Cervical CA: What is Advanced Stage? If the tumor is early stage but >4cm (IB2 or IIA2), it is often treated as advanced stage (category 1) but also h

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1 PROGRAMA 2 Taller Internacional Multidisciplinario de Cancer de Mama y Cuello Uterino Racional del tratamiento combinado con Quimioterapia e Irradiación. Resultados en Cáncer de Cérvix avanzado Higinia R. Cárdenes, MD PhD Professor Radiation Oncology

2 Cervical CA: What is Advanced Stage? If the tumor is early stage but >4cm (IB2 or IIA2), it is often treated as advanced stage (category 1) but also has surgical options (category 2B or 3) Parametrial invasion (IIB) Distal vaginal invasion (IIIA) Pelvic Side wall invasion (IIIB) Hydronephrosis IIIB Bladder or rectum invasion (IVa) Distant Metastatic (IVb) not considered for this talk Lymph node metastases (N1 or FIGO IIIB)

3 Staging Work-Up Complete H&P EUA (recommended) Cystoscopy (St IIB or if symptoms) Proctoscopy (St IIB or if symptoms) Radiological Evaluation Chest X-Ray IVP and Barium Enema (FIGO Staging) CT scan of the Abdomen & Pelvis MRI Pelvis: LUS and parametrial invasion PET CT Scan: Detection of regional (pelvic +/- PA) nodes R/O distant metastasis

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5 Advanced Stage Cervical Cancer 5-year survival IIB 60-70% IIIA IIIB 35-45%

6 Incidence of Pelvic and Para-aortic aortic nodes Pelvic PA IA2 2-8% 0% IB 10-20% 5-10% IIA 25-30% 10-15% 15% IIB 30-40% 15-20% III-IVAIVA 45-60% 25-30% Importance of adequate staging of PN nodes in LACC

7 Adjuvant CT+RT In High-Risk Cervical Cancer

8 Concurrent chemo-radiation therapy Results of these five trials led to NIH alert in 1999: Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer However, Only 3/5 trials had a RT alone arm Only 1/3 trials in Advanced disease had a RT alone arm!!!

9 Concurrent CT+RT in cervical cancer Rationale for using Cisplatin Excellent Intrinsic Activity Cisplatin is the most active cytotoxic agent for metastatic and recurrent cervical cancer Cytotoxic Effect: death rate of tumor cells GTV reoxygenation of hypoxic tumor cells & cell progression cell killing Synergistic Effect: Cisplatin Excellent radiosensitizer in animal models Inhibits repair of RT-induced SLD Sensitizes hypoxic cells to radiation Reduces fraction of hypoxic cells Promotes synchronization of cells into a sensitive phase of the cell cycle

10 Concurrent chemo-radiation therapy Study FIGO St Randomization RR Death Keys Peters Rose Morris Whitney IB2 IB-IIA IIA (postop) IIB-IVAIVA IB2-IVAIVA IIB-IVAIVA RT vs RT+WC 0.54 RT vs RT+FC 0.5 RT+HU vs RT+WC 0.61 RT+HUvs RT+HFC 0.58 EFRT vs RT+FC 0.52 RT+HU vs RT+FC 0.72

11 GOG-123: Cisplatin + RT + adjuvant EFH compared with RT + adjuvant EFH in bulky St IB Keys HM et al, NEJM 340: 1154, year PFS 63% (RT) vs 79% (RT+CT) p< year survival 74% (RT) vs 83% (RT+CT) p= pts with tumors 4cm, (-) LN s (CT/ Lymphangiogram) RT + EFH vs RT + weekly CDDP + EFH Median FU = 36 months Grade 3-4 toxicity: 35% CT+RT vs 13% RT

12 Long-term Follow-up. GOG 123 Stehman et al AJOG 2007; 197: 503 Median FU 101 months. RR for progression RR for death 0.63 No difference in long-term toxicity

13 Authors conclusion In GOG-71 that assessed the value of EFH after RT, surgery was associated with a significant reduction in the rate of pelvic relapses, but the overall risk of recurrence was not significantly reduced (RR, 0.76; 95 percent CI, 0.52 to 1.12) and there was no significant difference in survival (relative risk of death, 0.91). It is reasonable to conclude on the basis of these results and our results that the elimination of hysterectomy from both regimens would not have affected the increase in survival associated with the use of cisplatin. Therefore, radiotherapy in combination with treatment with cisplatin should be adequate for patients with bulky stage IB cervical cancer.

14 GOG 109: Concurrent CT + Pelvic RT vs Pelvic RT alone as adjuvant Tx after radical surgery in high-risk early-stage cervical cancer Peters WA et al, JCO 18: , 1613, years PFS 4 years OS 63% RT vs 80% CT+RT 71% RT vs 81% CT+RT P = P = pts with cst IA2, IB and IIA. S/P radical hysterectomy + LND. (+) pelvic nodes, (+) parametrium, (+) margins EBRT alone vs EBRT + [CDDP + 5-FU] x 4

15 CT+RT in Early Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK-GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (days) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) GOG-123 Keys, 1999 FIGO IB2 Median FU 36 months 45 + LDR, 30 3y RT + EFH RT+CT+EFH [Weekly CDDP] (23-95) 50 (21-93) 90%, 4 cycles 74% 83% 37% 21% 13% 35% GOG-109 Peters, 2000 Adjuvant IA2-IIA 85% LN+ Median FU 36 months 49.3Gy, 29 fxs No ICB % pts >45 Gy 4y Surgery + RT S + RT + CT [CDDP + 5-FU] 116 pts 127 pts 41 (38-65) 43 (35-79) P= % 89% 60%, 4 cycles 71% 81% 34% 16% 4% 17%

16 CT+RT in Early Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK-GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (days) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) GOG-123 Keys, 1999 FIGO IB2 Median FU 36 months 45 + LDR, 30 3y RT + EFH RT+CT+EFH [Weekly CDDP] (23-95) 50 (21-93) 90%, 4 cycles 74% 83% 37% 21% 13% 35% GOG-109 Peters, 2000 Adjuvant IA2-IIAIIA 85% LN+ Median FU 36 months 49.3Gy, 29 fxs No ICB % pts >45 Gy 4y Surgery + RT S + RT + CT [CDDP + 5-FU] 116 pts 127 pts 41 (38-65) 43 (35-79) P= % 89% 60%, 4 cycles 71% 81% 34% 16% 4% 17%

17 Definitive CT+RT Locally Advanced Cervical Cancer

18 Prognosis by FIGO Staging System 5-year Survival after Definitive RT Stage IB 85-90% Stage IIA 75-80% Stage IIB 60-70% Stage III 35-45% Stage IVA 10-15%

19 Concurrent chemo-radiation therapy Results of five randomized trials led to NIH alert in 1999: Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer However, Only 1/3 trials in Advanced disease had a RT alone arm!!! RTOG

20 Randomized Trials Concurrent CT + RT Study FIGO St Randomization RR Death Keys IB2 RT vs RT+WC 0.54 Whitney IIB-IVA RT+HU vs RT+FC 0.72 Rose IIB-IVA RT+HU vs RT+WC 0.61 RT+HU vs RT+HFC 0.58 Morris IB2-IVA EFRT vs RT+FC 0.52 Peters IB-IIA RT vs RT+FC 0.5 (postop)

21 GOG-85: Randomized comparison of 5FU+CDDP vs HU as an adjunct to RT in St IIB-IVA IVA cervical cancer with negative PA-nodes Whitney CW et. al. J Clin Oncol 17: , 1348, 1999 RR of progression/death of the CF group to the HU group was 0.79 Relative mortality rate of the CF group to the HU group was 0.74 (90% CI, 0.58 to 0.95) 388 pts randomized to RT + CF vs RT + HU (-) PA nodes [Extraperitoneal PA-LND] Severe hematological toxicity more common in the HU group (24%) than in the CF group (4%) CF with RT offers better PFS and overall survival than HU in patients with locally advanced carcinoma of the cervix

22 GOG-120: A randomized comparison of HU vs HU+5-FU+CDDP vs weekly CDDP with RT in patients with Stages IIB, III and IVA carcinoma of the cervix with (-) PA-LND Rose PG et. al. N Engl J Med 340: 1144, 1999 RR of progression of disease/death was 0.57 in the WC group and 0.55 in the HFC group, as compared with the HU RR of death was 0.61 in the WC group and 0.58 in the HFC group as compared with the HU group 575 pts with St IIB-IVA, with (-) PA nodes [Extraperitoneal PA-LND] Median FU 35 months Grade 3-4 toxicity more than double in the HFC group Regimens containing CDDP improve survival rates and PFS Weekly CDDP is less toxic, and has been established as the preferred regimen for the GOG

23 GOG-120: Long-Term Follow-up Rose PG et. al. JCO 2007; 25: 2804 Stage IIB Stage III 526 pts with St IIB-IVA, IVA, median FU 8.5 years Improvement in PFS and OS for both Cisplatin-containing arms compared with HU Similar results noted for St IIB and III disease

24 GOG-165: Randomized comparison of prt vs prt+ weekly Cisplatin vs RT+PVI 5-FU in patients with Stage IIB, IIIB and IVA, (-) PA nodes Lanciano R. et al, JCO 23: 8289, y PFS: 57% (RT+CDDP) vs 50% (RT+ 5-FU) Death Rate: 36% (RT+CDDP) vs 45% (RT+5-FU)

25 CT+RT in Advanced Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK- GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (weeks) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) GOG-85 Whitney, 1999 No RT alone arm!! FIGO IIB-IVA IVA 62% IIB LDR, 40 If no ICB, TD= 61.2 Allowed Tx duration up to 10 wks % receiving <85% of prescribed dose RR death: CF vs HU = 0.74 Late toxicity RT+ CF RT+HU wks 11.6 wks 6.8% 9.4% 91% 85% 68% CF 43% 53% GOG-120 Rose, 1999 No RT alone arm!! WC HFC H FIGO IIB-IVAIVA 52% IIB Median FU 35m LDR TD= 80.8 St IIB - 81Gy St III-IVA Allowed Tx duration up to 10 wks 9 wks 9.3 wks 8.9 wks % pts receiving within 15% of Point A dose 90% 85% 84% % pts receiving 80% of CT 83% 79% 65.5% RR of death: WC vs HU = 0.61 HFC vs HU = % WC 66% HFC Local progression 19% 20% 30% Grade 3-4 toxicity more than double in the HFC group GOG-165 Lanciano, 2005 RT alone Plv RT + CDDP Plv RT+PVI-5FU FIGO IIB-IVA 24 pts Median FU, 40.4m 45+LDR 40 or HDR 30 in 5 fxs % 90% % pts completing 5 cycles 74% 86% 4 years 68% 61% LRR / Distant 16% / 18% 14% / 29% 58% 32%

26 CT+RT in Advanced Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK- GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (weeks) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) GOG-85 Whitney, 1999 No RT alone arm!! RT+ CF RT+HU FIGO IIB-IVAIVA 62% IIB LDR, 40 If no ICB, TD= 61.2 Allowed Tx duration up to 10 wks 9.1 wks % receiving <85% of prescribed dose 6.8% 9.4% wks 91% 85% RR death: CF vs HU = % CF 43% 53% Late toxicity GOG-120 Rose, 1999 No RT alone arm!! WC HFC H FIGO IIB-IVA IVA 52% IIB Median FU 35m LDR TD= 80.8 St IIB - 81Gy St III-IVA Allowed Tx duration up to 10 wks 9 wks 9.3 wks 8.9 wks % pts receiving within 15% of Point A dose 90% 85% 84% % pts receiving 80% of CT 83% 79% 65.5% RR of death: WC vs HU = 0.61 HFC vs HU = % WC 66% HFC Local 19% 20% 30% Grade 3-4 toxicity more than double in the HFC group GOG-165 Lanciano, 2005 RT alone Plv RT + CDDP Plv RT+PVI-5FU FIGO IIB-IVA 24 pts Median FU, 40.4m 45+LDR 40 or HDR 30 in 5 fxs % 90% % pts completing 5 cycles 74% 86% 4 years 68% 61% LRR / Distant 16% / 18% 14% / 29% 58% 32%

27 CT+RT in Advanced Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK-GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (weeks) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) GOG-85 Whitney, 1999 No RT alone arm!! RT+ CF RT+HU FIGO IIB-IVAIVA 62% IIB LDR, 40 If no ICB, TD= 61.2 Allowed Tx duration up to 10 wks 9.1 wks 11.6 wks % receiving <85% of prescribed dose 6.8% 9.4% 91% 85% RR death: CF vs HU = % CF 43% 53% Late toxicity GOG-120 Rose, 1999 No RT alone arm!! WC HFC H FIGO IIB-IVAIVA 52% IIB Median FU 35m LDR TD= 80.8 St IIB - 81Gy St III-IVA Allowed Tx duration up to 10 wks 9 wks 9.3 wks 8.9 wks % pts receiving within 15% of Point A dose 90% 85% 84% % pts receiving 80% of CT 83% 79% 65.5% RR of death: WC vs HU = 0.61 HFC vs HU = % WC 66% HFC Local 19% 20% 30% Grade 3-4 toxicity more than double in the HFC group GOG-165 Lanciano, 2005 FIGO IIB-IVA 65% IIB 45+LDR 40 or HDR 30 in 5 fxs % pts completing 5 cycles 4 years LRR / Distant Acute RT alone Plv RT + CDDP Plv RT+PVI-5FU 24 (Cls) Median FU, 40.4m Overall weeks 96% 90% 74% 86% 68% 61% 16% / 18% 14% / 29% 58% 32%

28 CT+RT in Advanced Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK-GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (weeks) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) GOG-85 Whitney, 1999 No RT alone arm!! RT+ CF RT+HU FIGO IIB-IVAIVA 62% IIB LDR, 40 If no ICB, TD= 61.2 Allowed Tx duration up to 10 wks 9.1 wks 11.6 wks % receiving <85% of prescribed dose 6.8% 9.4% 91% 85% RR death: CF vs HU = % CF 43% 53% Late toxicity GOG-120 Rose, 1999 No RT alone arm!! WC HFC H FIGO IIB-IVAIVA 52% IIB Median FU 35m LDR TD= 80.8 St IIB - 81Gy St III-IVA Allowed Tx duration up to 10 wks 9 wks 9.3 wks 8.9 wks % pts receiving within 15% of Point A dose 90% 85% 84% % pts receiving 80% of CT 83% 79% 65.5% RR of death: WC vs HU = 0.61 HFC vs HU = % WC 66% HFC Local 19% 20% 30% Grade 3-4 toxicity more than double in the HFC group GOG-165 Lanciano, 2005 RT alone Plv RT + CDDP Plv RT+PVI-5FU FIGO IIB-IVA 65% IIB 24 (Cls) Median FU, 40.4m 45+LDR 40 or HDR 30 in 5 fxs Overall weeks 96% 90% % pts completing 5 cycles 74% 86% 4 years 68% 61% LRR / Distant 16% / 18% 14% / 29% Acute 58% 32%

29 RTOG 90-01: 01: Phase III Randomized Study: Pelvic RT+CT vs EFRT for high risk cervical carcinoma Morris M et. al. N Engl J Med 340: 1137, year DFS 67% (prt+ct) vs 40% (EFRT) 5-year survival 73% (prt+ct) vs 58% (EFRT) 403 pts, St IB-IIA ( 5cm or + pelvic nodes), IIB, III & IVA, (-) PA nodes Randomization: Pelvic RT + [CDDP + 5-FU] x 2-3 cycles vs EFRT Acute tox. more significant in the CT+RT arm but no difference in late tox. Improvement in DFS, OS (IB-IIB), Distant relapse and LRR rate with prt+ct

30 RTOG Updated Results 5y Overall survival prt+ct, 73% vs EFRT,52% p< Eifel P et. al., JCO 22: 872, y Overall survival St IB-IIB: IIB: [70% pts] prt+ct, 79%; EFRT, 55%, (p<0.0001) St III-IVA: IVA: [30% pts] prt+ct, 59%; EFRT, 45% - NS Median FU time for 228 surviving pts 6.6 years CT + RT resulted in: 52% reduction in the risk of death 58% reduction in the risk of LRR 52% reduction in the risk of distant metastasis

31 Concurrent CDDP+RT vs RT alone for pts with locally advanced cervix cancer N=253 pts, cst IB-IIA bulky and cst IIB-IVA Pelvic RT + CDDP 40 mg/m 2 /wk vs RT alone Median FU: 82 months Median duration of Tx 50d (CT+RT), 51d (RT) % Late complications 6% (CT+RT), 12% (RT) 3y Pelvic control rate 83% (CT+RT), 78% (RT) No statistical difference between arms NCI Canada Pearcey RG et. al. JCO 20: 966, y survival 62% (CT+RT) vs 58% (RT) RTOG y Surv, 73%

32 CT+RT in Advanced Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK-GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (days) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) RTOG Morris, 1999 FIGO IB, IIA ( 5cm or (+) Plv LNs), IIB, III & IVA (-) PA LNs 70% IIB 45+ LDR 40 TD 85 Gy Mean Point A dose 89Gy % pts completing 2 courses of CT 5 years IB-IIB IIB / III- IVA No difference in St III-IVA IVA (30% Pts) LRR / Distant Acute / Late Plv RT+[FU+CDDP] EBRT Median FU, 43m % 84% 81% NA 77%* / 63% 58%* / 57% P= % / 14% 35% / 33% 45% / 12% 4% / 11% NCI Canada Pearcey, 2000 Plv RT + CDDP RT alone FIGO IB-IIA 5cm, IIB-IVA Median FU, 82m 45+ LDR (41 to 61) 51 (49 to 62) 98% 99% 86% pts received > 90% of the dose of CDDP 5 years 66% 58% NS Pelvic/Distant Recurrences 27% / 44% 33% / 34% Acute 31.5% 3%

33 CT+RT in Advanced Stage Cervical Cancer TRIAL AUTHOR, YEAR RANDOMIZATION RISK-GROUP # PTS Median FU Median RT Dose [EBRT+ ICB] Gy Duration (days) RT Compliance CT Compliance Overall Survival Recurrence Rate Toxicity Grade 3-4 (%) RTOG Morris, 1999 Plv RT + [FU+CDDP] EBRT FIGO IB, IIA ( 5cm or (+) Plv LNs), IIB, III & IVA (-) PA LNs 70% IIB Median FU, 43m 45+ LDR 40 TD 85 Gy Mean Point A dose 89Gy % 84% % pts completing 2 courses of CT 81% NA 5 years IB-IIB IIB / III- IVA No difference in St III-IVA IVA (30% Pts) 77%* / 63% 58%* / 57% P=0.002 LRR / Distant Acute / Late 19% / 14% 35% / 33% 45% / 12% 3% / 11% NCI Canada Pearcey, 2000 Plv RT + CDDP RT alone FIGO IB-IIA 5cm, IIB-IVA <10% IIIB Bilateral parametrium or IVA Median FU, 82m 45+ LDR (41 to 61) 51 (49 to 62) 98% 99% 86% pts received > 90% of the dose of CDDP 5 years 66% 58% NS Pelvic/Distant Recurrences 27% / 44% 33% / 34% Acute 31.5% 3%

34 Pelvic Failures (First Site) CDDP-Based Chemotherapy Total # Pts % LRR Non CDDP Control Total # Pts % LRR GOG (CF) 25% 191 (HU) 30% GOG (WC) 19% 177 (HU) 30% GOG (HFC) 20% RTOG % 193 (RT) 35% NCI-C % 123 (RT) 33% TOTAL % %

35 Why the discrepancy? Potential explanations: Median overall Tx time NCI-Canada RTOG trial GOG trials days 58 days days NCI Canada was the only study that mandated Hgb 11 g/dl Shorter Tx time and higher Hgb levels may have provided less opportunity for improvement with CT Tx prolongation of 8-10 days will potentially increase pelvic failure rate by 10-15% and CT may be partially compensating for this loss Differences in PA nodes evaluation Surgical staging (GOG) and Lymphangiogram (RTOG) versus CT scan alone (NCI-Canada) Potential inclusion of more pts with undetected PA-LN mets in the NCI-Canada Reduction in the benefit of locoregional Tx

36 JCO, 2011; 29: pts, IIB-IVA Weekly CDDP (40 MG/M2) + GEM (125 MG/M2) + RT followed by [CDDP+GEM] x 2 cycles Weekly CDDP+RT 60% cst IIB, 36% cst IIIB Median FU 46.9 months Toxicity grade grade 3 87% vs 46% 2 Tx-related deaths in the GEM arm Cost-effectiveness analysis of this regimen: Smith B et al. Gynecol. Oncol, 2013; 130(3): Radiation and gemcitabine/cisplatin for patients with stage IIB to IVA cervical cancer are not cost-effective. The increased financial burden of radiation with gemcitabine/cisplatin and associated toxicities appears to outweigh the benefit of increased 3-year PFS and is primarily dependent on chemotherapy drug costs.

37 Primary Objective PFS, 3 years Secondary Objectives Arm A Arm B P value RTOG years 74% 65% % 5 years Overall Survival 87% 69% HR, % 5 years Time to Progressive disease, TtPD Tumor Response Rate, TRR Local Failure Rate, LFR HR, % 93% NS 11% 16% NS 19% 5 years Distant Failure 8% 16% % 5 years Grade 3 Acute Toxicity 87% 46% %

38 Meta-Analysis Green JA et al, Lancet 358: 781, 2001 Review of 19 randomized Trials of CT+RT for cervical cancer ( ) 4580 pts randomized, 3656 evaluable 16% absolute improvement in PFS (47% to 63%) Benefit on both local control and distant failures 12% absolute improvement in survival (40% to 52%) Greater beneficial effect in trials that included a high proportion of St I and II pts (p=0.009) Increased acute toxicity with CT+RT, but insufficient data with regard to late toxicity OS Concomitant CT+RT improves OS and PFS and reduces local and distant recurrence in selected patients with cervical cancer, which may give a cytotoxic and sensitisation effect.

39 Meta-analysis. analysis. Chemo-radiotherapy for Cervical Cancer Meta-Analysis Collaboration 13 RCT comparing RT vs CT+RT 6% improvement in 5-year survival with CT+RT (hazard ratio [HR] 0.81, P.001). A larger survival benefit was seen for the two trials in which CT was administered after CT+RT. Significant survival benefit for both the group of trials that used platinum-based (HR 0.83, P.017) and non platinum-based (HR 0.77, P.009) TX, No difference in the benefit by RT or CT dose or scheduling. CT+RT also reduced local and distant recurrence and improved DFS. Suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute toxicity increased with CT+RT, but data were too sparse for an analysis of late toxicity. JCO, 2008; 26: 5802

40 Meta- Analysis 2010 Updated individual patient data (IPD) from all RCTs to assess the effect of CT+RT on all outcomes Performed analyses to investigate whether the effect of CT+RT differed by trial or patient characteristics 13 trials that compared CT+RT vs RT, there was a 6% improvement in 5-year survival with CT+RT (HR = 0.81, P < 0.001). A larger survival benefit was seen for the two trials in which CT was administered after CT+RT Survival benefit for platinum-based (HR = 0.83, P = 0.017) and non-platinum based (HR = 0.77, P = 0.009) CT+RT CT+RT reduced local and distant recurrence and progression and improved DFS There was a suggestion of a difference in the size of the survival benefit with tumour stage, but not across other patient subgroups. Acute haematological and GI toxicity were increased with CT+RT, but data were too sparse for an analysis of late toxicity.

41 Meta-Analysis Number of trials Number of patients Green, pts randomized, 3656 evaluable Meta-Analysis Collaboration, 2008 Cochrane Meta- Analysis, 2010 Improvement in PFS 16% absolute benefit (47% to 63%) Benefit on both local control and distant failures % absolute benefit at 5 years (50% to 58%) Benefit on both local control and distant failures % absolute benefit at 5 years (50% to 58%) Benefit on both local control and distant failures Improvement in OS 12% absolute survival benefit (40% to 52%) HR % absolute 5- year survival benefit (60% to 66%) HR, % absolute 5- year survival benefit (60% to 66%) HR = 0.81 Comments Greater beneficial effect in trials that included a high proportion of St I and II pts (p=0.009) HRs translate to 5-year survival benefits of 10% for St IB- IIA 7% for St IIB 3% for St III-IVA There was a suggestion of trend in the relative effect of CT+RT by stage (P = 0.017), with the decreasing benefit with increasing stage as above

42 Meta-Analysis Number of trials Number of patients Green, pts randomized, 3656 evaluable Meta-Analysis Collaboration, 2008 Cochrane Meta- Analysis, 2010 Improvement in PFS 16% absolute benefit (47% to 63%) Benefit on both local control and distant failures % absolute benefit at 5 years (50% to 58%) Benefit on both local control and distant failures % absolute benefit at 5 years (50% to 58%) Benefit on both local control and distant failures Improvement in OS 12% absolute survival benefit (40% to 52%) HR % absolute 5- year survival benefit (60% to 66%) HR, % absolute 5- year survival benefit (60% to 66%) HR = 0.81 Comments Greater beneficial effect in trials that included a high proportion of St I and II pts (p=0.009) HRs translate to 5-year survival benefits of 10% for St IB- IIA 7% for St IIB 3% for St III-IVA There was a suggestion of trend in the relative effect of CT+RT by stage (P = 0.017), with the decreasing benefit with increasing stage as above

43 Meta-Analysis Number of trials Number of patients Green, pts randomized, 3656 evaluable Meta-Analysis Collaboration, 2008 Cochrane Meta- Analysis, 2010 Improvement in PFS 16% absolute benefit (47% to 63%) Benefit on both local control and distant failures % absolute benefit at 5 years (50% to 58%) Benefit on both local control and distant failures % absolute benefit at 5 years (50% to 58%) Benefit on both local control and distant failures Improvement in OS 12% absolute survival benefit (40% to 52%) HR % absolute 5- year survival benefit (60% to 66%) HR, % absolute 5- year survival benefit (60% to 66%) HR = 0.81 Comments Greater beneficial effect in trials that included a high proportion of St I and II pts (p=0.009) HRs translate to 5-year survival benefits of 10% for St IB- IIA 7% for St IIB 3% for St III-IVA There was a suggestion of trend in the relative effect of CT+RT by stage (P = 0.017), with the decreasing benefit with increasing stage as above

44 CT+RT vs RT alone in cervical cancer. RCT Srivastava K et al. Asia Pac J Clin Oncol, 2013; 9: CRT become the standard of care for treating almost all cervical carcinoma patients on the basis of the NCI alert. The disease burden in developing countries is more advanced with poor general condition than in patients in the trials prompting the NCI alert. RCT: RT vs CT+RT (weekly CDDP), St IB-IVA 305 patients: RT alone (150) and CRT (155) Median follow up was 34 months LRFS at 2 years was 55 and 54% for the RT and CRT group, respectively, with a median LRFS time of 27 and 30 months for the RT and CRT group, respectively, (P = 0.624) OS at 2 years was 58 and 60%, with a MST of 31 and 34 months for the RT and CRT group, respectively; (P = 0.9) The toxicity profile, both acute and late, were comparable in both groups; CONCLUSION: the addition of cisplatin did not improve outcome. In the Indian subcontinent where patients present at late stages with poor general condition and limited access to good supportive care, RT alone still remains a valid option.

45 Concomitant CDDP+RT+HDR-ICB versus RT alone for Stage IIIB epidermoid cervical cancer: a RCT Zuliani AC et al. J Clin Oncol, 2014; 32: pts with stage IIIB SCC squamous cervical cancer randomized to Cisplatin plus RT (72) or RT alone (75) The CRT group had significantly better DFI No improvement in survival with CRT Excluding hematological toxicity there was not significant difference between groups in acute toxicity No difference in late toxicity No difference in patterns of failure, including distant failures between the groups Conclusion: In IIIB cervical cancer, the addition of cisplatin offers a small but significant benefit in DFI, with acceptable toxicity HR, 0.52; 95% CI, 0.29 to 0.93; P =.02 HR, 0.67; 95% CI, 0.38 to 1.17; P =.16

46 P. Rose & S. Lappas, Gynecol Oncol, 2000; 78: 3-6 Incremental costs ($) per year of life gained for CDDP-based CT+RT regimens (published survival) SWOG 8797: CDDP+5FU (adjuvant) GOG 123: weekly CDDP 6758 GOG 85: CDDP+5FU GOG 120: Weekly CDDP 2384 GOG 120: 3 drugs regimen 9229 RTOG 90-0: CDDP+5FU 14235

47 Cisplatin-based Chemo-RT Summary of Randomized trials 6 large randomized trials 3 trials CT+RT vs RT alone Diverse population: early-stage high-risk - locally advanced dis. No impact in survival in the NCI-Canada Study More than 1800 pts randomized Increase in relative progression-free survival and relative survival by 30-50% 1999 NCI consensus statement: Strong consideration should be given to the incorporation of concurrent cisplatinbased chemotherapy with radiation for women who require radiation therapy for the management of cervical cancer

48 Potential Limitations of CT+RT Serkies et al, IJROBP 2004; 60: Increased acute gastrointestinal and hematological toxicity, generally reversible Hematological toxicity 49% (Grade 3-4, 5%) GI toxicity 38% (Grade 3-4, 10%) Limitations in treatment delivery Reduction in number of cycles of CDDP Average of 4 cycles Only 45% pts received 5 cycles Full doses and timely planned CDDP in only 26% pts 20% pts not compliant with CT schedule Prolongation of RT treatment time The intended total point A dose of 80 Gy was delivered in 34 patients (60%)

49 Effect of treatment time Song S et al. Cancer, 2013; 119: with stage IB2 to IIIB cervical cancer All patients received WPRT+CT+ICB The effect of treatment time on outcome was examined with univariate and multivariate analyses The median time to complete all RT was 68 days. The 3-year cumulative incidence of PF and DF were 18% and 23% On multivariate analysis, time to completion of BT >56 days was associated with increased PF (HR, 3.8; 95% CI, ; P =.02) The 3-year PF for >56 days versus 56 days was 26% versus 9% (P =.04) Treatment time was not associated with DF Treatment prolongation was found to be associated with delay in starting BT and higher incidence of acute grade 3/4 toxicities In the setting of CT+RT, treatment time >56 days is detrimental to pelvic control but is not associated with an increase in DF

50 Importance of Hemoglobin Crogan M. et al, Cancer 86: , 1999 Objective: Importance of hemoglobin levels during RT 605 pts treated with RT, with median FU 41 months Univariate Analysis Initial Hgb, average weekly nadir during RT & blood transfusion correlated with LC, DFS & OS Multivariate Analysis Only significant prognostic factor was the AWNH AWNH 12 Improved survival and decreased LRR and distant mets 5-y survival and AWNH Hgb 12 74% Hgb % p< Hgb < 11 45%

51 Dunst J. et al, IJROBP 2003; 56: pts cst IIB-IVA, EBRT+HDR - ICB without CT Results Tumor oxygenation, pre- RT 1980 cgy Angiogenesis (MVD) pre-tx Bx s Relationship between anemia, tumor hypoxia and angiogenesis Impact of oxygenation, HgB level and angiogenesis on outcome Mid-Tx anemia strongest impact in LRR and survival Correlation between mid-tx Hgb, tumor oxygenation and MVD Mid-Tx tumor oxygenation more significant that pre-tx values Poor prognostic group: anemia, tumor oxygenation and angiogenesis

52 Association of Hgb levels with survival GOG Study Winter, W et al; Gynecol Oncol 2004; 94: pts treated on two prospective GOG trials (GOG 120 and 165), treated with cisplatin based CT+RT 278 pts (cst II), 216 pts (cst III-IV) < 10% pts transfused In the Cox MVA: the AWNH level during the late portion of the Tx was the most significant prognostic factor for PFS Mean Hbg levels progressively declined from baseline throughout tx for both cst II and III-IV

53 Association of Hgb levels with survival GOG Study Winter, W et al; Gynecol Oncol 2004; 94: St II St III-IV

54 Human Erythropoietin 30-35% pts with cervical cancer treated with RT have Hgb at presentation < 12 gr/dl Anemia has been associated with poor LC, DFS and survival (Canadian trial, Grogan M et al) 24% increment in survival with Hgb >12 gr/dl The increment in survival exceeds that shown by the use of concurrent CT+RT in the reported randomized trials GOG-191 trial: CDDP+RT +/- Erythropoietin Closed - rate of DVT s Final analysis pending

55 GOG 191 Phase III : RT+CDDP+/- Erythropoietin Thomas G et al, Gynecol Oncol 2008; 108: eligible pts, FIGO IIB-IVA Trial stopped prematurely because of concerns regarding TEE with Epo Median FU 37 months PFS, 3 y: CT+RT, 65%; CT+RT+Epo, 58% OS, 3 y: CT+RT, 75%; CT+RT+Epo, 61% % of TEE: CT+RT, 8%; CT+RT+Epo, 19% Impact of maintaining Hgb level >12 gr/dl on PFS, OS or LC remains unclear

56 6/1/2015 Indiana university School of Medicine

57 Conclusions Cervical cancer is a preventable disease However, worldwide remains a major health issue Identification of population at risk, early screening and HPV vaccination Patients with early stage disease have favorable outcome Identification of reliable factors to predict recurrence risk Definition of risk-groups to adequately tailor therapy Multidisciplinary approach Integration of surgery, radiation therapy and chemotherapy

58 Conclusions Five out of six randomized Phase III trials demonstrated that cisplatin-based CT, when given concurrently with RT, prolongs survival in patients with locally advanced cervical cancer, FIGO stages IB-IVA, as well as in those women with high risk" stages IB-IIA disease after radical hysterectomy However, only 2 of 4 trials in advanced disease had a radiation alone arm and only 1 trial showed benefit for CT+RT over RT alone (RTOG 90-01)

59 Conclusions Concurrent cisplatin-based CT reduced the risk of recurrence by 30%-50% across a spectrum of treatment prescriptions It is unclear whether these results are applicable to all stages of cervical cancer, since only 30% of the patients had stage III- IVA Two Meta-analysis showed very minimal benefit for CT+RT in advanced cervical cancer

60 Conclusions Currently available data do not allow conclusions to de drawn as to which drugs or regimens are optimal in the treatment of cervical cancer Until further data become available, it is reasonable to suggest that weekly cisplatin should be the regimen of choice, concurrently with radiotherapy, PRIMARILY in patients with early stage disease, EXCELLENT performance status with FULL ACCESS to external beam RT and brachytherapy and ADEQUATE SUPPORTIVE CARE In order to keep the overall treatment time limited to 8 weeks

61 Follow-Up Pelvic examination and pap smears at regular intervals Every 3 months for the first 2 years Every 4 months the 3 rd year Every 6 months years 4 th and 5 th Yearly thereafter Biopsy if evidence of new lesions or abnormal pap smear Imaging studies as needed If new symptoms: back pain, LLEE lymphedema, respiratory and/or unexplained constitutional symptoms

62 Current Investigations Education / Prevention / Vaccination Evaluation of new chemotherapy & radiosensitizer agents Evaluation of Molecular Targeted Therapy Implementation of 3-dimensional treatment planning and IMRT Imaged-guided Intracavitary Brachytherapy CT/MRI and PET-based ICI

63 CERVICAL CANCER Is the use of Cisplatin-based chemo-radiation therapy, which has become the new standard of care of locally advanced cervical cancer, COST-EFFECTIVE?

64 P. Rose & S. Lappas, Gynecol Oncol, 2000; 78: 3-6 Overall costs for the resources consumed during CT were calculated by adding the costs per cycle times the number of cycles administered Total incremental costs / incremental survival = incremental cost per patient benefited (ICPB) (IC / YLG) = ICPB / published survival

65 P. Rose & S. Lappas, Gynecol Oncol, 2000; 78: 3-6 Incremental costs ($) per year of life gained for CDDP-based CT+RT regimens (published survival) SWOG 8797: CDDP+5FU (adjuvant) GOG 123: weekly CDDP 6758 GOG 85: CDDP+5FU GOG 120: Weekly CDDP 2384 GOG 120: 3 drugs regimen 9229 RTOG 90-0: CDDP+5FU 14235

66 P. Rose & S. Lappas, Gynecol Oncol, 2000; 78: 3-6 IC/YLG ratios of $ $ or more have been considered acceptable for the introduction of more costly new therapies, by healthcare economists and ethicists CDDP-based CT+RT ratios fall well below this benchmark favorable pharmacoeconomic profile Costs for inpatient administration are substantially greater (3.8-9 fold) CONCLUSION: Outpatient administration of weekly CDDP is the most cost-effective

67 GRACIAS