A pilot trial of TAC (paclitaxel, doxorubicin, and carboplatin) chemotherapy with filgastrim (r-metHuG-CSF) support followed by radiotherapy in patients with "high-risk" endometrial cancer

OBJECTIVES: To determine the toxicity, tolerability, and feasibility of delivering combination chemotherapy with subsequent radiation therapy to women with high-risk endometrial cancer and to evaluate the long-term bowel toxicity of this regimen. METHODS: The trial was approved by the Dana Farber/Partners Cancer Care (DFPCC) Institutional Review Board (IRB). Patients with stage 3 or stage 4 endometrial cancer or patients with high-risk histology and any stage disease were prospectively entered. Complete surgical staging and a normal gated blood pool scan were required prior to entry. Patients were treated with three cycles of paclitaxel (160 mg/m(2) ), doxorubicin (45 mg/m(2)) and carboplatin (AUC 5) (TAC) all on day 1 of a 21-day schedule as an outpatient with G-CSF support. At the conclusion of chemotherapy, patients received radiation therapy (4500 cGy to the whole pelvis) commencing within 35 days of the last cycle of chemotherapy. Paraaortic radiation and/or vaginal brachytherapy were allowed at the discretion of the treating radiation oncologist. RESULTS: Twenty patients were entered onto the trial from November 2000 through February 2003. Eighteen patients successfully completed the trial, and two patients came off trial during chemotherapy (both later completed planned radiation therapy). Patients were initially stage 1 (n = 3), stage 3 (n = 14), and stage 4 (n = 3). Papillary serous was the dominant histology with 13 patients. Chemotherapy was given on average within 32 days of surgery (range 11-63 days) and radiation was initiated on average within 14 weeks of surgery (range 10-18 weeks). Chemotherapy was well tolerated, with 57 total cycles delivered of a planned 60 cycles. Two patients required dose modification in two cycles (two patients in cycle 3 secondary to hematologic toxicity). No grade 3 or grade 4 neurotoxicity was reported. There were six episodes of grade 3 short-term toxicity with radiation therapy reported in a single patient. Late radiotherapy toxicity included bowel obstruction requiring laparotomy in two patients and grade 3 constipation in one patient. Late radiation toxicity data are still being collected as follow-up continues. CONCLUSIONS: The TAC chemotherapy regimen is well tolerated and three cycles were delivered successfully with G-CSF support without evidence of the neurotoxicity or cardiac toxicity reported with the cisplatin containing TAP regimen. Standard radiation was deliverable following TAC therapy without excessive toxicity. Further study of this regimen with subsequent radiation therapy is warranted in patients at risk for systemic and regional recurrence of their malignancy.     

高危子宫内膜癌卡铂和紫杉醇联合化疗后静脉血栓发生情况分析#br#

Objective?To analyze the incidence and influencing factors of venous thrombosis after carboplatin and paclitaxel combined chemotherapy in high-risk endometrial carcinoma. Methods?A total of 98 patients with high-risk endometrial cancer who were treated in our hospital were selected and treated with carboplatin+paclitaxel (TC) chemotherapy. According to the occurrence of venous thrombosis after chemotherapy, they were divided into the occurrence group and the non-occurrence group, and the influence of chemotherapy was analyzed. Logistic multivariate regression analysis was used to summarize the related factors affecting the occurrence of venous thrombosis. Results?The incidence of venous thrombosis in patients was 17.35%. The most common site of thrombosis was the subclavian vein (7 cases, 41.18%). FIGO stageⅢ, D-dimer≥0.5 mg/L before chemotherapy, traditional puncture, and cubital puncture were independent risk factors for venous thrombosis after TC chemotherapy for high-risk endometrial cancer, and puncture of the precious vein was a protective factor (P<0.05). Conclusion?Patients with high-risk endometrial cancer have a higher risk of venous thrombosis in upper extremity veins after chemotherapy with TC regimen, and the influencing factors include clinical stage, coagulation function status, puncture method, puncture site, and blood vessel selection.     

Phase I clinical trial of weekly paclitaxel, weekly carboplatin, and concurrent radiotherapy for primary cervical cancer

OBJECTIVES: Standard primary treatment for locally advanced cervix cancer is radiation (RT) with concomitant platinum-based chemotherapy (CT). Incomplete local control and the appearance of distant disease herald poor survival and warrant evaluation of new primary strategies. Paclitaxel and carboplatin are active agents in recurrent cervical carcinoma, have potent, synergistic in vitro radiosensitization, and are cytotoxic in weekly schedules. This study was done to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly paclitaxel/carboplatin chemoradiotherapy in locally advanced cervix cancer. METHODS: Women with primary, previously untreated, squamous cell or adenocarcinoma of the cervix, FIGO stage IB(2) to IVA, negative para-aortic lymph nodes, adequate organ function and performance status were eligible. Pelvic RT (45 Gy over 5 weeks--180 cGy/day, four-field) was followed by two brachytherapy applications (Point A low dose rate (LDR): 90 Gy, high dose rate (HDR): 75 Gy). Concurrent weekly CT was paclitaxel 50 mg/m(2) and carboplatin, starting at AUC 1.5 and escalating in three-patient cohorts by AUC 0.5 (Max AUC 3.5). Dose escalation followed a 4-week observation period for toxicity. A grade III-IV toxicity prompted up to three additional patients per dose level. A second event defined DLT. CT was administered concurrently throughout brachytherapy. RESULTS: Fifteen patients were enrolled and treated over four dose levels until DLT was reached. Median age was 44 years (range, 23-70); stages: IB2: 1, IIB: 9, IIIA: 1, IIIB: 4. Median RT treatment time was 61 days (range, 55-79). Fourteen patients received brachytherapy (LDR: 8, HDR: 6), and one received external RT only due to cervical stenosis. The median number of weekly CT cycles was seven (range, 6-7). One CT dose was dropped in one patient for a grade II thrombocytopenia. One grade III ANC was observed at dose level II (AUC 2.0) but not seen in three additional patients. At dose level IV (AUC 3.0), two grade III-IV ANC toxicities were observed in two patients (DLT). Nine patients had grade II anemia. One patient had grade III anemia. Grade III/IV nonhematologic toxicity was rare (1/15 GI-nausea/vomiting, 1/15 pneumonia, 1/15 hypokalemia). The MTD of carboplatin is AUC 2.5 with paclitaxel 50 mg/m(2). Median follow-up is 17 months; three patients have recurred and two have died. The estimated 2-year PFS and OS are 80% and 86%. CONCLUSIONS: Weekly paclitaxel and carboplatin chemoradiation is feasible and active. The MTD for a phase II trial is 50 mg/m(2) and AUC 2.5, respectively.     

Serous carcinoma of the uterus treated with cisplatin, doxorubicin and etoposide

Chambers JT, Rutherford TJ, Baker L, Kohorn EI, Schwartz PE, Carcangiu ML, Chambers SK. Serous carcinoma of the uterus treated with cisplatin, doxorubicin and etoposide. Int J Gynecol Cancer 1998; 8 : 193–196.
Twenty-one patients with serous endometrial cancer were treated on a protocol of cisplatin, doxorubicin, and etoposide. Seven patients had stage I and two stage II disease, six patients had stage III, and six stage IV disease. All patients underwent surgery prior to receiving chemotherapy. All patients treated in an adjuvant fashion were clinically free of disease with a median follow-up of 28 months. However, only eight of the 12 patients with advanced disease were clinically free of disease with a median disease-free interval of 11 months. Furthermore, four patients have died of disease. Overall, seven of 21 (33%) patients developed neutropenic fever. The disease-free interval in the patients with advanced disease was poor and the protocol was only moderately well tolerated.     

Dactinomycin in the treatment of recurrent or persistent endometrial carcinoma: A Phase II study of the Gynecologic Oncology Group

OBJECTIVES: The search for effective systemic chemotherapy for endometrial cancer is ongoing. Complete responses to current drugs or regimens are infrequent, and overall survival for patients with disease not amenable to surgery or radiation therapy is poor. Dactinomycin has proven activity against a wide variety of solid tumors but has not been tested against endometrial cancer. Using pharmacokinetic data supporting an intermittent, single-dose schedule, this Phase II Gynecologic Oncology Group study was conducted to determine the antitumor activity and toxicity of dactinomycin in patients with persistent or recurrent endometrial adenocarcinoma. METHODS: Eligibility was limited to patients with measurable disease, adequate renal, hepatic, and bone marrow function, and no more than one prior chemotherapy regimen. Treatment consisted of 2 mg/m(2) slow intravenous push of dactinomycin over 15 min with courses repeated every 4 weeks. RESULTS: A total of 27 patients were entered in this study between April 1996 and September 1996; all were evaluable for toxicity and 25 were evaluable for response. Overall, 12/25 (48%) patients had received prior radiation therapy and all had received prior chemotherapy. Sites of measurable disease were pelvis (9 patients) and distant (16 patients). There was 1 complete response and 2 partial responses for an overall objective response rate of 12%. Aside from emesis (grade 3, 2 patients; grade 4, 2 patients) significant nonhematologic toxicity was rare. The most common toxicity was neutropenia (grade 3, 2 patients; grade 4, 10 patients). CONCLUSION: Toxicity was deemed acceptable but the limited effectiveness of dactinomycin precludes further clinical development in this patient population.     

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer

Objective

The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC).

Methods

Patients with stage IC-IV OC were randomized to either GC (gemcitabine 1000 mg/m², days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m² plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m² every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint.

Results

Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P = .199). Despite high censoring rates (> 52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P = .013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR = 1.22; 95% CI = 0.99-1.52; P = .067).

Conclusions

GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.     

Intraperitoneal cisplatin and paclitaxel versus intravenous carboplatin and paclitaxel chemotherapy for Stage III ovarian cancer: a cost-effectiveness analysis

OBJECTIVE: To evaluate the cost-effectiveness of intraperitoneal cisplatin and paclitaxel chemotherapy as front-line treatment for patients with Stage III epithelial ovarian cancer following optimal primary cytoreductive surgery. METHODS: Based on Gynecologic Oncology Group protocols #172 and #158, a decision analysis model was created to compare two treatment strategies for patients with optimal residual disease Stage III ovarian cancer: (1) inpatient intravenous paclitaxel (24 h) and intraperitoneal cisplatin plus outpatient intraperitoneal paclitaxel chemotherapy (IP/IV), and (2) outpatient intravenous paclitaxel (3 h) and carboplatin chemotherapy (IV/IV). The cost-effectiveness of each strategy was evaluated from the perspective of society. RESULTS: Cost-effectiveness analysis revealed that the strategy of IP/IV chemotherapy had an overall cost per patient of $39,861 and effectiveness of 5.16 QALYs compared to $18,822 and 4.59 QALYs for IV/IV chemotherapy. The IP/IV chemotherapy strategy was associated with an additional 0.56 QALYs at an incremental cost of $21,039. The incremental C/E ratio for IP/IV chemotherapy was $37,454/QALY. Inpatient treatment accounted for 43.2% of the cost of IP/IV chemotherapy. Sensitivity analysis testing confirmed the robustness of the model. CONCLUSIONS: In this model, IP/IV chemotherapy was associated with a modest extension in quality-adjusted survival time but was also more costly than IV/IV chemotherapy. On balance, the IP/IV strategy can be considered a good healthcare value. However, these data also suggest that efforts to reduce the cost of IP/IV chemotherapy, such as through development of an ambulatory regimen with equivalent therapeutic efficacy but an improved toxicity profile, would improve the overall value of this adjuvant treatment program.     

Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer

ObjectiveTo analyze the response to dose-dense chemotherapy of weekly paclitaxel and 3-weekly carboplatin in recurrent ovarian cancer, and to report results of literature review.Materials and methodsPatients accepted weekly paclitaxel 80 mg/m² on day 1, 8, 15 and carboplatin on day1 at area under curve (AUC) 6 every 21 days were reviewed for the response rate, progression-free survival, overall survival, and toxicity during January 2012 to April 2016 in Chang Gung Memorial Hospital at Linkou, Taiwan.ResultsSixteen patients with recurrent ovarian cancer, including 1 platinum-resistant, 7 partially platinum-sensitive, and 8 platinum-sensitive, accepted a median of 6 cycles of chemotherapy (range 3–10). The overall response rate (ORR) and complete response (CR) rate were 93.8%, and 62.5%, respectively. The median PFS of all patients were 10.9 months (range 4.3–40.5). The median time to response (TTR) was 29.0 days (range 19.6–38.4). The median disease-free survival (DFS) after CR was 5.6 months (range 1.2–34.2). Grade 3 at least toxicity included anemia (6.3%), neutropenia (50%), and thrombocytopenia (18.8%).Twenty-nine articles on phase I, II, III, or retrospective studies of dose-dense chemotherapy with weekly paclitaxel were reviewed.ConclusionThis is the first report using Japanese Gynecologic Oncology Group 3016 protocol, weekly paclitaxel and 3-weely carboplatin, on recurrent ovarian cancer. The current study showed high ORR and CR with tolerable toxicities. Our study suggested dose-dense chemotherapy with paclitaxel, especially combining carboplatin created high efficacy probably by anti-angiogenesis. However, consolidation or maintenance therapy is needed to prolong DFS.     

奥先达联合紫杉醇或卡铂联合紫杉醇治疗卵巢上皮癌的多中心随机对照初步研究

目的:比较奥先达联合紫杉醇或卡铂联合紫杉醇治疗卵巢上皮癌的疗效和安全性。方法:2010年8月到2012年4月入组了Ⅱ期以上行满意的肿瘤细胞减灭术的卵巢上皮癌患者182例。术后将患者随机分为奥先达组(92例)和卡铂组(90例),分别采用奥先达或卡铂联合紫杉醇方案治疗。奥先达剂量80mg/m2,或卡铂AUC=5,第2天给药;紫杉醇135mg/m2,第1天给药,21天1个疗程。研究两组患者治疗的近期疗效和药物安全性。结果:奥先达组、卡铂组患者完成的治疗周期数分别为5.02±1.63和5.39±1.30。奥先达组化疗第3、6个周期结束时,CA125下降到正常水平的比率分别为80.00%和86.36%,卡铂组为72.88%和86.00%,两组比较均无统计学差异;治疗后两组患者的KPS、QOL评分均明显改善,但两组间比较无统计学差异。奥先达组恶心呕吐发生率为3.26%,卡铂组为5.56%;奥先达组和卡铂的Ⅲ～Ⅳ度白细胞减少的发生率分别为10.87%和23.33%,两组差异有统计学意义(P<0.05);两组的其他毒性反应发生率无统计学差异(P>0.05)。结论:奥先达联合紫杉醇治疗卵巢上皮癌近期疗效与卡铂方案相似,但其毒副反应较轻,患者耐受性好。     

内镜在子宫内膜癌诊治中的应用

宫腔镜下子宫内膜活检提高了子宫内膜癌诊断的准确率,可能导致癌细胞的逆行性扩散,但对预后无明显影响。宫腔镜下癌灶切除术联合孕激素治疗为有生育要求的早期患者带来新的治疗方法。腹腔镜下全面分期手术应用于早期子宫内膜癌的治疗是安全可行的,且具有术中出血及术后疼痛少,住院时间短,恢复快,术后感染、盆腹腔粘连及淋巴囊肿形成少,生活质量高等优点,对患者预后无不良影响。术中举宫器的使用尚有争议。     

Phase III comparison of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) vs. doxorubicin and cisplatin (AC) in women with advanced primary or recurrent metastatic carcinoma of the uterine endometrium

OBJECTIVES: The North Central Cancer Treatment Group Phase III trial compared efficacy of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with doxorubicin plus cisplatin (AC) for patients with advanced endometrial cancer. METHODS: Twenty-eight patients were randomly assigned to treatment with doxorubicin 30 mg/m2 + cisplatin 70 mg/m2 IV q 4 weeks vs. methotrexate 30 mg/m2 IV days 1, 15, and 22, vinblastine 3 mg/m2 IV days 2, 15, and 22, doxorubicin 30 mg/m2 IV day 2, and cisplatin 70 mg/m2 day 2 of a 4-week cycle. The trial was terminated prematurely due to slow accrual. RESULTS: Prior to early closure of the protocol, there were 15 patients entered on the AC regimen and 13 to the MVAC regimen. There were 3 PR (20%) for AC and 3 CR (23%) and 3 PR (23%) for MVAC. Median PFS was 4.0 months for AC and 6.9 months for MVAC. Median survival was 13.2 months for AC and 16.8 months for MVAC. Toxicity was substantial for MVAC vs. AC with severe leukopenia seen in 69% vs. 33% of patients and severe thrombocytopenia 23% vs. 0%. No treatment-related deaths were seen. DISCUSSION: MVAC and AC are active regimens in the treatment of advanced/recurrent or metastatic endometrial cancer. The premature closure of the protocol resulted in small patient numbers that left the protocol underpowered to address the primary objective of demonstrating improved CR rate for MVAC over AC. MVAC has substantial toxicity compared to AC and is not substantially superior to AC. MVAC cannot be considered as a standard for treatment in this patient population.