First-line gemcitabine and carboplatin in advanced ovarian carcinoma: a phase II study

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1 DOI: /j x Gynaecological oncology First-line gemcitabine and carboplatin in advanced ovarian carcinoma: a phase II study SK Tay, a A Ilanchadran, b TY Tan b a Department of Obstetrics and Gynecology, Singapore General Hospital, Singapore, Republic of Singapore b National Cancer Centre Singapore, Hospital Drive, Singapore, Republic of Singapore Correspondence: SK Tay MD, Department of obstetrics and Gynecology, Singapore General Hospital, Outram Road, Singapore 1908, Republic of Singapore. tay.sun.kuie@sgh.com.sg Accepted 31 August 200. Published OnlineEarly 2 November 200. Objectives To evaluate tumour response rate and toxicities of gemcitabine and carboplatin in chemonaive subjects with advanced epithelial ovarian cancer. Design Setting A phase II study. Gynaecologic oncologic unit. Population Twenty chemonaive International Federation of Gynecology and Obstetrics (FIGO) stage IIIc and stage IV subjects with ovarian cancer. Main outcome measures Tumour response, disease free and overall survival and toxicity. Methods Intravenous gemcitabine 1000 mg/m 2 on day 1 and day 8 and carboplatin at area under centre (AUC) = 5 on day 1 were administered three weekly for six cycles. Subjects who received more than three cycles of chemotherapy were eligible for assessment of tumour response, while all the cycles of chemotherapy were assessed for toxicities. Results The mean age of the subjects was 57.3 years, and the median follow up was 38.7 months. Of the 18 eligible subjects analysed, 11 (1.1%) showed a complete clinical response, and the overall response rate was 83.3% (15/18). The median overall survival was 29.2 [95% (confidence interval) CI ] months, and the median progression-free survival was 11. (95% CI ) months. WHO grade 3 anaemia, neutropenia and thrombocytopenia was 7., 9.5 and 0%, respectively, on day 8, and 15.5, 12.2 and 15.5%, respectively, on day 15. Two subjects required a total of three hospital admissions for neutropenic sepsis, and two required five hospital admissions for platelet transfusion for severe thrombocytopenia. Conclusion Chemonaive advanced ovarian cancer showed a high response rate to combined gemcitabine and carboplatin chemotherapy. The subjects developed moderate adverse reactions. Phase III study to evaluate the role of combined gemcitabine and carboplatin as first-line chemotherapy in ovarian cancer is warranted. Keywords Anaemia, anti-tumour activity, chemotherapy, neutropenia, thrombocytopenia. Please cite this paper as: Tay S, Ilanchadran A, Tan T. First-line gemcitabine and carboplatin in advanced ovarian carcinoma: a phase II study. BJOG 200;113: Introduction Epithelial ovarian cancer is most commonly diagnosed in advanced stages and the outcome of treatment is dismal. The most important determinants in the prognosis of this cancer are the subject s age, stage and histological types of the cancer, volume of residual tumour at the end of surgery and tumour response to adjuvant chemotherapy. 1 The introduction of platinum-based chemotherapy regime in combination with paclitaxel has resulted in a quantum leap in the outcome of chemotherapy for ovarian cancer. An overall 5-year survival rate of 40% and a disease-free 5-year survival rate of 20% can be achieved. 2 5 In spite of this, advanced ovarian cancer remains an incurable disease for the majority of women. In practice, the patient s quality of life should assume a pivotal role in the disease management. The importance of minimising adverse effects from the treatment cannot be overemphasised. Paclitaxel and carboplatin combination is better tolerated than paclitaxel and cisplatin combination. Nonetheless, adverse reactions of paclitaxel can be severe and debilitating, particularly, neuropathy, arthralgia, myalgia and alopecia. 7 Single agent gemcitabine, a novel nucleoside analogue, has shown considerable anti-tumour activity in ovarian cancer Experience of gemcitabine and carboplatin used as first-line chemotherapy in several solid tumours has further shown that 1388 ª RCOG 200 BJOG An International Journal of Obstetrics and Gynaecology

2 Gemcitabine and carboplatin for ovarian cancer nonhaematological toxicities of this regimen are uncommon and mild We were therefore interested to investigate if gemcitabine and carboplatin show adequate anti-tumour activity and acceptable toxicity profile for them to be recommended for chemonaive patients with advanced epithelial ovarian cancer. We report here the results of a phase II study of first-line gemcitabine and carboplatin in advanced epithelial ovarian cancer. The primary endpoints are tumour response, disease-free interval, overall survival rate and toxicity of grade 3 or more. Method and patients This prospective phase II study was approved by the institutional and national ethical committees for clinical trials. The subjects in the study were nonpregnant adults who were capable of giving an informed consent. The diagnosis of epithelial ovarian cancer was assessed by the independent institutional pathologists and the FIGO stage IIIC or IV was confirmed by oncologists on the gynaecological tumuor board. All the subjects were chemonaive and had good performance status, with Eastern Cooperation Oncology Group (ECOG) grade 0 in 15 subjects and grade 1 in 5 subjects. 14 The primary surgery performed was classified into three groups: optimal, suboptimal and biopsy only. Optimal surgery referred to total hysterectomy, bilateral salpingooophorectomy (TAHBSO), omentectomy and complete resection of all visible intra-abdominal and intrapelvic and retroperitoneal tumours. There was no macroscopic residual tumours. Suboptimal surgery referred to presence of gross residual tumour of 2 cm or more despite maximal tumour debulking operation. The biopsy-only group of subjects had inoperable tumours in whom a tumour biopsy only was obtained for histological diagnosis. The subjects were assessed clinically for performance status, adverse drug reactions and tumour conditions. Laboratory investigations included serum electrolytes, urea and creatinine, and liver function test before and 1 week after each administration of the chemotherapy. Serum CA125 was measured at four weekly interval, and computed tomography scan of the abdomen and pelvis was performed before chemotherapy and at the end of the third and sixth cycle of chemotherapy. The subjects were followed up at three monthly interval with clinical examination and serum CA125 assay. Radiological investigations were carried out whenever tumour recurrence or progression was suspected. The chemotherapy regime consisted gemcitabine 1000 mg/m 2 body weight on day 1 and day 8, and carboplatin at AUC = 5 on day 1. Both the drugs were administered by intravenous infusion at an outpatient setting. Gemcitabine dosage was reduced by 20% if grade 3 toxicity assessed by WHO criteria was encountered. Onganisetron was the mainstay antiemetics during chemotherapy. Clinical response was assessed by an independent gynaecologic oncologist with the traditional criteria: clinical complete response was defined as complete resolution of all the tumours on clinical and radiological examinations and normalisation of serum CA125 levels. A partial response was defined as shrinkage of measurable tumours (sum of products of two largest perpendicular diameters) by more than 50% without any new lesions. Stable disease was defined as reduction of measurable tumours by less than 50% without new lesions. All other changes with tumour growth or new tumour nodules were defined as progressive disease. spss version 10.0 was used for Kaplan Meier survival analysis for progression-free survival and overall survival. Results A total of 20 subjects were enrolled for the study. The mean age (95% CI) was 57.3 ( ) years, and the characteristics of the tumours are summarised in Table 1. Of them, 1 completed cycles of chemotherapy, 1 received 5 and 1 received 4 cycles. These 18 subjects were eligible for the analysis of tumour response to the chemotherapy. Two subjects who received only one cycle of chemotherapy were excluded from the analysis of tumour response, but were included in toxicity study. Table 1. Patient demographics, tumour characteristics and types of surgery Patient demographics No. of cases Performance status Disease stage (FIGO) IIIC 17 IV 3 Histological type Serous papillary Grade 2 7 Grade 3 8 Mucinous Grade 2 1 Endometrioid Grade 2 2 Clear cells Grade 3 1 Adenocarcinoma Grade 3 1 Type of surgery TAHBSO 1 omentectomy Optimal 4 Suboptimal 12 Biopsy only 4 ª RCOG 200 BJOG An International Journal of Obstetrics and Gynaecology 1389

3 Tay et al. In term of tumour response, four subjects with complete surgery were assessed by changes in serum CA125 levels, while the remaining 14 cases were assessed by both serum CA125 levels and objective tumour response clinically and radiologically. The overall response rate to combined gemcitabine and carboplatin chemotherapy was 83.3% (15/18), with complete response in 11 (1.1%) subjects (Table 2). The median follow up was 38.7 [95% confidence interval (CI) ] months. At the time of writing, nine subjects had died of their disease. The median overall survival was 29.2 (95% CI ) months (Figure 1), and the median progression-free survival was 11. (95% CI ) months (Figure 2). Of the 18 subjects assessed for tumour response to combined gemcitabine and carboplatin chemotherapy, 13 (72.2%) had relapsed or progressive disease. Six of them received a second line chemotherapy with paclitaxel and carboplatin. Of the four patients who had a clinical complete response to gemcitabine carboplatin, two showed clinical complete response and two showed partial response to paclitaxel carboplatin. Of the two subjects who had an initial partial response to gemcitabine carboplatin, one showed partial response and the other showed a progressive disease to paclitaxel carboplatin. The toxicity of gemcitabine carboplatin chemotherapy was predominantly bone marrow suppression. WHO grade 3 anaemia was encountered in 7.% of 10 cycles on day 8 and 15.5% of 90 cycles on day 15 (Table 3). None of them required blood transfusion for anaemia. WHO grade 3 neutropenia was encountered in 9.5% of 10 cycles on day 8 and Table 2. Type of tumour response to gemcitabine and carboplatin chemotherapy Type of response No. of cases Percentage Complete Partial Stable 1 5. Progressive % of 90 cycles on day 15 (Table 3). Two subjects required a total of three hospital admissions for neutropenic sepsis. Thrombocytopenia was not encountered on day 8, but WHO grade 3 thrombocytopenia was encountered in 15.5% Cumulative survival Follow-up interval (months) Figure 1. Overall survival rate by Kaplan Meier analysis. Cumulative survival Follow-up (months) Censored Censored Figure 2. Progression-free interval by Kaplan Meier analysis. Table 3. The most prominent toxicity Parameter Haematological toxicity (WHO grade): no. of subjects (%) Day 8 of cycle (n 5 10)* Day 15 of cycle (n 5 90)* Haemoglobin 1 (15.1) 40 (37.7) 42 (39.) 8 (7.) 5 (5.) 2 (28.9) 45 (50.0) 14 (15.5) White blood cell 2 (24.5) 35 (33.0) 35 (33.0) 10 (9.5) 17 (18.9) 18 (20.0) 44 (48.9) 11 (12.2) Platelet 105 (99.1) 1 (0.9) (45.) 19 (21.1) 1 (17.8) 14 (15.5) * included in analysis ª RCOG 200 BJOG An International Journal of Obstetrics and Gynaecology

4 Gemcitabine and carboplatin for ovarian cancer of 90 cycles on day 15 (Table 3). Two subjects required five hospital admissions for platelet transfusion for severe thrombocytopenia. There was a significant cumulative bone marrow suppression effect of the combined gemcitabine and carboplatin chemotherapy. haemoglobin concentration, neutrophil and platelet counts declined with successive cycles of chemotherapy, as shown in their values on day 1 in each cycle of chemotherapy in Figure 3A C. The values on day 8 and day 15 showed the immediate bone marrow suppressive effect of the chemotherapy on individual cycles of chemotherapy. In this study, gemcitabine dose reduction by 20% was needed in eight subjects, and omission of day 8 gemcitabine in three subjects. None of them needed delay of chemotherapy by more than 1 week. WHO grade 1 alopecia was seen in all the subjects. Nausea and vomiting and skin rashes were mild and infrequent. There was no peripheral neuropathy encountered in this series of subjects. A B Haemoglobin concentration (g/dl) Neutrophil counts Day 1_HB Day 8_HB Day 15_HB Discussion The patient and tumour characteristics of the subjects of this study are typical of those seen in advanced epithelial tumour. 1 Only four of them had optimal debulking surgery, with hysterectomy, bilateral salpingo-oophorectomy and omentectomy; 12 (0%) had a suboptimal surgery and another 4 (20%) had a biopsy alone. The prognosis of these subjects was poor. Sixteen (80%) subjects completed six cycles of chemotherapy, one received five and one received four cycles. These 18 subjects were eligible for the analysis of tumour response to the chemotherapy. The overall response rate of 83.3%, with 1% clinical complete response rate, to combined gemcitabine and carboplatin chemotherapy is remarkable and comparable with that observed with first-line paclitaxel carboplatin and paclitaxel cisplatin chemotherapy After a median follow up was of 38.7 (95% CI ) months, the median overall survival was 29.2 (95% CI ) months (Figure 1), and the median progression-free survival was 11. (95% CI ) months (Figure 2). These results are promising when compared with a median overall survival rate of 3 39 months for subjects treated with paclitaxel/platinumcontaining chemotherapy as reported in a systemic review of three large studies, which included stage II cancer in addition to stage III and stage IV cancer. 5 More interestingly, our results are very similar to the experience of Bauknecht et al., who, in a phase II study with gemcitabine and cisplatin as first-line treatment of people older than 0 years with FIGO stage IIIC or stage IV epithelial ovarian carcinoma, found an overall response rate of 2.2% (95% CI, %) and a median survival of 27.7 months (95% CI, months). 18 Also, Nogue et al. reported a similar study with C Platelet counts gemcitabine and cisplatin, with an overall clinical response rate of 70.7% (95% CI %), a median overall survival of 23.4 months (95% CI months) and a median progression-free survival time of 10.4 months (95% CI months). 19 In this respect, our study suggests that the Day 1_WBC Day 8_WBC Day 15_WBC Day 1_PLT Day 8_PLT Day 15_PLT Figure 3. Immediate and cumulative bone marrow suppressive effects: changes in haematological parameters with chemotherapy. (A) haemoglobin level. HB, haemoglobin. (B) neutrophil counts. WBC, white blood cell. (C) platelet count. PLT, platelets. ª RCOG 200 BJOG An International Journal of Obstetrics and Gynaecology 1391

5 Tay et al. combination of gemcitabine and carboplatin seems to be as efficacious as combined gemcitabine and cisplatin; in the same way, paclitaxel and carboplatin is equally efficacious as paclitaxel and cisplatin. 20 The most prominent toxicity of gemcitabine carboplatin chemotherapy was bone marrow suppression. WHO grade 3 anaemia was encountered in 7.% on day 8 and 15.5% on day 15, and neutropenia in 9.5% on day 8 and 12.2% on day 15. Two subjects required a total of three hospital admissions for neutropenic sepsis. Thrombocytopenia was not encountered on day 8, but WHO grade 3 thrombocytopenia was encountered in 15.5% on day 15. Two subjects required five hospital admissions for blood transfusion for severe thrombocytopenia. Gemcitabine dose reduction by 20% was needed in eight subjects, and omission of day 8 gemcitabine in three subjects. None of them needed a delay of chemotherapy by more than 1 week. Our experience concurred with those of Favaretto et al. 13 It is noteworthy that the bone marrow suppression had a cumulative effect over the span of six cycles of chemotherapy. WHO grade 1 alopecia was seen in all the subjects. Nausea and vomiting and skin rashes were mild and infrequent. There was no peripheral neuropathy encountered in this series of subjects. These experiences were starkly different from a study combining cisplatin with gemcitabine, where grade 3 nausea/vomiting and alopecia occurred in 25. and 9.5% of subjects, respectively. 5 Compared with combined paclitaxel and carboplatin where grade 4 alopecia and flushes are seen in all the subjects, and peripheral neurotoxicity, particularly, sensory neuropathy in 34% of subjects; combined gemcitabine and carboplatin appeared a much to be desired chemotherapy regime for a better quality of life. 20 Conclusion This phase II study showed that gemcitabine plus carboplatin is an active chemotherapeutic regime for advanced epithelial ovarian cancer. When used as first-line chemotherapy, the overall response rate is comparable with the experience seen with paclitaxel plus carboplatin. Gemcitabine plus carboplatin appears to have a more acceptable toxicity profile than gemcitabine plus cisplatin or paclitaxel plus carboplatin.theresultsofthisstudy indicate that a randomised phase III study of gemcitabine plus carboplatin compared with the standard chemotherapy for advanced epithelial ovarian cancer is warranted. j References 1 Chi DS, Liao JB, Leon LF, Venkatraman ES, Hensley ML, Bhaskaran D, et al. Identification of prognostic factors in advanced epithelial ovarian carcinoma. Gynecol Oncol 2001;82: Neijt JP, ten Bokkel Huinink WW, van der Burg ME, van Oosterom AT, Willemse PH, Vermorken JB, et al. Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 1991;27: Advanced Ovarian Cancer Trialists Group. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Br Med J 1991;303: Tay SK, Chang TC. An evaluation on the policy of routine treatment of advanced epithelial ovarian carcinoma by debulking surgery and combined platinum-cyclophosphomide chemotherapy in Singapore. Int J Gynecol Cancer 199;: Hogberg T, Glimelius B, Nygren P; SBU-group. Swedish Council of Technology Assessment in Health Care. A systematic overview of chemotherapy effects in ovarian cancer. Acta Oncol 2001;40: Neijt JP, Engelholm SA, Witteveen PO, Tuxen MK, Sorensen PG, Hansen M, et al. Paclitaxel (175 mg/m 2 over 3 hours) with cisplatin or carboplatin in previously untreated ovarian cancer: an interim analysis. Semin Oncol 1997;24(5 Suppl 15):S Mayerhofer K, Bodner-Adler B, Bodner K, Leodolter S, Kainz C. Paclitaxel/carboplatin as first-line chemotherapy in advanced ovarian cancer: efficacy and adverse effects with special consideration of peripheral neurotoxicity. Anticancer Res 2000;20: D Agostino G, Amant F, Berteloot P, Scambia G, Vergote I. Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer. Gynecol Oncol 2003;88: Underhill CR, Parnis FX, Highley MS, Ahern J, Harper PG, Hansen H, et al. Multicenter phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. Anticancer Drugs 2001;12: von Minckwitz G, Bauknecht T, Visseren-Grul CM, Neijt JP. Phase II study of gemcitabine in ovarian cancer. Ann Oncol 1999;10: Iaffaioli RV, Tortoriello A, Facchini G, Caponigro F, Gentile M, Marzano N, et al. Phase I II study of gemcitabine and carboplatin in stage IIIB IV non-small-cell lung cancer. J Clin Oncol 1999;17: Ng EW, Sandler AB, Robinson L, Einhorn LH. A phase II study of carboplatin plus gemcitabine in advanced non-small-cell lung cancer (NSCLC): a hoosier oncology group study. Am J Clin Oncol 1999;22: Favaretto AG, Aversa SM, Paccagnella A, Manzini Vde P, Palmisano V, Oniga F,et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study. Cancer 2003;97: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5: du Bois A, Luck HJ, Meier W, Mobus V, Costa S, Richter B, et al. Carboplatin plus paclitaxel as first-line chemotherapy in previously untreated advanced ovarian cancer. German AGO Study Group Ovarian Cancer. Arbeitsgemeinschaft Gynakologische Onkologie. Semin Oncol 1997;24(4 Suppl 11): Ozols RF, Young RC. Chemotherapy of ovarian cancer. Semin Oncol 1991;11: McGuire WP, Hoskin WJ, Brady MR, Kucera PR, Partridge EE, Look KY et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med 199;334:1. 18 Bauknecht T, Hefti A, Morack G, Villena-Heinsen C, Wallwiener D, Elling D, et al. Gemcitabine combined with cisplatin as first line treatment in patients 0 years or older with epithelial ovarian cancer: a phase II study. Int J Gynecol Cancer 2003;13: Nogue M, Cirera L, ArcusaA, Batiste-Alentorn E, Balil A, FontA, et al. Phase II study of gemcitabine and cisplatin in chemonaive patients with advanced epithelial ovarian cancer. Anticancer Drugs 2002;13: Ozols RF. Paclitaxel plus carboplatin in the treatment of ovarian cancer. Semin Oncol 1999;2(1 Suppl 2): ª RCOG 200 BJOG An International Journal of Obstetrics and Gynaecology