Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia

The Oncologist ® Guidelines for the Treatment of Recurrent and Metastatic Cervical Cancer MICHAEL FRIEDLANDER, MICHELLE GROGAN Department of Medica...
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Guidelines for the Treatment of Recurrent and Metastatic Cervical Cancer MICHAEL FRIEDLANDER, MICHELLE GROGAN Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia Key Words. Recurrent · Metastatic · Cervical cancer · Treatment

L EARNING O BJECTIVES After completing this course, the reader will be able to: 1. Describe the natural history and prognosis of patients with recurrent and/or metastatic cervical cancer. 2. Be able to select appropriate treatment options for patients with recurrent cervical cancer. 3. Be able to identify which patients with locally recurrent cervical cancer are potentially curable with pelvic exenterative surgery. 4. Describe the role and limitations of chemotherapy in the treatment of patients with metastatic cervical cancer. CME

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A BSTRACT Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease is still problematic, and there are relatively few randomized trials to guide treatment decisions. This paper reviews the approach to management of patients who relapse after primary treatment

for cervical cancer. Patients who are still potentially curable with radical treatment are identified, and the various treatment strategies are discussed. However, most women are treated with palliative intent, and the literature on palliative management is reviewed together with the levels of evidence. The Oncologist 2002;7:342-347

BACKGROUND Patients with cervical cancer may develop pelvic recurrence, distant metastases, or a combination of both. A 10%20% recurrence rate has been reported following primary surgery or radiotherapy in women with stage IB-IIA cervical tumors with no evidence of lymph node involvement, while up to 70% of patients with nodal metastases and/or more locally advanced tumors will relapse [1-4]. As the bulk of a pelvic tumor increases, the proportion of patients with disease recurrent or persistent in the pelvis as the only site of

failure is greater than the proportion developing distant metastases. Perez et al. reported a total pelvic failure rate of 10% in stage IB, 17% in stage IIA, 23% in stage IIB, 42% in stage III, and 74% in stage IVA after radiotherapy alone [5]. The 10-year actuarial incidence of distant metastases was 3% in stage IA, 16% in stage IB, 31% in stage IIA, 26% in stage IIB, 39% in stage III, and 75% in stage IVA [6]. In patients who develop distant metastases, the most frequently observed metastatic sites were lung (21%), para-aortic nodes (11%), abdominal cavity (8%), and supraclavicular nodes

Correspondence: Michael Friedlander, M.D., Department of Medical Oncology, Prince of Wales Hospital, High Street Randwick NSW 2031, Australia. Telephone: 612-9382-2606; Fax: 612-9382-2588; e-mail: [email protected] Received February 27, 2002; accepted for publication June 17, 2002 ©AlphaMed Press 1083-7159/2002/$5.00/0

The Oncologist 2002;7:342-347 www.TheOncologist.com

Friedlander, Grogan (7%) [6]. Bone metastases occurred in 16% of patients, predominantly involving the lumbar and thoracic spine. Patients who relapsed in lymph nodes had a median survival of 24 weeks, while those who relapsed in other organs had a median survival of only 12 weeks [6]. While these figures relate to only one series, they serve to illustrate the generally poor outcomes of patients with metastatic cervical cancer. The majority of recurrences occur within 2 years of diagnosis, and the prognosis is poor, with most patients dying as a result of uncontrolled disease. In a retrospective review of over 500 patients treated at the University of Kentucky, 31% of patients developed tumor recurrence, 58% of these recurred within 1 year and 76% within 2 years [7]. In this series, only 6% of patients with recurrent tumor survived 3 years. While it is possible to identify subgroups of patients with recurrent cervical cancer who have a substantially better prognosis than this and in whom the objective of treatment is cure, 50%-60% of patients have disease situated beyond the pelvis, which, with few exceptions, is incurable, and treatment is given with palliative intent, as is the case for most patients with pelvic side wall involvement by recurrent cervical cancer. Treatment decisions should be based on the performance status of the patient, the site of recurrence and/or metastases, the extent of metastatic disease, and prior treatment. Patients with recurrent/metastatic cervical cancer may experience a variety of symptoms including pain, anorexia, vaginal bleeding, cachexia, and psychological problems, among others. The specific management of these symptoms will not be described further in these guidelines. This exclusion in no way underestimates the crucial importance of control of these symptoms to the well-being of the patient. Management of these symptoms is the first priority for the physician treating patients with recurrent cervical cancer. The coordinated efforts of a team of professionals is required. The membership of the team will depend on the patient, the goals of management, and the particular problems faced by the individual. The team should include gynecologic oncologists, radiation and medical oncologists, palliative care physicians, specialized nursing staff, and psychologists, but may also require the services of stomatherapists and a specialized pain team. These guidelines relate to the management of patients who relapse after primary treatment for cervical cancer. Patients who are still potentially curable with radical treatment are identified, and the approach to management for the majority of patients not amenable for curative treatment is discussed in detail. The level of evidence for the most part is level III or IV, due to the paucity of randomized controlled trials of treatment for patients with recurrent cervical cancer. The evidence rating system is based on a rating system developed by the U.S. Preventative Services Task Force:

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level I is evidence obtained from a systematic review of all relevant randomized trials; level II is evidence from at least one randomized trial; level III is evidence from well-controlled case studies; and level IV is evidence based on expert opinion. These guidelines have been drawn up after a review of the literature and are intended to provide an evidence-based approach to treatment decision-making. Local Recurrence Following Radiation Most patients who relapse locally after primary radiotherapy are not candidates for further radiotherapy, and pelvic exenterative surgery is the only potentially curative approach for these patients (Table 1). The 5-year survival rate for patients who undergo total pelvic exenteration ranges from 30%-60% [8-13]. Identification of the clinical and histopathological factors that predict recurrence and survival after pelvic exenteration may improve our ability to better select patients who are potentially curable with radical surgery. The prognostic factors that have been identified include disease-free interval, size of recurrence, and preoperative lateral side wall fixation [8-13]. The prognosis is better for patients with a disease-free interval greater than 6 months, recurrence 3 cm) central recurrence in one series [19]. The major prognostic factors associated with survival following salvage radiation in patients with recurrent pelvic disease include disease-free interval, site of recurrence (i.e., central versus pelvic side wall), and size [15-19]. Higher doses of radiation can be delivered with brachytherapy and increase the likelihood of local control for patients with small volume central recurrences. Patients with large volume central or pelvic side wall recurrences have poor prognoses, and efforts should be made to detect pelvic recurrences early to enhance the chance for long-term survival. There have been a number of phase II studies using concurrent chemotherapy and radiotherapy, which appears to be associated with superior results compared with those achieved with radiotherapy alone, but there have not been any randomized trials of combined chemoirradiation compared with radiation alone [20, 21]. However, in light of the recently published randomized trials that have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy in women with International Federation of Gynecology and Obstetrics stages IB2 to IVA [22-25], consideration should be given to incorporate concurrent cisplatin-based chemotherapy with radiation therapy in patients with locoregional recurrence following prior radical surgery. The Role of Systemic Chemotherapy in Metastatic Cervical Cancer There are a large number of chemotherapeutic agents with “activity” in metastatic cervical cancer [28-38] (Table 3). Cisplatin is the single most active agent to treat cervical cancer [25-27]. In the Gynecologic Oncology Group (GOG) studies, involving approximately 800 patients, cisplatin was associated with a response rate of 29% [26-28]. The response rate was greater at 31% with 100 mg/m2 compared with 21% at 50 mg/m2, but this was not associated with any significant

Table 2. Guideline—local recurrence of cervical cancer following surgery

Level of evidence

Radiation therapy is indicated in patients with locally recurrent cervical cancer following radical surgery.

III

Concurrent chemotherapy with either fluorouracil and/or cisplatin with radiation should be considered and may improve outcome.

III

Pelvic exenteration may be an alternative (particularly if a fistula is present) to radical radiotherapy and concurrent chemotherapy in selected patients without pelvic side wall involvement.

III

improvement in progression-free or overall survival [27]. The response rate of other platinum compounds, such as carboplatin, is possibly lower (15%), but the two agents have not been compared in a randomized trial [29, 30]. Cisplatin is associated with response rates of 20%-30% and a median survival of about 7 months. The impact of chemotherapy on palliation and survival is unclear. There have not been any randomized studies comparing chemotherapy with best supportive care or studies that have specifically investigated the impact of chemotherapy on symptom control and quality of life. One study demonstrated that the combination of cisplatin and methotrexate was associated with a significant increase in survival compared with a single inactive agent, hydroxyurea [39]. In another relatively small study of cisplatin-based chemotherapy, it was demonstrated that, while

Table 3. Guideline—systemic chemotherapy in metastatic cervical cancer

Level of evidence

Cisplatin is the single most active agent to treat cervical cancer.

II

The response rate (31%) with 100 mg/m2 cisplatin is higher than that with 50 mg/m2 (21%), but is not associated with any improvement in progression-free or overall survival.

II

Cisplatin-based combination therapy is associated with a higher response rate and longer progression-free survival than single-agent cisplatin therapy, but there is no difference in overall survival.

II

Response rates to chemotherapy are consistently higher in patients with good performance status and extrapelvic disease, and low in previously irradicated sites.

III

The impact of chemotherapy on palliation and survival is unclear.

III

Friedlander, Grogan

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only 30% of patients had an objective response to treatment, 67% had palliation of their pain [40]. The wide range of reported response rates to the same agent suggests that patient characteristics and selection bias exert major impacts on response rates. Even within the GOG studies of cisplatin, the response rates varied from 17%-50% [26-28]. The finding of a significantly lower response in previously irradiated sites is a consistent finding in most studies [41, 42]. Cisplatin-based combinations have been reported to be associated with response rates in excess of 50% in some studies, but the decision as to whether one should treat patients with single agents or combination chemotherapy is unclear [43-47]. The GOG randomized 454 patients with metastatic cervical cancer to receive either cisplatin alone, cisplatin plus mitolactol, or cisplatin plus ifosfamide [48]. The cisplatin/ifosfamide combination was associated with a higher response (31% versus 17%) and longer progressionfree survival compared with cisplatin alone [49]. However, the median times to progression or death were only 4.6 and 3.2 months, respectively. Survival was better among those patients with initial good performance status and greater age. Although combination chemotherapy with cisplatin and ifosfamide was associated with an improved response rate and progression-free survival, this was at the cost of greater toxicity and no improvement in overall survival [48]. A number of new agents (e.g., paclitaxel, vinorelbine, irinotecan, and gemcitabine) have been combined with cisplatin in phase II studies in patients with either locally advanced and/or recurrent cervical cancer [49-54]. High response rates have been observed (40%-66%), particularly among patients with locally advanced disease at presentation [49-54]. Similar findings have been observed with older cisplatin-based combinations, and randomized trials are essential before adopting such combinations for routine use outside clinical trials. The preliminary results of a large GOG study comparing cisplatin alone (50 mg/m2) with cisplatin (50 mg/m2) plus paclitaxel (135 mg/m2 over 24 hours) in 280 patients with recurrent or stage IV B squamous cell carcinoma of the cervix were presented at the American Society of Clinical Oncology meeting in May 2001 [55].The combination produced a significantly higher response rate compared with cisplatin

alone (36.2% versus 19.4%, p = 0.002). The combination regimen also was associated with higher rates of complete response (20% versus 8%) and partial response (27% versus 18%). These higher response rates translated into a significantly longer progression-free survival (p = 0.001) but no significant difference in overall survival (median 9.7 versus 8.8 months). Interim results suggested that the combination also improved various health-related quality-oflife parameters, but the quality-of-life data were incomplete at the time of presentation. Radiotherapy for Metastatic Cervical Cancer Local treatment with radiation therapy to sites of symptomatic involvement in patients with metastatic disease has an important role to play in the alleviation of pain arising from skeletal metastases and symptoms associated with cerebral metastases [56]. Meta-analyses have shown that short courses of radiotherapy are as effective as long courses in the relief of bone pain, and similar results were found in the treatment of cerebral metastases (Table 4). In view of the shortened life expectancy of patients with metastatic cervical cancer, palliative radiotherapy should be given via larger fractions over shorter periods of time than conventional radical courses of treatment [57]. CONCLUSIONS Cervical cancer, despite being potentially preventable, remains an important cause of morbidity and gynecological cancer deaths throughout the world. The natural history is well understood, and randomized trials have established the optimal treatment strategies for patients with potentially curable disease at initial diagnosis. The management of patients with recurrent or metastatic disease has not been subjected to the Table 4. Guidelines—radiotherapy for metastatic disease

Level of evidence

Short courses of radiotherapy are as effective as longer courses for painful bone metastases.

I

Short courses of radiotherapy are as effective as longer courses for cerebral metastases.

II

Table 5. Summary of outcomes for patients with recurrent cervical cancer Recurrence

Treatment

Outcome

Central

Pelvic exenteration

30%-60%: 5-year survival

Local recurrence following surgery

Chemotherapy and radiotherapy

Distant metastases

Cisplatin-based chemotherapy

6%-77%: 5-year survival 17%-50% response: 4-9 months median survival

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same degree of investigation, and there are relatively few randomized trials to guide treatment decision-making (Table 5). The aim of this paper is to highlight the gaps in our knowledge

Treatment of Recurrent and Metastatic Cervical Cancer and stimulate more rigorous investigation, while at the same time providing an evidence-based foundation for treating women with recurrent and metastatic cervical cancer.

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