At University of California in San Diego, a generally stable and strong 73-year-old patient was seeking to enter an immunotherapy trial for his slowly progressing bladder cancer.

He was then enrolled for an atezolizumab, or Tecentriq trial in June last year. But after six weeks, he stopped participating, and died two months later.

The drug has just been approved to treat bladder cancer patients.

In addition, researchers have observed a number of cases recently, whereby anti-PD-1 or anti-PD-L1 immunotherapies not only failed to stop patients' cancer, but instead made tumours grow faster.

They published a study that looked at 155 cases in the journal Clinical Cancer Research last week. Of the total, eight patients who were fairly stable before immunotherapy treatment failed the therapy within two months.

Six saw their tumours enter a hyperactive phase, where the tumours expanded by between 53% and 258%.

Suggestive rather than conclusive findings

“There’s some phenomenon here that seems to be true, and I think we cannot just give this therapy randomly to the patient,” Shumei Kato, an oncologist at UC San Diego, and the author of the study.

Razelle Kurzock, the principal investigator of the paper, emphasises that the findings are more suggestive than conclusive, and that "further investigation is urgently needed."

But Kato's paper is not the first. Last year, cancer researchers at the Gustave Roussy Institute in France also published similar findings and were then considered controversial by some - since they were not widely confirmed by other oncologists.

However, these two papers are still not enough to convince other oncology experts such as Vinay Prasad, assistant professor in the Division of Haematology Oncology at Oregon Health and Science University.

"Tumour growth is not a precise measurement, and if you measure lots of people, some will have faster growth just because of the error in the test," he said, adding that Kato's paper does not state if growth happens "beyond the chance rate."

Furthermore, those in Kato's paper who experienced the hyper-progression of tumours shared specific genetic characteristics. The immunotherapies failed in six patients where amplifications were seen in the MDM2 gene family and two of ten patients with altered EGFR gene.

Two papers with similar findings cannot be ignored

But the fact that the Gustave Roussy team published similar findings - out of 131 patients, 12 patients or 9% showed hyper-progressive growth after immunotherapy treatment - cannot be ignored.

The lead author of that study, Stephane Champiat stated that the research raised more questions than answers but added that the new study "makes me more confident."

Champiat also suggested other factors that could be associated with the effect. In his study, patients older than 65 showed hyper-progressive growth instead - twice the rate of younger patients.

"Is it specific to older patients? I don't think so. Do they have higher risk? Maybe," Champiat said. "And I think it's probably different from one tumour type to another tumour type."

Immunotherapies not as great as promised

However, this also complicates treatment strategies for oncologists studying this phenomenon as some patients exhibit "pseudo-progression", in which tumour scans show apparent growth then instead the cancer is being attacked by masses of immune cells.

This is what both groups initially believed, therefore keeping their patients whose cancer have hyper-progressed on the immunotherapy treatment.

This also adds on to the argument for more caution among oncologists who have witnessed exceptionally strong results from immunotherapies as most patients in fact do not respond well to immunotherapy treatments, for unknown reasons.

In a study by Prasad and Dr Nathan Gay, also of Oregon Health and Science University, of the 30% of Americans suffering from cancer who qualify for immunotherapy, only 26% actually experience tumour shrinkage.

Furthermore, the less intrusive side effects of immunotherapies can be fatal when they happen.

Approach to immunotherapy cannot be changed yet

But the latest studies are too small to justify a change in patients' and doctors' approach to immunotherapy.

“With these small numbers, you’re always stuck being a little unsure,” says Elad Sharon, a cancer researcher at the US National Cancer Institute in Maryland. Like Kurzock, he suggested that larger studies that make tumour images available for analysis by outside scientists are needed.

“At the end of the day, while I find this interesting, I think the main point is if you use drugs where” randomised control trials “show benefit, you will be good,” Prasad said.

However, immunotherapies are usually approved without randomised control trials so “don’t be surprised if you harm patients. True for all drugs. Even, almost surely, immunotherapy,” Prasad said. MIMS

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