Doctor Steve Abel

Choice of Chemotherapy and Duration of Treatment

Generally, choice of adjuvant chemotherapeutic agents for early-stage disease has been extrapolated from management of advanced-stage ovarian cancer. See the section on Advanced Ovarian Carcinoma, later in this chapter. Many of the investi-gational trials in early-stage ovarian cancer compared cisplatin-based combination chemotherapy to radiation therapy 18-20 (Table 8-5). Meta-analyses of these types of trials have shown no significant difference between chemotherapy and radiation therapy for disease-free and overall survival.21

Carboplatin replaced cisplatin as the standard platinum in treating ovarian cancer after several studies concluded that carboplatin and cisplatin had equivalent efficacy in treating advanced disease.22 ICON-2 demonstrated that single-agent carboplatin effected the same median survival and 2-year survival (33 months and 60%) as the combination of cyclophosphamide-doxorubicin-cisplatin in advanced disease.23 As in advanced disease, platinum-based chemotherapy can be considered standard treatment for early ovarian cancer; however, a universally accepted regimen is not evident. Two international multicenter trials of adjuvant therapy in early ovarian cancer, ACTION9 and ICON-1,14 allowed either single-agent carboplatin or cisplatin combination regimens for eligibility.

Since 1995, most research in chemotherapy for advanced disease has focused on incorporating paclitaxel into front-line treatment, and the combination of carboplatin and paclitaxel is currently the preferred treatment for advanced disease.24 However, the number of trials with paclitaxel regimens in early ovarian cancer are limited.25,26 No trials have compared combination platinum-paclitaxel with nonpaclitaxel regimens in early ovarian cancer. Without such direct comparisons, regimens other than carboplatin-paclitaxel would seem acceptable (Fig. 8-5).

The optimal duration of adjuvant therapy in early ovarian cancer is unknown. Table 8-6 shows the outcomes of trials using various regimens from three to six cycles. The GOG has conducted the only randomized trial comparing two different durations.29 This study compared three to six cycles of adjuvant carboplatin-paclitaxel in high-risk early ovarian cancer patients who had been completely staged. It found no significant difference in the risk of cancer recurrence or 5-year survival (25% versus 20% and 81% versus 83%, respectively). Of note was the significantly greater toxicity in the six-cycle arm. The authors concluded that following complete surgical staging, three cycles of carboplatin and paclitaxel constitute a reasonable treatment option

Table 8-5. Trials Comparing Adjuvant Cisplatin with Radiation Therapy in
Early-Stage Ovarian Cancer
Trial N Stage Treatment	Survival
Vergote et al (1992)18 340 I, II, III Cisplatin vs 32P	75% DFS for cisplatin
	81% DFS for 32P

Chiara et al (1994)19	70	IA grade 3—IIC	CP vs WAR	74% DFS for chemo 50% DFS for WAR
Bolis et al (1995)7	161	IC	Cisplatin vs 32P	81% OS for cisplatin 79% OS for 32P
Kojs et al (2001)20	150	IA grade 2-IIC	CAP vs WAR	81% 5-year DFS for both

CAP, cyclophospharnide/doxorubicin/cisplatin; CP, cyclophosphamide and cisplatin; DFS, disease-free survival; OS, overall survival; WAR, whole abdomen radiation therapy.

Modified from Winter-Roach B, Hooper L, Kitchener H: Systematic review of adjuvant therapy for early stage (epithelial) ovarian cancer. Int J Gynecol Cancer 13(4):395-404, 2003.

CAP, cyclophospharnide/doxorubicin/cisplatin; CP, cyclophosphamide and cisplatin; DFS, disease-free survival; OS, overall survival; WAR, whole abdomen radiation therapy.

Modified from Winter-Roach B, Hooper L, Kitchener H: Systematic review of adjuvant therapy for early stage (epithelial) ovarian cancer. Int J Gynecol Cancer 13(4):395-404, 2003.

Table 8-6. Duration of Adjuvant Chemotherapy in Early-Stage Ovarian Cancer

Trial N Stage and Grade Treatment No. Cycles Survival

Rubin (1993)27 62 Stages IA, B, grades 2-3, IC CP, CAP 6 73% 5-year DFS

Shimada (2005)28 100 Stages I, II, all grades CAP or CT 3 100% 5-year OS for low risk

89% for high risk

Bamias (2006)25 69 Stages IA, B, grades 2, 3 Carboplatin 4 79% 5-year DFS

Stages IC, II, any grade Paclitaxel 87% 5-year OS

Bell (2006)29 427 Stages IA, B, grade 3 Carboplatin 3 75% 5-year DFS

Stages IC, II, any grade Paclitaxel 6 80% 5-year DFS

CAP, cyclophosphamide-doxorubicin-cisplatin; CP, cyclophosphamide and cisplatin; CT, carboplatin-paclitaxel.

Carboplatin-paclitaxel AUC 5-6, 175 mg/m2 q 3-4 weeks

Single-agent carboplatin AUC 5-7.5 q 3-4 weeks

Single-agent cisplatin 50 mg/m2 q 3-4 weeks

Cyclophosphamide-cisplatin 500 mg/m2, 50 mg/m2 q 3-4 weeks

Figure 8-5. Acceptable chemotherapy regimens for non-clear cell early stage ovarian cancer.

Preferred

Carboplatin AUC 5-6/paclitaxel 175 mg/m2 q 3-4 weeks or

Investigational

Cisplatin plus irinotecan (Doses to be determined)

Figure 8-6. Options for treating clear cell carcinoma of the ovary.

for women with high-risk, early-stage epithelial ovarian cancer. Three additional cycles of carboplatin-paclitaxel chemotherapy are, at best, likely to provide only a modest reduction in the absolute risk of recurrence, yet are associated with increased toxicity.

Clear cell histology is generally considered an aggressive epithelial carcinoma with a worse prognosis, stage for stage,17,30,31 or at least in stage I.32,33 Other data do not support these opinions.34,35 In advanced disease, the overall response rate (RR) to platinum-based chemotherapy is 11% compared with 72% for serous histology.31 The addition of paclitaxel to platinum appears to improve the RR: 56% compared with 27% for platinum without paclitaxel.36 More recently, a retrospective review reported that platinum with irinotecan resulted in a higher RR than paclitaxel/platinum (43% versus 32%) and also resulted in a significantly improved progression-free survival in optimally debulked patients.37 In keeping with the general pattern of extrapolating from advanced disease, the current recommended option for adjuvant treatment of early-stage clear cell carcinoma would be combination paclitaxel-carboplatin. Although combination cisplatin-irinotecan appears promising, at this point it should be considered investigational (Fig. 8-6).