Promising results of Phase II and III studies suggest that oxaliplatin will become an important addition to the drugs already used to treat ovarian cancer, as well as an alternative to currently used platinum compounds. So said Dr Jean‐Louis Misset, from the St Louis Hospital in Carrolton, France, speaking in New York at the Chemotherapy Foundation Symposium as he reviewed the positive experiences with oxaliplatin as a single agent and in combination regimens.
‘Oxaliplatin has proven efficacy in advanced ovarian cancer as a single agent and in combination chemotherapy,’ he said.
‘This newer platinum compound has a favourable toxicity profile compared with other platinum compounds, and oxaliplatin combines favourably in advanced ovarian cancer with other drugs including topotecan.’
Mismatch repair deficiency, which is present in untreated ovarian cancer cells, is associated with resistance to cisplatin and carboplatin, Dr Misset explained. However, the presence of mismatch repair deficiency does not compromise response to oxaliplatin, providing a strong pre‐clinical rationale for use of this agent.
Favourable toxicity profile
Available platinum agents such as cisplatin and carboplatin have different side‐effect profiles, and both agents have drawbacks. Cisplatin can cause renal toxicity, haematopoetic deficiency, and cumulative persistent neurotoxicity.
Carboplatin, a newer platinum compound, is associated with severe haematologic toxicity, which makes it difficult to use in fragile patients such as the elderly, Dr Misset said.
Compared with both predecessors, oxaliplatin has a favourable toxicity profile. ‘Oxaliplatin is free of renal toxicity and can be administered without hydration in an outpatient setting; it is also almost completely free of haematologic toxicity, especially in treatment‐naive patients.’
These properties make it suitable for treatment, even in patients who have compromised renal function.
In addition, as pilot studies have shown, oxaliplatin is suitable for use at full dose in combination with other agents, even those with severe haematologic toxicity, Dr Misset continued.
The major toxicity of oxaliplatin is peripheral neuropathy, which can be acute and cumulative after eight or nine cycles. Oxaliplatin can be used for six cycles with no cumulative neuropathy.
Experience with oxaliplatin
Three Phase II studies in patients who relapsed on previous platinum therapy demonstrated response rates of 15% to 30% with one‐year overall survival when oxaliplatin was used.
‘Response rates were higher in platinum‐sensitive patients,’ Dr Misset said. ‘Some response was also seen in platinum‐insensitive patients. This suggests that there is a lack of cross‐resistance with oxaliplatin, which is related to mismatch repair.’
Studies comparing single‐agent oxaliplatin versus paclitaxel (by the European Organization for Research and Treatment of Cancer) and versus topotecan (Trial EFC 7419) showed response rates of 10% to 16% with oxaliplatin. In both studies, Dr Misset commented, time‐related parameters were at least as good with oxaliplatin as with paclitaxel and topotecan.
First‐line combination chemotherapy
Dr Misset and his colleagues conducted a Phase II‐III study from 1992 to 1998 comparing high‐dose chemotherapy with cisplatin/cyclophosphamide versus oxaliplatin/cyclophosphamide in 182 patients with advanced ovarian cancer who had received no prior chemotherapy.
Patients had a good performance status. The vast majority (more than 80%) had extensive disease and significant residual disease (more than 2 cm), so they were not optimally debulked at trial entry.
Patients were randomised to receive either full‐dose oxaliplatin at 130 mg/m2 or cisplatin at 100 mg/m2 in combination with cyclophosphamide at 1,000 mg/m2 every three weeks for six cycles.
‘We chose these doses because we wanted to avoid criticism about potential undertreatment in the control group,’ Dr Misset explained.
Results of the study showed similar efficacy with both treatment arms, with the main difference between them being safety. Median progression‐free survival was 13 months in the oxaliplatin arm of the study and 13.3 months in the control arm; median survival times were 36 and 25.1 months, respectively.
‘These time‐related parameters are similar to what we've observed with taxane‐containing combinations in ICON [The International Collaborative Ovarian Neoplasm] 3,’ Dr Misset said.
Oxaliplatin demonstrated less haematologic toxicity, with less anaemia, transfusion requirements, and fewer cycles delayed due to haematologic toxicity compared with the cisplatin‐containing arm.
No gastrointestinal toxicity was observed in the cisplatin‐containing arm of the study versus 3% in the oxaliplatin arm; nausea and vomiting occurred in significantly more patients in the cisplatin‐containing arm (28% vs 0%, respectively). Grade 3 neurotoxicity was 0% with oxaliplatin versus 1% in controls. Dr Misset emphasised that neurotoxicity is seen with oxaliplatin only after eight or nine cycles, but not with six cycles of treatment.
This small study suggested that oxaliplatin could be a better alternative to other platinum compounds in combination chemotherapy.
‘Oxaliplatin is free of renal toxicity and can be administered without hydration in an outpatient setting; it is also almost completely free of haematologic toxicity, especially in treatment‐naïve patients.’
Another study he described was a Phase II trial that evaluated sequential firstline chemotherapy with four cycles of the combination of gemcitabine and oxaliplatin (GEMOX, which has become popular in Europe) followed by four cycles of carboplatin/paclitaxel.
Early results in 20 patients showed an 84% response rate (4 complete responses, 12 partial responses) after the first four cycles; the response rate rose to 89% with the additional four cycles of carboplatin/paclitaxel.
An ongoing study, EFC‐3312, is evaluating the combination of oxaliplatin and paclitaxel as first‐line chemotherapy in sub‐optimally debulked patients with ovarian cancer. Patients are treated with paclitaxel at 175 mg/m2 plus oxaliplatin at 130 mg/m2 every three weeks for six cycles.
Fourteen patients are evaluable, 12 of whom have had a minimum follow‐up of one year. Thirteen patients have been restaged; eight pathological complete responses were observed, with no secondary progression at a minimum follow‐up of 10 months.
There were five patients with a partial response or stable disease; two of them have had secondary progression.
Although it was not a true comparison, Dr. Misset said that the results of EFC‐3312 are encouraging when looked at next to those of GOG 158 (which compared cisplatin/paclitaxel with carboplatin/paclitaxel in optimally debulked Stage III patients).
‘We are encouraged to go further with this study,’ he said.
In summary, ‘combination chemotherapy is the hallmark of progress. When we have results as good as what we found with single‐agent oxaliplatin, we are optimistic about improved combinations in the future.’
Session co‐moderator Dr Carmel Cohen, professor of obstetrics and gynaecology in the Derald H Ruttenberg Cancer Center of Mount Sinai School of Medicine, commented: ‘The work as presented by Dr. Misset has great promise.
‘The challenge is to achieve in confirmatory trials and a broad experience what has been demonstrated in pilot studies. Hopefully further studies will confirm what Dr Misset has reported here.’
Mismatch repair deficiency, which is present in untreated ovarian cancer cells, is associated with resistance to cisplatin and carboplatin, but the presence of mismatch repair deficiency does not compromise response to oxaliplatin, providing a strong preclinical rationale for use of this agent, said Dr Jean‐Louis Misset.
‘Combination chemotherapy is the hallmark of progress. When we have results as good as what we found with single‐agent oxaliplatin, we are optimistic about improved combinations in the future.’
© 2004 Lippincott Williams & Wilkins, Inc.