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Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology

Cervical Cancer: Evolutions in the Standard of Care. Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member

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Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology

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  1. Cervical Cancer:Evolutions in the Standard of Care Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member University of Arizona Cancer Center-Phoenix Arizona USA

  2. The Global Burden of Cancer to Women Worldwide New Cases Annually Deaths Annually • 9% of all new cancer cases • 8% of total cancer deaths • 85% of deaths occur indeveloping countries Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.

  3. Age-Standardized Cervical Cancer Rates in 2008 Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.

  4. Papillomaviruses inHuman Cancer •1842: Rigoni-Stern – prostitutes higherincidence of cervical cancer than nuns •1951: George Otto Gey- HeLa(Henrietta Lacks) cells •1928: GeorgiousPapanicolaou- “Pap smear” •1983: HaraldzurHausen- discovers HPV •2008: HaraldzurHausen- wins Nobel Prize HaraldzurHausen

  5. Infection With Oncogenic HPV Is Necessary to Cause Cervical Cancer1 Non-oncogenic Infections Oncogenic Infections Commonly caused by HPV types 16 & 18 Persistent Infection Persistent Infection Mild Cervical Lesions Non-oncogenic infections do not lead to precancerous lesions or cervical cancer2 Precancerous Lesions Cervical Cancer Mild Cervical Lesions/ Genital Warts Most HPV infections will clear, and most cervical lesions will not progress3-5 1. Walboomers J et al. J Pathol. 1999;189:12-19. 2. Trottier H, Franco E. Vaccine. 2006;24S1:S4-15. 3. Moscicki A et al. Vaccine. 2006;24S3:42-51. 4. Einstein M. Cancer Immunol Immunother.2008;57:443-51. 5. Östör A.Int J GynecolPathol. 1993;12:186-92.

  6. Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS Tumor Hypoxia and Viral OncogenesDrive Angiogenesis in Cervical Neoplasia HPV E6 p53 degradation TSP-1 VEGF angiogenesis Anti-VEGF therapy Displacement of HDAC1, HDAC4, HDAC7 HIF1α HPV E7 pRb inactivation p21-RB pathway dysregulation Tewari KS, et al. GynecolOncol 2000;77:137-48. Monk BJ, et al. J ClinOncol. 2009;27(7):1069-74. http://www.microbiologybytes.com/virology/Papillomaviruses.html

  7. Evolution of an HPV infection HPV Disappearance 1-2 y3,4,6 ~6–9 mo5,6 Colposcopy demonstrates abnormal vasculature and angiogenesis dependent progression CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HR, high risk. 1. Schiffman M, Kjaer SK. J Int Cancer Natl Monogr. 2003;31:14-19; 2. Ostör AG. Int J Gynecol Pathol. 1993;12:186-192;

  8. Radical hysterectomy • Used to treat cervical cancers with invasion > 3mm but confined to the cervix and vagina < 4 cm (Stage IA2 –IB1) • Removal of parametrium and upper vagina

  9. Wertheim Wertheim E: Zurfrage der radikaloperationbeimuteruskebs. Arch Gynecol 61:627, 1900 Wertheim E: Discussion on the diagnosis and treatment of carcinoma of the uterus. BMJ 2:689, 1905 Wertheim E: The extended abdominal operation for carcinoma uteri. Translated by Grad H Am J Obstet Dis Women Child 66:169, 1912

  10. Acceptable Alternatives to Radical Abdominal Hysterectomy and Lymphadenectomy forStage IA2 and IB1 Cervical Cancer • Radical traechelectomy (or cone) and nodes (Fertility sparing) • Intracavitary brachytherapy and pelvic RT +/- chemo • Laparoscopic radical hysterectomy and nodes • Robotic radical hysterectomy and nodes • Simple hysterectomy and nodes

  11. When is RT or Chemo/RT Indicated After Radical Hysterectomy? Radiation if two of the following: • deep invasion, large tumor or vascular invasion • GOG 92 (Sedlis A et. al GynOnc 73:177-183, 1999) Chemo-RT if one of the following: • Positive margin, parametrial extension, positive node • GOG 109 (Peters WA et. al. J Clinic Oncol 18:1606-1613, 2000) RT=Radiation therapy

  12. Early Stage Intermediate Risk Cervical Cancer • Large, deeply invasive tumors with vascular invasion limited to the cervix after radical hysterectomy • GOG 92 established to role of postoperative pelvic radiation (Sedlis et al Gyn Oncol 73, 177–183 1999)

  13. GOG/KGOG 263(GOG 92 Replacement) Stage IA2-IB2: Large, deeply invasive tumors with vascular invasion limited to the cervix after radical hysterectomy Pelvic Radiation RANDOMIZE Pelvic Radiation and Weekly cisplatin (CCRT) PI = SANG YOUNG RYU N = 480 Primary Endpoint = RFS

  14. Early Stage High Risk Cervical Cancer • Positive nodes, parametrial extension, positive margins after radical hysterectomy • GOG 109 established the role of postoperative cisplatin and pelvic radiation (Peters WA et al J Clin Oncol. 2000 Apr;18(8):1606-13) OS Probability

  15. RTOG 0724 (GOG 109 Replacement) Stage IA2-IB2: Positive nodes, parametrial extension, positive margins after radical hysterectomy Pelvic Radiation and Weekly cisplatin (CCRT) RANDOMIZE Pelvic Radiation and Weekly cisplatin (CCRT) followed by carboplatin + Paclitaxel x 4 cycles PI = Anuja Jhingran N = 400 Primary Endpoint = DFS

  16. What is the Global Standard Therapy for Stage IB2 - IVA? • External beam pelvic radiation (40 to 60 Gy) • Brachytherapy (8,000 to 8,500 cGy to Point A) • I.V. Cisplatin chemotherapy • Cisplatin 40mg/m2 (Max dose 70mg) IV q wk during RT (6wks) • GOG 120 (Rose PG et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. NEJM 340(15):1144, 1999 Monk et al J Clin Oncol 25:2952-2965. 2007

  17. Standard Anterior and Lateral External-beam Irradiation Ports Used to Treat LocallyAdvanced Cervical Carcinoma Limited to the Pelvis Monk et al J Clin Oncol 25:2952-2965. 2007

  18. THE OUTBACK TRIAL/GOG 0274A Phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone Linda Mileshkin on behalf of ANZGOG Kathleen Moore on behalf of the GOG ClinicalTrials.gov Identifier: NCT01414608

  19. Design • Stage IB2-IVa • Cervical cancer: • Stratify for • FIGO stage • Pelvic nodal involvement • Uterine +ve on MRI 4 cycles Carboplatin + Paclitaxel Standard chemoXRT Standard chemoXRT ClinicalTrials.gov Identifier: NCT01414608

  20. Summary of Primary Treatment • Early stage cervical cancer usually cured with radical local excision • Randomized trials have established role of adjuvant CCRT • CCRT used to treat locally advanced disease • Tumor stage, tumor grade, race, age and angiogenesis independently prognostic • Anti-angiogenic agents rationale and underdevelopment

  21. Chemotherapy for Recurrent Cervical Cancer - Lessons Learned in the 80’s and 90’s • Platinum-based therapies most effective • Cisplatin more active than carboplatin • Two ways to increase response without prolongation in Survival • Increase platinum dose • Add Ifosfomide to cisplatin • Single agent cisplatin at 50 mg/m2 became standard

  22. GOG 204 Regimen 1 Paclitaxel 135 mg/m2 over 24 hours and CDDP 50 mg/m2 repeated q 3 wks for 6 cycles Primary Stage IVB or recurrent/persistent carcinoma of the cervix measurable disease GOG performance status 0-1 ANC  1500/µl platelets 100,000/µl serum creatinine 1.5 mg/dl no CNS disease no past or concomitant invasive cancer no prior chemotherapy (unless concurrent with radiation) R A N D O M I Z E Regimen 2 Vinorelbine30 mg/m2 IV bolus day1 and 8 and CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles Regimen 3 Gemcitabine 1000mg/m2 IV day 1 and 8 and CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles Regimen 4 Topotecan0.75 mg/m2 over 30 minutes days 1, 2, & 3 CDDP 50 mg/m2 IV day 1, q 3 wks for 6 cycles ALL REGIMENS Quality of life Assessment: Baseline Before cycle 2 Before cycle 5 9 mo. after study entry at follow-up visit BJ Monk et al J ClinOncol. 2009 Oct 1;27(28):4649-55.

  23. By Treatment Group 1.0 0.9 Treatment Alive Alive Alive Alive Dead Dead Dead Dead Total Total Total Total CIS+PAC 29 74 103 0.8 CIS+VIN 23 85 108 CIS+GEM 20 92 112 CIS+TOP 22 89 111 0.7 0.6 Proportion Surviving 0.5 0.4 0.3 0.2 0.1 0.0 0 12 24 36 Months on Study GOG 204: Overall Survival BJ Monk et al J ClinOncol. 2009 Oct 1;27(28):4649-55.

  24. (www.jcog.jp/en/) Multicenter (30 Specialized Institutions), Randomized Phase III Trial JCOG 0505 Trial Design R A N D O M I Z E* Standard arm: TP Paclitaxel 135mg/m224hd1 Cisplatin 50mg/m2 2h d2 Stage IVB, persistent or recurrent cervical cancer; not amenable to curative surgery / radiotherapy every 21 days for 6 cycles • * Balancing factors: • Tumors outside of the prior irradiation field • (yes or no) • PS 0-1 or 2 • SCC or non-SCC • Institution Experimental arm: TC Paclitaxel 175mg/m23hd1 Carboplatin AUC 5 1h d1 ClinicalTrials.gov Identifier:NCT00295789 Kitagawa R, et al. J ClinOncol. 2012;30(Suppl): Abstract 5006.

  25. (www.jcog.jp/en/) 25253 patients enrolled and randomly assigned Trial Profile 2/21/2006 ～ 11/20/2009 127assigned to TP 126 assigned to TC 4 ineligible 5 ineligible 25Maximum 6 cycles of treatment until disease progression or unacceptable toxicity 123 efficacy analysis 125 safety analysis 121 efficacy analysis 126 safety analysis Kitagawa R, et al. J ClinOncol. 2012;30(Suppl): Abstract 5006.

  26. (www.jcog.jp/en/) Best Response – RECIST v1.0Women With Target Lesions ** Fisher’s exact test * NE due to missing data Kitagawa R, et al. J ClinOncol. 2012;30(Suppl): Abstract 5006.

  27. Overall Survival (www.jcog.jp/en/) HR: 0.994 [90% CI: 0.789-1.253 (<1.29)] noninferiority one-sided P = .032# #stratified Cox regression with “tumors outside prior irradiation field[yes/no]” as strata Kitagawa R, et al. J ClinOncol. 2012;30(Suppl): Abstract 5006.

  28. Beyond GOG 204 Novel Agents and Non-platinum Doublets

  29. Failed first-line cytotoxic drug treatment • 125 mg/m(2) IV over 30 minutes on days 1, 8, and 15 of each 28 day cycle • Median PFS = 5.0 months • Median OS = 9.4 months • 10 (28.6%; CI 14.6%-46.3%) of 35 patients = PR • 15 patients (42.9%) had SD Alberts DS, et al. GynecolOncol. 2012;127(3):451-455.

  30. Anti-VEGF antibodies (bevacizumab) Anti-VEGFR antibodies P P P P P P P P Agents Targeting the VEGF Pathway VEGF Soluble VEGFRs (VEGF-TRAP) VEGFR-1 VEGFR-2 Endothelial cell Small-molecule inhibitors Podar and Anderson. Blood. 2005;105:1383.

  31. GOG 227-C • Persistent or recurrent squamous cervical cancer • 1-2 prior cytotoxic regimens (not including initial chemo-RT) • Measurable disease • GOG PS ≤ 2 Bevacizumab 15 mg/kg IV q 21 days until disease progression or prohibitive toxicity Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD. J Clin Oncol. 2009 Mar 1;27(7):1069-74.

  32. GOG 227-C Bevacizumab PFS of Bev (Blue) versus GOG Historical Database(Failing one or two cytotoxic regimens, not including chemo-RT) GOG Historical Database(Failing one or two cytotoxic regimens, not including chemo-RT) Monk BJ et al J Clin Oncol. 2009 Mar 1;27(7):1069-74.

  33. GOG 240 Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 ANC 1500/µL Platelets 100,000/µL Serum creatinine1.5 mg/dL No CNS disease No past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation) Regimen 1** Paclitaxel* + CDDP 50 mg/m2 Regimen 2** Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg R A N D O M I Z E Regimen 3** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan0.75 mg/m2 over 30 mins days 1-3 Regimen 4** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan 0.75 mg/m2 over 30 mins days 1-3 + Bevacizumab 15/mg/kg ALL REGIMENS Quality of life Assessment: Baseline Before cycle 2 Before cycle 5 9 mo. after study entry at follow-up visit * 135 mg/m2 over 24 or 175 mg/m2 over 3 hours ** Cycles repeated q21 days to progression/toxicity Open to enrollment April 6, 2009 Closed to enrollment Jan 3, 2012 Sample size = 452 OS HR reduction of 30% Study Chair = KS Tewari ClinicalTrials.govIdentifier: NCT00803062 TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43.

  34. GOG 240 – Non-platinum Objective Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 ANC 1500/µL Platelets 100,000/µL Serum creatinine1.5 mg/dL No CNS disease No past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation) Regimen 1** Paclitaxel* + CDDP 50 mg/m2 Regimen 2** Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg R A N D O M I Z E Regimen 3** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan0.75 mg/m2 over 30 mins days 1-3 Regimen 4** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan 0.75 mg/m2 over 30 mins days 1-3 + Bevacizumab 15/mg/kg ALL REGIMENS Quality of life Assessment: Baseline Before cycle 2 Before cycle 5 9 mo. after study entry at follow-up visit * 135 mg/m2 over 24 or 175 mg/m2 over 3 hours ** Cycles repeated q21 days to progression/toxicity Open to enrollment April 6, 2009 Closed to enrollment Jan 3, 2012 Sample size = 452 OS HR reduction of 30% Study Chair = KS Tewari ClinicalTrials.govIdentifier: NCT00803062 TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43.

  35. GOG 240 – Bevacizumab Objective Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 ANC 1500/µL Platelets 100,000/µL Serum creatinine1.5 mg/dL No CNS disease No past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation) Regimen 1** Paclitaxel* + CDDP 50 mg/m2 Regimen 2** Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg R A N D O M I Z E Regimen 3** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan0.75 mg/m2 over 30 mins days 1-3 Regimen 4** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan 0.75 mg/m2 over 30 mins days 1-3 + Bevacizumab 15/mg/kg ALL REGIMENS Quality of life Assessment: Baseline Before cycle 2 Before cycle 5 9 mo. after study entry at follow-up visit * 135 mg/m2 over 24 or 175 mg/m2 over 3 hours ** Cycles repeated q21 days to progression/toxicity Open to enrollment April 6, 2009 Closed to enrollment Jan 3, 2012 Sample size = 452 OS HR reduction of 30% Study Chair = KS Tewari ClinicalTrials.govIdentifier: NCT00803062 TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43.

  36. HR 1.20 (98.74% CI 0.82-1.76; 1-sided p=0.880) • Median OS: 15 m (CP) and 12.5 m (TP) • RR: 38.4% (CP), 28.7% (TP) [2-sided p=0.0364] • CR: n=26 (CP), n=16 (TP) p=NS GOG 240 – Non-platinum Objective 1.0 0.9 0.8 Cisplatin-Paclitaxel backbone 0.7 0.6 0.5 Proportion Surviving Topotecan-Paclitaxel backbone 0.4 0.3 0.2 0.1 0.0 0 12 24 Months on Study Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.

  37. GOG 240 – Non-platinum Objective Overall Survival - Prior Platinum Exposure Cisplatin-Paclitaxel backbone Cisplatin-Paclitaxel backbone Topotecan-Paclitaxel backbone Topotecan-Paclitaxel backbone HR 1.35 (95% CI 0.676-2.688) RR: 54% (CP) vs 42% (TP) HR 1.18 (95% CI 0.84-1.65) RR: 34% (CP) vs 24% (TP) Prior Cisplatin No Prior Cisplatin Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.

  38. GOG 240 – Bevacizumab Objective Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 ANC 1500/µL Platelets 100,000/µL Serum creatinine1.5 mg/dL No CNS disease No past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation) Regimen 1** Paclitaxel* + CDDP 50 mg/m2 Regimen 2** Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg R A N D O M I Z E Regimen 3** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan0.75 mg/m2 over 30 mins days 1-3 Regimen 4** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan 0.75 mg/m2 over 30 mins days 1-3 + Bevacizumab 15/mg/kg ALL REGIMENS Quality of life Assessment: Baseline Before cycle 2 Before cycle 5 9 mo. after study entry at follow-up visit * 135 mg/m2 over 24 or 175 mg/m2 over 3 hours ** Cycles repeated q21 days to progression/toxicity Open to enrollment April 6, 2009 Closed to enrollment Jan 3, 2012 Sample size = 452 OS HR reduction of 30% Study Chair = KS Tewari ClinicalTrials.govIdentifier: NCT00803062

  39. GOG 240 – Bevacizumab Objective 1.0 0.9 0.8 0.7 0.6 Proportion Progression-Free 0.5 0.4 0.3 0.2 0.1 0.0 0 12 24 36 Months on Study TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43. Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS

  40. Cisplatin + Paclitaxel Cohort N=229 GOG 240 – Bevacizumab Objective 1.0 0.9 0.8 0.7 0.6 0.5 Proportion Surviving 0.4 0.3 0.2 0.1 0.0 0 12 24 36 Months on Study TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43. Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS

  41. GOG 240: OS and Prognostic Factors 0.0 0.5 1.0 1.5 2.0 2.5 Experimental Better Control Better = HR does not cross 1.0 TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43. Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS

  42. GOG 240: Treatment Exposure andSpecific Adverse Events *p<0.05 TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43. Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS

  43. FACT for Cervical Cancer – Trial Outcome Index • Physical well-being (7 items) • Functional well-being (7 items) • Cervix Cancer subscale (15 items) • Score range: 0-116 points • Clinically meaningful change: 4-5 points • Compliance with completion of HRQoL questionnaires ranged from 96% pre-cycle 1 to 63% 9 mos post-cycle 1 and was balanced across arms GOG 240: Health Related Quality of Life Yost KJ, Eton DT. Eval Health Prof 2005;28:172-91.

  44. Patients receiving bevacizumab reported 1.2 points lower on average (not significant) GOG 240: Mean FACT-Cx TOI 120 Chem Alone Chemo + Bev 110 100 90 80 70 60 98.75% CI -4.1 – 1.7 P=0.3 Score 50 40 30 20 10 0 Pre-cycle 1 Pre-cycle 2 Pre-cycle 5 5 mos post cycle 1 9 mos post cycle 1 Assessment Time TewariKS et al N Engl J Med. 2014 Feb 20;370(8):734-43. Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS

  45. Progress in Survival in Advanced and Recurrent Cervical Cancer GOG 240 Cisplatin + Palcitaxel + Bevacizumab Months     GOG 64 Cisplatin Year

  46. Adding Bevacizumab to Chemotherapy Improves Survival Bev = bevacizumab; NSCLC = non-small cell lung cancer; IFL = Irinotecan, 5-FU, leucovorin;PC = paclitaxel and carboplatin; TP = paclitaxel and cisplatin; TT = topotecan and paclitaxel http://www.gene.com/download/pdf/avastin_prescribing.pdf

  47. Summary of Treatment for Recurrent Disease • Only pelvic exenteration curative for central pelvic recurrences • Cisplatin doublets plus bevacizumab standard in treating metastatic disease • Will bevacizumab gain regulatory approval?

  48. Thank You

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