Locally advanced non-small cell lung cancer: search for the optimal radiotherapy continues

Lung cancer is a leading cause of death worldwide. Although immune checkpoint inhibitors (ICI) have improved the prognosis of unresectable locally advanced non-small cell lung cancer (LA-NSCLC), the 5-year progression-free survival (PFS) rate in the PACIFIC trial is 33.1%, and the 5-year overall survival (OS) rate is 42.9% (1). With approximately 70% of the patients experiencing a relapse, better treatment strategies for concurrent chemoradiotherapy (cCRT) are needed. In the PACIFIC trial, the rate of locoregional and distant recurrence was not clearly shown; however, based on real-world data, the 2-year local recurrence-free rate was 67.5% in programmed death ligand 1-positive patients who received durvalumab after cCRT versus 42.8% in patients who received cCRT alone (2). The control of recurrence in local regions was significantly associated with OS in patients with LA-NSCLC receiving CRT (3). Therefore, the control of locoregional recurrence is a very important issue.

Wu et al. reported on a non-randomized controlled trial of hypofractionated cCRT of 4 Gy × 10 fractions followed by stereotactic ablative radiotherapy (SABR) for unresectable LA-NSCLC (4). The adaptive SABR boost was immediately directed at the residual metabolically active area based on an interim ¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) at 8–9 fractions, consisting of an additional 25 Gy (low dose, 5 Gy × 5 fractions), 30 Gy (intermediate dose, 6 Gy × 5 fractions), or 35 Gy (high dose, 7 Gy × 5 fractions). The evaluation mainly focused on maximum tolerated dose (MTD) and safety. The study involved 28 patients, of which 24 (86%) had stage III disease, with a median follow-up of 18.2 months. The MTD was not exceeded, and three dose-escalation cohorts were completed. The incidence of grade 3 or higher non-hematologic toxic effects was 5 of 28 (18%). Two treatment-related deaths (7%), both due to pulmonary toxicities (one from acute pneumonitis and the other from late respiratory failure), occurred in the high-dose cohort. Thus, the mortality was 2 out of 9 (22%) in the high-dose cohort. In the low-dose cohort, one grade 3 bronchial stenosis and one grade 3 esophageal stenosis occurred. No grade 3 or higher toxicities were observed in the intermediate-dose cohort. The 2-year local control rates were 74.1%, 85.7%, and 100.0% for the low, intermediate, and high-dose cohorts, respectively. The 2-year OS rates were 30.0%, 76.2%, and 55.6% for the low, intermediate, and high-dose cohorts, respectively.

High biologically effective dose (BED), ranging from 93.5 Gy (with α/β =10 for tumor tissue) to 116 Gy, which was completed in three weeks, were achieved through the authors' efforts in dose planning. Tumor regrowth is effectively inhibited by reducing overall treatment time. And several important features of the radiation scheme in this study should be noted. First, adaptive radiation therapy strategies using FDG-PET/CT during the treatment course to replan for SABR boost were employed. Second, the starting radiation dose was 40 Gy in 10 fractions. Finally, three sequential doses of SABR boost were administered to each cohort.

For several decades, the standard dose of cCRT for patients with LA-NSCLC has been 60 Gy in 2-Gy fractions, although many studies have been conducted to increase radiation dose to improve local control rates. RTOG 0617 did not show superiority of high-dose radiation; the 5-year OS and PFS rates in the standard dose of 60 Gy group and high dose of 70 Gy were 32.1% and 23%, and 18.3% and 13% (P=0.055), respectively (5). In that trial, factors associated with better OS were standard radiation dose, tumor locations away from the heart, treatment at higher volume centers, esophagitis/dysphagia score, smaller planning target volume, and the reduction of heart dose (5). Promising methods to improve radiotherapy are: using advanced irradiation technology and adapting treatment volume during treatment, using more sophisticated imaging technology to precisely define the area to be irradiated, and increasing the individual dose to the tumor while reducing that to adjacent normal organs. Irradiation and imaging techniques continue to be developed to increase the dose to lesions and minimize it to normal organs, such as four-dimensional CT, intensity-modulated radiation therapy, volumetric modulated arc therapy, and advanced image-guided radiation therapy with cone-beam CT (6). For adaptive radiation therapy during treatment courses, CT imaging, magnetic resonance imaging, or FDG-PET/CT have reportedly been used (7). FDG-PET is also recommended for initial planning of the radiation field for LA-NSCLC (8). The mid-treatment adaptive radiotherapy approach using FDG-PET/CT reassessment significantly increases tumor dose and reduces complications in normal tissues (9). PET-assessed metabolic shrinkage is greater than CT-assessed anatomic shrinkage (10). Re-evaluating radiation dose with PET-CT allows targeting of the remaining aggressive areas without increasing toxicity. In the study by Wu et al., the median percentage of residual FDG-active tumor volume was 83.3% at the time of interim FDG-PET/CT, and equieffective doses at 2 Gy per fraction (EQD2) was 86.7 Gy of intermediate-dose cohort. Target volume reductions of 20–40% have been reported when evaluated with PET-CT following 40–60 Gy of conventional radiotherapy (9,11). However, how much the target volume should be reduced at interim evaluation remains unclear. Based on previous studies, Wu et al. hypothesized a 20–30% reduction in the target volume following the initial dose. Assessment after 8–9 fractions revealed that the actual target volume reduction approximated this hypothesis, albeit slightly lower than anticipated (4). A phase 2 single-arm study demonstrated that adaptive radiotherapy-escalated radiation dose to the mid-treatment FDG-PET-avid region (up to a total dose of 86 Gy in 30 daily fractions) resulted in a median EQD2 of 90 Gy. In-field local control at two years was 82%, and 2-year PFS was 31% [Kong et al., (12)]. However, the subsequent randomized phase 2 trial did not show an improvement in the primary endpoint of 2-year locoregional PFS (59.5% vs. 54.6%, P=0.66) [RTOG 1106, (13)]. An exploratory analysis of 2-year in-field local control was 75.6% for the adaptive RT group and 58.5% for the standard RT group. Two-year in-field control is favorable among these three trials investigating dose-escalated radiotherapy with reassessment radiation with FDG-PET/CT: 85.7% (in the intermediate-dose cohort by Wu et al.), 82% (Kong et al.), and 75.6% (RTOG 1106). However, no randomized controlled trial has confirmed the superiority of any specific technique. Biological adaptive radiotherapy using mid-treatment FDG-PET/CT is a promising strategy; however, the optimal diagnostic imaging modality and timing of indications remain unclear, as does the need for personalized radiation therapy.

Wu et al. delivered 40 Gy in 10 fractions before SABR boost. To deliver a higher BED, a higher radiation dose per fraction and a shortened course of treatment are reasonable methods (6). SABR has demonstrated superior local control and OS outcomes compared to conventional fractionated non-ablative regimens in treating early-stage NSCLC (14). However, a randomized phase 3 trial of radiotherapy with 60 Gy in 15 fractions did not show improved OS and revealed increased grade 2 toxicities compared to 60 Gy in 30 fractions for patients with stage II or III NSCLC ineligible for cCRT (15). In an exploratory analysis of a limited number of patients from the primary enrolling site, a trend of improved local control and distant metastasis was observed in the hypofractionated group. Relatively low toxicities influenced the outcomes of the patient population with poor performance status. Most toxicities were related to the organs at risk, including the esophagus. While hypofractionated radiation therapy is promising, further research is required to establish its advisability and determine the optimal dose per fraction in LA-NSCLC.

Wu et al. delivered an additional SABR boost of 25, 30, or 35 Gy (five fractions in each cohort). SABR or higher dose per fraction to central/ultracentral tumors are potentially fatal. The toxicities include central airway necrosis, tracheoesophageal fistulas, and bronchopulmonary hemorrhage. Central tumors are often defined as tumors within 2 cm of the trachea or proximal bronchial tree, and central tumors are further subdivided into central and ultracentral tumors. Ultracentral tumors are defined as tumors adjacent to the trachea or proximal bronchial tree (16). The systematic review and meta-analysis of SABR to ultracentral tumors published by the International Stereotactic Radiosurgery Society demonstrated that severe toxicity was generally low, with a 6% risk of grade 3 or 4 toxicity, predominantly related to pneumonitis. Grade 5 toxicity was 4%, with most events (58%) owing to hemoptysis (16). The report by Wu et al. did not provide details on the percentage of patients with central/ultracentral tumors. As most patients had N2 or N3 lymph node metastases, most of them were also likely to have had central/ultracentral disease. Five of 28 patients experienced grade 3 or higher toxicities. There was one case of grade 3 bronchial stenosis and one esophageal stenosis that occurred in the low-dose cohort, and one radiation dermatitis and sepsis occurred in high-dose events. Grade 5 pulmonary toxicities occurred only in the high-dose cohort (75 Gy), and no grade 3 or higher toxicities occurred in the intermediate-dose cohort (70 Gy). Therefore, the authors concluded that patients treated with 70 Gy in 15 fractions had the most promising therapeutic effects and a favorable toxicity profile. Due to the high mortality (22%) in the high-dose cohort, the very high radiation dose is not applicable to routine clinical practice. The extremely high radiation dose would not be applicable to large tumors or those adjacent to mediastinal structures because of the critical organ damage. The optimal dose and scheme of fractionation are unknown because of the limited sample size. The International Stereotactic Radiosurgery Society recommends that doses of 60 Gy/8 fractions or 60 Gy/15 fractions may be appropriate for ultracentric tumors based on the systematic review (16). There are several early-phase studies investigating the efficacy of SABR boost after cCRT (17,18). Reported local control rates are favorable; however, there are many varieties of SABR doses, fractions, and radiation regimens of cCRT. Another possible therapeutic method of SABR was examined in a study; this method has demonstrated early efficacy and safety of SABR to the primary tumor followed by conventional fractionated cCRT to the involved lymph nodes, and a phase 3 NRG LU-008 trial evaluating this regimen is ongoing (19). It is difficult to draw conclusions from varying radiation methodologies among multiple studies, and results from larger studies are awaited.

Wu et al.’s study had several limitations. First, this study was conducted before durvalumab consolidation therapy was approved, and only one patient was treated with ICI consolidation therapy. Therefore, the efficacy and safety of ICI consolidation were not evaluated. It is unclear whether ICI can be administrated after radiotherapy proposed by Wu et al. Second, most patients (86%) in the Wu et al. study had unresectable stage III disease, but also included stage II patients who refused surgery, which differs from the PACIFIC study in which all patients had unresectable stage III disease. Differences in patient backgrounds may affect the evaluation of treatment efficacy.

Despite improvements in local control owing to advancements in radiotherapy, further progress in improving survival outcomes for LA-NSCLC remains a critical clinical need. Synergistic effects of the ICI combination with SABR or hypofractionated radiation therapy are expected in this context. In a phase 2 trial, the addition of nivolumab to SABR for patients with NSCLC with early-stage or isolated lung recurrence without lymph node metastasis has been reported to improve 4-year event-free survival and tolerable toxicity (20). For the LA-NSCLC, a small phase 2 single arm study of durvalumab with consolidation SABR following cCRT was performed (NCT03589547). Another phase 2 trial is ongoing to evaluate two radiation regimens combining durvalumab with either conventional fractionated radiotherapy or hypofractionated radiotherapy (55 Gy in 20 fractions) in patients with stage III NSCLC who are ineligible for chemotherapy to investigate the efficacy and toxicities of immunomodulation for hypofractionated radiotherapy (21). To date, no completed clinical trial has specifically evaluated the combination of ICI and SABR or hypofractionated radiation therapy for LA-NSCLC (22). Therefore, the results of these ongoing clinical trials are eagerly anticipated, as they are crucial for elucidating the efficacy and safety profile of this combination therapy.

In conclusion, further multidisciplinary research is needed to determine the best strategy to optimize individual treatment for patients with LA-NSCLC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1716/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1716/coif). M.T. reports that she has received grants from AstraZeneca K.K. and received honoraria as a speaker from AstraZeneca K.K.. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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