Complete Consolidative Radiotherapy May Have Survival Benefits in ES-SCLC

James Ninia, MD

Yale School of Medicine

Compared with incomplete consolidative radiotherapy, complete consolidative radiotherapy generally improved progression-free survival (PFS) and overall survival (OS) among patients with extensive-stage small cell lung cancer (ES-SCLC), according to James Ninia, MD.

When focusing on patients with oligometastatic disease only, OS did not significantly improve with the complete consolidative modality. Based on these findings, more work may be necessary to clarify whether the overall disease burden or the aggressiveness of local therapy is driving these observed outcome differences.

Ninia, a third-year resident of radiation oncology at the Yale School of Medicine, spoke with CancerNetwork^® about research he presented at the 2024 American Society of Radiation Oncology (ASTRO) Annual Meeting comparing outcomes with complete vs incomplete consolidative radiotherapy among those with ES-SCLC.¹ He detailed the study’s methodology, efficacy findings based on factors such as treatment modality and disease burden, and the potential next steps for research in the ES-SCLC population.

Looking ahead, Ninia noted that his colleagues should acknowledge how the extent of a patient’s disease burden may play a role in the outcomes associated with specific radiotherapy modalities.

“For future clinical trials involving SCLC, the [people] who are designing these trials, whether they work in industry or academics, should consider stratifying their analysis based on overall disease burden or completeness of consolidated radiotherapy to help us better elucidate which of these [factors] is driving these observed differences in patient outcomes that we’re seeing,” Ninia stated.

CancerNetwork: What was the rationale for assessing complete vs incomplete consolidative radiotherapy in patients with ES-SCLC?

Ninia: For patients with limited metastatic burden, metastasis-directed radiotherapy has previously been shown to be associated with improved survival for certain types of cancer in multiple clinical trials, including the phase 2 SABR-COMET trial [NCT01446744] and a few others.² However, patients with metastatic SCLC, what we would call ES-SCLC, were not included in these prior trials.

Moreover, patients with ES-SCLC are also routinely offered consolidated radiotherapy for any residual intrathoracic disease that they might have after first-line chemotherapy. This is based on a trial called the phase 3 CREST trial [NTR1527].³ This was done before immunotherapy was approved for SCLC, and the trial showed that patients who got radiation to residual intrathoracic disease after chemotherapy were more likely to be alive 2 years later than patients who did not.

Based on this, prior work in our department had shown that some patients with SCLC who have this limited disease burden which we termed oligometastatic SCLC do better after getting consolidated chest radiation after first-line chemotherapy than those with significant disease burden, which we termed polymetastatic. Our thought was to see whether offering radiotherapy to any additional sites of residual disease outside of the thorax might be playing a role in some of these findings or not.

What do the data show regarding the efficacy of the complete consolidative radiotherapy modality compared with the incomplete consolidative modality?

Ninia: We retrospectively looked at a group of patients treated at our institution in New Haven, Connecticut from 2013 to 2020. We identified, in the end, 70 patients for whom we had enough records to include in our analysis. Among those 70 patients, 28 of them received complete consolidation, whereas the other 42 [received] incomplete consolidation. Of those 70, 36 of them [had] oligometastatic [disease]. Of 36 patients [with] oligometastatic [disease], 24 underwent complete consolidation therapy.

Not surprisingly, we found that patients with oligometastatic [disease] were more likely to undergo complete consolidation than those with polymetastatic [disease], probably, in part, because giving radiation treatments to all those sites of disease is easier when there are less of them to target.

When we looked at all our patients with SCLC who [received] complete consolidation therapy, we found that [receiving] complete consolidation therapy was associated with a better PFS [and] better OS. The 1-year OS rate was 89.3% in patients who [received] complete consolidation vs 52.5% in those [who received] incomplete. At 2 years, it was 48.4% vs 19.7%, and the P-value for that was significant; it was 0.012.

We stratified by disease burden based on the relationship that we noted between whether patients got complete consolidation and their actual burden of disease. When we only looked at those who got who [had] oligometastatic disease and whether they received complete consolidation, we found that the PFS benefit remained. Those patients still did have a statistically significant PFS benefit. [A benefit of] 41.7% vs 0% at 1 year with a P-value of .005 [was shown].

Unfortunately, these patients did not have an OS benefit that was statistically significant compared [with] those receiving incomplete consolidation when we only looked at patients who [had] oligometastatic [disease].

What are the next steps for researching these radiotherapy modalities in those with ES-SCLC or other patient populations?

Ninia: [It is] fortuitous that there is an open and ongoing clinical trial that is seeking to evaluate this question as one of its secondary objectives, prospectively. This goes by a couple of different names––[it has] been called the phase 2/3 RAPTOR trial [NCT04402788],⁴ or you might hear it referred to as NRG-LU007––this trial is open here at Yale, as well as at many other centers around the country.

The primary purpose of this trial is to see whether the benefits of consolidated thoracic radiation that were observed in the CREST trial still apply in this era now where many patients with SCLC are getting immunotherapy with atezolizumab. As a secondary objective of this trial, they are also looking to prospectively evaluate whether patients who receive complete consolidation have better OS or PFS than those who get incomplete consolidation; the same question that they are trying to evaluate prospectively.

We here at Yale had some pretty promising retrospective data that are limited by our relatively small sample size and some other limitations, but given that these results are relatively promising, it is a good idea for practitioners around the country to try to encourage their patients to consider enrolling on this trial so that we can better understand the impact of offering consolidated radiotherapy to our patients.

Are there any patient subgroups who may particularly benefit from treatment with complete consolidative radiotherapy?

Ninia: We did look at this question, and we didn’t find any patient subgroups who may particularly benefit from this treatment. We did find a couple [subgroups] for whom it might benefit a little bit less. This is all very preliminary, but we did find on multivariate analysis that patients who had brain metastases had worse outcomes after receiving complete consolidation radiation, as well as any patients who may have had plural involvement at diagnosis. Those were 2 [groups] where we saw those patients do a little bit worse.

When we stratified our analysis by disease burden, we still didn’t see an OS benefit, but we did still see a strong PFS benefit. I’m not sure if they would particularly benefit from the treatment because we did see an OS benefit for the full cohort. It’s likely that offering this treatment to those patients is just logistically easier. If they have fewer sites of disease, there’s fewer sites to radiate; the treatment itself is often less toxic when there are smaller fields and things like that with the radiation.

What do you hope your colleagues take away from this presentation?

Ninia: The very notion of labeling some patients with ES-SCLC as having oligometastatic [disease] might itself be considered controversial. SCLC is often considered to be a systemic disease, and labeling some of these patients who have metastatic [disease] as oligometastatic would be considered by some to be inappropriate. We’re getting some increasingly convincing data that there is some impact of disease burden on outcomes, whether we want to label that as oligometastatic or not. We have to contend with this idea that for SCLC, our ability to offer certain treatments based on disease burden likely plays a role in some of our patient outcomes.

References

1. Ninia JG, Verma N, Laird JH, et al. Complete vs. incomplete consolidative radiotherapy in patients with extensive-stage small cell lung cancer. Presented at the 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting; September 29 – October 2, 2024; Washington, DC. Abstract 2109.
2. Harrow S, Palma DA, Olson R, et al. Stereotactic radiation for the comprehensive treatment of oligometastases (SABR-COMET): extended long-term outcomes. Int. J. Radiat. Oncol. 2022;114(4):611-616. doi:10.1016/j.ijrobp.2022.05.004
3. Slotman BJ, Tinteren HV, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015;385(9962):36-42. doi:10.1016/S0140-6736(14)61085-0
4. Testing the addition of radiation therapy to the usual immune therapy treatment (atezolizumab) for extensive stage small cell lung cancer, the RAPTOR trial. ClinicalTrials.gov. Updated October 4, 2024. Accessed October 16, 2024. https://tinyurl.com/yc3zmz6e