Chemotherapy for recurrent cervical carcinoma David H. Moore

Purpose of review If chemotherapy becomes the only treatment option for cervical cancer, the prognosis has traditionally been regarded as dismal. Data from several recent trials have demonstrated significant improvements in outcome with specific cisplatin-containing combinations. The purpose of this review is to highlight the evolution of phase III trials leading to current treatment standards. Recent findings Given the modest activity of single-agent cisplatin, devoid of any meaningful impact on survival, prospective studies focused on other drugs that might prove either more effective than, or could be used in combination with, cisplatin. Both paclitaxel and topotecan, in combination with cisplatin, yielded superior response rates and progressionfree survival without diminishing patient-reported quality of life; however, only cisplatin plus topotecan also improved overall survival. Furthermore, patient-reported quality of life is not diminished despite the greater acute toxicity of combination regimens. Summary Despite these chemotherapeutic advances, median survival is still less than one year and most patients do not respond to treatment. It is important that investigators identify those patients who should participate in investigational trials of non-platinum-containing regimens. The next generation of clinical trials should explore emerging biological therapies. Keywords cervical cancer, chemotherapy, clinical trials, paclitaxel, platinum, topotecan Curr Opin Oncol 18:516–519. ß 2006 Lippincott Williams & Wilkins. Gynecologic Oncology of Indiana, Indianapolis, Indiana, USA Correspondence to David H. Moore, MD, Gynecologic Oncology of Indiana, 5255 East Stop 11 Road, Suite 310, Indianapolis, IN 46237, USA Tel: +1 317 851 2555; fax: +1 317 851 2566; e-mail: [email protected] Current Opinion in Oncology 2006, 18:516–519 Abbreviations GOG MVAC

Gynecologic Oncology Group methotrexate plus vinblastine plus doxorubicin plus cisplatin

ß 2006 Lippincott Williams & Wilkins 1040-8746

Introduction When cervical cancer is beyond curative treatment with surgery or radiation therapy, the prognosis is poor and palliation is the primary objective. The pursuit of an effective chemotherapy for these patients has long been an objective of gynecological and medical oncologists. Every year meeting abstracts and journal articles describe various agents or regimens with high response rates in small phase II studies that later prove ineffective or toxic when scrutinized in larger, multi-institutional trials. Only through the conduct of a well-designed phase III study may the merits of a particular drug or combination be tested and compared with an accepted treatment standard. For three decades the Gynecologic Oncology Group (GOG) has been without equal in its sustained clinical development of systemic chemotherapy for cervical cancer. The purpose of this review is to highlight pertinent phase III GOG trials leading to the currently identified treatment standards.

Platinum compounds As a result of its recognized activity against other solid tumors, the GOG initiated a phase II study of cisplatin 50 mg/m2 at an infusion rate of 1 mg/min every 3 weeks in patients with stage IVB or recurrent cervical cancer. Among the 22 patients who had not received previous chemotherapy, the response rate was 50% (three complete responses, eight partial responses). The response rate was 17% (no complete responses, two partial responses) in the group of 12 patients who had received previous chemotherapy [1]. Although later series with larger patient numbers reported lower response rates, generally in the 20–30% range, the activity of cisplatin was confirmed. To explore the use of cisplatin in the treatment of cervical carcinoma further, the GOG conducted a study of cisplatin at three dose schedules to determine if improved results could be achieved through increased dose intensity. A total of 581 women were entered on this trial and 497 were considered evaluable. Although the objective response rate increased from 21 to 31% (P ¼ 0.015) by increasing the cisplatin dose from 50 to 100 mg/m2 every 3 weeks, there was no associated improvement in the complete response rate, progressionfree interval, or overall survival; furthermore, higher cisplatin doses were associated with greater nephrotoxicity and myelosuppression [2]. In a subsequent GOG study, 380 patients were randomly assigned to receive 50 mg/m2 cisplatin given as a short (1 mg/min) compared with a 24-h infusion. The overall response rate was essentially identical (18%) in each group. Although

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Chemotherapy for cervical carcinoma Moore 517

gastrointestinal toxicity (nausea and emesis) was lower in the prolonged infusion group, the incidence of other adverse effects, such as nephrotoxicity, myelosuppression, neurotoxicity, did not differ [3]. Recognizing the activity and associated toxicity profile of cisplatin, the GOG initiated a randomized phase II study of the platinum analogs carboplatin and iproplatin. Clinical experience indicated minimal nephrotoxicity or neurotoxicity, and both drugs could be administered in an outpatient setting without previous hydration. The study was conducted from July 1984 to July 1987 and 394 patients were entered. The starting dose of carboplatin (400 mg/m2) was reduced to 340 mg/m2 in patients who had received previous radiation therapy. Similarly, the starting dose of iproplatin (270 mg/m2) was reduced to 230 mg/m2 doses in previously irradiated patients. Both treatments were repeated every 28 days. The objective response rates were 15% for carboplatin and 11% for iproplatin. Although the study was not designed to compare either analog with cisplatin, these response rates were lower than those reported for cisplatin. Furthermore, after treatment failure there were several patients who subsequently went on to receive cisplatin. For 22 of these patients follow-up data were available, and the secondary response rate to cisplatin (18%) was higher than the primary response rate to either analog. The GOG concluded: ‘this finding seems to be further evidence that cisplatin must remain the drug of choice for advanced squamous cell cancer of the cervix’ [4].

Development of cisplatin combinations Given the modest activity of cisplatin and the consequent lack of a meaningful impact on survival, the GOG strove to identify other drugs that were either more effective than, or could be used in combination with, cisplatin. A number of agents were studied in phase II trials and proved to be inactive. The GOG, however, conducted a phase II study of mitolactol (dibromodulcitol) and reported a 29% response rate [5]. Other phase II studies, conducted both by the GOG and other groups, identified ifosfamide as an active agent with response rates ranging from 16 to 40% [6–8]. After subsequent phase I studies determined the feasibility of administering these agents in combination with cisplatin, the GOG conducted a phase III trial (GOG protocol 110) of cisplatin versus cisplatin plus dibromodulcitol versus cisplatin plus ifosfamide. Compared with cisplatin alone, cisplatin plus ifosfamide had a significantly higher response rate (33 versus 19%) and progression-free interval (4.6 versus 3.2 months) with no significant improvement in survival. Furthermore, adverse side-effects were significantly higher in the ifosfamide-containing arm. Peripheral and central neurotoxicity were more frequent and more severe with cisplatin plus ifosfamide compared with cisplatin alone. Central nervous system toxicity ranged

from confusion to somnolence to coma or seizures. There were two treatment-related deaths in patients receiving cisplatin plus ifosfamide. One patient had a cardiorespiratory arrest while comatose and the other developed renal failure and refused dialysis. The eligibility criteria for the study were modified to include only patients with serum albumin levels of 3.0 g/dl or greater and serum creatinine within normal limits for the institution. Patients with bilateral hydronephrosis were ineligible. There were no further cases of fatal central nervous system toxicity, but lesser degrees of encephalopathy were still observed in patients receiving cisplatin plus ifosfamide [9]. Several studies suggested that the addition of bleomycin to the combination of cisplatin plus ifosfamide yielded higher response rates and may also improve survival. The GOG initiated a phase III study (GOG protocol 149) comparing the combination of cisplatin plus ifosfamide with or without bleomycin. These regimens proved essentially identical in terms of objective response rates (approximately 32%), progression-free survival, and overall survival [10].

Gynecologic Oncology Group protocols 169 and 179 Discordant results from GOG protocol 110 (improved response rates and progression-free survival contrasted with increased toxicity and no improvement in overall survival), combined with the availability of validated instruments to assess patient-reported quality of life, prompted a fundamental change in the design of future prospective trials in patients with recurrent/metastatic cervical cancer. Patient-reported quality of life was deemed an essential study endpoint in this patient population with poor median survival. The first randomized controlled study of palliative chemotherapy in cervical cancer prospectively to obtain quality of life measurements in addition to traditional clinical outcomes measures was the phase III trial (GOG protocol 169) of cisplatin plus paclitaxel versus cisplatin. The GOG had previously reported a 17% response rate for paclitaxel against advanced squamous cell carcinoma of the cervix [11]. The combination of cisplatin and paclitaxel was subsequently evaluated in a phase II study. Among the 47 patients enrolled in the study, 41 were evaluable for response (and 40 had received previous radiation therapy). The most frequent dose-limiting toxicity was neutropenia, and two patients died from neutropenic sepsis. Nineteen patients responded to treatment, including five complete responders, for an objective response rate of 46% [12]. A total of 264 eligible patients were randomly assigned on GOG protocol 169. Objective response rates were 19% (6% complete response, 13% partial response) for cisplatin compared

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518 Gynecologic Cancer Table 1 Survival rates for the three Gynecologic Oncology Group protocols (110, 169 and 179) Protocol

Regimen

No. of patients

OR (%)

CR (%)

PFS (months)

OS (months)

GOG 110

P P þ IFX P P þ Topo P P þ Topo

140 151 134 130 145 148

19 31 19 36 13 26

6 13 6 15 3 10

3.2 4.6 3.0 4.9 2.9 4.6

8.0 8.3 8.9 9.9 7.0 9.2

GOG 169 GOG 179

CR, complete response; GOG, Gynecologic Oncology Group; IFX, ifosfamide; OR, odds ratio; OS, overall survival; P, paclitaxel; PFS, progressionfree survival; Topo, topotecan.

with 36% (15% complete response, 21% partial response) for cisplatin plus paclitaxel (P ¼ 0.002). The median progression-free survival was also improved with the addition of paclitaxel but overall survival was not improved (8.7 months for cisplatin compared with 9.7 months for cisplatin plus paclitaxel). Although toxicity, particularly myelosuppression, was more common in the group of patients receiving paclitaxel, this did not result in a worsening of quality of life [13]. A GOG phase II study identified topotecan as a drug with significant activity against cervical carcinoma [14]. In-vitro studies showed that topotecan and cisplatin are synergistic [15]. According to studies conducted by the North Central Cancer Treatment Group, the methotrexate plus vinblastine plus doxorubicin plus cisplatin (MVAC) regimen yielded a 66% response rate in 19 patients with advanced/recurrent cervical cancer, with a median overall survival of 11.5 months. Three patients survived more than 3 years [16]. Other investigators also reported objective tumor responses in more than half of patients with MVAC chemotherapy [17,18]. The GOG initiated a phase III trial (GOG protocol 179) comparing cisplatin with cisplatin plus topotecan compared with MVAC, again with quality of life included among the outcomes measures. The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths among 63 patients. A total of 293 eligible patients were randomly selected to receive one of the cisplatin-containing regimens. Objective response rates were 13% (3% complete response, 10% partial response) for cisplatin compared with 26% (10% complete response, 16% partial response) for cisplatin plus topotecan (P ¼ 0.004). Progression-free survival was also better among patients receiving combination chemotherapy. The median survival for patients receiving cisplatin compared with cisplatin plus topotecan was 6.5 versus 9.4 months, respectively (P ¼ 0.014). This was the first prospective trial, conducted by the GOG or any group, to identify a chemotherapy drug/regimen yielding a survival advantage for this patient population [19]. Furthermore, despite increased toxicity, the cisplatin plus topotecan combination did not significantly reduce the patient-reported quality of life [20].

Future directions Although GOG protocol 179 resulted in a statistically significant improvement in overall survival with the cisplatin plus topotecan combination, median survival in this study was not appreciably different from that for the two previous GOG phase III trials (see Table 1). The reasons for this may include an increasing previous use of concurrent chemotherapy for patients with locally advanced cervical cancer undergoing primary radiation therapy. For example, there was an approximate twofold increased use of concurrent chemotherapy among patients who received cisplatin plus topotecan on GOG 179 (58%) compared with cisplatin plus paclitaxel on GOG 169 (31%). As the standard of primary care has changed, the characteristics of patients participating in these salvage chemotherapy trials have also changed and survival remains poor. Other cooperative groups have reported poor objective response rates and survival for patients who have received ‘radiosensitizing’ chemotherapy [21]. Two recent phase II trials have identified vinorelbine as an active agent against cervical carcinoma [22,23]. The GOG conducted a phase II study of cisplatin plus vinorelbine (GOG protocol 76-Z) and reported a response rate of 30% and only mild toxicity [24]. Gemcitabine has been shown to have limited activity against cervical cancer [25]; however, studies have demonstrated synergy between gemcitabine and cisplatin in vitro and in vivo [26], and the combination has been reported to result in response rates of 40–95% in small phase II trials in advanced cervical cancer patients [27–30]. As a followup to these studies, the GOG has initiated a randomized phase III study (GOG protocol 204) of cisplatin plus one of four drugs: paclitaxel, topotecan, vinorelbine, or gemcitabine, in stage IVB, recurrent, or persistent carcinoma of the cervix. Patient-reported quality of life is once again a primary study endpoint.

Conclusion Both paclitaxel and topotecan, in combination with cisplatin, have yielded superior response rates and progression-free survival without diminishing patientreported quality of life; however, only cisplatin plus

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Chemotherapy for cervical carcinoma Moore 519

topotecan has also improved overall survival. Despite improved outcome with these cisplatin-containing combinations, median survival is less than one year, and most patients do not respond to treatment and are thus subjected to treatment-related toxicity without a meaningful benefit. It is important that investigators identify clinical and tumor-related factors predictive of nonresponse to platinum-based therapies, thereby identifying patients who preferably should participate in investigational trials of non-platinum-containing regimens. The next generation of clinical trials should also incorporate emerging biological therapies in their design.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 544). 1

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13 Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 2004; 22:3113–3119. 14 Muderspach LI, Blessing JA, Levenback C, et al. A phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 2001; 81:213–215. 15 Johnson RK, McCabe FL, Yu Y. Combination regimens with topotecan in animal tumor models. Ann Oncol 1992; 3:85 (Abstract). 16 Long HJ, Cross WG, Wieand HS, et al. Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in advanced/recurrent carcinoma of the uterine cervix and vagina. Gynecol Oncol 1995; 57:235–239. 17 Papadimitriou CA, Dimopoulos MA, Giannakoulis N, et al. A phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in the treatment of metastatic carcinoma of the uterine cervix. Cancer 1997; 79:2391–2395. 18 Murad AM, Medina L, Andrade CA, et al. Phase II open label multicentric trial of MVAC – methotrexate (M), vinblastin (V), doxorubicin (A), and cisplatin (C) plus granulocyte colony stimulating factor (Filgrastim) in advanced recurrent cervical carcinoma: final report. Proc ASCO 1995; 14:276 (Abstract). 19 Long HJ, Bundy BN, Grendys EC, et al. Randomized phase III trial of cisplatin  with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol 2005; 23:4626–4633. This was the first prospective randomized trial in advanced/metastatic cervical carcinoma to demonstrate a survival advantage for combination chemotherapy (cisplatin plus topotecan) over cisplatin alone. 20 Monk BJ, Huang HQ, Cella D, Long HJ. Quality of life outcomes from a  randomized phase III trial of cisplatin with or without topotecan in advanced carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 2005; 23:4617–4625. Published as a companion article to Ref. [19], this study showed that cisplatin plus topotecan resulted in greater acute toxicity but did not diminish quality of life when compared with single-agent cisplatin. 21 Smith HO, Jiang CS, Weiss GR, et al. Tirapazamine plus cisplatin in advanced  or recurrent carcinoma of the uterine cervix: a Southwest Oncology Group study. Int J Gynecol Cancer 2006; 16:298–305. This phase II trial demonstrated a 5% response rate to cisplatin plus tirapazamine in patients who had previously received chemotherapy concurrent with radiation therapy. 22 Morris M, Brader KR, Levenback C, et al. Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix. J Clin Oncol 1998; 16:1094–1098.

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26 Peters GJ, Bergman AM, Ruiz van Halperen VW, et al. Interactions between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995; 22:72–79. 27 Duenas-Gonzalez A, Lopez-Graniel C, Gonzalez A, et al. A phase II study of gemcitabine and cisplatin combination as induction chemotherapy of untreated locally advanced cervical carcinoma. Ann Oncol 2001; 12:541–547. 28 Burnett AF, Roman LD, Garcia AA, et al. A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 2000; 76:63–66. 29 Lorvidhaya V, Chitaparanarux I, Kamnerdpaphon P. Gemcitabine and cisplatin in patients with metastatic cervical cancer [Abstract #1554]. Proc ASCO 2000; 19:39. 30 Mahouf H, Bouzid K. Gemcitabine and cisplatin in recurrent, advanced or metastatic cervical squamous cell carcinoma [Abstract #801]. Proc ASCO 2001; 20:207.

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