Proton therapy leads to significantly lower risk of side effects in cancer compared to traditional radiation

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Proton therapy leads to significantly lower risk of side effects severe enough to lead to unplanned hospitalizations for cancer patients when compared with traditional radiation, while cure rates between the two groups are almost identical.

The findings come from an expanded analysis of the largest review of its kind, performed by researchers in the Perelman School of Medicine at the University of Pennsylvania, to evaluate whether or not patients undergoing radiation therapy at the same time as chemotherapy experienced serious adverse events within 90 days.

Researchers found proton therapy reduces the relative risk of these side effects by two-thirds. JAMA Oncology published the findings today.

“This is exciting because it shows that proton therapy offers a way for us to reduce the serious side effects of chemo-radiation and improve patient health and wellbeing without sacrificing the effectiveness of the therapy,” said the study’s lead author Brian Baumann, MD, an adjunct assistant professor of Radiation Oncology at Penn and an assistant professor of Radiation Oncology at Washington University School of Medicine in St. Louis.

Proton therapy has a few key differences from traditional photon radiation. Photon radiation typically uses multiple X-ray beams to deliver radiation to the tumor target but unavoidably deposits radiation in the normal tissues beyond the target, potentially damaging those tissues as the beam exits the body.

Proton therapy is an FDA-approved alternative radiation treatment that directs positively charged protons at the tumor.

They deposit the bulk of the radiation dose to the target with almost no residual radiation delivered beyond the target, reducing damage to surrounding healthy tissue and potentially reducing side effects.

For this study, researchers evaluated side effects including pain or difficulty swallowing, difficulty breathing, nausea, or diarrhea, among others. Researchers focused on grade-three effects or higher, defined as side effects severe enough for patients to be hospitalized.

They evaluated data on 1,483 cancer patients receiving radiation and chemotherapy at the same time. Of these, 391 patients received proton therapy, while 1,092 underwent photon treatment.

All patients had non-metastatic cancer and were undergoing treatment intended to be curative. Patients with brain cancer, head and neck cancer, lung cancer, gastrointestinal cancer, and gynecologic cancer treated with concurrent chemo-radiation were included.

The primary outcome was whether or not patients experienced adverse side effects that were grade-three or higher within 90 days of treatment. In the proton group, only 11.5 percent of patients (45) did, compared to 27.6 percent of patients (301) in the photon group.

A weighted analysis of both patient groups, which controlled for other factors that may have led to differences between the patient groups, found that the relative risk of a severe toxicity was two-thirds lower for proton patients compared to photon patients.

“We know from our clinical experience that proton therapy can have this benefit, but even we did not expect the effect to be this sizeable,” said senior author James Metz, MD, chair of Radiation Oncology, leader of the Roberts Proton Therapy Center at Penn, and a member of Penn’s Abramson Cancer Center.

Importantly, overall survival and disease-free survival were similar between the two groups, suggesting that the reduction in toxicity seen with proton therapy did not come at the cost of reduced effectiveness.

Researchers say these results hint at the promise of proton therapy as a way to deliver intensified systemic therapy and/or higher dose radiation therapy more safely, which could improve survival outcomes.

In fact, data showed that while older patients with more comorbidities were more likely to receive proton therapy, they experienced fewer side effects.

“This tells us proton therapy may allow older patients to receive the most effective combined treatments, and that older, sicker patients can more safely be included in clinical trials that use proton therapy,” Baumann said.

While researchers say further research is needed, they point out that this study is the best information we have so far as randomized controlled trials continue to prove difficult to complete.

Provided by Perelman School of Medicine at the University of Pennsylvania


Importance  Concurrent chemoradiotherapy is the standard-of-care curative treatment for many cancers but is associated with substantial morbidity. Concurrent chemoradiotherapy administered with proton therapy might reduce toxicity and achieve comparable cancer control outcomes compared with conventional photon radiotherapy by reducing the radiation dose to normal tissues.

Objective  To assess whether proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy.

Design, Setting, and Participants  This retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent from January 1, 2011, through December 31, 2016, at a large academic health system. Three hundred ninety-one patients received proton therapy and 1092, photon therapy. Data were analyzed from October 15, 2018, through February 1, 2019.

Interventions  Proton vs photon chemoradiotherapy.

Main Outcomes and Measures  The primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3). Secondary end points included Eastern Cooperative Oncology Group (ECOG) performance status decline during treatment, 90-day adverse events of at least CTCAEv4 grade 2 that limit instrumental activities of daily living, and disease-free and overall survival. Data on adverse events and survival were gathered prospectively.

Modified Poisson regression models with inverse propensity score weighting were used to model adverse event outcomes, and Cox proportional hazards regression models with weighting were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach.

Results  Among the 1483 patients included in the analysis (935 men [63.0%]; median age, 62 [range, 18-93] years), those receiving proton therapy were significantly older (median age, 66 [range, 18-93] vs 61 [range, 19-91] years; P < .01), had less favorable Charlson-Deyo comorbidity scores (median, 3.0 vs 2.0; P < .01), and had lower integral radiation dose to tissues outside the target (mean [SD] volume, 14.1 [6.4] vs 19.1 [10.6] cGy/cc × 107P < .01). Baseline grade ≥2 toxicity (22% vs 24%; P = .37) and ECOG performance status (mean [SD], 0.62 [0.74] vs 0.68 [0.80]; P = .16) were similar between the 2 cohorts. In propensity score weighted–analyses, proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least grade 3 (0.31; 95% CI, 0.15-0.66, P = .002), 90-day adverse events of at least grade 2 (0.78; 95% CI, 0.65-0.93, P = .006), and decline in performance status during treatment (0.51; 95% CI, 0.37-0.71; P < .001). There was no difference in disease-free or overall survival.

Conclusions and Relevance  In this analysis, proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival. Prospective trials are warranted to validate these results.


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