Carboplatin in combination therapy for ovarian cancer

Cancer Treatment

Reviews

(1988)

15 (Supplement

B) 9-15

Carboplatinincombinationtherapyfor ovariancancer W. W. ten Bokkel Huinink,* M. E. L. van der Burg, A. T. van Oosterom, J. P. Neijt, M. George, J. P. Guastalla, C. H. N. Veenhof, N. Rotmensz, 0. Dalesio and J. B. Vermorken Amsterdam, Rotterdam, Leiden, Utrecht, Paris, Lyon and Brussels, for the Gynaecological Cooperative Group for the European Organization for Research and Treatment of Cancer

Cancer

Cisplatin-containing combination chemotherapy may result in prolonged remissions and improved survival for patients with ovarian cancer. In two randomized prospective studies the CHAP-5 chemotherapy regimen, developed by the Netherlands Joint Ovarian Cancer Study Group, has proven its value in patients with ovarian cancer (4, 5). The CHAP-5 regimen consists of an alternating scheme of doxorubicin given on day 1 and cisplatin on days l-5 and a combination of hexamethylmelamine and cyclophosphamide given orally on days 15-28. Cisplatin is probably the most active drug in this combination, but also the most toxic. Replacement of cisplatin by an analogue would be a major step forward in the treatment of ovarian cancer if indeed toxicity is reduced and the antitumour effect is maintained. Carboplatin has been studied in ovarian cancer patients at the Royal Marsden Hospital London, U.K. since 1981. Antitumour activity was observed even in phase I studies after failure of cisplatin-containing treatment. In a randomized study, Wiltshaw (7) has shown that carboplatin is far less toxic than cisplatin and equally active against ovarian cancer when used as first line treatment. Carboplatin does not exhibit neuro- or ototoxicity and even sophisticated methods for the study of nephrotoxicity have not shown major disturbance of renal function. Phase I trials revealed mild gastrointestinal toxicity, mainly nausea and vomiting and myelosuppression, as the major side effect of carboplatin. As a result of phase I studies a dose of 40&450 mg/ m2 i.v. q 5 weeks was recommended (1). Replacement of cisplatin by carboplatin in combination chemotherapy therefore seems justified by the expected better tolerance and improved quality of life during treatment. A feasibility study was undertaken to see if carboplatin could safely replace cisplatin in

* The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. Other participants in this study were M. Piccart (Brussels), L. Beekx (Nijmegen), K. J. Roozendaal (Amsterdam), T. Splinter (Rotterdam), A. Herruzo (Granada), M. Aapro (Geneva), J. J. Croles (Den Bosch), L. Siegenbeek van Heukelom (Alkmaar), J. H. van Lijf (Enschede), A. C. J. M. Holdrinet (Breda), W. P. M. Breed (Eindhoven), K. D. van der Stadt (Heemstede), D. Becquard (Antwerp), C. A. M. Swart (Haarlem), A. Lacave (Oviedo) 030%7372/88/1580009+

07 $03.00/O

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1988 Academic

Press Limited

10

TEN

BOKKEL

HUININK

ET AL.

the CHAP-5 regimen (6). After study seemed warranted.

this pilot

experience

a randomized

Randomized

III trial

comparing

CHAP-5

phase

Patients suffering from histologically IV were eligible for randomization.

prospective

with

large scale

CHAC-1

verified ovarian cancer, FIG0 stage IIB, The exclusion criteria were as follows:

C, III and

Performance status WHO > 3; Age > 70 years; A life expectancy of < 2 months; A creatinine clearance of < 60 ml/min or a serum creatinine of > 1.2 mg% ( > 110 ,umol/l), or bilirubin > 25 pmol/l; Any previous treatment with chemotherapy or radiotherapy; WBC < 4.0 x IO’/1 or platelets < 120 x log/l; Any serious heart failure or other cardiac disease; A staging procedure carried out more than 6 weeks before the start of chemotherapy; Expected problems of follow up; A second malignant disease with the exception of a radically treated in situ carcinoma of the uterine cervix or basal cell carcinoma of the skin. Trial After diagnosis and staging, were stratified for: (1) (2) (3) (4)

preferably

design with

aggressive

cytoreductive

surgery,

patients

FIG0 stage; Residual tumour volume, ( > 1 .O cm and < 1 .O cm diameter); Performance status (WHO 0, 1, 2, 3); Histological grade.

After stratification the patients were randomized between CHAP-5 or CHAC- 1. After 3 courses of chemotherapy all patients were evaluated by clinical examination, X-ray investigations and ultrasound. If primary debulking surgery had not been possible previously, another attempt to remove as much tumour as possible had to be undertaken after this evaluation to see if any change in the tumour situation made a second attempt feasible. After 6 courses patients were evaluated definitively for response with clinical investigations, CT and ultrasound. If no signs of tumour were found, restaging laparoscopy followed by laparotomy was mandatory and was executed according to a strict surgical protocol. Patients who achieved complete remission were given 3 more courses of chemoTable

1. Chemotherapy

regimens

CHAP-5 Cisplatin 20 mg/m* d x 5 Doxorubicin 35 mg/m’ d 1 Hexamethylmelamine 150 mg/m’ Cyclophosphamide 100 mg/m* Orally d 14-28

CHAC-1 Carboplatin Doxorubicin

350 mg/m’d 1 35 mg/m’ d 1

Hexamethylmelamine 150 mg/m* Cyclophosphamide 100 mg/m’ Orally d 14-28

CARBOPLATIN Table

2. Dose

WBC Platelets

AND

modification

> 4.0 x 109/l > 120 x log/1

WBC Platelets

3.S4.0 75-120

x 109/l x log/1

WBC Platelets at day

< 3.0 x 109/l < 75 x log/1 1 and 15

OVARIAN in case 100%

CANCER

11

of myelosuppression of all cytotoxic

agents

50% of CTX and DOX 75% of carboplatin 100% of HMM and cisplatin No treatment during 1 week Restart treatment with WBC > 3.0 x log/l and platelets > 75 x 109/l

Leucocyte and platelet counts were determined on day 1, 15 and 22 and at the start of the next cycle. Doses modified as above.

therapy if the encountered toxicity allowed it. Patients who had failed to achieve a complete remission after 6 courses continued treatment as long as toxicity allowed and a continuing improvement of the tumour status could be demonstrated. The dose modification for myelosuppression is given in Table 2. Preliminary

results

of the randomized

phase

III trial

CHAP-5

vs. CHAC-1

341 patients were entered in the trial by March 1986. Of these, 264 were evaluated by the data center and the study coordinator, 13 1 allocated for treatment with CHAP-5 and 133 for treatment with CHAC-1. The rest are too early for evaluation. It should be emphasized that any conclusion drawn from this first presentation of results will be very preliminary and may change considerably during further analysis. Patients’ characteristics are given in Table 3 and seem well balanced between the 2 treatment arms. The stratification by treatment arm is given in Table 4. Thirteen patients were found to be ineligible for the study, 7 had been allocated to treatment with CHAP-5, 6 to CHAC-I chemotherapy. Two patients had no malignant Table

3. Patient

characteristics Treatment CHAP-5

Age: median range Performance status: median range Residual disease: no residual disease < 1 cm 2 1 cm Cell type: serious cystadenoc. undiff. endometr. adenoc. mucinouscystadenoc. clear cell other missing

CHAC-

(27?0)

(0-i)

64

12 48 110

15 49 105

54 51 13 10 5 34 3

66 58 13 11 2 19 2

1

TEN

12 Table

4.

BOKKEL

Stratification

HUININK

ET

AL.

by treatment

Treatment CHAP-5 Stratification: Figo stage:

IIB IIC III IV

Residual tumor: < 1 cm 2 1 cm Performance 0 1 2 3

CHAC-

1

Total

10 6 117 37

15 6 124 26

25 12 241 63

56 114

66 105

122 219

92 58 17 3

86 62 17 6

178 120 34 9

75 89 6

76 92 3

151 181 9

status:

Histology: well differentiated undifferentiated unknown

disease, in 3 the WHO performance scale did not fulfil the entry criteria. Creatinine clearances were found to be too low in 3 other patients and one suffered from severe cardiac disease; two patients had a delay in treatment due to postoperative complications. Two patients had been previously treated with chemotherapy or radiotherapy. Twentyone patients were not evaluable for response: in 4 patients the treatment was never initiated, 8 patients refused further treatment after the first cycle and in 9 the treatment was not given according to the protocol. Haematological toxicity encountered either by CHAP-5 or CHAC-I is gken in Table 5. Renal toxicity and worst degree of non-haematological toxicity are listed in Tables 6 and 7. Due to haematological toxicity, dose modification according to the protocol was applied as given in Table 8. Preliminary

evaluation

of response

to treatment

The response to treatment in patients with residual disease after the primary staging and cytoreductive surgical procedure is given in Table 9. Statistical analysis of these very preliminary data does not reveal any significant difference in response rate between the two treatment arms. Table

5. Haematological

toxicity

Treatment

WBC ( x log/l) median range Platelets ( x log/l) median range

CHAP-5

CHAC-

2.0 1S3.8

2.0 0.74.4

65 16-337

65 15-274

1

CARBOPLATIN Table

Grade

6. Renal

AND

OVARIAN

CANCER

toxicity

of toxicity

Increase

of serum

< 1.25 1.26 2.5-5 5.1-10 > 10

0

1 2 3 4

Table

x x x x x

pret. pret. pret. pret. pret.

CHAP-5

CHAC-

?z= 115

*=

creat. val. val. val. val. val.

59 53 2 0 1

7. Worst degree of non-haematological toxicity over all cycles by treatment (WHO grading)

Treatment CHAP-5 (160 patients) o/0 with tox. (% grade 3/4) Nausea/vomiting Diarrhea Infection Allergy Cardiac Hair Neurotoxicity Ototoxicity

Table

CHAC- 1 (161 patients) 0/0 with tax. (% grade 3/4)

99 (74) 24 (2)

91 19 12 5 4 81

(60) (‘1 (0.5) (0.5) (0) (48) 18 (0) ‘1 (0)

16 (2)

4 (1) 2.5 (1) 99 (72) 54 (8) ‘0 (0)

8. Percentage modifications cycle

of of

patients treatment

with by

Treatment Cycle number 1A 1B 2A 2B 3A 3B 4A 4B 5A 5B 6A 6B

CHAP-5 2 66 60 79 70 74 65 89 70 95 82 100

(%) CHAC-1

(%) 2 76 69 84 79 81 64 92 75 89 74 92

1 115

73 41 I 0 0

14

TEN Table

BOKKEL

9. Response residual

HUININK

ET

to treatment disease

in

AL. patients

with

Treatment CHAP-5 Complete response Microscopic disease Partial response No change Progrtssion Early death

40 (32.2%) 12 (9.7%) 17 (13.7%) 9 (7.2%) 30 (24.2%)

2 (1.6%)

CHAC34 11 12 13 43 5

1

(26.8%) , (8.7%) (9.4%) (10.2%) (33.8%) (3.9%)

Discussion This study is now closed. Further analysis will continue as more patients reach the point of final evaluation. Comparison of the antitumour activity at this moment does not reveal any statistical difference between the carboplatin-based treatment and the cisplatin-based treatment protocol. No data are available yet about duration of response. The toxicity pattern observed in the patients treated with CHAC-1 is much milder and more tolerable than that observed in patients treated with the cisplatin-based regimen, notwithstanding equal haematological toxicity. From the toxicities given in Table 5, it is clear that both regimens are given at maximum tolerated doses. The relative lack of neurotoxicity in patients treated with CHAC-1 is of special note. Nausea and vomiting lasted only 1 day if patients were treated with CHAC-1 and 5 days when treated with CHAP-5. Post-treatment nausea also is much shorter with carboplatin than cisplatin. The nephrotoxicity of platinum, especially if given on a 5 day regimen, nearly always necessitates hospital admission for forced diuresis. Carboplatin may be administered on an outpatient basis. Based on this preliminary analysis it seems that carboplatin may replace cisplatin in the treatment of ovarian cancer, if further analysis including survival figures come to the same conclusions as this report. Summary Cisplatin today is a cornerstone of combination chemotherapy for ovarian cancer. Carboplatin seems equal to cisplatin in antitumour activity, but has a different toxicity profile. After a feasibility study, a randomized phase III study in ovarian cancer stage II, III, and IV was undertaken, comparing carboplatin with cisplatin in combination with cyclophosphamide, doxorubicin and hexamethylmelamine. Preliminary analysis of this study reveals no statistically significant difference in response rate. Notwithstanding equal haematological toxicity, the other side effects evoked by carboplatin in combination treatment are much milder than those evoked by cisplatin. Further analysis will be necessary to draw definite conclusions about the results obtained. Acknowledgements The EORTC Lung Cancer Cooperative group wishes to express its gratitude to the BristolMyers Company for their support for this study and the provision of carboplatin.

CARBOPLATIN

AND

OVARIAN

CANCER

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