Innovations in the Management of Advanced Cervical Cancer: Focus on Multidisciplinary Care

The management of carcinoma of the cervix represents a remarkable dichotomy. On the one hand, we have the well-established, truly major public health success associated with population-based screening for the malignancy; more recent, increasingly solid evidence for the actual prevention of the disease as a result of effectively implemented human papillomavirus (HPV) vaccination strategies; and, finally, the documented survival benefits associated with the delivery of a multimodality radiation plus systemic chemotherapy, or chemoradiation, approach in the management of locally advanced disease.^1,2 However, on the other hand, one must now consider the unquestionably objective marginal effectiveness of current therapeutics directed to favorably influence the natural history of recurrent or metastatic cancers.

Today, the medical community possesses diagnostic tools that can detect with great sensitivity and specificity very early-stage invasive disease and pre-cursor abnormalities such as high-grade dysplasia and carcinoma in situ of cervical cancer that, in the large majority of cases, can be effectively managed with the elimination of the potential for tumor progression. Further, vaccination against the HPV types known to be etiologic in causing 70% to 90% of all cervical cancers has the potential to rather dramatically reduce the risks of the development of a cancer responsible for 600,000 new cases and over 300,000 deaths worldwide each year.^1,2

Yet, when cervix cancer is detected with documented metastatic disease or the malignancy recurs following definitive local therapy with either surgery or radiotherapy, currently available systemic antineoplastic strategies, unfortunately, remain distressingly limited in their clinical utility.

Systemic Cytotoxic Chemotherapy for Cervical Cancer

Cisplatin has been the cornerstone of the chemotherapeutic management of carcinoma of the cervix for more than 4 decades.^1,2 Over this extended time interval, randomized trials have explored various doses and schedules for delivery of this agent in the malignancy with no evidence for the superiority of a more intensive program in the management of metastatic or recurrent disease than 50 mg/m² delivered on a schedule of every 3 weeks.

Carboplatin has also been examined for its utility in this clinical setting and, although clearly active, is somewhat less preferred compared with cisplatin due to the frequent prior use of pelvic radiation in disease management. Under these circumstances, carboplatin, being more marrow suppressive than cisplatin, is associated with a greater risk of producing serous bone marrow suppression and subsequent infection.

Cisplatin-based combination chemo-therapy regimens have been extensively explored over the past several decades in the management of metastatic and recurrent disease. Today, the most widely employed combination regimen is likely cisplatin plus paclitaxel, although cisplatin plus topotecan has also been approved by the FDA for use in this clinical setting.^1,2

One clinically relevant difficulty associated with determining optimal chemo-therapy in the management of cervical cancer is the established role played by cisplatin-based chemoradiation in the multimodality management of high-risk and locally advanced disease. Several landmark phase 3 randomized trials confirmed the overall survival benefits associated with the concurrent administration of cisplatin and external beam radiation in these difficult clinical set-tings.^1,2 As a result, for a patient who sub-sequently experiences evidence of persistent or recurrent disease following the delivery of cisplatin as a radiosensitizer (eg, 50 mg/m² per week during external beam radiation), the continued utility of platinum-based chemotherapy remains quite uncertain.

However, as is the well-documented experience in ovarian cancer, limited retrospective data suggest that patients with cervical cancer who previously received cisplatin-based therapy, likely as a component of a chemoradiation regimen and who recur after a reasonably extended period of time, have a reasonable opportunity to experience clinical benefit following reintroduction of this class of agents. In 1 report, patients with a platinum- free interval (PFI) between 12 and 23 and those with PFI greater than 24 months achieved an objective response rate (ORR) of 22% versus 55%, respectively.³

In an effort to develop a non–platinum-based systemic chemotherapy program that might be effectively utilized where a patient has previously received cisplatin as a component of a chemoradiation strategy, the National Cancer Institute–affiliated Gynecologic Oncology Group (GOG) directly compared the combination of cisplatin plus paclitaxel to a non–platinum-containing regimen of paclitaxel plus topotecan in metastatic or recurrent carcinoma of the cervix.² Unfortunately, the results failed to reveal any evidence for the superiority of the non–platinum-containing regimen despite the prior delivery of platinum to this patient population. Further, the 2-drug combination of paclitaxel and topotecan might represent the 2 most “active” nonplatinum cytotoxic agents in the malignancy. No other experience is required to emphasize the magnitude of the limited utility of cytotoxic drugs in cervical cancer.

Although other single agents in this class may be used to provide some degree of palliative relief for individual patients with cervical cancer, the overall efficacy of such a strategy is marginal, with ORRs anticipated to be less than 10%. In addition, tumor regressions in this set-ting are generally of short duration.

It should also be noted that the likelihood of a clinical response being observed in the setting of recurrent or metastatic cervix cancer will be reduced in body regions (eg, pelvis) previously exposed to external beam radiation, likely due to limited blood supply and the presence of a resistant cancer cell population. GOG investigators observed several clinical features that predicted a reduced likelihood of response in an analysis of their experience with platinum-based chemotherapy in addition to previous pelvic radiotherapy. These features included performance status higher than 0, prior treatment with a chemosensitization regimen, time interval from diagnosis to first recurrence of less than 1 year, presence of pelvic disease, and being African American.⁴

Bevacizumab in the Systemic Management of Cervical Cancer

GOG Investigators subsequently examined the efficacy of the antiangiogenic agent, bevacizumab (Avastin), in a group of patients with persistent and recurrent cervical cancer and observed an ORR of 11% (n = 46 patients) with a median duration of response of 6.2 months.⁵ The toxicity profile of the agent was similar to that observed and anticipated in a relatively heavily pretreated patient population.

These data led to the initiation of a some-what complex randomized trial (NCT00803062) with a 2 × 2 factorial design examining the addition of bevacizumab to a regimen of cisplatin plus paclitaxel or paclitaxel plus topotecan in patients with recurrent, persistent, or metastatic cervical cancer. The addition of bevacizumab led to a statistically significant improvement in median overall survival (17.0 vs 13.3 months, respectively; HR, 0.71; P = .004).^6,7

The FDA has approved bevacizumab for the treatment of metastatic cervical cancer; however, the addition of the agent to cytotoxic chemotherapy is restricted to a patient population with a reasonably good performance status (Table⁸). Further, the adverse effects of bevacizumab, particularly wound healing and the potential for vascular complications, need to be carefully considered for patients undergoing surgery of curative or palliative intent as a component of a multidisciplinary treatment plan.

Table. Approval Snapshot⁸ Bevacizumab (Avastin)

Immunotherapeutic Approaches in Cervical Cancer Management

The current focus in innovative strategies for the management of advanced cervical cancer is in the domain of immunotherapy. Similar to clinical situations across cancer types, several checkpoint inhibitors have been examined in patients who have recurrent or persistent disease after primary treatment, including cisplatin-based therapies. Evidence of therapeutic benefit, including objective responses (approximately 10%-20%) often of unexpected prolonged duration (> 6 months), has been confirmed.^9-14

In addition, a number of novel strategies, including combination checkpoint inhibitors, tumor vaccines, and adoptive T-cell therapies, are under active investigation in the management of recurrent and persistent cervical cancer.² Investigators anticipate that over the next several years, 1 or more of these approaches will be demonstrated to favorably affect the natural history of this difficult malignancy.

References

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2. Tewari K, 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
3. Matoda M, Tanigawa T, Omatsu K, et al. Platinum-free interval in second-line chemotherapy for recurrent cervical cancer. Int J Gynecol Cancer. 2013;23(9):1670-1674. doi:10.1097/IGC.0b013e3182a80a07
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6. Tewari KS, Sill MW, Long JH, et al. Improved survival with bevacizumab in advanced cervical cancer. doi:10.1056/NEJMoa1309748. N Engl J Med. 2014;370(8):734-743. Published correction in N Engl J Med. 2017;377(7):702.
7. Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomized, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017;390(10103):1654-1663. doi:10.1016/S0140-6736(17)31607-0
8. Avastin. Prescribing information. Genentech Inc; 2020. Accessed October 20, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125085s336lbl.pdf
9. Dyer BA, Zamarin D, Eskandar RN, et al. Role of immunotherapy in the management of locally advanced and recurrent/metastatic cervical cancer. J Natl Compr Canc Netw. 2019;17(1):91-97. doi:10.6004/jnccn.2018.7108
10. Tewari KS. Immune checkpoint blockade in PD-L1-positive platinum-refractory cervical cancer. J Clin Oncol. 2019;37(17):1449-1454. doi:10.1200/JCO.19.00119
11. Frenel J-S, Le Tourneau CL, O’Neil B, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. 2017;20(36):4035-4041. doi:10.1200/JCO.2017.74.5471
12. Chung HC, Ros W, Deford JP, et al. Efficacy and safety of pembrolizumab in previously treated cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37(17):1470-1478. doi:10.1200/JCO.18.01265
13. Naumann RW, Hollebecaue A, Meyer T, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial. J Clin Oncol. 2019;37(31):2825-2834. doi:10.1200/JCO.19.00739
14. Santin AD, Deng W, Frumovitz M, et al. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). Gynecol Oncol. 2020;157(1):161-166. doi:10.1016/j.ygyno.2019.12.034