Phase I trial of carboplatin-cyclophosphamide and iproplatin-cyclophosphamide in advanced ovarian cancer: a Southwest Oncology Group study

Cancer Treament

Reviews (1985)

12 (Suj@w~nt

A), 83%92

Phase I trial of carboplatin-cyclophosphamide and iproplatin-cyclophosphamide in advanced ovarian cancer: a Southwest Oncology Group study* David Alberts,’ Nancy Mason,’ Earl Hammond’ and Gunther Deppe3

Surwit,’

Sheldon

Weiner,’

Neel

’ Arizona Cancer Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona 85724, U.S.A. ’ Billings CCOP, 1230 N. 30th Street, Billings, Montana 59101, U.S.A. 3 Section, Gynecologic Oncology, Department of Obstetrics and Gynecology, Wayne State University Medical Center, P.O. Box 02188, Detroit, Michigan 48201, U.S.A.

The Southwest Oncology Group has carried out a phase I clinical trial of carboplatin plus cyclophosphamide and iproplatin plus cyclophosphamide in 20 patients with stages III and IV ovarian cancer prior to initiating a phase III trial to compare these platinum analogcyclophosphamide combinations with standard cisplatin-cyclophosphamide therapy. Myelosuppression proved the dose-limiting toxicity of both the carboplatin (300 mg/m’) plus cyclophosphamide (600 mg/m*) and iproplatin (180 mg/m*) plus cyclophosphamide (600 mg/m*) regimens. Evaluating up to six courses of therapy (repeated at 4-week intervals), the median nadir WBC and platelet counts associated with carboplatin-cyclophosphamide therapy were 1800 (range, 900-4000) and 69 000 per ~1, respectively, and those associated with iproplatin-cyclophosphamide therapy were 1400 (110&1600) and 140000 per ~1, respectively. Although the starting doses of carboplatin and iproplatin required a median decrease of 25%, the median doses of each administered through six courses of therapy were 300 and 180 mg/m*, respectively. Neither nephrotoxicity nor neuropathy were experienced by the patients, but mild to moderate nausea and vomiting occurred in more than 75% of those treated with either drug combination. Alopecia of mild to severe degree was observed in 40% of patients. Although the results of this phase I trial are still preliminary, we can recommend for future phase III trials 300 mg/m* carboplatin and 180 mg/m* iproplatin when combined with 600 mg/m* cyclophosphamide repeated at 4-week intervals for six treatment courses.

Introduction Cisplatin

appears

ovarian

cancer.

*This Institutes

work was supported of Health, Bethesda,

030557372/85/12A0083+

to be the

most

active

In doses of cisplatin

single

agent

of 100 mg/m2

in the

by Grants CA32102, CA13612, Maryland 20205, U.S.A.

10$03.00/0

treatment

CA14028

and

0 1985 Academic 83

of advanced

epithelial

every 3 to 4 weeks, the clinical

complete

CA35274

from

the

Press Inc.

(London)

National Limited.

84

D. ALBERTS

ET

AL.

plus partial response rates exceed 50% and the pathologically proven complete response rates may be as high as 30% in patients with stages III and IV disease who have received no prior chemotherapy (l-3). Unfortunately, these doses of cisplatin are associated with a relatively high incidence of cumulative nephrotoxicity and dose-limiting neurotoxicity (l-3). Recently, two new analogs of cisplatin, carboplatin (NSC-241240, CBDCA, JM8, cisdiammine1, 1 -cyclobutane dicarboxylato-platinum II) (2-4) and iproplatin (NSC256927, CHIP, JM9, bis-dichloro-transidihydroxy-dis-isopropylamine-platinum IV) (5) have undergone clinical trials in the treatment of patients with advanced ovarian cancer. The preliminary reports from phase II and III trials suggest that both of these agents may be as active and considerably less toxic than cisplatin in the treatment of this disease (3-5). In these recent clinical trials carboplatin and iproplatin were associated with an insignificant incidence of nephrotoxicity and neurotoxicity. Their dose-limiting toxicities were leukopenia and thrombocytopenia. There is considerable evidence to suggest that combination chemotherapy regimens including cisplatin are significantly more effective than single agents in producing complete responses (clinically and pathologically proven), overall objective response rates, and in prolonging the progression-free interval in patients with advanced ovarian cancer (6-l 3). Although the combination of cyclophosphamide-doxorubicin-cisplatin has become standard chemotherapy for these patients in the United States (12-15), there is little evidence that this regimen represents an improvement over the two-drug combinations of cisplatindoxorubicin ( 12) or cisplatin-cyclophosphamide (9, 16). Decker et al. (9) have shown that the two-drug combination of cisplatin-cyclophosphamide was associated with significantly longer disease-free and overall survival durations than were observed in patients treated with cyclophosphamide alone. Preceding the initiation of a phase III randomized trial to compare cisplatincyclophosphamide with carboplatin-cyclophosphamide and iproplatin-cyclophosphamide in patients with measurable disease, stages III and IV ovarian cancer, the Southwest Oncology Group has carried out a phase I clinical trial to determine the highest doses of carboplatin and iproplatin that can be combined safely with cyclophosphamide in the treatment of patients with advanced ovarian cancer. Included in this report are the preliminary results of this phase I clinical trial.

Methods

and patient

selection

All patients entered into this phase I trial had a diagnosis of FIG0 stage III or IV ovarian carcinoma of epithelial type and had not previously received cytotoxic chemotherapy or abdominal or pelvic radiation therapy. All patients were registered within 6 weeks ofinitial surgical exploration which was designed to include bilateral salpingo-oophorectomy, total abdominal hysterectomy, omentectomy and inspection and removal of all pelvic and intraabdominal masses measuring greater than 0.5 cm in diameter. All patients were younger than 75 years of age and had a SWOG performance status (PS) of O-2 (i.e. Karnofsky PS of 70-100). Patients were required to have adequate liver function (serum bilirubin < 2 mg/dl) and adequate renal function (serum creatinine < 1.5 mg/dl). Patients with a history of septicemia, severe infection, severe gastrointestinal symptoms, or bleeding were excluded from the study. Also excluded were patients with unclassified cases of ovarian

PHASE

I TRIAL

IN

ADVANCED

OVARIAN

CANCER

cancer or borderline malignancies. To be eligible for study all patients reviewed consent forms written according to Federal guidelines.

Parameters

evaluated

during

85

signed institutionally

study

Pretreatment evaluation consisted of history and physical examination, Complete blood cell (CBC) count, renal panel, liver function tests and, when available, serum OC-125 ovarian tumor antigen test. An initial chest roentgenogram and other appropriate radiographs were obtained as indicated. During the study, CBC counts, vital signs and drug toxicities were monitored weekly. Toxicity information was monitored centrally by weekly phone calls by one research nurse. CBC counts, renal panel and liver function tests were performed prior to each therapy course. Upon completion ofsix courses of therapy, all initially abnormal studies were to be repeated. Patients with no clinical evidence of disease were scheduled to undergo ‘second-look’ exploratory laparotomy to document complete remission.

Toxicity

and response

criteria

Toxicity criteria were those of the Southwest Oncology Group. The criteria pertinent to this study are summarized in Table 1. Although this was primarily a phase I study, patients were observed for response according to the following criteria: complete response-total disappearance of all clinical evidence of disease for a minimum of 6 weeks; partial response-at least a 50% reduction in the size of all measurable tumor masses as measured by the sum of the products of their greatest perpendicular diameters; mixed response-25< 50% reduction in the size of all measurable tumor masses as measured by the sum of the products of their greatest perpendicular diameters; no response-steady state or response less than mixed response; increasing disease-unequivocal increase of at least 25% in the size of any measurable lesion and/or appearance of new lesions.

Table

1. Summary

of relevant

SWOG

toxicity

criteria

Grade Toxicity WBC//d Platelets//J Serum creatinine mg/dl

0 3 4000 > 100000

< 1.5

1

2

3000-3999

75 000-99

2oocL-2999

999

50 OOOS74 999

3

4

100&1999 25 00049

< 1000 999

> 1.5-2.0

> 2.IS3.0

Nausea and vomiting

None

Nausea, no vomiting

Vomiting ( < 6 episodes) can be prevented by Rx

Vomiting (> 6 episodes) despite adequate antiemetics

> 3.0

Alopecia

None

< 25% hair loss

25% to 75% hair loss

> 75% hair loss

< 25 000

Il.

86

Drug

ALBEKTS

administration

E7

AL.

and dosing

schedule

Carboplatin was supplied in 150 mg vials as a white lyophilized powder with 150 mg of mannitol, prepared by the National Cancer Institute, Bethesda, Maryland. It was reconstituted with 9.8 ml of sterile water for injection, USP, and the entire reconstituted dose was further diluted into 250 ml D5W. The drug was administered by intravenous (i.v.) infusion over 30 minutes. Iproplatin was supplied in 50 mg vials as a lyophilized cream colored cake with 125 mg of mannitol, prepared by the National Cancer Institute. It was reconstituted with 10 ml of sterile water for injection, USP, and the entire reconstituted dose was further diluted into 250 ml D5W. The drug was administered by i.v. infusion over 30 minutes. Cyclophosphamide (NSC 26271), which is commercially available, was reconstituted in approximately 150 ml of normal saline or D5W. The drug was administered as a rapid i.v. infusion over a period of 15-30 minutes. The starting doses for the phase I trial were: carboplatin, 300 mg/m2 plus cyclophosphamide, 600 mg/m2, or iproplatin, 180 mg/m2, plus cyclophosphamide, 600 mg/m2, every 4 weeks for a total of six courses. All patients were to receive at least two courses of therapy (an adequate trial) before being removed from the study due to progression of disease. Treatment courses were to be repeated at the starting dose level unless a toxicity of grade three or four (see Table 1) was experienced during the preceding 4 weeks. Therapy related grade three or four myelotoxicity or life-threatening toxicity of any other type required 25% or 50% reductions in drug doses, respectively, on subsequent therapy courses. Carboplatin and iproplatm were to be omitted from a treatment course if the pretreatment serum creatinine was > 1.5 mg/d 1 and reinstituted when the serum creatinine returned to < 1.5 mg/d 1. The doses of carboplatin and iproplatin selected for the planned phase III trial were to be those associated with grade three myelotoxicity in six of ten patients in the absence of other drug related life-threatening toxicities.

Results Between December 1984 and June 1985,20 patients were entered into this phase I clinical trial from six Southwest Oncology Group institutions (Table 2). Ten were assigned to treatment with carboplatin (300 mg/m2)-cyclophosphamide (600 mg/m2), and ten patients were treated with iproplatin (180 mg/m2)-cyclophosphamide (600 mg/m2). The median age of patients treated with carboplatin-cyclophosphamide was 62 years, and the median age of patients treated with iproplatin-cyclophosphamide was 60 years. At study entry the median PS for patients treated with carboplatin-cyclophosphamide was 1.5 and that for patients treated with iproplatin-cyclophosphamide was 1. Five of the ten patients treated with carboplatin-cyclophosphamide had clinically measurable disease prior to the start of therapy, whereas only two patients treated with iproplatin-cyclophosphamide had measurable disease. The rest of the patients were found to have non-measurable disease, either optimal or suboptimal, following initial surgical exploration. Shown in Table 3 are the nadir, WBC, PMN and platelet counts experienced by each of the 20 patients following the first course of combination chemotherapy. Note that the median nadir WBC was 2600 per ~1 in patients treated with carboplatincyclophosphamide and 2200 per ~1 in patients treated with iproplatin-cyclophosphamide.

PHASE Table

I TRIAL

2. Patient

Pati&t

IN

ADVANCED

CANCER

87

characteristics

PS

stage

Carboplatin-Cyclophosphamide 300 q/In2 600 q/m* 1 55 0

111

Age

2 3 4 5

60 40 63 54

2 1 1 0

III III III III

6

55

1

III

7

69

2

III

a 9

63 65

2 2

III III

10

64

2

III

Iproplatin-Cyrlophosphamide 180 mg/m’ 600 mg/m2 1 50 I 2 3 4 5 6 7 8 9 10

OVARIAN

54 44 51 65 75 41 69 72 73

1 1 0 0 2 1 2 0 0

111 III 111 IV III III IV III III III

Meas.

disease

Non-meas. disease

12 x 7 cm mass seen on CT scan suboptimal optimal optimal 20 cm abd. mass on PE 1 Z- 15 cm pelvic mass & 5 cm LUQ mass on PE abd. mass seen on CT scan optimal 5 cm LUQmass on PE 12 cm pelvic mass meas. on CT scan optimal

pelvic mass seen on CT scan suboptimal optimal suboptimal mass on PE optimal optimal suboptimal optimal suboptimal

Three of the nine evaluable carboplatin-cyclophosphamide treated patients experienced life-threatening neutropenia following the first course of treatment. Two out of the six iproplatin-cyclophosphamide treated patients experienced life-threatening neutropenia during their first course of treatment. Shown in Table 4 are the nadir WBC, PMN and platelet counts experienced by each of the 20 patients during all courses of therapy. Note that of the nine evaluable carboplatincyclophosphamide treated patients, live experienced grade three leukopenia (median WBC count was 1800/~1), whereas only one of the nine patients experienced grade three thrombocytopenia. Of the five fully evaluable iproplatin-cyclophosphamide treated patients, all five experienced grade three (WBC < 2000 and > lOOO/pl) leukopenia. Only two of 20 patients experienced grade three or four thrombocytopenia. In addition to myelosuppression, nausea and vomiting was the most common toxicity associated with either analogue treatment. Seven of nine evaluable patients treated with

88

D. ALBERTS Table

3. Hematologic

data

Nadir WBC per /Ll x lo3

Patient

Carboplatin-Cyclophosphamide 300 mg/m* 600 mg/m* 1 2 3 4 5 6 7 8 9 10 Median range Iproplatin-Cyclophosphamide 180 mg/m* 600 mg/m2 1 2 3 4 5 6 7 8 9 10 Median range a Too

early

from

first

ET

AL.

course

of chemotherapy

Nadir PMN per pl x lo3

Nadir platelet per fiul x lo3

1.7 2.6 6.1 1.6 0.9 4.5 2.7 3.8 2.2 P

0.5 0.8 3.5 0.0 0.1 2.0 1.3 1.7 0.8 a

133 240 28 61 200 65 139 182 a

2.6 (0.9, 6.1)

0.8 (0.0, 3.5)

W&240)

2.5 4.0 2.2 1.6 2.1 1.3 a a a a

1.1 2.4 0.6 0.2 1.3 0.4 a a a a

222 266 131 159 250 34 a a a a

2.2 (1.3, 4.0)

0.8 (0.2, 2.4)

190 (34, 266)

59

133

to evaluate.

carboplatin-cyclophosphamide experienced nausea and vomiting with the median grade of toxicity being two (Table 5). All six fully evaluable patients treated with iproplatincyclophosphamide experienced at least mild nausea and vomiting. Alopecia was observed in three of the nine evaluable patients treated with carboplatin-cyclophosphamide and in three of the six patients treated with iproplatin-cyclophosphamide. There was no evidence of either drug-induced nephrotoxicity or neuropathy. One of the 15 evaluable patients experienced mild tinnitus. As shown in Table 6, five of nine evaluable patients treated with carboplatin-cyclophosphamide and four of six patients treated with iproplatincyclophosphamide required dose reductions during treatment. The median doses of the platinum analogs administered in all courses of therapy were 300 mg/m2 for carboplatin and 180 mg/m2 for iproplatin. The median dose reduction for both of the cisplatin analogs was 25%. As shown in Table 7, of the seven evaluable patients treated with carboplatincyclophosphamide at the time of treatment initiation, two have shown a clear-cut objective response, and one has had evidence of a mixed response. Four other patients remain

PHASE Table

4. Combined

I TRIAL hematologic

data

Median range

Median range a Too early

all courses

89

CANCER

of chemotherapy

1.7 1.8 4.0 0.9 0.9 3.6 1.1 3.5 2.2 P

0.5 0.6 2.1 0.0 0.1 1.5 0.3 1.7 0.8 a

59 69

1.8 (0.9, 4.0)

0.6 (0.0, 2.1)

6 3 3 2 2 1 1 1 1 1

1.4 1.3 1.6 1.6 1.1 1.3 a a a a

0.7 0.3 0.6 0.2 0.0 0.4 a D a a

86 185 120 159 169 34 a * a a

1.5 (1, 6)

1.4 (1.1, 1.6)

0.4 (0.0, 0.7)

140 (34, 185)

6 4 3 3 3 3 2 2 2 1

,l$

Iproplatin-Cyclophosphamide 180 mg/m2 600 mg/m” 1 2 3 4 5 6 7 8 9 10

for

OVARIAN

Nadir platelet per ~1 x lo3

CO”!-SC5

Carboplatin-Cyclophosphamide 300 mg/tT? 600 mg/m’ 1 2 3 4 5 6 7 8 9 10

ADVANCED

Nadir PMN per pl x lo3

NO.

Patient

IN

WBC

perplx

lo3

170 28 61 185 62 139 182 a

(28,?35)

to evaluate.

without evidence of cancer. Of the five evaluable patients treated with iproplatincyclophosphamide, one has shown evidence of a partial response lasting 2.5 + months. Mixed responses, which may become objective, complete and partial responses with further courses of therapy, were seen in an additional three patients in the two study arms.

Discussion Carboplatin and iproplatin are two new platinum analogs which have a different spectrum of toxicities than cisplatin and appear to have similar activity in the treatment of advanced ovarian cancer (225). In a recently reported phase III trial comparing carboplatin and cisplatin in patients with measurable disease, stages III and IV ovarian cancer, carboplatin was associated with a similar clinical complete response rate but considerably less toxicity than cisplatin (2,3). Although phase III trials have not been completed for the comparison ofiproplatin and cisplatin in patients with ovarian cancer, the results of phase II trials with

90

ET AL.

D. ALBERTS Table

5. Severest

Patient

grade

of toxicity

WBC

Plt

Carboplatin-Cyclophosphamide 300mg/m2 600 mg/m* 1 3 2

2 3 4 5 6

3 0 4 4

2 0 3 2

1

0

7

3

2

8

1

0

9 10

a

2

0

PB4)

P,231

Median range

P

Renal

Abd. pain

0 0 0 0 0 0 0 0 0 a

1 0 0 0 0 0 0 0 0 .

COPOJ

COPlj

Nausea and vomiting

Alopecia

2 2

0 0

1

2 3 0 0 0 0

3 0 2 2 1 0 a

ioh

Tin&us

0 0 1

0 0 0 0 0

1 a

0 a

coP3j

COP')

Iproplatin-Cyclophosphamide 180 mg/m’ 600 mg/m’

2 3

3 3 3

0 0

j: 6 7 8 9

3 3 a a a

0 3 P a a

10

B

a

1

Median range

(383)

1

$3)

“Too early to evaluate. b Pt. also experienced grade

0 0 0 0 0 0 P P a a

0 0 0 0 0 0 a a P a

COPOj

COPO,

3

0

1 0 0

0 0 0

2 P P B B

2 0 a a a a

0 0 P a a B

(1,‘2)

COP31

COPO!

1 1 1

2 1

4 granulocytopenia.

the former agent suggest that it is also extremely active as a single agent and does not possess either nephrotoxicity or neurotoxicity (5). Because of their excellent antitumor activities and better patient tolerance, the Southwest Oncology Group has designed a phase III randomized trial to compare these two new platinum analogs with cisplatin when combined with cyclophosphamide in patients with measurable disease, stages III and IV ovarian cancer. We have carried out a phase I trial to determine the highest doses ofboth carboplatin and iproplatin that could be safely combined with a fixed dose of cyclophosphamide (600 mg/m2) in the treatment ofgood performance status patients who have had no prior chemotherapy. The preliminary results of our trial suggest that carboplatin, 300 mg/m2, and iproplatin, 180 mg/m2, when combined with cyclophosphamide on an every 4-week dosing schedule, are associated with at least grade three leukopenia but no other severe or life-threatening toxicities in the majority of patients. Because both carboplatin and iproplatin may cause cumulative bone marrow toxicity, it is unlikely that higher doses of either agent than those used in this trial would prove tolerable in the majority of patients over a 6-month treatment

PHASE Table

6. Dose

I TRIAL

IN

ADVANCED

OVARIAN

CANCER

91

adjustments

NO. patients’

NO. adjusted

Median y0 decreased

Median dose administered

Carhoplatin-Cyclophosphamide 300 mg/m’ 600 mg/m’ 9

5

25

300 mg/m*

Iproplatin-Cyclophosphsmidr 180 mg/m’ 600 mg/m’ 6

4

25

180 mg/m’

‘Only includes patients who have completed weeks of blood count evaluation.

at least 1 course of therapy

followed

by 4

period. Thus, we believe that the 300 mg/m2 dose ofcarboplatin and the 180 mg/m2 dose of iproplatin are the maximal, safe doses of these two agents which can be used in combination chemotherapy of good risk ovarian cancer patients. Aside from their dose-limiting myelotoxicities, both carboplatin and iproplatin are extremely well tolerated agents when compared to cisplatin. In this study neither ofthe new platinum analogs were associated with either nephrotoxicity or neurotoxicity and nausea and vomiting were only mild to moderate in severity in all but one patient. Clearly, either of these agents, when combined with cyclophosphamide, is extremely well tolerated by the ovarian cancer patient. Although this study was designed as a phase I dose-finding trial, it is of importance to note that both drug combinations showed a high degree of antitumor activity. No patient had evidence of disease progression and of the patients evaluable for tumor response, all showed evidence of at least a 25% reduction in tumor volume. Obviously, final conclusions concerning the best dosing schedule for either carboplatin or iproplatin, when combined with cyclophosphamide, will depend upon completion of six full cycles of therapy in the majority of our patients. The present results must be interpreted with the knowledge that the trial has reached only an intermediate point of evaluation.

Table

7. Response

No. patients evaluablc for response

NO. objective responders

NO. mixed responders

No. nonresponders

NO. clinical DFS

Carboplatin-Cyclophosphamide 300 mg/m’ 600 mg/m2 7

2

1

0

4

Iproplatin-Cyclophosphamide 180 mg/m’ 600 mg/m’ 5

1

2

0

2

92

D. ALBERTS

E7-

AL.

References 1. Wiltshaw, E., Subramarian, S., Alexopoulos, C. & Barker, G. H. (1979) Cancer of the ovary: a summary of experience with cis-dichlorodiammineplatinum(I1) at the Royal Marsden Hospital. Cancer Treat. Rep. 62: 5555558. 2. Wiltshaw, E., Evans, D. B., Jones, A. C., Baker, J. W. & Calvert, A. H. (1983) JM8, successor to cisplatin in advanced ovarian carcinoma? Lancet 1: 587. 3. Wiltshaw, E., Evans, B. & Harland, S. (1985) Phase III randomized trial of cisplatin versus JM8 (carboplatin) in 112 ovarian cancer patients, stages III and IV. Proc. Am. Sot. Clin. Oncol. 4: 17. 4. Evans, B. D., Kankipati, S. R., Calvert, A. H., Harland, S. J. & Wiltshaw, E. (1983) Phase II study ofJM8, a new platinum analog, in advanced ovarian carcinoma. Cancer Treat. Rep. 67: 99771000. 5. Sessa, C., Cavalli, F., Kaye, S., Howell, A., Huinink, Wt. B., Wagener, T., Pinedo, H. & Vermorken, J. (1985) Phase II study of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) in advanced ovarian carcinoma. Proc. Am. Sot. Clin. Oncol. 4: 13. 6. Young, R. C., Myers, C. E., Ozols, R. F. & Hogan, W. M. (1982) Current concepts in cancer: ovarytreatment for stages III and IV. Znt. 3. Radiat. Oncol. Biol. Phys. 8: 899-902. 7. Greco, F. A., Julian, C. G., Richardson, R. L. et al. (1981) Advanced ovarian cancer: brief intensive combination chemotherapy and second-look operation. O&r. Gynecol. 58: 199205. 8. Greco, F. A., Burnett, L. S., Wolff, S. N. et al. (1982) Limited residual advanced ovarian cancer-a curable neoplasm? Proc. Am. Sot. Clin. Oncol. 1: 106. 9. Decker, D. G., Fleming, T. R., Malkasian, G. D. et al. (1982) Cyclophosphamide plus cis-platinum in combination: treatment program for stage III or IV ovarian carcinoma. O&et. Gynecol. 60: 481-487. 10. Bruckner, H. W., Cohen, C. J., Goldberg, J. D. et al. (1981) Improved chemotherapy for ovarian cancer with cis-diamminedichloroplatinum and adriamycin. Cancer 47: 2288-2294. 11. Vogel, S. E., Kaplan, B. H. & Pagano, M. (1982) Diamminedichloroplatinum-based combination chemotherapy is superior to melphalan for advanced ovarian cancer when age is > 50 and tumor diameter > 2 cm. Proc. Am. Sot. Clin. Oncol. 1: 119. 12. Bruckner, H. W., Cohen, C. J., Goldberg, J. et al. (1983) Ovarian cancer: comparison of adriamycin and cisplatin k cyclophosphamide. Proc. Am. Sot. Clin. Oncol. 2: 152. 13. Sturgeon, J. F. G., Fine, S., Gospodarowicz, M. K. et al. (1982) A randomized trial ofmelphalan alone versus combination chemotherapy in advanced ovarian cancer. Proc. Am. Sot. Clin. Oncol. 1: 108. 14. Stehman, F. B., Ehrlich, C. E., Einhorn, L. H. et al. (1983) Long-term follow-up survival in stage III-IV epithelial ovarian cancer treated with cis-dichlorodiammine platinum, adriamycin, and cyclophosphamide (PAC). Proc. Am. Sot. Clin. Oncol. 2: 147. 15. Williams, C. J., Arnold, A. et al. (1982) Chemotherapy of advanced ovarian carcinoma: initial experience using a platinum based combination. Cancer 49: 1778-l 783. 16. Piccart, M., Speyer, J., Wernz, J., Noumoff, J., Beckman, M., Beller, U., Dubin, N. & Muggia, F. (1985) Advanced epithelial ovarian cancer: update with impressive survival utilizing cisplatin (100 mg/ms/cycle) and cyclophosphamide. Proc. Am. Sot. Clin. Oncol. 4: 17.