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ANTICANCER RESEARCH 25: 3559-3564 (2005)

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

ARISTIDES POLYZOS1, CHRISTOS KOSMAS2, HELEN TOUFEXI1, NICHOLAS MALAMOS2, ANTONIOS LAGADAS1, CHRISTOS KOSMIDIS1, PANAGIOTIS GINOPOULOS3, NICHOLAS ZIRAS4, KOSTAS KANDILIS4 and VASSILIS GEORGOULIAS5

1Medical Oncology Unit, Laikon General Hospital, University of Athens School of Medicine; 2Medical Oncology Unit, Helena-Venizelou Hospital, Athens; 3Department of Medical Oncology, Agios Andreas Hospital, Patras; 4Department of Medical Oncology, Metaxa Cancer Hospital, Pireus; 5Department of Medical Oncology, University General Hospital Heraklion, Crete, Greece

Abstract. The role of combination regimens (range, 2-17) and the median survival 11 months (range, 1- in the management of ovarian cancer patients with tumors 40); the 1-year survival was almost 50%. Myelotoxicity was resistant to platinum compounds has not yet been defined. moderate, with grade 3 and 4 occurring in 23% This multicenter prospective phase II study evaluated the of the patients, grade 3-4 thrombocytopenia in 6% and activity and toxicity of the -plus-irinotecan febrile neutropenia in 13%. Grade 3 was observed combination in ovarian cancer patients whose tumors were in 2% of the patients. There was one treatment-related death resistant to platinum compounds and who had been exposed due to sepsis. In conclusion, the combination of docetaxel to . Treatment consisted of docetaxel 60 mg/m2 i.v. plus irinotecan with rhG-CSF support, appears to be a followed by irinotecan 200 mg/m2 i.v. both on day 1 followed moderately effective regimen with acceptable toxicity for by prophylactic recombinant human granulocyte-colony platinum-resistant, paclitaxel-pretreated ovarian cancer stimulating factor (rhG-CSF) support from days 2 to 6, every patients. Further investigation in comparative studies is 3 weeks. Thirty-one patients were enrolled in the study. The required to define the role of combination versus single agent median age was 60 years, and the median performance chemotherapy in this group of patients. status (ECOG) was 1. Eight (26%) patients had primary tumors resistant to platinum, while the rest of the population The standard front-line for advanced had tumor recurrence within 6 months from the last ovarian cancer is currently a combination of platinum agent treatment. Four chemotherapy cycles per patient were (cisplatin of ) and paclitaxel (1, 2). However, administered, with the delivered dose intensity at 75% of the despite the high response rate and prolonged median planned dose for both agents. Among 30 patients evaluable survival time observed with these regimens, over 80% of for response, there were 2 (7%) complete and 4 (14%) patients relapse requiring further treatment. Recurrent partial responses (overall response rate 20%; (95% disease is classified as being either sensitive or resistant to confidence interval, CI, 11%-33%). Stable disease was platinum compounds according to the time elapsed from the recorded in 8 (28%) patients and progressive disease in 15 last chemotherapy cycle and the disease relapse (3). (51%). The median response duration was 4.5 months Retreatment with cisplatin or carboplatin offers a response (range, 3-12), the median time to progression 5 months rate of 30% when the disease is considered potentially platinum-sensitive (4). For platinum-resistant disease, chemotherapy relies on other chemotherapeutic agents, such as , liposomal , , Correspondence to: Aristides Polyzos, MD, Assoc. Professor of or that, as salvage treatment, yield Medicine, 1st Department of Propaedeutic Medicine, Laikon response rates between 10% and 30% (5-9). To date, General Hospital, 17, Agiou Thoma St., Goudi, GR 11527, Athens, sensitivity or resistance has not been considered for the Greece. Tel: 0030-210-7706606, Fax: 0030-210-7791839, e-mail: r- [email protected] selection of a second-line treatment. Therefore, in order to establish an effective second-line chemotherapy regimen, it is Key Words: Docetaxel, irinotecan, cisplatin resistance, ovarian important to use agents which are not cross-resistant to the cancer. initial standard paclitaxel/platinum regimen.

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Docetaxel is a new taxane derived from the needles of concurrent infection, pre-existing diarrhea, intestinal paralysis or Taxus baccata. While it inhibits disassembly like obstruction. The study was approved by the Ethics and Scientific paclitaxel, it has different effects on Tau binding sites and Committees of the participating centers, and all patients gave their informed consent in order to participate in the study. on microtubule-associated proteins (9, 10). Docetaxel was found, in several in vitro and in vivo studies, to have a potent Treatment plan. Treatment was given on an outpatient basis and cytotoxic activity and an incomplete cross-resistance to comprised the administration of docetaxel (Taxotere®; Aventis paclitaxel (11, 12). This finding has been substantiated by Pharma, Bridgewater, USA) 60 mg/m2 followed by irinotecan the results of several phase II studies, which demonstrated (Campto®; Aventis Pharma) 200 mg/m2; both drugs were given as a the activity of docetaxel against paclitaxel-resistant tumors 1-hour i.v. infusion. The dose and schedule of drug administration in breast and ovarian cancer (13, 14). Furthermore, other were based on previous phase I, II studies (30). Antiemetic studies have shown the activity of docetaxel in platinum- treatment consisted of dexamethasone (8 mg) plus ondansetron (24 mg) given as i.v. bolus before chemotherapy. Premedication for resistant ovarian cancer (15-18). Similarly, I docetaxel hypersensitivity reactions and to prevent skin toxicity and inhibitors have been shown to display considerable activity fluid retention consisted of oral dexamethasone (8 mg) given 12, 8 against ovarian cancer. Topotecan has been considered an and 1 hour before docetaxel and 24, 36 and 42 hours post-infusion. effective agent in both the first- and second-line setting, in For the early cholinergic adverse effects induced by irinotecan combination with cisplatin (5, 19). Irinotecan hydrochloride administration, atropine (1 mg) was given subcutaneously, and for (CPT-11) is a semisynthetic, water-soluble derivative of the late diarrhea high-dose (4 mg initial dose, followed , a plant alkaloid obtained from Camptotheca by 2mg every 2 hours until diarrhea-free) was administered. Recombinant human granulocyte-colony stimulating factor acuminata. Irinotecan, like topotecan, inhibits topo- (rhG-CSF) (Granocyte®; Aventis Pharma) (5 Ìg/kg/day) was given isomerase I, an intranuclear enzyme that relieves torsion in from days 2 to 6. The regimen was administered every 3 weeks for DNA induced by replication (20). Irinotecan has expressed a maximum of 6 cycles, unless there was evidence of disease significant in vitro and in vivo activity in several tumors, progression, unacceptable toxicity or patient refusal. Treatment including ovarian cancer (21-24). In clinical trials, its activity cycles were delayed for up to 2 weeks, unless the patient had was documented in both the first-and second-line setting in recovered from hematological and non-hematological toxicity. combination with cisplatin (25-28). Before the next course was started, the count had to be ≥1.5x109/L and platelet ≥100x109/L with no diarrhea, and and It is interesting that, although combination chemotherapy renal function had to meet the eligibility criteria. The doses of both regimens have also been administered in ovarian cancer docetaxel and irinotecan were reduced by 25% in the event of grade patients with tumors resistant to platinum compounds, their 4 hematological toxicity. The irinotecan dose was reduced by 25% in efficacy and toxicity have not yet been defined (29). Based the event of ≥ grade 3 diarrhea. on these data, a prospective phase II study was conducted to evaluate the efficacy and toxicity of the docetaxel-plus- Patient evaluation. Baseline evaluations included: patient history, irinotecan combination as salvage treatment in ovarian physical examination, chest X-rays, complete blood count with cancer patients whose tumors were resistant to cisplatin and differential and platelet count, standard blood chemistry and ECG. Computed tomography (CT) scans of the chest, abdomen, who had been pretreated with paclitaxel. pelvis and whole body bone scintigraphy were performed at study entry and CT scan of the brain whenever clinically Patients and Methods indicated. Complete blood counts with differential and platelet counts were performed twice weekly or daily in case of grade 3/4 Patient population. Patients were required to have: a) histologically neutropenia, thrombocytopenia or febrile neutropenia until confirmed epithelial ovarian carcinoma with manifestations of hematological recovery; blood chemistry and physical locoregional or metastatic bidimensionally measurable disease; b) examination were performed every 3 weeks. Patients were either primary tumors resistant (non-responding or progressing) to evaluated before each cycle for lesions assessable by physical platinum-based combinations or recurring within 6 months from examination. Pelvic examination was performed at baseline and the previous platinum-based treatment; c) paclitaxel as part of their after 3 and 6 cycles. All patients were evaluated by the prior chemotherapy regimen. Other eligibility criteria included: a appropriate imaging studies indicative of the measurable target life expectancy of at least 3 months, Eastern Cooperative Oncology lesions every 2 chemotherapy cycles. Group (ECOG) performance status (PS) ≤2, age ≤75 years, hematological parameters and blood chemistry indicating normal Tumor evaluation and criteria for response. Tumor response was organ function [(absolute neutrophil count ≥1.5x10 q/L, platelet assessed after every 2 cycles using the World Health Organization count ≥100x10 q/L, hemoglobin ≥10 g/dL, normal total bilirubin, (WHO) response criteria (31). An independent radiologist AST ≤2.5 times the upper limit of normal value (ULN), alkaline reviewed all tumor responses. Response duration was calculated phosphatase ≤6 x ULN and creatinine clearance ≥60 ml/min)]. from the day on which at least a 50% reduction in tumor volume Exclusion criteria included: prior treatment with docetaxel or was documented until the first documentation of progressive topotecan, sensitivity to platinum, or a previous chemotherapy disease. Time to tumor progression (TTP) was calculated from the regimen that did not contain platinum. Patients were excluded first day of drug administration to the first documentation of tumor from the study if there was a history of prior malignancies, progression. Overall survival was measured from the date of first

3560 Polyzos et al: Salvage Treatment of Ovarian Cancer with Docetaxel and Irinotecan

Table I. Patients’ characteristics. Table II. Clinical response to chemotherapy.

Patients % No. Percentage of all patients (n=31) Eligible patients 31 100 Age (years) Complete response 2 7 Median Range 60 (37-75) Partial response 4 13 Performance Status (ECOG) Overall response rate 6 20 (95% CI 11%-33%) 01962Stable disease 8 27 1619Progressive disease 16 53 2619 Stage (FIGO) CI=Confidence interval IIIc 19 61 Median duration of response 4.5 (3-12) months IV 12 39 Median time to progression 5 (2-17) months Tumor histology Median survival 11 (1-40) months Serous 14 45 One-year survival overall 14/31=45% Endometrioid 6 19 Mucinous 2 7 Adenocarcinoma 6 19 Mixed 3 10 Tumor Grade duration, time to progression (TTP) and overall survival were 1515 estimated using the Kaplan-Meier method. Dose intensity was 2826 2 31652expressed in mg/m /week. Unknown 2 7 Involved sites Results Omentum-mesentery-ascites 25/12 80/39 Pelvic-retroperitoneal-lymph nodes 10 32 Liver 7 23 Patient characteristics. From June 1999 to September 2002, Pleura 4 13 31 patients were enrolled, and their characteristics are listed Number of prior in Table I. All patients had received carboplatin plus Mean 1.5 paclitaxel as first-line chemotherapy. Concerning resistance Median 2 to platinum, 8 (26%) patients had primary tumors refractory Range 1-3 Interval from previous chemotherapy to platinum compounds. The rest of the patient population treatment (months) had received second-line treatments with either paclitaxel- Median 3 -cisplatin or cisplatin-ifosfamide and had tumor Range 2-4 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 drug administration to death. Patients without progression who ascitis (n=12 patients), while retroperitoneal disease was died during the study were considered treatment failures. present in 10 patients and liver disease in 7. A total of 128 chemotherapy cycles were administrated with a median of 4 Monitoring for toxicity. Toxicity evaluations were graded according cycles per patient (range 1-8). to the National Cancer Institute (NCI) common toxicity criteria (31). Hematological and clinical chemistry parameters were Response and survival data. Thirty patients were assessable measured at baseline and then at least weekly throughout for response and 31 for toxicity. One patient stopped treatment. Liver function was monitored at each cycle. chemotherapy before the third cycle because of Statistical methods. The primary objective of the study was the deterioration of her performance status. Two (7%) patients overall response rate. All analyses were based on the intent – to – achieved a complete response and 4 (13%) a partial treat population. Confidence intervals (CI) for response rates were response for an overall response rate of 20% (95% CI 11- calculated according to the method described by Simon (32). 33%). Eight (27%) patients had stable disease and 16 (53%) Simon’s two-stage mini-max design was used to allow for early patients progressive disease. The median time to achieve an termination of the trial in the event of a poor response rate. An objective response was 3 (range 2-4) months, and the optimized two-stage plan for accrual was used at a first-stage design with 16 patients. It was calculated that, with an anticipated median response duration was 4.5 (range 3-12) months. The RR of approximately 30% (minimum level of activiy to be of median time to progression was 5 (range 2-17) months, and interest), the sample size required for having confidence limits of the median survival was 11 (range 1-40) months. Responses ±8% would be 32 patients. The survival distributions for response were observed in all sites of disease such as liver (n=1

3561 ANTICANCER RESEARCH 25: 3559-3564 (2005)

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

3562 Polyzos et al: Salvage Treatment of Ovarian Cancer with Docetaxel and Irinotecan

Irinotecan, the second agent applied in the present study, docetaxel combinations such as with vinorelbine, even when has been less extensively investigated than topotecan. administered with prophylactic G-CSF, have proved to be Nevertheless, its anti-tumor activity in ovarian cancer, either myelotoxic with a 20% incidence of febrile neutropenia as first-line treatment with cisplatin or as second-line (35). Even when given as front-line treatment in ovarian chemotherapy, has been documented (25-28). In a more cancer patients with cisplatin, irinotecan may result in a high recent study, irinotecan 60 mg/m2 was given on days 1, 8 and incidence of grade 3-4 neutropenia, ranging from 50% to 15 and was combined with cisplatin on day 1 as first-line 60% (27-28). No other severe toxicities were noted in the treatment in patients with ovarian cancer. An impressive 76% present study. Hypersensitivity reactions, due to docetaxel, objective response rate was achieved, while 8% complete were very rare and mild in severity, most probably because responses were documented (28). The same investigators of the strict premedication policy with corticosteroids and have also reported that this regimen yielded a 33% clinical antihista- mines. No significant evidence of fluid retention objective response in patients with recurrent ovarian cancer syndrome was observed. (28). The combination of docetaxel and irinotecan applied in In conclusion, the combination of docetaxel plus the present study resulted in a moderate response rate of irinotecan in platinum-resistant paclitaxel-pretreated 20%, which is within the range of response rates achievable ovarian cancer manifested a moderate response rate, which by single agents registered in the second-line setting for the is in the range of single agents registered for second-line treatment of ovarian tumors (3-9). Responses have been treatment. The regimen can be administered on an reported both in patients who received paclitaxel only once, outpatient basis, has an acceptable toxicity and yields a as well as in those who have been retreated with the drug. It median survival of almost one year. Our results, in is interesting that, in a study from Finland, where the same accordance with those of other investigators (14, 34, 35), agents, doses and schedule were applied, the obtained results suggest that a docetaxel-containing regimen may be were rather different. In that study, despite the fact that half moderately effective in ovarian cancer patients with of the patients were considered to have "chemosensitive" and cisplatin-resistant paclitaxel-pretreated tumors, particularly half "chemoresistant" disease, the observed response rate in those not progressing during paclitaxel treatment or those both groups was 63% (34). These differences should be who have a long taxane-free interval. The role of attributed to the enrolled study populations, since only half combination chemotherapies in the management of ovarian of the patients in the Finnish study had received paclitaxel cancer patients with platinum-resistant tumors needs to be and only one platinum regimen as initial treatment (34). defined. Further comparative studies with quality of life The docetaxel-irinotecan combination given in the consideration are warranted. present study resulted in a 20-week time-to-progression interval and a 44-week overall survival. A factor that References contributed to the increase of the median survival was the relatively high percentage of patients recorded with stable 1 McGuire WP, Hoskins WJ, Brady MF et al: disease. In most studies, with ovarian cancer patients and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334: treated with second-line chemotherapy, the reported TTP is 1-6, 1996. in the range of 12-14 weeks, and the median survival is in 2 Piccart MJ, Bertelsen K, James K et al: Randomized intergroup the range of 40-60 weeks (3-9). trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in Docetaxel has also been combined with other new agents. women with advanced epithelial ovarian cancer: three-year A recent study has evaluated the combination of docetaxel results. J Natl Cancer Inst 92: 699-708, 2000. and vinorelbine supported by prophylactic rhG-CSF as 3 Markman M, Rothman R, Hakes T et al: Second line platinum second-line chemotherapy for patients with platinum- therapy in patients with cisplatin. J Clin Oncol 9: 389-393, 1991. 4 Eisenhauer EA, Vermorken JB and Van Glabbeke M: resistant paclitaxel-pretreated ovarian cancer. The observed Predictors of response to subsequent chemotherapy in platinum response rate was 23.5%, a result similar to our finding of a pretreated ovarian cancer: a multivariate analysis of 704 median survival of 9.3 months (35). patients. Ann Oncol 8: 963-968, 1997. The toxicity profile of the docetaxel-irinotecan 5 Swisher EM, Mutch DG, Rader JS et al: Topotecan in combination with prophylactic G-CSF administration in the platinum- and paclitaxel-resistant ovarian cancer. Gynecol present study was acceptable, given that both agents are Oncol 66: 480-486, 1997. myelotoxic and that the patients were pretreated. The main 6 Lund B, Hansen OP, Theilade K et al: Phase II study of toxicities were neutropenia and febrile neutropenia, Gemcitabine (2’, 2’’ – difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86: 1530-1533, 1994. occurring in 23% and 13% of patients, respectively. It is 7 Bajetta E, Leo AD, Biganzoli L et al: Phase II study of interesting that docetaxel as a single agent resulted in a high vinorelbine in patients with pretreated advanced ovarian cancer: (86%) incidence of grade 3-4 neutropenia when it was activity in platinum-resistant disease. J Clin Oncol 14: 2546- administered to pretreated patients (14, 15). Other 2551, 1996.

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