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BUENOS AIRES — Pretreatment with pharmacologic doses of oral L-arginine enhances the effect of radiation therapy in patients with unresectable brain metastases related to solid tumors, according to a study published in Science Advances. This allows greater local control of the disease and could provide an affordable way to optimize the effect of radiation, or even other treatments, on primary or metastatic tumors.

Leandro Cerchietti

“The magnitude of the result was surprising, because unresectable brain metastases are serious complications of the disease and have a major impact on quality of life, owing to the symptoms, and a short survival time, approvedpharmacynvx ” said principal investigator Leandro Cerchietti, MD, from the Division of Hematology and Oncology at Weill Cornell Medicine in New York City.

It was also surprising “because previous studies on other radiosensitizers have shown them to be quite toxic and/or lacking the degree of effectiveness that would allow them to be used in clinical practice,” he told Medscape.

Mónica Castro

The study, conducted in collaboration with researchers at other sites in the United States and Argentina, combines work on lab mice with metabolic, vascular, and preliminary studies on the efficacy and safety in human patients, all of which represent a good example of translational research “that allows the integration of something observed in the clinical realm with findings from functional studies on preclinical models,” explained Mónica Castro, MD, head of the translational research unit at the Ángel Roffo Cancer Institute, University of Buenos Aires, in Argentina, and one of two senior study investigators.

In the main phase 1/2 clinical trial, 63 patients with brain metastases related to solid tumors — such as non-small cell lung cancer (51%), triple-negative breast cancer (21%), and melanoma (8%) — were randomized to receive oral L-arginine 10 g or placebo prior to each fraction of radiation. The whole-brain radiation therapy protocol consisted of a total dose of 32.0 Gy, administered in 20 fractions, followed by a boost of 22.4 Gy that adhered to the same fractionation schedule. The investigators used the Fisher’s exact test or the Cox-Mantel test to compare responses.

The majority of patients had an uncontrolled primary tumor, multiple metastatic sites, and multiple brain metastases. The median follow-up after the end of the treatment was 5 months (range, 1 – 55 months).

L-arginine was well tolerated and did not produce short- or long-term (more than 6 months) adverse events. The overall response rate was significantly higher in the L-arginine group than in the placebo group (77.4% vs 22.0%; P < .001), as was the symptomatic response rate (93.5% vs 50.0%; P = .002).

Complete neurologic responses were three times more likely in patients pretreated with L-arginine than in those pretreated with placebo, although the difference was not significant (29.0% vs 9.4%; P = .059). And at 6 months, patients in the L-arginine group were four times more likely to be free from neurologic progression than patients in the placebo group (82.0% vs 20.0%; P < .0001).

Median overall progression-free survival was longer in the L-arginine group than in the placebo group (5 vs 2 months [range, 4 – 6 vs 0 – 4 months]; P = .0007), although most of the patients in the L-arginine group died from progression of the extracranial disease, the investigators note.

“This study shows that, when used under these conditions, L-arginine at pharmacologic doses is a safe and effective treatment, in that it doesn’t increase the adverse effects of radiotherapy,” said Cerchietti.

Tumors “Addicted” to Nutrients

L-arginine, commonly used as a supplement for erectile dysfunction or lack of sexual desire, is a substrate of the nitric oxide synthase enzyme, which produces nitric oxide in tissue. Nitric oxide is a gas that has been shown, in relatively high concentrations, to induce chemo- and radiosensitization in preclinical models and in patients with solid tumors.

This study helps to clarify the role of nitric oxide. Tumors become “addicted” to certain nutrients, such as glucose, which they use to grow, to produce other cancer cells, and to repair certain molecules that have been damaged by treatment, Cerchietti explained.

Cancer cells consume glucose and release lactate as the byproduct. They also express proteins like nitric oxide synthase 2, which they use to maintain themselves and proliferate, although too much activity by this enzyme can be toxic and cause cellular stress, he said.

“What L-arginine does is hyperactivate nitric oxide synthase 2 and cause cellular stress, such that the cancer cell stops consuming glucose (and releasing lactate) and loses the capacity to repair itself and proliferate. If, at this point, we administer radiation therapy, the effect of the rays is amplified and causes the cancer cell to die. In other words, the cell is metabolically more sensitive to the cancer-fighting effects of radiotherapy,” he added.

This understanding of the mechanism can be used to produce maximum benefits from L-arginine.

“For example, the cellular stress that L-arginine induces on cancer cells lasts, more or less, 1 hour, so that’s when radiation should be administered. It’s also useful for understanding why there is sensitization in cancer cells but not in other cells, which helps to reduce the chances of toxic effects without altering the activity of immune cells that attack the tumor. In fact,” Cerchietti pointed out, “we’re now studying how to use this mechanism to increase the effect of immunotherapies instead of using radiation.”

Around 90% of patients with brain metastases from breast cancer and lung cancer express nitric oxide synthase 2 and would be candidates for radiosensitization with L-arginine. However, Cerchietti emphasized, this was a “proof-of-concept” trial. More evidence is needed before such pretreatment becomes part of routine clinical practice, the researchers explain.

The findings “would have to be replicated on a larger scale before we could bring the conclusions to the clinical setting. Nonetheless, we have an interesting picture before us, not only in terms of treatment associated with radiotherapy, but also with other modalities, like immunomodulation,” Castro told Medscape.

Clinical trials in patients with other characteristics (such as metastatic recurrence after surgery) and with different modes of radiotherapy will likely begin, Cerchietti said. Other tumors that express nitric oxide synthase 2 or that decrease lactate production after the administration of L-arginine (something that can be determined noninvasively with MRI) “could also benefit from this approach, which include metastatic tumors in other places and primary tumors in which radiotherapy plays a therapeutic role,” although studies are needed to confirm this.

The use of L-arginine as a radiosensitizer seems to be “very promising,” said Alejandro Muggeri, MD, an oncologist who specializes in brain tumors and metastases at the FLENI Institute and the Favaloro Foundation, both in Buenos Aires, and who was not involved in the study.

It might also be useful for improving the outcomes of radiosurgery, which is “what we tend to use when there are fewer than 15 brain metastases,” he told Medscape.

However, more information about the participants in the two study groups — such as age, Karnofsky functional status score, and number of brain metastases each had (all of which are prognostic factors) — is needed to make a comprehensive evaluation of the clinical trial results, Muggeri said. “More studies are needed. Let’s hope that they’ll have good results!”

Cerchietti received funding from Bristol Myers Squibb not connected to this work, and holds a patent issued to Cornell University in connection to this work. Castro and Muggeri have disclosed no relevant financial relationships.