Timing Isn’t Everything, Right?

Abstract & Commentary

Synopsis: Nearly 70% of patients achieving a CR after primary therapy eventually recurred. Most recurrences occurred more than 6 months from completion of primary chemotherapy, and the use of second line agents at the time of recurrence was effective. In this study, the median time from CR to start of third-line agent at 43 months compares favorably with the median PFS of 28 months following 12 months of Taxol reported in GOG 178 and challenges the concept of consolidation chemotherapy in ovarian cancer. A randomized trial to evaluate when to institute second line agents should be performed.

Source: McMeekin DS, et al. Gynecol Oncol. 2004; 95(1):157-164.

Results from a recently published randomized clinical trial addressing the use of consolidation chemotherapy strongly suggested that the strategy improved progression-free survival in selected ovarian cancer patients. Early trial termination and recommended cross-over from the control arm limited any conclusion of an overall survival benefit, concerning some clinicians who contend the added toxicity from prolonged therapy must be accompanied with an overall survival advantage to change the standard of care. McMeekin and colleagues attempted to address this latter issue by evaluating the survival outcomes of patients in complete remission and approached by their wait and see clinical standard. In this approach patients completing primary therapy were observed until clinical progression was documented.

At that point treatment was recommended and administered. From 217 reviewed patients, 59 met a strictly defined parallel enrollment criteria—that is, they met eligibility criteria for the published randomized trial. However, all of these patients were given their second chemotherapy at the time of a documented recurrence. Times to second- and third-line chemotherapy as well as overall survival were generated. With a median follow-up of 51 months, nearly two-thirds of the patient cohort recurred. The median time to progression for this group overall was 20 months. All but 2 patients received second-line chemotherapy at that time and from this cohort, all but 7 patients received a third-line treatment. The time from complete remission to the start of this therapy was 43 months. Relative to the randomized consolidation trial, this treatment time point would be similar to the progression-free survival time point a patient given consolidation chemotherapy and followed to recurrence (the start of their third-line treatment). By way of reference, the experimental cohort (12 months of paclitaxel) in that study had a median progression-free survival of 28 months or 40 months from complete remission. McMeekin et al concluded that while it would be improper to compare the outcomes of the two studies directly, observations from their wait and see policy suggest that overall survival may rival that achieved by consolidation.

Comment by Robert L. Coleman, MD

Additional therapy after successful completion of a planned first-line regimen (consolidation) has become a popular strategy to address the 70%-plus recurrence risk ovarian cancer patients experience after achieving a primary complete remission.1 Many different modalities have been evaluated including radiation therapy, immunotherapy, high-dose chemotherapy, intraperitoneal therapy and standard chemotherapy. Given the wide variance in patient cohorts and likely benefactors of these modalities, the most proper methodology to evaluate these treatments is a randomized clinical trial. Although many such trials have been conducted, to date, the only published clinical trial demonstrating any survival benefit, albeit progression-free survival, is the GOG/SWOG intergroup trial (GOG-178) comparing 3 cycles of paclitaxel (control) to 12 cycles of the same therapy.2 The benefit demonstrated by the additional cycles of chemotherapy in this trial was sufficiently large to trip an early stopping rule agreed to and set ahead of the trial’s initiation. Adhering to the recommendations outlined by the Data Safety Monitoring Board overseeing the trial, its principal investigators closed the trial to further entry, released interim results, and recommended that patients participating in the trial but randomized to the control group be offered extended therapy. While the recommendations were completely legitimate given the trial’s design, some have argued the primary endpoint, progression-free survival, is insufficient to alter standard of care in this setting. Citing incurability and long term toxicity, advocates of this position argue only a trial demonstrating improved longevity warrant adoption of any new such treatment paradigms.

The current trial by McMeekin et al raises another point in that in the long run whether one initiates therapy at recurrence or before recurrence (consolidation) you may end up at the same place—equivalent survival. The trial’s results are curious and speculative. If one attributes consolidation treatment as the patient’s second-line, a time off therapy until recurrence was 28 months on the median—or 40 months from initiation. Waiting to treat until recurrence, in a similar cohort as presented, left one-third of patients without having to receive any therapy—they hadn’t recurred.

Those that did were off treatment for 20 months and by the time they progressed again 43 months had passed; curiously closed to that seen in the randomized trial. But given the retrospective nature of its design, it can only be hypothesis generating. In fact, one could argue that the efficacy of the two trials’ third-line therapy might not be equivalent. That is, the likelihood of response and survival in a patient receiving consolidation but remaining off therapy for 28 months might be superior to a patient remaining off therapy for less than 10 months. While difficult to estimate the survival difference, it is clear following the results of ICON-IV many clinicians would opt for combination chemotherapy in the former cohort, which demonstrated an overall survival benefit over non-taxane, platinum-based therapy. Patients in the McMeekin trial would likely be treated with this combination at second-line and something else, likely single agent at third-line. It is clear that this issue needs to be readdressed. A randomized controlled clinical trial involving two treatment arms vs no treatment is planned by the GOG.

References

1. Markman M, et al. J Clin Oncol. 2003;21:2460-2465.

2. Parmar MK, et al. Lancet. 2003;361:2099-2106.