Call for Improved Immune-Sparing Strategies for High-Dose RT for NSCLC

Higher doses of radiation sustained by the host immune system were associated with tumor progression and reduced survival in patients receiving definitive treatment for stage III non-small-cell lung cancer (NSCLC), researchers reported.

“Tailoring radiotherapy to spare the immune system may be an important future direction to improve outcomes in this population,” wrote Sameer K. Nath, MD, of the University of Colorado in Denver, and colleagues.

As shown in their study online in the International Journal of Radiation Oncology, a higher modeled estimated dose of radiation to immune cells (EDRIC) correlated with a greater risk of grade 3 or higher lymphopenia (P=0.004), and an EDRIC above 7.3 Gy translated to a median overall survival (OS) of just 14.3 months, while an EDRIC below 5.1 Gy was associated with a median OS of 28.2 months.

“We show that the estimated dose of radiation to immune cells is an important predictor of tumor control and survival,” Nath said in a statement. “In fact, it ends up being one of the most important predictors. It’s a really thought-provoking finding because radiation effects on the immune system isn’t something the field has focused on in the past.”

The findings echo those of the RTOG 017 phase III randomized trial, which in 2017 reported that 5-year survival rates in stage III NSCLC patients were better in the standard-dose than the high-dose arm. OS and progression-free survival (PFS) rates in the two arms were 32.1% versus 23% (P=0.004) and 18.3% versus 13% (P=0.055), respectively, in favor of standard dosing.

Study Details

The new study identified 117 stage III NSCLC patients, 53% of whom were female, treated with definitive fractionated radiation from 2004 to 2017 at the University of Colorado Cancer Center. The median age of patients was 63 (range of 36-89), 75.2% were Caucasian, and 49.6% were current smokers.

The median EDRIC was 6.1 Gy (range of 2.5-10.0), with 60% of patients undergoing intensity-modulated radiotherapy and 92% receiving concurrent platinum-based chemotherapy.

EDRIC was calculated as a function of the number of radiation fractions and mean doses to the lung, heart, and the rest of the body, using the model of Jin and colleagues, who in 2017 suggested that radiation-induced immune toxicity could drive tumor progression and death in stage III NSCLC.

With a median follow-up of 15.7 months (range of 2.8-124.5 months), 77% of patients were followed until death, and 90 deaths occurred. On multivariate analysis, including total prescription radiation dose, planning target volume, and chemotherapy utilization, EDRIC was found to be independently associated with the following hazard ratios:

• OS: 1.17 (P=0.03)

• Local PFS 1.17 (P=0.02)

• Disease-free survival 1.15 (P=0.04).

In the entire cohort, the 3- and 5-year local PFS rates were 20.8% and 5.0%, respectively. Local PFS was significantly reduced in patients with an EDRIC of over 7.3 Gy versus those with an EDRIC less than 5.1 Gy (HR 1.89, P=0.03).

The median local PFS times for patients with an EDRIC above 7.3 Gy and below 5.1 Gy were 11.5 and 15.0 months, respectively, with the greatest effect occurring at doses above 6.3 Gy, the team reported.

“What is really exciting is that now that we have ways to estimate this radiation dose — we can look at sparing the immune system as an organ at risk,” Nath said. “We think it is a modifiable risk factor. Now we can focus on methods to minimize dose and in doing so, we will be able to maximize the benefit of radiation to these patients.”

He suggested it may help to reduce the time over which radiation is delivered and the number of treatments to restrict the number of immune cells damaged.

“Given the exquisite sensitivity of leukocytes to radiation, our findings suggest there may be an inherent tradeoff between increasing radiation dose to improve tumor cell killing and a competing trend of immunosuppression that counteracts the benefits of higher doses of radiation therapy,” the investigators wrote.

They called for more research on the feasibility of optimizing radiotherapy programs to protect the immune pool. Such strategies could include more focused radiation to spare areas that contain more circulating immune cells, directing radiation away from the heart and lung, and using functional lung imaging to avoid vulnerable areas.

‘Important Insights, Reaffirms Emerging Evidence’

Asked for his perspective, Robert Samstein MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York City, who was not involved with the research, said the study offers important insights and reaffirms emerging evidence that the dose to lymphoid organs and immune cells may have an impact on long-term tumor control.

“Unfortunately, it remains extremely complicated to understand how best to implement these concerns in practice and balance delivering an effective tumoricidal radiation dose to the tumor,” said Samstein. “Radiation oncologists are always looking to better optimize the dose distribution for high-dose radiation treatments, and this work certainly suggests potential modifications that could be tested in a prospective fashion in the future.”

Also commenting, Kristina Young, MD, PhD, a radiation oncologist at the Oregon Clinic in Portland, said that further investigation into dose, fractionation, and inclusion of elective lymph nodes is critical in understanding the immune-modulatory effects of radiation. “Future clinical trials will have to be mindful of these and many other factors that may influence radiation response and patient outcomes,” she said.

Young added that recent investigation into the immune-stimulatory effects of radiation have prompted evaluation of tumor immune infiltrate, with preliminary evidencing suggesting that peripheral lymphocyte counts do not necessarily correlate with what is happening within the tumor, where T cell infiltration is often increased by radiation, even with standard fractionation and dosing.

Earlier this month, MedPage Today reported that more radiation to the heart contributed to early mortality and cardia morbidity in NSCLC patients.

Study limitations, Nath and co-authors said, included its retrospective nature and single-center design, which could have resulted in selection bias, unknown confounding variables, and lack of structured follow-up. In addition, with treatments given over long periods, there may have been significant variation in staging, diagnostic work-up, and planning. Furthermore, the results could not be extended to patients receiving consolidating immunotherapy since none in this study had this option.

Finally, the team said, the survival outcomes were lower than those seen in national trials, a finding likely attributable to the careful patient selection for enrollment in national trials, as well as this study’s higher proportions of patients with a Karnofsky Performance Scale Index less than 70 (26%) and stage IIIb disease (48%). And, because EDRIC must be modeled, it is subject to all model limitations and assumptions as well as the shortcomings of surrogate metrics.