Cancer Chemother Pharmacol (1990) 26:101 - 104
ancer hemothe.rapyand harmacolo © Springer-Verlag
1990
Phase II study of carboplatin in patients with nonresected lung cancer Japan Cooperative Oncology Group on Lung Cancer* Received 30 June 1989/Accepted 21 November 1989
Summary. A multicenter phase II trial of carboplatin, a new platinum analog of cisplatin, was carried out in bronchogenic carcinoma at 17 institutions throughout Japan. Of 139 patients enrolled in this trial, 10 were excluded from analysis as inevaluable and the remaining 129 were judged to be evaluable for response and toxic effects by the Extramural Review Committee. Patients were treated i. v. with either 300 or 400 mg/m2 carboplatin every 4 weeks. Responses and toxic effects were assessed at both dose levels. The overall response rate was 17.8% (23/129), with response rates of 28.4% (19/67) for small-cell disease, 7.1% (2/28) for squamous-cell carcinoma, and 6.9% (2/29) for adenocarcinoma. The most frequent toxic effects were thrombocytopenia and leukopenia, with a platelet count of 9.5 ~dl, a WBC count of _->3,500 I.tl, a platelet count of ~ 10× 104 ~1, serum creatinine levels of -4 weeks since any prior chemotherapy or radiation therapy was required. Informed consent was obtained from all patients. Carboplatin was given at a dose of 300 mg/m-~in patients with a PS of 2 or 3 and in those who had been heavily pretreated. Patients with a PS of ~< I and those who had not undergone prior chemotherapy received
102 Table 1. Patient characteristics
Eligible Evaluable Sex: men/women Age: median (range) Performance status 0 - I/2-3
Table 3. Response rates acccording to dose Total
300 mg/mz 400 mg/m 2
139 129 95/34 71 (33-86) years 66/63
36 32 26/7 72 (41-84) years 9/23
103 97 69/27 71 (33-86) years 57/40
Histology: Small-cell Squamous Adenocarcinoma Large-cell Adenoidocystic
67 28 29 4 1
17 8 5 1 1
50 20 24 3 0
Prior chemotherapy: No Yes
78 51
18 14
60 37 10 30 57
Dose Pati- CR PR MR NC PD CR+PR Chi(mg/m 2) ents(n ) patients squaretest Overall
300
33
0
400
96
0 21
8 50
300
17
0
2
I
400
50
0
17
Non300 small-cell 400
15
0
0
2
47
0
4
6 31
Smallcell
2
3
16
7
2 20 8
12 2•33 (6.1%) P 50% in the sums of the products of the perpendicular diameters of all measurable lesions for at least 4 weeks. A minor response (MR) was defined either as a reduction in the range of 25% -50% in the sums of the products of the perpendicular diameters of all measurable lesions or as a PR that did not last for >4 weeks. No change (NC) was defined as a reduction of 25% in the products of the perpendicular diameters of all measurable lesions.
Results
A total o f 139 patients with n o n r e s e c t e d p r i m a r y lung c a n c e r were recruited in this trial. T e n patients were excluded from analysis as inevaluable: three d i e d o f disease progression prior to c o m p l e t i o n o f the 4 - w e e k o b s e r v a t i o n period, five were e x c l u d e d because o f dose violations, one
Small-cell: Stage I/II 4 III 17 IV 46 Non-small-cell: Stage I/II 7 III 20 IV 35
PR
MR NC PD
CR+PR patients
0 0 0
2 7 10
0 1 2
2 8 17
0 1 17
2/4 (50.0%) 7/17 (41.2%) 10/46 (21.7%)
0 0 0
1 3 0
1 3 4
5 12 22
0 2 9
1/7 (14.3%) 3/20 (15.0%) 0/35 (0%)
refused subsequent treatment after the first c o u r s e and had no f o l l o w - u p data available, and one was e x c l u d e d b e c a u s e o f c o m b i n a t i o n treatment with other c y t o t o x i c agents. T h e r e m a i n i n g 129 patients were fully e v a l u a b l e f o r r e s p o n s e and toxic effects. In all, 1 1 patients with stage I o r II disease were included in this trial b e c a u s e they were _-> 80 years o f age (3), had received prior c h e m o t h e r a p y (3), or d e v e l o p e d c o m p l i c a t i o n s in the C N S or the lung (5). Table I s h o w s patient characteristics. A total o f 23 patients a c h i e v e d a PR, but n o n e attained a CR. T h e response rate for five cell types are p r e s e n t e d in T a b l e 2. R e s p o n s e rates in patients with s m a l l - c e l l disease, s q u a m o u s - c e l l c a r c i n o m a , and a d e n o c a r c i n o m a w e r e 28.4% (19/67), 7.1% (2/28), and 6.9% (2/29), r e s p e c t i v e l y . Response rates according to dose are g i v e n in T a b l e 3. A total o f 21 patients achieved a P R at the 400 m g / m 2 dose, 17 (34.0%) with small-cell and 4 (8.5%) with n o n - s m a l l cell disease, and 2 responders (1 1.8%) at the 300 mg/m2 dose were o b s e r v e d in patients with s m a l l - c e l l c a r c i n o m a . R e s p o n s e rates according to d i s e a s e stage are s h o w n in Table 4. In patients with small-cell disease, r e s p o n s e rates for stages I/II, III, and IV were 50.2%, 4 1 . 2 % , and 21.7%, respectively. F o r n o n - s m a l l - c e l l c a r c i n o m a , r e s p o n d e r s were o b s e r v e d in stages I/II and III. R e s p o n s e rates a c c o r d ing to PS are given in Table 5. A m o n g the patients with
103 Table 7. Toxic effects
Table 5, Response rates according to PS
Patients CR (n) Small-cell: PS 0 7 1 26 2 16 3 18 Non-small-cell: PS 0 3 1 30 2 23 3 6
PR
MR NC PD
0 0 0 0
I 9 2 7
1 1 0 I
5 10 7 5
0 6 7 5
1/7 9/26 2/16 7/18
(14.3%) (34.6%) (12.5%) (38.9%)
0 0 0 0
2 2 0 0
0 I 5 2
I 24 11 3
0 3 7 1
2/3 2/30 0•23 0/6
(66.5%) (6.7%) (0) (0)
Table 6. Response rates according to chemotherapy
Dose (m od'm2)
Prior chemotherapy Yes
No
Small-cell: 300 400
1110 6/26 7/36
(10.0%) (23.1%) (19.4%)
300 400
0/4 0/I 1 0/15
(0) (0) (0)
Subtotals
1/7 11/24 12/31
(14.3%) (45.8%) (38.7%)
0/I 1 4/36 4/47
(0) (11.1%) (8.5%)
Non-small-cell:
Subtotals
Incidence
CR+PR patients
small-cell disease, response rates for PS 0, 1,2, and 3 were 14.3%, 34.6%, 12.5%, and 38.9%, respectively. On the other hand, the responders with non-small-cell carcinoma were observed in PS 0 and t, with response rates of 66.5% and 6.7%, respectively. Response rates according to prior chemotherapy are given in Table 6. Of 31 patients with small-cell carcinoma who had received no previous chemotherapy, 1 (14.3%) achieved a PR when treated with 300 m~m2 carboplatin every 4 weeks, and 11 (45.8%) achieved a PR when treated at a dose of 400 mg/m2; of 36 patients who had received prior chemotherapy, 1 (10.0%) at the 300 mffm 2 dose and 6 (23.1%) at the 400 mg/m2 dose achieved a PR. Of 47 patients with non-small-cell carcinoma who had received no prior chemotherapy, only 4 (11.1%) achieved a PR at a dose of 400 mg/m2; of 22 patients who had been pretreated with cisplatin-containing regimens, 2 who had been responsive to cisplatin also responded to carboplatin. The median duration of response in patients with small-cell and non-small-cell carcinoma was 49 days (range, 28-119 days) and 46 days (range, 28-56 days), respectively. Survival of patients with small-cell disease ranged from 4 to 180+ weeks, with a median of 27 weeks; in all, 2 patients are still alive, 60 died, and 5 were lost to follow-up. Survival of patients with non-small-cell carcinoma ranged from 4 to 154+ weeks, with a median of 37 weeks; 3 patients are still alive, 55 died, and 4 were lost to follow-up. The most frequent side effects encountered were myelosuppression and gastrointestinal toxicity. Details are
300 mg/m2 (n = 32) Number of patients (%)
Leukocytes:
I00 IU 1 (3) Vomiting 4 (13) Anorexia 9 (28) Malaise 5 (16) Diarrhea 1 (3) Fever 4 (13) Abdominalpainand discomfort 0 Stomatitis • 0 Constipation 0 Glossitis 0 Alopecia 0
Chisquare400 mg/m2 test (n = 97) Number of patients (%)
50 (52) P
ancer hemothe.rapyand harmacolo © Springer-Verlag
1990
Phase II study of carboplatin in patients with nonresected lung cancer Japan Cooperative Oncology Group on Lung Cancer* Received 30 June 1989/Accepted 21 November 1989
Summary. A multicenter phase II trial of carboplatin, a new platinum analog of cisplatin, was carried out in bronchogenic carcinoma at 17 institutions throughout Japan. Of 139 patients enrolled in this trial, 10 were excluded from analysis as inevaluable and the remaining 129 were judged to be evaluable for response and toxic effects by the Extramural Review Committee. Patients were treated i. v. with either 300 or 400 mg/m2 carboplatin every 4 weeks. Responses and toxic effects were assessed at both dose levels. The overall response rate was 17.8% (23/129), with response rates of 28.4% (19/67) for small-cell disease, 7.1% (2/28) for squamous-cell carcinoma, and 6.9% (2/29) for adenocarcinoma. The most frequent toxic effects were thrombocytopenia and leukopenia, with a platelet count of 9.5 ~dl, a WBC count of _->3,500 I.tl, a platelet count of ~ 10× 104 ~1, serum creatinine levels of -4 weeks since any prior chemotherapy or radiation therapy was required. Informed consent was obtained from all patients. Carboplatin was given at a dose of 300 mg/m-~in patients with a PS of 2 or 3 and in those who had been heavily pretreated. Patients with a PS of ~< I and those who had not undergone prior chemotherapy received
102 Table 1. Patient characteristics
Eligible Evaluable Sex: men/women Age: median (range) Performance status 0 - I/2-3
Table 3. Response rates acccording to dose Total
300 mg/mz 400 mg/m 2
139 129 95/34 71 (33-86) years 66/63
36 32 26/7 72 (41-84) years 9/23
103 97 69/27 71 (33-86) years 57/40
Histology: Small-cell Squamous Adenocarcinoma Large-cell Adenoidocystic
67 28 29 4 1
17 8 5 1 1
50 20 24 3 0
Prior chemotherapy: No Yes
78 51
18 14
60 37 10 30 57
Dose Pati- CR PR MR NC PD CR+PR Chi(mg/m 2) ents(n ) patients squaretest Overall
300
33
0
400
96
0 21
8 50
300
17
0
2
I
400
50
0
17
Non300 small-cell 400
15
0
0
2
47
0
4
6 31
Smallcell
2
3
16
7
2 20 8
12 2•33 (6.1%) P 50% in the sums of the products of the perpendicular diameters of all measurable lesions for at least 4 weeks. A minor response (MR) was defined either as a reduction in the range of 25% -50% in the sums of the products of the perpendicular diameters of all measurable lesions or as a PR that did not last for >4 weeks. No change (NC) was defined as a reduction of 25% in the products of the perpendicular diameters of all measurable lesions.
Results
A total o f 139 patients with n o n r e s e c t e d p r i m a r y lung c a n c e r were recruited in this trial. T e n patients were excluded from analysis as inevaluable: three d i e d o f disease progression prior to c o m p l e t i o n o f the 4 - w e e k o b s e r v a t i o n period, five were e x c l u d e d because o f dose violations, one
Small-cell: Stage I/II 4 III 17 IV 46 Non-small-cell: Stage I/II 7 III 20 IV 35
PR
MR NC PD
CR+PR patients
0 0 0
2 7 10
0 1 2
2 8 17
0 1 17
2/4 (50.0%) 7/17 (41.2%) 10/46 (21.7%)
0 0 0
1 3 0
1 3 4
5 12 22
0 2 9
1/7 (14.3%) 3/20 (15.0%) 0/35 (0%)
refused subsequent treatment after the first c o u r s e and had no f o l l o w - u p data available, and one was e x c l u d e d b e c a u s e o f c o m b i n a t i o n treatment with other c y t o t o x i c agents. T h e r e m a i n i n g 129 patients were fully e v a l u a b l e f o r r e s p o n s e and toxic effects. In all, 1 1 patients with stage I o r II disease were included in this trial b e c a u s e they were _-> 80 years o f age (3), had received prior c h e m o t h e r a p y (3), or d e v e l o p e d c o m p l i c a t i o n s in the C N S or the lung (5). Table I s h o w s patient characteristics. A total o f 23 patients a c h i e v e d a PR, but n o n e attained a CR. T h e response rate for five cell types are p r e s e n t e d in T a b l e 2. R e s p o n s e rates in patients with s m a l l - c e l l disease, s q u a m o u s - c e l l c a r c i n o m a , and a d e n o c a r c i n o m a w e r e 28.4% (19/67), 7.1% (2/28), and 6.9% (2/29), r e s p e c t i v e l y . Response rates according to dose are g i v e n in T a b l e 3. A total o f 21 patients achieved a P R at the 400 m g / m 2 dose, 17 (34.0%) with small-cell and 4 (8.5%) with n o n - s m a l l cell disease, and 2 responders (1 1.8%) at the 300 mg/m2 dose were o b s e r v e d in patients with s m a l l - c e l l c a r c i n o m a . R e s p o n s e rates according to d i s e a s e stage are s h o w n in Table 4. In patients with small-cell disease, r e s p o n s e rates for stages I/II, III, and IV were 50.2%, 4 1 . 2 % , and 21.7%, respectively. F o r n o n - s m a l l - c e l l c a r c i n o m a , r e s p o n d e r s were o b s e r v e d in stages I/II and III. R e s p o n s e rates a c c o r d ing to PS are given in Table 5. A m o n g the patients with
103 Table 7. Toxic effects
Table 5, Response rates according to PS
Patients CR (n) Small-cell: PS 0 7 1 26 2 16 3 18 Non-small-cell: PS 0 3 1 30 2 23 3 6
PR
MR NC PD
0 0 0 0
I 9 2 7
1 1 0 I
5 10 7 5
0 6 7 5
1/7 9/26 2/16 7/18
(14.3%) (34.6%) (12.5%) (38.9%)
0 0 0 0
2 2 0 0
0 I 5 2
I 24 11 3
0 3 7 1
2/3 2/30 0•23 0/6
(66.5%) (6.7%) (0) (0)
Table 6. Response rates according to chemotherapy
Dose (m od'm2)
Prior chemotherapy Yes
No
Small-cell: 300 400
1110 6/26 7/36
(10.0%) (23.1%) (19.4%)
300 400
0/4 0/I 1 0/15
(0) (0) (0)
Subtotals
1/7 11/24 12/31
(14.3%) (45.8%) (38.7%)
0/I 1 4/36 4/47
(0) (11.1%) (8.5%)
Non-small-cell:
Subtotals
Incidence
CR+PR patients
small-cell disease, response rates for PS 0, 1,2, and 3 were 14.3%, 34.6%, 12.5%, and 38.9%, respectively. On the other hand, the responders with non-small-cell carcinoma were observed in PS 0 and t, with response rates of 66.5% and 6.7%, respectively. Response rates according to prior chemotherapy are given in Table 6. Of 31 patients with small-cell carcinoma who had received no previous chemotherapy, 1 (14.3%) achieved a PR when treated with 300 m~m2 carboplatin every 4 weeks, and 11 (45.8%) achieved a PR when treated at a dose of 400 mg/m2; of 36 patients who had received prior chemotherapy, 1 (10.0%) at the 300 mffm 2 dose and 6 (23.1%) at the 400 mg/m2 dose achieved a PR. Of 47 patients with non-small-cell carcinoma who had received no prior chemotherapy, only 4 (11.1%) achieved a PR at a dose of 400 mg/m2; of 22 patients who had been pretreated with cisplatin-containing regimens, 2 who had been responsive to cisplatin also responded to carboplatin. The median duration of response in patients with small-cell and non-small-cell carcinoma was 49 days (range, 28-119 days) and 46 days (range, 28-56 days), respectively. Survival of patients with small-cell disease ranged from 4 to 180+ weeks, with a median of 27 weeks; in all, 2 patients are still alive, 60 died, and 5 were lost to follow-up. Survival of patients with non-small-cell carcinoma ranged from 4 to 154+ weeks, with a median of 37 weeks; 3 patients are still alive, 55 died, and 4 were lost to follow-up. The most frequent side effects encountered were myelosuppression and gastrointestinal toxicity. Details are
300 mg/m2 (n = 32) Number of patients (%)
Leukocytes:
I00 IU 1 (3) Vomiting 4 (13) Anorexia 9 (28) Malaise 5 (16) Diarrhea 1 (3) Fever 4 (13) Abdominalpainand discomfort 0 Stomatitis • 0 Constipation 0 Glossitis 0 Alopecia 0
Chisquare400 mg/m2 test (n = 97) Number of patients (%)
50 (52) P
