Treatment of metastatic and recurrent cervix cancer with chemotherapy: a randomised trial comparing hydroxyurea with cisdiamminedichloro-platinum plus methotrexate. Adriamycin versus adriamycin and bleomycin in advanced epidermoid carcinoma of the cervix. Adriamycin plus bleomycin versus cyclophosphamide plus vincristine in advanced carcinoma of the uterine cervix. Phase II trial of carboplatin or iproplatin in cervical cancer. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. Comparison of the therapeutic effects of adriamycin alone versus adriamycin plus vincristine versus adriamycin plus cyclophosphamide in the treatment of advanced carcinoma of the cervix. A randomized pilot study comparing two regimens in the treatment of squamous cell carcinoma. Single-agent chemotherapy for recurrent carcinoma of the cervix. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. Quality of life (QOL) outcomes from a randomized trial of cisplatin versus cisplatin plus paclitaxel in advanced cervical cancer: a Gynecologic Oncology Group study. Treatment of recurrent and metastatic carcinoma of the cervix: comparison of doxorubicin with a combination of vincristine and 5-fluorouracil. Phase II studies of bleomycin, cyclophosphamide, doxorubicin and cisplatin, and bleomycin and cisplatin in advanced cervical carcinoma. Chemotherapy of gynecologic cancer with nitrosoureas: a randomized trial of CCNU and methyl-CCNU in cancers of the cervix, corpus, vagina, and vulva. A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study. A randomized phase II trial of trimetrexate or didemnin B for the treatment of metastatic or recurrent squamous carcinoma of the uterine cervix: a Southwest Oncology Group trial. Topotecan in combination with cisplatin for the treatment of stage IVB, recurrent, or persistent cervical cancer. Clinical results and quality of life analysis for the MVAC combination (methotrexate, vinblastine, doxorubicin, and cisplatin) in carcinoma of the uterine cervix: A Gynecologic Oncology Group study. Phase II randomized study of doxorubicin, vincristine, and 5-FU versus cyclophosphamide in advanced squamous cell carcinoma of the cervix. Report of an early stopped randomized trial comparing cisplatin vs. cisplatin/ifosfamide/ 5-fluorouracil in recurrent cervical cancer. Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study. Combination chemotherapy in the treatment of advanced squamous cell carcinoma of the cervix. A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study.
In a randomised trial comparing single-agent chemotherapy (hydroxyurea) to combination chemotherapy in advanced cervix cancer, response was seen in 57% (including 13% CR) of patients receiving the combination (DDP + MTX) regimen. Responding patients survived significantly longer (11 months) than either those receiving hydroxyurea or those not responding to combination chemotherapy (4 months). Two patients remain in complete remission for 14+ and 17+ months. nan The paper reports the results of a prospective controlled study with two drug combinations (adriamycin plus bleomycin versus cyclophosphamide plus vincristine) in 34 consecutive patients with advanced or recurrent carcinoma of uterine cervix. Despite adequate dosage, the incidence of complete and partial remission was low (10% vs 20%) and not superior to that usually obtained with single agent chemotherapy. By adding objective improvement, the over all response rate was 47% and 26%, respectively. The duration of complete plus partial remission was 7.5 and 7.2 months, the median survival for responders 19 and 8.3 months, respectively. After cross over, adriamycin plus bleomycin yielded response in 4/10 patients, cyclophosphamide plus vincristine objective improvement in 1/3 patients. Since the control of advanced cervical carcinoma remains difficult, a combined modality approach with radiotherapy plus adjuvant chemotherapy for stages IIB and III appears worth of trial. From July 1984 to November 1987, 89 patients with recurrent measurable squamous-cell cancer of the uterine cervix were randomized in a single institution to receive treatment with either carboplatin (CBDCA) or iproplatin (CHIP). Objective response rates were similar: 2 complete regressions (CRs) and 10 partial regressions (PRs) were recorded both in the 46 evaluable patients treated with CBDCA (response rate, 26.1%; 95% confidence interval, 15-41%) and in the 40 evaluable patients treated with CHIP (response rate, 30%; 95% confidence interval, 17-47%). The median duration of response was 5.5 months for CBDCA and 6 months for CHIP; the median survival was 7.5 and 7.6 months, respectively. Both drugs were given in an outpatient setting and myelosuppression (thrombocytopenia) was the predominant toxicity. Analysis of all toxic events yielded additional interesting observations: the occurrence of moderate to severe platelet nadirs beyond cycle 1 was confined to CHIP, a higher incidence of gastrointestinal toxicity during treatment with CHIP, and five moderate to severe complaints of asthenia (recorded as neurologic events) during CHIP therapy versus only one during treatment with CBDCA. Because of its antitumor activity and its toxicologic advantage, a future role for CBDCA in the treatment of cervical cancer appears likely. The Gynecologic Oncology Group has conducted a randomized prospective trial comparing cisplatin 50 mg/m2 every 21 days (regimen 1), 100 mg/m2 every 21 days (regimen 2), and cisplatin 20 mg/m2 for five consecutive days repeated every 21 days (regimen 3). Four hundred ninety-seven evaluable patients have been accrued on this study. The response rates were 20.7%, 31.4%, and 25.0%, for regimens 1, 2, and 3, respectively; the complete remission rates were 10.0%, 12.7%, and 8.6% for regimens 1, 2, and 3, respectively. The median duration of response ranged from 3.9 to 4.8 months, the median progression-free interval from 3.7 to 4.6 months, and the median survival time from 6.1 to 7.1 months. The difference in response rates for regimens 1 and 2 is statistically significant (P = .015) but less than the magnitude originally considered clinically significant. The differences in complete remission rates, response duration, progression-free interval, and survival times are not statistically significant. The following types of toxicity were observed: serum creatinine level greater than 2 mg/dL and/or BUN level greater than 40 mg/dL was 7%, 14%, and 17% on regimens 1, 2, and 3, respectively; leukocyte count less than 4,000/microL was 27%, 44%, and 41% on regimens 1, 2, and 3, respectively. Nausea and vomiting occurred in 74 patients (83%). The regimen consisting of a 100-mg/m2 single dose has produced a statistically significant higher response rate than the 50 mg/m2 regimen while producing no appreciable differences in complete remission rate, response duration, progression-free interval, or survival. In addition, the higher dose regimen was associated with greater myelosuppression and nephrotoxicity. nan Thirty-five patients with epithelial carcinomas not considered to be surgically resectable were randomized to receive two different chemotherapy regimens. Regimen 1 was CCNU followed by bleomycin, and Regimen 2 was a combination of CCNU, bleomycin, methotrexate, and vinblastine. Five of 14 patients treated with CCNU-bleomycin had partial responses. Three of 15 patients treated with the four-drug combination had a partial response. The toxicity of the four-drug regimen was significantly greater than that of the two-drug regimen, while the response rate was greater among those patients treated with two drugs. No significant clinical infections occurred despite the fact that leukopenia and thrombocytopenia were more severe and frequent with the four-drug regimen. Most importantly, the two-drug regimen is well tolerated as an outpatient procedure. Two of the two-drug and one of the four-drug recipients were converted from an inoperable to an operable state. In view of the fact that there has not heretofore been an effective chemotherapeutic regimen for Stage III and IV squamous carcinoma, this is a significant observation. It is of note that patients with squamous cell carcinoma of the head and neck were those who responded best to this treatment, although the treatment is worthy of consideration for advanced squamous carcinoma in other areas. A randomized study of 59 patients with recurrent squamous carcinoma of the cervix originally treated with radiotherapy is reported. Patients were randomized on recurrence to either Hexamethylmelamine, Adriamycin, or Cytoxan as first agent. When analysis was restricted to 37 patients with easily evaluable disease, Cytoxan had a significantly greater response rate (23.1%, 3/13) than Hexamethylmelamine (0%, 0/14) (p = 0.098). The response rate of Adriamycin was 20% (2/10). There was no evidence of a significant effect of first agent on survival time taken from the start of chemotherapy. The number of months from diagnosis to the start of chemotherapy (p = 0.04) and the patients' response status (p = 0.002) did however have significant effects on survival time. There was no evidence of a significant effect of first agent on survival time after treatment change but response to first agent did have a significant effect on survival (p = 0.05). Hexamethylmelamine had a greater frequency of severe toxicity (50%, 10/20) than Adriamycin (10.5%, 2/19) (p = 0.014) and Cytoxan (10%, 2/10) (p = 0.014). Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone.
                Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival.
                CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05).
                CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival. Chemotherapy can profoundly affect patients' quality of life (QOL), yet few clinical trials in advanced cervical cancer have included QOL outcomes. Our purpose was to assess the impact of cisplatin (C) versus cisplatin plus paclitaxel (CP) on overall QOL and pain in cervical cancer patients.
                QOL was assessed using FACT-Cx, consisting of the Functional Assessment of Cancer Therapy (FACT-G) plus a cervix cancer-specific subscale, the Brief Pain Inventory-Short Form (BPI-SF), and a neurotoxicity subscale. Time points were: baseline (prior to randomization) and prior to chemotherapy cycles 2, 3, and 4.
                Overall (FACT-G) scores did not differ significantly between arms at the fourth assessment (C = 70.3 (19.6); CP = 72.8 (17.4)). Scores were stable over time and considerably lower than the general population norms. The BPI-SF revealed a decline in pain scores in both arms from the first to fourth assessments. The CP arm produced a significantly higher response rate and progression-free survival (PFS) but not overall survival (OS). Greater myelosuppression was reported in the combination arm. The rate of QOL drop-out for any reason was higher for C (53%) compared to CP (38%) (P < 0.05). At the fourth time point, 60% of living patients in both arms completed a QOL assessment.
                There was no significant difference in overall QOL scores between treatment arms or serially. Combined with QOL results, the significant increase in response and PFS in the CP arm and the higher drop-out rate in the C arm suggest a better outcome for the combination regimen despite its increased myelosuppression. nan In a randomized phase II trial of two cisplatin-based chemotherapy regimens, 45 patients with advanced cervical carcinoma received a combination of bleomycin, cyclophosphamide, doxorubicin, and cisplatin (BCAP), and 45 others received bleomycin plus cisplatin (BP). BCAP was repeated every 4 weeks, and BP was given at 3-week intervals. Although 19 of 43 (44%) evaluable patients receiving BCAP and 16 of 42 (38%) evaluable patients receiving BP experienced tumor regression, only 22% of those receiving BCAP and 21% of those on BP survived 1 year after beginning treatment. Among bidimensionally measurable patients, 15 of 27 (56%) and 8 of 25 (32%) receiving BCAP and BP, respectively, achieved tumor regression. One patient died of bleeding resulting from severe myelosuppression on BCAP, and two others succumbed to pulmonary toxicity of bleomycin on the BP regimen. Although active against cervical carcinoma, these regimens have limited therapeutic value at this advanced stage of the disease. nan A total of 394 patients with advanced, measurable squamous carcinoma of the uterine cervix and no prior chemotherapy were randomized to therapy with either carboplatin or iproplatin. There were 23 patients ineligible for the study and 10 patients who were not evaluable; the remaining 361 patients were evaluable for response and adverse effects. Randomization was well balanced for age, performance status, and prior therapy. Both platinum analogs were given every 28 days with starting doses of 400 mg/m2 for carboplatin (340 mg/m2 if the patient underwent prior radiation) and 270 mg/m2 for iproplatin (230 mg/m2 if the patient underwent prior radiation). These doses are equivalent to cisplatin doses of 75 to 100 mg/m2. Hematologic toxicity was dose-limiting, among which thrombocytopenia was slightly more common than leukopenia. Gastrointestinal toxicity was also prominent with both agents; however, iproplatin was significantly more toxic than carboplatin (P less than .001). Renal, otic, and peripheral nervous system toxicities were absent or infrequent with both analogs. No electrolyte abnormalities were observed. The percentage of planned dosages that were actually administered was 100% of carboplatin doses and 85% of iproplatin doses (P less than .0001). The reduction in iproplatin dose was apparently due to gastrointestinal toxicity. Response rates were similar for both agents (15% for carboplatin, 11% for iproplatin) and appear to be inferior to those noted with the parent compound, cisplatin. Phase II trial reports have suggested that the addition of bleomycin to the combination of cisplatin and ifosfamide may improve response rates and possible survival in squamous carcinoma of the cervix. This study prospectively evaluates the combination of bleomycin to this regimen in women with histologically proven advanced recurrent or persistent squamous cell carcinoma of the cervix.
                Eligible women were randomized to receive either cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CI) versus bleomycin 30 units over 24 hours on day 1 followed by cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CIB). Three hundred three women were enrolled onto this trial, of which 287 were assessable.
                There were no significant differences between CI and CIB with regard to response rates (32% v 31.2%, respectively), progression-free survival (PFS), or overall survival. PFS and survival were associated with initial performance status (PS). Patients with a PS of 0 experienced a lower rate of failure (P =.013) and a lower risk of death (P =.009) compared with patients with PS of 2. The most frequent grade 3/4 toxicities were leukopenia, neutropenia, anemia, thrombocytopenia, and nausea and vomiting. Neither regimen was associated with a significant increase in incidence of these toxicities.
                The CI regimen was virtually identical to CIB with regard to response rate, PFS, survival, and toxicity profile. Thus, the addition of bleomycin in the dose-schedule employed to cisplatin and ifosfamide did not improve outcome in patients with advanced cervical cancer. Patients with measurable metastatic or recurrent squamous carcinoma of the uterine cervix who had failed prior surgery or radiation therapy were enrolled on this randomized phase II study. Twenty-seven eligible patients were assigned to receive didemnin B at either 2.6 mg/m2 iv every 28 days (sixteen patients) or at 5.6 mg/m2 (eleven patients). Sixteen patients were assigned to receive 12 mg/m2/day iv trimetrexate for 5 days, repeated every 21 days. Toxicity for didemnin B was characterized by nausea and vomiting (78% of patients), anemia (59%), mild diarrhea (11%), and episodic hypersensitivity (three patients). Toxicity for trimetrexate included nausea and vomiting (69%), leukopenia (51%), mild thrombocytopenia (38%), anemia (63%), and diarrhea (31%). No antitumor responses were observed for either agent. Neither trimetrexate nor didemnin B at these doses and schedules is recommended for the treatment of advanced squamous carcinoma of the uterine cervix. Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
                In a randomized multicenter study enrolling 293 eligible patients, topotecan plus cisplatin (TC) was compared with cisplatin monotherapy. The TC regimen consisted of cisplatin 50 mg/m2 IV over 1 hour on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1, 2, and 3 every 21 days.
                There was a clinically relevant and statistically significant improvement in overall survival in the TC treatment arm. Median overall survival was 9.4 months (95% confidence interval [CI]:7.9-11.9) in the TC arm, compared to 6.5 months (95% CI:5.8-8.8) with cisplatin alone. The unadjusted hazard ratio for overall survival between treatment arms was 0.76 (95% CI: 0.59-0.98, P = .033) favoring the combination arm. The most common toxicities with TC included myelosuppression, nausea and vomiting, mucositis, rash, and hepatotoxicity.
                This report describes the FDA's review supporting this first approval of a chemotherapeutic drug for advanced cervical cancer based on demonstration of a survival benefit. The Gynecologic Oncology Group (GOG) compared methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with topotecan and cisplatin (TC) or cisplatin alone (C) in advanced cervical cancer. The primary endpoint was overall survival (OS), with response rate, progression-free survival (PFS), and quality of life (QOL) as secondary objectives.
                Eligible patients were randomly allocated to receive either cisplatin 50 mg/m2 q 3 weeks (C) or cisplatin 50 mg/m2 day 1 and topotecan 0.75 mg/m2 days 1-3 q 3 weeks (TC) or methotrexate 30 mg/m2 days 1, 15, and 22, vinblastine 3 mg/m2 days 2, 15, and 22, doxorubicin 30 mg/m2 day 2, and cisplatin 70 mg/m2 day 2 q 4 weeks (MVAC). QOL was assessed at four time points using the Functional Assessment of Cancer Therapy-Cervix (FACT-Cx), Neurotoxicity Subscale (FACT/GOG-NTX subscale), and Brief Pain Inventory (BPI).
                One hundred eighty-six patients (C = 60; TC = 63; MVAC = 63) were enrolled before MVAC was closed by the GOG Data Safety Monitoring Board after four treatment-related deaths occurred on that arm. MVAC produced a 22% overall response rate (95% CI: 0.13 to 0.34) and median PFS and OS of 4.4 months and 9.4 months, respectively. Compared with C and TC, there was more hematologic toxicity with MVAC. There were no appreciable differences in QOL scores after controlling for baseline scores.
                MVAC's clinical activity tended to be similar to that of TC but with an unacceptable risk of death from sepsis at this dose and schedule. Nevertheless, QOL, as measured by these instruments, was not substantially impaired by this regimen. Sixty-one evaluable patients with advanced squamous cell carcinoma of the cervix were treated in a randomized fashion with either doxorubicin, vincristine, and 5-FU in combination (AVF) or with cyclophosphamide (CTX). Of 31 patients treated with AVF, only three (10%) responded (one complete response and two partial responses). Of 30 patients treated with CTX, there were two (7%) with partial responses. Two patients responded to AVF after failing CTX; one patient responded to CTX after failing AVF. Neither of these regimens was predictably useful in our patient population. This paper reports on an early stopped prospective randomized phase III trial comparing cisplatin, ifosfamide and 5-fluorouracil (PIF) with cisplatin monotherapy in the treatment of recurrent cervical cancer. The aim of the study was to compare response rates, survival, side effects and quality of life. Cisplatin monotherapy was given in a dose of 37.5 mg/m(2) on days 1 + 2 of 4-week schedules. In the PIF regimen, cisplatin was given in the same manner, ifosfamide in a dose of 2 g/m(2) on days 1 + 2 together with mesna 0.5 g/m(2), 5-fluorouracil 500 mg/m(2) on days 1 + 2, and folinic acid 30 mg/m(2) also on days 1 + 2. This regimen was also given in 4-week schedules. The intention had been to include 200 patients in the trial but because of poor accrual the trial was stopped prematurely. Twenty-four patients were included, 3 of which not eligible, and of the remaining 21 patients, 11 were randomized to the cisplatin group and 10 to the PIF group. Median survival for the cisplatin group amounted to 13 months and for the PIF regimen to 12.3 months. The most important side effects were hematologic, with more thrombocytopenia and leukopenia in the PIF regimen. The response rate for the PIF regimen was 40% (4 partial remissions) and 9% for the cisplatin group (1 complete remission). No firm conclusions can be drawn from this trial due to the low number of participants. Still, we believe that the response and survival rates observed with PIF are interesting and that it is important to report all trials, even if they are stopped earlier than intended.
                Copyright (c) 2005 S. Karger AG, Basel. We undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix.
                One hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m(2), daily, on days 1-3 and cisplatin 70 mg/m(2) on day 2) or the same combination with the addition of paclitaxel 175 mg/m(2) on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis.
                A modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P = 0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P = 0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P = 0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P = 0.046) and 0.75 for death (P = 0.124) compared with the doublet.
                The ITP combination merits further investigation in randomized phase III studies. nan In this study, 331 patients with advanced or recurrent squamous cell carcinoma of the cervix no longer amenable to control with surgery or radiotherapy were randomized to receive cisplatin 50 mg/m2 as either a continuous infusion over 24 hr or a more rapid infusion at a rate of 1 mg/min. Antiemetic therapy was standardized for the initial course of both regimens as metoclopramide 60 mg at the time of and at 3 and 6 hours after initiation of cisplatin. The overall frequency of objective regression of disease was 18%; the response rate in each regimen was essentially identical. The continuous infusion regimen was associated with a significantly greater percentage of patients who experienced no nausea and vomiting (34% versus 18%, P = 0.002). Other adverse effects included nephrotoxicity, peripheral neuropathy, myelosuppression, and ototoxicity. Both the frequency and severity of these were essentially the same for each regimen.