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Radiation prior to immune checkpoint inhibitor therapy may lower toxicity
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Ten percent of patients with lung cancer who received thoracic radiation therapy with immune checkpoint inhibitors experienced severe toxicities, according to a retrospective study presented at the Multidisciplinary Thoracic Cancers Symposium.
However, none of the patients who received radiation therapy before immune checkpoint inhibitors experienced severe toxicities.
“Treatment with immune checkpoint inhibitors and thoracic radiation therapy carried a modest risk for side effects,” Kamran A. Ahmed, MD, a resident in radiation oncology at Moffitt Cancer Center, said during a press conference. “Our study indicates the risk for thoracic radiation therapy– and immune checkpoint inhibitor–related pneumonitis may be highest when thoracic radiation therapy is delivered after immune checkpoint inhibitor therapy.”
Ahmed and colleagues analyzed 29 patients (median age, 64 years; range 41-77; 55% women) with metastatic lung cancer treated with thoracic radiation therapy and immune checkpoint inhibitors between February 2012 and May 2016.
Most patients (79%) presented with non–small cell lung cancer, and 69% had an ECOG performance status of 1. Patients had a median of three (range, 2-8) metastatic sites.
Patients received radiation therapy within the 6 months preceding or 6 months following initiation of immune checkpoint inhibitors, given as anti–PD-1 therapy or anti–PD-L1 therapy alone or in combination with anti–CTLA-4 therapy.
Seventeen patients (59%) received immune checkpoint inhibitors a single agent, and 12 patients received them in a combination. All patients received therapy until their disease progressed.
The severity of treatment-related toxicity, namely pneumonitis, served as the primary outcome. Median follow-up was 6.6 months (range, 0.5-40.4) following treatment.
Researchers used the Kaplan-Meier method to determine PFS and OS estimates from initiation of immune checkpoint inhibitor therapy.
Fifty-two percent of patients received thoracic radiation therapy concurrently with or after an immune checkpoint inhibitor. The other 14 patients were administered radiation 2 weeks to 5.5 months before they began immune checkpoint therapy, with a median interval of 2.2 months (range, 0.4-5.5) between radiation therapy and immune checkpoint therapy.
Total radiation doses ranged from 10 to 70 Gy delivered in one to 35 fractions.
Median PFS for all patients was 3.8 months (95% CI, 1.9-8), and median OS was 9.2 months (95% CI, 5.1-not reached).
Three patients (10%) experienced severe treatment-related toxicities, all of whom received radiation after immune checkpoint inhibitor therapy. One patient experienced grade 5 toxicity 2 weeks following radiation, and two patients reported grade 3 pneumonitis between 2 and 4 months postradiation.
None of the patients who received radiation therapy first experienced severe radiation-related toxicity.
One patient who died during the trial was treated with total dose of 20 Gy radiation in five fractions. The patient experienced severe pneumonitis after 16 Gy of radiation treatment, leading to hospitalization. That patient also reported comorbidities, which included pericardial effusion and congestive heart failure that could have contributed to the patient’s death.
Two patients who experienced pneumonitis continued with thoracic radiation without further toxicities, Ahmed said.
“We strongly advocate for ongoing studies to assess the synergistic effect of thoracic radiotherapy and immune checkpoint inhibitors and ongoing toxicity evaluations, particularly in the instance where thoracic radiation therapy is delivered before or concurrently with immune checkpoint inhibitors based on preclinical rationale and our own toxicity evaluation, which revealed known severe pneumonitis when thoracic radiation therapy and immune checkpoint inhibitors are sequenced in this fashion,” Ahmed said. – by Chuck Gormley
Reference:
Ahmed KA, et al. Abstract 10. Presented at: Multidisciplinary Thoracic Cancers Symposium; March 16-18, San Francisco.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Jeffrey D. Bradley, MD
Immunotherapy has made a huge splash in non–small cell lung cancer after the publication of two trials in The New England Journal of Medicine, in which patients clearly benefited from nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck).
These are not curative drugs, so patients will likely relapse. However, patients could receive these drugs at an earlier stage when the disease is curable — moving the therapy earlier from stage IV to stage III. The routine therapy for patients with stage III disease is chemotherapy and radiation therapy. If introduced into a setting where there is curative disease, patients could receive immunotherapy, rather than chemotherapy, with radiation therapy.
This is one of the first studies in which researchers looked at patients who had radiation therapy and anti–PD-1 therapy nearly simultaneously, and the reported toxicity was about 10%. It is a retrospective study — which is its weakness — and there are a lot of prospective studies ongoing now trying to figure out if we can do this safely.
This study gives a signal that the risk might be around 10%; however, because checkpoint inhibitors in this study were given to some patients before radiation, some patients during radiation and some patients after radiation, it is hard to evaluate the true risk. People can recover from pneumonitis with prednisone, so 10% toxicity is not too high; that is encouraging.
There are two settings where radiation therapy and immunotherapy would be helpful. There is the idea that you can give immunotherapy and a large ablative dose of radiation to create an inflammatory response on the tumor and recruit the patient’s immune cells and create a vaccine from the tumor itself. That is one strategy, which uses one or a few large fractions of radiation to enhance the immune system. That is very different from what is routinely used — weeks of radiation therapy — which might deplete the immune system and make these drugs not work.
We need to pay attention to radiation strategy. Most people are trying to shorten the radiation course with these drugs and test them with fewer fractions of radiation.
References:
Braher J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1504627.
Garon EB, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1501824.
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