DISAPPEARANCE OF METASTASES IN MELANOMA

March 7, 2012 — A "rare phenomenon" in the treatment of cancer — in which a patient has a systemic response after localized radiotherapy — is reported in a brief report published in the March 8 issue of the New England Journal of Medicine.

The event, known as the abscopal effect, occurred in a 40-year-old woman with metastatic melanoma who was being treated with the immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb).

The patient is a working single mother who had been on maintenance therapy with ipilimumab at the time of her radiotherapy, said her oncologist, Jedd Wolchok, MD, PhD, from the Memorial Sloan-Kettering Cancer Center in New York City.

Dr. Wolchok, who is a coauthor of the brief report, spoke to Medscape Medical News about the case.

The patient had enrolled in a phase 2 trial of ipilimumab in September 2009, after a surveillance computed tomography (CT) scan showed right hilar lymphadenopathy and a pleural-based tumor sitting along the spine. Twelve weeks after the initiation of ipilimumab, the patient had stable disease, but with a slight enlargement of the pleural mass. For this reason, she was permitted to continue on maintenance therapy, with a dose of the drug every 12 weeks.

Toward the end of 2010, the patient, who had continued with the maintenance therapy, began progressing symptomatically, with new splenic lesions and an enlarging of the pleural-based mass, which eventually caused pain.

To treat the patient's pain, palliative radiotherapy was initiated. "Job number 1 is always to take care of the patient, so we took care of the patient," Dr. Wolchok explained to Medscape Medical News. In other words, the treatment team was not seeking to hit a treatment home run with localized radiation to the paraspinal mass.

However, at the time of the radiotherapy in December 2010, Dr. Wolchok had an idea.

"In the back of my mind, there was the thought that we might induce the abscopal effect," he explained.

There are "plenty of examples in the animal literature" of the abscopal effect, but it is "very rare" in general, said Dr. Wolchok. "There is maybe 1 other case in melanoma," he said.

After the radiotherapy, the patient received 1 more dose of ipilimumab. Four months later, in April 2011, the irradiated tumor was considerably smaller, which was "not terribly surprising," he continued.

"More surprising" was the fact that the distant disease outside the radiation field had regressed, said Dr. Wolchok. A new CT scan in October 2011 revealed that, 10 months after the radiotherapy, the patient continued to have "minimal disease."

Dr. Wolchok and his coauthors entertained the possibility that the patient's outcome was a delayed response to ipilimumab.

"Delayed responses occurring 18 to 20 weeks after ipilimumab treatment are well known; yet, in our opinion, the 19-month interval between the start of ipilimumab and disease response, with radiotherapy having been administered in the interim, is more supportive of an abscopal effect," they write.

The team also investigated the patient's blood and detected a number of correlates of her immune response. For example, they observed changes in tumor-directed antibody levels and immune cell populations that occurred at the time of the abscopal effect.

Take-Home Message

Dr. Wolchok's patient was "thrilled" by this unexpected outcome. She is an "extraordinary human being" who never took a sick leave from work, despite having received multiple treatments for her cancer, and continues to be the head of her family. "We were able to provide her with treatments that fit into the rest of her life," he said.

Beyond the good news for a single patient, the happy accident of the abscopal effect has implications for other patients on ipilimumab and for cancer research, the authors note.

This case "suggests new therapeutic avenues to pursue," write the authors. Clinical trials to prospectively validate this approach are under way in prostate cancer (NCT00861614) and melanoma (NCT01449279).

More immediately, clinicians administering ipilimumab might try radiation along with the drug in some patients, such as those "who need palliation for symptomatic lesions."

"You might be able to improve the therapeutic index of ipilimumab by giving it with radiation," he said.

Dr. Wolchok explained how ipilimumab and radiation might work together.

"Radiation treats cancer by causing DNA damage," he said. "If cancer cells die, that debris is very interesting to the immune system, which has the job of cleaning up the body."

It is "not surprising" that the immune system by itself will not sufficiently respond to such debris, he continued. "But if you have an activated immune system, you may get a synergy," he summarized, referring to the immune system effect of ipilimumab.

A number of the coauthors report financial ties with Bristol-Myers Squibb.

N Engl J Med. 2012;366:925-931. Abstract