Cervical cancer is the third most common cancer in women worldwide and is diagnosed in over 12,000 women in the United States each year.1 Among minorities, cervical cancer has increased in incidence each year, with a global annual death rate of 275,000.2 Worldwide it remains one of the most common causes of cancer death among women. The human papilloma virus (HPV) is the primary cause of cervical cancer worldwide, and is implicated in over 99% of cases.3
Progress in the management of cervical cancer has been slow. Over the last 60 years, 2 major advances were accomplished. First, the introduction of the PAP smear as a screening method in the 1950s, which led to a 60% or higher decrease in death from cervical cancer.4 Second, though 50 years later, several randomized trials demonstrated a 30% to 60% reduction in the risk of death with the addition of cisplatin to radiation therapy, which led the National Cancer Institute to issue a clinical alert.5 Current treatment for cervical cancer can yield cures in 80% to 90% of women with early stage I and II cervical cancer and 60% in stage II. However, the prognosis for women with advanced or recurrent cervical cancer remains poor.6 More recently, the development of targeted therapies that selectively target specific molecular pathways involved in tumorigenesis may lead to other major advances in the management of cervical cancer. We review the literature behind current and emerging therapies in advanced and recurrent cervical cancer and their role in clinical practice.
For the vast majority of patients with recurrent or metastatic disease, chemotherapy has represented the only treatment option. However, it is important to remember that in patients with limited metastatic disease in the para-aortic nodes, central pelvic recurrences, or solitary lung metastasis, long-term survival can be achieved with surgical resection and\or radiation therapy.5-12
Several chemotherapy agents have activity in previously untreated advanced cervical cancer. Traditionally, cisplatin has been considered the most active drug.13 Other agents with documented activity include ifosfamide, paclitaxel, topotecan, irinotecan, capecitabine, and pemetrexed.14-19 Current evidence suggests that platinum-based combination regimens may be more effective. The combination of cisplatin and paclitaxel yields a higher response rate and improved progression free survival (PFS) compared with single-agent cisplatin but does not improve overall survival (OS).20 However, there are potential benefits to quality of life. The combination of cisplatin and topotecan compared with single-agent cisplatin showed an improvement in overall response rate (ORR), PFS, and OS.21 On the other hand, the toxicities were significant, with 78% of patients in the study requiring unanticipated hospital admissions for supportive care and management of toxicities.
The efficacy of 4 platinum-based doublets was evaluated in a large randomized trial.22 Patients were randomly assigned to cisplatin in combination with either paclitaxel, vinorelbine, gemcitabine, or topotecan. This study reported that vinorelbine, gemcitabine, and topotecan were not superior to paclitaxel in terms of OS, although a trend in response rate (RR), PFS, and OS favored paclitaxel.
Due to its more favorable toxicity profile, the combination of carboplatin plus paclitaxel could be a reasonable alternative to paclitaxel. In an unpublished phase 3 randomized trial, 253 women with recurrent or metastatic cervical cancer were treated with paclitaxel or carboplatin and paclitaxel.23 Overall no significant differences were observed in PFS (6.9 months vs 6.21 months; hazard ratio [HR], 1.04; 95% CI, 0.80-1.35) or OS (18.3 months vs 17.5; HR, 0.99; 90% CI, 0.79-1.25; noninferiority P = .032). Paclitaxel was associated with more febrile neutropenia (16% vs 7.3%), grades 2 through 4 nausea and vomiting (36.8% vs 23%), and increased serum creatinine grades 2 through 4 (9.6% vs 4.8%). Carboplatin and paclitaxel was associated with more arthralgias (22.2% vs 11.2%), myalgias (16.7% vs 7.2%), motor neuropathy (8% vs 4%), and sensory neuropathy (27% vs 14.4%). It should be noted though, that in women not previously treated with cisplatin, carboplatin plus paclitaxel resulted in a much lower median OS compared with the standard doublet of cisplatin and paclitaxel (13 vs 23 months; HR, 1.57; 95% CI, 1.06-2.32; P = .838).23 Therefore, in platinum-naïve patients, a cisplatin-based regimen is still the preferred treatment of choice with a superior response rate compared to carboplatin. The results of these studies are summarized in Table 1.
Treatment options after first-line platinum-based therapy are limited. Many chemotherapy agents and several targeted agents have been evaluated, but in general have limited activity. Topotecan, vinorelbine, and pemetrexed are among the most active agents, while docetaxel, gemcitabine, vinorelbine, erlotinib, cetuximab, sunitinib, lapatinib, and pazopanib were found to have minimal activity.24-33 The results of these studies are summarized in Table 2.
The most promising experimental therapy to date in cervical cancer is targeting angiogenesis to block the growth of nutrient-supplying blood vessels in cancerous tumors with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab. A phase 2 multicenter trial evaluating single-agent bevacizumab therapy among women with persistent or recurrent squamous cell carcinoma of the cervix was reported.34 Study participants consisted of 46 patients with measurable disease who had been treated with no more than 1 or 2 non–cisplatin-based cytotoxic regimens or any prior cisplatin-based chemotherapy, and had good performance status, with adequate hematologic, renal, hepatic, and coagulation function. The median age was 46 years. Most patients were Caucasian (69.6%). Almost half (47.8%) had a Gynecologic Oncology Group (GOG) performance status of 0. The most common histology (93.5%) was squamous cell carcinoma. All patients had at least 1 prior chemotherapy regimen. The majority of the patients had prior radiation (82.6%) and prior hysterectomy (56.5%). The median duration of response was 6.21 months (range, 2.83 to 8.28 months). The median PFS and OS times were 3.40 months (95% CI, 2.53-4.53 months) and 7.29 months (95% CI, 6.11-10.41 months), respectively. Five patients (10.9%) had partial responses. Grade 3 or 4 adverse events (AEs) included hypertension (n = 7), thromboembolism (n = 5), gastrointestinal (n = 4), anemia (n = 2), other cardiovascular (n = 2), vaginal bleeding (n = 1), neutropenia (n = 1), and fistula (n = 1). One death occurred due to infection. The study suggested that the activity of single-agent bevacizumab compared favorably with cytotoxic chemotherapy drugs.
Since 2006, small studies have suggested that the combination of bevacizumab and chemotherapy was highly active in advanced cervical cancer.35,36 However, the most significant and practice-changing study for the management of advanced cervical cancer was recently reported by the GOG. In protocol GOG 240, women diagnosed with recurrent, persistent, or metastatic cervical cancer who had no prior chemotherapy except for chemotherapy used concurrently with radiation therapy for locally advanced nonmetastatic disease, were enrolled into a phase 3 randomized study.37 A total of 452 women were enrolled into a factorial 2 × 2 design study where approximately half the patients received topotecan with paclitaxel and the other half received cisplatin and paclitaxel. Additionally, about half of the patients in each of these treatment groups received bevacizumab with their chemotherapy. The addition of bevacizumab to combination chemotherapy was associated with an improvement of 3.7 months in median OS (Table 1). The difference in OS translated into an HR for death of 0.71 in favor of the addition of bevacizumab (P = .004). Response rates were 48% with bevacizumab and 36% with chemotherapy alone (P = .008). There was significantly more toxicity in patients who received bevacizumab. However, this represented the usual toxicities associated with bevacizumab. Grade 2+ hypertension was seen in 29% of patients versus 2% in those who received chemotherapy alone. Grade 3+ thromboembolic events occurred in 8% of bevacizumab-treated patients and 1% of patients who received only chemotherapy. Grade 3+ gastrointestinal fistula occurred in 3% of the bevacizumab group but in none of the patients who received chemotherapy without bevacizumab. Despite the toxicities, the addition of bevacizumab showed acceptable safety, and patients did not report a statistically significant decrease in patient-reported quality of life. As a secondary outcome in the study, topotecan-paclitaxel did not outperform cisplatin-paclitaxel, even among patients with prior exposure to cisplatin. The study did not distinguish the differences in toxicity profile between the combination chemotherapy regimens. However based on previous trials, it is expected that the use of topotecan-paclitaxel causes more fatigue, leukopenia, and neutropenia, and significantly more thrombocytopenia and anemia compared with cisplatin-paclitaxel.23
As mentioned, except for bevacizumab, the role of other targeted therapies in cervical cancer so far remains undetermined. However, it is important to remember that these trials have typically been conducted in a nonenriched patient population. In terms of chemotherapy agents, there has been renewed interest in the potential role of fluoropyrimidines. Several trials have reported modest activity for single-agent capecitabine.18,38,39 Recently encouraging activity was reported in a phase 2 study with S-1.40 S-1 is an oral fluoropyrimidine consisting of tegafur, a prodrug of 5-fluorouracil, gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, which degrades fluorouracil, and oteracil, which inhibits the phosphorylation of fluorouracil in the gastrointestinal tract, thereby reducing the gastrointestinal toxic effects of fluorouracil. In this study, 36 patients received a median of 4 cycles with an ORR of 30.6%. The median time to progression and the median survival time were 5.2 and 15.4 months, respectively. These promising results have led to a randomized phase 3 study evaluating the efficacy and safety of S-1 with cisplatin versus single-agent cisplatin in patients with stage IVB, recurrent, or persistent carcinoma of the cervix.41
There have been significant advances in the past several years with regard to immunotherapy for cancer, beginning a new era of research in oncology. By identifying T cells that target cervical cancer HPV oncoproteins, and enriching for and expanding these T cells ex vivo, efforts are being made to attack cervical tumors that have not been immunologically targeted before. The hope is that immunotherapy and adoptive T-cell therapy can induce regression of cervical cancer.
A novel study investigated use of human papillomavirus-targeted tumor-infiltrating lymphocyte therapy.42 In this ongoing study, T cells were harvested from tumor tissue and cultured. The cultures were then tested for HPV viral protein E6 and E7 reactivity. The most reactive cultures were selected for infusion and then expanded. Billions of these expanded T cells were then infused into the patient. Nine patients have received tumor-infiltrating lymphocytes. One patient achieved partial response and 2 patients achieved a complete response. These complete responses were still ongoing at 22 months and 15 months after treatment. Most common toxicities included grade 3 and 4 myelosuppression, neutropenia, fever, and diarrhea. This study provided preliminary encouraging results, and completion of this study is eagerly awaited.
Another promising agent in development is live attenuated Listeria monocytogenes-based immunotherapy (ADXs11-01). ADXS11-001 is a drug that is designed to create a Th-1 type immunologic response, generating CD8+ T cells that target HPV-E7-transformed cells while simultaneously suppressing the immunologic tolerance within the lesions.43 In a recent phase 2 study of ADXS11-001 in the treatment of persistent or recurrent cervical cancer, patients previously treated with chemotherapy, radiotherapy, or both were randomized to either 3 or 4 dosages of ADXS11-001 with cisplatin.44 In the study, 18-month survival was 28% and 12-month survival was 36%. There was an 11% ORR, with an average duration of 10.5 months after 1 cycle of ADXS11-001. Prior therapy, baseline performance status, and the addition of cisplatin had no effect on survival or response. Current studies are needed to optimize the dosage and inclusion of multiple cycles with other agents to determine whether ADX11-001 can be used as an active agent against recurrent cervical cancer.
Based on these results, other immunotherapies such as nivolumab and ipilimumab are currently being evaluated in phase 2 trials.45-48 Nivolumab and ipilimumab are monoclonal antibodies that target and block 2 different receptors that negatively regulate T-cell activation (PD-1 and CTLA-4, respectively), impacting the tumor’s defense against the immune system and boosting the immune system’s ability to fight the tumor. Inhibition leads to compromised activation and suppressed effector functions such as proliferation, cytokine secretion, and tumor cell lysis that block “immune checkpoints.”
The results of the GOG 240 were encouraging and resulted in improved oncologic outcomes, suggesting that the use of bevacizumab in combination with chemotherapy may become the standard of care for recurrent, advanced, or metastatic cervical cancer. As a consequence of this study, bevacizumab was approved by the FDA for use in cervical cancer in August 2014.
Additional studies are needed to determine whether bevacizumab is beneficial in combination with second-line chemotherapies or in patients with less advanced disease. Recently, Schefter et al published the complete results of RTOG 0417, exploring the safety and efficacy of the addition of bevacizumab to chemoradiation therapy.49 This phase 2 study showed that treatment was well tolerated and encouraging efficacy results were reported. These results warrant further investigation regarding whether bevacizumab can be used in patients who are not chemotherapy naïve or have been diagnosed with earlier stage cancers.
Despite the strong evidence suggesting improved OS in patients who receive bevacizumab in addition to combination chemotherapy, there is a significant cost of bevacizumab that must be taken into account when providing treatment. The cost of chemotherapy plus bevacizumab may exceed $ 50,000. A cost-effectiveness decision model was recently published and reported that the cost of combined treatment was $53,784 compared with $5,688 for chemotherapy alone.50 Therefore, the 3.7 month OS advantage with chemotherapy and bevacizumab came at an incremental cost-effectiveness ratio of $155K per quality-adjusted life year, which approaches common cost-effectiveness standards. Moderately discounting the cost of bevacizumab or using a lower dose significantly affects its affordability.
The role of immunotherapy is a promising and exciting new area of research that can potentially lead to further advancements in the treatment of locally advanced, recurrent, or metastatic cervical cancer. Development of the immune checkpoint blockade PD-1 and CTLA-4 inhibitors has shown promise and will need to be further studied as a means to achieve a durable response in cervical cancer.
Affiliations: Drs Yu and Garcia are from the University of Southern California, Norris Comprehensive Cancer Center.
Disclosures: Drs Yu and Garcia report that they have no relevant financial conflicts of interest to disclose.
Address correspondence to: Agustin A. Garcia, MD, [email protected].
- Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29. http://www.ncbi.nlm.nih.gov/pubmed/24399786.
- International Agency for Research on Cancer. Cervical Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012. World Health Organization; 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=cervix. Accessed December 13, 2014.
- Walboomers JM, Jacobs MV, Manos MM, et al. Human papilloma-virus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12-19.
- Reis LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_05_cervix_uteri.pdf. Accessed December 13, 2014.
- NCI Press Office. NCI Issues Clinical Announcement on Cervical Cancer: Chemotherapy Plus Radiation Improves Survival. http://www.nih.gov/news/pr/feb99/nci-22.htm. Accessed December 13, 2014.
- American Cancer Society. Cervical cancer: survival rates by stage. http://www.cancer.org/Cancer/CervicalCancer/DetailedGuide/cervical-cancer-survival. Accessed December 13, 2014.
- Rutledge FN, Smith JP, Wharton JT, O’Quinn AG. Pelvic exenteration: analysis of 296 patients. Am J Obstet Gynecol. 1977;129:881-892.
- Friedlander M, Grogan M. U.S. Preventative Services Task Force. Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist. 2002;7:342-347.
- Lim MC, Lee HS, Seo SS, et al. Pathologic diagnosis and resection of suspicious thoracic metastases in patients with cervical cancer through thoracotomy or video-assisted thoracic surgery. Gynecol Oncol. 2010;116:478-482.
- Tran PT, Su Z, Hara W, et al. Long-term survivors using intraoperative radiotherapy for recurrent gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2007;69:504-511.
- Marnitz S, Dowdy S, Lanowska M, et al. Exenterations 60 years after first description: results of a survey among US and German Gynecologic Oncology Centers. Int J Gynecol Cancer. 2009;19:974-977.
- Long III HJ. Management of metastatic cervical cancer: review of the literature. J Clin Oncol. 2007;25:2966-2974.
- Thigpen T, Shingleton H, Homesley H, Lagasse L, Blessing J. Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Cancer. 1981;48:899-903.
- Coleman RE, Harper PG, Gallagher C, et al. A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol. 1986;18:280-283.
- Fleming GF, Fowler JM, Waggoner SE, Copeland LJ, Greer BE, et al. Paclitaxel has moderate activity in squamous cervix cancer. a Gynecologic Oncology Group study. J Clin Oncol. 1996;14:792-795.
- Muderspach LI, Blessing JA, Levenback C, Moore JL Jr. 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.
- Verschraegen CF, Levy T, Kudelka AP, et al. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol. 1997;15:625-631.
- Garcia AA, Blessing JA, Darcy KM, et al. Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: a gynecologic oncology group study. Gynecol Oncol. 2007;104:572-579.
- Goedhals L, van Wiyk AL, Smith BL, Fourie SJ. Pemetrexed (Alimta, LY231514) demonstrates clinical activity in chemonaive patients with cervical cancer in a phase II single-agent trial. Int J Gynecol Cancer. 2006;16:1172-1178.
- 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.
- 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.
- Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27:4649-4655.
- Kitagawa R, Katsumata N, Shibata T, et al. A randomized, phase III trial of paclitaxel plus carboplatin (TC) versus paclitaxel plus cisplatin (TP) in stage IVb, persistent or recurrent cervical cancer: Japan Clinical Oncology Group study (JCOG0505). J Clin Oncol. 2012;30(suppl; abstr 5006).
- Bookman MA, Blessing JA, Hanjani P, Herzog TJ, Andersen WA. Topotecan in squamous cell carcinoma of the cervix: A phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000;77:446-449.
- Muggia FM, Blessing JA, Method M, et al. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92:639-643.
- Miller DS, Blessing JA, Bodurka DC, Bonebrake AJ, Schorge JO; Gynecologic Oncology Group. Evaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2008;110:65-70.
- Lorusso D, Ferrandina G, Pignata S, et al. Evaluation of pemetrexed (Alimta, LY231514) as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group. Ann Oncol. 2010;21:61-66.
- Garcia AA, Blessing JA, Vaccarello L, et al. Phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Am J Clin Oncol. 2007;30:428-431.
- Schilder RJ, Blessing J, Cohn DE. Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2005;96:103-107.
- Mackay HJ, Tinker A, Winquist E, et al. A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma: NCIC CTG Trial. Gynecol Oncol. 2010;116:163-167.
- Monk BJ, Mas Lopez L, Zarba JJ, et al. Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clin Oncol. 2010; 28:3562-3569.
- Schilder RJ, Sill MW, Lee YC, Mannel R. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Int J Gynecol Cancer. 2009;19:929-933.
- Santin AD, Sill MW, McMeekin DS, et al. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;122:495-500.
- Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2009;27:1069-1074.
- Wright JD, Viviano D, Powell MA, et al. Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer. Gynecol Oncol. 2006;103:489-493.
- Takano M, Kikuchi Y, Kita T, et al. Complete remission of metastatic and relapsed uterine cervical cancers using weekly administration of bevacizumab and paclitaxel/carboplatin. Onkologie. 2009;32:595-597.
- Tewari KS, Sill MW,Long HJ, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734-743.
- Look KY, Blessing JA, Michener CM, Rubin S, Ramirez PT. Phase II evaluation of capecitabine in refractory nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Int J Gynecol Cancer. 2008;18:773-778.
- Lorvidhaya V, Chitapanarux I, Phromratanapongse P, et al. Phase II study of capecitabine (Ro 09-1978) in patients who have failed first line treatment for locally advanced and/or metastatic cervical cancer. Gan To Kagaku Ryoho. 2010;37:1271-1275.
- Katsumata N, Hirai Y, Kamiura S, et al. Phase II study of S-1, an oral fluoropyrimidine, in patients with advanced or recurrent cervical cancer. Ann Oncol. 2011;22:1353-1357.
- ClinicalTrials.gov. Phase III study of S-1 + cisplatin vs cisplatin in cervical cancer. NCT00770874.
- Hinrichs CS, Stevanovic S, Draper L, et al. HPV-targeted tumor-infiltrating lymphocytes for cervical cancer. J Clin Oncol.2014;32:5s(suppl; abstr LBA3008).
- Wallecha A, French C, Petit R, Singh, R, Amin A, Rothman J. Lm-LLO-based immunotherapies and HPV-associated disease. J Oncol. 2012;2012:542851.
- Basu P, Mehta AO, Jain MM, et al. ADXS11-001 immunotherapy targeting HPV-E7: final results from a phase 2 study in Indian women with recurrent cervical cancer. J Clin Oncol.2014;32:5s(suppl; abstr 5610).
- Nivolumab in Treating Patients With Persistent, Recurrent, or Metastatic Cervical Cancer. ClinicalTrials.gov website. NCT02257528.
- Princess Margaret Hospital Phase 2 Consortium. Ipilimumab in Treating Patients With Metastatic or Recurrent Human Papilloma Virus-Related Cervical Cancer. ClinicalTrials.gov website. NCT01693783.
- Lheureux S. Butler MO, Fleming GF, Hirte HW, et al. A phase 1/2 study of ipilimumab in women with metastatic or recurrent HPV-related cervical carcinoma: a study of the Princess Margaret and Chicago N01 Consortia. J ClinOncol. 2014;32:5s(suppl; abstr TPS5631).
- Chemoradiation Therapy and Ipilimumab in Treating Patients With Locally Advanced Cervical Cancer. ClinicalTrials.gov website. NCT01711515.
- Schefter TE, Winter K, Kwon JS, et al. A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin. Int J Radiat Oncol Biol Phys. 2012;3:1179-1184.
- Phippen NT, Leath CA 3rd, Havrilesky LJ, Barnett JC. Bevacizumab in recurrent, persistent, or advanced stage carcinoma of the cervix: Is it cost-effective? Gynecol Oncol. 2015;136:43-47.