There is significant interest in investigating consolidation or maintenance strategies in ovarian cancer for patients in both primary and secondary complete clinical remission. The factors predicting an initial complete response to primary chemotherapy have been well documented and include stage, debulking status, and histology.[16
] The likelihood of second response following first relapse depends on the TFI and the choice of agent, with most studies having a subset of patients who return to a complete clinical remission. However, the predictive factors and subsequent outcome for this subset are generally not reported separately.[12
] Patients in second complete clinical remission are particularly suitable for studies of consolidation strategies, but the lack of agreed-upon endpoints makes pilot trials of this approach difficult to interpret. This study sought to 1) assess the median duration of second complete response using patients selected by strict criteria, 2) characterize the duration of second complete response in relation to the first complete response, and 3) determine the proportion of patients remaining in second complete remission at interval time points. Each of these outcome measures has the potential to be considered for future clinical trial endpoints.
The frequency of achieving a second complete clinical remission varies and directly depends on multiple factors such as the agent employed, whether used singly or in combination, platinum-sensitivity status, and TFI.[12
] It also depends on the definition of complete clinical remission. For example, some have proposed that CA-125 is more accurate than WHO or RECIST criteria in ovarian cancer and should preferentially be used; others have defined complete clinical response as having resolution of radiographic evidence of disease (but allowing non-specific abnormalities up to 1 cm), while others have required completely normal CT imaging.[21
First, we have reported the median duration of PFS in this study to be 17.8 months (95% CI 13.2-24.9 mos) following primary therapy. This is similar to the median PFS of 18.5 months recently reported in a trial with 1,308 patients receiving primary paclitaxel and carboplatin treatment in a comparable group.[14
] The median TFI in our patient population was 15.2 (range, 4.3-72 mos) representing a moderately platinum-sensitive group. The median duration of PFS2 in our patients of 10.8 months (9.6-12.2 mos) also falls in the range of reported PFS after second-line therapy, but this range comprises data from trials that include both completely (the minority) and partially (the majority) responding patients such as those treated with carboplatin (5.8 ms; 95% CI, 5.2-7.1 mos), gemcitabine with carboplatin (8.6 mos; 95% CI, 7.9-9.7 mos), liposomal doxorubicin with carboplatin (9.4 mos), and paclitaxel with carboplatin (12 mos).[13
] A retrospective review of patients with a TFI of only 6 months who received a heterogeneous group of treatments for recurrent disease showed a median time to recurrence after second-line therapy of 5 months (range, 1-20 mos). This illustrates the importance of TFI, but this study did not distinguish the proportion of patients with completely responding disease.[25
] Clearly the length of the TFI has a major impact on the likelihood of subsequent response (including complete responses), and has been shown to affect PFS following second-line therapy. [26
] However, the impact on the duration of second complete
response was unknown. Our study therefore provides the data suggesting that primary TFI may not be a predictor for longer duration of second complete remission when compared with the first. We also demonstrated, as expected, that optimal debulking is associated with a statistically longer duration of PFS1 (24.7 v 14.1 mos, P
= 0.0079), as is well established. [27
] However, in this selected patient population, the duration of the second PFS from a second complete response is similar whether or not optimal debulking is achieved (10.9 v 10.6 mos, P
= ns). This finding has been documented in other studies with regard to debulking status. [28
] This can also be extrapolated from the data of Eisenhauer et al., [29
] where the importance of tumor extent in prognosis (post-op residuals varying widely) affected PFS1, but the greater consistency in PFS2 disease (disease volumes at re-tretament) may be more congruent.
Therefore, patients who are able to achieve a second complete response (and represent a selected population) may all behave in a similar fashion irrespective of initial characteristics, but this needs validation in a larger data set.
Second, we also examined the duration of second complete response in comparison to first complete response. A recent report on patients receiving treatment for relapsed ovarian cancer [11
] showed that second responses exceed the first response in only 3% of 121 assessable patients, but did not separately report the outcome of the complete responders. Furthermore, the duration of first response could not be used to predict the length of the second response. Our data likewise showed that a longer second response (even using the most stringent criteria to select complete responders) occurred in only 3/35 patients (8%), with differences in duration of 0.3, 1.7, and 6.7 months, respectively. No particular distinguishing characteristics of these patients could be identified. It should be noted that the patient with the 0.3-month difference had a PFS1 of 15.2 months, so achieving a similar duration could be considered clinically meaningful. The numbers are insufficient to determine whether the 3% described by Markman et al., [11
] including partial and completely responding patients, differs from the 8% seen in our patients relapsing from complete response. It is reasonable to conclude, however, that the phenomenon of having a second response longer than first is infrequent, even if one confines the analysis to second complete responders.
Third, we have documented the proportion of patients who remain in remission at a given time point (). When designing a phase II study for second-line treatment where we expect a short median PFS, it may be better to use a binary endpoint such as the 6, 9, 12 month PFS rate. Since this endpoint is binary and observed by the specified time point, traditional phase II design, as is common for tumor-response endpoints, can be utilized. All patients will then be assessed by this fixed time, and this will allow greater uniformity of results across trials.
Clearly the potential for bias exists in our retrospective study. Our numbers are small as a result of the strict eligibility criteria, which aimed to identify the “best” group of patients who would have the potential for showing the longest duration of second complete remission. Our numbers were further diminished by excluding patients that achieved second complete clinical remission by our criteria, but then entered pilot consolidation trials and received investigational therapy. As more clinical trials for recurrent disease include a maintenance or consolidation portion, it is essential that we continue to characterize patient populations such as in this study in order to build the benchmarks necessary to select promising agents from future exploratory studies.
In summary, we have shown that 1) the median PFS from second complete remission is relatively short, and not dissimilar to those reported for patients progressing from partial responses or stable disease; 2) the phenomenon of having a second response longer than first as previously described remains infrequent (8%), even in this ideal second complete clinical remission population when retreated with the same or similar agents; 3) the proportion of patients remaining in complete remission at give time points is readily quantified. The latter 2 endpoints should further be explored as future clinical trial outcome measures.