Dose dense chemotherapy in the adjuvant treatment of ovarian cancer Natasha Banerjee, MD

Ovarian cancer Malignant transformation of ovarian surface epithelium, contiguous with peritoneal epithelium. 6th most common cancer in women. Most patients present with advanced disease and have a poor prognosis. Risk factors: family history, nulliparity, early menarche, late menopause, increasing age. BRCA1: lifetime risk 39-46% BRCA2: 12-20% Reduced risk associated with: OCP use, pregnancy, lactation, tubal ligation.

Ovarian cancer Pathologic grade 1-3. Subtypes: serous (most common), mucinous, endometrioid, clear cell, transitional, squamous, mixed, undifferentiated. Fallopian tube and primary peritoneal cancers resemble epithelial ovarian cancers (same embryonic precursors).

Genetic factors HOXA7 controls extent of differentiation and grade of ovarian tumors. Sex steroids regulate HOX throughout the menstrual cycle. Protracted exposure of ovarian epithelium to sex hormones may lead to inappropriate HOX activation  proliferation and genetic mutations. Somatic mutations in TP53, PTEN, KRAS, PI3K, AKT1, BRCA may contribute.

Model of carcinogenesis Type I tumors Arise in a stepwise fashion from lower grade tumors. Low grade serous, mucinous, endometrioid, clear cell carcinomas. Type II tumors Arise de novo. High grade serous carcinomas, malignant mixed mesodermal tumors, undifferentiated carcinomas. Have frequent TP53 mutations, genomic instability, and BRCA mutations.

FIGO staging 2002 Stage I: limited to ovaries Stage II: tumor involves one or both ovaries with pelvic extensions Stage III: tumor involves one or both ovaries with peritoneal metastasis outside the pelvis or RP or inguinal node metastasis Stage IV: distant metastasis to liver or visceral organs or pleural effusion

Complete surgical staging TAH and BSO, examination of all peritoneal surfaces, infracolic omentectomy, biopsies of pelvic and para-aortic LNs and clinically uninvolved areas, peritoneal washings. Optimal cytoreduction confers survival advantage. 10% in cytoreduction = 5.5% increase in median survival. Optimal cytoreduction = residual disease < 1 cm, or no visible disease. +/- RP nodal dissection.

Adjuvant chemotherapy No chemo for well differentiated stage IA or IB More than 90% will have long term disease free survival. High grade, stage IC, and stage II benefit from adjuvant platinum based chemo. Standard of care (consensus 2005) is carboplatin AUC 5-7.5 and paclitaxel 175 mg/m2 q21 days for 6 cycles. Many phase III trials have shown no benefit with addition of a third drug.

Long term results of dose-dense paclitaxel and carboplatin vs Long term results of dose-dense paclitaxel and carboplatin vs. conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016) Katsumata, et al. Lancet Oncology, August 2013 Originally published in the Lancet, 2009

Dose-dense concept Goal: administer same cumulative dose of chemo over a shorter period. Example: Carboplatin and paclitaxel every 3 wks vs. Carboplatin D1 and paclitaxel D1, 8, 15 every 3 weeks

Gompertzian model Smaller tumors grow faster. Large cell kill at one time  smaller tumors  grow faster between treatment cycles.

Norton Simon Model Increasing dose density of chemotherapy increases efficacy by minimizing regrowth between chemotherapy cycles. Dose dense benefit first proven in breast cancer, with weekly paclitaxel instead of every 3 weeks.

JGOG 3016, 2009 637 patients with stage II-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. Randomized, controlled, open label study. Patients enrolled from April 2003-Dec 2005. Randomized to first line: 6 cycles paclitaxel (180 mg/m2) + carbo AUC 6 q21 days, or 6 cycles dose-dense paclitaxel (80 mg/m2) on D1, 8, 15 + carbo AUC 6 on D1, q21 days.

Trial Profile 637 patients screened 637 patients screened 317 assigned to dose dense 320 assigned to conventional 5 excluded : 1 double cancer 1 other primary cancer 1 previous chemotx 1 stage 1C disease 1 active cancer in past 5 yrs 1 excluded: 1 carcinosarcoma 312 included in primary and long-term analysis 319 included in primary and long-term analysis

Surgical options Radiology Interval debulking surgery after 2-4 cycles of chemotherapy Secondary debulking or second-look surgery after 6 cycles of chemotherapy, or both. Radiology Radiological studies at baseline and after 2, 4, and 6 cycles of chemotherapy. After completing treatment, assessment q3mos for 2 years and then q6mos. Follow up: physical exam, CA-125, CT done only for rising CA-125 or symptoms of relapse.

JGOG 3016, 2009 Primary endpoint: progression free survival Secondary endpoints: overall survival and toxicity Median follow-up: 29 months

Primary endpt: PFS 28 months in dose-dense group 17.2 months in conventional treatment group HR = 0.71, 95% CI, 0.58 – 0.88, p=0.0015

Secondary endpt: OS at 3 yrs 72.1% in dose dense group 65.1% in conventional group HR = 0.75, 95% CI, 0.57 – 0.98, p=0.03

Toxicities Early discontinuation more common in dose dense group (53% vs 37%), primarily due to toxicities. Most common adverse event was neutropenia (92% in dose dense vs 88% in conventional, not significant). More grade 3 and 4 anemia in dose dense group (69% vs 44%, significant). Other toxicities (peripheral neuropathy) similar.

Long term follow up Median follow-up 76.8 months. 631 evaluable patients. 426 patients had progressed or died. 307 deaths recorded. Number of patients receiving subsequent chemo (platinum/non-platinum) similar in both groups, but data not reported.

Long term follow up: PFS 28.2 months in dose dense group 17.5 months in conventional group HR 0.76, 95% CI 0.62-0.91, p=0.0037

Long term follow up: OS 100.5 months in dose dense group 62.2 months in conventional group HR 0.79, 95% CI 0.63-0.99, p=0.039

Long term follow up: 5 year OS 58.7% in dose dense group 51.1% in conventional group

Survival by stratification PFS and OS for patients with residual disease > 1 cm was higher in dose dense group PFS: 17.6 mos vs 12.1 mos, HR 0.71, p=0.0029 OS: 51.2 mos vs 33.5 mos, HR 0.75, p=0.0027 PFS and OS for patients with residual disease < 1cm not significantly different PFS: Not reached vs 60.9 mos, HR 0.74, p=0.08 OS: not reached vs not reached, HR 0.76, p=0.23

Survival by subtype Serous subtypes Clear-cell or mucinous subtypes PFS better in dose dense group (28.7 vs 17.5 mos) OS better in dose dense group (100.5 vs 61.2 mos) Statistically significant Clear-cell or mucinous subtypes Difference in PFS and OS not statistically significant PFS 18.7 vs 16.7 mos OS not reached vs 62.2 mos

Multivariate analysis Adjusted for prognostic variables. Dose dense regimen had significantly better PFS and OS. Factors associated with poor PFS and OS: Stage III or IV disease. Residual disease at least 1 cm. Poor performance status (ECOG 1-2 vs 2-3). Lower relative dose intensity of paclitaxel. Factors that did not influence overall survival: Dose reductions of carboplatin. Treatment delays of chemotherapy. Lower relative dose intensity of carboplatin.

Conclusions These long term results reinforce the dose dense regimen as standard of care in this group. Long term adverse events not studied. In original study, dose dense associated with higher rates of anemia. This study was done in Japan. OS for pts resected to <1cm residual disease better than published studies from Europe and US.

Conclusions Greatest benefit seen in patients with: <1cm residual disease serous or non-clear cell, non-mucinous histology. Clear cell and mucinous tumors seem to have distinct tumor biology, more high grade. Standard chemo drugs have only modest activity. Consider targeted agents for future study in these subtypes.