ROLE OF ADJUVANT CHEMO IN CARCINOMA EM..pptx

ROLE OF CHEMO RT IN MANAGEMENT OF CA ENDOMETRIUM

1. ROLE OF ADJUVANT CHEMORADIATION IN CARCINOMA ENDOMETRIUM DR.S.PRAVEEN KUMAR

2. CHEMORT IN CARCINOMA ENDOMETRIUM ADJUVANT THERAPY FOR HIGH RISK EARLY STAGE DISEASE MULTIMODAL APPROACH IN LOCALLY ADVANCED DISEASE PALLIATIVE ROLE IN ADVANCED /METASTATIC DISEASE

3. INDICATIONS

4. EVIDENCES

5. NSGO-EC-9501/EORTC-55991(2010) Pelvic RT (44 Gy). RT was given before CT in the sequential radiotherapy and chemotherapy (RT–CT)-arm. Optional vaginal brachytherapy had to be decided before randomisation. Amendment 1 allowed the choice of sequence of RT and CT before randomisation. CT consisted of four courses of doxorubicin/ epirubicin 50 mg/m2 + cisplatin 50 mg/m2 every 4 weeks Amendment 2 on August 2004 (291 patients included) allowed alternative CT regimens, including: paclitaxel 175 mg/m2 + epirubicin 60 mg/m2 or doxorubicin 40 mg/m2 + carboplatin AUC 5 or paclitaxel 175 mg/m2 + carboplatin AUC 5–6 every 3 weeks.

6. MaNGO ILIADE III study (2010) CT had to start within 30 days after surgery and consisted of doxorubicin 60 mg/m2 + cisplatin 50 mg/m2 every 3 weeks for three cycles. The interval between CT and RT had to be less than 4 weeks, while patients allocated to RT alone had to start within 40 days after surgery. Pelvic RT was given with 1.8 Gy fractions; total dose 45 Gy. For patients with para-aortal metastases, a para-aortal field was added up to L1/L2. Vaginal brachytherapy was added for women with cervical stromal involvement

7. PFS

8. OS

9. PORTEC 3 (2018) To investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer open-label, international, randomised , phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both) , endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m² given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² )

10. PORTEC3 5YR OS 5 YR FFS RT ONLY 76.7 68.6 CHEMORT 81.8 75.5

11. STAGE III 5YR OS 5 YR FFS RT ONLY 69.8 58 CHEMORT 78.7 69.3 SEROUS 5YR OS 5 YR FFS RT ONLY 57.7 47.7 CHEMORT 71.2 57.7

12. RISK FACTORS FOR RELAPSE/DEATH report from MSKCC on 192 patients with Stage III (FIGO 2009) endometrial cancer, the following three factors emerged as independent predictors of relapse and death from endometrial cancer: >50% myometrial invasion , positive peritoneal cytology , and aggressive histology, defined as grade 3 endometrioid, serous, clear cell, or undifferentiated. The 5-year relapse rates were 13% for patients with no risk factors, 27% for patients with one risk factor and 62% for patients with two or more risk factors ( P < .001). The corresponding 5-year rates of death from endometrial cancer were 11%, 20%, and 56% ( P < .001). Therefore, for patients with Stage III disease with two or more risk factors , especially positive peritoneal cytology, full systemic chemotherapy (six cycles of paclitaxel and carboplatin) is preferred over chemoradiation. For those with only one risk factor (e.g., lymph node involvement only), using chemoradiation similar to PORTEC-3 seems reasonable.

13. GOG 259 -PELVIC RT VS VBT + CHEMO (2019) Randomized phase III trial was performed in eligible patients with endometrial canc er stage I endometrioid histology high-intermediate–risk criteria, stage II disease, or stage I to II serous or clear cell tumors. Treatment was randomly assigned between RT (45 to 50.4 Gy over 5 weeks) or VCB followed by intravenous paclitaxel 175 mg/m 2  (3 hours) plus carboplatin (area under the curve, 6) every 21 days for three cycles. median age of the 601 patients was 63 years, and 74% had stage I disease. Histologies included endometrioid (71%), serous (15%), and clear cell (5%). With a median follow-up of 53 months,

14. GOG 259 -PELVIC RT VS VBT + CHEMO (2019) T he 60-month RFS was 0.76 (95% CI, 0.70 to 0.81) for RT and 0.76 (95% CI, 0.70 to 0.81) for VCB/C (hazard ratio, 0.92; 90% confidence limit, 0.69 to 1.23). T T he 60-month overall survival was 0.87 (95% CI, 0.83 to 0.91) for RT and 0.85 (95% CI, 0.81 to 0.90) for VCB/C (hazard ratio, 1.04; 90% confidence limit, 0.71 to 1.52). Vaginal and distant recurrence rates were similar between arms. Pelvic or para-aortic nodal recurrences were more common with VCB/C (9% v 4%). There was no heterogeneity of treatment effect with respect to RFS or overall survival among clinical or pathologic variables evaluated.

15. CHEMORT OR CHEMO? GOG 258(2023) 736 patients with Stage III and IVA or Stage I or II serous or clear cell endometrial cancer with positive cytology were randomized to six cycles of carboplatin plus paclitaxel or postoperative external-beam RT with concurrent cisplatin (50 mg/m2) on weeks 1 and 4 followed by four cycles of carboplatinplus paclitaxel. At a median follow-up of 47 months, there was no difference in 5-year RFS (59% chemoradiation vs 58% in chemotherapy-only arm). Overall survival rates were not reported. Chemoradiation was associated with lower rates of vaginal recurrence (2% vs 7%) and pelvic/para-aortic recurrence (11% vs 20%) but more distant recurrence (27% vs 21%).

16. DOSING REGIMEN- EXTERNAL BEAM External beam dose 45-50Gy. CT treatment planning and IMRT for normal tissue sparing IMRT is preferred to minimise toxicity IGRT with orthogonal imaging, volumetric imaging to ensure appropriate coverage of targets If postop gross residual disease –boost to a total of 60-70 Gy If gross nodal disease - boost to a total of 60-65Gy

17. DOSING REGIMEN- BRACHYTHERAPY When? – as soon as vaginal cuff healed 6-8wks but not exceed 12 weeks Dose to depth of vaginal surface or depth of 0.5cm. Dose depend on use of EBRT Target upper two third of vagina. Longer segment of extensive LVSI or positive margins For postop HDR brachy - 6 Gy /5#to vaginal surface or 7Gy/3# or 5.5Gy/4# prescribed to 5mm below vaginal surface HDR Brachy as boost to EBRT 4-6Gy/2-3#

18. ONGOING TRIALS GOG 238- to evaluate role of adjuvant chemoradiation in Stage I/II, serous or clearcell carcinoma PORTEC 4A- to evaluate a personalized approach to adjuvant therapy in high risk carcinoma based on molecular profiling GOG 233- To evaluation addition of chemotherapy to RT in Stage II carcinoma endometrium TAPER TRIAL- de-escalated adjuvant treatment directed by tumour molecular status for  POLE -mutated and p53wt/no-specific molecular profile (NSMP) early-stage endometrial cancers.

19. CONCLUSION Concurrent Chemoradiation followed by four cycles of paclitaxel plus carboplatin -excellent outcomes for most patients. The preferred form of radiation is pelvic/extended field IMRT Patients who are at high risk for peritoneal relapse should be treated with full systemic therapy. Molecular profiling are confirmed, could further help optimize the type of adjuvant therapy to consider; POLEmut - RT alone, MMRd - consider immunotherapy with RT P53abn and NSMP consider investigational agents +/- radiation.

20. Thank you