Chemotherapy in Cervical Cancer
Bradley J. Monk, MD. FACS, FACOG
Associate Professor
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Chao Family Comprehensive Cancer Center
University of California Irvine, Medical Center
Orange, California, 92868
Despite significant advancements in the screening and treatment of cervical dysplasia, cervical cancer remains a threat to thousands of women annually. In 2004, there will be approximately 10,520 new cases of cervical cancer in the United States, with 3,900 deaths, making it the third most common malignancy of the female genital tract and the sixth most common solid tumor in women (1). Importantly, cervical cancer is still a major cause of death in developing countries. It is generally the number one or two cancer related killer of women among these nations, with nearly 500,000 new cases still being diagnosed worldwide every year.
Essentially all cancers of the uterine cervix including non-sqauamous tumors are related to chronic infections with the human papillomavirus (HPV). Vaccine strategies are in development that will undoubtedly reduce the incidence of this disease although decades of implementation will be required. Cigarette smoking is an important risk factor in the development of squamous cell carcinoma of the cervix.
The treatment of cervical cancer varies with stage and not with cell type. Squamous and non-squamous (Adenocarcinomas) tumors are generally treated similarly although some feel that non-squamous tumors have a worse prognosis when compared stage for stage. In the United States, the majority of cervical carcinoma patients are diagnosed with early stage disease. Among the 13,458 staged patients with cervical carcinoma registered by the SEER program between 1973 and 1987, 71% were diagnosed with FIGO stage I-IIA tumors (2). Most of these women with early lesions are cured with surgery or radiation (RT) alone. However, patients with metastatic disease or those with more advanced lesions are at significant risk of recurrence and account for the majority of cervical cancer deaths in the United States. These deaths occur despite current surgical and radiotherapy protocols, often as a direct result of local or in-field treatment failure (3).
Among women with the earliest stage (Stage IA1 or micro-invasive) of cervical cancer, a simple hysterectomy is generally recommended. Conventional treatment of patients with stage IA2 and IB1 lesions consists of either radical hysterectomy with bilateral pelvic lymph node dissection or RT combining whole pelvic teletherapy with local brachytherapy. These treatment modalities are considered equally efficacious with respect to local control and survival if lesions are small and nodal metastasis absent. Surgery is often preferred to radiotherapy in younger women because ovarian function is eliminated and sexual function is often compromised following RT. In addition, the late complications of RT can be avoided when patients are treated with surgery alone.
Southwest Oncology Group (SWOG) Protocol 8797/Gynecologic Oncology Group (GOG) Protocol 109 addressed the role of adjuvant RT and chemotherapy (CT) after radical hysterectomy and lymphadenectomy (4). This study evaluated women, found to have positive pelvic lymph nodes (as in the current case) and/or microscopic involvement of the parametrium and/or positive surgical margins, who were randomly allocated to receive either pelvic RT alone or RT in combination with CT (intravenous bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil 1,000 mg/m2 every three weeks for four cycles). The results of this clinical trial demonstrated that progression-free survival (PFS) and overall survival (OS) were significantly improved with the addition of CT (hazard ratio 2.01, P=0.003 and 1.96, P=0.007, respectively). Five-year survival for the adjuvant RT + CT group was projected to be 81% in this “high-risk” group of patients. The impact of using a shorter regimen (6 versus 12 weeks) that does not contain fluorouracil is unknown but probably would have little affect on the ultimate outcome of women with high risk factors after radical hysterectomy(5). Indeed, cisplatin administered weekly for six weeks at a dose of 40 mg/m2 (maximum of 70 mg) has become standard when radiation is administered to women with large or locally advanced tumors (stage IB2 – IVA) when surgery is not feasible (6).
Except in very unusual circumstances where recurrent lesions can be treated with RT or surgery (generally when located in the central pelvis), almost all women who develop recurrent cervical cancer die of their disease on average after 7 to 10 months of palliative therapy. Until recently, the standard regimen in this setting has been systemic cisplatin at 50 mg/m2 administered every 3 weeks. This regimen has yielded response rates in the range of 18 to 21% with a median survival of 8 to 9 months. Adding paclitaxel, doubling the cisplatin dose, or adding ifosfamide all have been shown by the GOG to increase response rates but not to a degree that results in prolongation of survival. The combination of paclitaxel and cisplatin was generally felt to be the most active regimen of these 3 choices increasing the response rate to 37% as well as prolonging the progression-free survival (7). However, because of the lack of a clear survival advantage, increased neuropathy, increased cytopenia and associated alopecia, this combination can not be routinely recommended. Importantly, the paclitaxel and cisplatin combination was studied before cisplatin was used with radiation in treating primary lesions, a fact known to reduce the response rates to cisplatin or cisplatin combinations in the recurrent setting.
Recently, the GOG reported a randomized phase III Trial of cisplatin versus cisplatin plus topotecan in the treatment of stage IVB, recurrent or persistent carcinoma of the cervix. This study was the first to show that adding a second drug (in this case topotecan 0.75 mg/m2 days 1, 2 and 3) to the standard regimen of single agent cisplatin 50 mg/m2 administered every 3 weeks resulted in a highly significant prolongation of survival (9.4 versus 6.5 months, p=0.017) (8). In addition, this combination was found to be well tolerated and not associated with a decrease in quality of life (9). Interestingly, the response rate (13%) to cisplatin alone in this trial was surprisingly low and was most likely related to the new era of upfront chemo-radiation. In other words, now that chemotherapy is used with radiation to treat cervical cancers initially, recurrent cancers seem to now be more resistant and respond less frequently to salvage treatment as a result of this prior chemotherapy.
Biologic agents have not yet been studied in this disease, however, other cisplatin containing doublets have shown promising activity in phase II trials. Significant activity of carboplatin containing regimens have been reported, however, it is generally recognized that these regimens are inferior to cisplatin containing regimens based on prior GOG studies. Cisplatin containing doublets are the standard of care in the setting of recurrent cervical cancer. Cisplatin doublets with gemcitabine (10) and vinorelbine (11) are currently being compared to topotecan within the GOG (Protocol 204). This four arm study also includes a paclitaxel containing doublet since the prior paclitaxel study (7) was completed before chemotherapy was commonly added to RT, a common occurrence as mentioned above before the development of recurrent disease.
In summary, surgery is ideal for young healthy women with small lesions. Occasionally, radiation, usually with chemotherapy, is recommended if high risk factors are discovered intra-operatively. Larger tumors are treated without surgery using a combination of radical radiation (external and internal therapy) and weekly cisplatin chemotherapy. Finally, for those with recurrent, metastatic or widespread lesions (stage IVB) participation in the four arm GOG protocol 204 (cisplatin + topotecan, cisplatin + gemcitabine, cisplatin + vinorelbine, cisplatin + paclitaxel) is recommended. Alternatively, cisplatin and topotecan is preferred, off study, given its survival advantage in the recently reported GOG trial.
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5. Rose PG. Chemoradiotherapy: the new standard care for invasive cervical cancer. Drugs 2000;60:1239-44.
6. Yessaian A, Magistris A, Burger RA, Monk BJ. Radical Hysterectomy Followed by Tailored Postoperative Therapy in the Treatment of Stage IB2 Cervical Cancer: Feasibility and Indications for Adjuvant Therapy. Gynecol Oncol. 2004 Jul;94(1):61-6..
7. Moore DH, McQuellon RP, Blessing JA, et al. A randomized phase III study of cisplatin versus cisplatin plus 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.
8. Long HJ, Bundy BN, Grendys EC, et al. Randomized phase III trial of cisplatin (P) vs cisplatin plus topotecan (T) vs MVAC in stage IVB, recurrent or persistent carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Proceedings of the 35th SGO Annual Meeting. San Diego, CA. February 2004.
9. Monk BJ, Huang H, Wenzel L, Cella D, Long HJ. “Quality of Life Outcomes from a Phase III trial of Cisplatin vs. Cisplatin Plus Topotecan in Stage IVB, Recurrent of Persistent Carcinoma of the Cervix: Results of GOG Protocol 179”. Proceedings of the 35th SGO Annual Meeting. San Diego, CA. February 2004.
10. Mutch DG, Bloss JD. Gemcitabine in cervical cancer. Gynecol Oncol 2003;90: S8-15.
11. Morris M, Blessing JA, Monk BJ, McGehee R, Moore DH. Phase II Study of Cisplatin and Vinorelbine in Persistent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study. J Clin Oncol, In Press.
