Stages IIB, III, and IVA Cervical Cancer Treatment
Standard Treatment Options for Stages IIB, III, and IVA Cervical Cancer
The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy. Survival and local control are better with unilateral rather than bilateral parametrial involvement. Patterns-of-care studies in stages IIIA and IIIB patients indicate that survival is dependent on the extent of the disease, with unilateral pelvic wall involvement predicting a better outcome than bilateral involvement, which in turn predicts a better outcome than involvement of the lower third of the vaginal wall. These studies also reveal a progressive increase in local control and survival paralleling a progressive increase in paracentral (point A) dose and use of intracavitary treatment. The highest rate of central control was seen with paracentral (point A) doses of more than 85 Gy.
Radiation therapy with concomitant chemotherapy
Strong consideration should be given to the use of intracavitary radiation therapy and external-beam radiation therapy (EBRT) to the pelvis combined with cisplatin or cisplatin/fluorouracil (5FU).[5-12]
Evidence (radiation therapy with concomitant chemotherapy):
- Five randomized, phase III trials have shown an overall survival (OS) advantage for cisplatin-based therapy given concurrently with radiation therapy,[5-10] but one trial that examined this regimen demonstrated no benefit. The patient populations in these studies included women with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.
- Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach.
- The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.
Evidence (low-dose rate vs. high-dose rate intracavitary radiation therapy):
- Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and improved outpatient management. The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[14,15]
- In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[16-18][Level of evidence: 1iiDii]
- In an attempt to improve upon standard chemoradiation, a phase III randomized trial compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin (experimental arm) with concurrent cisplatin plus radiation (standard chemoradiation) in patients with stages IIB to IVA cervical cancer.[Level of evidence: 1iiA] A total of 515 patients from nine countries were enrolled. The schedule for the experimental arm was cisplatin (40 mg/m2) and gemcitabine (125 mg/m2) weekly for 6 weeks with concurrent EBRT (50.4 Gy in 28 fractions) followed by brachytherapy (30–35 Gy in 96 hours) and then two adjuvant 21-day cycles of cisplatin (50 mg/m2) on day 1 plus gemcitabine (1,000 mg/m2) on days 1 and 8. The standard arm was cisplatin (40 mg/m2) weekly for 6 weeks with concurrent EBRT and brachytherapy as described for the experimental arm.
- The primary endpoint was progression-free survival (PFS) at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4%; 95% confidence interval [CI], 68%–79.8% vs. 65.0%; 95% CI, 58.5%–70.7%); overall PFS (hazard ratio [HR], 0.68; 95% CI, 0.49–0.95); and OS (HR, 0.68; 95% CI, 0.49–0.95). Patients in the experimental arm had increased hematologic and nonhematologic grade 3 or 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment.
A subgroup analysis showed an increased benefit in patients with a higher stage of disease (stages III–IVA vs. stage IIB), which suggested that the increased toxic effects of the experimental protocol may be justified for these patients. Additional investigation is needed to determine which aspect of the experimental arm led to improved survival (i.e., the addition of the weekly gemcitabine, the adjuvant chemotherapy, or both) and to determine quality of life during and after treatment, a condition that was omitted from the protocol.
The addition of adjuvant chemotherapy following chemoradiation therapy is currently being evaluated as part of a large multinational clinical trial. The OUTBACK trial (NCT01414608) is randomly assigning women to receive cisplatin (40 mg/m2 weekly for 5 doses) with whole-pelvic radiation therapy (standard chemoradiation therapy) with or without standard chemoradiation therapy plus adjuvant carboplatin (AUC 5 + paclitaxel 155 mg/m2).
Lymph Node Management
Patients who are surgically staged as part of a clinical trial and are found to have small-volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy. Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in patients with low-volume (<2 cm) nodal disease below L3. A single study (RTOG-7920) showed a survival advantage in patients who received radiation therapy to para-aortic nodes without histologic evidence of disease. Toxic effects are greater with para-aortic radiation than with pelvic radiation alone but were mostly confined to patients with previous abdominopelvic surgery.
If postoperative EBRT is planned following surgery, extraperitoneal lymph–node sampling is associated with fewer radiation-induced complications than a transperitoneal approach. Patients who underwent extraperitoneal lymph–node sampling had fewer bowel complications than those who had transperitoneal lymph–node sampling.[22,24,25]
The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy. In addition, prospective data points to improvement in outcomes for patients who undergo resection of positive para-aortic lymph nodes before curative intent chemoradiation therapy; however, only patients with minimal nodal involvement (<5mm) benefited.
Other Treatment Options
For patients who complete EBRT and have bulky cervical disease such that standard brachytherapy cannot be placed anatomically, interstitial brachytherapy has been used to deliver adequate tumoricidal doses with an acceptable toxicity profile.
Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[29-33] Multiple regimens have been used; however, almost all utilize a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy. As a result, although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early stage disease (stages IB, IIA, or IIB).
EORTC-55994 (NCT00039338) randomly assigned patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. With OS as the primary endpoint, this trial may delineate whether there is a role for neoadjuvant chemotherapy for this patient population.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69 (11): 2796-806, 1992. [PUBMED Abstract]
- Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer. A study of patterns of care. Cancer 69 (2): 482-7, 1992. [PUBMED Abstract]
- Lanciano RM, Martz K, Coia LR, et al.: Tumor and treatment factors improving outcome in stage III-B cervix cancer. Int J Radiat Oncol Biol Phys 20 (1): 95-100, 1991. [PUBMED Abstract]
- Monk BJ, Tewari KS, Koh WJ: Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions. J Clin Oncol 25 (20): 2952-65, 2007. [PUBMED Abstract]
- Whitney CW, Sause W, Bundy BN, et al.: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17 (5): 1339-48, 1999. [PUBMED Abstract]
- Morris M, Eifel PJ, Lu J, et al.: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340 (15): 1137-43, 1999. [PUBMED Abstract]
- Rose PG, Bundy BN, Watkins EB, et al.: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340 (15): 1144-53, 1999. [PUBMED Abstract]
- Keys HM, Bundy BN, Stehman FB, et al.: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (15): 1154-61, 1999. [PUBMED Abstract]
- Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al.: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8): 1606-13, 2000. [PUBMED Abstract]
- Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999. [PUBMED Abstract]
- Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002. [PUBMED Abstract]
- Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26 (35): 5802-12, 2008. [PUBMED Abstract]
- Pearcey R, Brundage M, Drouin P, et al.: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (4): 966-72, 2002. [PUBMED Abstract]
- Nag S, Chao C, Erickson B, et al.: The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 52 (1): 33-48, 2002. [PUBMED Abstract]
- Nag S, Erickson B, Thomadsen B, et al.: The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 48 (1): 201-11, 2000. [PUBMED Abstract]
- Patel FD, Sharma SC, Negi PS, et al.: Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 28 (2): 335-41, 1994. [PUBMED Abstract]
- Hareyama M, Sakata K, Oouchi A, et al.: High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial. Cancer 94 (1): 117-24, 2002. [PUBMED Abstract]
- Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, et al.: Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys 59 (5): 1424-31, 2004. [PUBMED Abstract]
- Dueñas-González A, Zarbá JJ, Patel F, et al.: Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 29 (13): 1678-85, 2011. [PUBMED Abstract]
- Dueňas-González A, Orlando M, Zhou Y, et al.: Efficacy in high burden locally advanced cervical cancer with concurrent gemcitabine and cisplatin chemoradiotherapy plus adjuvant gemcitabine and cisplatin: prognostic and predictive factors and the impact of disease stage on outcomes from a prospective randomized phase III trial. Gynecol Oncol 126 (3): 334-40, 2012. [PUBMED Abstract]
- Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecol Oncol 43 (1): 51-4, 1991. [PUBMED Abstract]
- Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. Int J Radiat Oncol Biol Phys 23 (3): 501-9, 1992. [PUBMED Abstract]
- Rotman M, Pajak TF, Choi K, et al.: Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA 274 (5): 387-93, 1995. [PUBMED Abstract]
- Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecol Oncol 33 (3): 283-9, 1989. [PUBMED Abstract]
- Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. Int J Radiat Oncol Biol Phys 31 (4): 717-23, 1995. [PUBMED Abstract]
- Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. Am J Obstet Gynecol 160 (5 Pt 1): 1055-61, 1989. [PUBMED Abstract]
- Gouy S, Morice P, Narducci F, et al.: Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 31 (24): 3026-33, 2013. [PUBMED Abstract]
- Pinn-Bingham M, Puthawala AA, Syed AM, et al.: Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results. Int J Radiat Oncol Biol Phys 85 (3): 714-20, 2013. [PUBMED Abstract]
- Ferrandina G, Margariti PA, Smaniotto D, et al.: Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery. Gynecol Oncol 119 (3): 404-10, 2010. [PUBMED Abstract]
- Ferrandina G, Distefano MG, De Vincenzo R, et al.: Paclitaxel, epirubicin, and cisplatin (TEP) regimen as neoadjuvant treatment in locally advanced cervical cancer: long-term results. Gynecol Oncol 128 (3): 518-23, 2013. [PUBMED Abstract]
- Zanaboni F, Grijuela B, Giudici S, et al.: Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study. Eur J Cancer 49 (5): 1065-72, 2013. [PUBMED Abstract]
- Manci N, Marchetti C, Di Tucci C, et al.: A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Gynecol Oncol 122 (2): 285-90, 2011. [PUBMED Abstract]
- Gong L, Lou JY, Wang P, et al.: Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2-IIB cervical cancer. Int J Gynaecol Obstet 117 (1): 23-6, 2012. [PUBMED Abstract]
- Benedetti-Panici P, Greggi S, Colombo A, et al.: Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 20 (1): 179-88, 2002. [PUBMED Abstract]