Multiple attempts to improve the survival of patients with solid tumors by extending the duration of treatment, including with platinum-based chemotherapy in advanced ovarian cancer, have generally (but not universally) failed to demonstrate clinical utility of this management approach [10
Thus, the initial finding of a significant impact of 12 cycles of single agent monthly paclitaxel on the median PFS (7 months) in advanced ovarian cancer in women who had attained a clinically-defined complete response to a regimen which included paclitaxel was met, by some, with genuine disbelief [1
]. For example, it was stated by several commentators that the initial analysis of PFS was based on a total of only 54 events. Overall, there are approximately four times as many PFS events now (224) as there were in the initial analysis (54). PFS between the study arms continues to be highly statistically significant.
Others expressed a feeling that even with this substantial modification in the pattern of disease recurrence, such treatment was not justified in the absence of a documented improvement in overall survival, due to the potential toxicities (principally neuropathy) associated with this therapeutic regimen. That subsequently reported ovarian cancer studies, with somewhat different designs compared to the current trial, failed to reveal any benefit associated with administering single agent topotecan after the completion of a primary platinum/paclitaxel chemotherapy program has only heightened concern for the apparent uniqueness of the effects associated with “maintenance” paclitaxel [14
It should also be noted that another ovarian cancer randomized single agent paclitaxel maintenance chemotherapy trial, with a smaller patient population (approximately 100 women in a “clinically-defined complete response”) and a shorter duration of therapy (every 3-weeks for 6 cycles) failed to reveal evidence of improvement in outcome associated this strategy [15
What can be concluded from this analysis of survival from the SWOG-9701/GOG-178 study? As predicted by many, it is unfortunately clear that the total sample size available for an evaluation of overall survival is simply inadequate to make any definite statements regarding the impact of this management approach. This analysis is confounded by the fact a number of patients (6%) randomized to the 3-cycle arm actually received more prolonged (> 3 cycles) treatment with paclitaxel, based on the reported results leading to closure of the study by the DSMC.
It is relevant to note here that the GOG is conducting a confirmatory trial for the current study. The importance of this effort in further documenting both the impact of taxane “maintenance” therapy on PFS, and (most importantly) overall survival in advanced ovarian cancer, cannot be overstated.
Of interest, an exploratory analyses performed on the data generated from this trial, but not prospectively defined when this study was designed, regarding the impact of extended paclitaxel treatment for patients with a baseline (pre-maintenance therapy) CA-125 antigen level of ≤ 10 is potentially of clinical relevance. As shows, even within the traditionally regarded ‘normal’ range (i.e. ≤35), baseline CA-125 is highly predictive of survival (Cox model p=0.01 including treatment and stratification factors).
Overall survival by CA-125 (≤10 versus >10 – 35)
It is reasonable to speculate the patient population with baseline CA-125 antigen levels ≤ 10 had the lowest total body burden of residual malignant cells. These data support the provocative concept that 12 additional monthly cycles of single agent paclitaxel may be sufficient to produce a major favorable impact on survival (both progression-free and overall) with this extent of persistent microscopic and macroscopic cancer, but not when larger volumes are present. It will be important to evaluate this specific issue in the ongoing GOG paclitaxel maintenance chemotherapy trial. Of course, it is relevant to also acknowledge that patients with the lowest baseline CA-125 levels experience a superior outcome, independent of the subsequent delivery of any maintenance strategy (9).
Finally, how might the survival results (both PFS and overall) from this phase 3 trial be utilized by oncologists, and their patients with advanced ovarian cancer who are found to have achieved a clinically-defined complete response to platinum-taxane chemotherapy? If a patient has not experienced excessive toxicity from primary treatment (e.g., grade 2–3 neurotoxicity), and she wishes to consider a management option to prolong the time to disease progression (both objective and symptomatic), and possibly improve overall survival, it is appropriate to discuss with her the following:
- This multi-center randomized study has shown that the administration of up to 12-cycles of single agent paclitaxel delivered on a monthly schedule may significantly delay the time to disease progression.
- The “cost” of continuing treatment will include alopecia until treatment is stopped, the risk of the initial development, or worsening, of a peripheral neuropathy, and the need for monthly office visits to receive intravenous paclitaxel.
- Unfortunately, based on existing data it is not possible to determine whether, or not, this management strategy will favorably impact overall survival.