Data Help Refine Optimal Radiotherapy Approaches in Small Cell Lung Cancer

Completed studies have quashed the need for additional clinical trials evaluating different fractions and dosing of radiotherapy for patients with limited-stage small cell lung cancer (LS-SCLC), according to Walter J. Curran, MD; however, he added that ongoing research examining adaptive therapy and techniques such as FLASH radiotherapy could help improve outcomes in this patient population.

“I don’t think there is a need for more fractionation studies [in LS-SCLC]. Adaptive therapy can expand the benefit, and motion management is complicated but necessary,” Curran said during a presentation at the 22nd Annual Winter Lung Cancer Conference®, an event held by Physicians’ Education Resource, LCC.1 Curran is chief of the Piedmont Oncology Institute, Piedmont Healthcare, in Atlanta, Georgia.

Establishing the Radiotherapy Standard of Care in LS-SCLC

Curran began by highlighting that the incidence of SCLC has continued to decline, which he associated with the decrease in tobacco use in the United States. He also explained that similar to lung cancer as a whole, the incidence of SCLC is increasing in women and decreasing in men, making it a more gender-neutral malignancy.

He also explained how the updated staging criteria have affected a diagnosis of LS-SCLC vs extensive-stage SCLC (ES-SCLC), which he said is crucial to distinguish when determining whether a patient could be a candidate for radiotherapy.

“The strict staging criteria for SCLC are to use TNM [classification]. Yet, most of us think of LS-SCLC vs ES-SCLC,” Curran said. “Radiotherapy has changed, as has SCLC, but it’s important to emphasize those patients with contralateral cervical clavicular nodes, cervical nodes, axillary nodes, pleural and pericardial effusions, cardiac mass, and chest wall mass—most are considered [to have] M1 [disease], but not all of them. Some are T4 in the new staging system, but all of them would render a patient ineligible to be considered [for] LS-SCLC.”

Despite the increased use of PET scans that could potentially identify a patient’s disease as ES-SCLC over LS-SCLC, the incidence of these 2 stages of the disease has remained consistent, Curran said.

The standard use of radiotherapy in LS-SCLC was established around the turn of the century. Data from the INT 0096 study showed that the use of hyperfractionated radiotherapy given at 45 Gy twice per day over 3 weeks led to a 10% absolute overall survival (OS) advantage at 5 years compared with 45 Gy once per day over 5 weeks (P = 0.04).2

This study was led by Andrew T. Turrisi, III, MD, who served as Curran’s second attending while training at the University of Pennsylvania. “I would argue with him as he was designing the study that 45 Gy once per day was not the standard then, and it was a weak control group,” Curran said. “That being said, it became the one study where the superiority of one radiotherapeutic regimen over another was demonstrated in survival.”

In recent years, the phase 3 CONVERT trial (NCT00433563) sought to establish the optimal radiotherapy dose and schedule when given in tandem with chemotherapy in patients with LS-SCLC. Findings published in The Lancet Oncology in 2017 showed that at a median follow-up of 45 months (interquartile range, 35-58), patients treated twice-daily concurrent chemoradiation (n = 274) experienced a median OS of 30 months (95% CI, 24-34) compared with 25 months (95% CI, 21-31) for given once-daily concurrent chemoradiation (n = 273; HR, 1.18; 95% CI, 0.95-1.45; P = .14).3

“[There was] no difference in median OS and equivalent pulmonary and esophageal toxicity [in CONVERT],” Curran said. “My view right now is we don’t really need to do any more fractionation studies in LS-SCLC. We beat that horse to death, and the reality is, you could do a single fraction per day [over] 6 or 7 weeks, or the Turrisi regimen, with similar expectancy. How do we build on that platform?”

Other Ways to Improve Radiotherapy in SCLC

Although Curran said studies looking at different fractionations may no longer be necessary, he explained that radiotherapy methods can still be improved to bolster outcomes in SCLC.

“Intensity-modulated radiotherapy is already in use in SCLC—it is really the standard of care for stage III non–small cell lung cancer or LS-SCLC,” he said.

Curran also highlighted other methods currently being evaluated, including proton therapy; motion management for tumors and non-targets; adaptative radiation retreatment planning; and FLASH radiotherapy. Specifically, regarding motion management, Curran detailed that this is a challenge in thoracic radiotherapy because a patient’s breathing and heartbeat could cause the tumor to shift during treatment, potentially exposing more normal tissue to radiation.

“If you have a target, let’s say inside the skull, [for example], the skull doesn’t move much with respiratory breathing, and it can be immobilized pretty easily, so [any] margin [with radiotherapy] is not because of motion or uncertainty,” Curran said. “However, that’s not the case in lung cancer [and] thoracic tumors.”

Methods to address movement management include abdominal compression, which involves the use of a device compressing the upper abdomen to limit diaphragmatic excursion. Having patients hold their breath while receiving treatment is also a consideration, although Curran raised concerns about this method. Gating radiotherapy also allows for the beam to be activated only during specific parts of the breathing cycle to allow for increased on-target delivery. With the tracking method, the beam aperture moves with target motion. Lastly, 4D planning for individual patients can be used for adaptive radiotherapy; with this approach, dose distribution is generated on a patient-specific basis to adapt to changes and motion over time.

“If you look at which of these techniques your radiation oncology colleagues might use, the most commonly used is gating,” Curran noted. “Conventional [radiotherapy] is used, but lots of normal lung gets radiotherapy if you do conventional. Breath hold is really challenging for people who are already in respiratory distress, and it creates, in my experience, a lot of anxiety for people on the table. Tracking can be done with only certain radiotherapy devices, so gating is what your colleagues probably do.”

Gating radiotherapy allows patients to breathe freely during treatment, he explained. It leads to increased delivery time, based on the percentage of the respiratory cycle during the treatment. Curran noted that coaching is recommended to establish a respiratory pattern. An image-guided approach and implanted fiducials are required for gating in order to reduce the margin.

Adaptive Planning and FLASH Radiotherapy

Adaptive planning involves adjusting treatment plans based on changes to tumor anatomy after the start of treatment. For example, Curran said if a patient started treatment with chemotherapy and radiation, an adaptive plan could be created to target the current location of the tumor in the event it decreased in size after the start of treatment.

“Adaptive planning] is not going to happen if you’re using the Turrisi regimen because the patient is done with treatment before there’s probably a chance for imaging response,” Curran said. “However, just as [adaptive planning] can be done in NSCLC treatment, it can be done [in LS-SCLC.] It can result in a reduced dose to the heart, esophagus, lungs, and smaller target bones.”

ding FLASH radiotherapy, Curran detailed that device improvements have allowed for increased levels of radiation to be delivered in a faster manner. If a device is capable of giving 40 to 120 Gy per second, a patient with LS-SCLC could receive a 60-Gy dose in one second, he said.

Along with addressing potential motion management issues, FLASH could address other challenges faced with radiotherapy in LS-SCLC.

“One of the reasons that radiotherapy results in decreased immune competency is the fact that you have a beam on for 2 minutes to the thorax [as a patient’s] circulatory system is circulating much of their blood system through it,” Curran explained. “If you’re given that same treatment in 2 seconds, the immune system—however we define it—is receiving less radiation.”

Curran concluded by noting that defining the target and non-target tissues is crucial for FLASH radiotherapy, and ongoing studies are further examining this method within the lung cancer field.

References

1. Curran W. Limited-stage small cell lung cancer 2025. Presented at: 22nd Annual Winter Lung Cancer Conference; January 31-February 2, 2025; Hollywood, FL.
2. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265-271. doi:10.1056/NEJM199901283400403
3. Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18(8):1116-1125. doi:10.1016/S1470-2045(17)30318-2