'Groundbreaking': Prophylactic Radiotherapy Ups Survival 

Liam Davenport

October 26, 2022

SAN ANTONIO — Radiotherapy for painful bone metastases is a standard of care, but a new study that looked at earlier use of the modality had an unexpected result. It showed that prophylactic radiotherapy given to patients with cancer and asymptomatic bone metastases not only reduces skeletal-related events and hospitalizations, but also  offers a survival benefit.  

In the first study of its kind, almost 80 patients with more than five high-risk metastases were randomly assigned to receive either prophylactic radiotherapy or standard care.

The patients who underwent radiotherapy showed a reduction in a composite of skeletal-related events, and none had to be admitted to hospital. But the results also showed a 55% improvement in overall survival compared with those in the control group, giving these patients an additional 8 months of life.

"It's thought-provoking that radiation to prevent pain could potentially prolong life," commented lead author Erin F. Gillespie, MD, radiation oncologist at Memorial Sloan Kettering Cancer Center in New York City.

"It suggests that treating to cure the cancer is not the only thing that can help people live longer," she said in a statement.  

Gillespie added that the overall survival difference "was not expected", but that there is "certainly a rationale and mechanisms to explain this," with previous studies showing that palliative care "has the ability to improve overall survival."

She presented the research here at the American Society for Radiation Oncology (ASTRO) Annual Meeting on October 23.

The results were welcomed enthusiastically by experts not involved in the trial.

"Groundbreaking" was the description used on Twitter by Stuart Burri, MD, a radiation oncologist with Southeastern Radiation Oncology and Levine Cancer Institute, Charlotte, North Carolina.


"Provocative" was the term used by Shankar Siva, MD, PhD, a radiation oncologist at the Peter MacCallum Cancer Centre, Melbourne, Australia.

Speaking to Medscape Medical News, Siva said that the use of radiotherapy for symptomatic bone pain is a "well-established standard of care," but the question addressed by the current study — in which radiotherapy was used for asymptomatic bone metastases — was "whether we can bring forward this treatment to improve outcomes".

He emphasized that the prevention of skeletal-related events is "really important for patients," and while the finding of improved overall survival benefit was "unexpected," it makes the case for considering radiotherapy as a prophylactic treatment.

"It's akin to saying: if you see someone drowning, you should really throw them a life vest," Siva explained. "It seems intuitive" that if you see someone who has some poor risk features that increase the likelihood of catastrophic events such as spinal cord compression, "you try this treatment up front."

But up to now "we just didn't have the proof" that up-front treatment would be effective, and this study is a "really important step" in providing that, he added.

As for the magnitude of the survival benefit, Siva said that, "if this was drug A, then there would be a very large and interested pharmaceutical market chasing after this."

However, "one advantage" of the intervention being radiotherapy is that it's already a standard of care and "it's ubiquitous and widely accessible."

"There's no added huge incremental cost to society, to the payer, or to the patient," he said. "This is a major win" as it is simply "moving forward a treatment that would otherwise" be less effective when given later.

Although this study was a relatively small, phase 2 trial and therefore needs confirming in further trials, Siva said that, overall, the results are "very promising" and for his practice he would now "have to think twice about whether to withhold radiotherapy" in patients with asymptomatic bone metastases.

Gillespie acknowledged that "more work is needed to optimize the appropriate use" of radiotherapy in order "to avoid overtreatment," but also on how to identify these patients while they still have asymptomatic bone metastases "since we may not always see them." 

At a press conference held during the meeting, Iris C. Gibbs, MD, professor of radiation oncology, Stanford Cancer Center, Stanford, California, said studies like the current one "illustrate the importance of the role of the radiation oncologist not only in the treatment of cancer, but also in our role in the overall healthcare and delivery system and health of our patients, for example, on issues around cost containment, by prevention of hospitalizations, or morbidity."

Study Details

For this study, Gillespie and colleagues randomly assigned patients with high-risk asymptomatic bone metastases to radiotherapy or no radiotherapy, stratifying the patients by primary tumor histology, and also by the planned standard of care, whether systemic therapy or surveillance.

The patients were required to be age 18 or older, and have an ECOG performance status of 0–2, a solid tumor malignancy, and more than five metastatic sites on imaging. At least one of those metastases should have been high-risk, defined as bulky disease of >2 cm, or involving the hip, shoulder or sacroiliac joints, the long bones, or the junctional spine and/or posterior element.

The team randomly assigned 78 patients from three institutions, and data was evaluable on 35 patients (with 62 lesions) in the radiotherapy arm and 36 patients (with 49 lesions) in the control group.

The median age of the patients was 61-65 years, and around half were female. The most common histologies were lung, breast, and prostate cancer, and 90% were planned to have systemic therapy. About half of patients had received a bone-modifying agent.

The primary endpoint of the study was skeletal-related events, defined as pathologic fracture, cord compression, surgery for instability, or radiotherapy for pain.

A skeletal-related event occurred in just 1.6% of patients given prophylactic radiotherapy vs 29% in the no radiotherapy arm (P < .001).

This difference held even when the team removed radiotherapy for pain from the combined endpoint, at an event rate of 0% vs 12.5% (P = .008).

After a median follow-up of 2.4 years, the median overall survival was 1.7 years with radiotherapy vs 1 year with no radiotherapy, at a hazard ratio on multivariate analysis of 0.45 (P = .011).

There were also no hospitalizations among the patients who received radiotherapy vs 4 in the untreated arm (P = .045), and there was also a significant improvement in scores on the Brief Pain Inventory (P = .039).

In terms of safety, grade 2 or higher adverse events were experienced by 38% of patients in the radiotherapy arm vs 21% in the control group, with 13% and 3%, respectively, deemed to be potentially treatment-related. The most common events were nausea, emesis, erythema, fatigue, and diarrhea, the majority of which were grade 2.

Gillespie said that future research questions for prophylactic radiotherapy include: "Does this apply to someone early in the course of their metastatic disease who may not have any symptomatic lesions?"

"At what point would they benefit from intervention with radiation? There are many patients with multiple sites of metastases, but how do we identify those lesions that are most likely to become problematic?"

She added that, "once we confirm this is the right thing to do, how do we ensure patients who might benefit get access to this treatment?"

No funding was declared for this study. Gillespie reported relationships with the National Institutes of Health and the Agency for Healthcare Research and Quality. Other authors reported numerous relationships with industry.

American Society for Radiation Oncology (ASTRO) Annual Meeting 2022: Abstract LBA 04. Presented October 23.

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