Crossover study with cisplatin or carboplatin in advanced ovarian cancer

GYNECOLOGIC ONCOLOGY

39, 146-149 (19%)

Crossover Study with Cisplatin or Carboplatin in Advanced Ovarian Cancer L. REPETTO,*J S. CHIARA,* S. MAMMOLITI,* T. GUIDO,” M. BRUZZONE ,* V. SECONDO,t G. DONADIO,$ F. ODICINO,~ N. RAGNI,§ P. F. CONTE,* AND R. ROSSO* *htituto

Nazionale

per la Ricerca sul Cancro,

Genoa;

TOspedale

Ginecologica,

Galhera,

Universitd

Genoa;

.$Gspeda[e

S. Giovanni,

Torino;

and BClinica

Ostetrica

e

di Genova, Genoa, Italy

Received March 15, 1990

Fifty-seven patients who had progressed during or relapsed after randomized first-line combination chemotherapy containing cisplatin or carboplati were entered into a crossover study in which the analog not previously assigned was administered alone as salvage treatment. Carboplatin and cisplatin were administered at doses of 400 and 100 mg/m’, respectively, every 28 days. Among the 24 patients enrolled in the cisplatin arm, 6 (25%) objective responses(OR@ (3 complete, 3 partial) were observed, whereas 3 partial responseswere obtained in the 33 carboplatintreated patient (9%). Analysis of results, according to response to first-line chemotherapy, demonstrated that the patients who progressed were sensitive only to cisplatin second-line treatment (OR: 3/12), with no responders among carboplatin-treated patients (OR: O/11). All patients were treated on an outpatient basis and therapy-related toxic effects were mild, consisting chiefly of myelosuppression, and more frequent in the carboplatiq group. In our opinion, carboplatin 400 mg/m* per cycle is scarcely effective in patients with refractory or relapsed ovarian cancer pretreated with cisplatin regimens, whereas cisplatin 100 mg/m* per cycle appears to be an effective salvage therapy even in patients not responding to carboplatin. The dose of carboplatin should be further escalated especially in refractory patients. Q 1990 Acad& Press, Inc.

icities [l]. Moreover the lack of effective salvage treatment for refractory or relapsed patients requires the utilization of pon-cross-resistant drugs whose toxicity is not cumulative with primary treatment [2]. Among second-generation cisplatin analogs, carboplatin appears the most effective. Phase I studies have shown that carboplatin causes myelotoxicity, particularly thrombocytopenia, but not nephrotoxicity. In phase II trials responses were seen in ovarian cancer patients both previously treated and previously untreated with cisplatin [3-51. However, the optimal dose, dose intensity, and in particular the equivalent dose of cisplatin and carboplatin have not been found, and the platinum analog of choice for first-line treatment remains undetermined. In an attempt to retain the therapeutic benefit of platinum derivatives without additional toxicity, we have performed a crossover study in which ovarian cancer patients failing front-line combination chemotherapy including cisplatin or carboplatin were switched to the platinum analogs as salvage treatment. PATIENTS AND METHODS

INTRODUCTION

Between March 1985 and October 1987, 164 patients with advanced ovarian cancer entered a randomized study comparing cisplatin 50 mg/m*, Adriamycin 45 mg/m*, and cyclophosphamide 600 mg/m* (PAC) versus inconsequential toxicity of cisplatin have stimulated the carboplatin 200 mg/m*, Adriamycin 45 mg/ms;2, and search for platinum analogs either more active or less cyclophosphamide 600 mg/m* (CAC), on Day 1 and toxic than cisplatin. In particular, emesis and neurologevery 28 days thereafter. Details of this trial have been ical side effects are the most important dose-limiting toxpublished elsewhere [6]. Patients who were no longer responding to front-line ’ To whom requests for reprints should be addressed at Istituto therapy or who had relapsed after an initial objective Nazionale Ricerca Cancro, Viale Benedetto XV, 10, 16132-Genoa, Italy. response were entered into a crossover study in which

The major role of cisplatin in the treatment of patients with advanced ovarian cancer has been established. The effective antitumor activity and the manageable but not

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Copyright 8 1990by AcademicPress,Inc. All rights of reproductionin any form reserved.

CISPLATIN

VERSUS CARBOPLATIN

AS SECOND LINE IN OVARIAN

TABLE 1 Characteristicsof the PatientsEntering the CrossoverStudy of Cisplatin versusCarboplatin Second-line treatment Carboplatin

Cisplatin

33 54 (43-68)

24 56 (36-70)

16 15 2

13 9 2

2 31 6 (4-12)

24 7 (2-12)

6 13 8 3 3

1 11 11 1 -

15 17 1

11 12 1

Number of patients Median age (range) ECOC PS 0 1 2 First-line chemotherapy PC PAC CAC Median numberof courses (range) Response to first-line chemotherapy Complete response Partial response Stable disease Progressive disease Not evaluable Residual disease at crossover >5 cm 2-5 cm <2 cm

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CANCER

All the patients had undergone aggressive surgery and the majority presented with bulky residual disease after operation. The median number of chemotherapy courses for the entire group of patients was six and at least two cycles of front-line treatment were administered before the regimen was considered ineffective and the crossover made to the platinum analog. The median intervals between the end of first-line treatment and the start of second-line therapy were 4 months (range l-40) and 2 months (range 1-16) in the carboplatin and cisplatin groups, respectively. At the beginning of second-line treatment 23 patients were nonresponders and 34 patients were in relapse after receiving front-line therapy. An objective response to PAC or PC regimens was obtained in 19 patients (57%), with complete responses in 6 patients and stable or progressive disease in 11 patients (33%); the remaining 3 patients were not evaluable. After treatment with CAC, 12 patients (50%) presented an objective response, with a complete response in 1 patient and stable or progressive disease in 12 (50%) patients. At the time of entry into the crossover study, all but 2 patients had measurable disease. RESULTS

the drug not previously assigned was administered as second-line monochemotherapy. Thus 57 patients were treated, 33 with carboplatin 400 mg/m* every 28 days and 24 with cisplatin 100 mg/m* every 28 days. In addition, 6 patients from previous studies, all including CDDP-based chemotherapy (PC or PAC), were enrolled in the carbolatin arm. Carboplatin 400 mg/m* was administered in 250 ml of 5% dextrose or normal saline and given iv over 30 min. Cisplatin 100 mg/m* was administered on an outpatient basis divided in equal doses for 2 consecutive days; the drug was delivered in 100 ml normal saline following prehydration and 40 mg furosemide iv; after CDDP infusion, 1.5 liters normal saline with 30 mEq KC1 and 2 mEq MgSO was given in 2 hr. Characteristics of the patients are listed in Table 1.

All 57 patients treated with carboplatin or cisplatin were evaluable for response to therapy, survival, and toxicity. The median numbers of cycles were 2 (range l-7) and 4 (range l-5) in the carboplatin- and cisplatintreated groups, respectively. Six of twenty-four (25%) patients had an objective response (3 complete, 3 partial) in the cisplatin arm, whereas only 3 of 24 (%) carboplatin-treated patients had an objective response (partial). (P = ns). Table 2 summarizes the results of treatment according to response to first-line therapy. Objective response rates in patients previously responding to first-line treatment were 13% (3/22 patients) in the carboplatin group and 25% (3/12 patients) in the cisplatin group; moreover, disease stabilization was observed in 18% of patients receiving carboplatin and in 25% of patients receiving cisplatin. No responses were observed

TABLE 2 Responseto CrossoverTreatment in Refractoryand RelapsedPatients Carboplatin Relapsed Complete response Partial response Stable disease Progressive disease

3 4 15

Cisplatin

Refractory

Total

Relapsed

Refractory

Total

4 7

-

2 1 3 6

1 2 5 4

3 3 8 10

3 8 22

148

REPETTO ET AL.

Entered CDDP 24 cmcA33

treated patients. No dosage reduction or treatment discontinuation was required because of hematological or other toxicity.

D& 20 23

p=ns.

DISCUSSION

I

I 6

I 12

I 16

, 24

, 30

mos

FIG. 1. Crossover study: survival curves.

in carboplatin-treated patients who had stable or progressive disease while receiving cisplatin-based chemotherapy, whereas 3 patients (25%) refractory to carboplatin combination achieved an objective response after salvage treatment with cisplatin. Median survival times were 6 and 9 months for carboplatin and cisplatin groups, respectively (Fig. 1). All patients were treated on an outpatient basis and treatment-related toxic effects are presented in Table 3. Hematological toxicity was more frequent in the carboplatin group. A severe degree of leukopenia was noted in 21% of the carboplatin patients and in 8% of the cisplatin group; thrombocytopenia was observed in 21% of patients treated with carboplatin and in no patients treated with cisplatin. However, differences in toxicity between the treatment groups are not significant. No renal or neurologic toxicity was observed in carboplatin-

Results of the study demonstrate that carboplatin 400 mg/m2 per cycle is scarcely effective in refractory or relapsed ovarian cancer patients previously treated with cisplatin-based chemotherapy, whereas cisplatin 100 mg/m2 per cycle appears to be an effective salvage regimen even in patients pretreated with carboplatin. In our hands, cisplatin elicited an average response rate of 25% in carboplatin-pretreated patients, with three refractory patients responding to salvage treatment. Carboplatin was moderately active (13% response rate) only in those patients who had responded to prior therapy with cisplatin. However, the absence of severe hematological toxicity may indicate that the dose of 400 mg/m2 is too low. In fact, in our series, myelosuppression induced by carboplatin was mild, with only a small number of patients experiencing grade 3 or 4 toxicity; it was easily manageable in all cases and did not require dose reduction or treatment discontinuation. Thus, in our opinion the dose intensity of platinum derivatives is crucial in relapsed or refractory patients: the use of carboplatin 400 mg/m2 in ovarian cancer patients previously treated with cisplatin is not likely to be of benefit. The dose of carboplatin should be further escalated in this group of patients. It has been reported that carboplatin 800 mg/m2 is an effective salvage regimen in patients who have previously responded to cisplatin 50 to 100 mg/m2, with a response rate of 27% [7]. These authors suggest that highdose carboplatin produces results similar to those of high-dose cisplatin with a different pattern of toxicity.

TABLE 3

Toxicity of Crossover Treatment with Cisplatin or Carboplatin Carboplatin

Emesis Leukopenia Anemia Thrombocytopenia Fever Diarrhea Mucositis Renal Neurotoxicity Ototoxicity

Cisplatin

All grades (%)

Grades 3 and 4 (%o)

All grades (%I

Grades 3 and 4 m

28133 (85) 16/33 (48) 17133 (51) U/33 (45)

16/33 (48) 7/33 (21) 8/33 (24) 7/33 (21) -

22124 (91) 7124 (29) 7124 (29) 2/24 (8) 2124 (8) 2124 (8) 4/24 (16) 5/24 (21)

15/24 (62) 2/24 (8) 4/24 (16) -

2133(6) 3133 (9) 3133 (9)

z/24 (8)

CISPLATIN

VERSUS CARBOPLATIN

AS SECOND LINE IN OVARIAN

Although in vitro studies reveal that the pharmacologic equivalency ratio of carboplatin to cisplatin is 4: 1 [8], our experience suggests that patients pretreated with carboplatin 200 mg/m’ can be salvaged with an intermediate dose of cisplatin (100 mg/m*), whereas patients pretreated with cisplatin 50 mg/m* require high doses of carboplatin (about 800-1000 mg/m’). Clinical cross-resistance between cisplatin and carboplatin has already been reported [7-91. The formation of the same DNA adducts in patients and human ovarian cancer cell lines treated with either cisplatin or carboplatin suggests that platinum analogs produce the same cytotoxic lesion, which is considered the primary determinant of cross-resistance between platinum analogs [lo-131. Kjorstad et al. [ 141reported an objective response rate of 31% (2 complete and 10 partial responders) in patients who relapsed after an initial response to cisplatin and a rate of 6% (one partial responder) in patients refractory to cisplatin-based chemotherapy. In the study of Marsoni et al. [15] 94 patients previously treated with cisplatin plus Adriamycin received carboplatin 300 mg/m*; the response rate was 24% in responding patients; no response was observed in patients progressing on cisplatin. In both studies the myelosuppression was comparable to that in our series. These and other reports [16] generally conclude that platinum analogs are effective only in patients who have previously responded to cisplatin and the analog is preferred in re-treating patients because of the reduced nonhematological toxicity. It, however, remains to be determined what the equivalent dose of the two analogs is and whether high-dose carboplatin (>800 mg/m*) can be safely repeated either alone or combined with an alkylating agent in previously treated ovarian cancer patients. It appears that even higher doses should be tested in patients whose disease is refractory to cisplatin. ACKNOWLEDGMENT This work was supported in part by Bristol-Myers Squibb Company, Wallingford, Connecticut.

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