Are Cancer Patients Better Off in a Clinical Trial?

Megan Brooks

January 26, 2022

It's an assumption many oncologists make: Patients with cancer do better, in general, when treated in a clinical trial.

Yet there is little hard evidence to support this idea.

And some experts worry that overly optimistic perceptions of the benefits of clinical trials may give false hope to patients.

"It behooves us to be honest in our communications with patients," said Charles Shapiro, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, in New York City. "Patients may or may not do better in clinical trials. We don't know."

The uncertain benefits of experimental drugs may be especially relevant in early-stage research. A 2018 analysis from the Biotechnology Innovation Organization found that of oncology therapies tested in phase 1 trials between 2006 and 2015, the likelihood of receiving US Food and Drug Administration approval was only 5%. The probability of approval increased with the trial phase: 8% from phase 2 to approval, 33% from phase 3, and nearly 83% from a new drug or biologics license application.

But even for drugs that are eventually approved, the benefits patients experience in clinical trials may be marginal or unclear if, for instance, trials use surrogate endpoints to assess efficacy.

"Care in a clinical trial may be a little bit better because you're in this highly regulated process, but it's hard to truly define what that benefit may be," Timothy Pawlik, MD, PhD, MPH, surgical oncologist at the Ohio State University Comprehensive Cancer Center, told Medscape Medical News. "It may be relatively negligible and shouldn't be oversold as a reason to enter a clinical trial."

That said, the overall importance of clinical trial research should not be in question.

"The only way we make progress in cancer therapeutics is in clinical trials," Shapiro told Medscape Medical News. That's the "societal reason."

Pawlik, chair of the Department of Surgery at the Ohio State University Wexner Medical Center, agreed, calling clinical trials the "backbone" of evidence-based treatment guidelines.

"By very definition, the hypothesis of a clinical trial is that we are improving upon the standard of care," Amy Tiersten, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, in New York City, told Medscape Medical News.

Perceptions About Clinical Trials

Some patients who participate in clinical trials will have better outcomes, Tiersten said, "possibly because they are exposed to agents that are potentially more effective than older therapies [or] possibly because they may be followed more closely and by more people — for instance, a research team in addition to the clinical team."

However, being too confident that clinical trials offer the best treatment and relaying such information to patients during trial recruitment may ultimately be misleading.

That's what a group of researchers concluded when they interviewed 57 physicians and nurses in oncology and hematology.

The research, led by Zandra Engelbak Nielsen, RN, Department of Oncology, Copenhagen University Hospital, in Denmark, initially explored how physicians and nurses perceived the benefits of oncology clinical trials compared with standard care. The team then performed a literature review evaluating the evidence on whether clinical trial participation does lead to better care.

Among those interviewed, Nielsen and colleagues found most believed treatment in the context of a clinical trial to be superior — to provide an elevated level of care, a better chance of longevity, and greater relief of pain — compared to standard care.

Many interviewees saw recruiting patients to cancer clinical trials, even phase 1 studies, as a way to give them access to cutting-edge treatment. One physician said that "when you agree to do a study, you should feel at ease, knowing that included patients are being given the best possible [treatment], so you are sure of that."

Some felt a moral duty to recruit patients to clinical trials. One physician said: "We're supposed to give the best there is and the one with the most evidence, and...for many diagnoses, we don't know what's the best possible treatment.... It's almost unethical sometimes not to try to enroll patients in studies."

These findings align with previous research exploring oncologists' perceptions of clinical trials. One study, for example, found that oncologists held "extremely favorable attitudes toward trials as a source of high-quality patient care."

Some interviewees in Nielsen's study did acknowledge the limitations, uncertainties, and risks associated with clinical trial participation, especially in phase 1 trials and for patients with more advanced disease.

One nurse said, "There are many ethical dilemmas. Yes. We talk about that a lot in particular with phase 1 trials, where the drugs are so novel that we strictly don't know whether they work."

Interviewees also discussed the challenges of providing hope amidst this uncertainty. One participant said: "In certain studies, there's probably over-confidence in the effect of a treatment, especially when it's purely experimental.... In many cases the chances are slim.... Both the patient and ourselves would like to believe that it is more fruitful than it oftentimes is."

Another noted: "The patients would rather not think about the experimental treatment possibly being worse, and really, I do not think we want to either. And we do not talk much about that."

Are Patients Better Off?

When reviewing the literature, Nielsen and colleagues found that overall, the evidence does not support the perception that patients with cancer do better in clinical trials, even when considering the development of targeted therapies and immunotherapies in recent years.

The team screened for primary research conducted after January 2009 that compared outcomes for patients treated in and outside of oncology drug clinical trials.

Of the nine studies evaluated, three reported a "positive trial effect" — longer median overall survival — but each came with notable limitations, such as failing to account for confounders or using a retrospective design.

Given that the belief in trial superiority is largely "unfounded," the authors cautioned that hyping a trial's benefits to patients in a recruitment context "is tantamount to providing misleading information."

A previous analysis, published in 2004 in The Lancet, reached a similar conclusion after evaluating 24 published articles of outcomes among cancer patients enrolled and not enrolled in clinical trials. The authors found that "despite widespread belief that enrolment in clinical trials leads to improved outcomes in patients with cancer, there are insufficient data to conclude that such a trial effect exists."

The bottom line, Pawlik explained, is that, in general, "clinical trials are definitely good...for medicine and for patients." However, knowing whether a clinical trial is going to provide a "meaningful benefit to that one individual patient that is in front of you in clinic can be very tricky," he said.

That is why physicians need to be careful about overselling the benefits of clinical trials to themselves and to patients.

"When we are discussing a trial with an individual patient, we need to help them understand that there is equipoise, that there is something unknown," Pawlik said. In other words, it's important to communicate that "we don't know if A is better than B — that's why we're doing the trial. It can be challenging to articulate to the patient that [a particular treatment] may help or it may not."

Shapiro has financial relationships with UptoDate, 2nd MD, and Anthenum. Tiersten has received research support from Pfizer, Novartis, and Eli Lilly. Pawlik has disclosed no relevant financial relationships.

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