Phase Ii Trial Experience With Ip Cisplatin In Ovarian Cancer

Predictably, based on its central role in the management of ovarian cancer, much of the initial phase II trial effort (both single-agent and combination chemotherapy regimens) in the malignancy focused on cisplatin (30-37).

Further, with few exceptions, the early phase II IP trials in ovarian cancer were directed toward treating women with this strategy as a "second-line" treatment approach. Exploration of the activity of IP cisplatin in this particular clinical setting permitted a most interesting, and rather unique, analysis.

Because essentially all patients entered into the phase II, second-line, IP cisplatin-based trials had received the same agent (or the equivalent drug, car-boplatin) delivered intravenously as a component of primary chemotherapy, the activity of IP cisplatin could be indirectly compared to the activity of systemi-cally delivered cisplatin (or carboplatin). In addition, because the IP delivery followed documentation of the extent of response to the intravenous treatment program, it was reasonable to speculate that any "observed biological activity" of the second-line approach was related to the specific route of delivery, rather than only the effect of cisplatin itself, because the "cisplatin effect" would have been seen with the intravenous regimen (46).

It is essential to note that any such comparisons (to be described later in this chapter) are merely "hypothesis generating," or supportive of further clinical investigation. In the absence of data from prospective randomized phase III trials examining the impact of treatment on survival, it is completely unknown if the observation of "additional tumor cell kill" actually benefits patients.

As rather accurately predicted by the preclinical studies, substantially more "biological activity" (surgically defined tumor shrinkage, conversion of "positive" second-look laparotomies to "negative" third-look procedures) was observed for second-line IP cisplatin in patients with small-volume disease, compared with those individuals with larger tumor masses (47). This point is emphasized by the extensive published experience of the Gynecologic Cancer program of the Memorial Sloan-Kettering Cancer Center with second-line, cisplatin-based IP chemotherapy in ovarian cancer (Table 3) (47).

In addition, and not necessarily predicted by the previously conducted pre-clinical evaluations, the accumulating data in this area revealed another highly relevant limitation of IP cisplatin. The Memorial Sloan-Kettering group demonstrated impressive surgically defined biological activity for IP cisplatin in patients with ovarian cancer whose malignancy had previously responded to intravenous cisplatin, but who persisted in having "small-volume residual disease" at the time of a second-look laparotomy (47). However, the group also showed that there was essentially no activity observed with this regional strategy in patients with similarly defined small-volume disease, except where the

Table 3

Surgically Documented Complete Response Rate to Second-Line Cisplatin-Based IP Chemotherapy of Ovarian Cancer (47)

Largest Residual Tumor Mass

Microscopic >1 cm

Prior response to intravenous cisplatin 6/13 (46%) 2/16 (13%)

No prior response to intravenous cisplatin 1/4 (25%) 0/23 (0%)

cancer had actually failed to exhibit evidence of a response to the primary cis-platin-based intravenous chemotherapy program.

Thus, these data provide strong support for the concept that the high concentrations of platinum achievable within the peritoneal cavity (10-20-fold greater than present within the systemic circulation) are able to overcome a modest level of resistance to the agent, in that additional cell kill is observed when disease is found to persist in the setting of documentation of a response to the intravenous treatment. In sharp contrast, where the tumor has shown itself to possess an inherent major level of resistance, the concentration of platinum present within the peritoneal cavity after regional drug delivery is unable to produce a biologically relevant effect. Notably, these data are quite consistent with the previously published experience with high dose intravenous chemotherapy and autologous bone marrow transplantation used in the management of ovarian cancer (48).

Several phase II single-agent cisplatin- and combination cisplatin-based IP chemotherapy trials have been reported, with similar levels of observable surgically documented biological activity (30-37). The results of these studies do not suggest the superiority of any particular cisplatin-based regional treatment strategy, including the use of "high dose" IP cisplatin (combined with sodium thiosulfate rescue) (8,36).

Again, in the second-line setting, what the data make quite clear is that patients with ovarian cancers that are inherently resistant to platinum (documented by failure to respond to primary chemotherapy), or those with larger volume disease (maximum tumor mass >1 cm in maximum diameter) are highly unlikely to benefit from this therapeutic strategy (47). Conversely, for those individuals whose cancers have responded to initial chemotherapy, but microscopic or small-volume macroscopic disease (<0.5 cm maximum diameter) persists, a substantial percentage of such patients (30-40%) may be anticipated to attain the state of "surgically documented complete response" (if this surgery were performed) after treatment with an IP cisplatin-based regimen.

Unfortunately, evidence of a biological effect (e.g., objective tumor shrinkage or conversion of a "microscopically positive" second-look surgery to "micro scopically negative third-look surgery") does not necessarily signify that patients have experienced clinical benefit (e.g., improved symptoms or progression-free and overall survival) from the strategy. Only appropriately designed prospective randomized phase III trials can definitively address this question.

However, it is interesting to note that several groups have reported an impressive experience with long-term (>4-5 yr) survival for ovarian cancer patients treated with second-line cisplatin-based IP chemotherapy (49-52). Whether this favorable outcome reflects the benefits of this management approach, the natural history of disease in a subset of patients with favorable biological characteristics (e.g., initial response to chemotherapy with minimal disease at second-look surgery), or a combination of these two factors remains unknown in the absence of data from a phase III trial.

A final cisplatin-based IP phase II trial experience is worthy of particular mention. Investigators at the Memorial Sloan-Kettering Cancer Center treated a group of ovarian cancer patients who were found to be without histologic evidence of disease at the time of performance of a second-look laparotomy with three cycles of IP cisplatin and etoposide (53). The researchers subsequently compared the risk of documented disease relapse in this population to a contemporaneous "historical control" group at their institution that was in an identical clinical state, and would have been eligible for entry into this phase II trial, but for various reasons (e.g., patient/physician choice) did not receive this consolidation strategy. Interestingly, the investigators found that the rate of ultimate relapse was greater (54% vs 39%) in the historical control group (53).

Although it is appropriate to conclude that such published retrospective comparisons to historical controls should generally be ignored, as the most likely explanation for the finding is that the nonrandomized "experimental study arm" population simply had more favorable "baseline clinical characteristics" that could account for this "apparent favorable outcome," the exact opposite was the case in this analysis. In fact, the historical control group, which was found to have the greater risk of relapse, possessed the more favorable baseline features, including having a higher percentage of individuals who were stage II (39% vs 8%), and a lower percentage of individuals with suboptimal disease (20% vs 33%) when primary chemotherapy was initiated.

Again, although not a randomized trial, these data are quite provocative, and suggest another setting where IP cisplatin-based chemotherapy may be rationally employed.

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