Phase II trial of capecitabine in recurrent squamous cell carcinoma of the cervix

PURPOSE: To determine the efficacy and safety of capecitabine in women with inoperable, recurrent, or metastatic squamous cell cervical cancer. PATIENTS AND METHODS: In a phase II IRB approved trial, capecitabine was given at a dosage of 2000 mg/m2/day orally in a divided dose daily for 14 days followed by a 7-day rest period. A standard dose modification scheme was used with one allowed dose reduction or dose escalation. National Cancer Institute criteria for progression, response, and toxicity were utilized. Quality of life data were obtained using the Memorial Symptom Assessment Scale and Functional Assessment for Cancer Therapy, which included a subscale for cervical cancer. RESULTS: Twenty of 23 enrolled patients were evaluable for response. Stable disease was noted in 5 patients, with a median duration of response of 3.5 months (range, 3-6.5 months). No partial or complete responses were seen. Common grade 3 toxicities were fatigue (30.4%); abdominal pain, constipation, hand-foot syndrome, nausea, and vomiting (8.7% each); as well as dyspnea, headache, and coagulopathy (4.3% each). There were no grade 4 toxicities. All patients with previous exposure to infused 5-FU had evidence of progression. No statistically significant changes in quality of life were noted from baseline to post-cycle 2. CONCLUSION: Single-agent capecitabine in patients with recurrent cervical cancer resulted in no objective responses. Although capecitabine is a well-tolerated regimen, as a single agent, it offers minimal benefit in a poor-prognosis cervical cancer population.     

Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

Purpose

The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix.

Patients and methods

Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤ 2. Treatment consisted of cetuximab 400 mg/m² initial dose followed by 250 mg/m² weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2-stage group sequential design.

Results

Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n = 25, 71.4%) or 2 (n = 10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n = 5), GI (n = 4), anemia (n = 2), constitutional (n = 3), infection (n = 2), vascular (n = 2), pain (n = 2), and pulmonary, neurological, vomiting and metabolic (n = 1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology.

Conclusion

Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology.     

A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix

OBJECTIVE: The aim of this study was to determine the response rate and toxicity of cis-platinum and gemcitabine in advanced, recurrent, or persistent squamous cell carcinoma of the cervix. METHODS: From July 1997 to January 1999, we conducted a Phase II trial in patients with advanced, persistent, or recurrent carcinoma of the cervix. The schedule employed 1250 mg/m(2) of gemcitabine on days 1 and 8 and 50 mg/m(2) of cis-platinum on day 1 in a 21-day cycle. Eligibility criteria were a GOG performance status of 0-2, adequate bone marrow reserve, serum creatinine less than 1.8 mg%, and a lesion which could be measured in two dimensions. None of the patients had received prior chemotherapy other than radiation sensitizers. Standard GOG toxicity and response criteria were used. RESULTS: Nineteen patients were enrolled into the trial. Two patients were inevaluable because of inadequate trial of drug. Seventeen patients were evaluable for response and toxicity. The median age of the patients was 47 years (range 24-72). The median number of cycles delivered was 5 (range 2-8). The incidence of grade 4 neutropenia and anemia was 2.4 and 1.2%, respectively. Two patients developed a single episode of grade 3 gastrointestinal toxicity. The overall response rate was 41% (7/17). There was 1 complete response of 14 months duration and 6 partial responses. Among those patients not previously irradiated, the response rate was 57% (4/7). Among the radiated patients, the response rate was 30% (3/10) with all responses occurring in the radiation field. CONCLUSION: This combination of cis-platinum and gemcitabine is a well-tolerated regimen which exhibits high activity in advanced, recurrent, or persistent squamous cell cervical cancer.     

Phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervical carcinoma

OBJECTIVE: This trial investigated the safety and efficacy of paclitaxel and topotecan combination chemotherapy for patients with advanced cervical cancer (ACC). METHODS: Patients with recurrent, persistent, or metastatic ACC and an ECOG performance status < or =2 were treated with 175 mg/m(2) paclitaxel on Day 1 and 1 mg/m(2) topotecan on Days 1-5 of a 21-day cycle with G-CSF support and the standard pretreatment regimen for paclitaxel. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Fifteen patients were enrolled, and 86 cycles of therapy (median, 5; range, 1-14) were administered. Grade 3/4 toxicities included anemia (47%), leukopenia (27%), neurotoxicity (13%), thrombocytopenia (13%), and diarrhea (13%). Among 13 evaluable patients, 7 (54%) responded (1 complete and 6 partial; 95% confidence interval = 29.2%, 76.8%). Three (23%) patients experienced stable disease. Progression-free and overall survival were 3.77 and 8.62 months, respectively. CONCLUSION: The combination of paclitaxel/topotecan was generally well tolerated and active in the relapsed, recurrent, or metastatic ACC setting, with response rates comparable with those of other current ACC systemic therapies.     

Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group Study

OBJECTIVE: The Gynecologic Oncology Group (GOG) has studied a number of drugs to determine their activity in patients with previously treated squamous and nonsquamous cancer arising in the uterine cervix. A Phase II study with intravenous vinorelbine was initiated for this purpose in patients with Stage IVB, recurrent, or persistent nonsquamous carcinomas who had received one prior chemotherapy or were not eligible for other studies. METHODS: Eligible patients had to have measurable disease, GOG performance status of 0-2 and adequate bone marrow, liver, and renal function. The treatment consisted of vinorelbine 30 mg/m(2) on days 1 and 8, repeated every 21 days. Tumor measurements and toxicities were recorded every treatment cycle. RESULTS: Thirty patients were enrolled with 28 patients deemed eligible and evaluable. Only two confirmed partial responses (7.1%) were noted. Neutropenia was the most common toxicity with 9 of 28 (32%) experiencing either grade 3 or 4 changes. Anemia was severe in seven. Neuropathy was more than mild in three patients. Severe events, such as fatigue, hypertension, or pulmonary changes attributed to drug administration, occurred only in one or two instances. CONCLUSION: With the dose schedule and assessment criteria employed, vinorelbine had only minimal activity in nonsquamous cancer of the cervix.     

Evaluation of tamoxifen in persistent or recurrent nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

This study was undertaken to estimate the antitumor activity of tamoxifen in patients with persistent or recurrent nonsquamous cell carcinoma of the cervix. Furthermore, the nature and degree of adverse effects from tamoxifen in this cohort of individuals was examined. Tamoxifen citrate was to be administered at a dose of 10 mg per orally twice a day until disease progression or unacceptable side effects prevented further therapy. A total of 34 patients (median age: 49 years) were registered to this trial; two were declared ineligible. Thirty-two patients were evaluable for adverse effects and 27 were evaluable for response. There were only six grades 3 and 4 adverse effects reported: leukopenia (in one patient), anemia (in two), emesis (in one), gastrointestinal distress (in one), and neuropathy (in one). The objective response rate was 11.1%, with one complete and two partial responses. In conclusion, tamoxifen appears to have minimal activity in nonsquamous cell carcinoma of the cervix.     

Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: a gynecologic oncology group study

PURPOSE: To evaluate the anti-tumor activity and adverse events of capecitabine in advanced, persistent or recurrent squamous cell carcinoma of the cervix, and to explore biomarkers with the potential to predict capecitabine response and toxicity. EXPERIMENTAL DESIGN: Eligible, consenting patients were treated with a starting dose of 2500 mg/m(2)/day or 1800 mg/m(2)/day (divided into two doses given every 12 h) for 14 days of each 21-day cycle. Prior chemotherapy was allowed only in the context of radiation "sensitization". Genotyping in the 5' and 3' ends of thymidylate synthase (TS) was performed in DNA from pretreatment blood. Relative gene expression of TS, dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) was quantified in RNA extracted from paraffin-embedded tumor. RESULTS: All patients had prior radiotherapy and 22 received a radiation sensitizer. A partial response was observed in 4 of 26 (15%) evaluable patients. An additional 35% of patients achieved stable disease while 42% experienced increasing disease. The most common serious non-hematological toxicities were gastrointestinal and dermatologic. Exploratory analyses suggested that: a germline polymorphism in the 3' or the 5' end of TS was not associated with TS gene expression, relative tumor expression of TS, DPD and TP were not correlated, and relative tumor expression of TP may predict severe anemia. CONCLUSIONS: Based on the modest response rate, this trial was closed without a second stage of accrual; single agent capecitabine was not selected for further study in advanced persistent or recurrent squamous cell carcinoma of the cervix previously treated with radiation or chemoradiation.     

Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study

OBJECTIVES: Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1-cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma. METHODS: An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50-65 microg/m(2)) as a 1-h infusion followed by cisplatin (50 mg/m(2)). The combined treatment was administered every 21 days. RESULTS: Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 microg/m(2) and 50% received bryostatin at 65 microg/m(2). Seventy-one percent completed two cycles of treatment. The most common grade II-III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses. CONCLUSIONS: Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials.     

Phase II trial of cisplatin in advanced or recurrent cancer of the vagina: a Gynecologic Oncology Group Study

Twenty-six patients with advanced or recurrent cancer of the vagina no longer amenable to control with surgery and/or radiotherapy were entered into a phase II study of cisplatin 50 mg/m2 intravenously every 3 weeks. Two were deemed ineligible because of a primary site of origin other than vagina. Two were deemed inevaluable, one because of the lack of measurable disease and the other because she never received drug. The remaining 22 included a variety of histologies (16 squamous cell carcinomas, 2 adenosquamous carcinomas, 1 clear cell carcinoma, 1 leiomyosarcoma, and 2 carcinomas not otherwise specified). One complete responder was observed among the 16 patients with squamous cell carcinoma. Adverse effects were tolerable and were essentially those reported in other series. These results suggest that cisplatin has insignificant activity in advanced or recurrent squamous cell carcinoma of the vagina at least at the dose and schedule tested. No comment can be made regarding the activity of cisplatin in other histologies.     

A phase II trial of topotecan in patients with advanced,persistent, or recurrent endometrial carcinoma: a gynecologic oncology group study

OBJECTIVE: To estimate the antitumor activity of topotecan in women with advanced, persistent, or recurrent endometrial carcinoma previously treated with chemotherapy, and to determine the nature and degree of toxicity of topotecan in this cohort of patients. MATERIALS AND METHODS: Eligible patients were those who had failed one prior chemotherapy regimen. Topotecan 0.5 to 1.5 mg/m(2) was administered iv daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. RESULTS: Of 29 patients entered, 28 were evaluable for toxicity and 22 were evaluable for response. Patient characteristics included a median age of 65, with 41% having prior radiation and 14% having prior hormonal therapy. Nine patients (41%) had a performance status (PS) of 0, 11 (50%) had a PS of 1, and 2 (9%) had a PS of 2. Patients received from 2 to 11 (with a median of 4) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 17 (61%) patients, leukopenia in 11 (39%), and thrombocytopenia in 7 (25%). Two deaths were considered potentially related to treatment. There was one (4.5%) complete and one (4.5%) partial response; 12 (55%) patients maintained stable disease and eight (36%) experienced increasing tumor. CONCLUSION: Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent endometrial carcinoma previously treated with chemotherapy.     

Cisplatin and pentoxifylline in advanced or recurrent squamous cell carcinoma of the cervix: a phase II trial of the Gynecologic Oncology Group

OBJECTIVE: The aim of this study was to determine the antitumor activity and toxicity of cisplatin and pentoxifylline in previously treated patients with squamous cell carcinoma of the cervix. METHODS: A Gynecologic Oncology Group (GOG) Phase II trial of recurrent squamous cell cervical cancer using standard GOG response and toxicity criteria was performed. RESULTS: A total of 47 patients with advanced or recurrent squamous cell carcinoma of the cervix were entered. The starting dose was 75 mg/m(2) of cisplatin every 21 days and 1600 mg of pentoxifylline PO every 8 h for nine doses during each course. Forty patients were evaluable for response and 44 were evaluable for toxicity. Of the 40 evaluable patients, 37 had received prior radiotherapy and 35 had received prior chemotherapy. A median of three courses were given (range: 1-7). Among evaluable patients, 1 had a complete response (2.5%) and 3 had a partial response (7.5%) for an overall objective response rate of 10%. The complete responder had not previously had chemotherapy. Grade 3 or 4 toxicity was predominantly nausea and vomiting (32%) and hematologic toxicity (23%). CONCLUSIONS: The combination of cisplatin and pentoxifylline at the dose and schedule tested has limited activity in previously treated advanced or recurrent cervical cancer.     

Phase II trials of cisplatin and piperazinedione in advanced or recurrent squamous cell carcinoma of the vulva: A gynecologic oncology group study

Thirty-eight patients with advanced or recurrent squamous cell carcinoma of the vulva no longer amenable to control with surgery and/or radiotherapy were entered onto one of two phase II studies. One was deemed ineligible because of a primary site of origin other than vulva. Of the remaining 37, 13 patients received piperazinedione 9 mg/m2 iv every 3 weeks. No objective regressions were observed. Five patients were judged to have had stable disease, while eight demonstrated increasing disease. The other 24 patients received cisplatin 50 mg/m2 iv every 3 weeks. Of the 22 who were evaluable for response because of the presence of measurable disease, no objective regression of disease was observed. Ten had stable disease, while the remaining 12 had increasing disease. Adverse effects were tolerable for each study agent and were essentially those reported in other series for these two drugs. These results suggest that neither agent is active in advanced or recurrent squamous cell carcinoma of the vulva at least at the dose and schedule tested.     

A phase II trial of cisplatin and 5-fluorouracil with allopurinol for recurrent or metastatic carcinoma of the uterine cervix: a Southwest Oncology Group trial

On the strength of recent evidence of the activity of the combination of cisplatin and 5-fluorouracil against squamous malignancies of the esophagus and head and neck, this regimen was evaluated in a phase II trial against metastatic or recurrent squamous carcinoma of the uterine cervix. Cisplatin was administered at a dosage of 100 mg/m2 iv bolus and 5-fluorouracil was continuously infused iv at a dosage of 1000 mg/m2/day for 4 days. In an effort to determine whether the toxicities of 5-fluorouracil could be ameliorated by coadministration of allopurinol, patients were randomized to receive allopurinol, 900 mg orally, an odd or even courses of therapy beginning 5 days before 5-fluorouracil administration and continuing until conclusion of the infusion. Fifty-two eligible patients received 177 evaluable courses of treatment. The overall response rate was 28% (8 complete responses and 6 partial responses). Toxicity was confined to nausea and vomiting (81% of courses), anemia (47%), leukopenia (37%), oral mucositis (15%), diarrhea (6%), and thrombocytopenia (4%). Allopurinol produced no improvement in treatment-related toxicities. Allopurinol did not permit substantial increases in 5-fluorouracil dosage.     

A Phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a gynecologic oncology group study

OBJECTIVE: The toxicity and activity of intravenous topotecan were assessed in a multicenter Phase II study (GOG 76-U) in patients with advanced, recurrent, or persistent squamous cell carcinoma of the uterine cervix. METHODS: Intravenous topotecan was administered at 1.5 mg/m2 per day for 5 consecutive days every 4 weeks in patients without prior chemotherapy, aside from chemosensitizing agents used in conjunction with radiotherapy. The study required histologic confirmation of primary diagnosis, adequate performance status, and measurable disease to assess response. A two-stage design for accrual was used to allow for early termination of the study should inadequate response or excessive toxicity be an issue. Modifications of dose were based on hematologic toxicity. Treatment was continued until progression of disease was documented or adverse effects prohibited further therapy. RESULTS: A total of 49 patients were entered on study: of these 5 were never treated, and 1 was not evaluable for response. More than 88% (38 of 43 patients) had received prior radiotherapy. A median of two courses were administered per patient with a range of 1 to 14 cycles. Grade 4 neutropenia occurred in 68% and grade 4 thrombocytopenia in 18% of patients. Nonhematologic toxic effects were infrequent and not dose-limiting. The overall response rate (complete and partial) was 18.6%. The median progression-free survival was 2.4 months. CONCLUSIONS: Topotecan administered at this dose and schedule demonstrated moderate activity albeit at a cost of substantial hematologic toxicity in patients with advanced, recurrent, or persistent squamous cell carcinoma of the cervix.     

Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

PURPOSE: Vinorelbine is being explored by the Gynecologic Oncology Group (GOG) for its possible use in advanced or recurrent squamous cell carcinoma of the uterine cervix. The objective of this Phase II trial was to evaluate a days 1 and 8 every-21-days schedule and determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients with measurable disease and satisfactory baseline bone marrow, liver, and kidney functions were treated with vinorelbine 30 mg/m(2) given on days 1 and 8 every 21 days. A two-stage sampling design was used, proceeding to a second stage accrual if sufficient activity was documented in the first 25 patients. RESULTS: The study did proceed to the second stage and accrued 44 patients. There were six objective responses (one complete, five partial) for a response rate of 13.7% (95% confidence interval: 5.2-27.4%). There were three patients with response in extra-pelvic sites (including the complete response) and three with response in the pelvis. The overall frequency of grades 3 and 4 neutropenia was 41%, whereas neuropathy was reported in 27% and was severe in three. Treatment-related pain, very severe in two instances, was also reported in 27%. CONCLUSION: Vinorelbine has moderate activity in a pretreated population with squamous cell carcinoma of the cervix. Accordingly, vinorelbine in this days 1 and 8 schedule is being studied further in combination with cisplatin by the GOG.