The current standard of care for women with platinum-sensitive, recurrent ovarian cancer is a combination of the chemotherapeutic drugs carboplatin and paclitaxel.

However, the majority of patients prescribed these drugs for this condition still relapse within a year. Identifying which patients are most likely to relapse, and using this to inform initial treatment, would be a useful step forward. Some evidence has emerged that patients who experience myelo-suppression as a side effect of paclitaxel have better clinical outcomes than those who do not.

The CALYPSO study is a large Phase III trial comparing the safety and efficacy of a newer chemotherapy combination, carboplatin with liposomal doxorubicin (CPLD) with that of carboplatin-paclitaxel (CP) in patients with recurrent ovarian cancer.

The initial results of this study have been reported and show progression-free survival times to be longer with CPLD than with CP, although not dramatically so.

A large, international team led by Chee K. Lee from the University of Sydney, New South Wales, Australia, has now used data from the CALYPSO trial to investigate whether patients who experience leukopenia or sensory neuropathy as side effects of these treatments have better outcomes than those who do not.

A total of 975 patients were recruited into the CALYPSO trial. Lee and co-workers included 608 of these in their study cohort: all those patients who received at least one cycle of chemotherapy drugs; did not progress or die in the first month of the trial therapy; did not receive growth factors as prophylaxis against leukopenia and had a measured nadir blood count during the first chemotherapy cycle.

Patients were classified as leukopenic if they had a low nadir white blood cell count (< 4.0 x 109 cells / litre) during the first chemotherapy cycle or if they later developed febrile neutropenia or severe infection, and as neuropathic if sensory neuropathy developed or worsened during treatment. The demographic characteristics of patients with and without these side effects were similar.

Taking all patients together, there was a small but statistically significant increase in progression free survival in those patients who experienced leukopenia (11.0 months versus 10.2 months). However, when the patients were separated into treatment arms the results were more clear-cut.

Leukopenia was clearly prognostic of longer progression free survival in patients taking carboplatin-paclitaxel (hazard ratio 0.63 adjusted to 0.66 when baseline prognostic factors were included; adjusted 95% confidence interval 0.49-0.90, p = 0.01) but not for those treated with CLPD (hazard ratio 0.95; 95% confidence interval 0.70-1.29, p = 0.73).

The survival benefit of leukopenia increased with the severity of the side effect. Similar, but less marked, results were seen with neuropathy: incidence of this side effect was again predictive of significant improvement in progression free survival in the CP arm only (adjusted hazard ratio 0.77; 95% confidence interval 0.62-0.95, p = 0.02).

Lee and co-workers summarised their results as representing a 34% reduction in the risk of disease progression with the incidence of leukopenia, and a 24% reduction in the risk of progression with the incidence of sensory neuropathy, both in patients taking CP only.

However, they also stressed the fact that the trial had found CLPD to be the more successful treatment. In fact, the median progression free survival of patients taking CP who experienced either or both side effects was similar to that of all those in the CLPD arm.

The study authors speculate that the relationship between lack of CP-induced toxicity and poor treatment outcome may be a result of the drug concentration in the tumour being sub-optimal in those patients, possibly due to genetic differences in, for example, P450-based drug metabolism.

Alternatively, cytotoxicity may partly depend on genetic features that are similar in tumour and normal cells in the same patient. Research and clinical trials to further explore mechanisms of cytotoxicity and to investigate the possible efficacy of toxicity-related dosage regimens is recommended.

References

Lee, C.K., Gurney, H., Brown, C. and 13 others (2011). Carboplatin–paclitaxel-induced leukopenia and neuropathy predict progression-free survival in recurrent ovarian cancer. Brit. J. Cancer 105, 360-365. DOI:10.1038/bjc.2011.256

Pujade-Lauraine, E., Wagner, U., Aavall-Lundqvist, E. and 15 others (2010). Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum sensitive ovarian cancer in late relapse. J Clin Oncol 28: 3323–3329