Doxorubicin-cisplatin-vinblastine combination chemotherapy of advanced endometrial carcinoma: A Southwest Oncology Group study

GYNECOLOGIC

ONCOLOGY

26, 193-201 (1987)

Doxorubicin-Cisplatin-Vinblastine Combination Chemotherapy Advanced Endometrial Carcinoma: A Southwest Oncology Group Study’

of

DAVID S. ALBERTS, M.D.,* NANCY L. MASON, B.S.,* ROBERT V. O’TOOLE, M.D.,? ROBERT D. HILGERS, M.D.,$ SAUL E. RIVKIN, M.D.,5 JOHN G. BOUTSELIS, M.D.,? REGINALD P. PUGH, M.D.,” VAINUTIS K. VAITKEVICIUS, M.D.,’ J. BENJAMIN GREEN, M.D.,# AND NOBURU OISHI, M.D.** *University $lJniversity

of Arizona of Net%,

College of Medicine: fOhio Stare Unirvrsity School of Medicine: Mexico; $Ptr,qet Sound Oncology Consortium; “Allegheny Heulth, Education & Resemch; ‘Wayne State University Medictrl Center: #Scott & White Clinic: und **Cunrer Center qf Hawaii

Received October 29, 1985 A combination of doxorubicin (30 mg/m’ iv), cisplatin (50 mg/m’ iv). and vinblastine (5 mg/m’ iv) repeated every 3-4 weeks was used to treat 55 patients with advanced stage III or IV or recurrent disease. Of the 42 fully evaluable patients, there were 3 complete responders (7%) and IO partial responders (24%). Responses were of short duration (median of 8 months, range 3-15 months) and the median survival of all evaluable patients was only 10 months from the start of therapy. Leukopenia was the major toxicity and was at least moderate in two-thirds of patients. We conclude that the addition of cisplatin and vinblastine to doxorubicin does not improve the clinical utility of doxorubicin in patients with advanced endometrial cancer. o 1987 Academic PXS. inc.

INTRODUCTION

After progestational agent therapy failure, doxorubicin has proven the most active single agent for patients with recurrent and/or metastatic adenocarcinoma of the endometrium [l-3]. Response rates to doxorubicin therapy in patients with measurable, metastatic disease are in the range of 30-35% [l-3]. More recently, cisplatin has shown a moderate degree of activity in phase II trials [4] and attempts have been made to add this agent to cyclophosphamide plus doxorubicin in order to improve on the response rate associated with the latter agent ’ This investigation was supported in part by the following awarded by the National Cancer Institute, DHHS: CA-20319, 28862, CA-32734, CA-12644, CA-13238, CA-13612, CA-37981, 35261, CA-04915, CA-36020, CA-03389, CA-12213, CA-21116, Southwest Oncology Group (SWOG-8103) Operations Office, San Antonio, Tex. 78229.

PHS Cooperative Agreement grants CA-04920, CA-35117, CA-14028, CACA-03096, CA-03392, CA-04919, CAand CA-32102. Address for reprints: 5430 Fredericksburg Road, Suite 618,

193 0090-8258/87 $1.50 Copyright 0 1987 by Academic Press, Inc. All rights of reproduction in any form reserved.

194

ALBERTS

ET

AL.

[5]. The vinca alkaloids have been used rarely in the treatment of these patients, but have been shown to be additive to both doxorubicin and cisplatin in vivo

[61. In vitro evaluation of standard anticancer drug activity against fresh human endometrial cancers using human tumor cloning assays [7,8] has shown doxorubicin, cisplatin, and vinblastine to be the three most potent agents tested [93. On the basis of these in vitro data and the need to develop more effective chemotherapy regimens for advanced endometrial cancer, the Southwest Oncology Group has carried out a phase II study of these three agents in the treatment of patients with advanced metastatic and/or recurrent disease. PATIENTS

AND METHODS

Patients. Patients were eligible for this protocol if they had a pathologically proven diagnosis of adenocarcinoma or adenosquamous carcinoma of the endometrium and had received no prior cytotoxic chemotherapy. Patients had either recurrent disease (postsurgery and/or radiation therapy) or FIG0 stage 111 or IV disease at diagnosis. The disease was required to be clinically measurable, either by radiologic techniques or physical examination. All patients were required to have a SWOG performance status (PS) of O-2 (i.e., Karnofsky PS of 70-loo), adequate hematopoietic function [i.e., white blood cell (WBC) count B 4000/~1, platelet count b lOO,OOO/~l], adequate renal function (serum creatinine s 1.5 mg/dl), and adequate liver function (i.e., total serum bilirubin of < 2.0 mg/dl). In addition, all pathology materials had to be submitted for review by a panel of Southwest Oncology Group pathologists. Patients with a history of myocardial infarction or congestive heart failure were excluded from the study. Concomitant treatment with progestational agents was not permitted; however, patients were stratified according to prior versus no prior hormonal therapy. To be eligible for study, all patients signed institutionally reviewed consent forms written according to Federal guidelines. All patients had baseline history and physical examinations, complete blood cell (CBC) counts, renal panel, urinalysis, and liver function tests. An initial chest roentgenogram and other radiographs were obtained as indicated. During treatment, CBCs were obtained weekly. Prior to each course of therapy, CBCs, renal panel, and appropriate radiographs were performed. Liver function tests were repeated every 6-8 weeks. Although not required, non-invasive heart studies, IVP, and barium enema were to be repeated as indicated. TOXICITY

AND RESPONSE

CRITERIA

Criteria of the Southwest Oncology Group were used to evaluate toxicity and response. Toxicity criteria pertinent to this study are summarized in Table 1. 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 to <50% reduction in the size of all measurable tumor masses as measured by the sum of the products of their greatest perpendicular

COMBINATION

SUMMARY

195

CHEMOTHERAPY

TABLE I SWOG TOXICITY CRITERIA

OF RELEVANT

Grade Toxicity

0

WBC/$ Platelets/PI Serum creatinine mg/dl Nausea and vomiting

I

2

3

4

I ,000-l ,999 25,000-49,999 >3.0

< 1,000 <25,000

>4,000 > 100,000 Cl.5

3,000-3,999 75,000-99,999 >1.5-2.0

2,000-2,999 50,000-74,999 >2.0-30

None

Nausea. no vomiting

Vomiting (<6 episodes) can be prevented by Rx

Vomiting (>6 episodes despite adequate antiemetics

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. DRUG ADMINISTRATION

AND DOSING SCHEDULE

The starting doses for patients with adequate bone marrow reserve (i.e., ~65 years of age, no recent pelvic irradiation, no history of severe or life-threatening leukopenia or thrombocytopenia) were: doxorubicin, 30 mg/m2 iv on Day 1, cisplatin, 50 mg/m* iv on Day 1, and vinblastine, 0.2 mg/m’ iv on Day 1. Starting doses for patients with inadequate bone marrow reserve (i.e., >65 years of age, recent pelvic irradiation, prior history of severe or life-threatening leukopenia or thrombocytopenia) were: doxorubicin, 20 mg/m’ iv on Day 1, cisplatin, 50 mg/m* on Day 1, and vinblastine, 0.15 mg/m2 iv on Day 1. Courses of treatment were repeated at 3- to 4-week intervals, as tolerated, for a total of 12 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 myelotoxicity, or the absence of myelotoxicity, necessitated dose modification. If leukopenia of grade 3-4 (see Table 1) or thrombocytopenia of grade 2-4 was experienced during the preceding 4 weeks, a 16.5% reduction in doxorubicin dose and a 25% reduction in vinblastine dose were required on subsequent therapy courses. Doses of doxorubicin and vinblastine were increased 33 and 25%, respectively, in the case of grade 1 leukopenia or in the absence of thrombocytopenia. Prior to each course of cisplatin, the serum creatinine was required to be less than or equal to 1.5 mg/dl and there was to be no evidence of moderate or severe peripheral neuropathy. RESULTS Patient Characteristics

Sixty-four patients were registered into this phase II trial. Nine patients were considered ineligible following pathology review and 13 patients were only partially

196

ALBERTS

ET

AL.

evaluable (i.e., six died prior to completion of one full course of therapy; five did not complete a full course of therapy; and two received no treatment). Thus, 42 patients (66%) were fully evaluable for both response and toxicity to treatment with doxorubicin-cisplatin-vinblastine. Patient characteristics for the 42 fully evaluable patients are shown in Table 2. The median age of the patients was 64 years (range 33-77). Sixteen patients had received prior progestational agent therapy and 26 had not. The median performance status (SWOG) was I (range O-2). Thirteen had stage III disease and 29 had stage IV disease upon entry into the study. The majority of the patients (24) had lung metastases and 6 had liver metastases. Response Data The overall objective response rate was 30.9% with 7.1% having a complete clinical response (Table 3). An additional 14.3% of the patients had a >25% regression of tumor metastases (i.e., mixed response), but did not meet the criteria for the achievement of a partial response. Almost 55% of patients showed either no response or increasing disease during treatment. Prior treatment with progestational therapy appeared to have no significant effect on response to the chemotherapy regimen. Of the 26 fully evaluable patients who had received no prior hormonal therapy, 23% responded to the three drug combination, whereas of those 16 patients who had received progesterone 44% responded (P = 0.14). Shown in Fig. 1 are the actuarially derived response and survival duration curves, respectively, for the 42 fully evaluable patients. The median duration of response for the 13 objective responders was 8 months (range 3 to 15 months). The median duration of survival (Fig. 1) for the 42 fully evaluable patients was only 10 months. When the 55 fully and partially evaluable patients are analyzed together, their median duration of survival was 6.5 months (range 0.5 to 40 months). Only 9 of the fully evaluable patients remain alive for a median of 19.5 months (range 14 to 40 months). Toxicity Dnta Leukopenia was the major toxicity encountered by these patients. The median nadir WBC in the 42 fully evaluable patients for all courses of therapy was 2400/~1 (range 300 to 77’00/~*.1). Severe thrombocytopenia was rarely encountered with only two patients having nadir platelet counts of less than 50,000/~1. Shown in Table 4 are the severest degrees of myelotoxicity experienced by the 42 patients. Note that more than 71% of the patients had at least moderate leukopenia at some point during therapy. There were no drug related deaths, but one of the patients did experience drug-induced septicemia, requiring hospitalization and antibiotic therapy (Table 5). There were no episodes of treatment related bleeding. Two patients (5%) experienced severe, drug-related decreases in creatinine clearance, but none required treatment for renal failure. Nineteen percent of patients experienced severe nausea and vomiting. Mild (2%) and moderate (5%) peripheral neuropathy

COMBINATION

TABLE PATIENT

Patient (No.) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Median Range Ratio

CHARACTERISTICS

(Years)

Prior hormonal (Yes/No)

63 75 64 66 72 64 71 63 62 67 67 60 72 56 71 62 68 51 63 72 72 61 69 59 61 56 72 33 59 75 75 52 63 67 60 12 56 61 62 75 55 77

No Yes Yes No No No No No Yes Yes No Yes No No No Yes No No Yes Yes Yes No No No Yes No No No Yes Yes No No No Yes Yes No No No Yes No No Yes

Age

Rx

64 (33,77)

197

CHEMOTHERAPY

2

(FULLY

EVALUABLE

Performance status (0, 1, or 2)

PATIENTS

-

Stage (III or IV)

1

ONLY)

-~

Lung involv. (Yes)

IV IV III IV IV IV IV IV IV IV IV IV 111 IV IV III 111 111 IV IV 111 III IV IV IV IV IV IV IV IV 111 III III III IV IV IV IV IV III 111 IV

1 2 2 I 2 1 0 1 2 2 2 2 2 0 1 0 1 I I 0 I 2 1 1 0 2 1 2 2 0 I I 2 I 0 1 0 I 0 2 1

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes -

Yes Yes -

Liver involv. (Yes) Yes Yes Yes Yes Yes Yes -

Yes

I (0, Yes:No

= 66:26

2) 1II:IV

= 13:29

Yes

= 24

Yes

= 6

198

ALBERTS

ET

TABLE

RESWNSE DATA FOR FULLY

AL.

3

EVALUABLE

PATIENTS

Number patients

Complete response Partial response Mixed response No response Increasing disease

occurred in 7% of patients. because of neurotoxicity.

5%

3 IO 6 I? 11

(clinical)

7.1 23.8 14.3 28.6 26.2

In no patient was it necessary to terminate

therapy

DISCUSSION

Doxorubicin remains the single most active agent in the treatment of advanced and recurrent endometrial cancer with objective response rates in the range of 35-40% [l-3]. Unfortunately, complete response is relatively uncommon and response and survival durations are of short duration. Although the initial results

OC 0

3

5

8

12

15

I8

21

24

TIME (MONTHS)

FIG. 1. 55 partially vinblastine

Response and survival duration plus fully evaluable endometrial drug regimen.

curves (actuarial) carcinoma patients

for 13 fully treated with

evaluable responders the doxorubicin-cisplatin-

and

COMBINATION

TABLE SEVEREST DEGREE OF MYELOTOXICITY

Degree of toxicity (grade)

199

CHEMOTHERAPY

4 IN FULLY

Leukopenia

None (0) Mild (1) Moderate (2) Severe (3) Life threatening (4) Fatal (5) Unknown

5 7 11 14 5 0 0

EVALUABLE

(%)

PATIENTS

Thrombocytopenia

(11.9) (16.7) (26.2) (33.3) (11.9) (0.0) (0.0)

(%)

34 (80.9) 3 (7.1) 2 (4.8) 1 (2.4) I (2.4) 0 (0.0) I (2.4)

of adding cyclophosphamide to doxorubicin appeared encouraging in terms of improved response rates [ IO,1 11, a prospective randomized trial has not confirmed their additive effects [12]. More recently, the addition of cisplatin and cyclophosphamide to doxorubicin has appeared to markedly enhance response rates L.51,but response durations continue to be of relatively short duration [ 131. The results of the present phase II trial of the addition of cisplatin and vinblastine to doxorubicin once again suggest that combinations of drugs including doxorubicin are unlikely to significantly improve therapy for advanced endometrial cancer. It is possible that the doses of doxorubicin (i.e., 30 mg/m* every 3-4 weeks) and cisplatin (50 mg/m* every 3-4 weeks) when combined with vinblastine were too low to allow potentiation of their effects; however, two-thirds of the evaluable patients experienced at least moderate myelotoxicity. Trope et al. [14], who used higher doses of doxorubicin in their trial, reported prolonged complete responses in two of 19 patients treated with a combination of doxorubicin (50 mg/m’ Day 1) plus cisplatin (50 mg/m* Day 1). TABLE NON-MYELOPOIETIC

TOXICITIES

5

IN FULLY

EVALUABLE

PATIENTS

Toxic patients No.

%

Drug-induced septicemia, requiring hospital and antibiotic Rx (moderate)

2

Drug-related

t of serum creatinine (moderate)

2

Drug-related Severe Mild

J, of creatinine clearance

7 5 2

Peripheral neuropathy Severe Moderate Mild

7 2 2 2

Severe nausea/vomiting

19

Severe diarrhea

200

ALBERTS

ET

AL.

It is disappointing that the results of the human tumor clonogenic assay, suggesting doxorubicin, cisplatin, and vinblastine to be the three most active cytotoxic agents in vitro against human endometrial cancer, did not translate into an improved clinical result when the three drugs were combined. Although clonogenic assays have proven predictive for single agent response in patients with ovarian cancer [ 15-181, they have yet to be shown to be useful in the prediction of response to single agents or combinations of agents in the treatment of endometrial cancer. It is of considerable interest that prior treatment with hormonal therapy appeared to have no significant effect on subsequent response to chemotherapy. Unfortunately, none of the 16 patients who had received prior progestational agent therapy had experienced an objective response to hormonal manipulation. Nevertheless, we can conclude that hormonal therapy is unlikely to play an adverse role in response to chemotherapy in patients with advanced endometrial cancer. Obviously, new directions are needed in the design of therapy for the patient with advanced endometrial cancer. Until more active and specific drugs are developed it is unlikely that combination chemotherapy with or without doxorubicin will significantly effect the course of advanced disease. REFERENCES 1. Donovan, J. F. Non-hormonal chemotherapy of endometrial adenocarcinoma: A review, Cancer 34, 1587-1592 (1974). 2. Thigpen, J. T., Buchsbaum, H. J., Mangan, C., and Blessing, J. A. Phase II trial of adriamycin in the treatment of advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group Study, Cancer Treat. Rep. 63, 21-27 (1979). 3. Horton, J., Begg, C. B., Arsenault, J., Bruckner, H. W., Creech, R., and Hahn, R. G. Comparison of adriamycin with cyclophosphamide in patients with endometrial cancer, Cancer Treaf. Rep. 62, 159-161 (1978). 4. Deppe, G. Chemotherapy of endometrial carcinoma, in Chemotherapy of gynecologic cunc’er (G. Deppe, Ed.). Alan R. Liss, New York, pp. 139-150 (1984). 5. Turbow, M. M., Thornton, J., Ballon, S., Koretz, M. M., and Torti, F. M. Chemotherapy of advanced carcinoma with platinum, adriamycin and cyclophosphamide (PAC), Proc. Amer. Sot. C/in. Oncol. 1, 108 (1982). 6. Speer, R. J., Lapis, S., and Ridgway, H. Cis-platinous diamminodichloride in combination therapy of leukemia L1210, Wadley Med. Bull. 1, 103-109 (1971). 7. Hamburger, A. W., and Salmon, S. E. Primary bioassay of human tumor stem cells, Sciewe 197, 461-463 (1977). 8. Salmon, S. E., Hamburger, A. W., Soehnlen, B., e( al. Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs, N. Engl. J. Med. 298, 1321-1327 (1978). 9. Alberts, D. S., and Salmon, S. E. Unpublished data (1985). 10. Muggia, F. M., Chia, G., Reed, L. J., and Romney. S. L. Doxorubicin-cyclophosphamide: Effective chemotherapy for advanced endometrial adenocarcinoma. Amer. J. Obsret. Gynecol. 128, 314-319 (1977). 11. Seski, J. C., Edwards, C. L., Gershenson, D. M., and Copeland, L. J. Doxorubicin and cyclophosphamide chemotherapy for disseminated endometrial cancer. Obsrer. Gynecol. 58, 88-91 (1981). 12. Thigpen, T., Blessing, P., DiSaia, and Ehrlich, C. (for the Gynecologic Oncology Group). A randomized comparison of adriamycin with or without cyclophosphamide in the treatment of advanced or recurrent endometrial carcinoma, Proc. Amer. Sot. Clin. Oncol. 4, 115, Abstract C-448 (1985).

COMBINATION

CHEMOTHERAPY

201

13. DeOliveira, C. F., van der Berg, M. E. L., Osorio, M. T., van Oosterom, A. T., Namer, M., Neijt, J. P., Rotmer, S. Z. N., and Vermorken, J. B. Chemotherapy of advanced endometrial carcinoma with cyclophosphamide, adriamycin and cisplatin (CAP), Proc. Third Europ. Conf. C/in. Oncol. 3, 45, Abstract 155 (1985). 14. Trope, C., Johnsson, J. E., Simonsen, E., Christiansen, H., Cavallin-Stahl, E., and Horvaty, G. Treatment of recurrent endometrial adenocarcinoma with a combination of doxorubicin and cisplatin, Amer. J. Obster. Gynecol. 149, 379-381 (1984). 15. Alberts, D. S., Salmon, S. E., Chen, H. S. G., Surwit, E. A., Soehnlen, B., Young, L., and Moon, T. E. In vitro clonogenic assay for predicting response of ovarian cancer to chemotherapy, Lancer 2, 340-342 (1980). 16. Alberts, D. S., Chen, H. S. G., Salmon, S. E., Surwit, E. A., Young, L., Moon, T. E., Meyskens, F. L., Jr., and co-investigators from the Arizona-New Mexico Cloning Group. Chemotherapy of ovarian cancer directed by the human tumor stem cell assay, Cancer Chemorher. Pharmacol. 6, 279-285 (1981). 17. Welander, C. E., Homesley, H. D., and Jobson, V. W. In vitro chemotherapy testing of gynecologic tumors: basis for planning therapy? Amer. J. Obsret. Gynecol. 147, 188-195 (1983). 18. Welander, C. E., Morgan, T. M., and Homesley, H. D. Multiple factors predicting reponses to combination chemotherapy in patients with ovarian cancers, in Human tumor cloning (S. E. Salmon, and J. M. Trent, Eds.), Grune and Stratton, New York, pp. 521-534 (1984).