It is understandable that those responsible for paying the bills associated with the increasingly staggering costs of antineoplastic pharmaceutical agents would seek objective measures that could meaningfully help assess their value. Unfortunately, this task, as rational as it might appear to be, is more complex than what one might anticipate, despite quite vociferous rhetoric to the contrary at times.
Take, for example, the reasonably assumed gold standard for any therapeutic strategy in the management of malignant disease: an approach with evidence demonstrating a statistically significant improvement in overall survival (OS) within a well-designed and conducted phase 3 randomized trial. There has been much discussion regarding this topic, including the use of so-called surrogate end points such as progression-free survival (PFS) to define clinical benefit.
The specific aim of this essay is to highlight data from older published experiences within the gynecologic cancer arena that, in the opinion of this commentator, can help inform this ongoing debate.
Four phase 3 randomized clinical trials—the first 2 dealing with primary chemotherapy of advanced ovarian cancer1,2 and the second 2 conducted for women with potentially platinum-sensitive recurrent disease3,4—will be the focus of this discussion. The primary antineoplastic therapeutic studies were initiated by the Gynecologic Oncology Group, whereas the second-line trials were undertaken by various pharmaceutical company sponsors. All 4 were of regulatory-approval quality, with the results published in major oncology journals.1-4 The intent is to compare the survival outcomes of the 2 primary studies, with a similar exercise conducted for the second-line trials. It is crucial to acknowledge here that such cross-trial comparisons, although common within the oncology community, are fraught with great hazard because there is always the potential for the research populations in the individual trials to be quite different, making it difficult to glean meaningful conclusions from such an analysis.
As a result, before providing the survival data, there will be a brief discussion highlighting similarities and 1 major difference between the study groups in the primary chemotherapy trials1,2 and information in the recurrent-disease investigative efforts suggesting the research populations closely resembled each other.3,4
The 2 primary ovarian cancer studies, which focused on exploring the role of a new cytotoxic agent, paclitaxel, when combined with cisplatin, were conducted by the same group of gynecologic oncologists, with the second trial opening immediately following patient-entry closure on the first trial. Of note, entry requirements for the 2 investigative efforts were very similar.
However, either by virtue of the formal eligibility criteria or concerns of patients, their families, or the treating oncologists, individuals with known or suspected heart disease were far less likely to participate in the initial paclitaxel trial. This was due to existing worries at the time of study initiation that paclitaxel posed a potentially serious risk of cardiac adverse effects.
But by the time the second trial was initiated, solid evidence had emerged that paclitaxel was not— by itself—excessively cardiotoxic. Rather, the highly concerning sudden life-threatening events were secondary to hypersensitivity reactions.5 As a result, exclusion from this second study based on a recognized or suspected cardiac history was far less of a clinical concern.
That said, women were randomly assigned to receive identical regimens (dose and schedule) of cisplatin plus paclitaxel in the 2 consecutive studies, received care from the same group of surgeons, and had no difference in the second-line (and later) drugs available to them at the time of disease progression. The findings regarding survival data were as follows: The median OS in the initial study was 38 months,1 whereas the median OS in the second trial was only 26.3 months,2 a rather striking reduction of almost 1 year.
Again, recognizing legitimate concerns with cross-trial comparisons, the short time interval between the 2 studies, disease management delivered by the same group of oncologists, and essentially identical eligibility criteria (except as noted previously) and chemotherapy regimens (drugs, dosages, schedules), it is reasonable to speculate that the substantial observed survival differences were far more likely to be secondary to relevant comorbidities (cardiac and related medical conditions) than the direct effect of treatment or the malignancy itself.
There is surely an important message here when we measure differences in survival between carefully selected populations who participate in cancer trials and patients with the same cancer but with common comorbid conditions treated outside the confines of a trial.
The second 2 studies offer a different perspective on the real world of cancer care—specifically, the availability over time of multiple, increasingly effective therapeutics leading to many malignancies objectively becoming more like chronic conditions: manageable over a period of multiple years rather than several months.
In 2006, investigators reported the median PFS (8.6 months) and OS (18.0 months) of a group of women with recurrent ovarian cancer treated with a regimen of carboplatin plus gemcitabine (the investigative arm of a phase 3 trial).3 The second study, the phase 3 OCEANS trial (NCT00434642) published 6 years later in a similar patient population and employing the same chemotherapy regimen (as the control arm) reported a median PFS of 8.4 months and OS of 35.2 months.4
It is critical to highlight here that the direct effect of the 2-drug chemotherapy regimen as reasonably measured by the PFS results did not differ in 2 studies (8.6 vs 8.4 months), suggesting acceptable similar individual patient characteristics and responses to the treatment program. However, the striking difference in OS (which almost doubled—from 18.0 months in the first trial to 35.2 months in the second study) between the populations requires an explanation.3,4
Again, it is reasonable to suggest that the observation is due to an expanded spectrum of meaningfully beneficial therapeutic strategies available to oncologists (including drugs, radiation, surgery, and other interventional options) in the era encompassed within the time frame of the later study compared with the first, all of which permitted an enhanced opportunity to extend a patient’s survival after she completed the trialbased regimen.
As with the primary chemotherapy experience, this analysis of outcomes from 2 older, well-designed and conducted studies offers data relevant to current debates regarding the most appropriate interpretation of cancer clinical trials.
References
- McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334(1):1-6. doi:10.1056/NEJM199601043340101
- Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2000;18(1):106-115. doi:10.1200/JCO.2000.18.1.106
- Pfisterer J, Plante M, Vergote I, et al; AGO-OVAR; NCIC CTG; EORTC GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24(29):4699-4707. doi:10.1200/JCO.2006.06.0913
- Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045. doi:10.1200/JCO.2012.42.0505
- Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Paclitaxel-associated hypersensitivity reactions: experience of the gynecologic oncology program of the Cleveland Clinic Cancer Center. J Clin Oncol. 2000;18(1):102-105. doi:10.1200/JCO.2000.18.1.102