Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer

Available online at www.sciencedirect.com R

Gynecologic Oncology 88 (2003) 266 –269

www.elsevier.com/locate/ygyno

Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer Giuseppe D’Agostino,a,b Frederic Amant,a Patrick Berteloot,a Giovanni Scambia,b and Ignace Vergotea,* a

b

Department of Gynecologic Oncology, University Hospitals Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy Received 11 July 2002

Abstract Objective. To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer. Methods. Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m2, was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days. Results. Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1–5). Median platinum-free interval was 3 (range, 1–11) months and median paclitaxel-free interval was 6 (range, 1–36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1–10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20 –50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6 –29), 15 disease stabilizations (⬎16 weeks) (36.6%; 95% CI, 21.9 –51.3), and 19 progressions (46.3%; 95% CI, 31.0 – 61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. Conclusions. This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Gemcitabine; Single-agent; Recurrent ovarian cancer; Phase II

Introduction Ovarian cancer is the gynecological malignancy with the highest mortality [1]. Cytoreductive surgery and the introduction of platinum/taxane based-chemotherapy in the past decade have improved progression-free and overall survival. However, the majority of ovarian cancer patients still relapse within 2 years of the end of primary treatment and * Corresponding author. Department of Gynecologic Oncology, University Hospitals Leuven, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Fax: ⫹32-16-344629. E-mail address: [email protected] (I. Vergote).

die of disease within 5 years from their initial diagnosis [2]. The management of tumor recurrence remains a clinical challenge, since the chance of response to a secondary treatment is currently less than 20% [3], especially if the disease is platinum resistant [4]. To improve this outcome, several clinical trials are now exploring the possibility of incorporating new drugs into the first-line chemotherapy regimen [5]. Furthermore, new biological agents and molecularly targeted therapies aimed to overcome drug resistance with less toxic effects are under investigation [6]. Pharmaceutical research has also been focusing on the synthesis of new antineoplastic compounds whose profiles

0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(03)00011-8

G. D’Agostino et al. / Gynecologic Oncology 88 (2003) 266 –269

match ease of administration and low toxicity, to warrant the probability of cure with a minor impact on patient quality of life. Gemcitabine, a novel nucleoside analogue that replaces natural deoxycytidine into the DNA strand and blocks DNA synthesis, seems to respond to these requirements, since it combines an effective antiproliferative property with safety and tolerability [7]. This drug proved to be highly active in a variety of solid tumors [8], and several studies have been performed using gemcitabine in ovarian cancer patients, with response rates of approximately 20% even in platinum-resistant cases, with low and well-tolerated hematological and nonhematological toxicity [9 –12]. In this phase II study gemcitabine has been given to a subset of ovarian cancer patients with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, and who, in most cases, had already failed a further salvage treatment.

267

Table 1 Patient characteristics Characteristic Patients Entered Evaluable Median age (range) Median performance status (range) Histological type Serous Clear cells Mucinous Others Median platinum-free interval (range) Median taxol-free interval (range) No. of prior chemotherapy regimens 1 2 3 4 5

No.

%

50 41 57 (24–83) 1 (0–2)

100 82

40 5 1 4 3 months (1–11) 6 months (1–36)

80 10 2 8

4 24 14 7 1

8 48 28 14 2

Patients and methods Patients with a documented primary or secondary platinum/paclitaxel resistance were evaluated. Resistance to cytotoxic agents was defined as progression during or relapse within 6 months after stopping first-line therapy. Patients who had previously experienced a clinical remission under platinum or paclitaxel, and relapsed after a treatment-free interval of more than 6 months, had been retreated with platinum and/or paclitaxel before entering the study. Many patients were also treated with other drugs such as topotecan, hexamethylmelamine, oxaliplatin, or other phase I or II investigational drugs, prior to inclusion in this trial. Inclusion criteria were as follows: radiological evidence of one-dimensional, measurable (⬎2 cm) lesions; age over 18 years; Eastern Cooperative Oncology Group performance status ⱕ 2 [13]; life expectancy ⬎ 12 weeks; absolute neutrophile count ⱖ 1.5 ⫻ 109/L; platelet count ⬎ 150 ⫻ 109/L; bilirubin and creatinine levels ⬍ 1.5⫻ the upper limit of normal. Patients were ineligible in case of the following: significant heart disease including any history of ischemic heart disease, any history of arrhythmia requiring treatment, or clinically significant valvular disease; other investigational cytotoxic drugs given within 30 days prior to entry into the study; symptomatic central nervous system metastases; uncontrolled severe infection and/or medical problems unrelated to malignancy that would limit full compliance with the study or expose them to extreme risk. Informed consent was obtained from all patients prior to enrollment into the study. Gemcitabine, 1000 mg/m2, was administered on days 1, 8, and 15 by 30-min intravenous infusion; cycles were repeated every 28 days until disease progression or unacceptable toxicity. Granulocyte-colony stimulating factor was administered subcutaneously at the dose of 5 ␮g/kg daily, in the case of absolute neutrophile count ⬍ 500/␮L persisting for ⬎5 days or complicated by fever, and continuing until the reversal of neutropenia. All

the patients received an antiemetic prophylaxis (metoclopramide) prior to the application of chemotherapy. Complete blood count and platelets were performed on a weekly basis, while a routine 12-channel biochemistry was performed on days 1 and 15 of each cycle, unless otherwise clinically required. Chemotherapy-induced toxicity was graded according to the National Cancer Institute common toxicity criteria [14]. In the case of hemoglobin ⬍ 9 g/dL, absolute neutrophile count ⬍ 1000/␮L, and/or platelet count ⬍ 100,000/␮L, treatment was postponed by 1 week. In the patients who had delayed treatment for ⬎2 weeks, treatment was discontinued and an alternative regimen was considered. In the presence of grade 4 neutropenia or thrombocytopenia, the doses of gemcitabine were reduced by 20 –50% in the next cycles (20% dose level ⫺1; 50% dose level ⫺2). Clinical evaluation of response (including computed tomographic scan) was planned every two cycles, and response registered according to the Response Evaluation Criteria in Solid Tumors guidelines [15].

Results From September 1996 to March 2002, 50 patients were enrolled at the Department of Gynecologic Oncology of the University Hospitals, in Leuven, Belgium. Patient characteristics, including the number of prior chemotherapeutic regimens, are detailed in Table 1. The median age was 57 (range, 24 – 83) years. Six patients had also received whole abdomen radiotherapy. In the majority of cases, further previous treatments consisted of drugs such as topotecan, doxorubicin, hexamethylmelamine, oxaliplatin, and cyclophosphamide. Most patients had a pelvic recurrence, and 24 of them (48%) also had extraperitoneal disease (liver, pleura, lungs, abdominal wall, or lymph nodes). Twenty-

268

G. D’Agostino et al. / Gynecologic Oncology 88 (2003) 266 –269

Table 2 Hematological toxicity Toxicity

Hemoglobin Neutrophils Platelets

Grade 3

Grade 4

No. of patients

(%)

No. of cycles

(%)

No of patients

(%)

No of cycles

(%)

8 12 4

(16) (24) (8)

10 33 8

(4.7) (15.7) (3.8)

1 9 0

(2) (18) (0)

1 13 0

(0.5) (6.2) (0)

five patients (50%) had more than one measurable lesion. Forty-one patients were treated primarily with a platinumand paclitaxel-based first-line chemotherapy. The remaining nine had received a platinum-based regimen as up-front chemotherapy and were subsequently treated with taxol. In 38 cases (76%) with primary platinum sensitivity, rechallenge with a platinum compound was attempted prior to enrollment into this study, and in all cases the platinum-free interval was calculated from the last dose of the last platinum regimen. Median platinum-free interval was then 3 (range, 1–11) months and median paclitaxel-free interval was 6 (range, 1–36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1–10). As shown in Table 2, severe hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). Neutropenic fever, requiring hospitalization, was observed in only 1 patient, whereas thrombocytopenia was never complicated by bleeding episodes or platelet transfusion. Blood transfusions were given to 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was administered to 4 patients (8%). Nonhematological toxicity was mild and manageable, since only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Rash and dyspnea were observed in 1 and 1 patient, respectively, and only 1 patient experienced shivering during gemcitabine infusion. A 20 –50% dose reduction was required for 36 (72%) patients (56% of cycles). An overview of the dose intensity is presented in Table 3: 24 patients (48%) received an average dose of gemcitabine per cycle corresponding to more than 80% of the full dose; 21 patients (42%) received an average 50 – 80% of the full dose, whereas ⬍50% of the full dose was administered to 3 patients (6%). Forty-one patients (82%) are so far evaluable for re-

sponse (Table 4). Nine patients had an early progression resulting in death from progressive disease after only one course of chemotherapy and were not evaluable. Seven partial responses (17%; 95% confidence interval [CI], 6 –29) have been registered. One partial response occured in a patient progressing 4 months after primary treatment, 5 other partial responses occurred in patients progressive on their salvage treatment (4 platinum rechallenges), and for the seventh patient gemcitabine was the fourth-line chemotherapy. Median duration of the response was 21 (range, 8 – 64) weeks. Fifteen disease stabilizations (37%; 95% CI, 22–51) lasting more than 16 weeks were also observed, with a median duration of 22 (range, 17– 82) weeks. In seven cases (47%) stabilization of disease resulted for longer than 24 weeks. Overall median time-to-progression was 18 (range, 4 –94) weeks. Nineteen patients progressed on gemcitabine treatment (46.3%; 95% CI, 31.0 – 61.6).

Discussion Recurrence of disease is the major clinical problem in the management of ovarian cancer. During the last decade, progress made in clinical research has led to the introduction in clinical practice of such a quantity of new active drugs that physicians now have many options when disease relapses. Disappointingly, when the tumor is platinum resistant, the reported response rates are lower than 20%, regardless of therapy [16]. In this study gemcitabine proved to be well tolerated in heavily pretreated ovarian cancer patients. The overall 17% rate of clinical remissions, with a further 37% of disease stabilizations achieved in platinum- and paclitaxel-resistant disease, confirms our previously reported interim analysis [17], and is similar to the rates observed in previous studies testing single-agent gemcitabine in patients with recurrent Table 4 Clinical response of women treated with single-agent gemcitabine (n ⫽ 41)

Table 3 Dose intensity of single-agent gemcitabine Mean dose (mg/m2/cycle)

%

No. of patients

%

Response

No. of patients

%

⬎2400–3000 1500–2400 ⬍1500

⬎80 50–80 ⬍50

24 21 3

48 42 6

Complete remission Partial remission Stable disease Progressive disease

0 7 15 19

0 17.1 36.6 46.3

G. D’Agostino et al. / Gynecologic Oncology 88 (2003) 266 –269

ovarian cancer [18,19]. Our findings are also slightly superior to those observed in a recent wide randomized study comparing two other promising drugs currently used as second-line treatments for ovarian cancer, namely, liposomal doxorubicin and topotecan, which achieved an objective response of 12.5% and 6.5%, respectively, in the subset of platinum-resistant patients [16]. Although it is recognized that the direct comparison of response rates across nonrandomized phase II studies is hazardous, our findings seem encouraging, considering also that the median duration of disease stabilization was 18 weeks in our study, quite reassuring in this group of patients, especially since partial responses and disease stabilizations have been shown to achieve a similar survival after second-line chemotherapy [20,21]. More than half the patients suffered from grade 3 or 4 hematological toxicity. However, neutropenic fever was observed in only one patient, and thrombocytopenia was never complicated by bleeding episodes or platelet transfusion. A high number of blood transfusions has been employed in many cases to warrant quality of life. Furthermore, it should also be noted that a dose reduction was necessary in 56% of the cycles, confirming the efficacy of gemcitabine, even when used at a reduced dosage. These toxicity data, also comparable to previous reports [18,19], rate gemcitabine among the most safe agents used in the salvage treatment of patients with ovarian cancer, and stimulate further considerations regarding this drug: the postulated synergism with cisplatin [22] and the nonoverlapping toxicity profiles warrant the introduction of gemcitabine into the standardized platinum/paclitaxel chemotherapy, to potentiate the response rate and prolong the progression-free survival of chemotherapy-naive ovarian cancer patients [5]. On the other hand, the need to increase the chances of response to salvage treatment of platinumresistant ovarian cancer patients may lead to reconsider the use of drug combinations even in the second-line setting, where it is currently discouraged because of higher toxicity and lack of any evidence of benefit in terms of survival [3]. In this context, however, the rationalized choice of drugs with different mechanisms of action and toxicity patterns could see gemcitabine playing a leading role [23,24] and might result in an improved clinical outcome for these patients with a poor prognosis.

References [1] Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2000. CA Cancer J Clin 2002;52:23– 47. [2] McGuire WP, Ozols RF. Chemotherapy of advanced ovarian cancer. Semin Oncol 1998;25:340 – 8.

269

[3] Colombo N, Parma G, Bocciolone L, Sideri M, Franchi D, Maggioni A. Role of chemotherapy in relapsed ovarian cancer. Crit Rev Oncol Hematol 1999;32:221– 8. [4] Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991;9:389 –93. [5] Bookman M. Developmental chemotherapy in ovarian cancer: incorporation of newer cytotoxic agents in a phase III randomized trial of the Gynecologic Oncology Group (GOG-0182). Semin Oncol 2002; 29(S1):30 –1. [6] Ozols RF. Future directions in the treatment of ovarian cancer. Semin Oncol 2002;29(S1):32– 42. [7] Plunkett W, Huang P, Searcy CE, Gandhi V. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol 1996; 23(S10):3–15. [8] Barton-Burke M. Gemcitabine: a pharmacological and clinical overview. Cancer Nurs 1999;22:176 – 83. [9] Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP. Phase II study of gemcitabine (2⬘, 2⬘-difluorodeoxycytidine) in previously treated ovarian cancer. J Natl Cancer Inst 1994;86:1530 –3. [10] Shapiro JD, Millward MJ, Rischin D, Michael N, Walker V, Francis Pa, et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996;63:80 –93. [11] Hansen SW, Tuxen MK, Sessa C. Gemcitabine in the treatment of ovarian cancer. Ann Oncol 1999;10(S1):51–3. [12] Markman M, Kennedy A, Webster K, Zanotti K, Kulp B, Peterson G, et al. Phase II trial of single-agent gemcitabine (GEM) in platinum (PLAT)/paclitaxel (PAC) refractory ovarian cancer (ROC). Proc Am Soc Clin Oncol 2001;20:A813. [13] 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;5:49 –55. [14] National Cancer Institute common toxicity criteria, Version 2.0 Revised March 23, 1998, http://ctep.info.nih.gov/CTC3/default.htm. [15] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–16. [16] Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomised phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001;19:3312–22. [17] Coenen M, Berteloot P, Amant F, Vangramberen M, Vergote I. Gemcitabine in platin-paclitaxel resistant ovarian carcinoma. Proc Am Soc Clin Oncol 2000;19:A1603. [18] Orlando M, Mandachain M. Gemcitabine in ovarian cancer. Semin Oncol 2001;28(S10):62–9. [19] Markman M. Second-line treatment of ovarian cancer with singleagent gemcitabine. Semin Oncol 2002;29(S.1):9 –10. [20] Cesano A, Lane SR, Poulin R, Ross G, Fields SZ. Stabilization of disease as a useful predictor of survival following second-line chemotherapy in small cell lung cancer and ovarian cancer patients. Int J Oncol 1999;15:1233– 8. [21] Cesano A, Lane SR, Ross GA, Fields SZ. Stabilization of disease as an indicator of clinical benefit associated with chemotherapy in non small cell lung cancer patients. Int J Oncol 2000;7:587–90. [22] Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Braakhuis BJ. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995;22(S11):72–9. [23] Thigpen T. the role of gemcitabine-based doublets in the management of ovarian carcinoma. Semin Oncol 2002;29(S1):11– 6. [24] D’Agostino G, Ferrandina G, Garganese G, Salerno MG, Lorusso D, Farnetano MG, et al. Phase I study of gemcitabine and liposomal doxorubicin in relapsed ovarian cancer. Oncology 2002;62:110 – 4.