Clinically Important Updates in Cervical Cancer Management

Bradley J. Monk, MD

Bradley J. Monk, MD

The American Cancer Society has estimated that in 2019 in the United States, approximately 13,240 new patients will receive a diagnosis of cervical cancer and 4170 individuals will die from the disease. However, because of effective screening programs using cytology and/or high-risk human papillomavirus (HPV) DNA testing in industrialized nations, incidence and mortality rates have declined.1 In 2018, the FDA granted an expanded indication for the HPV vaccine Gardasil 9 for men and women aged 27 to 45 years.²

Updates to FIGO Staging

In 2018, the International Federation of Gynecology and Obstetrics (FIGO) revised its staging system for cervical cancer with the following updates:

• FIGO 2018 stage IB now includes 3 subgroups increasing with tumor size:

o Stage IB1 involves invasive carcinoma >5 mm depth of stromal invasion and <2 cm in greatest dimension.

o Stage IB2 (formerly 2014 FIGO stage IB1) involves

invasive carcinoma >2 and <4 cm in greatest dimension.

o Stage IB3 (formerly 2014 FIGO stage IB2) involves

invasive carcinoma >4 cm in greatest dimension.

• FIGO 2018 stage IIIC is designated for disease with lymph node involvement:

o Stage IIIC involves pelvic and/or para-aortic nodes, regardless of tumor size and extent.

o Stage IIIC1 involves pelvic lymph node metastasis only. o Stage IIIC2 involves para-aortic lymph node metastasis.

• Therapy for FIGO 2018 stages IA to IB2:

o Surgery is acceptable. Cervical conization or extrafascial hysterectomy can be considered with FIGO stage IA. Trachelectomy with laparoscopic pelvic lymphadenectomy can be attempted as a fertility- preserving option for cervical lesions <2 cm in diameter. Radical hysterectomy can be considered in FIGO stage IB2.

• Therapy for FIGO 2018 stages IB3 to IVA:

o Multimodality therapy consists of concurrent chemoradiation (weekly cisplatin 40 mg/m2) comprising external-beam radiation therapy with systemic chemotherapy (CCRT) then intracavitary brachytherapy.

• Management of FIGO 2018 stages IVB and recurrent disease:

o From the GOG-0204 trial, paclitaxel 135 mg/m2 over 24 hours plus cisplatin 50 mg/m2 every 21 days emerged as the palliative standard, with an associated median survival of 7 to 12 months. Transition to a 3-hour outpatient paclitaxel regimen is common. The Japanese Clinical Oncology Group demonstrated significant noninferiority with substitution of carboplatin (area under the curve 5) for cisplatin in the phase III clinical trial JCOG0505 (HR, 0.994) but noted that carboplatin was associated with shorter overall survival among cisplatin-naïve patients.¹

The rationale to study antiangiogenesis therapy in GOG-0240, a phase III open-label randomized study of chemotherapy doublets with and without bevacizumab (Avastin) at 15 mg/kg every 21 days until progression, was based on clinical, pathologic, molecular, and therapeutic factors.¹Genitourinary and/or rectovaginal fistulas were new adverse events occurring in 8.6% of patients being treated with bevacizumab. All fistulas occurred in preirradiated patients. The triplet regimen was approved by the FDA on August 14, 2014,3 and designated category 1 by the National Comprehensive Cancer Network.⁴

Active Clinical Trials

Evidence for activity of checkpoint inhibitors is accumulating. The cervical cancer cohort of 77 women with refractory disease in the KEYNOTE-158 phase II study of pembrolizumab (Keytruda) demonstrated an objective response rate of 14.3%, with all 13 responses in PD-L1— positive tumors.⁵On June 12, 2018, the FDA granted pembrolizumab at 200 mg every 3 weeks accelerated approval as a second-line agent along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx Kit.⁶

Investigators have launched the confirmatory, front- line, placebo-controlled phase III randomized KEYNOTE- 826 trial studying platinum-based chemotherapy plus optional bevacizumab with and without pembrolizumab (NCT03635567), as well as the frontline phase III randomized BEATcc trial evaluating triplet therapy with cisplatin, paclitaxel, and bevacizumab with or without atezolizumab (Tecentriq; NCT03556839).

A second-line, phase III randomized trial, EMPOWER CERVICAL-1/GOG 3016, activated in 2017, is comparing the anti—PD-1 agent cemiplimab (Libtayo) to physician&rsquo;s choice of chemotherapy (NCT03257267).

Finally, CALLA is a 714-patient prospective international randomized clinical trial among women with newly diagnosed locally advanced high-risk cervical cancer (NCT03830866). Progression-free survival associated with standard CCRT will be compared with CCRT plus durvalumab (Imfinzi) followed by durvalumab mono- therapy for up to 24 months or until progression from the date of randomization.

References

1. Tewari KS, Monk BJ. Evidence-based treatment paradigms for management of invasive cervical carcinoma.J Clin Oncol. 2019;37(27):2472-2489. doi: 10.1200/JCO.18.02303.
2. FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old. FDA website. fda.gov/news-events/press-announcements/fda-approves-expanded-use-gardasil-9-include-individuals-27-through-45-years-old. Published October 5, 2018. Accessed October 17, 2019.
3. FDA approves Genentech&rsquo;s Avastin plus chemotherapy for treatment of advanced cervical cancer [news release]. South San Francisco, CA: Genentech; August 14, 2014. gene.com/media/press-releases/14571/2014-08-14/fda-approves-genentechs-avastin-plus-che. Accessed October 17, 2019.
4. NCCN Clinical Practice Guidelines in Oncology. Cervical Cancer, version 5.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cervical.pdf. Published September 16, 2019. Accessed October 17, 2019.
5. Cheol Chung H, Ros W, Delord J-P, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.J Clin Oncol. 2019;37(17):1470-1478. doi: 10.1200/JCO.18.01265.
6. FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. FDA website. fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-cervical-cancer-disease-progression-during-or-after-chemotherapy. Published June 12, 2018. Accessed October 17, 2019.