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Cervix landmark trials- kiran

Cervix landmark trials

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Cervix landmark trials- kiran

  1. 1. LANDMARK CLINICAL TRIALS IN CERVIX CANCER Dr . Kiran Kumar BR Reference: 1.Perez & Brady’s Principles and Practice of Radiation Oncology Seventh Edition 2.FIGO Cancer Report 2018
  2. 2. Out Line • Early Lesions • Locally Advanced Lesions • Metastatic Setting • Role of Neoadjuvant Chemotherapy
  3. 3. Early Lesions: Surgery Versus Radiation Landoni et al. published results of a prospective, randomized trial of radiation therapy versus surgery; 469 women with stage IB and IIA cervical carcinoma were referred for treatment and 343 were randomized (172 to surgery and 171 to radiation therapy). Postoperative irradiation was delivered after surgery for women with surgical stage pT2b or greater, <3 mm of cervical stromal invasion and cut-through margins, or positive pelvic nodes. Median follow-up was 87 (range 57–120) months.
  4. 4. Results The overall and disease-free actuarial 5-year survival for all patients were 83% and 74%, respectively, and did not differ significantly between the groups.
  5. 5. Results
  6. 6. After a median follow-up of 87 months (range, 57 to 120 months), 5- year overall survival and DFS rates were nearly identical in the surgery and radiation therapy groups (83% and 74%, respectively). Recurrent disease developed in 86 women: 42 (25%) in the surgery group and 44 (26%) in the radiation therapy group. Forty-eight patients (28%) in the surgery group had severe morbidity, compared with 19 (12%) in the radiation therapy group (P = .0004). The combination of surgery and radiation therapy had the worst morbidity, especially urologic complications.
  7. 7. 5-year actuarial survival stratified by cervical diameter was similar in the surgery and radiotherapy groups (diameter 4 cm: 87% vs 90%; diameter >4 cm: 70% vs 72%; figure 3, table 3). 5-year actuarial disease-free survival for the surgery and radiotherapy groups was 80% and 82%, respectively, for patients whose cervical diameter was 4 cm or smaller, and 63% and 57% for those with a diameter larger than 4 cm; the betweengroup differences were not significant. The two groups did not differ significantly as regards squamous histological type: overall 5-year survival rates were 84% in surgery-group patients and 88% in radiotherapy-group patients; overall disease-free survival was 76% and 78%, respectively. For rates of adenocarcinoma there was a significant advantage for patients who had surgery compared with those who had radiotherapy in both overall survival (70% vs 59%, p=0·05) and disease-free survival (66% vs 47%, p=0·02).
  8. 8. Conclusion Most women with stage Ib–IIa cervical cancer can be treated successfully with radiotherapy, whereas a judicious selection of patients is necessary before planning primary radical surgery. Histological type should be included in the selection criteria, because our data show that radiotherapy was less effective than surgery for adenocardinoma of the cervix. This finding should resolve some of the conflicting approaches to this issue. Results suggest that the optimum candidates for primary radical surgery are women with normal ovarian function and cervical diameters of 4 cm or smaller, whereas radiotherapy is preferable for postmenopausal women. Women whose cervical diameters are larger than 4 cm should be identified before surgery so that they can benefit from tailored treatment: radical radiotherapy, with the option of concomitant radiosensitising chemotherapy to improve the local control of the disease, or cisplatin based chemotherapy followed by radical surgery.
  9. 9. Randomized study between radical surgery and radiotherapy for the treatment of stage IB–IIA cervical cancer: 20-year update (2017) Minimum follow-up was 19 years. Thirty-three patients (10%) died of intercurrent disease (31 cases) or fatal complications (2 cases). Twenty-year overall survival is 72% and 77% in the 2 treatment groups (p=0.280), respectively. Conclusion: The results of the study seem to suggest that there is no treatment of choice for early stage cervical carcinoma in terms of survival. Long term follow-up confirms that the best treatment for the individual patient should take into account clinical factors such as menopausal status, comorbidities, histological type, and tumor diameter.
  10. 10. Adjuvant Radiation
  11. 11. One randomized study showed improved recurrence-free survival with postoperative pelvic irradiation (46 to 50.4 Gy in 23 to 28 fractions) after radical surgery in the presence of positive pelvic nodes or node-negative high-risk factors in women with stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. There were 277 eligible patients with at least two of the following risk factors: greater than one-third stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter; 137 patients were randomized to pelvic radiation therapy and 140 to no further treatment. The results were updated by Rotman et al. 24 (17%) patients in the irradiation group and 43 (30.7%) in the no-further-treatment group had cancer recurrences.
  12. 12. In the radiation therapy group, 27 patients died of cancer, and in the no- further treatment group 40 died from cancer. There was a statistically significant reduction in risk of recurrence in the irradiation group, with recurrence-free rates at 2 years of 88% versus 79% for the irradiation and no- further-treatment groups, respectively. Overall survival difference did not reach statistical difference (P = .074; Fig. 73.19). Severe or life-threatening (GOG grade 3 or 4) adverse effects occurred in 9 patients (6.6%) in the radiation therapy group and 3 (2.1%) in the observation group. A meta-analysis of trials including stage IB1 to IIA cervical cancer found that women who received postoperative radiation had a significantly lower risk of disease progression at 5 years (RR = 0.6, 95% CI = 0.4 to 0.9). The risk of serious adverse events was not significantly higher if women received radiotherapy rather than no further treatment, possibly because the rate of adverse events was low.
  13. 13. Adjuvant Chemoradiation
  14. 14. Southwest Oncology Group 8797 was a study for women with FIGO stage IA2, IB, or IIA carcinoma of the cervix with metastatic disease in the pelvic lymph nodes, positive parametrial involvement, or positive surgical margins at the time of primary radical hysterectomy with total pelvic lymphadenectomy. Patients had confirmed negative PALNs; if the PALNs were not sampled, the patients had confirmed negative common iliac lymph nodes.
  15. 15. One hundred twenty-seven patients were randomized to treatment with pelvic EBRT with 5- FU infusion and cisplatin, and 116 were treated with irradiation alone. The 3- year survival for women on the adjuvant cisplatin/5-FU and RT arm was 87%, compared with 77% for women on the pelvic irradiation arm.438 The difference was statistically significant. An updated analysis with 5.2-year median follow-up reported 5-year overall survival of 80% versus 66%, favoring postoperative chemoradiation in high-risk patients
  16. 16. Trialsinthenon-metastaticsetting-LocallyAdvanced Theadvent of chemo-radiation therapy Prior to 1999 locally advanced(non- surgical/non-metastatic) cervical cancer was treated with radiation therapyand intracavitary therapy Long-term overall survival (OS)in stageIII wasabout 40-50% That all changedonApril 15,1999…
  17. 17. Stage IB2 (>4 cm) Cervical Cancer N0 by CT/FNA/Surgery PS 0-3 Suitable for hysterectomy Adequate organ function External Radiotherapy with Concurrent weekly Cisplatin (40 mg/m2, max 70 mg, x6) Intracavitary brachytherapy Extrafascial hysterectomy* External Radiotherapy with Intracavitary brachytherapy Extrafascial hysterectomy* Endpoints PFS,OS 75 Gy to point A, 55 Gy to point B *Extrafascial hysterectomy post irradiation was deemed necessary in 1992 when this study was initiated. That is no longer the case GOG-123 Weekly Cisplatin Chemotherapy during Irradiation Improves Survival and Reduces Relapses for patients with Bulky Stage IB Cervical Cancer Treated with Irradiation and Adjuvant Hysterectomy Keys,H.M., Bundy, B.N., Stehman,F.B., Muderspach, L.I., Chafe,W. E.,Suggs,C.L.,…Gersell, D. (1999). Cisplatin, Radiation, and Adjuvant Hysterectomy Comparedwith Radiation and Adjuvant Hysterectomy for Bulky Stage IB CervicalCarcinoma.New EnglandJournalof Medicine, 340(15), 1154–1161. https://doi.org/10.1056/NEJM199904153401503
  18. 18. PFS(%) 79* GOG-123 Weekly Cisplatin Chemotherapy during Irradiation Improves Survival and Reduces Relapses for patients with Bulky Stage IB Cervical Cancer Treated with Irradiation and Adjuvant Hysterectomy OS(%)- Median F/U of 36mo 85* Concurrent chemo-RT RT 74* 63*35* 15* Grade¾toxicity * Statisticallysignificant 96% Underwent hysterectomy(%) 90 n=369 Keys,H.M., Bundy, B.N., Stehman, F.B., Muderspach, L.I., Chafe,W. E.,Suggs,C.L.,…Gersell, D. (1999). Cisplatin, Radiation, andAdjuvant Hysterectomy Comparedwith Radiation and Adjuvant Hysterectomy for Bulky Stage IB CervicalCarcinoma.New EnglandJournal of Medicine, 340(15), 1154–1161.https://doi.org/10.1056/NEJM199904153401503
  19. 19. Stage IIB-IVA or Stage IB or IIA (>5 cm) or Biopsy-proven pelvic metastasis Cervical cancer KPS >60% Adequate organ function External Radiotherapy with Concurrent weekly Cisplatin + Fluoruracil infusion q3w Intracavitary brachytherapy External Radiotherapy with Intracavitary brachytherapy RTOG 9001 Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer Morris, M., Eifel, P.J., Lu, J., Grigsby, P.W., Levenback, C.,Stevens, R.E.,…Mutch, D. G.(1999). Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer. New England Journal of Medicine, 340(15), 1137–1143.https://doi.org/10.1056/NEJM199904153401501 Endpoints OS PFS
  20. 20. Morris, M., Eifel, P. J., Lu, J., Grigsby, P. W., Levenback, C., Stevens, R. E., …Mutch, D. G. (1999). Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer. New England Journal of Medicine, 340(15), 1137–1143. https://doi.org/10.1056/NEJM199904153401501 PFSat 24mo(%) RTOG-9001 Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer OS(%)- Median F/U of 43mo 67* 73* 58* 65* Locoregionaldiseasecontrol (%) * Statistically significant ConcurrentCisplatin/FU-RT RT 40*79* 86* Distant-metastasisfree(%) 67* n=403
  21. 21. GOG 85 (Whitney et al.) The GOG conducted randomized Protocol 85, in which patients with carcinoma of the cervix, a clinical stage of IIB to IVA, and negative para-aortic nodes were treated with external pelvic irradiation (51 Gy) combined with 30 Gy to point A with LDR brachytherapy. One hundred twenty- seven patients received 5-FU (IV infusion, 1 g/m2 for 4 days) and cisplatin (50 mg/m2 IV) on days 1, 29, and 30 to 33. 191 patients received hydroxyurea (80 mg/kg orally twice weekly). With a median follow-up for survivors of 8.7 years, the 5- year survival rate in the cisplatin/5-FU arm was 60%, compared with 47% for women in the hydroxyurea arm.
  22. 22. Stage IIB-IVA Cervical cancer N0 by CT and lymphadenectomy PS 0-3 Adequate organ function External Radiotherapy with Concurrent weekly Cisplatin (40 mg/m2, max 70 mg, x6) Intracavitary brachytherapy External Radiotherapy with Concurrent hydroxyurea Intracavitary brachytherapy Endpoints OS PFS RT dosages Stage II: 80.8 Gy to point A, 55 Gy to point B Stage III-IVA: 81 Gy to point A, 60 Gy to point B GOG-120 Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer Rose, P.G.,Bundy, B.N., Watkins, E.B., Thigpen, J.T., Deppe, G., Maiman, M. A., …Insalaco, S.(1999). Concurrent Cisplatin- Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer. New England Journal of Medicine, 340(15), 1144–1153. https://doi.org/10.1056/NEJM199904153401502 External Radiotherapy with Concurrent Cisplatin / FU / Hydroxyurea Intracavitary brachytherapy
  23. 23. GOG-120: Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer Rose,P.G.,Bundy, B.N., Watkins, E.B.,Thigpen,J.T., Deppe,G.,Maiman, M. A., …Insalaco, S.(1999). Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for LocallyAdvancedCervical Cancer.NewEnglandJournal of Medicine, 340(15), 1144–1153. https://doi.org/10.1056/NEJM199904153401502
  24. 24. GOG 120: Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer PFSat 24mo(%) OS(%)- Median F/U of 36mo 46* 67* 64*21* Grade¾Leucopenia * Statisticallysignificant ConcurrentCisplatin-RT ConcurrentCisplatin/FU/Hydroxyurea-RT Concurrenthydroxyurea-RT 47* 67* 66* 49* 23* n=526 Rose,P.G.,Bundy, B.N., Watkins, E.B.,Thigpen,J.T., Deppe,G.,Maiman, M. A., …Insalaco, S.(1999). Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for LocallyAdvancedCervical Cancer.NewEnglandJournal of Medicine, 340(15), 1144–1153. https://doi.org/10.1056/NEJM199904153401502
  25. 25. Pearcey et al. Pearcey et al. reported on a Canadian randomized study in which 127 patients with stage IB to IIA of >5 cm or IIB carcinoma of the cervix were randomized to be treated with 1.cisplatin (40 mg/m2 weekly) and RT 2. 126 patients were treated with RT alone (50.4 Gy to the pelvis combined with brachytherapy). With a median follow-up of 65 months, the 5-year survival rates were 59% and 56%, respectively (P = .43). There was a somewhat greater incidence of significant late morbidity in the RT-alone group (12% vs. 6%; P = .08).
  26. 26. Improved Treatment for Cervical Cancer — Concurrent Chemotherapy and Radiotherapy Thomas, G. M. (1999). Improved Treatment for Cervical Cancer ? Concurrent Chemotherapy and Radiotherapy. New England Journal of Medicine, 340(15), 1198–1200. https://doi.org/10.1056/NEJM199904153401509
  27. 27. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials. J Clin Oncol 26:5802-5812. © 2008 by American Society of Clinical Oncology
  28. 28. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials. J Clin Oncol 26:5802-5812. © 2008 by American Society of Clinical Oncology
  29. 29. Stage Absolute5-yrsurvivalbenefit Ib-IIa 10% IIb 7% III-IVa 3% Reducinguncertainties about the effects of chemoradiotherapyfor cervical cancer: asystematic review and meta-analysis of individual patient data from 18 randomizedtrials. Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials. Journal of Cl
  30. 30. New “standard-of-care” in stage IB2- IVA is concurrent Cisplatin and RT
  31. 31. Stage IIB-IVA squamous cervical cancer KPS >60% Adequate organ function External Radiotherapy with Concurrent Cisplatin and intracavitary RT Endpoints 6-mo and 12-mo DCR (disease-control rate) Is neo-adjuvant chemotherapy a better option for management of cervical cancer patients of rural India? Dastidar, G.A., Gupta, P., Basu,B., Basu,A., Shah,J.K., & Seal,S.L.(2016). Is neo-adjuvant chemotherapy abetter option for management of cervical cancer patients of rural India? Indian Journal of Cancer, 53(1), 56–9. https://doi.org/10.4103/0019-509X.180826 Rural-based Urban-based Neoadjuvant CT (Cisplatin + Vincristine + Bleomycin) x3 followed by RT and intracavitary RT n=200 n=390
  32. 32. Stage IB2 cervical cancer PS 0-2 Adequate organ function NACT (Vincristine + Cisplatin) followed by RHPPL Radical histerectomy and pelvic/para-aortic lymph-node dissection (RHPPL) Endpoints PFS and OS GOG-141: Treatment of ("bulky") stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the gynecologic oncology group. Eddy, G.L., Bundy, B.N., Creasman,W. T., Spirtos, N. M., Mannel, R.S.,Hannigan, E.,& O?Connor, D. (2007). Treatment of (?bulky?) stage IBcervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: Aphase III trial of the gynecologic oncology group. Gynecologic Oncology, 106(2), 362–369. https://doi.org/10.1016/j.ygyno.2007.04.007 n=291 Closed due to low accrual
  33. 33. Stage IB2, IIA2, IIB squamous cervical cancer By MRI 20-70 PS 0 or 1 Adequate organ function Neoadjuvant CT (BOMP: Cisplatin + Vincristine + Mitomycin + Bleomycin) x3, followed by Radical Surgery (NACT-RS) Radical surgery (RS) Phase III randomised controlled trial of neoadjuvant chemotherapy plus radicalsurgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102) n=134 Endpoint OS Post surgical RT if high risk pathology after RS Pelvic lymph node metastasis, parametrial involvement, or deep stromal invasion (⩾2/3). Katsumata, N., Yoshikawa, H., Kobayashi, H., Saito, T., Kuzuya, K., Nakanishi, T., …Japan Clinical Oncology Group. (2013). Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vsradical surgery alone for stages IB2, IIA2, and IIB cervical cancer: aJapan Clinical Oncology Group trial (JCOG0102). British Journal of Cancer, 108(10), 1957– 63. https://doi.org/10.1038/bjc.2013.179
  34. 34. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radicalsurgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102) Katsumata, N., Yoshikawa, H., Kobayashi, H., Saito, T., Kuzuya, K., Nakanishi, T., …Japan Clinical Oncology Group. (2013). Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vsradical surgery alone for stages IB2, IIA2, and IIB cervical cancer: aJapan Clinical Oncology Group trial (JCOG0102). British Journal of Cancer, 108(10), 1957– 63. https://doi.org/10.1038/bjc.2013.179
  35. 35. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radicalsurgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102) Katsumata, N., Yoshikawa, H., Kobayashi, H., Saito, T., Kuzuya, K., Nakanishi, T., …Japan Clinical Oncology Group. (2013). Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vsradical surgery alone for stages IB2, IIA2, and IIB cervical cancer: aJapan Clinical Oncology Group trial (JCOG0102). British Journal of Cancer, 108(10), 1957– 63. https://doi.org/10.1038/bjc.2013.179
  36. 36. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radicalsurgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102) Katsumata, N., Yoshikawa, H., Kobayashi, H., Saito, T., Kuzuya, K., Nakanishi, T., …Japan Clinical Oncology Group. (2013). Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vsradical surgery alone for stages IB2, IIA2, and IIB cervical cancer: aJapan Clinical Oncology Group trial (JCOG0102). British Journal of Cancer, 108(10), 1957– 63. https://doi.org/10.1038/bjc.2013.179
  37. 37. Stage IIB to IVA cervical cancer KPS ≥ 70% Adequate organ function Cisplatin + Gemcitabine (40 + 125 mg/m2, q1w) + concurrent RT, followed by intracavitary RT, followed by Adjuvant CT with Cisplatin + Gemcitabine (50 mg/m2 d1, 1000 mg/m2 d1 & d8, q21d) x2 cycles Cisplatin (40 mg/m2, q1w) + concurrent RT, followed by intracavitary RT Endpoint PFS @ 3-yr Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of thecervix. Dueñas-González, A., Zarb?, J.J., Patel, F.,Alcedo, J.C.,Beslija, S.,Casanova, L., …Orlando, M. (2011). PhaseIII, Open-Label, Randomized Study Comparing Concurrent Gemcitabine PlusCisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With StageIIB to IVACarcinoma of the Cervix. Journal of Clinical Oncology, 29(13), 1678–1685. https://doi.org/10.1200/JCO.2009.25.9663 n=515 Weekly Cis RT (external / intracavitary) Standard of care (control) Weekly Cis + Gem RT (external / intracavitary) Experimental arm Adjuvant Cis + Gem
  38. 38. PFSa3 años: 74% OSa3 años: 78.2% PFSa3 años: 65% OSa3 años: 69.1% CisRT Gemcitabina CisRT  Gemcitabine +CisRT:Gemcitabine 125 mg/m2 qW x6 +Cisplatio 40 mg/m2 qWx6(concurrent with RT). Thenintracavitary RT,followed by 2 cyclesof adjuvant CTwithCisplatin+ Gemcitabine.  CisRT:Cisplatin 40 mg/m2 qW x6 (concurrent with RT).Followedby intracavitary RT  HRpara PFS:0.68, p=0.02  HRpara OS:0.68, p=0.022 LACC GenCisRTenLACC Dueñas-González,A. et al. JClinOncol27:18s, 2009 (suppl; abstr CRA5507) LemaTeachFiles®- 2009 n=515 n=259 n=256 Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. FIGOStagesIIB-IVACervicalcancer(Locally-advancedCervicalCancer–LACC)
  39. 39. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. FIGOStagesIIB-IVACervicalcancer(Locally-advancedCervicalCancer–LACC) Dueñas-González,A. et al. JClinOncol27:18s, 2009 (suppl; abstr CRA5507) LemaTeachFiles®- 2009
  40. 40. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. PFSat 3-yrmo(%) OSat 3-yr(%) 74* 78* 46* Grade3/4 toxicities(%) * Statistically significant 65*86* 2 Treatment-related deaths(n) n=515 Cisplatin+Gemcitabine+RT(external andintracavitary), adjuvantCisplatin+ Gemcitabine Cisplatin+RT(external and intracavitary), 69* Dueñas-González, A., Zarb?, J.J., Patel, F.,Alcedo, J.C.,Beslija, S.,Casanova, L., …Orlando, M. (2011). PhaseIII, Open-Label, Randomized Study Comparing Concurrent Gemcitabine PlusCisplatinand Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix. Journal of Clinical Oncology, 29(13), 1678–1685. https://doi.org/10.1200/JCO.2009.25.9663
  41. 41. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. PFSat 3-yrmo(%) OSat 3-yr (HRwith 95%C.I.) 74* 0.68(0.49-0.95) 46* Grade3/4 toxicities(%) * Statistically significant 65*86* 2 Treatment-related deaths(n) n=515 Cisplatin+Gemcitabine+RT(external andintracavitary), adjuvantCisplatin+ Gemcitabine Cisplatin+RT(external and intracavitary), Dueñas-González, A., Zarb?, J.J., Patel, F.,Alcedo, J.C.,Beslija, S.,Casanova, L., …Orlando, M. (2011). PhaseIII, Open-Label, Randomized Study Comparing Concurrent Gemcitabine PlusCisplatinand Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix. Journal of Clinical Oncology, 29(13), 1678–1685. https://doi.org/10.1200/JCO.2009.25.9663
  42. 42. Stage IB1 & node positive, IB2, IIA, IIB, IIIB, or IVA disease cervical cancer PS 0-2 Adequate organ function Cisplatin (40 mg/m2, q1w) + concurrent RT, followed by intracavitary RT Endpoint OS OUTBACK: Cisplatin and Radiation Therapy With or Without Carboplatin and Paclitaxel in Patients With Locally Advanced Cervical Cancer clinicaltrials.gov - NCT01414608 (Moore K,NRG) Ongoing Weekly Cis RT (external / intracavitary) Standard of care (control) RT (external / intracavitary) Experimental arm Adjuvant Pacl + Carbo Cisplatin (40 mg/m2, q1w) + concurrent RT, followed by intracavitary RT, followed by Pacl + Carbo q3w x4 Weekly Cis
  43. 43. Neoadjuvant or Adjuvant chemotherapy are NOT current standards-of-care in LACC, but the issue is far from settled.
  44. 44. Trialsinthe metastatic,persistent/recurrentdisease Systemictherapy is often the onlyoption  Cisplatin, introduced in the 80’soffered modest short-term control inadvanced cervical cancer…
  45. 45. Coleman RL.TheGynecologicOncologyGroup'srole in the treatment of recurrent cervix cancer:Currentclinicaltrials. GynecologicOncology,Volume 110, Issue3, Supplement 2, September2008, PagesS77-S80 Earlytrials in metastatic cervicalcancer Trials • GOG43(1987) • GOG64(1989) • GOG77(1989) • GOG110(1997) • GOG149(2002) Research(C=Cisplatin) • C:50 mg/m2 vs100 mg/m2 • C:Short vslong infusion • CvsC+Ifosfamide(C/Ifo) • C/Ifo vsC/Ifo/Bleomycin
  46. 46. Coleman RL.TheGynecologicOncologyGroup'srole in the treatment of recurrent cervix cancer:Currentclinicaltrials. GynecologicOncology,Volume 110, Issue3, Supplement 2, September2008, PagesS77-S80 Earlytrials in metastatic cervicalcancer Trials • GOG43(1987) • GOG64(1989) • GOG77(1989) • GOG110(1997) • GOG149(2002) Summaryresults • Low-dose Cisplatin (50 mg/m2) • ORR:21% • Median OS:7.1mo • Carboplatin oirinotecán • • ORR:15% Median OS:6.2mo • • High-doseCisplatin improves ORRbut not OS Cisplatin plus Ifosfamide andBleomycin • ORR:31% • OS:8.5mo
  47. 47. Paclitaxel at an IV dose of 135 mg/m2 as a 24-hour infusion followed immediately by cisplatin at a dose of 50 mg/m2 cisplatin IV dose of 50 mg/m2 Stage IVB, recurrent, or persistent disease that was not amenable to curative treatment with surgery or radiation therapy PS 0-2 Adequate organ function Endpoints Response-rate, PFS or OS GOG-169: 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. n=280 Moore, D. H., Blessing,J.A., McQuellon, R.P., Thaler, H. T., Cella, D., Benda, J., …Rocereto, T.F.(2004). PhaseIII Study of Cisplatin With or Without Paclitaxel in StageIVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 22(15), 3113–3119. https://doi.org/10.1200/JCO.2004.04.170
  48. 48. GOG-169: 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. ORR(%) median PFS(mo) 36* 4.8* 2.8* 8.8 median OS(mo) * Statistically significant Paclitaxel +Cisplatin Cisplatin 19* 9.7 n=280 Moore, D. H., Blessing,J.A., McQuellon, R.P., Thaler, H. T., Cella, D., Benda, J., …Rocereto, T.F.(2004). PhaseIII Study of Cisplatin With or Without Paclitaxel in StageIVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 22(15), 3113–3119. https://doi.org/10.1200/JCO.2004.04.170
  49. 49. ORR(%) median PFS(mo) 36* 4.8* 2.8* 8.8 median OS(mo) * Statistically significant Paclitaxel +Cisplatin Cisplatin 19* 9.7 n=280 Moore, D. H., Blessing,J.A., McQuellon, R.P., Thaler, H. T., Cella, D., Benda, J., …Rocereto, T.F.(2004). PhaseIII Study of Cisplatin With or Without Paclitaxel in StageIVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 22(15), 3113–3119. https://doi.org/10.1200/JCO.2004.04.170 GOG-169: 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.
  50. 50. Cisplatin 50 mg/m(2) every 3 weeks (CPT) Cisplatin 50 mg/m(2) day 1 plus topotecan 0.75 mg/m(2) days 1 to 3 every 3 weeks (CT) Stage IVB, recurrent, or persistent disease that was not amenable to curative treatment with surgery or radiation therapy PS 0-2 Adequate organ function Endpoint OS GOG-179: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. Moore, D. H., Blessing,J.A., McQuellon, R.P., Thaler, H. T., Cella, D., Benda, J., …Rocereto, T.F.(2004). PhaseIII Study of Cisplatin With or Without Paclitaxel in StageIVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 22(15), 3113–3119. https://doi.org/10.1200/JCO.2004.04.170 n=294 median PFS(mo) 27* 4.6* 2.9* 6.5* Topetecan+Cisplatin Cisplatin 13* 9.4* n=294 median OS(mo) ORR(%) * Statistically significant
  51. 51. GOG-179: Randomized phase III trial of cisplatin with or without topotecanin carcinoma of the uterine cervix: a Gynecologic Oncology GroupStudy. Long, H. J.,Bundy, B.N., Grendys, E.C.,Benda, J.A., McMeekin, D. S.,Sorosky, J., …Gynecologic Oncology Group Study. (2005). Randomized PhaseIII Trial of Cisplatin With or Without Topotecan in Carcinoma of the Uterine Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 23(21), 4626–4633.https://doi.org/10.1200/JCO.2005.10.021
  52. 52. GOG-204: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. Cisplatin + Gemcitabine Cisplatin + Vinorelbine Stage IVB, recurrent, or persistent disease that was not amenable to curative treatment with surgery or radiation therapy Measurable disease PS 0-1 Adequate organ function Endpoint OS n=513 Cisplatin + Topotecan Cisplatin + Paclitaxel Monk, B.J.,Sill,M. W., McMeekin, D. S.,Cohn, D. E.,Ramondetta, L.M., Boardman, C.H., …Cella, D. (2009). PhaseIII Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 27(28), 4649–4655.https://doi.org/10.1200/JCO.2009.21.8909
  53. 53. GOG-204: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. Monk, B.J.,Sill,M. W., McMeekin, D. S.,Cohn, D. E.,Ramondetta, L.M., Boardman, C.H., …Cella, D. (2009). PhaseIII Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 27(28), 4649–4655.https://doi.org/10.1200/JCO.2009.21.8909
  54. 54. GOG-204: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. Monk, B.J.,Sill,M. W., McMeekin, D. S.,Cohn, D. E.,Ramondetta, L.M., Boardman, C.H., …Cella, D. (2009). PhaseIII Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 27(28), 4649–4655.https://doi.org/10.1200/JCO.2009.21.8909
  55. 55. GOG-204: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. Cisplatin + non-paclitaxel (either vinorelbine, gemcitabine or topotecan) Cisplatin + Paclitaxel Stage IVB, recurrent, or persistent disease that was not amenable to curative treatment with surgery or radiation therapy Measurable disease PS 0-1 Adequate organ function Endpoint OS n=513 Monk, B.J.,Sill,M. W., McMeekin, D. S.,Cohn, D. E.,Ramondetta, L.M., Boardman, C.H., …Cella, D. (2009). PhaseIII Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 27(28), 4649–4655.https://doi.org/10.1200/JCO.2009.21.8909
  56. 56. GOG-204: Phase III trial of four cisplatin-containing doublet combinations in stageIVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Groupstudy. ORR(%) 29 median PFS(mo) 5.8* 3.98-4.7* 10.1-10.3 median OS(mo) Cisplatin+ Paclitaxel Cisplatin+Non-paclitaxel doublet 23-26 12.9 n=513 * Statistically significant Monk, B.J.,Sill,M. W., McMeekin, D. S.,Cohn, D. E.,Ramondetta, L.M., Boardman, C.H., …Cella, D. (2009). PhaseIII Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 27(28), 4649–4655.https://doi.org/10.1200/JCO.2009.21.8909
  57. 57. GOG-204 GOG-179 GOG-169
  58. 58. Paclitaxel PlusCarboplatin VersusPaclitaxel PlusCisplatinin Metastatic or Recurrent CervicalCancer:TheOpen-LabelRandomizedPhaseIII Trial JCOG0505 Metastatic orrecurrent cervical cáncer ≤1 prior platinum No prior taxane Paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m2 over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeatedevery 3 weeks). Paclitaxel plus cisplatin (TP;paclitaxel 135 mg/m2 over 24 hours on day 1 and cisplatin 50 mg/m2 on day 2, repeated every 3weeks) Non-inferiority OS(HR<1.29) n =253 Kitagawa, R.,Katsumata, N., Shibata, T., Kamura,T., Kasamatsu,T., Nakanishi, T., …Yoshikawa, H.(2015). Paclitaxel PlusCarboplatin Versus Paclitaxel PlusCisplatin in Metastatic or Recurrent CervicalCancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505.Journal of ClinicalOncology : Official Journal of the American Society of ClinicalOncology, 33(19), 2129–35. https://doi.org/10.1200/JCO.2014.58.4391
  59. 59. Paclitaxel PlusCarboplatin VersusPaclitaxel PlusCisplatin in Metastatic or Recurrent Cervical Cancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505 Kitagawa, R.,Katsumata, N., Shibata, T., Kamura,T., Kasamatsu,T., Nakanishi, T., …Yoshikawa, H.(2015). Paclitaxel PlusCarboplatin Versus Paclitaxel PlusCisplatin in Metastatic or Recurrent CervicalCancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505.Journal of ClinicalOncology : Official Journal of the American Society of ClinicalOncology, 33(19), 2129–35. https://doi.org/10.1200/JCO.2014.58.4391
  60. 60. Paclitaxel PlusCarboplatin VersusPaclitaxel PlusCisplatin in Metastatic or Recurrent Cervical Cancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505 Kitagawa, R.,Katsumata, N., Shibata, T., Kamura,T., Kasamatsu,T., Nakanishi, T., …Yoshikawa, H.(2015). Paclitaxel PlusCarboplatin Versus Paclitaxel PlusCisplatin in Metastatic or Recurrent CervicalCancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505.Journal of ClinicalOncology : Official Journal of the American Society of ClinicalOncology, 33(19), 2129–35. https://doi.org/10.1200/JCO.2014.58.4391
  61. 61. In advanced cervical cancer paclitaxel plus either carboplatin or cisplatin is the chemotherapy of choice
  62. 62. Angiogenesis in Cervical Cancer
  63. 63. medscape.com
  64. 64. GOG-240: Improved survival with bevacizumab in advanced cervical cancer. Carcinoma of the cervix Primary stage IVB Recurrent/Persistent Measurable disease GOG PS 0-1 No prior chemotherapy for recurrence Paclitaxel + Cisplatin Paclitaxel + Cisplatin + Bevacizumab Endpoint OS n=452 Paclitaxel + Topetean Paclitaxel + Topetean + BevacizumabStratification factors Stage IVB vs recurrent/persistence GOG PS Prior cisplatin exposure as radio sensitizer Tewari, K.S.,Sill, M. W., Long, H. J., Penson, R.T., Huang, H., Ramondetta, L.M., …Monk, B.J.(2014). Improved Survivalwith Bevacizumabin Advanced Cervical Cancer. New EnglandJournal of Medicine, 370(8), 734–743. https://doi.org/10.1056/NEJMoa1309748
  65. 65. GOG-240: Improved survival with bevacizumab in advanced cervical cancer. Carcinoma of the cervix Primary stage IVB Recurrent/Persistent Measurable disease GOG PS 0-1 No prior chemotherapy for recurrence Chemotherapy + Bevacizumab n=452 Chemotherapy Endpoint OS Stratification factors Stage IVB vs recurrent/persistence GOG PS Prior cisplatin exposure as radio sensitizer Tewari, K.S.,Sill, M. W., Long, H. J., Penson, R.T., Huang, H., Ramondetta, L.M., …Monk, B.J.(2014). Improved Survivalwith Bevacizumabin Advanced Cervical Cancer. New EnglandJournal of Medicine, 370(8), 734–743. https://doi.org/10.1056/NEJMoa1309748
  66. 66. Tewari, K.S.,Sill, M. W., Long,H.J.,Penson,R.T.,Huang,H., Ramondetta, L.M., …Monk, B.J.(2014). Improved Survival with Bevacizumabin AdvancedCervical Cancer.New EnglandJournal of Medicine, 370(8), 734–743. https://doi.org/10.1056/NEJMoa1309748 GOG-240: Improved survival with bevacizumab in advanced cervical cancer. ORR(%) median PFS(mo) 48^ 8.2* 5.9* 13.3* median OS(mo) Chemotherapy+Bevacizumab Chemotherapy 36*17* n=452 * Statistically significant Bevacizumab increases toxicity: Hypertension of grade 2 or higher (25% vs. 2%), Thromboembolic events of grade 3 or higher (8% vs. 1%), and Gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).
  67. 67. GOG-240
  68. 68. In advanced cervical cancer chemotherapy plus bevacizumab improves outcomes, and should be considered a standard-of-care
  69. 69. Progress in survival in cervical cancer 4.5 9.0 13.5 18.0 1989 2005 2013 GOG-169 GOG-179 GOG-64 Cisplatin Cisplatin doublets (Paclitaxel or Topetecan) GOG-240 Chemotherapy + Bevacizumab medianOS(mo) Year Adding bevacizumab to chemotherapy improves survival
  70. 70. Systemictherapy in cervicalcancer Atthe beginning Only surgery and RTavailable Today Chemotherapy+ Bevacizumabin advanced disease Cisplatin in advanced disease in earlytrials Cisplatin+ RTin locally- advanced disease Cisplatin+ Paclitaxelin advanced disease Cisplatin+ Topotecan andother doubletsin advanced disease Unresolved Neoadjuvant and adjuvant chemotherapy in locally-advanceddisease Immunotherapy andtargeted therapy in advanceddisease
  71. 71. THANK YOU
  72. 72. Back-up slides
  73. 73. Cis + Pac + Bev (n=115) Cis + Pac (n=114) Events, n (%) Median OS, mos 69 (60.5) 14.3 67 (58.3) 17.5 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 12 3624 ProportionSurviving RR, % HR=0.68 (95% CI, 0.48-0.97) P=0.0348 45 (CR, n=9) 50 (CR, n=17) 2-sided P=0.5090 GOG 240 – Bevacizumab Objective Cisplatin + Paclitaxel Cohort N=229 Months on Study Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43. Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG,FACS
  74. 74. Progress in Survival in Advanced and Recurrent Cervical Cancer 0. 4.5 9. 13.5 18. 1989 1997 2002 2004 2005 2009 2013 •GOG 149 Cisplatin + Ifosfamide + Bleomycin   •GOG 169 Cisplatin + Palitaxel •GOG 179 Cisplatin + Topotecn   Months Year GOG 64 Cisplatin  • GOG 110 Cisplatin + Ifosfamide   GOG 240 Cisplatin + Palcitaxel + Bevacizumab  Adding Bevacizumab to Chemotherapy Improves Survival
  75. 75. 83 Alexandrov et al., Nature 2013 Schumacher et al, Science 2015 Neoantigen Load and Tumor Types: Possible use as a biomarker of activity for IO agent
  76. 76. •Thank you

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