Maurie Markman, MD

From the earliest moments of medical school instruction, through residency and fellowship training, physicians are taught the primacy of the randomized phase 3 trial in the hierarchy of evidence-based medicine.

What was simply unimaginable just a few weeks earlier regarding the potential impact of an infectious illness in the United States on jobs, schools, the economy, and personal and family safety has become a stream of daily pronouncements about the severity of the pandemic and how best to respond.

The conduct of randomized trials in surgical oncology, although highly appealing in concept, may be problematic, especially in complex settings where the skills, experience, and clinical judgment of individual surgeons and their institutions may vary greatly.

This has been a difficult time for public health policy and regulatory organizations struggling to deal with rapidly changing and unquestionably serious societal health-related issues and concerns. The list of problems these agencies must tackle is growing, and so are the questions about the strategies that should be used to address these threats.

Segments of the population have apparently rejected the well-documented clinical utility of vaccination for protecting individual and public health. An immediate specific concern is the contentious matter of measles vaccination, which has been well-reported in the lay press.

Clinical trials in oncology serve several purposes; these efforts ultimately help define and, potentially, modify the "standard of care" in routine cancer management.

The cancer treatment community's ultimate perception of a successfully completed phase III randomized trial depends in large part on how well the trial was conceived and structured. To permit adequate accrual in a timely manner and optimize the chances for a study to achieve success, the question it poses must be relevant to ensure interest by clinical investigators, referring clinicians, and potential research subjects. Further, the initiative must have adequate funding for data collection and analysis, translational laboratory investigations, and other trial components.

A better understanding of how unique germline variants affect the metabolism or elimination of individual agents or drug classes could lead to a truly revolutionary change in the way cancer is treated.

Even the most basic investigation into fundamental mechanisms of the development and progression of cancer in an in vitro system may generate data that, ultimately, prove vital to developing new approaches to prevent, diagnose, and treat malignant disease.

Placing the results of a single trial in the context of real-world, everyday practice is increasingly difficult because of the number of available options and the absence of studies that directly compare individual strategies.

Although hereditary cancer risk was defined solely by family history in the not-so-distant past, today increasingly robust data may help define an individual’s heightened lifetime risk based on the presence of specific molecular findings within the germline

When discussing the topic of vaccination to prevent serious childhood illness, an increasing number of individuals refuse to accept the unequivocally demonstrated value of this public health strategy despite the very low risk of harm.

The often intense and frequently highly focused effort to seek scientific purity in answering questions within cancer clinical trials raises serious concerns regarding the ethical foundation of certain studies.

Certain themes and questions about individualized, scientifically unanswerable dilemmas often recur when talking with patients and families about treatment.

Even if a disease is diagnosed as “incurable,” or progression to a state of incurability subsequently develops, the time between diagnosis and death is being prolonged and the quality of life improved with novel oncologic interventions, such that continued therapeutic efforts are justified.

There is no more important principle in the conduct of legitimate therapeutic investigation than ensuring the adequacy of informed consent of the prospective clinical trial participant.

With the revolution in our understanding of cancer’s basic molecular biology, it is increasingly evident that subgroups of cancer originating from specific regions of the body have unique natural histories and respond to very different therapeutics. For example, the importance of BRCA mutations, which define a subset of ovarian cancers impressively sensitive to PARP inhibitors, has striking altered the management of this group of gynecologic malignancies.

The cost of antineoplastic therapy and essential supportive care medications have a substantial negative impact on patients with cancer and their families.

Particularly in the oncology arena, there are several serious scientific, ethical, and pragmatic concerns associated with ongoing reliance on placebo-controlled studies.

Although concerns have been raised in recent years regarding the need for randomized trials to augment the body of clinical understanding, one critical issue that has failed to generate sufficient discussion is how the choice of the control arm affects the interpretation of an individual study’s outcome and potentially undermines the ethical basis for that particular study.

For clinical science, particularly oncology, there has never been a more exciting era than today.

Today, with the routine performance of single gene or germline panel testing, as well as a critical focus on prospective follow-up of individuals with incompletely understood germline variants, clinicians are developing an increasingly robust appreciation for the influence of an individual’s genetic background on the likelihood of developing specific malignancies or a group of malignant conditions.

It may be difficult for many who have not lived through an outbreak to appreciate how critical it is to never permit the disease to reappear.

Evidence generated from the randomized study design may be largely ignored by an individual or a community of physicians if the results or strategies being examined do not align with existing beliefs or bias, local practice and referral patterns, and other potentially highly relevant factors unrelated to the trial outcome.

The oncology clinical and research communities should demand that essential clinical trials and objectively valid evidence for efficacy and toxicity be obtained and reported before any regulatory agencies or national/international cancer societies support this strategy as a “standard of care” for cancer pain management.

It is critical to inquire what is wrong with hope, if it helps patients through their journey while not interfering with likely necessary end-of-life decisions when these are required to be made.

The recent technological advances in medicine and related fields have encouraged a belief among many that there is little technology will not be able to accomplish in improving cancer-related clinical outcomes, but it must be acknowledged that clinical medicine and cancer biology are extremely complex arenas.

Considering the decades of clinical investigation involving cytotoxic therapy of malignant disease, it is remarkable— even disconcerting—just how little is understood about the optimal delivery of this critical cancer treatment strategy.

The term statistically significant is almost certainly beautiful music to the ears of clinical investigators and pharma/biotech companies. However, concern develops when one inquires how the most common test of significance, the P value, is used in clinical investigative efforts and whether at times this is more harmful than helpful within the domain of cancer medicine.

The immediate future of clinical investigation in ovarian cancer is remarkably exciting, with a number of novel agents and combination strategies currently being examined in multiple clinical trials.