Docetaxel in Combination with Irinotecan (CPT-11) in Platinum-resistant Paclixatel-pretreated Ovarian Cancer

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1 Docetaxel in Combination with Irinotecan (CPT-11) in Platinum-resistant Paclixatel-pretreated Ovarian Cancer ARISTIDES POLYZOS 1, CHRISTOS KOSMAS 2, HELEN TOUFEXI 1, NICHOLAS MALAMOS 2, ANTONIOS LAGADAS 1, CHRISTOS KOSMIDIS 1, PANAGIOTIS GINOPOULOS 3, NICHOLAS ZIRAS 4, KOSTAS KANDILIS 4 and VASSILIS GEORGOULIAS 5 1 Medical Oncology Unit, Laikon General Hospital, University of Athens School of Medicine; 2 Medical Oncology Unit, Helena-Venizelou Hospital, Athens; 3 Department of Medical Oncology, Agios Andreas Hospital, Patras; 4 Department of Medical Oncology, Metaxa Cancer Hospital, Pireus; 5 Department of Medical Oncology, University General Hospital Heraklion, Crete, Greece Abstract. The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors resistant to platinum compounds has not yet been defined. This multicenter prospective phase II study evaluated the activity and toxicity of the docetaxel-plus-irinotecan combination in ovarian cancer patients whose tumors were resistant to platinum compounds and who had been exposed to paclitaxel. Treatment consisted of docetaxel 60 mg/m 2 i.v. followed by irinotecan 200 mg/m 2 i.v. both on day 1 followed by prophylactic recombinant human granulocyte-colony stimulating factor (rhg-csf) support from days 2 to 6, every 3 weeks. Thirty-one patients were enrolled in the study. The median age was 60 years, and the median performance status (ECOG) was 1. Eight (26%) patients had primary tumors resistant to platinum, while the rest of the population had tumor recurrence within 6 months from the last cisplatin treatment. Four chemotherapy cycles per patient were administered, with the delivered dose intensity at 75% of the planned dose for both agents. Among 30 patients evaluable for response, there were 2 (7%) complete and 4 (14%) partial responses (overall response rate 20%; (95% confidence interval, CI, 11%-33%). Stable disease was recorded in 8 (28%) patients and progressive disease in 15 (51%). The median response duration was 4.5 months (range, 3-12), the median time to progression 5 months Correspondence to: Aristides Polyzos, MD, Assoc. Professor of Medicine, 1st Department of Propaedeutic Medicine, Laikon General Hospital, 17, Agiou Thoma St., Goudi, GR 11527, Athens, Greece. Tel: , Fax: , r- e-poly@hol.gr Key Words: Docetaxel, irinotecan, cisplatin resistance, ovarian cancer. (range, 2-17) and the median survival 11 months (range, 1-40); the 1-year survival was almost 50%. Myelotoxicity was moderate, with grade 3 and 4 neutropenia occurring in 23% of the patients, grade 3-4 thrombocytopenia in 6% and febrile neutropenia in 13%. Grade 3 diarrhea was observed in 2% of the patients. There was one treatment-related death due to sepsis. In conclusion, the combination of docetaxel plus irinotecan with rhg-csf support, appears to be a moderately effective regimen with acceptable toxicity for platinum-resistant, paclitaxel-pretreated ovarian cancer patients. Further investigation in comparative studies is required to define the role of combination versus single agent chemotherapy in this group of patients. The standard front-line chemotherapy regimen for advanced ovarian cancer is currently a combination of platinum agent (cisplatin of carboplatin) and paclitaxel (1, 2). However, despite the high response rate and prolonged median survival time observed with these regimens, over 80% of patients relapse requiring further treatment. Recurrent disease is classified as being either sensitive or resistant to platinum compounds according to the time elapsed from the last chemotherapy cycle and the disease relapse (3). Retreatment with cisplatin or carboplatin offers a response rate of 30% when the disease is considered potentially platinum-sensitive (4). For platinum-resistant disease, chemotherapy relies on other chemotherapeutic agents, such as topotecan, liposomal doxorubicin, gemcitabine, vinorelbine or oxaliplatin that, as salvage treatment, yield response rates between 10% and 30% (5-9). To date, taxane sensitivity or resistance has not been considered for the selection of a second-line treatment. Therefore, in order to establish an effective second-line chemotherapy regimen, it is important to use agents which are not cross-resistant to the initial standard paclitaxel/platinum regimen /2005 $

2 Docetaxel is a new taxane derived from the needles of Taxus baccata. While it inhibits microtubule disassembly like paclitaxel, it has different effects on Tau binding sites and on microtubule-associated proteins (9, 10). Docetaxel was found, in several in vitro and in vivo studies, to have a potent cytotoxic activity and an incomplete cross-resistance to paclitaxel (11, 12). This finding has been substantiated by the results of several phase II studies, which demonstrated the activity of docetaxel against paclitaxel-resistant tumors in breast and ovarian cancer (13, 14). Furthermore, other studies have shown the activity of docetaxel in platinumresistant ovarian cancer (15-18). Similarly, topoisomerase I inhibitors have been shown to display considerable activity against ovarian cancer. Topotecan has been considered an effective agent in both the first- and second-line setting, in combination with cisplatin (5, 19). Irinotecan hydrochloride (CPT-11) is a semisynthetic, water-soluble derivative of camptothecin, a plant alkaloid obtained from Camptotheca acuminata. Irinotecan, like topotecan, inhibits topoisomerase I, an intranuclear enzyme that relieves torsion in DNA induced by replication (20). Irinotecan has expressed significant in vitro and in vivo activity in several tumors, including ovarian cancer (21-24). In clinical trials, its activity was documented in both the first-and second-line setting in combination with cisplatin (25-28). It is interesting that, although combination chemotherapy regimens have also been administered in ovarian cancer patients with tumors resistant to platinum compounds, their efficacy and toxicity have not yet been defined (29). Based on these data, a prospective phase II study was conducted to evaluate the efficacy and toxicity of the docetaxel-plusirinotecan combination as salvage treatment in ovarian cancer patients whose tumors were resistant to cisplatin and who had been pretreated with paclitaxel. Patients and Methods Patient population. Patients were required to have: a) histologically confirmed epithelial ovarian carcinoma with manifestations of locoregional or metastatic bidimensionally measurable disease; b) either primary tumors resistant (non-responding or progressing) to platinum-based combinations or recurring within 6 months from the previous platinum-based treatment; c) paclitaxel as part of their prior chemotherapy regimen. Other eligibility criteria included: a life expectancy of at least 3 months, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, age 75 years, hematological parameters and blood chemistry indicating normal organ function [(absolute neutrophil count 1.5x10 q/l, platelet count 100x10 q/l, hemoglobin 10 g/dl, normal total bilirubin, AST 2.5 times the upper limit of normal value (ULN), alkaline phosphatase 6 x ULN and creatinine clearance 60 ml/min)]. Exclusion criteria included: prior treatment with docetaxel or topotecan, sensitivity to platinum, or a previous chemotherapy regimen that did not contain platinum. Patients were excluded from the study if there was a history of prior malignancies, concurrent infection, pre-existing diarrhea, intestinal paralysis or obstruction. The study was approved by the Ethics and Scientific Committees of the participating centers, and all patients gave their informed consent in order to participate in the study. Treatment plan. Treatment was given on an outpatient basis and comprised the administration of docetaxel (Taxotere ; Aventis Pharma, Bridgewater, USA) 60 mg/m 2 followed by irinotecan (Campto ; Aventis Pharma) 200 mg/m 2 ; both drugs were given as a 1-hour i.v. infusion. The dose and schedule of drug administration were based on previous phase I, II studies (30). Antiemetic treatment consisted of dexamethasone (8 mg) plus ondansetron (24 mg) given as i.v. bolus before chemotherapy. Premedication for docetaxel hypersensitivity reactions and to prevent skin toxicity and fluid retention consisted of oral dexamethasone (8 mg) given 12, 8 and 1 hour before docetaxel and 24, 36 and 42 hours post-infusion. For the early cholinergic adverse effects induced by irinotecan administration, atropine (1 mg) was given subcutaneously, and for the late diarrhea high-dose loperamide (4 mg initial dose, followed by 2mg every 2 hours until diarrhea-free) was administered. Recombinant human granulocyte-colony stimulating factor (rhg-csf) (Granocyte ; Aventis Pharma) (5 Ìg/kg/day) was given from days 2 to 6. The regimen was administered every 3 weeks for a maximum of 6 cycles, unless there was evidence of disease progression, unacceptable toxicity or patient refusal. Treatment cycles were delayed for up to 2 weeks, unless the patient had recovered from hematological and non-hematological toxicity. Before the next course was started, the neutrophil count had to be 1.5x10 9 /L and platelet 100x10 9 /L with no diarrhea, and liver and renal function had to meet the eligibility criteria. The doses of both docetaxel and irinotecan were reduced by 25% in the event of grade 4 hematological toxicity. The irinotecan dose was reduced by 25% in the event of grade 3 diarrhea. Patient evaluation. Baseline evaluations included: patient history, physical examination, chest X-rays, complete blood count with differential and platelet count, standard blood chemistry and ECG. Computed tomography (CT) scans of the chest, abdomen, pelvis and whole body bone scintigraphy were performed at study entry and CT scan of the brain whenever clinically indicated. Complete blood counts with differential and platelet counts were performed twice weekly or daily in case of grade 3/4 neutropenia, thrombocytopenia or febrile neutropenia until hematological recovery; blood chemistry and physical examination were performed every 3 weeks. Patients were evaluated before each cycle for lesions assessable by physical examination. Pelvic examination was performed at baseline and after 3 and 6 cycles. All patients were evaluated by the appropriate imaging studies indicative of the measurable target lesions every 2 chemotherapy cycles. Tumor evaluation and criteria for response. Tumor response was assessed after every 2 cycles using the World Health Organization (WHO) response criteria (31). An independent radiologist reviewed all tumor responses. Response duration was calculated from the day on which at least a 50% reduction in tumor volume was documented until the first documentation of progressive disease. Time to tumor progression (TTP) was calculated from the first day of drug administration to the first documentation of tumor progression. Overall survival was measured from the date of first 3560

3 Polyzos et al: Salvage Treatment of Ovarian Cancer with Docetaxel and Irinotecan Table I. Patients characteristics. Patients % Eligible patients Age (years) Median Range 60 (37-75) Performance Status (ECOG) Stage (FIGO) IIIc IV Tumor histology Serous Endometrioid 6 19 Mucinous 2 7 Adenocarcinoma 6 19 Mixed 3 10 Tumor Grade Unknown 2 7 Involved sites Omentum-mesentery-ascites 25/12 80/39 Pelvic-retroperitoneal-lymph nodes Liver 7 23 Pleura 4 13 Number of prior chemotherapies Mean 1.5 Median 2 Range 1-3 Interval from previous chemotherapy treatment (months) Median 3 Range 2-4 drug administration to death. Patients without progression who died during the study were considered treatment failures. Monitoring for toxicity. Toxicity evaluations were graded according to the National Cancer Institute (NCI) common toxicity criteria (31). Hematological and clinical chemistry parameters were measured at baseline and then at least weekly throughout treatment. Liver function was monitored at each cycle. Statistical methods. The primary objective of the study was the overall response rate. All analyses were based on the intent to treat population. Confidence intervals (CI) for response rates were calculated according to the method described by Simon (32). Simon s two-stage mini-max design was used to allow for early termination of the trial in the event of a poor response rate. An optimized two-stage plan for accrual was used at a first-stage design with 16 patients. It was calculated that, with an anticipated RR of approximately 30% (minimum level of activiy to be of interest), the sample size required for having confidence limits of ±8% would be 32 patients. The survival distributions for response Table II. Clinical response to chemotherapy. duration, time to progression (TTP) and overall survival were estimated using the Kaplan-Meier method. Dose intensity was expressed in mg/m 2 /week. Results No. Percentage of all patients (n=31) Complete response 2 7 Partial response 4 13 Overall response rate 6 20 (95% CI 11%-33%) Stable disease 8 27 Progressive disease CI=Confidence interval Median duration of response 4.5 (3-12) months Median time to progression 5 (2-17) months Median survival 11 (1-40) months One-year survival overall 14/31=45% Patient characteristics. From June 1999 to September 2002, 31 patients were enrolled, and their characteristics are listed in Table I. All patients had received carboplatin plus paclitaxel as first-line chemotherapy. Concerning resistance to platinum, 8 (26%) patients had primary tumors refractory to platinum compounds. The rest of the patient population had received second-line treatments with either paclitaxelifosfamide-cisplatin or cisplatin-ifosfamide and had tumor recurrence within 6 months from the last exposure to platinum compounds. The median interval from the last chemotherapy cycle to enrollment was 3 months (range 2-4). The majority of patients had intraperitoneal disease with ascitis (n=12 patients), while retroperitoneal disease was present in 10 patients and liver disease in 7. A total of 128 chemotherapy cycles were administrated with a median of 4 cycles per patient (range 1-8). Response and survival data. Thirty patients were assessable for response and 31 for toxicity. One patient stopped chemotherapy before the third cycle because of deterioration of her performance status. Two (7%) patients achieved a complete response and 4 (13%) a partial response for an overall response rate of 20% (95% CI 11-33%). Eight (27%) patients had stable disease and 16 (53%) patients progressive disease. The median time to achieve an objective response was 3 (range 2-4) months, and the median response duration was 4.5 (range 3-12) months. The median time to progression was 5 (range 2-17) months, and the median survival was 11 (range 1-40) months. Responses were observed in all sites of disease such as liver (n=1 3561

4 Table III. Hematological and non-hematological toxicity per patient and per cycle. Patient Cycles Patient Cycles Patient Cycles Patient Cycles Toxicity Grade 2 Grade 3 Grade 4 Grade 3/4 Neutropenia 4 (13%) 8% 2 (6%) 2% 5 (16%) 6% 7 (22%) 23% Febrile neutropenia (13%) 6% 4 (13%) 6% Thrombocytopenia 6 (20%) 6% (6%) 2% 2 (6%) 6% Anemia 6 (20%) 8% 1 (4%) 8% (3%) 4% Diarrhea 4 (13%) 10% 2 (6%) 4% (6%) 2% Nausea/vomiting 2 (7%) 5% Alopecia 31 (100%) Mucositis 2 (6%) 8% Skin and nail toxicity 4 (13%) 10% patient), lymph nodes (n=5 patients) and intra-abdominal disease (n=6 patients). Subgroup analysis indicated that responses were achieved both in patients with primary tumors resistant to platinum compounds (2 patients) as well as in patients with secondary tumors resistant to cisplatin administration (n=4 patients). The efficacy of the regimen is presented in Table II. Compliance to treatment. A total of 12 treatment cycles (10%) were delayed for 3-14 days (median 7 days), mainly as a result of patients own choice due to difficulties in traveling from district areas (8 cycles) and 4 cycles due to neutropenia on the day of treatment. The delivered dose intensity was 75% of the planned dose for both agents due to delays and dose reductions. Toxicity. Despite rhg-csf administration, myelosuppression was the main toxicity of the combination. Five (16%) patients developed febrile neutropenia; one of them developed sepsis after the first course of treatment and eventually died despite the administration of antibiotics and rhg-csf. Grade 3-4 neutropenia was observed in 7 (23%) patients. Neutropenia was short lasting, and the neutrophil count usually returned to normal by day 20. Grade 4 thrombocytopenia was rare and occurred in 2 (6%) patients. Grade 2 and 3 anemia were noted in 20% and 4% of patients, respectively. Non-hematological toxicities were relatively rare and included diarrhea, nausea/vomiting and alopecia. Grade 3 diarrhea occurred in 2 (6%) patients and in 4% of cycles. Grade 2 nausea/vomiting was noted in 2 (7%) patients, while grade 2 alopecia was universal. Neurotoxicity could not be estimated, because all patients had received cisplatin and paclitaxel in the past. Toxicity is presented in Table III. Discussion Docetaxel has become an interesting agent in the treatment of ovarian cancer, either as first- or second-line chemotherapy (13-18). Docetaxel has also been found to be an effective agent, in ovarian cancer patients, whose tumors were considered cisplatin-resistant and who had been pretreated with paclitaxel (13-18). Although there is no standard definition of paclitaxel resistance, docetaxel has shown considerable activity against ovarian cancer progressing during paclitaxel treatment. In a phase II study, patients with paclitaxel-resistant malignant mixed Mullerian tumors received single agent docetaxel and achieved a 22% response rate with a median survival of 44 weeks (14). Using the same criteria for the definition of taxane resistance as those for platinum resistance, subgroup analysis has revealed that the response rate was 11% in patients with tumors "absolutely"- and 45% with tumors "relatively"-resistant to paclitaxel (14). This study has also demonstrated that: (i) responders to paclitaxel-based chemotherapy also responded to second-line docetaxel; and (ii) responders to docetaxel had received lower monthly and cumulative doses of paclitaxel (14). These findings suggest that the pattern of prior response to paclitaxel as well as the interval between the two taxanes exposure may determine the possibility of response to docetaxel (14). The mechanisms of docetaxel activity in paclitaxel-resistant tumors are not yet clear. Whether its effectiveness is mediated through its greater affinity to bind to tubulin as compared to paclitaxel remains under investigation (10). In our study population, all patients had received paclitaxel as initial treatment, while 15 of them had been treated upon tumor recurrence with a combination of paclitaxel, cisplatin and ifosfamide (33). 3562

5 Polyzos et al: Salvage Treatment of Ovarian Cancer with Docetaxel and Irinotecan Irinotecan, the second agent applied in the present study, has been less extensively investigated than topotecan. Nevertheless, its anti-tumor activity in ovarian cancer, either as first-line treatment with cisplatin or as second-line chemotherapy, has been documented (25-28). In a more recent study, irinotecan 60 mg/m 2 was given on days 1, 8 and 15 and was combined with cisplatin on day 1 as first-line treatment in patients with ovarian cancer. An impressive 76% objective response rate was achieved, while 8% complete responses were documented (28). The same investigators have also reported that this regimen yielded a 33% clinical objective response in patients with recurrent ovarian cancer (28). The combination of docetaxel and irinotecan applied in the present study resulted in a moderate response rate of 20%, which is within the range of response rates achievable by single agents registered in the second-line setting for the treatment of ovarian tumors (3-9). Responses have been reported both in patients who received paclitaxel only once, as well as in those who have been retreated with the drug. It is interesting that, in a study from Finland, where the same agents, doses and schedule were applied, the obtained results were rather different. In that study, despite the fact that half of the patients were considered to have "chemosensitive" and half "chemoresistant" disease, the observed response rate in both groups was 63% (34). These differences should be attributed to the enrolled study populations, since only half of the patients in the Finnish study had received paclitaxel and only one platinum regimen as initial treatment (34). The docetaxel-irinotecan combination given in the present study resulted in a 20-week time-to-progression interval and a 44-week overall survival. A factor that contributed to the increase of the median survival was the relatively high percentage of patients recorded with stable disease. In most studies, with ovarian cancer patients treated with second-line chemotherapy, the reported TTP is in the range of weeks, and the median survival is in the range of weeks (3-9). Docetaxel has also been combined with other new agents. A recent study has evaluated the combination of docetaxel and vinorelbine supported by prophylactic rhg-csf as second-line chemotherapy for patients with platinumresistant paclitaxel-pretreated ovarian cancer. The observed response rate was 23.5%, a result similar to our finding of a median survival of 9.3 months (35). The toxicity profile of the docetaxel-irinotecan combination with prophylactic G-CSF administration in the present study was acceptable, given that both agents are myelotoxic and that the patients were pretreated. The main toxicities were neutropenia and febrile neutropenia, occurring in 23% and 13% of patients, respectively. It is interesting that docetaxel as a single agent resulted in a high (86%) incidence of grade 3-4 neutropenia when it was administered to pretreated patients (14, 15). Other docetaxel combinations such as with vinorelbine, even when administered with prophylactic G-CSF, have proved to be myelotoxic with a 20% incidence of febrile neutropenia (35). Even when given as front-line treatment in ovarian cancer patients with cisplatin, irinotecan may result in a high incidence of grade 3-4 neutropenia, ranging from 50% to 60% (27-28). No other severe toxicities were noted in the present study. Hypersensitivity reactions, due to docetaxel, were very rare and mild in severity, most probably because of the strict premedication policy with corticosteroids and antihista- mines. No significant evidence of fluid retention syndrome was observed. In conclusion, the combination of docetaxel plus irinotecan in platinum-resistant paclitaxel-pretreated ovarian cancer manifested a moderate response rate, which is in the range of single agents registered for second-line treatment. The regimen can be administered on an outpatient basis, has an acceptable toxicity and yields a median survival of almost one year. Our results, in accordance with those of other investigators (14, 34, 35), suggest that a docetaxel-containing regimen may be moderately effective in ovarian cancer patients with cisplatin-resistant paclitaxel-pretreated tumors, particularly those not progressing during paclitaxel treatment or those who have a long taxane-free interval. 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