Adjuvant chemotherapy with a platinum agent is recommended for high-risk disease as it improves survival, and delays recurrence.rrr The commonly used treatment regimen of carboplatin and paclitaxel is used because of ease of administration, acceptable toxicity profile, and a large body of evidence demonstrating benefit with this regimen in higher stages of ovarian cancer. Patients with apparent stage I disease who have not been adequately staged, and where re-exploration is not considered, should also be offered adjuvant chemotherapy. Accurate surgical staging is critical in identifying those patients who truly have stage l or ll disease and in determining whether adjuvant therapy is required. It has been established that patients with stage IA or IB disease and well differentiated tumours have 5-year survival rates exceeding 90% and do not require any post operative adjuvant chemotherapy. In contrast, patients with early stage disease and unfavourable prognostic factors have a much higher risk for relapse (25% to 40%) and should be considered for adjuvant chemotherapy.
The evidence supporting adjuvant chemotherapy is derived from the ICON1 and ICON3 trials.rrr The ICON1 trial was a phase III multicentre international randomised controlled trial. Between August 1991 and January 2000, 477 patients post surgery for early stage ovarian cancer were randomised to adjuvant chemotherapy (n=241) or observation (n=236). Patients had ovarian carcinoma of epithelial origin, and were treated with various platinum-based regimens, including single agent carboplatin (AUC 5 mg/mL), cisplatin (75 mg/m2), CAP (cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and cisplatin 50 mg/m2), or platinum combination regimens. The trial included patients with stage I-III disease, and 93% of patients had FIGO stage I disease. Only three patients (2%) were given combination carboplatin, while 171 (81%) received single agent carboplatin, 21 (11%) were given combination cisplatin and one was given single agent cisplatin (<1%). The primary endpoint was overall survival (OS), and the secondary endpoint was recurrence free survival.
The subsequent ICON3 trial was a large phase III multicentre international randomised controlled trial which compared carboplatin (AUC 5-6 mg/mL) plus paclitaxel (175 mg/m2) against either single agent carboplatin (AUC 5-6 mg/mL) or IV CAP (cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and cisplatin 50 mg/m2). All regimens were given every 21 days for 6 cycles. Between February 1995 and October 1998, 2074 patients were enrolled, 1,421 patients were randomised to carboplatin and paclitaxel (n=943) or single agent carboplatin (n=478), and 653 were randomised to CAP (n=421) or carboplatin and paclitaxel (n=232). The primary endpoint was OS, and secondary endpoints were progression free survival (PFS) and toxicity.
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Efficacy
ICON1rr
After a median follow up of 51 months, adjuvant chemotherapy was associated with improved OS compared to observation (HR = 0.66, 95% CI 0.45-0.97; P = 0.03). Five-year OS was 79% in patients receiving adjuvant chemotherapy compared to 70% for those who did not receive adjuvant chemotherapy. Adjuvant chemotherapy was also associated with improved recurrence-free survival (HR = 0.65, 95% CI 0.46-0.91, P = 0.01), with five-year recurrence free survival of 73% with chemotherapy compared to 62% with observation. Quality of life (QoL) was not examined.
Kaplan-Meier curve for overall survivalr
© J Natl Cancer Inst 2003
ICON3r
After a median follow up of 51 months, there was no significant difference in OS with carboplatin plus paclitaxel compared to single agent carboplatin (HR = 0.98, 95% CI 0.85-1.12; P = 0.73) or CAP (HR = 0.99, 95% CI 0.81-1.22; P = 0.94). QoL data was not reported.
Kaplan-Meier curves for overall survival and progression free survivalr
© Lancet 2002
Toxicity
ICON1rr
Toxicity data was not reported.
ICON3r
Carboplatin plus paclitaxel was associated with higher rates of alopecia compared to carboplatin alone. Grade 2-3 sensory neuropathy occurred in 19% of patients with carboplatin plus paclitaxel compared to 1% with carboplatin and 3% with CAP. Febrile neutropenia was more common with CAP compared to carboplatin or carboplatin plus paclitaxel, and haematological adverse events were similar across all groups.
Moderate or severe toxicity seen during treatment (grade 3 to 4 except where stated)r
Toxicity |
Carboplatin as control |
CAP as control |
Carboplatin
(%) |
Paclitaxel plus carboplatin
(%) |
CAP
(%) |
Paclitaxel plus carboplatin
(%) |
Alopecia |
4 |
73 |
76 |
80 |
Nausea and vomiting |
9 |
9 |
23 |
10 |
Haematological* |
32 |
25 |
33 |
29 |
Fever requiring antibiotics* |
3 |
10 |
23 |
13 |
Sensory neuropathy
(grade 2/3) |
1 |
19 |
3 |
18 |
Motor neuropathy* |
< 1 |
3 |
1 |
1 |
Other** |
4 |
7 |
6 |
6 |
*Data was collected by the non-Italian centres only
**Including ototoxicity, renal toxicity, cardiac toxicity and stomatitis
© Lancet 2002