In recent years, prospective and retrospective analyzes of non-randomized, population-based data have attracted significant interest among cancer researchers, third-party payers, regulators, and health policy professionals. Enhancing the value of Phase 3 clinical trial data.
The success of efforts to critically analyze the unique contributions of specific components of care through the conduct of randomized trials, with the exception of the approach explored in the experimental arm of the trial, has been limited to the relative uniformity is required. Therefore, in such trials, patients with common, clinically relevant but potentially confounding comorbidities (e.g., history of severe mild or moderate cardiac, renal, or hepatic abnormalities) are routinely excluded from study enrollment. A concern here is that when other medical conditions are present, it may be more difficult to unambiguously assess the specific impact of the research approach on objective measures of efficacy such as survival and toxicity. However, because of well-recognized differences in characteristics between research subjects and individuals who receive regular care outside of clinical trials, well-designed testing of ‘real-world’ populations may It may provide a better picture of the real-world impact of clinical trials. Specific therapeutic intervention.
While considerable attention has recently been paid to the differences between randomized trials and real-world views of cancer treatment, another potentially interesting approach to explore is the possibility of very similar or identical A comparison of the results of another randomized trial investigating the research question. Here, it is properly recognized that the randomized populations in individual studies may differ considerably from each other, so shouldn’t such cross-trial comparisons be conducted? , it is appropriate to acknowledge one of the classic warnings to clinical investigators that it should be performed with great care.
But that’s exactly the point being emphasized here. Indeed, if the studies were essentially identical in design but reached different clinical conclusions, what does this observation tell us about the nature of the trial process and the interpretation of the results of the individual research studies? For example, consider the results of a well-designed, regulatory-quality clinical trial of an anti-cancer drug. These trials, at the time reported, have served as important components in establishing the standard of care in first-line chemotherapy management of epithelial cells. ovarian cancer.1,2
The studies described below specifically examined the role of paclitaxel as a component of first-line anti-tumor drug therapy in this malignancy, following the remarkable demonstration of significant clinical activity of this drug in platinum-resistant disease.3 The first compared the standard treatment regimen (cisplatin + cyclophosphamide) with an experimental combination of cisplatin + paclitaxel infused over 24 hours.1 This landmark study found that paclitaxel-containing regimens improved overall survival (OS) when compared to the combination of cisplatin and cyclophosphamide. These data supported a regimen that has become standard of care practice for the use of platinum- and taxane-based primary cytotoxic strategies.Four The above study quickly closed its tally, and its survival outcomes were unknown at the time. Consequently, in the absence of such critical data, it was decided to initiate an additional study conducted by the same group of investigators in the Gynecologic Oncology Group with essentially identical eligibility and disqualification criteria. rice field. In this second study of his, a randomly assigned patient population received either cisplatin alone, paclitaxel alone, or the same combination regimen employed in the first trial of cisplatin and paclitaxel. We examined a slightly different clinical problem.
There are some provocative questions that can be discussed in relation to the differences in the results of these two trials. Although this includes the impact of crossover from treatment with one of the two single agents to alternative antineoplastic agents, the specific points of this commentary are to emphasize that: Two landmark studies found fairly marked differences in OS between patient populations receiving the same combination chemotherapy regimen of cisplatin and paclitaxel.1,2
In the first trial, the median OS for combination regimens containing paclitaxel was 38 months. A second trial, conducted shortly after the development of the first trial was completed, found that treatment with this same regimen was employed in trials conducted by the same group of clinicians/clinical investigators and followed essentially the same entry criteria. (Eligibility and Ineligibility) applied. Median OS was 26.3 months, with a difference in survival of nearly 1 year.
Is there an explanation for this surprising and clinically difficult to ignore reduction in median OS associated with administration of the platinum/taxane combination regimen? , it is important to recognize the fact that, despite the fact that the clinical care of the two populations was provided by the same group of oncologists, they were separate trials with patients randomly assigned at different times.
Certain hypotheses can be made about the main reason for the difference in OS between the two studies. When the first primary ovarian cancer paclitaxel trial began, there was considerable and pertinent concern about the drug’s potential serious cardiac effects, with early trials reporting sudden deaths. , the earliest patients enrolled in this randomized study required active cardiac monitoring when a 24-hour paclitaxel infusion was initiated. Significantly decreased as a result of toxicity profile.
Due to previous concerns, we speculate that the first study population had an overall lower cardiovascular risk background (as a result of patient selection or physician recommendation) compared to the second study population. is reasonable. Moreover, the selection of patients for the second study occurred at a time when concerns about the severity of potential adverse cardiotoxicity were diminished. And the slightly inferior median OS in the second study was due, at least in part, to the presence of individuals with associated comorbidities (such as diabetes, mild renal impairment, and cerebrovascular disease). may be related to the relative increase in A woman with ovarian cancer.
Finally, this now classic experience serves as a highly relevant example of the dangers of attempting to directly compare survival outcomes in different groups of patients in the absence of adequate trial-based randomization. It should help.
- McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin vs. paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med1996;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 Onkol2000;18(1):106-115. doi:10.1200/JCO.2000.18.1.106
- McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: A unique anti-tumor agent with significant activity in advanced ovarian epithelial tumors. uninterned1989;111(4):273-279. Doi: 10.7326/0003-4819-111-4-273
- Armstrong DK, Alvarez RD, Bax FJ, et al. NCCN Guidelines Insights: Ovarian Cancer, Version 3.2022. J Natl Compr Canc Netw2022;20(9):972-980.doi:10.6004/jnccn.2022.0047