Cisplatin, Vinblastine, and Bleomycin Combination in the Treatment of Resistant High-Risk

Gestational Trophoblastic Tumors

MOHAMED AZAB, MD, MSC, JEAN-PIERRE DROZ, MD, CHRISTINE THEODORE, MD, JEAN-PIERRE WOLFF, MD, AND JEAN-LOUIS AMIEL, MD

Eight patients with high-risk gestational trophoblastic tumors (GTT) resistant to multiagent chemotherapy were treated with the combination of cisplatin, vinblastine, and bleomycin (PVB). All patients had a metastatic disease including three patients with two metastatic sites and two patients with brain metastases. Four patients achieved complete remission (CR) with the PVB regimen (50%). Three additional patients had partial remission (PR) of whom two were converted into CR by surgery of resistant residual lesions. One patient relapsed and the remaining five patients in CR were cured (62%). A multimodal approach was necessary in most patients as five of them had hysterectomy and two patients had a whole-brain irradiation. Toxicity was mild with no treatment related deaths.

Cancer 64:1829-1832, 1989.

ESTATIONAL TROPHOBLASTIC TUMORS (GTT) have G become one of the most curable human malignan- cies with an overall cure rate exceeding 90%.1-3

However, a subgroup of metastatic GTT patients pre- senting with high-risk riter ria'.^ have a less favorable prognosis as 10% to 25% of them would still succumb to this d i sea~e .~ -~ These patients need to be treated more aggressively with initial combination chemotherapy and if necessary, a multimodal approach. Methotrexate and dactinomycin were the first two drugs to be identified as most active in GTT.738 Several methotrexate and dacti- nomycin-containing combinations were developed in an attempt to improve the cure rate of high-risk patient^.',^,^^^ Patients failing on multiagent chemotherapy have a dismal progno~is.~." We have recently reported that these patients have the highest relative death risk on multivariate analysis' I .

In this report we evaluate our experience in the treat- ment of resistant high-risk GTT with a combination of cisplatin, vinblastine, and bleomycin (PVB).

Materials and Methods Between January 1977 and December 1985, 12 patients

with resistant high-risk GTT were treated with a combi-

From the Departments of Medical Oncology and Gynecologic On- cology, lnstitut Gustave-Roussy, Villejuif, France.

Address for reprints: Mohamed B. Azab, MD, MSc, Department of Medicine, Institut Gustave-Roussy, Rue Camille Desmoulins, France, 94800 Villejuif.

Accepted for publication April 28, 1989.

nation of cisplatin, vinblastine, and bleomycin (PVB). Although all 12 patients failed to achieve normal human chorionic gonadotropin (HCG) levels after several weeks of multiagent chemotherapy, we have excluded four pa- tients: the HCG level had slightly decreased before PVB treatment in two; in a third patient with massive pul- monary metastases, the bleomycin was rapidly withdrawn for fear of pulmonary toxicity; and finally, one patient received other cytotoxic agents alternating with PVB. Eight patients were fully evaluable for response and tox- icity of the PVB regimen.

The PVB protocol consisted of vinblastine 0.3 mg/kg intravenously (IV) on day 1, bleomycin 15 mg/day as a continuous infusion on days 1, 2, 3, and cisplatin 100 mg/m2 IV on day 2 with overhydration and mannitol diuresis to minimize renal toxicity.'* The treatment was repeated at 2 1 -day intervals. Before initiation of treatment all patients had a complete history and physical exami- nation, complete blood and platelet counts, serum HCG measurement, chest radiograph, and renal and hepatic function tests. All patients had abdominal hepatic and pelvic ultrasound examination, brain isotopic or com- puted tomography scan and lumbar puncture with cere- brospinal fluid examination for cytology, biochemistry, and HCG measurement. All serum HCG levels were de- termined by the beta-subunit radioimmunoassay initially described by Vaitukaitis et aLi3

Toxicity was evaluated by hematologic profiles along with blood chemistries daily during courses and weekly between. Toxicity was graded using the World Health Or-

1829

1830 CANCER November I 1989 Vol. 64

TABLE 1. Patient Characteristics ~~~

Antecedent Prior Patient Age pregnancy HCG* Metastases Histology WHO scoret chemotherapy

1 21 Term 21,100 Brain Chonocarcinoma 14 VA, MTX VA, ACD

2 30 Mole 70,000 Lung Choriocdrcinoma 13 VA, MTX brain

3 42 Mole 34 Pelvis Hydatiform mole 13 MTX MTX, ACD

4 44 Mole 92 Pelvis Chonocarcinoma 13 MTX VA, ACD

5 23 Term 195 Lung Chonocarcinoma 14 VA, MTX Pelvis

6 39 Mole 132,000 Lung Chonocarcinoma 14 MTX VA, ACD

7 26 Term 38,700 Lung Choriocarcinoma 12 VA. MTX VA, ACD

8 33 Nonmolar abortion 5610 Lung Choriocarcinoma 12 VA, MTX vagina VA. ACD

VA: vinca alkaloid; ACD: dactinomycin; MTX: methotrexate; HCG: human chorionic gonadotropin; WHO: World Health Organiration.

ganization (WHO) criteria.14 Chemotherapy was post- poned until recovery if total leukocyte count was less than 3000/mm3 or platelet count less than 1 O0,000/mm3. Chest radiographs were repeated before each new cycle but no routine respiratory function tests were undertaken. Com- plete remission (CR) was defined as three consecutive normal HCG levels determined weekly and partial re- mission (PR) was defined as a one log or greater fall in HCG value. All patients achieving CR were treated with at least two more cycles except for one patient. After CR, serum HCG was followed bimonthly for 3 months, monthly for the rest of the first year, every 3 months for the second year, and then every 6 months thereafter. We considered the patient to be cured if CR was maintained for at least 12 months. All patients in CR were followed for at least 24 months.

Results

Patient characteristics are shown in Table 1. All eight patients had metastatic GTT with initial high-risk score

* Serum HCG level before treatment with PVB. t Score at initial pre~entat i0n. l~

using the WHO scoring system.” Age ranged from 21 to 44 years (mean, 32), and serum HCG levels before PVB treatment ranged from 34 to 132,000 mIU/ml (mean, 32,341).

All but one patient had a histologic diagnosis of cho- riocarcinoma and two patients had brain metastases. All patients received prior multiagent chemotherapy con- taining methotrexate and dactinomycin. Our most-ap- plied primary combination chemotherapy consisted of weekly vincristine and methotrexate given sequentially with weekly vincristine and dactinomycin.16

The treatment outcome is summarized in Table 2. The CR rate to PVB alone was 50% (four CR/eight patients treated). In addition, three further patients had a PR; all of them underwent hysterectomy for residual uterine le- sions and two of them became complete responders. Two other hysterectomies were done just before chemotherapy and HCG serum levels were rising or in plateau before starting PVB treatment. These two patients later had a CR. The two patients with brain metastases received whole-brain irradiation (3000 cCy in 10 fractions) con-

TABLE 2. Treatment Results

CR duration Relapse Patient No. cycles Results Surgery RT (mo) after CR Cure

Brain 96+ - Yes 1 3 CR -

2 5 PR Hysterectomy (PR -+ CR) Brain 48+ - Yes 42+ - Yes 3 1 C R - - 41+ - Yes 30+ - Yes

4 4 C R Hysterectomy - 5 4 PR Hysterectomy (PR + CR) - 6 5 CR Hysterectomy - 4 Yes - 7 3 PR Hysterectomy - 8 4 Progression -

- - - - - - -

CR: complete remission; P R partial remission; RT: radiation therapy

No. 9 PVB TREATMENT OF RESISTANT HIGH-RISK GTT * Azab el al. 1831

comitant with PVB treatment. Thus a total of six patients had a CR at the end of treatment (PVB + surgery). One patient relapsed after 4 months, leaving five patients of eight (62%) who are currently alive with no evidence of disease.

The PVB treatment in the schedule we are reporting was well tolerated with no major toxicities (Table 3). Of particular interest is the absence of renal and neurotox- icity. No patient was hospitalized for sepsis due to gran- ulocytopenia. Treatment had to be delayed for 1 week in four patients, of whom two also had dose reduction.

Nausea and vomiting were moderate due to the use of antiemetic protocols and no patient refused therapy due to this side effect.

Discussion

Despite the excellent prognosis of GTT, 5% to 10% of patients still die from their disease. ’ Most of these patients show resistance to currently applied chemother- apy regimens with proven activity in this disease. Com- binations like MAC,’ modified Bagshawe,” and EMA/Co9 are all based on the activity of methotrexate, dactino- mycin, and more recently etoposide. Second-line non- cross-resistant chemotherapy combinations should be de- veloped to try to salvage patients with resistant tumors. The idea of using PVB regimen as salvage therapy for resistant GTT stems from its activity in germ cell tumors.” Besides, vinblastinel’, b le~mycin , ’~ and cisplatin20,21 had all shown activity in the treatment of GTT. In the case of vinblastine’* and cisplatin’” CR were reported in cases resistant to prior chemotherapy.

Since 1978 several reports have dealt with the activity of the PVB regimen in the treatment of high-risk GTT resistant to first-line combination chemotherapy with rather conflicting results.”-24 Amiel et al. first reported one CR in a patient with resistant GTT.” The activity was confirmed by two later reports, each dealing with two patients resistant to MAC and/or modified Bagshawe protocol^.^^^^^ Complete remission was obtained in the four patients by PVB treatment, however, one of them

TABLE 3. Treatment-Related Toxicity

Toxicitv Grade* No. of Datients

Nausea/vomiti ng I 2

Leukopenia 1 2

Thrombocytopenia 1 2

Mucosal 1 2

Alopecia 1 2

4 3 2 5 1 1 1 2 0 7

* WHO: World Health Organization grading system.14

had an ovarian germ cell tumor and not a GTT. Berkowitz er d6 also reported two complete remissions in three pa- tients treated with PVB after initial resistance to MAC and modified Bagshawe regimens.

These encouraging results were later overshadowed by less impressive outcome in further reports. Lurain et aL3 have treated one case with no response. Hammond and Sope?’ in a review of the Southeastern Regional Tro- phoblastic Disease Center’s experience described three CR in ten patients treated, of whom two relapsed and only one patient was cured ( 10%). However in these two series, details of cases treated and the schedule used were not given. Recently Gordon et al. reported in details their results with the PVB regimen in ten patients resistant to MAC therapy.24 Five complete remissions were obtained (50%), however only two patients were cured (20%). Most alarming was the important toxicity associated with this regimen to the extent that two patients (20%) died from treatment-related toxicity (sepsis) in the series of Gordon et ai. 24

In the current series, we report four complete remission of eight patients treated, which is identical to the 50% CR rate reported by Gordon er By using surgery to resect residual lesions we were able to convert another two pa- tients from PR to CR. With one patient relapsing, the overall cure rate of PVB regimen plus surgery was 62% (five of eight) which is much higher than that reported by Gordon et al. 24

It has previously been suggested that hysterectomy coincident with the institution of systemic chemotherapy significantly reduced the duration of hospitalization and the amount of chemotherapy needed to achieve remission regardless of whether or not metastases were present.26 The fact that five of our patients had a hysterectomy has certainly played a positive role in obtaining this high cure rate in resistant patients. The low cure rate in the series of Gordon et u L . ~ ~ might also be attributed to the important hematologic toxicity from which two patients died and six patients had dose reductions. This was probably due to the use of a higher dose of vinblastine in the first few cases treated (0.4 mg/kg) and much less likely due to a higher dose of bleomycin ( 1 5 mg/day for 5 days) in the schedule adopted by Gordon et ~ 1 . ~ ~

Randomized studies of PVB in testicular cancer have shown that 0.3 mg/kg of vinblastine is equally effective and less to xi^.^' In the study by Einhorn and Williarn~,’~ no sepsis was documented with the lower dose of vin- blastine which is similar to our results. Important he- matologic toxicity leads also to dose reduction and post- ponement of chemotherapy. This could be very detri- mental in view of the very high doubling time of GTT.”

Etoposide (VP- 16) has recently emerged as a major drug in the treatment of GTT leading to its integration in the first-line therapy of both l~w-risk’~ and high-risk patients.’

1832 CANCER November I 1989 Vol. 64

Combinations of etoposide, cisplatin with either d a c t i n ~ m y c i n ~ ~ or b l e ~ m y c i n ~ , ~ ' have shown promising results as salvage therapy for resistant GTT.

Randomized studies in germ cell tumors showed that VP- 16 could replace vinblastine in the PVB regimen (PVP-16 B) with less neuromuscular toxicity and slightly better results in high volume d i ~ e a s e . ~ * . ~ ~

Our results confirm a reasonable activity of PVB reg- imen, given in the schedule reported here, in the treatment of resistant GTT. This schedule was well tolerated with acceptable toxicity and no treatment-related deaths. The importance of a multimodal approach with resection of residual resistant lesions is stressed. Vinblastine could be substituted for by VP- 16 if the patient has not previously received this agent in the first-line treatment.

REFERENCES

1. Hammond CB, Borchert LG, Tyrey L, Creasman W. Parker L. Treatment of metastatic trophohlastic disease: Good and poor prognosis. Am J Obstei Gynecol 1973; 115:45 1-457.

2. Jones WB, Lewis JL Jr. Treatment of gestational trophoblastic dis- ease. Am J Obstei Gynecol 1974; 120:14-20.

3. Lurain JR, Brewer JI, Torok EE, Halpern B. Gestational tropho- blastic disease: Treatment results at the Brewer Trophoblastic Disease Center. Obsiet Gynecol 1982; 60:354-360.

4. Surwit EA, Alberts DS, Christian CD. Graham VE. Poor prognosis gestational trophoblastic disease: An update. Ohstet Gynecol 1984; 64:

5. Lewis JL Jr. Current status of treatment of gestational trophoblastic disease. Cancer 1976; 38:620-626.

6. Berkowitz RS, Goldstein DP, Bernstein MR. Modified triple che- motherapy in the management of high risk metastatic gestational tro- phoblastic tumors. Gynecol Oncol 1984; 19: 173- 1 8 1.

7. Li MC, Hertz R, Spencer DB. Effects ofmethotrexate therapy upon choriocarcinomas and chorioadenomas. Proc Soc E , Y ~ Biol Med 1956;

8. Ross GT, Stolbach LL, Hertz R. Actinomycin D in the treatment of methotrexate resistant trophoblastic disease in women. Cancer Re.s 1962; 22: 101 5- 1017.

9. Newlands ES, Bagshawe KD, Begent RHJ, Rustin GJS, Holden L, Dent J. Developments in chemotherapy for medium and high risk patients with gestational trophoblastic tumors (1979-1984). Br ./ Obs/ct Gyncml 1986; 93:63-69.

10. DuBeshter B, Berkowitz RS, Goldstein DP, Bernstein MR. Anal- ysis of treatment failure in high risk metastatic gestational trophoblastic disease. Gynecol Oncol 1988; 29: 199-207.

I I . Azab MB. Pejovic MH, Theodore C et al. Prognostic factors in gestational trophoblastic tumors: A multivariate analysis. Cancer 1988;

12. Hayes DM, Cvitkovic E, Golbey RB. High dose cis-platinum- diamminedichloride, amelioration of renal toxicity by mannitol diuresis. Cancer 1977; 39:1372-1381.

13. Vaitukaitis JL, Braunstein GD, Ross GT. A radioimmunoassay

21-26.

931361-366.

62:585-592.

which specifically measures human chorionic gonadotropin in the pres- ence of human luteinizing hormone. Am J Ohstet Gynecol 1972; 113: 751-758.

14. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer I98 1 ; 47:207-2 14.

15. World Health Organization Scientific Group. Gestational Tro- phoblastic Diseases, Technical Report Series 692. Geneva: World Health Organization, 1983; 1-8 I .

16. Amiel JL, Droz JP. La chimiothirapie des tumeurs placentaires. J Gynecol Obstet Bid Rcprod 1977; 6:261-270.

17. Einhorn LH, Donohue JP. Cisdiamminedichloroplatinum, vin- blastine and bleomycin combination chemotherapy in disseminated tes- ticular cancer. Ann Intern Med 1977; 87:293-298.

18. Hertz R, Lipsett MB, Moy RH. Effect of vinleukoblastine on metastatic chonocarcinoma and related trophoblastic tumors in women. Cancer Res 1960; 20:1050-1053.

19. Yim CM, Wong LC, Ma HK. Clinical trial of bleomycin in the treatment of gestational trophoblastic disease. Gynecol Oncol 1979; 8: 296-300.

20. Amiel JL, Droz JP, Tursz T. Tumeurs placentaires rksistantes aux chimiothtrapies habituelles: Traitment par le cis-diamminedichloropla- tinum. Deux cas. Nouv Presse Med 1978; 7:1933-1935.

2 1. Newlands ES. Preliminary experience with high dose cisplatinum and epipodophyllin derivative VP16-213 in resistant malignant teratomas and choriocarcinomas. Ciur Chemother 1978; 2: I3 15- 13 17.

22. Schlaerth JB, Morrow CP, DePetrillo AD. Sustained remission of choriocarcinoma with cis-platinum, vinblastine and bleomycin after failure of conventional combination drug therapy. Am J Obstef Gynecol

23. Hainsworth JD, Burnett LS, Jones HW, Anthony Greco F. Re- sistant gestational choriocarcinoma: Successful treatment with vinblas- tine, bleomycin and cisplatin (VBP). Cancer Treat Rep 1983; 67:393- 395.

24. Gordon AN, Kavanagh J J , Gershenson DM, Saul PB, Copeland U, Stringer A. Cisplatin, vinblastine and bleomycin combination therapy in resistant gestational trophoblastic Disease. Cancer 1986; 58: 1407- 1410.

25. Hammond CB, Soper JT. Poor Prognosis metastatic gestational trophohlastic neoplasia. Clin Ohsfrt Gynecol 1984; 27:228-239.

26. Hammond CB, Weed JC. Cume JL. The role of surgery in the current therapy of gestational trophoblastic disease. Am J Obsfet Gynecol 1980; 136:844-858.

27. Einhorn LH, Williams SD. Chemotherapy of disseminated tes- ticular cancer: A random prospective study. Cancer 1980; 46: 1339-1344.

28. Sunvit EA. The management of poor prognosis trophoblastic dis- ease. Semin Oncol 1982; 9:204-207.

29. Wong LC, Choo YC. Ma HK. Primary oral etoposide therapy in gestational trophoblastic disease. Cancer 1986; 58: 14-1 7.

30. Theodore C, Azab MB, Droz JP et at. Treatment of high-risk gestational trophoblastic disease with chemotherapy combinations con- taining cisplatin and etoposide. Cancer 1989; 64:1824-1828.

3 I . Willemse PHB, Aalders JG, Bouma J , Sleijfer DT. Chemotherapy- resistant gestational trophoblastic neoplasia treated successfully with cis- platin. etoposide and bleornycin. Ohstet Gynecol 1988; 7 1:438-440.

32. Williams SD, Birch R, Einhorn LH, Irwin L, Anthony Greco F, Loehrer PJ. Treatment of disseminated germ cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Eng JMed 1987; 316 1435- 1440.

33. Einhorn LH. Chemotherapy of disseminated germ cell tumors. Cancer 1987; 60570-573.

1980; 136:983-985.