Japanese Journal of Clinical Oncology 31:395-398 (2001)
© 2001 Foundation for Promotion of Cancer Research
Weekly 1 Hour Paclitaxel Infusion in Patients with Recurrent Gynecological Tumors: a Pilot Study
Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Intensifying the dose of paclitaxel given in a weekly schedule is useful towards improving the therapeutic index of paclitaxel in treating a variety of advanced and recurrent malignancies and is suitable for outpatient administration. This pilot study was carried out to evaluate the safety of weekly paclitaxel administration by 1 h infusion in the outpatient setting.
Methods: Eleven patients with recurrent gynecological tumors who had previously been treated with at least one platinum-based chemotherapy regimen participated in the study between May 1999 and March 2000. Paclitaxel was given at a dose of 70 mg/m2 as a 1 h infusion every week for at least 20 consecutive weeks unless lesions became progressive. Intravenous dexamethasone and cimetidine and oral diphenhydramine were administered 30 min before paclitaxel infusion.
Results: The 11 patients received a total of 166 cycles of therapy. All patients received 70 mg/m2 doses of paclitaxel without treatment delay. No hypersensitivity reactions were elicited. Grade 3 or 4 leukopenia and neutropenia occurred in 9 and 36% of the patients, respectively. Granulocyte colony-stimulating factor was required for only one patient and no patients experienced febrile neutropenia. Neurotoxicity was the most serious adverse effect and all patients experienced grade 1 or 2 peripheral neuropathy. Grade 1 or 2 myalgias were observed in 45% of the patients. Alopecia was universal. No Grade 3 or higher non-hematological toxicities were observed.
Conclusion: Weekly 1 h paclitaxel administration is considered safe as a salvage therapy for recurrent gynecological tumors, making its use more convenient and easier in the outpatient setting. The current results support further evaluation.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Since treatments for patients with recurrent gynecological tumors are mostly palliative, it is very important to maintain good quality of life (QOL) during the treatment period. One possible way to decrease the toxicity of treatment without compromising efficacy is to give lower doses more frequently. Paclitaxel (Taxol; Bristol Myers Squibb, Princeton, NJ) is an antineoplastic agent used to treat various carcinomas with a good response rate even when tumors are platinum resistant (1–4). Clinical development of the drug has led to different administration schedules of 1–3 and 24 h infusions, with doses ranging from 135 to 250 mg/m2 every 3 weeks (5–9). The observed toxicity profile seems to be both dose and schedule dependent, with decreased hematological toxicity reported in shorter infusion schedules. To maximize drug exposure, weekly schedules of paclitaxel (TXL) have also been investigated and some phase I/II studies have reported that 1 h infusion of TXL at doses of 60 up to 90 mg/m2 weekly yields low toxicity profiles (10–15). The decreased leukocyte toxicity associated with short infusion times allows for reduced inter-treatment periods, from the standard 3 weeks to a 1 week interval. Moreover, the response rate with weekly TXL administration appears comparable to that of the 3 week schedule (10–15). This strategy supports more frequent and prolonged formation of stable cellular microtubules with subsequent mitotic arrest, which forms the pharmacological basis for TXL’s antitumor activity. This pilot study was carried out to evaluate the safety of weekly TXL administration by 1 h infusion for recurrent gynecological tumors in the outpatient setting.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients with recurrent gynecological tumors, which developed after treatment with one or more platinum-based chemotherapy regimens, were eligible for the pilot study. All patients had at least one measurable lesion which had been documented radiographically. The eligibility criteria were as follows: performance status (PS) [World Health Organization (WHO)] <2, good general health with no history of cardiac disorder or congestive heart failure and an expected survival of at least 3 months. Before receiving treatment, laboratory tests showed that all patients conformed to the following criteria: white blood cell count, 4000–12 000/µl; platelet count, >100 000/µl; hemoglobin, >9.5g/dL; AST and ALT, less than twice the normal upper limit; total serum bilirubin, <1.5 mg/dl; serum creatinine, <1.5 mg/dl; creatinine clearance, >60 mg/min; and BUN, <25 mg/dl. Eligible patients provided written informed consent prior to treatment.
The treatment schedule was designed on the basis of previous reports describing weekly administrations of TXL (10–15). Chemotherapy consisted of TXL (70 mg/m2) in 250 ml of 5% glucose given in 1 h infusions. Infusions were repeated each week with no planned pause during the treatment period of at least 20 weeks, unless progressive disease was detected or intolerable non-hematological toxicity was observed. All patients were premedicated with dexamethasone (16–18 mg) i.v., cimetidine (50 mg) i.v. and diphenhydramine (50 mg) orally, 30 min prior to each weekly administration (16).
All patients were treated on an outpatient basis unless they had been hospitalized for other reasons before TXL therapy was initiated. A physician was present during the first 15 min of therapy. Blood pressure was monitored after the first 15 min of infusion.
Total blood cell counts were examined at least twice weekly and serum chemistry and liver function tests were monitored weekly. Before the next cycle was initiated, leukocyte counts were confirmed to be >2000/µl and platelets >100 000/µl, with liver and renal functions within the eligibility criteria. No premedication for neutropenia was given. Patients were evaluated for response to treatment. Patients who progressed were considered treatment failures and the therapy was stopped. Those with stable disease or objective tumor responses continued the therapy. The pilot study was approved by the Institutional Review Board of the Clinical Oncology Program at our institution.
Toxicity evaluations were based on WHO criteria. Although the determination of antitumor activity was not the primary objective of this study, all patients were assessed for responses by computed tomography and/or ultrasonography at least every 4–6 cycles.
The criteria for tumor responses were as follows: complete response (CR) was defined as the complete disappearance of all known disease for a minimum of 4 weeks; partial response (PR) was defined as a >50% reduction in the sum of the length–width products of measurable lesions for a minimum of 4 weeks; progressive disease (PD) was defined as a >25% increase in the sum of the products of all indicator lesions, reappearance of any lesion that had disappeared or appearance of any new lesion; and stable disease (SD) was defined as any situation that did not qualify as a response or progression.
The patients’ characteristics are listed in Table 1. Between May 1999 and March 2000, 11 patients entered the study. The median age was 60.2 years (range: 42–71 years) and the median performance status was 1 (range: 0–2). Four patients had epithelial ovarian cancer, one had recurrent granulosa cell tumor of the ovary, four had endometrial cancer, one had cervical cancer and one had malignant mesothelioma. Six of the 11 patients (five with ovarian tumors and one with endometrial cancer) had previously undergone heavy treatments with two or more platinum-based chemotherapies.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The 11 patients received a total of 166 cycles of therapy, with an average of 15 (range: 6–21) per patient. All patients received 70 mg/m2 doses of TXL without treatment delay and the actual dose intensity was 70 mg/m2/week. All patients were evaluated for toxicity and response.
Toxicity
No treatment-related deaths occurred in this study. Table 2 lists the non-hematological toxicities encountered during treatment. No hypersensitivity reactions to TXL were exhibited. Peripheral neuropathy occurred in all patients, but severe (grade 3 or 4) peripheral neuropathy was not observed. Grade 1 or 2 myalgias and fatigue were observed in 45 and 54% of the patients, respectively. Nausea/emesis, diarrhea and mucositis were uncommon and none of the patients needed antiemetic support. Alopecia was of moderate intensity. Although significant nail discoloration and onychorrexis were noted in two patients after the tenth cycle of TXL, their nails grew back completely after completion of the treatment. Following the fourth cycle, one patient with recurrent endometrial cancer had an episode of angina, but it was easily controlled with nitroid. She was able to continue the treatment and no dose reduction was necessary. Weight gain of more than 2 kg was observed without edema in two patients.
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Table 3 shows the hematological toxicities manifested in patients. Myelosuppression was commonly observed, but was mild to moderate in most patients. Grade 3 or 4 leukopenia and neutropenia occurred in one (9%) and four (36%) of the patients, respectively, and there were no episodes of febrile neutropenia. The median neutrophil nadir count was 1200/µl and the median time to nadir was 4 days after each TXL infusion. Patients with grade 3 neutropenia recovered before the next cycle without granulocyte colony-stimulating factor (G-CSF), but G-CSF support was necessary for one patient with grade 4 neutropenia after the fifth cycle of TXL. Thrombocytopenia was frequently observed, but was not severe. Grade 4 anemia was noted in one patient, who required red blood cell transfusion. There was no evidence of cumulative hematological toxicity.
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Response
Seven of the 11 cases realized the objective response. Two patients (18%) displayed SD and the remaining two (18%) manifested PD. The patient with serous adenocarcinoma of the ovary who was pretreated with TXL and carboplatin and the patient with cervical adenocarcinoma both realized CR. PR was observed in five patients: three with endometrial cancer, one with ovarian cancer and one with malignant mesothelioma. Two patients with ovarian cancer exhibited SD and their treatments continue at this time. Each patient with ovarian and endometrial cancer manifested PD.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The optimal management of patients with recurrent gynecological tumors has not yet been established. Most patients with ovarian cancer who have undergone heavy pretreatment with platinum- and/or TXL-based chemotherapies and patients with recurrent uterine adenocarcinoma scarcely respond to second-line drugs and the rates of cure are very low. The treatment of recurrent gynecological tumors, therefore, constitutes a challenge for the clinician. The choice of a second-line drug in this situation is dependent on toxicity and QOL considerations, in addition to efficacy. Weekly administration of TXL by 1 h infusion has been reported to have less toxicity and a promising effect in cases of pretreated gynecological cancers (10–14). Previous reports have demonstrated that weekly i.v. TXL administration in a 1 h infusion at doses of 60–90 mg/m2 is an acceptable salvage regimen (10–14). In the present study, we administered 70 mg/m2 of TXL without dose escalation in order to maintain dose density and to avoid adverse effects. All patients underwent this therapy without treatment delay. Hematological toxicity was less severe with the weekly schedule, despite the fact that the overall dose intensity was increased compared with the standard TXL dose of 175 mg/m2 (3 h infusion) every 3 weeks and the phase I/II trial dose of 135 mg/m2 (1 h infusion) every 3 weeks (5,8). Grade 3 or higher neutropenia was observed in 36% of patients and one patient with grade 4 neutropenia required G-CSF support. Thrombocytopenia (grade 2 or higher) was not observed. Non-hematological effects such as peripheral neuropathy, myalgias and fatigue were seen in almost all patients, but no grade 3 or 4 severities were encountered. These toxicities were similar to those in previous reports (10–15). We introduced short-course prophylaxis for TXL-related hypersensitivity as reported by Bookman et al. (16). Short premedication 30 min before TXL administration offers a safe and convenient alternative to avoid hypersensitivity reactions. Two patients (18%) showed body weight gains (>2 kg) during the treatment, probably because weekly administration of dexamethasone increased their appetites.
Additionally, responses were observed in patients with ovarian cancer, endometrial cancer and cervical cancer.
In conclusion, the low toxicity profile and short duration of therapy (1 h infusion) make this regimen advantageous for outpatient treatment, providing a favorable therapeutic option to maintain or improve the patient’s QOL better during cancer treatment. Hence this weekly 1 h TXL (70 mg/m2) regimen should be considered as a useful salvage therapy in the treatment of recurrent gynecological tumors.
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FOOTNOTES |
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+ For reprints and all correspondence: Toru Sugiyama, Department of Obstetrics and Gynecology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. E-mail: sugisama@med.kurume-u.ac.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Received February 21, 2001; accepted April 13, 2001.
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