International Collaborative Ovarian Neoplasm Trial 1 - (ICON 1) Study Question: Can platinum-based adjuvant chemotherapy improve outcomes in patients

with early stage epithelial ovarian cancer? Background: 30% of ovarian cancer confined to pelvis = early stage = Stage I and II 50% of these women experience a recurrent disease. Known therapies, but unknown survival advantage, include intraperitoneal radiation therapy, systemic chemotherapy, and total abdominal and pelvic radiation. International community began ICON1 study to look at effectiveness of immediate adjuvant chemotherapy after surgery. ICON was ran alongside ACTION study = (Adjuvant ChemoTherapy in Ovarian Neoplasm) Methods: Multicenter, open randomized trial. N = 477 in 84 centers of 5 countries (Italy, UK, Switzerland, Ireland, Brazil) Primary eligibility criteria = histologically confirmed ovarian carcinoma of epithelial origin AND that physician was uncertain whether to offer immediate adjuvant chemotherapy. Pertinent eligibility criteria = patients to have had removal of all visible tumour with a total abdominal hysterectomy and bilateral salpingo-oophorectomy, where appropriate, and omentectomy. Early stage ovarian (I or II) = ICON 1. Advanced-stage (3 or 4) = ICON 2 Follow-up data collected at 6 months and at 12 months. Adjuvant chemotherapy = 6 cycles of carboplatin alone (87%), CAP at intervals of 3 wks, cisplatin, carboplatin/cisplatin.

Statistical Evaluation: Kaplan-Meier and Mantel-Cox. Primary outcome = overall survival, from time of randomization to death from any cause. Secondary outcome = recurrence-free survival, recurrence or death from any cause. Results: 5 year survival = 70% in no chemotherapy versus 79% in adjuvant chemotherapy. 5 year recurrence-free survival = 62% in no chemotherapy versus 73% in adjuvant chemotherapy. Conclusion: The ICON 1 study suggests that platinum-based adjuvant chemotherapy improves. Limitations: o No restriction on FIGO staging or tumor grading, though >90% estimated to be stages I-IC. Therefore, surgical staging was less stringent, leading to criticism of having sub-optimal staging. o Open study Since this study: Swart 2007 confirmed the results above and showed that 10 year survival was 72% in chemotherapy arm versus 64% in non-chemotherapy arm. ACTION study = 448 participants from 1990 2000, open to all stage Ia and Ic, and Ib G2 and G3 with stringent surgical staging guidelines testing platin-based versus no treatment. Five-year survival was 76% among patients who had chemotherapy compared to 68% among those who did not. Multivariate Cox regression confirmed that staging adequacy and tumour grade were statistically significant prognostic factors. Concluded in 2009 that completeness of surgical staging in patients with early ovarian cancer was statistically significantly associated with better outcomes, and the benefits of adjuvant chemotherapy appears to be restricted to patients with sub-optimal surgical staging.

ICON studies: o ICON 2 = cyclophosamide/doxorubicin/cisplatin (CAP) versus carboplatin only in untreated, advanced-stage ovarian cancer o ICON 3 = effectiveness of paclitaxel with carboplatin in untreated cancer. o ICON 4 = effectiveness of platinum vs paclitaxel and platinum in platinum sensitive women with relapsed ovarian cancer. ACTION study = Adjuvant ChemoTherapy in Ovarian Neoplasm. o Compared adjuvant chemotherapy to observation alone after surgery, similar to ICON 1 but more patients were more optimally staged.