Ryo Kitagawa

Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505

PURPOSE In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen. PATIENTS AND METHODS Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29. RESULTS Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001). CONCLUSION TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.

Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: Efficacy and toxicity of a low cumulative radiation dose schedule ☆

OBJECTIVE A multicenter phase II trial was conducted to assess the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with high-dose-rate intracavitary brachytherapy (HDR-ICBT) using a low cumulative prescribed dose schedule in patients with locally advanced uterine cervical cancer. METHODS The Japanese Gynecologic Oncology Group (JGOG) study JGOG1066 enrolled patients with FIGO stages III-IVA uterine cervical cancer who had no para-aortic lymphadenopathy (>10 mm) assessed by CT. Patients received definitive radiotherapy (RT) consisting of external beam whole pelvic RT and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62-65 Gy prescribed at point A. Cisplatin 40 mg/m(2) weekly was administered concurrently with RT for 5 courses. RESULTS Of the 72 patients registered, 71 were eligible. With a median follow-up of 28 months, the 2-year progression-free survival rate and pelvic disease progression-free rate were 66% (95% CI, 54% to 76%) and 73% (95% CI, 61% to 82%), respectively. Progression-free survival decreased significantly with increased central tumor size (P=0.036). The 2-year cumulative late complication rates were 24% for all grades, 9% for grade 1, 12% for grade 2, 3% for grade 3, and 0 for grades 4/5. CONCLUSIONS The JGOG1066 demonstrated that CCRT using HDR-ICBT with a low cumulative RT dose schedule achieved comparable outcome as those achieved with global dose schedules (EQD2=85 Gy) with a lower incidence of late toxicity for locally advanced uterine cervical cancer in a Japanese population.

A Phase III Trial of Paclitaxel plus Carboplatin Versus Paclitaxel plus Cisplatin in Stage IVB, Persistent or Recurrent Cervical Cancer: Gynecologic Cancer Study Group/Japan Clinical Oncology Group Study (JCOG0505)

A randomized controlled trial has been started in Japan to compare the utility of palliative chemotherapy containing paclitaxel and carboplatin (TC) with paclitaxel and cisplatin (TP) as a standard treatment for patients with the newly diagnosed Stage IVB, persistent or recurrent cervical cancer who are not amenable to curative treatment with local therapy. This trial was designed to evaluate the non-inferiority of TC as measured by the number of hospitalized days as an indicator of quality of life (QOL) when compared with TP combination therapy. The primary endpoint is overall survival. Secondary endpoints are progression-free survival, response rates, adverse events, severe adverse events and the proportion of non-hospitalization periods compared with planned treatment periods.

Evidence-based guidelines for treatment of cervical cancer in Japan: Japan Society of Gynecologic Oncology (JSGO) 2007 edition

Clinical practice guidelines for gynecologic cancers have been published by the National Comprehensive Cancer Network and the National Cancer Institute. Whereas these guidelines form the basis for the standard of care for gynecologic malignancies in the United States, it has proven difficult to institute them in Japan due to differences in patient characteristics, health-care delivery systems, and insurance programs. Therefore, evidence-based guidelines for treating cervical cancer specifically in Japan have been under development. The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer. Opinions from within and outside the Japan Society of Gynecologic Oncology (JSGO) were incorporated into the final draft, and the guidelines were published after approval by the JSGO. These guidelines are composed of ten chapters and comprise three algorithms. Each chapter consists of a clinical question, recommendations, background, objectives, explanations, and references. The objective of these guidelines is to clearly delineate the standard of care for cervical cancer treatment in Japan in order to ensure equitable care for all Japanese women diagnosed with cervical cancer.

A multi-institutional phase II trial of paclitaxel and carboplatin in the treatment of advanced or recurrent cervical cancer

OBJECTIVE The aim of this prospective trial was to evaluate the efficacy and safety of the combination of paclitaxel and carboplatin (TC) in patients with metastatic or recurrent cervical cancer. METHODS This was a multicenter phase II trial of 3 weekly paclitaxel 175 mg/m(2) 3-hour iv day 1 followed by carboplatin AUC5 1-hour iv day 1 for maximum of 6 cycles until disease progression or prohibitive toxicity. Eligible patients had squamous or adenocarcinoma of the cervix with measurable stage IVB or recurrent, aged 20-75 years, Eastern Cooperative Oncology Group performance status 0-2, prior platinum-containing regimen 0-1, and no prior taxane. The primary endpoint was overall response rate (ORR) by RECIST. RESULTS 41 patients were enrolled, of which 39 were evaluable for analysis. 33 patients (84.6%) received prior radiotherapy. The confirmed ORR was 59% (95% CI, 43% to 75%); 5 patients (13%) achieved a complete response and median response duration was 5.2 months. The response rates for patients who had adenocarcinoma (n=10) and prior platinum-based chemotherapy<6 months (n=7) were 40.0% and 0%, respectively. The median progression-free survival and overall survival times were 5.3 and 9.6 months, respectively. The most frequent grade 3 or 4 adverse events were neutropenia (79%), anemia (46%), thrombocytopenia (15%), and fatigue (8%). No treatment-related death was seen. CONCLUSIONS TC seemed to be feasible and effective similar to other cisplatin-based doublets for the treatment of metastatic or recurrent cervical cancer. Phase III trial is warranted to establish the clinical benefits of this combination.

Practice pattern for postoperative management of endometrial cancer in Japan: A survey of the Japanese Gynecologic Oncology Group

OBJECTIVE To determine the current status of postoperative management of endometrial cancer in Japan by surveying members of the Japanese Gynecologic Oncology Group (JGOG). METHOD We conducted an original mail survey regarding the status of postoperative treatment including indication criteria, treatment procedures, and chemotherapeutic regimen among all 226 active member institutions of the JGOG. RESULTS A total of 199 institutions (88.1%) responded to the survey. A total of 4063 patients with endometrial cancer were treated at the member institutions of the JGOG over a year. As adjuvant therapy, chemotherapy (79.9%) was significantly (p<0.01) preferred over radiotherapy (13.0%) or hormonal therapy (7.1%). Furthermore, more than 50% of respondent institutions performed adjuvant therapy when patients exhibited International Federation of Gynecology and Obstetrics (FIGO) stage IB/G3/positive lymph-vascular space invasion (LVSI)/endometrioid adenocarcinoma or FIGO IB/G3/non-endometrioid histology, and more than 90% institutions administered adjuvant therapy when patients exhibited FIGO IC/G3/positive LVSI/endometrioid adenocarcinoma or FIGO stage IC/G3/regardless of LVSI/non-endometrioid histology. A combination of paclitaxel and carboplatin was the most preferred first-line regimen for adjuvant chemotherapy followed by combination regimens consisting of anthracycline and platinum. CONCLUSION The present survey provides relevant information regarding the current status of adjuvant therapy in Japanese patients with endometrial cancer.

Feasibility and acute toxicity of Concurrent Chemoradiotherapy (CCRT) with high-dose rate intracavitary brachytherapy (HDR-ICBT) and 40-mg/m2 weekly cisplatin for Japanese patients with cervical cancer: results of a Multi-Institutional Phase 2 Study (JGOG1066).

ObjectiveTo assess the feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high–dose rate intracavitary brachytherapy (HDR-ICBT) and standard dose delivery of cisplatin for Japanese patients with cervical cancer. Materials and MethodsThe phase 2 study included Japanese patients with International Federation of Gynecology and Obstetrics stage III to IVA uterine cervical cancer who had no para-aortic lymphadenopathy (>10 mm) assessed by computed tomography. Patients were 20 to 70 years of age and had Eastern Cooperative Oncology Group performance status of 0 to 1. The radiotherapy protocol consisted of whole-pelvis external beam radiotherapy and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62 to 65 Gy prescribed at point A. Cisplatin was administered weekly at a dose of 40 mg/m2 for 5 courses. ResultsBetween March 2008 and January 2009, 72 patients from 25 institutions were enrolled, and 71 patients were eligible and evaluable for compliance and severe toxicity. The median age of the patients was 57 years (range, 32–70 years). Sixty-five patients (92%) received the planned 5 courses of chemotherapy. Four patients had cisplatin dose reduction according to the protocol. Radiotherapy was completed per protocol in 68 patients (96%). Median overall treatment time was 50 days (range, 37–66 days). The following grade 3 or 4 acute adverse events were observed: neutropenia in 31 patients (44%), anemia in 10 patients (14%), diarrhea in 4 patients (6%), and anorexia in 3 patients (4%). ConclusionsConcurrent chemoradiotherapy with HDR-ICBT and standard weekly delivery of cisplatin was feasible with acceptable toxicity in Japanese patients with cervical cancer.Objective To assess the feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high–dose rate intracavitary brachytherapy (HDR-ICBT) and standard dose delivery of cisplatin for Japanese patients with cervical cancer. Materials and Methods The phase 2 study included Japanese patients with International Federation of Gynecology and Obstetrics stage III to IVA uterine cervical cancer who had no para-aortic lymphadenopathy (>10 mm) assessed by computed tomography. Patients were 20 to 70 years of age and had Eastern Cooperative Oncology Group performance status of 0 to 1. The radiotherapy protocol consisted of whole-pelvis external beam radiotherapy and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62 to 65 Gy prescribed at point A. Cisplatin was administered weekly at a dose of 40 mg/m2 for 5 courses. Results Between March 2008 and January 2009, 72 patients from 25 institutions were enrolled, and 71 patients were eligible and evaluable for compliance and severe toxicity. The median age of the patients was 57 years (range, 32–70 years). Sixty-five patients (92%) received the planned 5 courses of chemotherapy. Four patients had cisplatin dose reduction according to the protocol. Radiotherapy was completed per protocol in 68 patients (96%). Median overall treatment time was 50 days (range, 37–66 days). The following grade 3 or 4 acute adverse events were observed: neutropenia in 31 patients (44%), anemia in 10 patients (14%), diarrhea in 4 patients (6%), and anorexia in 3 patients (4%). Conclusions Concurrent chemoradiotherapy with HDR-ICBT and standard weekly delivery of cisplatin was feasible with acceptable toxicity in Japanese patients with cervical cancer.

Phase II trial of paclitaxel (T) and carboplatin (C) in patients with recurrent or metastatic cervical carcinoma

5048 Background: For patients (pts) with recurrent or metastatic cervical carcinoma, T plus cisplatin (P) were reported to improve the response rate (RR) and progression-free interval compared to P alone (Moore et al; Proc ASCO 2001) and has been shown as a new appropriate regimen. However, more effective and/or less toxic combinations are needed. C as a single agent has less RR but less overall toxicity than P. In order to evaluate the efficacy and safety of T plus C, we conducted the following phase II trial. METHODS Pts with recurrent or metastatic cervical carcinoma no longer amenable to curable surgery or radiatiotherapy (RTx), with measurable lesions, performance status (PS) 0-2, and adequate organ functions, received TC (paclitaxel 175mg/m2 3-hour i.v., carboplatin AUC 5 1-hour i.v.) every 3 weeks. Treatment was continued until progression or completion of 6 courses administration. Tumor response was evaluated every 2 cycles, and toxicities every cycle. RESULTS 28 pts (median age 49; range 29-67) were enrolled and 23 pts were assessable for response and toxicities. 21 pts (91%) had received RTx. The overall RR was 61% (95% CI, 41-78%), especially CR showed in 2 pts (9%). The median progression-free survival was 5.9 months (range 1.0-14.1). RRs according to PS, histological type (Hx), prior RTx for target lesions, and prior chemotherapy (CTx) are given in the table below. As day 1 hematological toxicities, Grade 4 was observed only in Anemia (4 pts; 17%). Non-hematological toxicity included grade 3 neuropathy in 2 pts (8%). Grade 3 febrile neutropenia was observed in 3 pts (13%), but they were managed without hospitalization or G-CSF administration. CONCLUSIONS TC is promising and feasible combination in pts with recurrent or metastatic cervical carcinoma and can be safely administered in outpatient clinic. On this basis, phase III study is planed to compare TC with T plus P. [Figure: see text] No significant financial relationships to disclose.

Radiotherapy quality assurance of the Japanese Gynecologic Oncology Group study (JGOG1066): a cooperative phase II study of concurrent chemoradiotherapy for uterine cervical cancer

BackgroundTo assess radiotherapy protocol compliance in a multi-institutional phase II study of concurrent chemoradiotherapy for patients with locally advanced cancer of the uterine cervix (JGOG1066).MethodsFor study protocol development, various radiotherapy parameters were examined and consensus was reached by Japanese radiation oncologists with cervical cancer treatment expertise. Quality assurance (QA) was also discussed and included in the protocol. A credentialing process was used to select institutions for participation in the study. Individual case reviews referring to 18 QA items were undertaken for each patient. Radiotherapy data were submitted to the Japanese Gynecologic Oncology Group (JGOG) data center and reviewed by the members of the radiotherapy committee. The QA evaluation was classed as per protocol, deviation, and violation.ResultsIndividual case reviews were performed on 69 of 72 patients entered in the study. In 24 patients (35%), there were no deviations for any QA items. There were also no deviations seen for 5 of the 18 items in 69 patients evaluated. Deviations of 64 QA items were seen in 45 cases, and violations were seen in 4 cases (4 items). The most common deviation concerned appropriate application for the external beam radiotherapy (EBRT) boost to involved nodes or parametrium (32 cases). The 4 violations were identified in the QA items regarding high-dose rate intracavitary brachytherapy.ConclusionsRadiotherapy protocol compliance was favorable except for the EBRT boost indications. The results of this study validate the quality of radiotherapy in JGOG1066, and indicate that the final analysis will provide meaningful results.

Practice patterns of adjuvant therapy for intermediate/high recurrence risk cervical cancer patients in Japan

Objective Although radiation therapy (RT) and concurrent chemoradiotherapy (CCRT) are the global standards for adjuvant therapy treatment in cervical cancer, many Japanese institutions choose chemotherapy (CT) because of the low frequency of irreversible adverse events. In this study, we aimed to clarify the trends of adjuvant therapy for intermediate/high-risk cervical cancer after radical surgery in Japan. Methods A questionnaire survey was conducted by the Japanese Gynecologic Oncology Group to 186 authorized institutions active in the treatment of gynecologic cancer. Results Responses were obtained from 129 facilities. Adjuvant RT/CCRT and intensity-modulated RT were performed in 98 (76%) and 23 (18%) institutions, respectively. On the other hand, CT was chosen as an alternative in 93 institutions (72%). The most common regimen of CT, which was used in 66 institutions (51%), was a combination of cisplatin/carboplatin with paclitaxel. CT was considered an appropriate alternative option to RT/CCRT in patients with risk factors such as bulky tumors, lymph node metastasis, lymphovascular invasion, parametrial invasion, and stromal invasion. The risk of severe adverse events was considered to be lower for CT than for RT/CCRT in 109 institutions (84%). Conclusion This survey revealed a variety of policies regarding adjuvant therapy among institutions. A clinical study to assess the efficacy or non-inferiority of adjuvant CT is warranted.