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
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
