Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study

Forty-nine evaluable patients with advanced or recurrent endometrial carcinoma who were no longer controllable with surgery, radiotherapy, and hormonal therapy and who had not received prior chemotherapy were treated with cisplatin 50 mg/m2 intravenously every 3 weeks. Two complete responses (4%) and eight partial responses (16%) were observed among the 49 patients. Twenty-two (45%) exhibited stable disease for at least 2 months, while 17 patients (35%) progressed less than 2 months after initiating chemotherapy. Adverse effects included mild leukopenia (31%), nausea and vomiting (72%), and mild azotemia (51%). Only 2 patients experienced life-threatening toxicity; one related to renal failure and the other to sepsis and shock. Cisplatin thus has definite activity when given at the dose and schedule tested to patients with endometrial carcinoma who have not received prior chemotherapy.     

Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVE: To estimate the antitumor activity of paclitaxel (Taxol) in patients with persistent or recurrent endometrial carcinoma who have failed prior chemotherapy. To determine the nature and degree of toxicity of paclitaxel in this group of patients. METHODS: Paclitaxel was administered as a 3-h infusion at an initial dose of 200 mg/m(2) every 21 days or 175 mg/m(2) for patients with prior pelvic radiation therapy. Dose modifications were based on nadir toxicity, both hematologic and nonhematologic, and were accomplished by dose level adjustments. The dose levels were 200, 175, 135, and 110 mg/m(2). Patients were evaluable for response after receiving one dose of paclitaxel and living 3 weeks. They were evaluable for toxicity after receiving any paclitaxel. RESULTS: Of the 44 patients evaluable for response, three patients (6.8%) achieved a complete response and nine patients (20.5%) had a partial response for an overall response rate of 27.3%. The 95% confidence interval for the true response rate was 15-42.8%. The median number of courses of paclitaxel to response was 2 (range: 1-4) and the median response duration was 4.2 months. The median overall survival was 10.3 months. Of 48 patients evaluable for toxicity, 28 experienced at least one episode of grade 3 or 4 neutropenia, with one treatment-related death. There were four patients who developed grade 3 neurotoxicity in this group of previously treated patients, most of whom had received cisplatin-containing chemotherapy. There was virtually no cardiac toxicity and only 3 of 48 patients experienced grade 3 or 4 gastrointestinal symptoms. CONCLUSIONS: Paclitaxel is an active agent in the treatment of endometrial cancer in patients who have had prior chemotherapy.     

A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study

BACKGROUND: Some endometrial cancers are hormonally dependent. A principal source of circulating estrogen is conversion of adrenal androstenedione by aromatase. Anastrozole (Arimidex) is an oral nonsteroidal aromatase inhibitor which is active in recurrent breast cancer. This Phase II study was undertaken to evaluate anastrozole in recurrent endometrial carcinoma. METHODS: Patients with advanced or recurrent endometrial cancer not curable with either surgery or radiation therapy and with measurable disease, a GOG (Zubrod) performance status of < or = 2, no more than one prior hormonal therapy regimen, and no prior chemotherapy were eligible. Anastrozole was administered at a dose of 1 mg/day orally for at least 28 days. RESULTS: Twenty-three patients were entered on this trial. On central pathology review, 9 of them had grade 2 and 14 had grade 3 tumors. One to 24 courses (median: 1) of therapy were administered. Two partial responses were noted (9%; 90% confidence interval 3 to 23%). Two additional patients had short-term stable disease. With the exception of 1 case of venous thrombosis, the toxicity profile was mild. Median durations of progression-free survival and overall survival are 1 and 6 months, respectively. CONCLUSIONS: Anastrozole has minimal activity in an unselected population of patients with recurrent endometrial cancer.     

Neoadjuvant therapy for advanced squamous cell carcinoma of the cervix: cisplatin followed by radiation therapy--a pilot study of the Gynecologic Oncology Group

Eleven patients with untreated advanced squamous cell carcinoma of the cervix (FIGO Stage IIIB and IVA, or positive paraaortic nodes) were treated with cisplatin 50 mg/m2 every 3 weeks for six courses prior to irradiation therapy (RT). Six patients completed six courses of cisplatin prior to RT with one complete and two partial responses (PR). Five other patients did not complete cisplatin therapy; two progressed after two and three courses, one had a PR after three courses and refused further therapy, one refused treatment after two courses and one elected to begin RT after one course. Two patients had reversible nephrotoxicity. No other major toxicity was noted. Six patients had stem cell assay prior to treatment and assay results were predictive of cisplatin response in five. Only one patient remains alive at 44+ months. Cisplatin chemotherapy prior to irradiation therapy is feasible and without substantial toxicity but is unlikely to be of benefit in patients with advanced cervical cancer.     

Phase II study of oxaliplatin as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVE: A phase II study was conducted to determine the efficacy of oxaliplatin therapy in patients with advanced or recurrent endometrial cancer who had received one prior platinum therapy. METHODS: Eligible patients were to have measurable disease and one prior chemotherapy regimen which could include cisplatin or carboplatin. Oxaliplatin 130 mg/m2 was administered intravenously over 2 h. This treatment was repeated every 21 days until progression of disease or adverse effects prohibited further therapy. RESULTS: Fifty-four patients were entered on study, of which 52 were eligible and 50 had had prior platinum therapy. The overall response rate was 13.5%, with three patients (5.8%) achieving a complete response and four patients (7.7%) achieving a partial response. Median duration of response was 10.9+ (range: 4.1-50.3+) months. Stable disease was reported in 15 (28.8%) patients, with an associated median duration of 5.4 (range: 2.2-19.6) months. Drug-related toxicities consisted of anemia, nausea and vomiting, and neurotoxicity. CONCLUSIONS: Oxaliplatin at the dose and schedule employed has limited activity in patients with advanced or recurrent endometrial carcinoma who have had previous platinum therapy.     

Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the objective response rate and toxicity associated with alternating megestrol acetate (MA) and tamoxifen citrate (T) in women with endometrial carcinoma. METHODS: Consenting patients with measurable recurrent or advanced endometrial carcinoma were eligible if they had not received prior cytotoxic or hormonal treatment. MA 80 mg BID x 3 weeks alternating with T 20 mg BID x 3 weeks orally was given. RESULTS: Of 61 patients entered, 56 eligible patients were evaluable for toxicity and response. Fifteen patients responded (12 complete, 3 partial) for an overall response rate of 27% (90% Confidence Interval: 17-38%). In 8 of 15 (53%) responders, response duration exceeded 20 months. The response rate was 38% in patients with histologic grade 1 tumors (n = 16), 24% in those with grade 2 disease (n = 17), and 22% among patients with grade 3 disease (n = 23). Women less than or equal to 60 years (n = 16) appear to have a better response rate than those >60 years (n = 40), 44% versus 20%. The response rate in patients with extra pelvic disease (n = 42) was 31% as compared to 14% in those with strictly pelvic and/or vaginal disease (n = 14). The median progression-free survival (PFS) was 2.7 months and median overall survival was 14.0 months. Two patients experienced a grade 4 thromboembolic event. Additional toxicities included one of each grade 3 gastrointestinal, grade 3 neurologic, and grade 3 genitourinary. CONCLUSION: A regimen of alternating megestrol acetate and tamoxifen is active in treating endometrial cancer and may result in a prolonged complete response (CR) in some patients.     

Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: The objectives of this study were to estimate the clinical response rate and toxicity of daily tamoxifen combined with intermittent weekly medroxyprogesterone acetate (MPA). METHODS: This study reports the results of 61 patients with measurable advanced or recurrent endometrial carcinoma enrolled on this study to be treated with tamoxifen 40 mg p.o. daily plus alternating weekly cycles of MPA 200 mg p.o. daily. RESULTS: One patient was excluded and two patients did not receive study treatment. The percent of patients responding (6 complete and 13 partial) was 33% (95% confidence interval [CI]: 21-46%) among 58 eligible patients who received therapy. Median progression-free survival (PFS) was 3 months and median overall survival (OS) was 13 months. CONCLUSION: The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Further investigation of this combination is appropriate.     

Impact of body mass index on treatment outcomes in endometrial cancer patients receiving doxorubicin and cisplatin: a Gynecologic Oncology Group study

OBJECTIVES: To evaluate the association between body mass index (BMI) and outcomes in women with advanced or recurrent endometrial cancer treated with doxorubicin/cisplatin. METHODS: Data from patients treated on five Gynecologic Oncology Group trials were retrospectively reviewed. BMI was categorized as normal (< 25), overweight (> or = 25 to < 30), obese (> or = 30 to < 40), and morbidly obese (> or = 40). BMI was analyzed for associations with demographics, clinical characteristics, toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 949 patients, 533 (56%) had recurrent disease, 227 (23.9%) had Stage IV disease, and 189 (19.9%) had Stage III disease. Mean BMI was 29.8; 29.6%, 27.0%, 33.2% and 10.2% of patients, respectively, were categorized as normal, overweight, obese, and morbidly obese. The mean BMI was significantly different when compared by age group (p<0.001), stage (p=0.047), histologic type (p=0.024), and tumor grade (p=0.014). Older patients and those with clear cell, poorly differentiated tumors, or stage IV disease had a lower BMI. No significant associations between PFS and BMI were detected. Increasing BMI was significantly associated with an increased risk of death in Stage III/IV (HR=1.86, 95% CI 1.16-2.99 for BMI > or = 40 vs. BMI < 25) but not recurrent patients. Higher BMI patients had less Grade 3/4 toxicities than normal patients (p<0.001) but this difference disappeared for obese patients receiving > or = 95% of the calculated dose. CONCLUSIONS: BMI was not predictive of PFS in this endometrial cancer population although morbidly obese patients had decreased OS in primary Stage III/IV patients. Toxicities decreased with increasing BMI, perhaps secondary to capped dosing.     

Doxorubicin-cisplatin-vinblastine combination chemotherapy of advanced endometrial carcinoma: a Southwest Oncology Group Study

A combination of doxorubicin (30 mg/m2 iv), cisplatin (50 mg/m2 iv), and vinblastine (5 mg/m2 iv) repeated every 3-4 weeks was used to treat 55 patients with advanced stage III or IV or recurrent disease. Of the 42 fully evaluable patients, there were 3 complete responders (7%) and 10 partial responders (24%). Responses were of short duration (median of 8 months, range 3-15 months) and the median survival of all evaluable patients was only 10 months from the start of therapy. Leukopenia was the major toxicity and was at least moderate in two-thirds of patients. We conclude that the addition of cisplatin and vinblastine to doxorubicin does not improve the clinical utility of doxorubicin in patients with advanced endometrial cancer.     

A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVE: A phase II study was conducted to determine the efficacy of single agent flavopiridol therapy in patients with recurrent or persistent endometrial adenocarcinoma refractory to established treatments. METHODS: Eligible patients with measurable disease who failed primary therapy including one cytotoxic regimen were eligible for the trial. They were treated with single agent flavopiridol (50 mg/m(2)/day, IV bolus days 1, 2, 3). Treatment was repeated every 21 days with dose adjustments made for toxicity. Patients were treated until progression of disease or adverse side effects precluded further therapy. RESULTS: A total of 26 patients were enrolled in the study of whom, 23 patients were eligible. There were no objective responses. Five patients had stable disease (22%), 15 (65%) had increasing disease, and response could not be assessed in 3 (13%). The most frequent side effects included anemia, neutropenia, and diarrhea, all of which appeared manageable. CONCLUSION: Flavopiridol as a single agent in the above dosing schedule appears to have minimal activity as second-line chemotherapy of endometrial adenocarcinoma.     

Phase II study of fulvestrant in recurrent/metastatic endometrial carcinoma: a Gynecologic Oncology Group study

Objectives.

To evaluate the activity and toxicity of fulvestrant in advanced, recurrent, or persistent endometrial carcinoma.

Methods.

Eligible patients with advanced, recurrent or persistent endometrial carcinoma not amenable to curative therapy were treated with fulvestrant at a dose of 250 mg by IM injection every 4 weeks for at least 8 weeks. Therapy was continued until evidence of progressive disease, or adverse effects prohibited further therapy. Response was assessed in patients with at least one target lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Immunohistochemical analysis of tumor tissue (histology or cytology) for estrogen and progesterone receptors was required from the metastatic or recurrent site.

Results.

Sixty-seven patients were enrolled in this study. Upon review, 14 patients were excluded. In the 22 estrogen receptor (ER) negative patients, no patients demonstrated either a complete or partial response, and 4 (18%) demonstrated stable disease (as best response). In the 31 ER positive patients, 1 (3%), 4 (13%) and 9 (29%) patients demonstrated a complete, partial response, and stable disease (as best response), respectively. The median progression free survival and overall survival in the ER negative patients were 2 and 3 months and in the ER positive patients 10 and 26 months. Treatment was well tolerated, and no patient discontinued therapy due to toxicity.

Conclusions.

Fulvestrant has minimal activity in advanced, recurrent, or persistent endometrial carcinoma.     

Phase II study of mitomycin,doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study

OBJECTIVE: Because of preliminary observations favoring the use of mitomycin, doxorubicin, and cisplatin (MAP) chemotherapy in leiomyosarcomas, the Gynecologic Oncology Group (GOG) decided to conduct a phase II clinical trial of this combination regimen in patients with advanced disease. METHODS: Patients with histologically confirmed uterine leiomyosarcoma who had not previously received cytotoxic drugs were considered for participation in this clinical trial. Eligible patients had measurable disease, GOG performance status 0-2, and adequate bone marrow, renal, and hepatic function according to standard criteria. Mitomycin 8 mg/m(2) and doxorubicin 40 mg/m(2) were each given by iv injection followed immediately by cisplatin 60 mg/m(2) in 1 liter of 0.45% saline plus mannitol 25 g. Patients who remained free from tumor progression or intolerable toxicity received at least three, to a maximum of six, cycles of MAP. RESULTS: Forty-one patients were registered, of whom 4 were determined ineligible (wrong cell type, 2; wrong site of origin, 1; inadequate pathology material, 1). Thirty-five of the 37 were evaluable for response after receiving from one to six (median three) cycles of MAP. Three patients (9%) achieved a complete response and 5 (14%) exhibited a partial response. The most common adverse effects were leukopenia (33 patients) and thrombocytopenia (30 patients). Pulmonary toxicity was seen in 10 patients and was a factor in the clinical deterioration and death of 2. CONCLUSION: MAP is active against advanced uterine leiomyosarcomas, but not remarkably so. Despite its low therapeutic index, this novel, possibly interactive, combination may serve as a forerunner to regimens that more efficiently exploit the enhancement of sarcoma cell kill under hypoxic conditions.