Elsevier

European Journal of Cancer

Volume 35, Issue 9, September 1999, Pages 1331-1337
European Journal of Cancer

Original Paper
Cisplatin (P), vinblastine (V) and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa(-theca) cell tumours of the ovary. An EORTC gynaecological cancer cooperative group study

https://doi.org/10.1016/S0959-8049(99)00142-2Get rights and content

Abstract

The aim of this study was to investigate the clinical activity and toxicity of a modified PVB regimen (cisplatin, vinblastine and bleomycin) in patients with advanced or recurrent, pure granulosa cell tumours (GCTs) or mixed granulosa-theca cell tumours (GTCTs). The PVB regimen consisted of cisplatin (P) 20 mg/m2 intravenous (i.v.) days 1–5, vinblastine (V) 0.15 mg/kg i.v. days 1–2 and bleomycin (B) 30 mg i.v. on day 2, and 15 mg on day 15, for 28 days. 38 eligible patients were entered in this trial. Prior to PVB all patients underwent surgery and 13 received postoperative radio- or other prior chemotherapy. The median number of PVB cycles was 4 in both groups. In the group of 25 patients who had received prior surgery only, 7 and 6 patients had complete and partial responses, respectively (response rate: 52%, 95% confidence limits: 31.3–72.2%). At a median follow-up of 39 months, 6 patients were alive with no evidence of disease, 6 were alive with disease, 12 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 13.9 months. The median survival was 25.4 months. 3-year survival was 49% (95% confidence limits: 29–69%). In the group of 13 patients who had previously received postoperative radio- or chemotherapy, 5 complete and 5 partial responses were observed on PVB (response rate: 77%, 95% confidence limit: 46.2–95.0%). At a median follow-up of 50 months, 6 patients were still alive, only 1 without evidence of disease, 6 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 19.3 months. The median duration of survival was 41.1 months. Accompanying toxicity was distributed in a similar pattern for both groups. Severe toxicity was mainly documented as haematological toxicity, nausea/vomiting and alopecia. Furthermore cisplatin-related peripheral neurotoxicity and mild/moderate signs of bleomycin-related pulmonary toxicity were observed. The present data confirm the therapeutic activity of the PVB regimen in advanced/recurrent GCTs. The response rate was moderately high compared with previous studies, with a median duration of response of 20 months for both groups.

Introduction

granulosa- and theca-cell tumours are rare functional sex cord-stromal ovarian tumours. As a group they comprise only 2–3% of all ovarian malignancies. Pure thecomas are regarded as benign tumours but pure or mixed granulosa cell tumours (GCTs) should all be regarded as potentially malignant, although recurrence and metastasis may be slow 1, 2, 3, 4. In their review of 305 patients with granulosa- and theca-cell tumours, Björkholm and Pettersson [4] reported that none of the thecoma patients died but that 21% of those with GCT died from their disease.

The majority of GCTs present as FIGO stage I as the hormonal symptoms make an early diagnosis possible 2, 3. When surgically treated the 5-year survival rate for stage I is 90%, but patients with advanced disease have a 5-year survival ranging from 0 to 22% 4, 5, 6.

In the majority of cases, the initial form of therapy is surgery [5]. The selection of patients for any postoperative treatment is controversial [7]. In patients with advanced disease, postoperative chemo-, or hormono- or radiotherapy should be considered. In those patients with recurrent or metastatic disease, therapy has not yet been standardised 5, 7.

Over the past decade, platinum-based combination chemotherapy has emerged as the most widely used postoperative treatment in GCTs. Although a number of responses have been reported in small series or case reports, the highest identified response rates were obtained with the PVB regimen (cisplatin, vinblastine and bleomycin), but toxicity was significant [7].

The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Co-operative Group initiated a prospective clinical trial to investigate the clinical activity of a modified PVB regimen and its additional toxicity in patients with poor prognosis GCTs. Adjustment of the regimen was achieved by reducing the cumulative doses of vinblastine and bleomycin per cycle and increasing the interval between successive cycles by a week compared with the original reported PVB 8, 9. The early results have been published in abstract form [10].

Section snippets

Patients and methods

38 patients with advanced or recurrent GCT of the ovary were entered into a prospective clinical trial conducted by the Gynaecological Cancer Co-operative Group of the European Organization for Research and Treatment of Cancer (EORTC/GCCG). All patients were treated with PVB combination chemotherapy. The dosage and schedule of administration of chemotherapy consisted of: cisplatin (P), 20 mg/m2 on days 1–5 by intravenous (i.v.) infusion over a 3-h period with (pre)hydration with normal saline;

Results

From December 1984 to June 1991, 53 patients were registered in the trial. Follow-up was not sufficient in 4 patients. 10 other patients were considered ineligible, 4 with incorrect histological diagnosis (adenocarcinoma 1, lymphoma 1, small cell carcinoma of the ovary 2) and 6 with ineligible staging (FIGO stage IIb 3, no measurable lesions 3). One eligible patient did not receive any treatment. During the premedication for cisplatin she suffered a pulmonary embolism and consequently

Discussion

The literature concerning the use of postoperative chemotherapy in advanced or recurrent GCTs consists mainly of some small series of case reports. Initially objective responses were reported with alkylating agents 12, 13, 14, 15, 16. Thereafter reports appeared on the use of doxorubicin [17], doxorubicin/bleomycin [18] and actinomycin/5-fluorouracil/cyclo-phosphamide 16, 19. These and other available reports suggested that GCTs were indeed responsive to single-agent and combination

Acknowledgements

Other contributors to the study were: P.G. Harper (London), C. Mangioni (Monza), C.F. de Oliveira, Coimbra; W. ten Bokkel-Huinink, Amsterdam; P.J.M. Bakker, Amsterdam; A. Kobierska, Gdansk; P. Zola, Torino; W.P.M. Breed, Eindhoven; M.E.L. van der Burg, Rotterdam; J.P. Neijt, Utrecht; K.J. Roozendaal, Amsterdam; A.T. van Oosterom, Leiden; J.E.G.M. Stoot, Heerlen; P.H.B. Willemse, Groningen; E. Ploch, Warsaw; C. Belloni, Milano. This publication was supported by a grant from the Dutch Cancer

References (30)

  • F.T Camlibel et al.

    Chemotherapy of granulosa cell tumors

    Am J Obstet Gynecol

    (1983)
  • S.B Kaye et al.

    Cyclophosphamide, adriamycin, and cis-platinum for the treatment of advanced granulosa cell tumor, using serum estradiol as a tumor marker

    Gynecol Oncol

    (1986)
  • D Pectasides et al.

    Cisplatin-containing regimen in advanced or recurrent granulosa cell tumours of the ovary

    Ann Oncol

    (1992)
  • E Aboud

    A review of granulosa cell tumours and thecomas of the ovary

    Arch Gynecol Obstet

    (1997)
  • E Björkholm et al.

    Granulosa-cell and theca-cell tumors. The clinical picture and long term outcome for the Radiumhemmet series

    Acta Obstet. Gynecol. Scand.

    (1980)
  • Cited by (53)

    • Ovarian sex-cord stromal tumours and small cell tumours: Pathological, genetic and management aspects

      2017, Critical Reviews in Oncology/Hematology
      Citation Excerpt :

      The majority of patients with stage I disease has an excellent prognosis without to be treated postoperatively (Savage et al., 1998). However, for patients with poor prognostic factors, adjuvant platinum based chemotherapy is considered either alone or in combination with doxorubicin and cyclophosphamide (CAP) (Gershenson et al., 1987; Pectasides et al., 1992; Uygun et al., 2003), vinblastine and bleomycin (PVB) (Zambetti et al., 1990; Pecorelli et al., 1999), etoposide or etoposide and bleomycin (BEP) (Gershenson et al., 1996; Homesley et al., 1999; Pautier et al., 2008). The response rates varied from 60 to 100% and duration of response 5–58 months.

    • Impedimetric detection of in situ interaction between anti-cancer drug bleomycin and DNA

      2013, International Journal of Biological Macromolecules
      Citation Excerpt :

      Considering the fact that BLM intercalates preferentially G-rich sites of double stranded DNA by inducing the strand breakage dsDNA [15,16], BLM can disturb to dsDNA structure more effectively and strongly due to the fact that dsDNA has more G-rich sites in comparison to ssDNA. The medicine treatment based on the mixture of BLM including other chemotherapy agents, such as cis-DDP [32] and MC [33] has been preferentially used for treatment of advanced granulosa cell tumours [32], head and neck carcinoma [33]. In order to understand electrochemically how BLM interacts with dsDNA in the presence of other anticancer agents; cis-DDP and MC, the set of experiments was also performed as the first time herein in the literature by using EIS technique for electrochemical monitoring of DNA interaction with BLM plus cis-DDP, or BLM plus MC.

    • Role of adjuvant radiotherapy in granulosa cell tumors of the ovary

      2011, International Journal of Radiation Oncology Biology Physics
      Citation Excerpt :

      Owing to the infrequent occurrence of GCT, early diagnosis, slow growth, and favorable outcomes, little investigation has been done of the role of adjuvant treatment of GCT. Advanced-stage GCTs have often been treated with adjuvant chemotherapy, usually cisplatin, vinblastine, and bleomycin (11, 14) or bleomycin, etoposide, and cisplatin (12, 15, 16), with response rates varying from 52% to 83%. However, both regimens induce severe toxicity, and long-term survival data are lacking.

    View all citing articles on Scopus
    View full text