Portec 3

CARCINOMA ENDOMETRIUM PORTEC TRIAL

1. Lancet oncology : February 12,2018 Dr . Muneer .A Dept of Radiation oncology

2. Before going to the details What is PORTEC 1? PORTEC 2?

3. The Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial was the first to randomly compare pelvic external-beam radiotherapy(EBRT) to no additional treatment (NAT). Between 1990 and 1997, 715 patients Median follow-up was 13.3 years

4. limitations Impact of low grade toxicity on HRQL are lacking in this trials Conformal techniques are not used

5. Randomised trial undertaken in 19 Dutch radiation oncology centres 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated system. The primary endpoint was vaginal recurrence. Secondary endpoints were  locoregional recurrence (pelvic or vaginal, or both) distant metastases overall and disease-free survival treatment-related toxic effects and quality of life

6. conclusions VBT is very effective in ensuring local control keeping to a minimum risk of vaginal recurrence. VBT achieves excellent vaginal control and rates of locoregional recurrence. Overall survival, and disease-free survival that are similar to EBRT Quality of life and gastrointestinal toxic effects are significantly better with VBT. VBT should be the adjuvant treatment of choice for patients with uterine confined-endometrial carcinoma of high intermediate risk

7. limitations Number of patients is low that under powers the study Change in grade I and grade II diseases in central pathological review. 44% to 79% in grade I 44% to 9% in grade II 13% In Retrospect were ineligible for trial It did not consider LVSI in risk factors It underscored the role of pathologists in the diagnosis of carcinoma endometrium

8. Lancet oncology : February 12,2018

9. Phase III, international, open- label,multicentre , randomised trial at 103 centers 686 patients of high risk endometrial cancer enrolled Nov 2006 to Dec 2013 Randomised to CHEMORADIOTHERPY vs RADIOTHERPAY alone (1:1) Medain follow-up 60.2 months

10. background Pelvic external beam radiotherapy has been the standard adjuvant treatment for women with high-risk endometrial cancer for many decades, although there is a paucity of evidence on improvement of survival. Randomised trials( lissoni et al , susumu et al) have compared adjuvant chemotherapy with external beam radiotherapy. Radiotherapy was shown to delay pelvic recurrence and chemotherapy was shown to delay distant metastases, but no differences in survival were found.

11. Retrospective studies reported substantial rates of pelvic recurrence if high-risk patients were treated without radiotherapy , supporting the combined use of pelvic radiotherapy with adjuvant chemotherapy, as first explored in the RTOG 9708 phase 2 trial Because the combination of radiotherapy and chemotherapy ( chemoradiotherapy ) seemed more effective than either treatment alone, and because data for toxicity and quality of life were lacking, the randomised PORTEC-3 trial was initiated to evaluate the benefit of chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer

12. ELIGIbility criteria Inclusion criteria Histologically confirmed endometrial carcinoma, with one of the following postoperative FIGO 2009 stages and grade: 1. stage IA ,grade 3 with documented LVSI 2. stage IB grade 3 3. stage II 4. stage IIIA or IIIC; or IIIB if parametrial invasion only 5. stage IA, IB, II, or III with serous or clear cell histology WHO-performance status 0-2 WBC ≥ 3.0 x 109/L. Platelets ≥ 100 x 109/L. Bilirubin ≤ 1.5 x UNL ASAT/ALAT ≤ 2.5 x UNL Written informed consent AGE ≥18, without upper limit Exclusion criteria Uterine sarcoma (including carcinosarcoma ) Previous malignancy < 10 yrs Previous pelvic radiotherapy, Hormonal therapy or chemotherapy for this tumor Bulky cervical involvement with radical hysterectomy Inflammatory bowel disease Residual macroscopic tumor after surgery Impaired cardiac function, prohibiting the infusion of large amounts of fluid during cisplatin therapy Peripheral Neuropathy > grade 2 Hearing impairment > grade 3, or born deaf

13. surgery Surgery comprised total abdominal or laparoscopic hysterectomy with bilateral salpingo-oophorectomy . Lymphadenectomy , whether systemic or sampling, was left to the discretion of participating centres, while lymph node debulking and para -aortic lymph-node sampling were recommended in cases of macroscopic positive pelvic nodes or para -aortic nodes (or both).

14. External beam radiotherapy Given in both treatment group Total dose 48.6 Gy 1.8 Gy fractions , 5 days a week Proximal vagina,Parametrial tissue Internal, external, and common iliac node upto L5- S1(with a margin of ≥2 cm above the highest involved lymph node). In case of cervical involvement (glandular, stromal , or both), a brachytherapy boost was given to the vaginal vault. Brachytherapy dose was equivalent to 14 Gy in 2 Gy fractions (with recommended scheme of 10 Gy high-dose rate [HDR] in fractions of 5 Gy ), specified at 5 mm from the vaginal vault surface. start within 4–6 weeks of surgery, but no later than 8 weeks.

15. chemoradiotherapy two cycles of intravenous cisplatin 50 mg/m2 in the first and fourth we ek of external beam pelvic radiotherapy, followed by four cycles of intravenous carboplatin AUC5 and paclitaxel 175 mg/m2 at 21-day intervals Adjuvant chemotherapy started within 3 weeks after completion of external beam pelvic radiotherapy, and with a 28-day interval from the second concurrent cycle

16. Toxicity endpoints cisplatin was postponed for 1 week. If recovery required more than 1 week cisplatin was discontinued neuropathy of grade 2 or worse Carboplatin was postponed or stopped in case of severe haematological toxicity. Paclitaxel was postponed for grade 2 neuropathy and stopped if recovery exceeded 1 week or grade 3 neuropathy developed

17. PRIMARY ENDPOINTS OVERALL SURVIVAL (time from date of randomisation to date of death from any cause). FAILURE-FREE SURVIVAL .(any relapse or death related to endometrial cancer or treatment, time from randomisation to date of first failure-free survival event. ) SECONDARY ENDPOINTS vaginal, pelvic, or distant recurrence treatment-related toxicity health-related quality of life Abdominal recurrences outside the pelvic area (peritoneal carcinomatosis , liver, and para -aortic lymph nodal metastases) were considered distant metastases

18. toxicity Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 baseline (after surgery), at completion of radiotherapy, each chemotherapy cycle, at 6-month intervals from randomisation until 5 years, At 3 years ,7 years and 10 years

19. results Chemoradiotherapy , n=330 Median follow up Median age Lymphadenectomy,lymphnode sampling or full surgical staging EBRT completion Vaginal brachy Radiotherapy, n=330 60.0 months 62 years 190 patients (58%) 329 patients (100%) 151 (46%) 60.7 months 62 years 192 patients (58%) 325 patients (99%) 158 (48%)

20. Both cycles of concurrent cisplatin were completed by 304 (92%) of 330 patients in the chemoradiotherapy group. Adjuvant chemotherapy was started by 304 (92%) patients, while 262 (79%) patients completed all four cycles of carboplatin and 233 (71%) patients completed all four cycles of paclitaxel . At least one dose reduction of cisplatin (to 40 mg/m2) was recorded for five (2%) patients, of carboplatin (from AUC5 to AUC4) for 36 (11%) patients, and of paclitaxel (from 175 mg/m2 to 135 mg/m2) for 50 (15%) patients. Chemotherapy was discontinued in 61 (18%) patients ; in 31 (9%) because of toxicity, patient decision in 20 (6%), disease progression in seven (2%), other reason (3%)

21. 5 YEAR OVERALL SURVIVAL CHEMORADIOTHERAPY 81・8% RADIOTHERAPY 76・7% p = 0.109

22. 5 YEAR FAILURE FREE SURVIVAL CHEMORADIOTHERAPY 75.5 % RADIOTHERAPY 68.6 % p = 0.02

23. SUBGROUP ANALYSIS, women with stage III endometrial cancer had significantly lower overall survival and failure-free survival than those with stage I–II disease patients with stage III endometrial cancer who have the highest frequency of recurrence , also had the greatest absolute benefit from the combined treatment. The smaller failure-free survival improvement for patients with stage I–II disease seems not to outweigh the cost in terms of toxicity and quality-of-life impairment. Pelvic control was high (91%) with radiotherapy alone.

24. Forest plot of multivariable analysis 5 YEAR over all SURVIVAL

25. Forest plot of multivariable analysis 5 YEAR FAILURE FREE SURVIVAL

26. In multivariable analysis for failure-free survival, only age group was found to be predictive of treatment effect, with a strong treatment-by-age effect (p=0・012) Women aged 70 years or older had the greatest benefit from chemoradiotherapy than younger women. Age is a well-known risk factor for endometrial cancer and a greater benefit of chemotherapy in older women has been reported previously .( susumu et al, colombo et al) (although selection of fitter older women in this randomised trial might have occurred )

27. RECCURRENCE OUTCOME

28. TOXICITY Chemoradiotherapy , n=330 GRADE 2 OR Worse GRADE 3 or worse Grade 2 or worse senosry neuropathy 3year 5 year Radiotherapy, n=330 308 (93%) 198 (60%) 20 (8%) 12 (9%) 144 (43%) 41 (12%) p=.0001 1(1%) p=.0001 0 p=.0001

29. conclusions treatment with chemoradiotherapy significantly improved 5-year failure-free survival for patients with high-risk endometrial cancer compared with radiotherapy alone but there was no significant difference in overall survival. women with stage III endometrial cancer, a significant improvement in failure free survival was found For each patient, the cost in terms of increased toxicity and longer treatment duration should be weighed against the benefit in terms of improvement in failure-free survival.

30. limitations Final analysis was time based rather than event based ( median follow-up: 5 years ). Studies regarding molecular characteristics and targeted agents needed to individualise treatment of women with high risk endometrial cancer.

31. PORTEC-4 TRIAL Randomised Phase III Trial Comparing Vaginal Brachytherapy (two doses schedules: 21 or 15 Gy HDR in 3 fractions) and Observation after Surgery in patients with Endometrial Carcinoma with High-Intermediate Risk Features A Dutch Gynaecological Oncology Group trial Result not yet published

32. Thank you