Adjuvant chemotherapy for early stage epithelial ovarian cancer Vanda Salutari Fondazione Policlinico Universitario A Gemelli U.O. Ginecologia Oncologica

The risk of relapse is not negligible 30%

The rationale of adjuvant CT after complete removal of disease ad adequate surgical staging is to eradicate any residual microscopic deposits of cancer cells responsible of potential recurrence of disease

ONE DISEASE MANY ISSUES Early stage ovarian cancer: To treat or not to treat? What type of chemotherapy? How many cycles? High grade serous ovarian cancer versus other histotypes

ONE DISEASE MANY ISSUES Early stage ovarian cancer: To treat or not to treat? What type of chemotherapy? How many cycles? High grade serous ovarian cancer versus other histotypes

1545 pts

comprehensively surgical staging Early stage ovarian cancer: To treat or not to treat? LOW RISK FEATURES Grade 1 and 2 Stage IA-IB comprehensively surgical staging OS 90% HIGH RISK FEATURES Stage IC and II Grade 3 Clear cell hystology OS 40-80% Chan JK, Gynecol Oncol 2010 Trope C, JCO 2007

Early stage ovarian cancer: To treat or not to treat? 3 Metanalyses: 1)Elit L Cancer 2004: 13 trials between 1965 and 2004 2) Winter Roach Cochrane Review 2012: 5 randomized trials between 1990 and 2003 involving 1277women, follow up of 46 to 121 months 3) Lawrie T: Cochrane Library, Dec 2015 5 randomized RCTs, no new studies met the inclusion criteria, 10-year follow up (ICON1): 1277 women

Trials of adjuvant chemotherapy versus no further treatment Study ID Participants Intervention 5-year survival rates 5-year survival/ statistics 10-year survival rates Adverse effects Comments Young 1990 48 treatment 44 observation Melphalan versus no further treat DFS 91% versus 98% OS 94% versus 98% Log rank test DFS P = 0.41 OS P = 0.43 NR 16% hadsevere myelosuppression 26% had gastrointestinal side effects. One death: myelopr disorder Trial under powered to show any real differences Bolis 1995 85 FIGO (1976) I A-I B Grade 2 and 3 Cisplatin 50 mg/m² × 6 Cycles versus no further treatment DFS 83% versus 64% OS 88% versus 82% DFS: HR 0.50; to 1. 19; P = 0.17 OS: HR 1.20 to 3.1; P = 0.71 Nausea and vomiting Leucopenia thrombocytoP Neuro tox renal tox There were patients with residual disease in both arms Tropé 2000 162 high risk stage I 36%pts had low volume RT Carboplatin 6 cycles AUC = 7 versus chemo at progression No difference between arms DFS 70% versus 71%,OS 86% versus 85% Dot reported ICON1 2003 447 FIGO I-II 93%FIGO stage 1 adjuvant platinum-based chemotherapy Versus treatment on PD (87% only platinum) OS 79% (adjuvant arm) versus 70% ( no treatment HRs OS: HR 0.66 to 0.97; P = 0.03 OS 73% (adjuvant arm) versus 64% (no treatment) Not reported Survival improvement with adjuvant therapy ACTION 2003 * 448 FIGO Ia- Ib grade 1-2-3 FIGO Ic- IIa FIGOI-IIa clear cell Adj platinumbased CT versus treatment on PD Cisplatin OR Carboplatin 33%sigle platinum OS 85% (adjuvant arm) versus 78% (no treatment OS: HR 0.69; to 1.08; P = 0.10 RFS: HR 0.63; P = 0.02 OS 77% (adjuvant 70% (no treatment) Subgroup analysis Showed that non-optimally staged patients in observation arm had significantly worse survival 1/3 OF PTS WERE NOT OPTIMALLY STAGED HIGH RISK: IA G3 I B G2 I C G3 ANY CLEAR CELL * LOW/INTERMEDIATE RISK: IA G1/G2 I B G1 I C G1

OS at 5 yrs CT NO CT CT NO CT OS at 10 yrs

PFS 5 yrs 10 yrs CT NO CT CT NO CT

SUBGROUP ANALYSIS BY SURGICAL STAGING OS PFS CT NO CT CT NO CT

SUBGROUP ANALYSIS BY RISK FACTORS OS PFS CT NO CT CT NO CT

LIMITS: Pts no prospectively stratified by surgical staging categories In ACTION trial only 1/3 of pts were optimally staged Evidence for pts with low and intermediate risk is incomplete (few pts in the trials) None of the included studies assessed the impact of adjuvant CT on QoL AE were poorly reported Findings for the subgroup analysis were ambiguous and low quality (ICON1 posthoc analysis)

ONE DISEASE MANY ISSUES Early stage ovarian cancer: To treat or not to treat? What type of chemotherapy? How many cycles? High grade serous ovarian cancer versus other histotypes

What type of chemotherapy? No evidences that a combination of carboplatin + paclitaxel for EOC is superior to carboplatin alone Studies comparing these two regimens are lacking Based on the results seen in advanced disease platinum based chemotherapy has been adopted for use in early stage disease but optimal adjuvant CT regimen is unknown A well designed trial is needed to identify the optimal CT regimen in this population

In absence of clear recomandations, single agent carboplatin seems a reasonable option for intermediate and high risk early EOC pts Which regimen can be regarded as standard comparator for future first line trials? The recomended standard in early stages (FIGO I-IIA) ovarian cancer patients in whom adjuvant CT is indicated should contain at least Carboplatin 5-7,5 AUC

73% 57% Median FU=38 months 62% 54% 80% 70% 63% 29%

1.3.2 Adjuvant systemic chemotherapy for stage I disease 1.3.2.1 Do not offer adjuvant chemotherapy to women who have had optimal surgical staging[11] and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib). 1.3.2.2 Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy consisting of six cycles of carboplatin. 1.3.2.3 Discuss the possible benefits and side effects of adjuvant chemotherapy with women who have had suboptimal surgical staging[11] and appear to have stage I disease.

EARLY OC WHAT TYPE OF CT IN SUMMARY Low quality data available to inform an optimal regimen Single agent carboplatin may be an acceptable alternative in I stages Well designed trials are needed to identify the optimal chemotherapy regimen in this population

ONE DISEASE MANY ISSUES Early stage ovarian cancer: To treat or not to treat? What type of chemotherapy? How many cycles? High grade serous ovarian cancer versus other hystotypes

24% reduction in recurrence rate in pts who underwent 6 cycles vs 3 cycles of CT A subgroup analysis showed statistically significant benefit only in serous tumors Non serous tumors was not influenced by the duration of CT

Relative risk of recurrence for OC pts receiving 6 vs 3 cycles of CT based on hystology RFS and OS OC pts receiving 6 vs 3 cycles of CT based on hystology

6 cycles vs 3 cycles may decrease recurrence in high risk serous OC OS was not different Further sudies are needed to confirm

ONE DISEASE MANY ISSUES Early stage ovarian cancer: To treat or not to treat? What type of chemotherapy? How many cycles? High grade serous ovarian cancer versus other histotypes

OC is not one disease Outcome depends on histotype

FIVE HISTOTYPES

CLEAR CELL OC: CURRENT STANDARD OF MANAGEMENT Guidelines recomend adjuvant CT for CCOC independently of stage but….. ACTION trial reported similar DFS for early stage treated or not with CT after surgery In optimally staged FIGO IA-IB disease adjuvant platinum based CT might confer survival advantage? Further studies are need……

MUCINOUS: CURRENT STANDARD OF MANAGEMENT 3-4 % of all OC 83% diagnosed at Stage I Early stage , well differentiated 5 yrs OS=90% Expansive growth pattern=good prognosis Adjuvant CT is usually not given for stage I mucinous OC(RajaF, ann oncol 2012, Jain A, 2013, ICON 1:19.5% of cases were mucinous: no difference in outcome between CT and not CT) Standard CT is less effective Future systemic treatment for mucinous OC may be similar to treatment used in colon k including EGFR or HER2-based therapy

THE FUTURE……

In stage I EOC, defects in transcription regulation are associated with poor prognosis. One of these functional signatures is based on 19 elements, called Barcode, which are differentially expressed between relapsing and not relapsing patients.

Stage I EOC Why some stage I patients relapse? Barcode expression level can be used in addition to clinical parameters to improve stage I tumor prognosis. Calura E., et al. Annals of Oncology 2016