1. Optimal Approaches for Patients With Recurrent or Metastatic Cervical Cancer This program is supported by an educational grant from AstraZeneca.

2. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Faculty Benjamin E. Greer, MD Professor University of Washington School of Medicine Medical Director Seattle Care Alliance Network Seattle, Washington

3. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Faculty Disclosures Benjamin E. Greer, MD, has no relevant financial relationships to disclose.

4. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Cervical Cancer: Epidemiology  Approximately 85% of global cervical cancers occur in developing countries [2] 1. American Cancer Society. 2015. 2. International Agency for Research on Cancer, World Health Organization. Cervical Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx IncidenceCasesDeaths United States [1] 12,9004100 Global [2] 528,000266,000

5. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Cervical Cancer: Vaccines  Persistent HPV infection is the most important factor in the development of cervical cancer  HPV vaccines now routinely available in Europe and United States [1] –Quadrivalent: females 9-26 yrs of age –Bivalent: females 9-18 yrs of age  Additional HPV vaccines in late-phase development –9-valent vaccine after 4-valent HPV vaccination [2] –9-valent L1 virus-like particle in females 9-15 yrs of age [3] 1. Yildirim JG, et al. Asian Pac J Cancer Prev. 2014;15:10053-10056. 2. ClinicalTrials.gov. NCT01047345. 3. ClinicalTrials.gov. NCT00943722.

6. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Treating stage IB2-IVA cervical cancer by imaging results NCCN Guidelines ® : Cervical Cancer v2.2015 Positive adenopathy by CT, MRI, and/or PET  Pelvic node positive, para-aortic node negative –Pelvic RT + cisplatin-containing chemotherapy + brachytherapy (category 1) ± para-aortic lymph node RT or –Extraperitoneal or laparoscopic LN dissection –Para-aortic negative: pelvic RT + concurrent cisplatin-containing chemotherapy + brachytherapy (category 1) –Para-aortic node positive: extended-field RT with concurrent cisplatin-containing chemotherapy + brachytherapy  Pelvic node positive, para-aortic node positive –Consider extraperitoneal or laparoscopic LN dissection, followed by extended-field RT with concurrent cisplatin-containing chemotherapy + brachytherapy  Distant metastases (biopsy confirmed as needed) –Systemic therapy ± individualized RT NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ): Cervical Cancer, version 2.2015.

7. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Treating stage IB2-IVA cervical cancer by node status NCCN Guidelines ® : Cervical Cancer v2.2015  Pelvic node positive, para-aortic node negative by surgical staging –Pelvic RT + cisplatin-containing chemotherapy + brachytherapy (category 1)  Para-aortic node positive by surgical staging (further radiologic workup as clinically indicated) –If negative for distant metastasis, extended-field RT + cisplatin-containing chemotherapy + brachytherapy –If positive for distant metastasis (consider biopsy of suspicious areas as indicated), systemic therapy ± individualized RT NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ): Cervical Cancer, version 2.2015.

8. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Cervical Cancer: Central Recurrence  Pelvic exenteration for central pelvic recurrent disease in selected cases –5-yr OS rate: ~ 50% –Surgical mortality rate < 5%  Negative effect on quality of life with frequent postoperative complications  Despite high morbidity rate, pelvic exenteration is potentially curative in pts with no other treatment options 1. Tanaka S, et al. Int J Clin Oncol. 2014;19:133-138. 2. Yoo HG, et al. J Gynecol Oncol. 2012;23:242-250. 3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ): Cervical Cancer, version 2.2015.

9. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Local/Regional Recurrence: Therapy for Relapse NCCN Guidelines ® for Cervical Cancer (v.2.2015)  No prior RT or failure outside of previously treated field (consider surgical resection, if feasible) –Tumor-directed RT + platinum-based chemotherapy ± brachytherapy –For additional recurrence, consider clinical trial, or chemotherapy, or best supportive care  Previous RT –Central disease: pelvic exenteration ± intraoperative RT (category 3 for IORT), or in carefully selected pts with small (< 2 cm) lesions, radical hysterectomy or brachytherapy –For additional recurrence, consider clinical trial, or chemotherapy, or best supportive care –Noncentral disease: tumor-directed RT ± chemotherapy, or resection with IORT for close or positive margins (category 3 for IORT), or clinical trial, or chemotherapy, or best supportive care NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ): Cervical Cancer, version 2.2015.

10. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Chemotherapy for Recurrent or Advanced Cervical Cancer  Recurrent or advanced cervical cancer has a poor prognosis  Since 1995, approximately 40 phase II GOG studies have been published –Results showed response rates < 10% in most studies Gien L, et al. GOG Symposium 2015.

11. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Chemotherapy for Recurrent or Advanced Cervical Cancer: Meta-analysis  35 phase II protocols  N = 1348  Only eligible and evaluated pts included (10% excluded): N = 1237 Gien L, et al. GOG Symposium 2015.

12. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Chemotherapy for Recurrent or Advanced Cervical Cancer: Response Rates  N = 1237  CR or PR: 154 (12.4%) –CR: 34 (2.7%) –PR: 120 (9.7%) Gien L, et al. GOG Symposium 2015.

13. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Chemotherapy for Recurrent or Advanced Cervical Cancer: Results  Sobering results with 11% PR among 1348 pts  Factors significant for tumor response are similar –Performance status –Prior platinum-based chemotherapy –Relapse within 1 yr –Black race Gien L, et al. GOG Symposium 2015.

14. Advances in Ovarian and Cervical Cancers: Case-Based Discussions Recurrent or Metastatic Cervical Cancer: Chemo ± Bevacizumab (GOG-240)  Regimens –Cisplatin/paclitaxel (CP) –Topotecan/paclitaxel (TP)  Bevacizumab associated with more toxicity: hypertension, thromboembolic events, and gastrointestinal fistula –Cisplatin/paclitaxel + bevacizumab –Topotecan/paclitaxel + bevacizumab Tewari KS, et al. N Engl J Med. 2014;370:734-743. 100 80 60 40 20 0 PFS (%) 0 6 12 18 24 Mos Since Randomization HR: 1.39 (95% CI: 1.09-1.77; 2-sided P =.008) Median PFS: 7.6 mos (CP) vs 5.7 mos (TP) CP with or without bevacizumab TP with or without bevacizumab 100 80 60 40 20 0 OS (%) 0 6 12 18 24 Mos Since Randomization HR: 1.20 (99% CI: 0.82-1.76; 1-sided P =.88) Median OS: 15.0 mos (CP) vs 12.5 mos (TP) CP with or without bevacizumab TP with or without bevacizumab Cisplatin Topotecan Events, n (%) 81 (35) 93 (42)

15. Advances in Ovarian and Cervical Cancers: Case-Based Discussions NCCN Recommended Regimens for Recurrent or Metastatic Cervical Cancer  First combination therapy: –Cisplatin/paclitaxel/bevacizumab (category 1) –Cisplatin/paclitaxel (category 1) –Topotecan/paclitaxel/bevacizumab (category 1) –Carboplatin/paclitaxel –Cisplatin/topotecan –Topotecan/paclitaxel –Cisplatin/gemcitabine (category 3)  Possible first-line single-agent therapy: –Cisplatin (preferred) –Carboplatin –Paclitaxel  Second-line therapy (all category 2B): –Bevacizumab –Docetaxel –5-FU –Gemcitabine –Ifosfamide –Irinotecan –Mitomycin –Topotecan –Pemetrexed –Vinorelbine NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ): Cervical Cancer, version 2.2015.

16. Go Online for More CCO Coverage of Ovarian & Cervical Cancer Additional CME-certified activities on Ovarian and Cervical Cancer clinicaloptions.com/oncology