Terapia adiuvante dopo trattamento conservativo: Quando? Quale?

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1 Terapia adiuvante dopo trattamento conservativo: Quando? Quale? Rocco De Vivo Oncologia Medica ULSS 6 Ospedale San Bortolo - Vicenza

2 OUTLINE Epidemiologic data (early stage and younger age EOC) Pathologic data (non-serous subtypes) Ovarian cancer in younger vs older population Risk assessment (grading, surgical staging) Adjuvant chemotherapy (when?) Adjuvant chemotherapy (what?) Retrospective studies Summary

3 Epithelial ovarian cancer (EOC) epidemiology The median age at diagnosis is 63 years EARLY DISEASE Fewer than 25% of women present with a stage I or II ovarian cancer (early disease) Only 3 17% of patients with ovarian cancer were age <40 years. ADVENCED DISEASE Approximately 10% of (early onset) cases are associated with inheritance of an autosomal dominant genetic aberration of DNA mismatch repair genes (BRCA1, BRCA2, HNPCC)

4 Epithelial ovarian cancer (EOC) pathology

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6 Epithelial ovarian cancer (EOC): non-serous subtypes Invasive mucinous subtype accounts for ~ 10% of EOC but 27% of stage I Pts. Once advanced or relapsed, has been associated with poorer survival and lower response rate to platinum containing chemotherapy. Pignata S et al. Activity of chemotherapy in mucinous ovarian cancer: results from the SOCRATES retrospective study. BMC Cancer 2008, 8: 252. Hess V et al. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol 22: ; Clear cell carcinoma subtype accounts for 4% to 12% of EOC in Western countries but more than 20% in Japan. It frequently presents as a large unilateral pelvic mass. The majority of Pts has a Stage I disease (~ 50%; mostly IC). It is often associated with endometriosis (~ 30%), deep venous thrombosis and hypercalcemia. Higher risk of recurrence in Stage I Pts (~ 30%). Low response to platinum-based chemotherapy. Itamochi H et al. Machanism of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci 2008; 99(no.4): Sugiyama T et al. Clinical characteristics of clear cell carcinoma of the ovary. Cancer 2000; 88:

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10 Relative infrequent disease Difficulties in performing studies (retrospective series)

11 1.4% 41.1% 57.3%

12 78.8% 58.8% 35.3%

13 Età Materna alla nascita (Italia) Madri 35aa: aumento >100% (primiparae), 75% (secondiparae) Il progressivo aumento delle età materna al concepimento potrebbe far aumentare Stefano Greggi, l incidenza XX Riunione di MITO, possibili casi di neoplasia Astolfi ovarica P & Zonta in LA, pazienti 2002 Novembre 2012, Milano desiderose di rimanere potenzialmente fertili.

14 Early disease (EOC) risk assessment SEER database between 1988 and 2001 of 8372 patients

15 Retrospective study on 1545 pts from 6 countries

16 168 consecutive Pts Median OS 36 months Median OS 17 months

17 ADJUVANT CHEMOTHERAPY OR OBSERVATION? Low risk Ia-Ib, Grade 1 Intermediate risk Ia-Ib, Grade 2 High risk G3, Ic all grades (cyst rupture during surgery), clear cell histology, nonoptimal surgical staging Consider adjuvant chemotherapy! Degree of differentiation is the most important independent prognostic factor in early-stage invasive EOC and should be used in clinical decision-making. Stage IA-B G1-2 Pts have >90% of RFS at 6 years with only optimal surgery. Stage IA-B G3 or IC-II Pts have substantial higher relapse risk (25-45%).

18 Which kind of adjuvant chemotherapy? Treatment of early disease after fertility preserving surgery (in the form of a unilateral salpingo-oophorectomy and complete staging, with preservation of the uterus and contralateral ovary) should be the same as in case of standard debulking surgery: AIOM: IA-B G3; IC 3-6 cycles carboplatin + paclitaxel or single agent carboplatin per 6 cycles ESMO: IA-B, G2-3; IC 6 cycles of single-agent carboplatin NCCN: IA-B, G2-3, IC 3-6 cycles carboplatin + paclitaxel NICE: IA-B G3; IC 6 cycles single agent carboplatin

19 The protocol asked the following question: in the opinion of the responsible clinician, does the patient require immediate chemotherapy? If the clinician was uncertain, was asked to consider entering the patient into ICON1, the earlier stage trial All visible tumor had to be removed. Thorough surgical staging, where possible, with total hysterectomy and bilateral salpingo-oophorectomy and omentectomy was recommended as the minimum procedures

20 HR 0.66; P =.03 HR 0.65; P =.01 ICON 1 (the earlier stage trial). Results of 477 randomized patients: Arm 5-year OS % 5-year RFS % Adjuvant treatment (6 cycles, plt-based) Delayed treatment 70 62

21 ICON 1 Long term post-hoc analysis Stage I OS: low/intermediate risk group HR 0.95 ( ), p=0.85 Absolute difference at 10 years =3% (75% 78%) Median FU= 9.2 y IA/IB G1/2, IC G1, no adj IA/IB G1/2, IC G1, adj Events Total patients PATIENTS at Risk IA/IB G1/2, IC G1, no adj IA/IB G1/2, IC G1, adj Years from randomisation A.C. Swart on behalf of ICON collaborators ASCO Annual Meeting abs

22 ICON 1 Long term post-hoc analysis Stage I OS: high risk group HR=0.48 ( ), p<0.001 Absolute difference at 10 years=17% (58% 75%) PATIENTS at Risk IA/IB G3, IC G2/3, clear cell, no adj IA/IB G3, IC G2/3, clear cell, adj Events Total patients Years from randomisation IA/IB G3, IC G2/3, clear cell, no adj IA/IB G3, IC G2/3, clear cell, adj A.C. Swart on behalf of ICON collaborators ASCO Annual Meeting abs

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25 Results of 448 (stage IA/B G2-3 and IC IIA any G) randomized patients: Arm 5-year OS% P 5-year RFS% P Adjuvant treatment (at least 4 cycles, Plt-based) Delayed treatment 78 68

26 completely staged 34% P =.7 incompletely staged 66% P =.03 The OS benefit of adjuvant chemotherapy appeared to be limited to patients with non-optimal staging, i.e., patients with more risk of unappreciated residual (stage III) disease.

27 After a median follow-up of 10.1 years completeness of surgical staging in patients with early ovarian cancer was found to be statistically significantly associated with better outcomes, and the benefit from adjuvant chemotherapy appeared to be restricted to patients with nonoptimal surgical staging.

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29 GOG 157: Compared to 3 cycles, 6 cycles of C and P do not significantly alter the recurrence rate in high risk early stage EOC but are associated with more toxicity.

30 5-y RFS 83% 5-y RFS 60% In this exploratory analysis of early-stage high risk ovarian cancer, our data suggest that six rather than three cycles of chemotherapy may decrease the recurrence of pts with serous tumors. Further studies are needed to confirm these findings.

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33 From 1982 to 2010, 240 pts with malignant ES/EOC treated with FSS:

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35 At median follow-up of 9 years, 27 pts had relapsed (11%) and 11 (5%) had died of progressive disease. Out of the 105 pts (45%) who tried to become pregnant, 84 (80%) were successful. Chemotherapy did not seem to affect fertility, and no congenital abnormalities were observed

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37 SUMMARY: Younger age EOC is a relative rare disease but with a possible increasing trend according to progressively older primiparae maternal age. More incidence in younger age of very early disease (stage IA), low grading (G1) and non-serous subtypes (mucinous, clear cell, endometrioid). Indication for adjuvant chemotherapy as for debulked early stage older patients. Clear efficacy of adjuvant chemotherapy in higher grading (G3), serous hystology, nonoptimal surgical staged patients. Adjuvant chemotherapy (without alkylating agents, anthracyclines) seems to not affect pregnancy rates after fertility sparing surgery.

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