Second-line chemotherapy with gemcitabine and carboplatin in paclitaxel-pretreated, platinum-sensitive ovarian cancer patients

Gynecologic Oncology 92 (2004) 152 – 159 www.elsevier.com/locate/ygyno

Second-line chemotherapy with gemcitabine and carboplatin in paclitaxel-pretreated, platinum-sensitive ovarian cancer patients A Hellenic Cooperative Oncology Group Study Christos A. Papadimitriou, a,* George Fountzilas, b Gerassimos Aravantinos, c Charalambos Kalofonos, d Lia A. Moulopoulos, e Evangelos Briassoulis, f Dimitra Gika, a and Meletios-A. Dimopoulos a b

a Department of Clinical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece First Department of Internal Medicine, Oncology Section, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece c Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece d Department of Medicine, Division of Oncology, University Hospital of Patras, Rion, Greece e Department of Radiology, Areteion Hospital, Athens University School of Medicine, Athens, Greece f Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

Received 17 March 2003

Abstract Objective. Patients with epithelial ovarian cancer (EOC) who relapse more than 6 months following completion of platinum-based primary chemotherapy are considered platinum-sensitive, and can be effectively retreated with cisplatin or carboplatin. The nucleoside analogue gemcitabine has proven activity in both platinum-sensitive and platinum-resistant disease. We conducted a phase II study using the combination of carboplatin and gemcitabine for the treatment of patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. Methods. Forty-three patients were treated with gemcitabine 1000 mg/m2, intravenously, over 30 min on days 1 and 8, and carboplatin at AUC 5 on day 1. Courses were administered every 3 weeks on an outpatient basis. Results. Among 37 patients with measurable or evaluable disease, 15 (40.5%) achieved an objective response including 10 complete and 5 partial responses. The median overall survival was 24.5 months, and the median time to progression for all patients was 9 months. The treatment was well tolerated without toxic deaths; the most common toxicities were Grade 3 or 4 neutropenia, anemia, and thrombocytopenia that occurred in 69%, 26%, and 24% of patients, respectively. Conclusions. The combination of carboplatin and gemcitabine is a well-tolerated outpatient regimen with activity in patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. However, a randomized prospective study is justified to define whether the addition of gemcitabine to single-agent carboplatin results in improved efficacy in this subset of patients. D 2003 Elsevier Inc. All rights reserved. Keywords: Platinum-sensitive relapsed ovarian cancer; Gemcitabine; Carboplatin; Second-line chemotherapy

Introduction The majority of patients with epithelial ovarian cancer (EOC) present at the time of diagnosis with advanced disease (FIGO stages III or IV) which has spread outside the pelvis. The current management of advanced EOC generally includes cytoreductive surgery followed by com* Corresponding author. Department of Clinical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Tatoiou 146, 14671 Nea Erythrea, Athens, Greece. Fax: +30-210-3381511. E-mail address: [email protected] (C.A. Papadimitriou). 0090-8258/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2003.09.021

bination chemotherapy [1]. The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of newly diagnosed patients with advanced EOC [2– 7]. Despite the progress that has been achieved by incorporating paclitaxel into first-line regimens, the majority of these women will develop recurrences and will die of their disease. Patients who relapse after achieving prior response usually receive second-line therapy. If patients relapse >6 months following completion of primary chemotherapy such as paclitaxel with a platinum analogue, they are still considered sensitive and may respond to a second course of

C.A. Papadimitriou et al. / Gynecologic Oncology 92 (2004) 152–159

the same drug(s) [8 –13]. Also, many other agents have been studied in recurrent or resistant EOC including topotecan, docetaxel, ifosfamide, oral etoposide, anthracyclines, vinorelbine, and gemcitabine. Unfortunately, second-line chemotherapy rarely results in prolonged survival [9,13]. The Hellenic Cooperative Oncology Group conducted a prospective phase II study to evaluate the activity and toxicity of the combination of carboplatin with gemcitabine in platinum-sensitive and paclitaxel-pretreated ovarian cancer patients.

Materials and methods Patient selection In the present study, we included patients with pathologically confirmed EOC that relapsed more than 6 months after the previous paclitaxel- and platinum-based chemotherapeutic regimen. All patients had treatment with paclitaxel as part of their previous platinum-based regimens. Other eligibility requirements included ECOG performance status of 0, 1, or 2; a granulocyte count of at least 1500/Al, a platelet count of at least 100,000/Al, a serum creatinine level of 1.7 mg/dl or less, a serum bilirubin of 2.0 mg/dl or less, and ALT and AST values of no more than twice the upper normal level. Patients had to enter the study within 4 weeks after relapse documentation. Before study entry, all patients underwent computed tomography of the abdomen and pelvis and chest X-ray followed by computed tomography of the chest if indicated. Complete physical and gynecological examination, urinalysis, creatinine and liver function tests, serum CA 125, performance status, and toxicity evaluations were conducted before each cycle. Appropriate imaging procedures were performed after every other course of therapy. All patients provided informed consent according to institutional guidelines. Treatment plan Chemotherapy was given on an outpatient basis and consisted of gemcitabine 1000 mg/m2 diluted in 500 ml of 0.9% saline and administered intravenously, over 30 min, on days 1 and 8. Carboplatin was dosed using the Calvert formula and infused over 1 h in 500 ml glucose 5%, immediately before gemcitabine on day 1. Carboplatin AUC was 5. Appropriate antiemetics were used before and after the administration of chemotherapy. Courses of gemcitabine and carboplatin were administered every 21 days for a maximum of six cycles. Chemotherapy was discontinued in case of progressive disease or unacceptable toxicity. On day 1 of each cycle, if the absolute granulocyte count was <1500/Al or the platelet count <100,000/Al, a maximum of 2 weeks’ delay was allowed for recovery. The dosage for the subsequent cycles was then reduced by 20% for both drugs. In this case, gemcitabine was given at a dose of 800

153

mg/m2 on days 1 and 8 and carboplatin was targeted at AUC 4. The doses for both gemcitabine and carboplatin were permanently reduced by 20%, as above, if dose-limiting toxicities occurred in preceding cycles, including febrile neutropenia, Grade 4 neutropenia or thrombocytopenia, and any Grade 4 non-hematologic toxicities. If these toxicities occurred again despite the dose reduction, the treatment had to be terminated. Within a cycle, the day 8 dose of gemcitabine was reduced by 20%, if the absolute granulocyte count was 1000– 1499/Al or the platelet count was 75,000 – 99,000/Al. Gemcitabine was omitted for a granulocyte count less than 1000/Al and a platelet count less than 75,000/Al. Granulocyte-colony stimulating factor (G-CSF) was not given prophylactically but it was offered therapeutically at the discretion of the investigators. Definition of response and toxicity WHO criteria for response and toxicity were used [14]. One dose of therapy was considered adequate for response assessment and patients experiencing toxic death were rated as nonresponders. Patients who had normalization of serum CA125 levels and complete resolution of all measurable or evaluable disease for at least 4 weeks were considered to have a clinical complete response (cCR). Partial response (PR) was defined as a z50% decrease in the sum of the products of the two largest perpendicular dimensions of bidimensionally measurable lesions for at least 4 weeks. Stable disease (SD) was defined as a regression not meeting the aforementioned criteria for objective response, with no progression for at least 3 months. All other cases were considered to have progressive disease (PD). Response duration was defined as the time from partial or complete response to the appearance of progressive disease. Time to progression was measured from the time of initiation of treatment to the time of last patient contact or documented progressive disease. Survival was measured from the time of initiation of therapy to the last patient contact or death. Dose intensity analysis Dose intensity is a measurement of the dose received as a function of time. We used the method described by Hryniuk and Goodyear [15]. A value for received dose intensity was calculated by dividing the cumulative dose treatment given to each patient. One dose interval was added to the treatment period of each patient to adjust for methodologic problems in dealing with those patients who received <6 cycles. The received dose intensity was calculated from the beginning of chemotherapy. Statistical analysis The primary endpoint of this nonrandomized phase II study was to evaluate the response rate. The secondary

154

C.A. Papadimitriou et al. / Gynecologic Oncology 92 (2004) 152–159

endpoints were survival and toxicity. The sample size determination was based on response rate. According to Simon’s two-stage optimal design, assuming that the expected overall response rate will be at least 50% and the minimum acceptable response rate 30%, a sample of 15 patients was required for the first step. If a minimum of 6 responses was observed, a sample size of 46 patients was adequate. Thereby, if at least 19 responses occurred, the probability of accepting a treatment with a real response rate less than 30% is 5%. On the other hand, the risk of rejecting a treatment (at the second stage) with a response rate of more than 50% is 20%. Time to progression and survival curves were constructed using the Kaplan – Meier product limit method [16]. Differences in survival were compared with the log rank statistical test using a microcomputer-assisted program. All analyses were performed with the use of SPSS 11.0.1 (SPSS, Inc., Chicago, IL).

Results Between June 1997 and July 1999, 48 patients with relapsed EOC were accrued to this study. Five patients were found ineligible. One patient had relapsed less than 6 months after the previous platinum-based first-line chemotherapy, 2 patients had not received paclitaxel as a part of their first-line chemotherapy, whereas 2 additional patients had received more than one prior chemotherapeutic regimens. The main characteristics of the 43 eligible patients are summarized in Table 1. Ninety percent of patients had an ECOG performance status of 2 or less; 70% of patients had tumors of serous histology; the initial FIGO stage was III or IV in 86% of patients; and in 55% of patients, the tumors were poorly differentiated. The combination of paclitaxel with a platinum analogue was the first-line treatment in 33 patients (77%). Ten patients (24%) were treated with a three-drug combination regimen that consisted of paclitaxel, cisplatin, and either epirubicin (12%) or ifosfamide (12%). A total of 217 cycles of gemcitabine and carboplatin was administered (median, six cycles; range, one to six cycles). Seven patients with stable disease received six cycles of chemotherapy. The median relative dose intensity for gemcitabine was 77%, and the median cumulative dose for carboplatin 4200 mg. Sixty percent of patients who completed six courses of chemotherapy received G-CSF (in one or more cycles).

Table 1 Patient characteristics Characteristic

No. of patients (%)

Total patients Age, years Median Range ECOGa performance status 0 1 2 3 Unknown Histologic type Serous Endometrioid Poorly differentiated Clear cell Mucinous Adenocarcinoma NOSb Tumor grade 1 2 3 Unknown Initial FIGOc stage I II III IV Unknown First-line chemotherapy Paclitaxel and cisplatin or carboplatin Paclitaxel, epirubicin and cisplatin Paclitaxel, ifosfamide and cisplatin Measurable/evaluable disease Yes No

43 63 44 – 76 16(37) 18(42) 5(12) 2(5) 2(5) 30(70) 3(7) 2(5) 2(5) 2(5) 4(9) 0 13(30) 25(58) 5(11) 1(2) 3(7) 28(65) 9(21) 2(5) 33(77) 5(12) 5(12) 37(86) 6(14)

a

Eastern Cooperative Oncology Group. Not otherwise specified. c International Federation of Gynecology and Obstetrics. b

physical and gynecological examination, serum CA 125, and computed tomography of the abdomen and pelvis. The median platinum-free interval for all patients was 13 months (range 6.5 –28.4 months). Nineteen (44%) patients relapsed <12 months and 24 (50%) patients relapsed z12 months following completion of primary chemotherapy. We observed 3 (16%) CRs and 2 (11%) PRs in the first group vs. 7 (39%) CRs and 3 (17%) PRs in the second group, respectively (Fisher’s exact test; P = 0.1). Remission duration and survival

Response Response was assessed in the 37 women (86%) who entered the study with measurable (30 patients) or evaluable disease (7 patients) (Table 2). Fifteen (40.5%) patients achieved an objective response (95% CI, 25– 58%) including 10 (27%) CRs and 5 (13.5%) PRs. All measurable or evaluable patients (ascites only) were evaluated by complete

After a median follow up of 43 months (range, 0.5– 55+ months), 38 patients (88%) demonstrated disease progression. The median overall survival was 24.5 months (range, 0.5– 55+ months) (Fig. 1). The median time to progression for all patients was 9 months (range, 0.5 – 55+ months) (Fig. 1). The median remission duration for complete and partial responders was 10 months (range, 4 –55+ months). The

C.A. Papadimitriou et al. / Gynecologic Oncology 92 (2004) 152–159 Table 2 Clinical response among women with measurable or evaluable disease (N = 37) Clinical response Complete response Partial response Objective response Stable disease Progressive disease

No. of patients(%) 10(27) 5(13.5) 15(40.5) 10(27) 12(32)

Table 3 Toxicity according to WHO criteria Toxicity grade

95% CI percentage range 14 – 44 4.5 – 29 25 – 58 14 – 44 18 – 50

median overall survival for patients who relapsed <12 months after completion of platinum-based first-line chemotherapy was 29 months (range, 1.9 –55+ months), whereas the corresponding survival for women who relapsed z12 months was 22 months (range, 0.5 –44 months) (log rank; P = 0.28). Toxicity Detailed toxicity data according to the WHO scale were available for all cycles (Table 3). Toxic non-hematologic reactions higher than Grade 2 were rarely observed and consisted primarily of Grade 2 nausea and emesis in 21% of patients. Twelve percent of patients had Grade 1 or 2 peripheral neuropathy. Two patients died of congestive heart failure, and one patient of cardiac arrest possibly due to acute myocardial infarction, but these three deaths were not clearly treatment related. Also, we did not observe any incident of renal or pulmonary toxicity. Grade 3 or 4 granulocytopenia occurred in 69% of patients, but only four episodes of neutropenic infection were documented that

155

Granulocytopenia Anemia Thrombocytopenia Alopecia Nausea/emesis Renal Stomatitis Diarrhea Peripheral neuropathy Hepatic Pulmonary Fatigue Allergy Infection

% of patients affected 0

1

2

3

4

10 7 43 81 60 100 93 100 88 93 100 71 91 79

7 21 17 12 19 0 5 0 7 5 0 19 2 12

14 45 17 5 21 0 2 0 5 0 0 7 5 7

52 26 14 2 0 0 0 0 0 2 0 2 0 2

17 0 10 0 0 0 0 0 0 0 0 0 2 0

The highest level of toxicity is recorded.

were successfully treated by antibiotics. Eighty-seven percent of patients developed moderate to severe anemia. Anemic patients were treated with epoetin-a at a dose of 10,000 units three times weekly. If the hemoglobin concentration increased by z1 g/dl after 4 weeks, the initial dose was maintained until a target hemoglobin of 12 g/dl was reached. Patients whose hemoglobin concentration did not increase by z1 g/dl after 4 weeks received higher doses of epoetin-a. Grade 3 thrombocytopenia occurred in 26% of patients. One patient (2%) developed Grade 4 allergic reaction associated with hypotension during the first 10 min of carboplatin infusion on day 1 of her fifth cycle. Allergy was successfully treated, but carboplatin administration was abrogated in the last cycle.

Discussion

Fig. 1. Time to progression (- - -) and overall survival (——).

The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen for the treatment of newly diagnosed patients with advanced EOC. Despite the progress that has been achieved by incorporating paclitaxel into first-line treatment, the majority of patients will develop recurrences. Nevertheless, recurrence after achieving a prior response to initial therapy with a platinum-based regimen does not mean immediate fatal outcome. Complete responders with disease-free intervals exceeding 6 months may respond again to second-line chemotherapy [17]. For these patients, treatment with carboplatin at the time of recurrence produces an approximately 30% response rate [18 – 21]. Similarly, these patients can often be effectively retreated with cisplatin [20,22,23], however, carboplatin has a better toxicity profile, since many of the patients will have residual neuropathy from prior paclitaxel and cisplatin treatment [24]. Several phase II studies have reported promising results with response rates of 50– 60% by combining a platinum analogue with paclitaxel [8,11,12,25], or alkylat-

156

C.A. Papadimitriou et al. / Gynecologic Oncology 92 (2004) 152–159

ing agents [26 – 28] in relapsed platinum-sensitive EOC. Retrospective analysis of the data gained by platinum-based combination regimens suggests an improved efficacy, but this has not been confirmed by randomized trials. The role of combination therapy for first relapse may be elucidated when the results of the study ICON IV become available. Furthermore, the ideal combination partner for platinum has not yet been defined. Gemcitabine (2V,2V-difluorodeoxy-cytidine) is a synthetic pyrimidine neocleoside analogue with proven activity as a single agent in several preclinical tumor models [29 –34]. In an early phase II study, Lund et al. [35] assessed the clinical activity of gemcitabine in patients with advanced EOC who had received prior platinum-containing chemotherapy. Eight patients achieved a partial response for an overall response rate of 19%. Seven of these eight responders were clinically resistant to first-line platinum-containing chemotherapy. Gemcitabine single agent has been evaluated within three additional phase II studies in platinum-pretreated patients with relapsed ovarian cancer. In these trials, response rates ranged from 14% to 22% [36 – 38]. Single-agent gemcitabine was also studied in patients with paclitaxel-pretreated and platinum-resistant advanced EOC [39] as well as in patients with platinum- and paclitaxel-refractory ovarian cancer [40] and mullerian tumors (including ovarian) [41] with response rates of 14%, 18%, and 19%, respectively. All these studies have utilized a 28-day schedule with gemcitabine given on days 1, 8, and 15. Several pilot studies have affirmed the feasibility of including gemcitabine in various drug combination protocols for the treatment of both previously treated and chemonaive patients with advanced EOC. In previously treated patients with platinum-sensitive disease, gemcitabine was combined with either cisplatin [42] or carboplatin [43,44] with objective response rates in 53 – 69% of patients. In three additional studies, gemcitabine was combined with cisplatin in platinum-resistant disease [45 –47]. Patients received gemcitabine at doses of 600 – 1250 mg/m2 plus cisplatin 30 –40 mg/m2 both on days 1 and 8 each 21-day cycle. In the study of Velasco et al. [45], cisplatin was also administered at 80 mg/m2 on day 1 only. The responses observed in the abovementioned trials indicate activity of the gemcitabine and cisplatin combination in heavily pretreated and platinum-resistant patients. In other studies, gemcitabine was combined with paclitaxel in both platinum-sensitive [48] and platinum-resistant EOC [49,50]. Recently, the activity of gemcitabine-based threedrug combination regimen was evaluated in women with recurrent EOC. Gemcitabine was combined with paclitaxel and cisplatin or carboplatin with the impressive response rate of 100% [51]. Response rates of 85% and 100% were reported by Gupta et al. [52] and Hansen et al. [53], respectively, for chemonaive patients with advanced disease who were treated with the gemcitabine, paclitaxel, and cisplatin combination regimen. High response rates were also observed in previously untreated FIGO stage III

or IV patients who received gemcitabine combined with cisplatin [54,55]. We did not perform a phase I trial to define the maximal tolerated doses of the two drugs of our combination. Thus, we adapted the dosing schedules of the gemcitabine and carboplatin combination used in phase I/II studies involving patients with advanced NSCLC. The combination of these two drugs was initially hampered by unacceptable platelet toxicity. In these trials, gemcitabine was administered on days 1, 8, and 15 with courses given every 28 days. Carmichael et al. [56] utilized a 28-day regimen with gemcitabine given at a fixed dose of 1000 mg/m2 on days 1, 8, and 15. Carboplatin was administered immediately before gemcitabine on day 1 at doses of AUC 4– 5.2. Grade 3 or 4 thrombocytopenia was dose limiting, occurring in 44% of patients. Grade 3 or 4 neutropenia occurred in 50% of patients. In a more recent trial, gemcitabine was no longer given on day 15 leading to a marked decrease in severe thrombocytopenia. The authors concluded that the combination of carboplatin at a dose of AUC 5 on day 8 with gemcitabine 1100 mg/m2 on days 1 and 8, every 28 days, was feasible and effective in advanced NSCLC [57]. In another phase II study, Edelman et al. [58] evaluated the concept of sequential chemotherapy in patients with stage IIIB and IV NSCLC. Treatment consisted of three cycles of carboplatin targeted at AUC 5.5 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days, followed by three cycles of paclitaxel. Noncumulative, reversible thrombocytopenia was the principal toxicity of the carboplatin and gemcitabine combination. In an attempt to abrogate the hematologic toxicity, we truncated Carmichael’s schema to a 21-day cycle, with carboplatin administered on day 1 at a dose of AUC 5 and gemcitabine on days 1 and 8. However, choosing the doses of our drugs from the NSCLC experience may not be valid because female patients, especially those with impaired performance status may tolerate treatment more poorly than men. We treated 48 patients with relapsed platinum-sensitive EOC during a period of 25 months. The response rate assessed in 37 women with measurable or evaluable disease was 40.5%, including 10 (27%) complete and 5 (13.5%) partial responses. The fact that twice as many responses were CRs as opposed to PRs possibly results from the relatively small volume disease of our study population. Seven patients (16%) presented with ascites only and 6 (14%) additional patients did not have measurable or evaluable disease. Thus, this selection could explain the median time to progression of 9 months for all patients. Furthermore, the median time to progression for all patients was 9 months, and the median overall survival 24.5 months, respectively. In a phase I/II study conducted by the AGO Ovarian Cancer Study Group, 26 patients with platinumsensitive EOC were treated with gemcitabine given at doses of 800 – 1000 mg/m2 on days 1 and 8, and carboplatin targeted at AUC 4 –5 on day 1 of a 21-day cycle [44]. In this trial, the overall response rate was 62.5%, and the

C.A. Papadimitriou et al. / Gynecologic Oncology 92 (2004) 152–159

progression-free and overall survival 10 and 18+ months, respectively. In another phase I/II trial, Orlando et al. reported on the efficacy of the gemcitabine and carboplatin combination in patients with relapsed platinum and paclitaxel-pretreated EOC [43]. In this study, a 28-day and a 21day schedule with fixed doses of both drugs were utilized. The response rate was 69%, and the median progressionfree survival 7 months. The objective response rate observed in our study was somewhat lower when compared with response rates referred in the two previously mentioned phase I/II trials. Our response rate was even lower than that observed in two previous studies conducted specifically in platinum-resistant patients [45,46]. Rose et al. reported that combining gemcitabine with cisplatin reverses cisplatin resistance and that the regimen is active in platinum- and multidrug-resistant ovarian and peritoneal carcinoma. Additionally, activity was also demonstrated in patients, who have previously been resistant to gemcitabine [46]. However, both of the above trials used cisplatin instead of carboplatin, and gemcitabine was administered with the platinum analogue on days 1 and 8. Preclinical studies have shown synergistic effects when gemcitabine and platinum are delivered in combination. The synergism might be due to gemcitabine’s ability to inhibit DNA repair after platinum-induced damage or cisplatin’s ability to inhibit ribonucleotide reductase and so enhance the phosphorylation and activation of gemcitabine [59,60]. Thus, our relatively low response rate could be due to a failure to optimally take advantage of the synergism between gemcitabine and carboplatin by not administering both drugs concomitantly with each treatment. On the other hand, the development of collateral sensitivity to the combination in the platinum-resistant state could be a possible reason for the observed high response rates. It should be also mentioned, that the median relative dose intensity for gemcitabine was 77% in our phase II study. Therefore, more intensified doses of the agent given with G-CSF support, especially in patients evaluated as having stable disease, could have resulted in a higher objective response rate. Finally, enhanced drug resistance by incorporating a third agent in first line chemotherapy in 24% of our patient could possibly explain our results. The progression-free and overall survival data of our study were comparable to those of two other trials evaluating carboplatin and paclitaxel in relapsed platinum-sensitive EOC [11,12]. These studies reported median progressionfree and overall survival of 9 and 11 months. The overall survival was 10 and 20.5 months, respectively. In a more recent trial involving 97 patients with platinum-sensitive recurrent disease, carboplatin combined with paclitaxel resulted in an objective response rate of 70%, and a median disease-free survival for complete responders of 8 months [25]. Thus, careful consideration of these results in the context of other carboplatin- and cisplatin – gemcitabine combinations is warranted to identify the optimal use of this synergistic drug interaction.

157

Myelotoxicity was the most relevant side effect of our phase II study. Sixty-nine percent of our patients developed Grade 3 or 4 neutropenia with only four episodes of neutropenic fever that were successfully treated by antibiotics. Du Bois et al. [44] reported Grade 4 neutropenia in 29 – 42% of courses at the three dose levels used with only one episode of neutropenic fever. Grade 3 or 4 anemia occurred in 26% and thrombocytopenia in 24% of our patients, respectively. These toxicities were similar to those reported in two other studies [43,44]. The trade off between carboplatin and cisplatin largely reflects the diminished nonhematological toxicities of carboplatin at the expense of greater hematological toxicities. However, combining gemcitabine, with myelosuppression as its principal toxicity, with carboplatin may limit this particular advantage. The more common non-hematological side effects were nausea and/or emesis. Twelve percent of patients developed Grade 2 peripheral neurotoxicity. The low incidence of peripheral neurotoxicity could have resulted from the fact that some patients had residual neuropathy from prior paclitaxel and cisplatin treatment. Grade 4 allergy was observed in one (2%) patient. We concluded that our regimen appears active in the management of patients with relapsed platinum-sensitive EOC. We observed responses in 40.5% of patients, and the median overall survival time was 24.5 months. The combination could be administered on an outpatient basis. Myelotoxicity was the most severe side effect. However, further evaluation in the context of prospective, controlled studies is justified to clearly define the role of gemcitabine and carboplatin combination in relapsed platinum-sensitive paclitaxel-pretreated EOC. Before proceeding with more definitive phase III trials, an extensive review of available phase II data should be conducted. Different dosing schedules may result in both reduced toxicity and enhanced response rates. Combination of gemcitabine and carboplatin together with each treatment may be necessary for optimal synergy. Such studies may be carried out before the planning of phase III studies. References [1] Ozols RF, Rubin SC, Thomas G, Robboy S. Epithelial ovarian cancer. In: Huskins WM, Perez CA, Young RC, editors. Principles and practice of gynecologic oncology. Second ed. Philadelphia: LippincottRaven Publishers; 1997. p. 919 – 86. [2] McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Patridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1 – 6. [3] Neijt JP. New therapy for ovarian cancer. N Engl J Med 1996; 334:50 – 1. [4] Du Bois A, Neijt JP, Thigpen JT. First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer—A new standard of care? Ann Oncol 1999;10(Suppl. 1):S35 – 41. [5] Ozols RF, Bundy BN, Fowler J, Clarke-Pearson D, Mannel R, Hartenbach E, et al. Randomized phase III study of cisplatin (CIS)/paclitaxel (PAC) versus carboplatin (CARBO)/PAC in optimal

158

[6]

[7]

[8]

[9] [10]

[11]

[12]

[13] [14] [15] [16] [17]

[18]

[19] [20]

[21]

[22]

[23]

[24]

[25]

C.A. Papadimitriou et al. / Gynecologic Oncology 92 (2004) 152–159 stage III epithelial ovarian cancer (OC): a Gynecologic Oncology Group trial (GOG 158) [abstract 1373]. Proc Am Soc Clin Oncol 1999;18:356a. Du Bois A, Lueck HJ, Meier W, Moebus V, Costas D, Bauknecht T, et al. Cisplatin/paclitaxel vs. carboplatin/paclitaxel in ovarian cancer: update of an Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group trial [abstract 1374]. Proc Am Soc Clin Oncol 1999;18:356a. Aravantinos G, Fountzilas G, Kosmidis P, Dimopoulos MA, Stathopoulos G, Pavlidis N, et al. Alternating carboplatin and cisplatin plus paclitaxel versus carboplatin plus paclitaxel for first line treatment of advanced ovarian cancer (AOC): updated results of a phase III Hellenic Cooperative Oncology Group Study [abstract 1538]. Proc Am Soc Clin Oncol 2000;19:389a. Goldberg JM, Piver MS, Hempling RH, Recio FO. Paclitaxel and cisplatin combination chemotherapy in recurrent epithelial ovarian cancer. Gynecol Oncol 1996;63:312 – 7. Ozols RF. Treatment of recurrent ovarian cancer: increasing option‘recurrent’ results. J Clin Oncol 1997;15:2177 – 80. Ozols RF, for the Ovarian Cancer Practice Guidelines Panel. Update on the NCCD Ovarian Cancer Practice Guidelines. Oncology 1997; 11(A):95 – 105. Rose PG, Fusco N, Fluellen L, Rodriguez M. Second-line therapy with paclitaxel and carboplatin for recurrent disease following firstline therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma. J Clin Oncol 1998;16:1494 – 7. Guastalla JP, Pujada-Lauraine E, Weber B, Cure H, Orfeuvre H, Mousseau M, et al. Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma. A multicenter GINECO (Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens) phase II study. Ann Oncol 1998;9:37 – 43. Sabbatini P, Sprongs D. Salvage therapy for ovarian cancer. Oncology 1998;12:833 – 44. Miller AB, Hogestraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207 – 14. Hryniuk KWM, Goodyear M. The calculation of received dose intensity. J Clin Oncol 1990;8:1935 – 7. Kaplan E, Meier F. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;58:457 – 81. Markman M, Hoskins W. Response to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated populations. J Clin Oncol 1992;10:513 – 4. Eisenhauer EA, Swenerton KD, Sturgeon FG, Fine S, O’Reilly SE. Phase II study of carboplatin in patients with ovarian carcinoma: a National Cancer Institute of Canada Trials Group Study. Cancer Treat Rep 1986;70:1195 – 8. Canetta R, Bragman K, Smaldone L, Rosencweig M. Carboplatin: current status and future prospects. Cancer Treat Rev 1988;15:17 – 32. Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 1990;36:207 – 11. Williams LL, Fudge M, Burnett LS, Jones HW. Salvage carboplatin therapy for advanced ovarian cancer after first-line treatment with cisplatin. Am J Clin Oncol 1992;15:331 – 6. Gershenson DM, Kavanagh JJ, Copeland LJ, Stringer CA, Morris M, Wharton JT. Re-treatment of patients with recurrent epithelial ovarian cancer with cisplatin-based chemotherapy. Obstet Gynecol 1989; 73:798 – 802. 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. Beker JS, Bertelsen K, du Bois A, et al. Advanced epithelial ovarian cancer: 1998 consensus statements. Ann Oncol 1999;10(Suppl. 1): 587 – 92. Dizon D, Hensley M, Sabbatini P, Poynor E, Hummer A, Venkatra-

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34] [35]

[36] [37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

man E, et al. Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma. J Clin Oncol 2002;20:1238 – 47. Van der Burg ME, Hoff AM, Van Lent M, Rodenburg CJ, van Puttten WL, Stoter G. Carboplatin and cyclophosphamide salvage therapy for ovarian cancer patients relapsing after cisplatin combination chemotherapy. Eur J Cancer 1991;27:248 – 50. Martoni A, Panetta A, Angelleli B, Melotti B, Pannuti F. A phase II study of carboplatin and cyclophosphamide in advanced ovarian carcinoma. J Chemother 1993;5:47 – 51. Lorusso V, Catino A, Leone B, Rabinovich M, Gargano G, Paradiso A, et al. Carboplatin plus ifosfamide as salvage treatment of epithelial ovarian cancer: a pilot study. J Clin Oncol 1993;11:1952 – 6. Hertel LW, Kroin JS, Misner JW, et al. Synthesis of 2-deoxy-2V,2Vdifluoro-D-ribose and 2-deoxy-2V,2V-difluoro-D-ribofuranosyl nucleosides. J Org Chem 1988;53:2406 – 9. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, et al. Evaluation of the antitumor activity of 2V,2V-difluoro-2V-deoxycytidine. Cancer Res 1990;50:4417 – 22. Braakhuis BJ, van Dongen GAMS, Vermorken JB, Snow GB. Preclinical in vivo activity of 2V,2V-difluorodeoxycytidine (gemcitabine) against head and neck cancer. Cancer Res 1991;51:211 – 4. Lund B, Kristyansen PEG, Hansen H. Clinical and preclinical activity of 2V,2V-difluorodeoxycytidine (gemcitabine). Cancer Treat Rev 1993;19:45 – 55. Boven E, Schipper H, Erkelens CAM, et al. The influence of the schedule and the dose of gemcitabine on the antitumor efficacy in experimental human cancer. Br J Cancer 1993;68:52 – 6. Peters GJ, Ackland SP. New antimetabolites in preclinical and clinical development. Exp Opin Invest Drugs 1996;5:637 – 79. Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP. Phase II study of gemcitabine (2V,2V-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 1994;86:1530 – 3. Neijt JP, Kaufmann M, Bauknecht T, et al. Gemcitabine in pretreated ovarian cancer [abstract 329]. Ann Oncol 1996;7(Suppl. 5):70. Friedlander M, Millward MJ, Bell D, Bugat R, Harnett P, Moreno JA, et al. A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 1998; 9:1343 – 5. von Minckwitz G, Bauknecht T, Visseren-Grul CM, Neijt JP. Phase II study of gemcitabine in ovarian cancer. Ann Oncol 1999;10:853 – 5. Shapiro JD, Millward MJ, Rischin D, et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996;63:89 – 93. Markman M, Kennedy A, Webster K, Zanotti K, Kulp B, Peterson G, et al. Phase 2 trial of single-agent gemcitabine (GEM) in platinum (PLAT)/paclitaxel (PAC) refractory ovarian cancer (ROC) [abstract 813]. Proc Am Soc Clin Oncol 2001;20:204a. Kudelka AP, Vershraegen CF, Edwards CL, Freedman R, Plunkett W, Stev N, et al. A preliminary report of a phase 2 study of gemcitabine in women with platinum refractory mullerian (ovarian, fallopian tube, and primary peritoneal) carcinomas [abstract 1357]. Proc Am Soc Clin Oncol 1999;18:377a. Kunkel LM, Evans SS, Dottino PR, Di Saia PJ, Nagourney RA. Cisplatin (CDDP) and gemcitabine (DEDC) in relapsed ovarian cancer [abstract 1379]. Proc Am Soc Clin Oncol 1998;17:357a. Orlando M, Nadal J, Chacon RD. Gemcitabine (G) and carboplatin (C) in patients (Pts) with relapsed ovarian cancer (ROC): a phase I – II study [abstract 1594]. Proc Am Soc Clin Oncol 2000;19:403a. Du Bois A, Lueck HJ, Pfisterer J, Schroeder W, Blohmer JU, Kimmig R, et al. Second-line carboplatin and gemcitabine in platinum sensitive ovarian cancer. A dose finding study by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Ovarian Cancer Study Group. Ann Oncol 2001;12:1115 – 20. Velasco A, Perez MM, Borrega P, Gomez-Bernal A, Arranz JA, Gonzalez-Beca R. Gemcitabine (GEM) and cisplatin (CIS) as treat-

C.A. Papadimitriou et al. / Gynecologic Oncology 92 (2004) 152–159

[46]

[47]

[48]

[49]

[50]

[51]

[52]

ment for patients with platinum resistant ovarian cancer (OC) and as consolidation treatment for patients with residual disease after first line chemotherapy [abstract 2478]. Proc Am Soc Clin Oncol 2001; 20:182b. Rose PG, Mossbruger K, Fusco N, Smrekar M, Eaton S, Rodriguez M. Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum—And multidrug-resistant ovarian and peritoneal carcinoma. Gynecol Oncol 2003;88:17 – 21. Nagourney RA, Brewer CA, Radecki S, Kidder WA, Sommers BL, Evans SS, et al. Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol 2003;88:35 – 9. Poole CJ, Perren T, Hogberg T, Cook J, Jenkins AH, Ridderheim M, et al. Phase I study to investigate the optimal dose and schedule of gemcitabine (G) and paclitaxel (P) in combination in patients with previously treated epithelial ovarian cancer [abstract 1380]. Proc Am Soc Clin Oncol 1998;17:357a. Roman L, Garcia AA, Facio G, Jeffers S, Santiago J, Munderspach L, et al. Phase II study of weekly paclitaxel and gemcitabine in platinum resistant ovarian cancer [abstract 877]. Proc Am Soc Clin Oncol 2001;20:220a. Jungnelius JU, Ridderheim M, Perren T, Gawande S, Roychowdhury D, Poole C. Optimal sequence leads to improved dose delivery for gemcitabine (G)/paclitaxel (P) combination in recurrent ovarian cancer: a phase I study [abstract 890]. Proc Am Soc Clin Oncol 2002;21:223a. Geertsen P, Hansen M, Stroyer I, Hansen S. Combination chemotherapy with platinum paclitaxel, and gemcitabine in patients’ with relapsed ovarian carcinoma [abstract 1395]. Proc Am Soc Clin Oncol 1999;18:361a. Gupta S, Arora R, John S, Nayak R, Vajpeyi R, Kilara G, et al. Gemcitabine, paclitaxel and cisplatin in chemotherapy naı¨ve ad-

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

159

vanced ovarian cancer: results of a multicenter phase II study [abstract 857]. Proc Am Soc Clin Oncol 2002;21:215a. Hansen SW, Anderson H, Boman K, Hansen M, Havsteen H, Rosenberg P, et al. Gemcitabine, carboplatin and paclitaxel (GCP) as firstline treatment of ovarian cancer FIGO stages IIB – IV [abstract 1379]. Proc Am Soc Clin Oncol 1999;18:357a. Belpomme D, Krakowsk I, Beauduin M, Petit T, Canon JL, Janssens J, et al. Gemcitabine (G) combined with cisplatin (C) is active and feasible as first-line treatment in patients with advanced epithelial ovarian cancer (OC): final results of a phase II study [abstract 859]. Proc Am Soc Clin Oncol 2002;21:215a. Shaharyar, Shami N, Mahmood I, Alauddin Z, Mahmood A, Chaudhry KM, et al. A phase II trial of gemcitabine and cisplatin combination chemotherapy in advanced epithelial ovarian cancer with bulky residual disease [abstract 2518]. Proc Am Soc Clin Oncol 2002;21:175b. Carmichael J, Allerheiligen S, Walling J. A phase I study of gemcitabine and carboplatin in non-small cell lung cancer. Semin Oncol 1996;23:55 – 9. Iaffaioli RV, Tortoriello A, Facchini G, et al. Phase I – II study of gemcitabine and carboplatin in non-small-cell lung cancer. J Clin Oncol 1999;17:921 – 6. Edelman MJ, Gandara DR, Lau DH, Lara P, Lauder IJ, Tracy D. Sequential combination chemotherapy in patients with advanced non small cell lung carcinoma: carboplatin and gemcitabine followed by paclitaxel. Cancer 2001;92:146 – 52. Van Moorsel CJA, Pinedo HM, Veerman G, et al. Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer. Br J Cancer 1999;80:981 – 90. Van Moorsel CJA, Pinedo HM, Veerman G, et al. Scheduling of gemcitabine and cisplatin in Lewis lung tumour bearing mice. Eur J Cancer 1999;35:808 – 14.