How unexpected results can lead cancer research and treatment in new directions

Our Pedro Ramirez, M.D., caused a stir at the Society of Gynecologic Oncology’s annual meeting in March when he reported unexpected findings in his Phase III study comparing minimally invasive surgery to open surgery for early-stage cervical cancer.

The trial had stopped signing up new patients early, because patients who underwent minimally invasive laparoscopic or robotic surgery for hysterectomy — rather than having open surgery — were nearly four times as likely to experience a cancer recurrence. Their mortality rates were higher, too, so it wasn’t safe to continue.

“We were very surprised,” says Ramirez, noting that the finding contradicted prior data.

Although the number of patients affected in the study was small (27 recurrences in 319 patients), the evidence was absolute. Two other studies, including one from MD Anderson, evaluating large national databases came to the same conclusion.

“Hopefully, the gynecologic oncology community will accept the results of these three studies and stop doing the minimally invasive procedure for cervical cancer,” Ramirez says. “Physicians have a responsibility to discuss with their patients the need for open surgery.”

Navigating the unexpected

It’s rare – but not unheard of – for a clinical study to uncover an unexpected truth, says George Wilding, M.D., vice president for clinical and interdisciplinary research.

He recalls when immunotherapy studies appeared to show that cancer was growing instead of shrinking.

“The tumor is infiltrated by immune cells, making it appear as if it’s getting bigger,” he explains.

With continued scientific research, immunologists like Jim Allison, Ph.D., ultimately unlocked secrets of the immune system, bringing cancer treatments such as checkpoint inhibitors and T-cell engineering into the mainstream.

“We’re all aware of the magazine covers that say something is the next best thing, and then it doesn’t turn out and we’re all disappointed again,” Wilding says of unexpected findings in general. “But, in immunotherapy, these are particularly exciting times. There are whole new classes of treatments and approaches that are showing really exciting results.”

Not all studies created the same

For Jennifer McQuade, M.D., the surprise was a counterintuitive finding in 2018 that linked obesity with improved survival rates in men with metastatic melanoma.

“We know obesity increases the risk of getting many cancers and is associated with worse survival in many cancers,” she says.

So there were reasons to think – based on the same biologic pathways – metastatic melanoma would be the same, says McQuade.

That’s why she had difficulty believing the initial study findings.

“At first, I had blinders on and totally missed the obesity paradox,” she says, describing the study’s contradiction to established evidence linking obesity to mortality risk.

She proceeded carefully and looked at five other groups before concluding that obese males on targeted therapy were more than twice as likely to survive metastatic melanoma at two years compared with normal-weight males.

There were similar results for obese males on immunotherapy, but not on chemotherapy – and not at all for females.

“The disappointment was that I’m a strong believer in a healthy diet and exercise,” says McQuade. “I went into this study looking for evidence to support that cancer patients may be able to influence their outcomes by controlling their weight.”

Instead, now we are examining the biological basis for this obesity paradox.

“One of the biggest things this study demonstrates is the importance of asking the question correctly,” she says. “If you don’t design the experiment well, and you get unexpected results, you don’t know if those results are correct or if you just didn’t ask the question correctly.”

Indeed, as Wilding says, when it comes to scientific research, the unexpected often begets something even more important and exciting.

A longer version of this story originally appeared in Messenger, MD Anderson’s quarterly publication for employees, volunteers, retirees and their families.

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