130
16.
17.
18.
19. 20.
vindesine (MiPE): A Southwest Oncology Group Study. Cancer Treat Rep 1986,70: 1101. Kris MG, Gralla RJ, Wertheim MS et al. Trial of the combination of mitomycin, vindesine and cisplatin in patients with advanced non-small cell lung cancer. Cancer Treat Rep 1986; 70: 1091. Ruckdeschel JC, Finkelstein DM, Mason BA, Creech RH. Chemotherapy for metastatic non-small-cell bronchogenic carcinoma: EST 2575, generation V - a randomized comparison of four cisplatin-containing regimens. J Clin Oncol 1985; 3: 72-9. GraJla RJ, Kris MG, Burke MT et al. The influence of the addition of mitomycin (M) to vindesine (V) plus cisplatin (P) in a random-assignment trial in 120 patients with non-small cell lung cancer. Proc Am Soc Clin Oncol 1986; 5: 182. Kramer MS. Clinical Epidemiology and Biostatistics. Springer, Berlin 1988, pp 146-98. Peto J. The calculation and interpretation of survival curves. In Buyse ME, Staquet MJ and Sylvester RJ (eds): Cancer Clinical Trials. Methods and Practice. Oxford University Press 1984; 361.
21. Breslow N. Comparison of survival curves. In Buyse ME, Staquet MJ and Sylvester RJ (eds): Cancer Clinical Trials. Methods and Practice. Oxford University Press 1984; 381. 22. Machin D, Campbell MJ. Statistical tables for the design of clinical trials. Blackwell Scientific Publications, Oxford 1987; 10-97. 23. Bennett JE, Dismukes WE, Duma RJ et al. A comparison of amphotericin B alone and combined with fluocytosine in the treatment of cryptococcal meningitis. New Engl J Med 1979; 301:126-31. Received 20 November 1990; accepted 21 August 1991. Correspondence to: Paris A. Kosmidis, M.D. Head, 2nd Department of Medical Oncology Metaxa Cancer Hospital Botassi 51 Piraeus, Greece