We have performed a phase I/II trial using carboplatin, epirubicin and capecitabine in platinum-sensitive patients with relapsed epithelial ovarian cancer. The rationale behind this regimen was that we had previously demonstrated a high response rate in patients treated with ECF for relapsed ovarian cancer at the Royal Marsden Hospital (Webb et al, 2000
), and wanted to investigate the feasibility of a more convenient route of administration for a fluoropyrimidine. We used capecitabine instead of 5-FU as this enables delivery of the fluoropyrimidine in an oral form rather than via a continuous infusion requiring a PICC line, without compromising on efficacy as shown for colorectal cancer in randomised trials (Hoff et al, 2001
; Van Cutsem et al, 2001
). We initially chose to administer continuous capecitabine to mirror continuously infused 5-FU, but this proved impractical.
In addition, carboplatin has been shown to be equally active as cisplatin in advanced ovarian cancer (Swenerton et al, 1992
; Taylor et al, 1994
; Ozols et al, 2003
), but is less toxic and easier to administer. This was the reason why we changed the cisplatin to carboplatin for the ECarboX regimen.
We found the ECarboX regimen to be active with three patients having a CR and eight patients a PR, giving an overall response rate (ORR) of 61.1%. CR was seen in patients at dose level 1 and dose level 3, PR was seen on all other dose levels. The median progression-free survival of 8.3 months is consistent with the results seen in this patient group in other phase I/II trials (Kose et al, 2005
However, ECarboX proved problematic to deliver as prescribed. The overall toxicity was high in terms of haematological side effects, although surprisingly no major infectious complications arose from the neutropenic episodes. Prolonged myelotoxicity was a significant feature even when administration of capecitabine was shortened. All other side effects were infrequent and manageable.
One patient's treatment was complicated by a cerebrovascular event and a deep venous thrombosis during cycle two. She was taken off study and treated with single-agent carboplatin. There are reports suggesting capecitabine can induce acute coronary syndromes (Schnetzler et al, 2001
; Frickhofen et al, 2002
), but no reports of cerebrovascular events caused by capecitabine exist. It remains unclear whether this patient's CVA was related to chemotherapy. The patient who developed intestinal obstruction following the first course of treatment was thought to have disease progression rather than a side effect from the regimen.
The management of patients with platinum-sensitive relapsed ovarian cancer is receiving increasing attention. A retrospective analysis (Dizon et al, 2002
) of patients who received carboplatin/paclitaxel at relapse demonstrated an OR of 69.7% and a progression-free interval of 13 months. A total of 61.9% of these patients had already received carboplatin/paclitaxel as first-line treatment. However, 77% had a treatment-free interval >12 months and therefore would be considered good-risk patients. Toxicity was acceptable although six patients required admission to hospital for adverse events.
The ICON4/AGO-OVAR-2.2 trial investigated carboplatin/paclitaxel vs
conventional platinum-based chemotherapy in women with relapsed ovarian cancer (Parmar et al, 2003
). In this trial, about 40% of patients had received a platinum/paclitaxel combination previously as first-line treatment. Response rates were higher in the carboplatin/paclitaxel arm (OR 66 vs
=0.06) as was the median progression-free survival (12 vs
9 months) and overall survival (29 vs
24 months, HR=0.82, P
However, there may be problems in re-treating patients with carboplatin/paclitaxel at relapse when they have received this combination at first line particularly if their treatment-free interval is 6–12 months. These patients frequently have a degree of residual peripheral neuropathy and have only just regained a normal length of hair; repeating and possibly exacerbating the former toxicity in a short space of time is not acceptable to many patients and their physicians, especially since these patients have a rather poor prognosis. Carboplatin/gemcitabine is a treatment option for patients with a potentially platinum-sensitive relapse. In a randomised study conducted by the AGO in 356 patients, the median progression-free survival was 8.6 months for patients treated with carboplatin/gemcitabine and 5.8 months for those receiving single-agent carboplatin, the response rate in the combination arm was 47.2 and 30.9% for carboplatin alone (Pfisterer et al, 2005
In the context of these different regimens, other combinations such as ECarboX are worthy of consideration. However, toxicity remains a major concern and the question that has to be raised is whether the potential risks outweigh the benefits.
One option would be to omit the anthracycline from the ECarboX regimen. Such an approach is supported by data from the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) group trial and the NSGO-EORTC-NCIC CTG gynaecological cancer intergroup trial. These were two large randomised trials of first-line chemotherapy, both of which have shown that the addition of epirubicin to carboplatin/paclitaxel is of no benefit (Kristensen et al, 2003
; Du Bois et al, 2004
The addition of epirubicin to a two-drug combination in the second-line setting may therefore be of doubtful value. Consequently we are currently evaluating the use of carboplatin in combination with capecitabine in a phase-2 trial. This two-drug combination may prove to be a suitable candidate for further randomised trials in relapsed ovarian cancer.