Chemotherapy for Recurrent Cervical Cancer PDF 2008

Cancer Treatment Reviews (2008) 34, 603– 613 available at www.sciencedirect.com journal homepage: www.elsevierhealth.com/journals/ctrv ANTI TUMOUR TREATMENT Chemotherapy for recurrent cervical cancer D. Pectasides *, K....

Cancer Treatment Reviews (2008) 34, 603– 613 available at www.sciencedirect.com journal homepage: www.elsevierhealth.com/journals/ctrv ANTI TUMOUR TREATMENT Chemotherapy for recurrent cervical cancer D. Pectasides *, K. Kamposioras, G. Papaxoinis, E. Pectasides Second Department of Internal Medicine, Propaedeutic, Oncology Section, University of Athens, ‘‘Attikon’’ University Hospital, Haidari, 1 Rimini, Athens, Greece Received 24 April 2008; received in revised form 7 May 2008; accepted 7 May 2008 KEYWORDS Summary Purpose: Cervical cancer is the second most common cancer of women worldwide Advanced; and one of the leading cause of death in relative young women. This review gives an outline of Persistent; chemotherapy of advanced, persistent or recurrent cervical cancer. Recurrent cervical Methods: We performed a literature search in the PubMed of almost all relevant articles cancer; concerning chemotherapy of advanced, persistent or recurrent cervical cancer. Chemotherapy Results: The available data from the literature is mainly composed of most recent reviews, phase II and randomized phase III clinical trials. Conclusion: Single-agent cisplatin remains the current standard therapy for advanced, persis- tent or recurrent cervical cancer. Several single-agents have been tested, but none has been found to be superior compared to cisplatin. Both topotecan and paclitaxel in combination with cisplatin, have yielded superior response rates and progression-free survival without diminish- ing patient quality of life. However, only the combination of cisplatin and topotecan has improved overall survival. It is important to identify clinical and tumor-related factors predic- tive of response to cisplatin-based chemotherapy. Future trials are necessary, not only to com- pare combinations of existing agents, but to incorporate biological agents (monoclonal antibodies or small molecules) to chemotherapy in order to improve the treatment results of advanced, persistent or recurrent cervix cancer. c 2008 Elsevier Ltd. All rights reserved. Introduction their disease. The recurrence rate of cervical cancer is between 10% and 20% for FIGO stages Ib–IIa and 50–70% Cervical cancer is the second most common cancer of wo- in locally advanced cases (stages IIb–IVa).2 Patients with men worldwide, accounting for an estimated 11,070 new recurrent disease or pelvic metastases have a poor progno- cases and 3870 deaths in USA for 2008.1 Nearly 1/3 of pa- sis with a 1-year survival rate between 15% and 20%.3 Treat- tients who present with invasive cervical cancer will die of ment of recurrent disease depends on previous treatment, site or extent of recurrence, disease-free interval and * Corresponding author. Tel.: +210 5831691, 210 6008610; fax: patient’s performance status. Both persistent and locally +210 5831690, 210 6008610. recurrent tumors are often characterized by progression E-mail address: [email protected] (D. Pectasides). and exhibit an anatomically complex topography rendering  0305-7372/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2008.05.006 604 D. Pectasides et al. curative treatment very difficult and rarely successful. The tients who received the higher dose of cisplatin (13% versus role of chemotherapy in patients with recurrent or meta- 10%). Response duration, progression-free survival, and sur- static disease is merely palliative. There is no standard, vival failed to be improved with the higher dose of cisplatin. but when chemotherapy is indicated, cisplatin administered However, lower toxicity rate was observed with the lower every 3 weeks seems to be a reasonable option inducing re- dose.3 Therefore, doubling the cisplatin dose is insufficient sponse rates ranging from 20% to 30% and an overall survival to overcome the inherent resistance of cervical cancer of 7 months.4,5 Although improvement in survival has to be cells. Thus, this established the recommended dose of desired, palliation of symptoms due to clinical regression of 50 mg/m2 as the standard therapy (response rate 20%, pro- metastases at a cost of minimal levels of toxicity is an gression-free survival 3–5 months, overall survival approxi- acceptable goal of treatment in patients with incurable mately 6 months) with whom other regimens should be cancer. compared. The high response rate noted in early clinical tri- This review summarizes and addresses the available liter- als included patients who were chemotherapy naı ¨ve, and la- ature on the treatment of patients with advanced, persis- ter studies included patients who had received prior tent or recurrent cervical cancer. chemotherapy, thus providing an explanation for the lower response rates in these later trials. Recognizing the activity and associated toxicity profile of cisplatin, platinum analogs Single agent chemotherapy were investigated in an effort to reduce toxicity, to ease administration in an outpatient setting, while maintain the The management of recurrent cervix carcinoma has not efficacy comparable to that of cisplatin. Carboplatin given improved significantly with the progress of modern chemo- at a dose of 400 mg/m2 every 4 weeks achieved response therapy. Several factors continue to influence chemothera- rates of 15–28% and median survival of 6–7 months.8,9 peutic response. First is the fact that carcinoma of the The total response rate for carboplatin from a number of cervix has limited sensitivity to cytotoxic agents, especially studies was 19%.10 At present, iproplatin is not available when it recurs in the irradiated pelvis. Second, the median for use in USA. However, it was evaluated as an investigator response duration is usually 3–7 months (although there are agent.11,12 In a Gynecologic Oncology Group study, a total of few cases of complete response with a reasonable duration 394 patients with advanced, measurable squamous carci- of remission). Third, there is a difficulty in showing a mean- noma of the uterine cervix and no prior chemotherapy were ingful increase in survival of the patient population as a randomized to therapy with either carboplatin (340– whole. Last, there is an impressive refractoriness among pa- 400 mg/m2) or iproplatin (230–270 mg/m2).6 These doses tients who have failed any prior chemotherapy. Thus, to the are equivalent to cisplatin doses of 75–100 mg/m2. Re- clinician chemotherapy is beneficial to a small percentage sponse rates were similar for both agents (15% for carbo- of patients. Many drugs have been studied for their activity platin, 11% for iproplatin). A third of patients developed in patients with recurrent or metastatic carcinoma of the grade 3 or 4 nuerotoxicity. Both of these drugs appear to cervix (Table 1). Using chemotherapy to treat metastatic be inferior to those noted with the parent compound, cis- or recurrent carcinoma of the cervix is relatively ineffec- platin; however, the duration of patient survival appears tive. Median survival ranges between 4 and 8 months. similar for all three compounds. Currently, there is no data Single-agent chemotherapy can be divided into those on the use of oxaliplatin in advanced cervical cancer. who received platinum-based therapy and those who re- The alkylating agents (cyclophosphamide, ifosfamide) ceived nonplatinum-based therapy. Cisplatin is regarded have been tested in advanced or recurrent cervix cancer as the most active agent in carcinoma of the cervix. The re- and achieved response rates ranging from 5% to 20% for sponse rate is 17–21%.3,6 Dose used range from 50 to cyclophosphamide13–15 and 8% to 50% for ifosfamide.16–20 100 mg/m2. Potter et al.7 reported 68 eligible patients The response rates of ifosfamide at a dose of 1.2 g/m2/ who were treated with cisplatin as the primary chemother- day for 5 days were much lower in a phase II trial that in- apeutic agent for recurrent squamous cell carcinoma of the cluded patients who had received prior cisplatin-based che- cervix. They reported an overall response rate of 40.2%. motherapy, with only three partial responses (two with Women who had isolated chest disease had a 6.3% complete pelvic and one with extrapelvic disease) (8%) seen in 36 response rate and an overall response rate of 73%. No com- patients.16 plete responses were seen in patients having localized pel- Anthracyclines have shown limited activity in advanced vic disease recurrence or persistence; however, 21% of or recurrent cervix cancer. Single agent doxorubicin has a these patients had a partial response. They concluded that reported 20% response rate and should be considered to isolated lung metastases were more likely to respond to cis- be an active drug alone or in combination for the treatment platin than were pelvic disease recurrences; however, loca- of recurrent squamous cell cervix carcinoma.21 Doxorubicin tion of recurrence did not significantly alter survival (22.7 was compared with doxorubicin plus vincristine and doxoru- months versus 14.1 months). The Gynecologic Oncology bicin plus cyclophosphamide and showed a 15.4% and 26% Group conducted a randomized prospective trial comparing response rate, respectively, as a single agent in pelvic and cisplatin 50 mg/m2, 100 mg/m2, and cisplatin 20 mg/m2 for extrapelvic disease.21 In a multicentre phase II trial piraru- five consecutive days, repeated every 21 days.3 Four hun- bicin was given at a dose of 20–25 mg/m2/day for 3 consec- dred ninety-seven evaluable patients have been accrued utive days to 31 patients with cervix cancer.22 No significant on this study. The response rates were 20.7%, 31.4%, and antitumoral activity was observed in patients who had failed 25.0%, respectively. The difference in response rates for to respond to previous chemotherapy. Promising antitu- regimens 1 and 2 was statistically significant (p =.015). Sim- moral activity was noticed in untreated cervico-uterine ilarly, the complete response rate was slightly better in pa- carcinomas with 19% partial responses and 12% complete Chemotherapy for recurrent cervical cancer 605 Table 1 Active single agents Drugs Dosage n RR (%) OS (mos) 48 2 Cisplatin 50 mg/m /3 wk 34 38 – Cisplatin49 50 mg/m2/3 wk 164 17 6.2 Cisplatin 50 mg/m2/24 h/3 wk 156 18 6.4 Cisplatin50 40 mg/m2/wk · 6 wk 67 27 – Cisplatin3 50 mg/m2/3 wk 150 20.7 7.1 100 mg/m2/3 wk 166 31.4 7.0 20 mg/m2/d · 5 d/3 wk 128 25 6.1 Carboplatin8 400 mg/m2/4 wk 41 15 – Carboplatin9 400 mg/m2/4 wk 39 28.2 – Carboplatin6 400 mg/m2/4 wk 175 15.4 6.2 Iproplatin 270 mg/m2/4 wk 177 10.8 5.5 Ifosfamide20 5 g/m2/24 h 30 33 – Ifosfamide17 1.5 g/m2/d · 5 d/4 wk 51 15.7 – Ifosfamide16 1.2 g/m2/d · 5 d/4 wk 27 11.1 – Cyclophosphamide13 8 mg/m2/d · 5 d/4 wk 76 20 15 Cyclophosphamide15 1.100 mg/m2/3 wk 30 7 6.5 Doxorubicin + vincristine21 60 mg/m2 + 1.5 mg/m2/3 wk 54 16.7 5.5 Epirubicin24 12.5 mg/m2/wk 24 4.0 – Mitoxantrone23 12 mg/m2/3 wk 25 8.0 – Pirarubicin22 25 mg/m2/d · 3/4 wk 31 19.0 – Idarubicin26 12.5 mg/m2/3 wk 18 0 – Esorubicin25 25 mg/m2/3 wk 28 0 – Vindesine35 2 mg/m2d · 2/wk 20 30 7 Vincristine51 0.25 mg/m2/d · 5 d/3 wk 11 0 – Vinblastine39 1.4 mg/m2/d · 5 d/3 wk 20 10 – Vinblastine38 9 mg/m2/3 wk 33 0 – Vinorelbine36 30 mg/m2/wk 41 17 – Vinorelbine37 30 mg/m2/wk 33 18.2 11 Etoposide40 37.5 mg/m2/d · 21 d/4 wk 44 9.1 7.7 Etoposide41 40 mg/m2/d · 21 d/4 wk 17 11.8 – Teniposide42 100 mg/m2/d · 3 d/4 wk 32 22 28 5-Fluoruracil43 425 mg/m2 + leucovorin 20 mg/m2/d · 5 d/4 wk 27 4.2 – 5-Fluoruracil44 425 mg/m2 + leucovorin 200 mg/m2/d · 5 d/4 wk 45 8.8 – Gemcitabine45 800 mg/m2/wk · 3 wk/4 wk 24 8.4 4.9 Methotrexate46 40 mg/m2/wk 23 16 – Methotrexate47 250 mg/m2 + VCR 1 mg/m2 29 17 – Paclitaxel27 170 mg/m2/24 h/3 wk 43 17 – Paclitaxel28 250 mg/m2/3 h/3 wk 24 21 7.3 Paclitaxel29 250 mg/m2/3 h/3 wk 32 26 – Topotecan30 1.5 mg/m2/d · 5 d/3 wk 41 12.5 6.6 Topotecan31 1.5 mg/m2/d · 5 d/3 wk 43 18.6 6.4 Irinotecan32 125 mg/m2/wk · 4 wk/6 wk 16 0 – Irinotecan34 125 mg/m2/wk · 4 wk/6 wk 42 21 6.4 Irinotecan33 350 mg/m2/3 wk 51 15.7 8.2 Abbreviations: RR, response rate; OS, overall survival; mos, months; VCR, vincristine; d, day; wk, week. responses. Other anthracycline derivatives (mitoxantrone, 2 cervix.27 In another study, 26 patients with squamous cell partial responses among 26 treated women,23 epirubicin, 4% cancer of the cervix were treated with paclitaxel at a dose response rate among 24 treated patients,24 idarubicin, no of 250 mg/m2 as a 3-h infusion with G-CSF support. Among responses among 28 treated patients25, and esorubicin, no 24 evaluable patients, there were five (21%) partial re- responses were noted among 18 treated women26) have sponses.28 An update of this phase II study demonstrated a shown response rate of less than 10%. 25% response rate (one complete response and seven partial Paclitaxel has broad activity against a number of solid tu- responses) among 32 evaluable patients.29 mors, including ovarian, breast, and endometrium carcino- Camptothecin derivatives (topotecan, irinotecan) have mas. The GOG reported a 17% RR using single-agent shown substantial activity in squamous cell cervix carci- paclitaxel at a dose of 170 mg/m2 (135 mg/m2 for patients noma. Gynecologic Oncology Group conducted a multicen- with prior pelvic radiation) given as a 24-h continuous intra- ter phase II study to evaluate the activity and toxicity of venous infusion in advanced squamous cell carcinoma of the topotecan for patients with previously treated squamous 606 D. Pectasides et al. cell carcinoma of the uterine cervix. The overall (complete 9.1%. In patients with no prior chemotherapy the response and partial) response rate among 40 evaluable patients with rate was 4/25 compared to 0/19 for those who had prior measurable disease was 12.5% and the median progression- therapy. The mean response duration was 2.7 months and free survival was 2.1 months.30 In another study 49 patients the median survival from treatment for all patients was with squamous cell carcinoma of the uterine cervix were 7.7 months. Similar results were reported by Rose et al.41 treated with topotecan at a dose of 1.5 mg/m2/day for five In another study 32 patients with advanced or recurrent cer- consecutive days every 4 weeks. The overall response rate vical cancer were treated with single-agent teniposide as (complete and partial) was 18.6% and the median progres- first-line chemotherapy at a dose of 100 mg/m2 intrave- sion-free survival was 2.4 months.31 Irvin et al.32 treated nously on days 1–3 every 3 weeks. Seven (22%) patients 16 patients with platinum-resistant squamous cell cervix had a partial response to therapy. Median time to treatment carcinoma with CPT-11 as second-line therapy. There were failure was 13 weeks and median survival was 28 weeks.42 no objective responses. European Organization for Research Antimetabolites (fluorouracil, gemcitabine) demon- and Treatment of Cancer/Early Clinical Studies Group con- strated little activity in advanced or recurrent carcinoma ducted a phase II trial to determine the efficacy and tolera- of the cervix. Twenty-four evaluable patients with recur- bility of irinotecan (CPT-11) in advanced or recurrent rent squamous carcinoma of the cervix were treated with cervical carcinoma.33 Patients were stratified into group A leucovorin 20 mg/m2 followed by 5-fluorouracil 425 mg/m2 (Pone measurable lesion in a previously unirradiated area, administered daily for 5 days every 4–5 weeks. There was with or without progressive disease in irradiated fields) or one partial response (4.2%).43 Higher dose of leucovorin group B (measurable new lesion[s] in an irradiated field). (200 mg/m2) proved no more effective than the lower dose The response rate was 15.7% overall, 23.5% for group A of leucovorin. The overall response rate was 8.8%.44 The (complete response, 2.9%), and zero for group B. The med- Gynecologic Oncology Group was conducted a study to ian time to progression and median survival were 4.0 and evaluate the activity and toxicity of gemcitabine (800 mg/ 8.2 months for group A and 2.5 and 4.2 months for group m2 weekly times three with 1 week off) in patients with pre- B, respectively. In another study 42 patients with prior che- viously treated squamous cell carcinoma of the uterine cer- motherapy-treated squamous cell cancer of the cervix were vix. The overall response rate (two partial responses) was treated with irinotecan.34 The overall response rate was 21% 8%. The median progression-free interval was 1.9 months and the overall median duration of survival was 6.4 months. and the overall survival was 4.9 months.45 Methotrexate at The vinca alkaloids (vindesine: response rate 30%, vin- a dose of 40 mg/m2 and high-dose methotrexate (200 mg/ cristine: response rate 0%, vinblastine: response rate 10%, m2) in combination with vincristine demonstrated similar vinorelbine: response rate 17%) have shown modest activity results (response rate 16% and 17%, respectively).46,47 in advanced or recurrent cervix cancer. Rhomberg35 re- ported six partial responses (30%) among 20 evaluable pa- tients with recurrent or metastatic cervical cancer treated Combination chemotherapy with vindesine (2 mg/m2) on two subsequent days per week. In a phase II study vinorelbine was administered at a dose of Combination chemotherapy includes drugs that have dem- 30 mg/m2 over 20 min on a weekly basis as a single agent in onstrated single agent-activity, nonoverlapping toxicity, chemonaı ¨ve cervical cancer patients with measurable met- and additive or synergistic activity with no increase in astatic and/or recurrent disease localized outside irradiated toxicity in order to improve response rates and probably areas. There were seven partial responders (17%).36 In an- survival. Cisplatin was combined with 5-fluoruracil,52–54 other phase II study 35 patients with advanced or recurrent bleomycin,55 ifosfamide,56,57 gemcitabine,58–60 vinorel- squamous cell carcinoma of the cervix were treated with bine,61 paclitaxel,62–64 and topotecan65 in phase II–III trials. vinorelbine 30 mg/m2 as a weekly intravenous infusion. These trials showed advantage in response rates when com- The overall response rate was 18% (1 complete response, pared with single-agent cisplatin, some of these advantage five partial responses). The mean response duration was in progression-free survival (cisplatin + ifosfamide,66 cis- 5.2 months and the median survival from treatment for all platin + paclitaxel,67 cisplatin + topotecan68) and survival patients was 11.0 months.37 Vinblastine was given at a dose advantage only the combination of cisplatin plus topotec- of 9 mg/m2 every 3 weeks to 33 evaluable patients with ad- an68 (Table 2). vanced squamous carcinoma of the uterine cervix recurrent The combination of cisplatin (100 mg/m2) with 5-fluor- after radiotherapy or surgery or first-line chemotherapy. No uracil (1000 mg/m2/day, days 1–5) was evaluated in 37 pa- responses were observed. Vinblastine in this dose and sche- tients with recurrent cervical carcinoma.53 The reported dule is inactive in previously treated patients with squamous response rate (68%) was impressive. The long-term results carcinoma of the cervix.38 In another phase II study 20 pa- of this study demonstrated a response rate of 49% (nine pa- tients with recurrent or metastatic squamous cell carci- tients achieved complete response).52 In another study the noma of the cervix were treated with continuous-infusion combination of cisplatin (50 mg/m2) with 5-fluoruracil vinblastine. Two (10%) patients had partial responses of 4 (1000 mg/m2/day, days 1–5) demonstrated a response rate and 7 months’ duration.39 of 21.8% and a median survival of 6.4 months.54 Thirty pa- Epipodophylins were tested in advanced or recurrent car- tients with metastatic carcinoma of the cervix were treated cinoma of the cervix and were found to have little activity. with a combination of cisplatin and bleomycin. Among 24 Morris et al.40 conducted a phase II study to evaluate the evaluable patients the objective response rate was 54% with efficacy and toxicity of prolonged oral etoposide as single a median duration of 3.5 months and a median survival of 6 agent chemotherapy in patients with advanced or recurrent months.55 Given the encouraging results of single-agent carcinoma of the cervix. The overall response rate was ifosfamide, the Gynecologic Oncology Group conducted a Chemotherapy for recurrent cervical cancer 607 Table 2 Active doublets Drug Regimen n RR (%) OS (mos) 53 2 Cisplatin 100 mg/m /3 wk 72 68 18 5-Fluoruracil 1000 mg/m2/d CI · 5 d Cisplatin52 100 mg/m2/3 wk 37 49 16 5-Fluoruracil 1000 mg/m2/d CI · 5 d Cisplatin54 50 mg/m2/3 wk 55 22 6.4 5-Fluoruracil 1000 mg/m2/d CI · 5 d Cisplatin55 120 mg/m2/3–4 wk 24 54 6 Bleomycin 10 mg/m2/d 1 bolus + 10 mg/m2/d5-7 CI Cisplatin56 20 mg/m2/d · 5 d/4 wk 30 50 25 Ifosfamide 2500 mg/m2/d · 5 d Cisplatin57 50 mg/m2/3 wk 44 38 8 Ifosfamide 1500 mg/m2/d · 5 d Cisplatin58 100 mg/m2/3 wk 40 57 – Gemcitabine 1000 mg/m2/d 1,8 Cisplatin59 33 mg/m2/wk · 18 11 37 6 Gemcitabine 100 mg/m2/wk · 18 Cisplatin60 50 mg/m2/3 wk 17 41 – Gemcitabine 1250 mg/m2/d 1,8 Cisplatin61 50 mg/m2/3 wk 50 64 – Vinorelbine 25 mg/m2/d 1,8 Cisplatin80 75 mg/m2/4 wk 67 30 – Vinorelbine 25 mg/m2/d 1,8,15 Cisplatin62 75 mg/m2/3 wk 41 46.3 10 Paclitaxel 135 mg/m2/24 h Cisplatin63 75 mg/m2/3 wk 34 7 9 Paclitaxel 175 mg/m2/3 h Cisplatin64 75 mg/m2/3 wk 20 45 7 Paclitaxel 135 mg/m2/24 h Carboplatin75 AUC 5-6 25 40 21 Paclitaxel 155-175 mg/m2/4 wk Carboplatin76 AUC 5 51 53 13 Paclitaxel 175 mg/m2/3 wk Carboplatin77 AUC 6 17 76 – Docetaxel 60 mg/m2 Cisplatin65 50 mg/m2/3 wk 32 28 10 Topotecan 0.75 mg/m2/d · 3 d Cisplatin81 60 mg/m2/4 wk 23 78 – Irinotecan 60 mg/m2/d 1,8,15 Cisplatin82 60 mg/m2/4 wk 29 59 – Irinotecan 60 mg/m2/d 1,8,15 Cisplatin83 50 mg/m2/3 wk 20 35 10.3 Mitomycin-C 10 mg/m2/6 wk Cisplatin84 50 mg/m2/4 wk 33 42 11.2 Mitomycin-C 6 mg/m2 Abbreviations: RR, response rate; OS, overall survival; mos, months; d, day; wk, week; CI, continuous infusion. trial comparing single-agent cisplatin with cisplatin–mito- ifosfamide, cisplatin),69–72 the Gynecologic Oncology Group lactol and cisplatin–ifosfamide (GOG-110)66 (Table 3). Cis- conducted a randomized phase III trial (GOG-149) compar- platin plus ifosfamide had a higher response rate (31.1% ing the combination of cisplatin plus ifosfamide with or versus 17.8%, p =.004) and longer progression-free survival without bleomycin.73 There were no significant differences time (4.6 and 3.2 months time p =.003) compared with cis- between cisplatin–ifosfamide and cisplatin–ifosfamide– platin alone. There was no significant difference in overall bleomycin regard to response rates (32% versus 31.2%, survival between cisplatin and either of the combinations. respectively), progression-free survival, or overall survival. Leukopenia, renal toxicity, peripheral neurotoxicity, and Neither regimen was associated with a significant increase CNS toxicity were more frequent with cisplatin plus ifosfa- in incidence of these toxicities. An early stopped (poor mide (p <.05). Based on these results and on promising accrual, only 21 patients – 10 in the PIF group, 11 in the responses of phase II trials evaluating BIP (bleomycin, cisplatin group) prospective randomized phase III trial 608 D. Pectasides et al. Table 3 Randomized phase III trials Drug Regimen n RR (%) PFS mos OS mos 78 2 Cisplatin 50 mg/m /3 wk 148 13 2.3 6.5 Cisplatin 50 mg/m2/3 wk 147 27 4.6 9.4 Topotecan 0.75 mg/m2/d · 3 d Cisplatin3 50 mg/m2/3 wk 150 20.7 3.7 7.1 Cisplatin 20 mg/m2/d · 5 d 128 25 3.8 6.1 Cisplatin 100 mg/m2 166 31.4 4.6 7 Cisplatin66 50 mg/m2/3 wk 140 17.8 3.2 8 Cisplatin 50 mg/m2/3 wk 151 31.1 4.6 8.3 Ifosfamide 5 g/m2 CI p = 0.004 p = 0.003 Cisplatin 50 mg/m2/3 wk 145 21.1 3.2 7.8 Mitolactol 180 mg/m2/d, d 2–6 Cisplatin67 50 mg/m2/3 wk 134 19 2.8 8.8 Cisplatin 50 mg/m2/3 wk 130 36 4.8 9.7 Paclitaxel 135 mg/m2/24 h p = 0.001 Cisplatin73 50 mg/m2/3 wk 146 32 4.6 8.5 Ifosfamide 5 g/m2 CI Cisplatin 50 mg/m2/3 wk 141 31.2 5.1 8.4 Ifosfamide 5 g/m2 CI Bleomycin 30 U CI Abbreviations: RR, response rate; OS, overall survival; mos, months; d, day; wk, week; CI, continuous infusion. comparing cisplatin, ifosfamide and 5-fluorouracil (PIF) with combined with carboplatin, response rate of 76% was ob- cisplatin monotherapy in the treatment of recurrent cervi- tained, and although no grade 3/4 neurotoxicity was re- cal cancer showed response rate for the PIF group 40% and corded, hematological toxicity was comparable to that of 9% for the cisplatin group and median survival 12.3 months combination of carboplatin and paclitaxel.77 for the PIF group and 13 months for the cisplatin group.74 Long et al.78 conducted a randomized phase III trial The Gynecologic Oncology Group conducted a randomized (GOG-179) comparing cisplatin versus cisplatin plus topo- phase III trial (GOG-169) comparing the combination of cis- tecan and a third arm consisting of MVAC (methotrexate, platin plus paclitaxel with single agent cisplatin.67 Among vinblasine, doxorubicin, cisplatin). The MVAC arm was 264 eligible patients, 134 received cisplatin and 130 re- closed by the Data Safety Monitoring Board after four treat- ceived cisplatin plus paclitaxel. The majority of all patients ment-related deaths occurred among 63 patients. Patients had prior radiation therapy. Objective responses occurred in receiving the combination of cisplatin plus topotecan had 19% (6% complete plus 13% partial) of patients receiving cis- statistically superior outcomes to those receiving cisplatin platin versus 36% (15% complete plus 21% partial) receiving alone, with median overall survival of 9.4 and 6.5 months cisplatin plus paclitaxel (p =.002). The median PFS was 2.8 (p =.017), median PFS of 4.6 and 2.9 months (p =.014), and 4.8 months, respectively, for cisplatin versus cisplatin and response rates of 27% and 13%, respectively. Nearly plus paclitaxel (p <.001). There was no difference in med- 60% of patients in both groups had received prior cisplatin ian survival (8.8 months versus 9.7 months). Although myel- therapy as a radiosensitizer, which could be responsible otoxicity was increased in the combination arm, there was for the development of cisplatin resistance, causing lower no significant difference in QOL scores. Experience with response and survival rates in the single cisplatin group. substituting carboplatin for cisplatin is limited in advanced The median survival for patients who received no prior cis- or recurrent uterine cervix cancer. Tinker et al.75 were platin was 15.4 months for the combination of cisplatin plus treated 25 patients with advanced or recurrent carcinoma topotecan versus 7.9 months for those with prior cisplatin- of the cervix with carboplatin and paclitaxel. There was a based chemoradiation. Toxicity for the combination of cis- 40% overall response rate (20% partial and 20% complete re- platin plus topotecan was significant with 70% experiencing sponses). The median progression-free survival was 3 grade 3 or 4 neutropenia, 18% febrile neutropenia, and 46% months and the median overall survival was 21 months. with grade 3 or 4 thrombocytopenia. There were no treat- Our experience using the combination of carboplatin and ment related deaths. There were no statistically significant paclitaxel in 51 eligible patients with measurable advanced differences in QOL despite more hematologic toxicity in the or recurrent cervical carcinoma demonstrated an overall re- combination arm.68 The quality of life assessment collected sponse rate of 53% [complete responses (16%), partial re- data using known validated assessment tools for 9 months sponses (37%)]. The response rate was higher in patients (four times) during chemotherapy. Gemcitabine has been with disease outside of a previously irradiaded site com- shown to have limited activity against cervical cancer. How- pared to those with disease in a previously irradiaded field ever, studies have demonstrated synergy between gemcita- (68% versus 30%) (p = 0.011). Patients previously treated bine and cisplatin.79 Gemcitabine in combination with with chemoradiation had a response rate of 28%, while cisplatin demonstrated response rate ranging between 36% those previously treated with radiotherapy alone the re- (cisplatin on a weekly basis) and 57% (cisplatin on a 3- sponse rate was 68% (p = 0.023).76 When docetaxel was weekly regimen) for advanced or recurrent disease59,60 Chemotherapy for recurrent cervical cancer 609 and 95% in previously untreated patients58. Two recent The addition of one more agent to active triplets was phase II trials have identified vinorelbine as an active agent associated with variable improvements in progression-free against cervical carcinoma.36,37 Vinorelbine in combination and overall survival. Twenty-nine patients with advanced/ with cisplatin demonstrated response rate ranging between recurrent cervix cancer who had not previously received 30% and 64% in previously untreated patients.80,61 The Gyne- cytotoxic chemotherapy were assigned to chemotherapy cologic Oncology Group is currently assessing the doublets treatment at 4-week intervals with methotrexate 30 mg/ of cisplatin with paclitaxel, vinorelbine, and gemcitabine m2 i.v., day 1, vinblastine 3 mg/m2 i.v., days 2, 15, and and compares these with the combination of cisplatin and 22, doxorubicin 30 mg/m2 i.v., day 2, and cisplatin 70 mg/ topotecan (GOG 0204). m2 i.v., day 2.91 Objective regressions were observed in In order to improve outcomes a third active agent was 19 patients (66%) including complete regression in 6 patients added to active doublets (Table 4). However, no triplet (21%) and partial regression in 13 patients (45%). Median was proved to be superior to single-agent cisplatin or active overall survival was 11.5 months. Similarly, Papadimitriou cisplatin-containing doublets in randomized phase III clinical et al.92 were treated 27 patients with stage IV primary or trials.73 Three recent phase II clinical trials have identified recurrent carcinoma of the uterine cervix with methotrex- that the TIP (paclitaxel, ifosfamide, cisplatin) combination ate, vinblastine, doxorubicin, and cisplatin (MVAC). The is an active regimen against recurrent or persistent squa- overall response rate was 52%, including 3 complete re- mous-cell cervical cancer with responses ranging between sponses (11%). Median overall survival was 11 months and 46% and 67%.84–86 The combination of cisplatin (50 mg/ median progression-free survival of the responders was 8 m2) or carboplatin (200 mg/m2), with ifosfamide and bleo- months. Toxicity was acceptable and included neutropenia, mycin demonstrated response rates 15–69%.69–71 Hains- alopecia, vomiting, and stomatitis. A combination chemo- worth et al.90 were treated 60 patients with advanced therapy regimen containing mitomycin-C, vincristine, bleo- squamous cell cervical carcinoma with paclitaxel 200 mg/ mycin, and cis-platin was administered every 6 weeks to 14 m2, 1-h intravenous infusion, days 1 and 22; carboplatin evaluable patients with advanced and/or recurrent squa- area under the concentration-time curve (AUC) 6.0 intrave- mous cell carcinoma of the cervix.93 Four patients (29%) nously, days 1 and 22; 5-fluoruracil 225 mg/m2/day, by 24-h achieved a complete response and two additional patients continuous intravenous infusion, days 1–35. The reported (14%) had a partial response to therapy, inducing an overall response rate was 65%, with 25% complete responses. response rate of 43%. In another study 20 patients with Table 4 Active triplets Drug Regimen n RR (%) PFS mos OS mos 69 2 Cisplatin 50 mg/m /3 wk 20 15 – 9 Ifosfamide 5 g/m2 CI Bleomycin 30 mg Cisplatin71 50 mg/m2/3 wk 49 69 10.2 Ifosfamide 5 g/m2 CI Bleomycin 30 mg CI Carboplatin72 200 mg/m2/4 wk 36 60 11 Ifosfamide 2 g/m2/d · 3 d CI Bleomycin 30 mg Cisplatin85 30 mg/m2/d · 3 d 30 53 12 Ifosfamide 1 g/m2/d · 3 d 5-Fluoruracil 500 mg/m2/d · 3 d Cisplatin86 75 mg/m2 45 67 – – Ifosfamide 5 g/m2 CI Paclitaxel 175 mg/m2/3 h Cisplatin87 75 mg/m2 57 46 8.3 18.6 Ifosfamide 1.5 g/m2/d · 3 d Paclitaxel 175 mg/m2/3 h Cisplatin88 50 mg/m2 45 47 8 19 Ifosfamide 1.5 g/m2/d · 3 d Paclitaxel 135 mg/m2/3 h Cisplatin89 50 mg/m2 44 34 6 10 Ifosfamide 3 g/m2 Mitomycin-C 50 mg/m2 Carboplatin90 AUC 6/3 wk 60 65 – – Paclitaxel 200 mg/m2/3 wk 5-Fluoruracil 200 mg/m2/d · 35 d CI Abbreviations: RR, response rate; PFS, progression-free survival; OS, overall survival; mos, months; d, day; wk, week; CI, continuous infusion. 610 D. Pectasides et al. locally advanced or metastatic cervical carcinoma were 2. Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT, treated with mitomycin, vincristine, bleomycin, and cis- Heintz AP, et al. Carcinoma of the cervix uteri. Int J Gynaecol platin (MOBP).94 Response rates after completion of MOBP Obstet 2003;83(Suppl. 1):41–78. were 72.1% (16.6% of patients had a complete response 3. Bonomi P, Blessing JA, Stehman FB, DiSaia PJ, Walton L, Major FJ. Randomized trial of three cisplatin dose schedules in and 55.5% had a partial response). Similarly, 90 patients squamous-cell carcinoma of the cervix: a Gynecologic Oncology with recurrent cervical carcinoma and no prior chemother- Group study. J Clin Oncol 1985;3(8):1079–85. apy were treated with low-dose (CLD) administration of cis- 4. Kesic V. Management of cervical cancer. Eur J Surg Oncol platin (CLD-BOMP).95 Objective responses were achieved in 2006;32(8):832–7. 68 patients (76%), with 25 (28%) complete responses and 43 5. Cadron I, Van Gorp T, Amant F, Leunen K, Neven P, Vergote I. (48%) partial responses. In another study, chemotherapy Chemotherapy for recurrent cervical cancer. Gynecol Oncol was given as initial therapy to 12 women with very advanced 2007;107(1 Suppl. 1):S113–8. squamous cell carcinoma of the cervix and to 19 women 6. McGuire 3rd WP, Arseneau J, Blessing JA, DiSaia PJ, Hatch KD, with recurrent disease.96 They received a median of four Given Jr FT, et al. A randomized comparative trial of carbo- courses of POMB which comprised vincristine and metho- platin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin trexate followed by folinic acid rescue, bleomycin and cis- Oncol 1989;7(10):1462–8. platin. Six of the 10 assessable patients receiving initial 7. Potter ME, Hatch KD, Potter MY, Shingleton HM, Baker VV. chemotherapy (60%) had a complete response (confirmed Factors affecting the response of recurrent squamous cell histologically in two) and two (20%) had a partial response. carcinoma of the cervix to cisplatin. Cancer 1989;63(7): Phase II trials with targeted therapy (monoclonal anti- 1283–6. bodies or small molecules) alone or in combination with 8. Weiss GR, Green S, Hannigan EV, Boutselis JG, Surwit EA, chemotherapy for the treatment of advanced, persistent Wallace DL, et al. A phase II trial of carboplatin for recurrent or recurrent cervix cancer are currently under way and or metastatic squamous carcinoma of the uterine cervix: a the results are awaited. The phase II trials, VEG105281 Southwest Oncology Group study. Gynecol Oncol 1990;39(3): (pazopanib + lapatinib versus pazopanib versus lapatinib), 332–6. 9. Arseneau J, Blessing JA, Stehman FB, McGehee R. A phase II GOG-0227E (cetuximab), 06-1098 (topotecan + cisplatin + study of carboplatin in advanced squamous cell carcinoma of bevacizumab), GOG-0076DD (cetuximab + cisplatin), the cervix (a Gynecologic Oncology Group study). Invest New GOG-0227B (SU5416), GOG-0227D (erlotinib), GOG-0227C Drugs 1986;4(2):187–91. (bevacizumab) are currently under investigation, and their 10. Varia MA, Bundy BN, Deppe G, Mannel R, Averette HE, Rose PG, results are awaited. Targeted therapy will give us hopefully et al. Cervical carcinoma metastatic to para-aortic nodes: some additional strategies for patients with advanced, extended field radiation therapy with concomitant 5-fluoroura- persistent or recurrent cervix cancer. cil and cisplatin chemotherapy: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 1998;42(5):1015–23. 11. McGuire WP, Blessing JA, Hatch K, DiSaia PJ. A phase II study of Conclusion CHIP in advanced squamous cell carcinoma of the cervix (a Gynecologic Oncology Group study). Invest New Drugs Both topotecan and paclitaxel in combination with cisplatin, 1986;4(2):181–6. have yielded superior response rates and progression-free 12. Lira-Puerto V, Silva A, Morris M, Martinez R, Groshen S, Morales- survival without diminishing patient quality of life. How- Canfield F, et al. Phase II trial of carboplatin or iproplatin in cervical cancer. Cancer Chemother Pharmacol 1991;28(5): ever, only the combination of cisplatin and topotecan has 391–6. improved overall survival. The currently active GOG 0204 13. Smith JP, Rutledge F, Burns Jr BC, Soffar S. Systemic chemo- that compares topotecan, paclitaxel, vinorelbine and gem- therapy for carcinoma of the cervix. Am J Obstet Gynecol citabine in combination with cisplatin should clarify which 1967;97(6):800–7. agent is better when combined with cisplatin. It is impor- 14. Malkasian Jr GD, Decker DG, Jorgensen EO. Chemotherapy of tant to identify clinical and tumor-related factors predictive carcinoma of the cervix. Gynecol Oncol 1977;5(2):109–20. of non-response to cisplatin-based chemotherapy, thereby 15. Omura GA, Vélez-Garcı ´a E, Birch R. Phase II randomized study identifying patients who should participate in trials of non of doxorubicin, vincristine, and 5-FU versus cyclophosphamide platinum-containing regimens. Future trials are necessary, in advanced squamous cell carcinoma of the cervix. Cancer not only to compare combinations of existing agents, but Treat Rep 1981;65(9–10):901–3. 16. Sutton GP, Blessing JA, Adcock L, Webster KD, DeEulis T. Phase to incorporate biological agents (monoclonal antibodies or II study of ifosfamide and mesna in patients with previously- small molecules) to chemotherapy in order to improve the treated carcinoma of the cervix. A Gynecologic Oncology Group treatment results of advanced, persistent or recurrent cer- study. Invest New Drugs 1989;7(4):341–3. vix cancer. 17. Sutton GP, Blessing JA, DiSaia PJ, McGuire WP. Phase II study of ifosfamide and mesna in nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1993; Conflict of interest statement 49(1):48–50. 18. Hannigan EV, Dinh TV, Doherty MG. Ifosfamide with mesna in All authors have no conflict of interest. squamous carcinoma of the cervix: phase II results in patients with advanced or recurrent disease. Gynecol Oncol 1991;43(2): 123–8. References 19. Cervellino JC, Araujo CE, Pirisi C, Sanchez O, Brosto M, Rossi R. Ifosfamide and mesna at high doses for the treatment of cancer 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer of the cervix: a GETLAC study. Cancer Chemother Pharmacol statistics, 2008. CA Cancer J Clin 2008;58(2):71–96. 1990;26 Suppl.:S1–3. Chemotherapy for recurrent cervical cancer 611 20. Meanwell CA, Mould JJ, Blackledge G, Lawton FG, Stuart NS, 36. Lhommé C, Vermorken JB, Mickiewicz E, Chevalier B, Alvarez Kavanagh J, et al. Phase II study of ifosfamide in cervical C, Mendiola C, et al. Phase II trial of vinorelbine in patients cancer. Cancer Treat Rep 1986;70(6):727–30. with advanced and/or recurrent cervical carcinoma: an EORTC 21. Wallace Jr HJ, Hreshchyshyn MM, Wilbanks GD, Boronow RC, Gynaecological Cancer Cooperative Group study. Eur J Cancer Fowler Jr WC, Blessing JA. Comparison of the therapeutic 2000;36(2):194–9. effects of adriamycin alone versus adriamycin plus vincristine 37. Morris M, Brader KR, Levenback C, Burke TW, Atkinson EN, versus adriamycin plus cyclophosphamide in the treatment of Scott WR, et al. Phase II study of vinorelbine in advanced and advanced carcinoma of the cervix. Cancer Treat Rep recurrent squamous cell carcinoma of the cervix. J Clin Oncol 1978;62(10):1435–41. 1998;16(3):1094–8. 22. Chauvergne J, Fumoleau P, Cappelaere P, Metz R, Armand JP, 38. Sutton GP, Blessing JA, Barnes W, Ball H. Phase II study of Chevallier B, et al. Phase II study of pirarubicin (THP) in vinblastine in previously treated squamous carcinoma of the patients with cervical, endometrial and ovarian cancer: study cervix. A Gynecologic Oncology Group study. Am J Clin Oncol of the Clinical Screening Group of the European Organization 1990;13(6):470–1. for Research and Treatment of Cancer (EORTC). Eur J Cancer 39. Kavanagh JJ, Copeland LJ, Gershenson DM, Saul PB, Wharton 1993;29A(3):350–4. FN, Rutledge FN. Continuous-infusion vinblastine in refractory 23. Muss HB, Sutton GP, Bundy B, Hatch KD. Mitoxantrone (NSC carcinoma of the cervix: a phase II trial. Gynecol Oncol 301739) in patients with advanced cervical carcinoma. A phase 1985;21(2):211–4. II study of the Gynecologic Oncology Group. Am J Clin Oncol 40. Morris M, Brader KR, Burke TW, Levenback CF, Gershenson DM. 1985;8(4):312–5. A phase II study of prolonged oral etoposide in advanced or 24. van der Burg ME, Monfardini S, Guastalla JP, de Oliveira C, recurrent carcinoma of the cervix. Gynecol Oncol Renard J, Vermorken JB. Phase II study of weekly 40 -epidoxo- 1998;70(2):215–8. rubicin in patients with metastatic squamous cell cancer of the 41. Rose PG, Blessing JA, Van Le L, Waggoner S. Prolonged oral cervix: an EORTC Gynaecological Cancer Cooperative Group etoposide in recurrent or advanced squamous cell carcinoma of study. Eur J Cancer 1992;29A(1):147–8. the cervix: a gynecologic oncology group study. Gynecol Oncol 25. McGuire WP, Blessing JA, Yordan E, Beecham J. Phase II study 1998;70(2):263–6. of esorubicin (40 -deoxydoxorubicin) in advanced or metastatic 42. Pfeiffer P, Cold S, Bertelsen K, Panduro J, Sandberg E, Rose C. squamous carcinoma of the uterine cervix: a Gynecologic Teniposide in recurrent or advanced cervical carcinoma: a Oncology Group study. Invest New Drugs 1989;7(2-3):235–8. phase II trial in patients not previously treated with cytotoxic 26. Hakes TB, Dougherty JB, Raymond V. Phase II study of therapy. Gynecol Oncol 1990;37(2):230–3. idarubicin in advanced cervical carcinoma. Am J Clin Oncol 43. Look KY, Blessing JA, Muss HB, Partridge EE, Malfetano JH. 5- 1986;9(3):262–3. fluorouracil and low-dose leucovorin in the treatment of 27. McGuire WP, Blessing JA, Moore D, Lentz SS, Photopulos G. recurrent squamous cell carcinoma of the cervix. A phase II Paclitaxel has moderate activity in squamous cervix cancer. A trial of the Gynecologic Oncology Group. Am J Clin Oncol Gynecologic Oncology Group study. J Clin Oncol 1996;14(3): 1992;15(6):497–9. 792–5. 44. Look KY, Blessing JA, Gallup DG, Lentz SS. A phase II trial of 5- 28. Kudelka AP, Winn R, Edwards CL, Downey G, Greenberg H, fluorouracil and high-dose leucovorin in patients with recurrent Dakhil SR, et al. Activity of paclitaxel in advanced or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology squamous cell cancer of the cervix. Clin Cancer Res Group study. Am J Clin Oncol 1996;19(5):439–41. 1996;2(8):1285–8. 45. Schilder RJ, Blessing JA, Morgan M, Mangan CE, Rader JS. 29. Kudelka AP, Winn R, Edwards CL, Downey G, Greenberg H, Evaluation of gemcitabine in patients with squamous cell Dakhil SR, et al. An update of a phase II study of paclitaxel in carcinoma of the cervix: a phase II study of the gynecologic advanced or recurrent squamous cell cancer of the cervix. oncology group. Gynecol Oncol 2000;76(2):204–7. Anticancer Drugs 1997;8(7):657–61. 46. de Palo GM, Bajetta E, Luciani L, Musumeci R, Di Re F, 30. Bookman MA, Blessing JA, Hanjani P, Herzog TJ, Andersen WA. Bonadonna G. Methotrexate (NSC-740) and bleomycin (NSC- Topotecan in squamous cell carcinoma of the cervix: a phase II 125066) in the treatment of advanced epidermoid carcinoma of study of the Gynecologic Oncology Group. Gynecol Oncol the uterine cervix. Cancer Chemother Rep 1973;57(4):429–35. 2000;77(3):446–9. 47. Hakes T, Nikrui M, Magill G, Ochoa Jr M. Cervix cancer: 31. Muderspach LI, Blessing JA, Levenback C, Moore Jr JL. A Phase treatment with combination vincristine and high doses of II study of topotecan in patients with squamous cell carcinoma methotrexate. Cancer 1979;43(2):459–64. of the cervix: a gynecologic oncology group study. Gynecol 48. Thigpen T, Shingleton H, Homesley H, Lagasse L, Blessing J. Cis- Oncol 2001;81(2):213–5. platinum in treatment of advanced or recurrent squamous cell 32. Irvin WP, Price FV, Bailey H, Gelder M, Rosenbluth R, Durivage carcinoma of the cervix: a phase II study of the Gynecologic HJ, et al. A phase II study of irinotecan (CPT-11) in patients Oncology Group. Cancer 1981;48(4):899–903. with advanced squamous cell carcinoma of the cervix. Cancer 49. Thigpen JT, Blessing JA, DiSaia PJ, Fowler Jr WC, Hatch KD. A 1998;82(2):328–33. randomized comparison of a rapid versus prolonged (24 h) 33. Lhommé C, Fumoleau P, Fargeot P, Krakowski Y, Dieras V, infusion of cisplatin in therapy of squamous cell carcinoma of Chauvergne J, et al. Results of a European Organization for the uterine cervix: a Gynecologic Oncology Group study. Research and Treatment of Cancer/Early Clinical Studies Group Gynecol Oncol 1989;32(2):198–202. phase II trial of first-line irinotecan in patients with advanced or 50. Lele SB, Piver MS. Weekly cisplatin induction chemotherapy in recurrent squamous cell carcinoma of the cervix. J Clin Oncol the treatment of recurrent cervical carcinoma. Gynecol Oncol 1999;17(10):3136–42. 1989;33(1):6–8. 34. Verschraegen CF, Levy T, Kudelka AP, Llerena E, Ende K, 51. Jackson DV, White DR, Spurr CL, Hire EA, Pavy MD, Robertson Freedman RS, et al. Phase II study of irinotecan in prior M, et al. Moderate-dose vincristine infusion in refractory chemotherapy-treated squamous cell carcinoma of the cervix. breast cancer. Am J Clin Oncol 1986;9(5):376–8. J Clin Oncol 1997;15(2):625–31. 52. Kaern J, Tropé C, Sundfoer K, Kristensen GB. Cisplatin/5- 35. Rhomberg WU. Vindesine for recurrent and metastatic cancer fluorouracil treatment of recurrent cervical carcinoma: of the uterine cervix: a phase II study. Cancer Treat Rep a phase II study with long-term follow-up. Gynecol Oncol 1986;70(12):1455–7. 1996;60(3):387–92. 612 D. Pectasides et al. 53. Kaern J, Tropé C, Abeler V, Iversen T, Kjørstad K. A phase II 69. Ramm K, Vergote IB, Kaern J, Tropé CG. Bleomycin–ifosfa- study of 5-fluorouracil/cisplatinum in recurrent cervical can- mide–cis-platinum (BIP) in pelvic recurrence of previously cer. Acta Oncol 1990;29(1):25–8. irradiated cervical carcinoma: a second look. Gynecol Oncol 54. Bonomi P, Blessing J, Ball H, Hanjani P, DiSaia PJ. A phase II 1992;46(2):203–7. evaluation of cisplatin and 5-fluorouracil in patients with 70. Kumar L, Bhargava VL. Chemotherapy in recurrent and advanced squamous cell carcinoma of the cervix: a Gynecologic advanced cervical cancer. Gynecol Oncol 1991;40(2): Oncology Group study. Gynecol Oncol 1989;34(3):357–9. 107–11. 55. Daghestani AN, Hakes TB, Lynch G, Lewis Jr JL. Cervix 71. Buxton EJ, Meanwell CA, Hilton C, Mould JJ, Spooner D, carcinoma: treatment with combination cisplatin and bleomy- Chetiyawardana A, et al. Combination bleomycin, ifosfamide, cin. Gynecol Oncol 1983;16(3):334–9. and cisplatin chemotherapy in cervical cancer. J Natl Cancer 56. Cervellino JC, Araujo CE, Sánchez O, Miles H, Nishihama A. Inst 1989;81(5):359–61. Cisplatin and ifosfamide in patients with advanced squamous 72. Murad AM, Triginelli SA, Ribalta JC. Phase II trial of bleomycin, cell carcinoma of the uterine cervix. A phase II trial.. Acta ifosfamide, and carboplatin in metastatic cervical cancer. J Oncol 1995;34(2):257–9. Clin Oncol 1994;12(1):55–9. 57. Coleman RE, Clarke JM, Slevin ML, Sweetenham J, Williams CJ, 73. Bloss JD, Blessing JA, Behrens BC, Mannel RS, Rader JS, Sood Blake P, et al. A phase II study of ifosfamide and cisplatin AK, et al. Randomized trial of cisplatin and ifosfamide with or chemotherapy for metastatic or relapsed carcinoma of the without bleomycin in squamous carcinoma of the cervix: a cervix. Cancer Chemother Pharmacol 1990;27(1):52–4. gynecologic oncology group study. J Clin Oncol 2002;20(7): 58. Dueñas-Gonzalez A, Lopez-Graniel C, Gonzalez A, Reyes M, 1832–7. Mota A, Muñoz D, et al. A phase II study of gemcitabine and 74. Cadron I, Jakobsen A, Vergote I. Report of an early stopped cisplatin combination as induction chemotherapy for untreated randomized trial comparing cisplatin vs. cisplatin/ifosfamide/ locally advanced cervical carcinoma. Ann Oncol 2001;12(4): 5-fluorouracil in recurrent cervical cancer. Gynecol Obstet In- 541–7. vest 2005;59(3):126–9. 59. Dueñas-Gonzalez A, Hinojosa-Garcı ´a LM, López-Graniel C, 75. Tinker AV, Bhagat K, Swenerton KD, Hoskins PJ. Carboplatin Meléndez-Zagla J, Maldonado V, de la Guerra J. Weekly and paclitaxel for advanced and recurrent cervical carcinoma: cisplatin/low-dose gemcitabine combination for advanced and the British Columbia Cancer Agency experience. Gynecol Oncol recurrent cervical carcinoma. Am J Clin Oncol 2001;24(2): 2005;98(1):54–8. 201–3. 76. Pectasides D, Papaxoinis G, Pectasides E, Xiros N, Sykiotis C, 60. Burnett AF, Roman LD, Garcia AA, Muderspach LI, Brader KR, Koumarianou A, et al. Carboplatin and paclitaxel in metastatic Morrow CP. A phase II study of gemcitabine and cisplatin in or recurrent cervical cancer. Int J. Gynecol Cancer 2008, in patients with advanced, persistent, or recurrent squamous cell press. carcinoma of the cervix. Gynecol Oncol 2000;76(1):63–6. 77. Nagao S, Fujiwara K, Oda T, Ishikawa H, Koike H, Tanaka H, 61. Pignata S, Silvestro G, Ferrari E, Selvaggi L, Perrone F, Maffeo et al. Combination chemotherapy of docetaxel and carboplatin A, et al. Phase II study of cisplatin and vinorelbine as first-line in advanced or recurrent cervix cancer. A pilot study. Gynecol chemotherapy in patients with carcinoma of the uterine cervix. Oncol 2005;96(3):805–9. J Clin Oncol 1999;17(3):756–60. 78. Long HJ 3rd, Bundy BN, Grendys Jr EC, Benda JA, McMeekin DS, 62. Rose PG, Blessing JA, Gershenson DM, McGehee R. Paclitaxel Sorosky J, et al. Randomized phase III trial of cisplatin with or and cisplatin as first-line therapy in recurrent or advanced without topotecan in carcinoma of the uterine cervix: a squamous cell carcinoma of the cervix: a gynecologic oncology Gynecologic Oncology Group study. J Clin Oncol 2005;23(21): group study. J Clin Oncol 1999;17(9):2676–80. 4626–33. 63. Papadimitriou CA, Sarris K, Moulopoulos LA, Fountzilas G, 79. Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Anagnostopoulos A, Voulgaris Z, et al. Phase II trial of paclit- Kuiper CM, Braakhuis BJ. Interaction between cisplatin and axel and cisplatin in metastatic and recurrent carcinoma of the gemcitabine in vitro and in vivo. Semin Oncol 1995;22(4 Suppl uterine cervix. J Clin Oncol 1999;17(3):761–6. ):72–9. 64. Piver MS, Ghamande SA, Eltabbakh GH, O’Neill-Coppola C. 80. Morris M, Blessing JA, Monk BJ, McGehee R, Moore DH. Phase II First-line chemotherapy with paclitaxel and platinum for study of cisplatin and vinorelbine in squamous cell carcinoma of advanced and recurrent cancer of the cervix-a phase II study. the cervix: a gynecologic oncology group study. J Clin Oncol Gynecol Oncol 1999;75(3):334–7. 2004;22(16):3340–4. 65. Fiorica J, Holloway R, Ndubisi B, Orr J, Grendys E, Boothby R, 81. Sugiyama T, Nishida T, Kumagai S, Nishio S, Fujiyoshi K, Okura et al. Phase II trial of topotecan and cisplatin in persistent or N, et al. Combination therapy with irinotecan and cisplatin as recurrent squamous and nonsquamous carcinomas of the neoadjuvant chemotherapy in locally advanced cervical can- cervix. Gynecol Oncol 2002;85(1):89–94. cer. Br J Cancer 1999;81(1):95–8. 66. Omura GA, Blessing JA, Vaccarello L, Berman ML, Clarke- 82. Sugiyama T, Yakushiji M, Noda K, Ikeda M, Kudoh R, Yajima A, Pearson DL, Mutch DG, et al. Randomized trial of cisplatin et al. Phase II study of irinotecan and cisplatin as first-line versus cisplatin plus mitolactol versus cisplatin plus ifosfa- chemotherapy in advanced or recurrent cervical cancer. mide in advanced squamous carcinoma of the cervix: a Oncology 2000;58(1):31–7. Gynecologic Oncology Group study. J Clin Oncol 1997;15(1): 83. Malviya VK, Deppe G, Schoenmaker M. Treatment of recurrent 165–71. cervical cancer with cis-platinum and mitomycin C: a phase II 67. Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, study. Am J Clin Oncol 1989;12(5):438–41. Benda J, et al. Phase III study of cisplatin with or without 84. Wagenaar HC, Pecorelli S, Mangioni C, van der Burg ME, paclitaxel in stage IVB, recurrent, or persistent squamous cell Rotmensz N, Anastasopoulou A, et al. Phase II study of carcinoma of the cervix: a gynecologic oncology group study. J mitomycin-C and cisplatin in disseminated, squamous cell Clin Oncol 2004;22(15):3113–9. carcinoma of the uterine cervix. A European Organization for 68. Monk BJ, Huang HQ, Cella D, Long 3rd HJ. Gynecologic Research and Treatment of Cancer (EORTC) Gynecological Oncology Group study. Quality of life outcomes from a Cancer Group study. Eur J Cancer 2001;37(13):1624–8. randomized phase III trial of cisplatin with or without topotecan 85. Fanning J, Ladd C, Hilgers RD. Cisplatin, 5-fluorouracil, and in advanced carcinoma of the cervix: a Gynecologic Oncology ifosfamide in the treatment of recurrent or advanced cervical Group study. J Clin Oncol 2005;23(21):4617–25. cancer. Gynecol Oncol 1995;56(2):235–8. Chemotherapy for recurrent cervical cancer 613 86. Zanetta G, Fei F, Parma G, Balestrino M, Lissoni A, Gabriele A, doxorubicin, and cisplatin in advanced/recurrent carcinoma of et al. Paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy the uterine cervix and vagina. Gynecol Oncol 1995;57(2): for recurrent or persistent squamous-cell cervical cancer. Ann 235–9. Oncol 1999;10(10):1171–4. 92. Papadimitriou CA, Dimopoulos MA, Giannakoulis N, Sarris K, 87. Dimopoulos MA, Papadimitriou CA, Sarris K, Aravantinos G, Vassilakopoulos G, Akrivos T, et al. A phase II trial of Kalofonos C, Gika D, et al. Combination of ifosfamide, paclit- methotrexate, vinblastine, doxorubicin, and cisplatin in the axel, and cisplatin for the treatment of metastatic and treatment of metastatic carcinoma of the uterine cervix. recurrent carcinoma of the uterine cervix: a phase II study of Cancer 1997;79(12):2391–5. the Hellenic Cooperative Oncology Group. Gynecol Oncol 93. Alberts DS, Martimbeau PW, Surwit EA, Oishi N. Mitomycin-C, 2002;85(3):476–82. bleomycin, vincristine, and cis-platinum in the treatment of 88. Choi CH, Kim TJ, Lee SJ, Lee JW, Kim BG, Lee JH, et al. advanced, recurrent squamous cell carcinoma of the cervix. Salvage chemotherapy with a combination of paclitaxel, Cancer Clin Trials 1981;4(3):313–6. ifosfamide, and cisplatin for the patients with recurrent 94. Weiner SA, Aristizabal S, Alberts DS, Surwit EA, Deatherage- carcinoma of the uterine cervix. Int J Gynecol Cancer Deuser K. A phase II trial of mitomycin, vincristine, bleomycin, 2006;16(3):1157–64. and cisplatin (MOBP) as neoadjuvant therapy in high-risk 89. Serkies K, Jassem J, Dziadziuszko R. Chemotherapy with cervical carcinoma. Gynecol Oncol 1988;30(1):1–6. mitomycin c, ifosfamide, and cisplatin for recurrent or 95. Shimizu Y, Akiyama F, Umezawa S, Ishiya T, Utsugi K, Hasumi K. persistent cervical cancer. Int J Gynecol Cancer 2006;16(3): Combination of consecutive low-dose cisplatin with bleomycin, 1152–6. vincristine, and mitomycin for recurrent cervical carcinoma. J 90. Hainsworth JD3rd, Burris 3rdHA, Meluch AA, Baker MN, Morris- Clin Oncol 1998;16(5):1869–78. sey LH, Greco FA. Paclitaxel, carboplatin, and long-term 96. Rustin GJ, Newlands ES, Southcott BM, Singer A. Cisplatin, continuous infusion of 5-fluorouracil in the treatment of vincristine, methotrexate and bleomycin (POMB) as initial or advanced squamous and other selected carcinomas: results of palliative chemotherapy for carcinoma of the cervix. Br J a phase II trial. Cancer 2001;92(3):642–9. Obstet Gynaecol 1987;94(12):1205–11. 91. Long HJ 3rd, Cross WG, Wieand HS, Webb MJ, Mailliard JA, Kugler JW, et al. Phase II trial of methotrexate, vinblastine,