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Two carboplatin-containing regimens for small cell lung cancer: preliminary results of a randomized phase II trial
Cancer
Treatment
Reuiews (1988)
15 (Supplement
B) 41-44
Twocarboplatin-containingregimensforsmaUcell lu.ngcancer:prelimharyresultsofarandomized phasenrial P. E. Postmus, A. Kirkpatrick, 0. Dalesio, F. J. Palmen, D. N. Carney, J. Fe&en, C. Vendrik, K. Roozendaal, J. Burghouts, A. Planting, E. Quoix, T. A. W. Splinter and J. G. McVie The EOR TC Lung Cancer Cooperative Group, Boulevard
de Waterloo
125, 1000 Brussels, Belgium
Introduction Carboplatin is a clinically active cisplatin analogue with useful clinical advantages over the parent compound. It produces less nausea and vomiting than cisplatin and has no significant nephrotoxicity ( 1). Cisplatin has been reported to have only a modest response rate against small cell lung cancer, SCLC (3). On the other hand, carboplatin has been reported to have remarkable activity in SCLC. In a phase II study, 3 complete responses (CR) and 15 partial responses (PR) were noted in 30 untreated extensive disease patients. Furthermore 2 CR’s and 3 PR’s were seen in 26 pretreated patients (5). The principal side effects were nausea and vomiting and myelosuppression. Also the combination of carboplatin with etoposide is claimed to be very active against SCLC with an 85% response rate. However, response duration and survival are disappointing (4). Despite the use of a lower dose of carboplatin (300 mg/m2) in this combination regimen than in the single agent study (400 mg/m2), the main toxicity was myelosuppression. Grade 3/4 leukopenia occurred in 44% of the patients. Combining carboplatin with other non-myelotoxic drugs with activity against SCLC might be feasible. Two active agents, ifosfamide and vincristine, are good candidates for such a regimen. Ifosfamide in a dose of 5 g/m2 in a 24-h infusion gave a major response in 50% of pretreated SCLC patients without significant myelosuppression in 61 courses (2). Vincristine has been used for over 15 years for SCLC and gives no myelosuppression. In this study we tested carboplatin in combination with ifosfamide or vincristine in untreated SCLC patients.
Materials
and methods
Patients and methods One hundred proven SCLC Correspondence University Hospital,
and twenty newly diagnosed patients with histologically or cytologically were entered in this multicenter study between April 1986 and June 1987. should be addressed to P. E. Postmus, M.D., Department Oostersingel59, 9713 EZ Groningen, The Netherlands.
0305~7372/88/15B0041+04
$03.00/O
of Pulmonary
0 41
1988 Academic
Diseases,
State
Press Limited
42
P. E. POSTMUS
ET
AL.
Up until now, 85 patients have been evaluated for response and toxicity. Forty-five patients had limited disease (LD) and 40 extensive disease (ED) according to standard staging criteria. Sixty-eight patients had a good performance score, ECOG 0 or 1, and 17 had ECOG 2 or 3. Patients were randomized after stratification for ECOG 0 or 1 versus 2 or 3 and LD versus ED (a third arm was included consisting of our standard regimen cyclophosphamide, doxorubicin and etoposide (CDE); data will be reported later).
Treatment Carboplatin (P) was administered in a dose of 400 mg/m’ in 250 ml dextrose 5% in a 30 min infusion. Vincristine (V) was administered as an i.v. bolus in a dose of 2 mg on day 1 and 8. Ifosfamide (I) was given as a 24-h infusion in a dose of 5 g/m*. Mesna (M), 0.6 g/m*, was given as an i.v. bolus with 200 ml mannitol (20%) before the ifosfamide infusion. During the ifosfamide infusion and the following 12 hours 3.75 g/m* mesna was given as a continuous infusion. Forced diuresis was established by giving 6 liter dextrose/saline in 38 h. The combinations IMP and VP were repeated once every 4 weeks for a total of 5 courses provided patients responded or remained stable.
Response and toxicity Response was evaluated after 2 and 5 courses. Tumor response was defined according to standard criteria: complete response (CR) was defined as the disappearance of all known disease for at least 4 weeks; partial response (PR) was defined as a reduction in the product of two diameters of a lesion by at least 50% for at least 4 weeks; stable disease (SD) was defined as a decrease of < 50% or an increase of < 25% in the size of one or more lesions. Response duration was measured from the start of treatment to progression. Toxicity was graded according to standard WHO criteria (7).
Results Response Thirty-eight patients in the IMP arm and 47 patients in the VP arm have been evaluated so far. Twenty-nine patients (76%) ac h’ teved a response in the IMP arm, including 5 CR’s (13%). In the VP arm 29 patients (62%) ac h ieved a response including 6 CR’s ( 13%). After 5 courses 18 out of 37 evaluable patients in the IMP arm were still in remission. Of the patients treated with VP only 12 out of 47 evaluable patients were still in remission at that time. Median response duration in the IMP arm was 16 weeks (range 10-58) and in the VP arm 14 weeks (range 9-54).
Toxicio Myelosuppression was mild in the VP arm, but it was more severe in the IMP arm. Leukocyte nadirs < 1.0 x log/1 were noted in 5.7% of the VP courses and 21.3% of the IMP courses. Platelet nadirs < 25 x IO’/1 occurred in 17.1 y0 of the VP courses and 2 1.4%
CARBOPLATIN
Table
AND
SMALL
CELL
1. Non-hematological
LUNG
side
CANCER
43
effects
Treatment IMP y. Pts
Side effect Nausea/vomiting
89
(32)
82
(12)
Alopecia Infection Neurotoxicity Diarrhea Renal creatinine Haematuria
87 (50) 23 (4) 12 (4) 13 4 6
53 17 41 8
(4) (6) (4)
2
Figures in parentheses are percentage patients with grade 3 & 4 toxicities.
of
of the IMP courses. Other toxicities were mild and are described in Table 1. One patient died during the first IMP course due to severe dehydration and aplasia-related septicemia. In one IMP patient, treatment was stopped because of severe subjective toxicity.
Discussion
The preliminary results of this randomized phase II study of carboplatin at a dose of 400 mg/m*, with a non-myelosuppressive drug active against SCLC, clearly demonstrate the feasibility of this approach. Hematologic toxicity of the VP combination is mild and comparable to the toxicity of carboplatin alone (5). The IMP combination gives more myelosuppression, probably caused by a mild myelosuppressive effect of ifosfamide. A higher response rate (76%) was found with carboplatin in combination with ifosfamide than in combination with vincristine (62%). This latter response rate is comparable to the activity of carboplatin alone in untreated SCLC patients (5). In both arms, the number of CR’s is low and the number of patients still in remission after 5 courses of either IMP or VP is also disappointingly low. An explanation for this might be the rather long period of 4 weeks between courses. For a tumor like SCLC with a rapid growth rate this might be too long. These two carboplatin-containing regimens are inferior to standard combination chemotherapy regimens, for example CDE (6)) with respect to both response rate and response duration. Failures on IMP and VP have been treated with CDE and some patients have responded. Only if carboplatin shows true non-cross resistance with currently used drugs will it find a place in the treatment of SCLC.
References 1. Calvert, A. H., Harland, dicarboxylate platinum
S. J. & Newell, D. R. (1982) Early clinical studies II. Cancer Chemother. Pharmacof. 9: 140-147.
with
cis-diammine
2. Cantwell, B., Harris, A., Bozzino, J., Co&, P., Nariman, S., Pearce, S., Gibson, High dose ifosfamide and mesna as cross over therapy after adriamycin, VP 16-213 for small cell lung cancer. Pm. AX0 3: 2 16. 3. Cavalli, F., Goldhirsch, A., Siegenthaler, P., Kaplan, S. & Beer, M. (1980) dichlorodiammine platinum (II) in small cell anaplastic carcinoma. Eur. J. Cancer 4. Smith,
I. E., Evans,
B. D., Gore,
M. E., Vincent,
M. D., Repetto,
L., Yarnold,
I, I-cyclobutane
J. & Hendrick, and vincristine
D. (1984) (VP-AV)
Phase II study 16: 617-623.
J. R. & Ford,
with
cis-
H. T. (1987)
44
P. E. POSTMUS Carboplatin (paraplatin; JM8) and etoposide cancer. J. Clin. Oncol. 5: 185-189.
(VP-16)
5. Smith, I. E., Harland, S. J., Robinson, B. A., Evans, Glees, J. P., Baher, J. & Ford, H. T. (1985) Carboplatin: of small cell lung cancer. Cancer Treat. Rep. 6% 43-46.
ET
AL.
as first-line
combination
B. D., Goodhart, a very active
therapy
for small-cell
lung
L. C., Calvert, A. H., Yarnold, J., new cisplatin analog in the treatment
6. Splinter, T., McVie, J., Dalesio, O., Kirkpatrick, A., Burghouts, J., Postmus, P., Veenhof, C., Giaccone, G., Kho, G., Bakker, W., ten Veide, G., Vendrik, C., van Zandwijk, Palmen, F., Rozendaal, K., v. d. Burgh, M., van Breukelen, F., Rinaldi, M., Kleisbaner, J., Gracia, J., Wils, J., Miech, G. & Festen, J. (1986) EORTC
08825:
induction
versus
induction
plus
maintenance
chemotherapy
in small
cell lung
cancer.
Proc.
ASCO 5: 188. 7. World offset
Health publication
Organization
(1979)
no. 48. Geneva.
WHO
handbook
for
reporting
the results
of cancer
treatment.
WHO
Treatment
Reuiews (1988)
15 (Supplement
B) 41-44
Twocarboplatin-containingregimensforsmaUcell lu.ngcancer:prelimharyresultsofarandomized phasenrial P. E. Postmus, A. Kirkpatrick, 0. Dalesio, F. J. Palmen, D. N. Carney, J. Fe&en, C. Vendrik, K. Roozendaal, J. Burghouts, A. Planting, E. Quoix, T. A. W. Splinter and J. G. McVie The EOR TC Lung Cancer Cooperative Group, Boulevard
de Waterloo
125, 1000 Brussels, Belgium
Introduction Carboplatin is a clinically active cisplatin analogue with useful clinical advantages over the parent compound. It produces less nausea and vomiting than cisplatin and has no significant nephrotoxicity ( 1). Cisplatin has been reported to have only a modest response rate against small cell lung cancer, SCLC (3). On the other hand, carboplatin has been reported to have remarkable activity in SCLC. In a phase II study, 3 complete responses (CR) and 15 partial responses (PR) were noted in 30 untreated extensive disease patients. Furthermore 2 CR’s and 3 PR’s were seen in 26 pretreated patients (5). The principal side effects were nausea and vomiting and myelosuppression. Also the combination of carboplatin with etoposide is claimed to be very active against SCLC with an 85% response rate. However, response duration and survival are disappointing (4). Despite the use of a lower dose of carboplatin (300 mg/m2) in this combination regimen than in the single agent study (400 mg/m2), the main toxicity was myelosuppression. Grade 3/4 leukopenia occurred in 44% of the patients. Combining carboplatin with other non-myelotoxic drugs with activity against SCLC might be feasible. Two active agents, ifosfamide and vincristine, are good candidates for such a regimen. Ifosfamide in a dose of 5 g/m2 in a 24-h infusion gave a major response in 50% of pretreated SCLC patients without significant myelosuppression in 61 courses (2). Vincristine has been used for over 15 years for SCLC and gives no myelosuppression. In this study we tested carboplatin in combination with ifosfamide or vincristine in untreated SCLC patients.
Materials
and methods
Patients and methods One hundred proven SCLC Correspondence University Hospital,
and twenty newly diagnosed patients with histologically or cytologically were entered in this multicenter study between April 1986 and June 1987. should be addressed to P. E. Postmus, M.D., Department Oostersingel59, 9713 EZ Groningen, The Netherlands.
0305~7372/88/15B0041+04
$03.00/O
of Pulmonary
0 41
1988 Academic
Diseases,
State
Press Limited
42
P. E. POSTMUS
ET
AL.
Up until now, 85 patients have been evaluated for response and toxicity. Forty-five patients had limited disease (LD) and 40 extensive disease (ED) according to standard staging criteria. Sixty-eight patients had a good performance score, ECOG 0 or 1, and 17 had ECOG 2 or 3. Patients were randomized after stratification for ECOG 0 or 1 versus 2 or 3 and LD versus ED (a third arm was included consisting of our standard regimen cyclophosphamide, doxorubicin and etoposide (CDE); data will be reported later).
Treatment Carboplatin (P) was administered in a dose of 400 mg/m’ in 250 ml dextrose 5% in a 30 min infusion. Vincristine (V) was administered as an i.v. bolus in a dose of 2 mg on day 1 and 8. Ifosfamide (I) was given as a 24-h infusion in a dose of 5 g/m*. Mesna (M), 0.6 g/m*, was given as an i.v. bolus with 200 ml mannitol (20%) before the ifosfamide infusion. During the ifosfamide infusion and the following 12 hours 3.75 g/m* mesna was given as a continuous infusion. Forced diuresis was established by giving 6 liter dextrose/saline in 38 h. The combinations IMP and VP were repeated once every 4 weeks for a total of 5 courses provided patients responded or remained stable.
Response and toxicity Response was evaluated after 2 and 5 courses. Tumor response was defined according to standard criteria: complete response (CR) was defined as the disappearance of all known disease for at least 4 weeks; partial response (PR) was defined as a reduction in the product of two diameters of a lesion by at least 50% for at least 4 weeks; stable disease (SD) was defined as a decrease of < 50% or an increase of < 25% in the size of one or more lesions. Response duration was measured from the start of treatment to progression. Toxicity was graded according to standard WHO criteria (7).
Results Response Thirty-eight patients in the IMP arm and 47 patients in the VP arm have been evaluated so far. Twenty-nine patients (76%) ac h’ teved a response in the IMP arm, including 5 CR’s (13%). In the VP arm 29 patients (62%) ac h ieved a response including 6 CR’s ( 13%). After 5 courses 18 out of 37 evaluable patients in the IMP arm were still in remission. Of the patients treated with VP only 12 out of 47 evaluable patients were still in remission at that time. Median response duration in the IMP arm was 16 weeks (range 10-58) and in the VP arm 14 weeks (range 9-54).
Toxicio Myelosuppression was mild in the VP arm, but it was more severe in the IMP arm. Leukocyte nadirs < 1.0 x log/1 were noted in 5.7% of the VP courses and 21.3% of the IMP courses. Platelet nadirs < 25 x IO’/1 occurred in 17.1 y0 of the VP courses and 2 1.4%
CARBOPLATIN
Table
AND
SMALL
CELL
1. Non-hematological
LUNG
side
CANCER
43
effects
Treatment IMP y. Pts
Side effect Nausea/vomiting
89
(32)
82
(12)
Alopecia Infection Neurotoxicity Diarrhea Renal creatinine Haematuria
87 (50) 23 (4) 12 (4) 13 4 6
53 17 41 8
(4) (6) (4)
2
Figures in parentheses are percentage patients with grade 3 & 4 toxicities.
of
of the IMP courses. Other toxicities were mild and are described in Table 1. One patient died during the first IMP course due to severe dehydration and aplasia-related septicemia. In one IMP patient, treatment was stopped because of severe subjective toxicity.
Discussion
The preliminary results of this randomized phase II study of carboplatin at a dose of 400 mg/m*, with a non-myelosuppressive drug active against SCLC, clearly demonstrate the feasibility of this approach. Hematologic toxicity of the VP combination is mild and comparable to the toxicity of carboplatin alone (5). The IMP combination gives more myelosuppression, probably caused by a mild myelosuppressive effect of ifosfamide. A higher response rate (76%) was found with carboplatin in combination with ifosfamide than in combination with vincristine (62%). This latter response rate is comparable to the activity of carboplatin alone in untreated SCLC patients (5). In both arms, the number of CR’s is low and the number of patients still in remission after 5 courses of either IMP or VP is also disappointingly low. An explanation for this might be the rather long period of 4 weeks between courses. For a tumor like SCLC with a rapid growth rate this might be too long. These two carboplatin-containing regimens are inferior to standard combination chemotherapy regimens, for example CDE (6)) with respect to both response rate and response duration. Failures on IMP and VP have been treated with CDE and some patients have responded. Only if carboplatin shows true non-cross resistance with currently used drugs will it find a place in the treatment of SCLC.
References 1. Calvert, A. H., Harland, dicarboxylate platinum
S. J. & Newell, D. R. (1982) Early clinical studies II. Cancer Chemother. Pharmacof. 9: 140-147.
with
cis-diammine
2. Cantwell, B., Harris, A., Bozzino, J., Co&, P., Nariman, S., Pearce, S., Gibson, High dose ifosfamide and mesna as cross over therapy after adriamycin, VP 16-213 for small cell lung cancer. Pm. AX0 3: 2 16. 3. Cavalli, F., Goldhirsch, A., Siegenthaler, P., Kaplan, S. & Beer, M. (1980) dichlorodiammine platinum (II) in small cell anaplastic carcinoma. Eur. J. Cancer 4. Smith,
I. E., Evans,
B. D., Gore,
M. E., Vincent,
M. D., Repetto,
L., Yarnold,
I, I-cyclobutane
J. & Hendrick, and vincristine
D. (1984) (VP-AV)
Phase II study 16: 617-623.
J. R. & Ford,
with
cis-
H. T. (1987)
44
P. E. POSTMUS Carboplatin (paraplatin; JM8) and etoposide cancer. J. Clin. Oncol. 5: 185-189.
(VP-16)
5. Smith, I. E., Harland, S. J., Robinson, B. A., Evans, Glees, J. P., Baher, J. & Ford, H. T. (1985) Carboplatin: of small cell lung cancer. Cancer Treat. Rep. 6% 43-46.
ET
AL.
as first-line
combination
B. D., Goodhart, a very active
therapy
for small-cell
lung
L. C., Calvert, A. H., Yarnold, J., new cisplatin analog in the treatment
6. Splinter, T., McVie, J., Dalesio, O., Kirkpatrick, A., Burghouts, J., Postmus, P., Veenhof, C., Giaccone, G., Kho, G., Bakker, W., ten Veide, G., Vendrik, C., van Zandwijk, Palmen, F., Rozendaal, K., v. d. Burgh, M., van Breukelen, F., Rinaldi, M., Kleisbaner, J., Gracia, J., Wils, J., Miech, G. & Festen, J. (1986) EORTC
08825:
induction
versus
induction
plus
maintenance
chemotherapy
in small
cell lung
cancer.
Proc.
ASCO 5: 188. 7. World offset
Health publication
Organization
(1979)
no. 48. Geneva.
WHO
handbook
for
reporting
the results
of cancer
treatment.
WHO