Modern radiotherapy in inoperable locally advanced non-small cell lung cancer: a review of techniques, dose fractionation, and immuno-synergistic strategies

Introduction

According to the latest global cancer statistics published in CA: A Cancer Journal for Clinicians, lung cancer is the leading cause of both new cases and deaths globally (1). Non-small cell lung cancer (NSCLC) makes up 85% of all lung cancer cases (2). Around 20–30% of NSCLC patients are diagnosed at the locally advanced stage, known as American Joint Committee on Cancer (AJCC) Stage III and are ineligible for curative surgery due to tumor invasiveness or comorbidities (3). Concurrent chemoradiotherapy (CCRT) remains the cornerstone treatment for these patients. However, the treatment effect remains unsatisfactory, achieving an overall survival rate of 32.1% over a 5-year period (4). Following the PACIFIC trial, locally advanced non-small cell lung cancer (LA-NSCLC) treatment has entered the era of immunotherapy, with the current standard of care being CCRT followed by durvalumab consolidation therapy (5).

Locoregional progression was found to be significantly linked to decreased survival in a study conducted by the Radiation Therapy Oncology Group (RTOG) analyzing seven chemoradiotherapy (CRT) trials (6). Even in the immunotherapy era, locoregional failure rates remain as high as 38.5%, underscoring that local recurrence remains the foremost challenge in radiotherapy for NSCLC (7). Consequently, improving radiation techniques and dose strategies to reduce local recurrence rates is a key research priority.

Traditional radiotherapy has reached a therapeutic plateau, while intensity-modulated radiotherapy (IMRT) and stereotactic body radiotherapy (SBRT) have enhanced precision and safety. Emerging technologies such as particle therapy and brachytherapy (BT) also show significant potential. Key challenges in radiotherapy for LA-NSCLC include rational selection of radiation modalities, optimization of target dose, refinement of fractionation schemes, and identification of optimal immunotherapy integration strategies. This review summarizes recent advances in radiotherapy techniques, dose strategies, and immunoradiation synergy for LA-NSCLC, aiming to inform clinical practice and future research.

Radiation techniques

IMRT

Compared to three-dimensional conformal radiotherapy (3D-CRT), IMRT utilizes inverse optimization and intensity modulation to achieve more conformal dose distributions. This technique enhances dose coverage of the primary tumor and involved lymph nodes while minimizing radiation exposure to organs at risk (OARs) (8). However, IMRT may increase low-dose radiation exposure to lung tissue, leading to elevated lung V5 but reduced V20, raising concerns about radiation pneumonitis (RP) and lymphopenia (9). Additionally, IMRT does not address respiratory motion-induced dose inaccuracies (10). Nevertheless, secondary analyses and long-term outcomes from the prospective RTOG 0617 trial demonstrated that lung V5 does not have any correlation with survival or predict toxicity, while lung V20 is associated with a higher likelihood of grade ≥3 pneumonitis (P=0.026) (11,12). RTOG 0617 also identified cardiac radiation dose as a critical survival predictor (13), with long-term follow-up confirming that IMRT significantly reduces cardiac V40 compared to 3D-CRT (16.5% vs. 20.5%, P<0.001) (12). Dess et al. further reported that IMRT reduces cardiac V30 and V50 (14).

Multiple retrospective studies support the clinical value of IMRT (15,16). For example, a study from Memorial Sloan Kettering Cancer Center reported a 2-year overall survival (OS) of 58% and median survival of 25 months in Stage III patients, suggesting favorable outcomes with IMRT compared to historical controls (15). While most comparative trials between 3D-CRT and IMRT are retrospective, and some meta-analyses indicate no significant survival differences (17) or similar esophageal and pulmonary toxicities (18), current evidence predominantly favors IMRT. Yom et al. evaluated 290 NSCLC patients (89% stage III) treated between August 2002 and August 2005, including 68 receiving IMRT and 222 receiving 3D-CRT. As a result, it was found that although the tumor volume in the IMRT group was larger, the incidence of treatment-related pneumonitis of grade 3 or above in the IMRT group was only 8%, while in the 3D-CRT group it was as high as 32% (P=0.002) (19). Similarly, Liao et al. reported reduced rates of grade ≥3 incidence of treatment-related pneumonitis with IMRT (20).

These retrospective findings prompted a secondary analysis of the large prospective RTOG 0617 trial, comparing IMRT (47% of 482 patients) with 3D-CRT (53%). Although IMRT-treated patients had larger tumors and a higher proportion of Stage IIIB disease, survival outcomes were comparable. Notably, IMRT was associated with lower rates of grade 3 pneumonitis (7.9% vs. 3.5%, P=0.039) (11). The latest long-term follow-up revealed superior 5-year OS with IMRT (30.8% vs. 24.6%) and a twofold reduction in grade ≥3 pneumonitis (3.5% vs. 8.2%, P=0.03) (12), providing strong evidence for IMRT’s superiority over 3D-CRT in clinical practice.

In summary, current data suggest that IMRT enables improved survival outcomes—or at least non-inferiority—compared to 3D-CRT in patients with larger, more complex tumors or compromised performance status, while reducing toxicity to critical organs like the heart and lungs. IMRT has thus become the cornerstone technique for LA-NSCLC treatment.

In the immunotherapy era, researchers are exploring the synergistic potential of IMRT with immune checkpoint inhibitors. A retrospective study by Tsukita et al. reported a grade ≥3 pneumonitis rate of only 7.4% with IMRT combined with durvalumab, alongside a 1-year progression-free survival (PFS) of 70.5%—higher than the PACIFIC trial’s 55.9%—highlighting its immunomodulatory promise (21). The ongoing prospective WJOG12019L trial recently reported promising 2-year results, showing 2-year PFS and OS rates of 44% and 73%, respectively. Half of the patients completed one year of durvalumab therapy, with no treatment-related deaths or grade 4 non-hematologic adverse events observed. Notably, a Japanese study comparing IMRT and 3D-CRT with concurrent chemoimmunotherapy revealed significantly lower cumulative incidence of grade ≥2 RP with IMRT (27.0% vs. 64.0%, P=0.013) (22).

SBRT

SBRT is a high-precision technique that delivers ablative radiation doses to tumors. Typically administered in 1–5 fractions, SBRT achieves a higher biologically effective dose (BED), improving local control (LC) and OS. However, for LA-NSCLC with mediastinal lymph node involvement, the single-fraction high-dose regimen may increase toxicity risks to adjacent structures like the esophagus or bronchi, necessitating meticulous target delineation (23). Although SBRT is the standard of care for inoperable early-stage NSCLC (24), its application in LA-NSCLC is limited by larger tumor volumes and central lesions adjacent to OARs. Additionally, SBRT carries a 19% risk of rib fracture (25), and its role in bulky thoracic tumors (e.g., LA-NSCLC) remains uncertain due to proximity to critical structures. Respiratory motion further complicates dose accuracy in SBRT (26). Current research on SBRT for LA-NSCLC explores three strategies: (I) SBRT boost after CRT; (II) upfront SBRT followed by CRT; and (III) SBRT replacing conventional radiotherapy with concurrent CRT to mediastinal lymph nodes (MLNs) (summarized in Table 1).

Using SBRT as a boost after conventional CRT is the most studied approach. Multiple trials (Table 1) demonstrate that SBRT boosts post-CRT improve LC but require caution due to fatal bleeding risks at higher doses, as reported by Hepel et al. (one grade 5 event) (27-33). Higgins et al. conducted a phase I dose-escalation study delivering 44 Gy in 22 fractions of CRT followed by an SBRT boost of 18–20 Gy in 2 fractions or 30–35 Gy in 5 fractions. Three dose-limiting toxicities were observed, with 10 Gy × 2 fractions (total BED₁₀ =92.8 Gy, assuming α/β =10) identified as the optimal regimen (31). Similarly, Wu et al. administered CRT (4 Gy × 10 fractions) followed by an SBRT boost of 25–35 Gy in 5 fractions. LC improved with dose escalation, but two grade 5 events occurred in the high-dose group (total BED₁₀ =115.5 Gy). The intermediate-dose group (total BED₁₀ =104 Gy) achieved the highest 2-year OS (76.2%), suggesting 70 Gy in 15 fractions as the preferred regimen (33). Feddock et al. treated residual tumors (<5 cm) post-CRT (59.4–60 Gy) with a 19.5–20 Gy SBRT boost in 2 fractions (maximum BED₁₀ =112 Gy). The findings of the study revealed that 11.4% of patients developed grade 3 RP in the acute phase, with 2.9% experiencing it in the late phase. Long-term follow-up data showed a crude LC rate of 78% for the entire group, with a median OS of 25.2 months. However, 65% of patients developed metastatic disease, and 29% experienced regional recurrence. Late toxicities included grade 3 RP in 11.9% of patients and late hemoptysis in 5.7% (27,29).

Williams et al. adopted a novel sequence, administering a 12 Gy × 2 fraction SBRT boost to the primary tumor followed by standard CRT (2 Gy × 30 fraction, total BED₁₀ =91.2 Gy) for Stage III NSCLC. This approach aimed to rapidly debulk the primary tumor and minimize SBRT-chemotherapy interactions. Only one grade 4 non-hematologic toxicity occurred, suggesting improved safety. Primary tumor control rates were 100% at 1 year and 92.3% at 2 years, though 2-year OS (50.3%) lagged behind PACIFIC trial outcomes. The results highlight the feasibility of upfront SBRT, warranting further investigation (34).

Across SBRT boost studies, the median CRT dose was 47.8 Gy (range, 10–28 fractions), with a median boost dose of 25.3 Gy (2–5 fractions). A total BED₁₀ of 90–105 Gy is recommended to balance efficacy and toxicity.

Combining SBRT for the primary tumor with conventional radiotherapy to MLNs (“SBRT + MLN”) has emerged as a promising alternative (35,36). Heinzerling et al. conducted a phase II multicenter single arm trial delivering SBRT (50–54 Gy in 3–5 fractions) to the primary tumor followed by 60 Gy in 2 Gy fractions to MLNs. Grade ≥3 pneumonitis occurred in 5% of patients, with 1.7% experiencing grade 3 esophagitis. The 2-year LC was 96.3%, demonstrating excellent LC. The 1-year PFS was 62.7%. Although the study did not meet its primary endpoint, the subgroup of patients who met PACIFIC criteria and received durvalumab consolidation achieved a superior 1-year PFS of 69.6% compared to 55.7% in the PACIFIC trial (36,37). These findings prompted the phase III LU-008 trial (NCT05624996), which will randomize 474 patients to compare this approach with standard CRT (38).

As demonstrated by Heinzerling et al., the subgroup receiving durvalumab consolidation within this protocol achieved a 1-year PFS of 69.6%, providing important clinical evidence for the synergistic effect between SBRT and immunotherapy. Current evidence suggests that SBRT may be more effective than conventional radiotherapy in activating systemic anti-tumor immune responses (39). Based on this rationale, multiple clinical investigations are actively underway: Wu et al. reported a case with only grade 2 acute esophagitis and no late toxicities (33). Coutu et al. designed a phase I/II trial evaluating SBRT with concurrent durvalumab for residual tumors post-definitive CRT, demonstrating preliminary safety and synergy (40). With the continued development of these studies, we anticipate that future evidence will provide definitive guidance for optimizing the clinical application of SBRT combined with immunotherapy.

SBRT shows promise in LA-NSCLC, particularly for patients ineligible for CRT. The ongoing phase III LU-008 trial will validate its potential to replace conventional radiotherapy.

While optimal dosing remains undefined and OAR constraints are critical, SBRT offers a viable option for select patients. Emerging integration with adaptive radiotherapy may further refine its application.

Particle therapy

Particle therapy (including proton and carbon ion modalities) leverages the Bragg peak characteristic of charged particles to deliver high tumoricidal doses while sparing adjacent normal tissues, demonstrating superior dose distribution compared to conventional photon radiotherapy. The absorbed dose remains relatively constant along most of the particle trajectory, culminating in a sharp dose peak (Bragg peak) at the end of the particle range (41), enabling maximal protection of OARs such as heart, lungs, and spinal cord (42).

Proton therapy (PT) exhibits a relative biological effectiveness (RBE) of 1.1, which is comparable to photons (43). Its physical properties allow for reduced radiation doses to the heart and its substructures, potentially lowering the risk of cardiac toxicity (44). Liao et al. reported a significantly lower mean cardiac dose with PT (5.9 Gy) versus photons (10.1 Gy, P=0.002) (45). Additionally, PT may mitigate hematologic toxicity. Studies identify thoracic vertebral V5, aortic V5, and lung V5–V50 as independent predictors of severe radiation-induced lymphopenia (46). In the immunotherapy era, PT’s ability to spare lymphocytes—critical for antitumor immunity, —warrants particular attention. However, PT’s limitations hinder its widespread adoption in LA-NSCLC. First, PT is more sensitive to anatomical uncertainties (e.g., density changes, respiratory motion) than photon therapy (47). Second, PT incurs substantially higher costs, with facility investments (€94.9 million vs. €23.4 million) and per-fraction expenses (€743 vs. €233) exceeding photon therapy by over fourfold (48).

Several non-randomized studies, building upon these theoretical advantages, have explored the role of PT in LA-NSCLC and reported favorable outcomes (49,50). In Chang et al.’s phase II prospective study, Stage III patients receiving 74 Gy (RBE) achieved a median OS of 26.5 months (51,52), surpassing the 20.3-month OS in the RTOG 0617 74 Gy photon cohort. Five-year OS was 29%, with lower toxicity (≥ grade 3 pulmonary complications: 12% vs. 20%; ≥ grade 3 esophagitis: 11% vs. 21%) (4). Nguyen et al.’s prospective trial corroborated these findings, reporting a median OS of 30.4 months and favorable safety (one Grade 4 esophagitis, 16 grade 3 events) (53).

However, a large-scale retrospective analysis of the National Cancer Database suggested that PT might be associated with improved survival; however, after propensity score matching, the difference in OS between the two groups did not reach statistical significance (54). More importantly, a randomized controlled trial conducted by MD Anderson Cancer Center fundamentally challenged this potential advantage. A phase II randomized trial by Liao et al. directly compared passive-scattering proton therapy (PSPT) with IMRT and found no significant differences in the primary endpoints of grade ≥3 RP (10.5% vs. 6.5%) or local failure (10.5% vs. 10.9%) (45). The trial investigators analyzed that the reasons may include the following: First, as a 3D conformal technique, PSPT requires larger safety margins due to physical uncertainties of the proton beam, which led to a reduction in low-dose lung irradiation volumes (V5–V10) but simultaneously significantly increased medium- to high-dose volumes (V20–V80). This unfavorable dosimetric trade-off directly explains why PSPT failed to significantly reduce the incidence of pneumonitis. Second, during the trial period, IMRT technology advanced rapidly with the introduction of automated optimization systems, while PSPT technology progressed relatively slowly, partly due to its high cost, further diminishing its competitiveness. Moreover, traditional photon-based dose-volume constraints may not be fully applicable to the distinct dose distribution characteristics of PSPT. It is noteworthy that although PSPT demonstrated clear dosimetric advantages in cardiac protection, this was not a pre-specified primary endpoint of the trial.

It is particularly important to note that the PSPT technology used in this trial does not represent the most advanced form of PT. The next-generation intensity-modulated proton therapy (IMPT), which utilizes pencil-beam scanning, can achieve more precise dose distributions and is expected to overcome the technical limitations of PSPT (55).

Current research on the next-generation IMPT technology is primarily based on retrospective data. A retrospective study by Nathan et al. comparing IMPT and IMRT in 79 LA-NSCLC patients found similar 1-year OS (68% vs. 65%, P=0.87), despite IMPT patients having worse baseline characteristics (median age 76 vs. 69 years, P<0.01) (56). Subsequent analyses revealed IMPT’s association with reduced ≥ grade 3 pneumonitis [hazard ratio (HR) 0.25, P=0.04] and cardiac events (HR 0.33, P=0.08), highlighting its safety profile (57). However, the level of evidence remains limited. Therefore, the ongoing phase III RTOG 1308 trial (NCT01993810) aims to compare IMPT with IMRT, with overall survival as the primary endpoint and cardiac toxicity assessment as an important secondary objective. The results of this trial will provide crucial level I evidence regarding the clinical value of IMPT.

In the immunotherapy era, the potential synergy between PT and immune checkpoint inhibitors is underpinned by its capacity to mitigate radiation-induced lymphopenia. A retrospective analysis demonstrated a significantly lower effective dose to immune cells (EDIC) with IMPT compared to IMRT (3.04 vs. 4.99 Gy, P<0.001) (58), a factor independently predictive of overall survival and disease control in LA-NSCLC (59). Corroborating these findings, Iocolano et al. reported that PT was associated with fewer unplanned hospitalizations (P=0.002) and a reduced incidence of ≥ grade 3 lymphopenia (P=0.003) (60), highlighting its clinical relevance in preserving immune competence during combinatory treatment.

PT offers dosimetric advantages for cardiac protection but has not demonstrated clear clinical superiority over IMRT in survival or toxicity outcomes. Given its substantially higher costs and technical limitations, the value of PT remains unproven. Definitive assessment of its clinical potential awaits results from trials such as RTOG 1308.

Carbon ion beams, characterized by high linear energy transfer (LET) and a RBE of 2.5–3.0 (61), induce predominantly DNA double-strand breaks in tumors, offering a distinct advantage over photon and proton therapies, which primarily cause single-strand breaks (62). Additionally, carbon ions exhibit reduced oxygen dependency, exerting stronger cytotoxicity against hypoxic cell (63). However, uncertainties in RBE estimation, limit their clinical application, as the radiobiological impact on normal tissues remains incompletely understood, and tumor LET distribution is heterogeneous. Furthermore, akin to external beam radiotherapy, carbon ion radiotherapy (CIRT) does not resolve respiratory motion challenges. Clinically, CIRT systems are bulky, inflexible, and cost-prohibitive—up to five times more expensive than photon therapy (64).

CIRT has demonstrated favorable LC and safety in early-stage (I) NSCLC (65,66). For LA-NSCLC, evidence remains sparse and largely retrospective. A prospective sequential phase I/II trial enrolled patients with stage IIA–IIIA LA-NSCLC. In the phase I dose-escalation study, doses were incremented in 4 Gy steps (68–72–76 Gy RBE). The 72 Gy RBE regimen delivered in 16 fractions was well-tolerated, with no severe toxicities. In phase II, 26 patients receiving 72 Gy RBE experienced no ≥ grade 3 toxicity. The cohort achieved 2-year LC and OS rates of 93.1% and 51.9%, respectively (67). A hypofractionated protocol (54 Gy RBE in 4 Gy fractions) from Gunma University also reported promising outcomes (68). Retrospective analyses suggest CIRT may outperform photon radiotherapy in ≥ grade 3 toxicity profiles, particularly for elderly patients or those with severe comorbidities (69,70). In the immunotherapy era, the combination of PACIFIC-regimen durvalumab with CIRT—potentially enhanced by carbon ions’ superior immunostimulatory effects compared to photons—holds promise for LA-NSCLC, warranting further investigation.

BT

BT achieves localized dose escalation through direct radioactive source implantation or tumor proximity, offering superior normal tissue sparing compared to external beam radiotherapy (EBRT) due to its physical dose gradient characteristics. In LA-NSCLC, primary BT modalities include high-dose-rate interstitial brachytherapy (HDR-BT) and iodine-125 seed implantation (I125-IBT) (71).

HDR-BT employs afterloading techniques to temporarily position radioactive sources (e.g., iridium-192) within tumor tissue (72), gaining attention for its minimally invasive nature and low complication rates. Its safety and efficacy have been validated across LA-NSCLC applications. In LA-NSCLC, HDR-BT primarily serves as a boost modality following standard CCRT. A Goethe University Frankfurt retrospective analysis of 16 stage III patients receiving 45–50 Gy CCRT plus 15 Gy HDR-BT boost reported 1-/3-year median OS rates of 56.2% and 12.5%, with LC rates of 68.9% and 43%, respectively—outcomes comparable to historical data (73). A case report utilizing 12 Gy single-fraction HDR-BT boost achieved complete tumor remission (74).

A prospective phase I/II trial evaluated HDR-BT as an alternative to conventional radiotherapy. A total of 26 patients were enrolled in the phase I trial. HDR-BT was administered to the primary lung foci at a single dose of 30 Gy (BED =120 Gy). IMRT was used to irradiate regional lymph nodes at a total dose of at least 70 Gy at 2.0–2.2 Gy per day. Synchronized or sequential chemotherapy was received as appropriate. The results showed that the median OS was 22.5 months, with 1- and 2-year OS rates of 90.9% and 67%, respectively (75). The phase II clinical trial involved 83 patients and resulted in a 5-year OS rate of 44.5% and a median OS of 38.0 months. Grade 3 acute esophagitis was observed in 5.3% of patients. No grade ≥3 acute pneumonitis or grade ≥2 late radiotherapy-related adverse events were reported., demonstrating favorable survival and low toxicity for HDR-BT with regional IMRT (76). These findings prompted initiation of a phase III multicenter RCT investigating HDR-BT as a radical radiotherapy replacement combined with nodal IMRT. This innovative approach leverages intratumoral source implantation with respiratory synchronization to eliminate motion uncertainty, while single-fraction eliminates setup errors. Cost analyses indicate 90% savings versus PT, though procedure-related risks (e.g., pneumothorax, hemorrhage) require consideration (77).

I125-IBT is utilized alone or in conjunction with other modalities for inoperable advanced NSCLC or localized recurrence post-surgery/chemoradiation (78). Studies have shown improved survival and quality of life with I125-IBT plus chemotherapy compared to conventional therapy (79). Additionally, combined I125-IBT and EBRT have shown promise in elderly LA-NSCLC patients with chest wall invasion, achieving a 1-year objective response of 71.4% and disease control rates of 90.5% without Grade >2 toxicity (80). However, a randomized trial found only modest symptom relief with I125-IBT + EBRT versus EBRT alone, lacking statistical significance (81). Clinical adoption is limited by risks of seed migration, vascular injury, prolonged radiation exposure, and insufficient data from small retrospective studies. The frequent nodal involvement of LA-NSCLC further restricts its utility, necessitating phase III validation.

Sui et al. reported three NSCLC patients (two stage III, one stage IV) treated with I125-IBT followed by anti-PD-1 therapy, achieving complete or partial responses without significant toxicity. While suggestive of synergy, larger trials are needed (82).

Current evidence suggests that HDR-BT may be an alternative treatment for LA-NSCLC, offering the potential to overcome treatment challenges. However, phase III comparisons against standard IMRT are needed to further investigate its effectiveness. I125-IBT is not recommended for routine LA-NSCLC management due to unproven survival benefits and safety risks. Future research should prioritize investigating HDR-BT-immunotherapy combinations and optimizing multimodal strategies.

The selection of radiotherapy techniques for LA-NSCLC requires evaluation by a multidisciplinary team. IMRT serves as the foundational technique for most patients, supported by high-level evidence and superior dose conformity. Particle therapy (protons/carbon ions) is suitable for elderly patients or those with severe comorbidities who cannot undergo standard CRT. SBRT, while established for early-stage disease, remains primarily investigational in the LA-NSCLC setting through clinical trials exploring dose escalation strategies. HDR-BT offers a potential alternative for delivering radical doses to carefully selected patients with peripheral lung tumors. A systematic comparison of these techniques is presented in Table 2.

Dose and fractionation

During the traditional period of radiotherapy, the typical dose for inoperable LA-NSCLC was 60–63 Gy given in daily fractions of 1.8–2.0 Gy. Despite this, suboptimal outcomes persisted, with local recurrence remaining a significant barrier to long-term survival. Analysis of 11 RTOG CRT trials revealed that each 1 Gy increase in BED improved LC by 3% and survival by 4% (83). The achievement of a BED exceeding 100 Gy resulted in LC rates exceeding 80% (84), prompting the exploration of dose escalation studies within conventional fractionation frameworks.

Early phase I/II trials investigated conventional fractionation dose escalation, leading to the landmark RTOG 0617 trial. However, the 74 Gy arm showed inferior survival compared to 60 Gy (5-year OS: 23% vs. 32.1%, P=0.055) (13), attributed to prolonged treatment duration and increased cardiac toxicity. Additional studies confirmed that there were limited overall survival benefits beyond 70 Gy (85), highlighting the challenges of traditional dose escalation approaches. Anatomic complexity of LA-NSCLC tumors and nodal involvement further complicates dose delivery, particularly for central lesions. The anatomic complexity of LA-NSCLC tumors and nodal involvement further complicates the delivery of optimal radiation doses, especially for central lesions. As a result, there has been a shift in focus towards altered fractionation techniques such as hyperfractionation [lower per-fraction doses (<1.8–2.0 Gy), multiple daily fractions with ≥6-hour intervals, and similar or reduced total treatment time] and hypofractionation [higher per-fraction doses (>2.0 Gy), fewer fractions, and/or shortened treatment duration] (86).

Hyperfractionated radiotherapy

The goal of hyperfractionated radiotherapy is to reduce the overall treatment time in order to counteract tumor repopulation. The CHART trial compared conventional radiotherapy (2 Gy × 30 fraction) with hyperfractionation (1.5 Gy × 36 fraction), demonstrating a 24% reduction in mortality risk (HR =0.89; P=0.02) and 9% survival improvement (P=0.004) (87). A meta-analysis further supported hyperfractionation’s survival benefit :12% mortality reduction; 3- and 5-year OS gains of 3.8% and 2.5%, (HR =0.88; P=0.009) but highlighted significantly increased acute esophagitis (P<0.001) (88). Despite potential efficacy, hyperfractionation’s toxicity burden and logistical challenges (e.g., weekend treatments) limit its adoption. The modified CHARTWEL trial, omitting weekend fractions, showed no survival difference (5-year OS: 11% vs. 7%; HR =0.92, P=0.43) (89), with other trials similarly failing to confirm superiority (90). Thus, hyperfractionation remains non-standard.

Hypofractionated radiotherapy

Hypofractionated radiotherapy is primarily utilized in the treatment of early-stage NSCLC, particularly through SBRT, which has shown improved survival outcomes in comparison to traditional fractionation methods (24). By increasing the BED through higher single doses, hypofractionated radiotherapy helps to inhibit tumor cell regrowth (86). Moreover, the reduced number of treatment sessions can alleviate the financial burden on patients. Nevertheless, safety remains a concern for LA-NSCLC, as hypofractionated radiotherapy may lead to increased toxicity in mediastinal regions.

Prospective clinical studies are certainly strong evidence of this. Relevant studies in recent years have shown that the risk of toxicity of hypofractionated radiotherapy in the context of synchronized radiotherapy needs to be carefully weighed (a summary of relevant selected clinical trials in the last 5 years is presented in Table 3). A systematic evaluation showed that the incidence of grade ≥3 esophagitis was 0-8% in non-synchronous radiotherapy trials, whereas it was significantly elevated to 23.5% with synchronous radiotherapy, with a risk of pneumonia of 11.8% (97). The only prospective randomized controlled trial recruited 103 patients comparing hypofractionation (4 Gy × 15 fraction) with conventional fractionation (2 Gy × 30 fraction). The trial was stopped early due to lack of efficacy during the interim analysis. The difference in 1-year overall survival was not statistically significant; therefore, hypofractionation was not found to be superior to conventional fractionation. This could be attributed to the lower BED in the image-guided radiotherapy (IGRT) group (84 Gy <100 Gy, which is still less than the equivalent dose of concurrent radiotherapy). Consequently, further large-scale phase III trials are necessary to confirm these findings (95).

Studies have utilized 3D-CRT and IMRT, however, the incidence of toxicity remains high, including grade 5 events (92-94). In an effort to balance efficacy and toxicity, researchers have explored the use of advanced radiotherapy techniques in conjunction with hypofractionated treatment. Prospective phase I-II studies have indicated that hypofractionated combined proton radiotherapy is well tolerated. For instance, Hope et al. discovered that hypofractionated PT at a dose of 2.5–3.53 Gy totaling 60 Gy per session, along with concurrent chemotherapy, led to promising survival rates. The 1- and 3-year OS rates were 89% and 49%, respectively, with no acute grade ≥3 esophagitis reported (91,96). Similarly, carbon ions in combination with hypofractionated radiotherapy have shown favorable outcomes, with 2-year LC and OS rates of 93.1% and 51.9%, respectively (67).

In the era of immunotherapy, there is growing interest in the consolidation of immunotherapy following low-fractionated radiotherapy. Studies have demonstrated that low-fractionated radiotherapy is more immunogenic and enhances the anti-tumor immune response compared to conventional fractionated radiotherapy (98). A phase I trial confirmed the feasibility of 60 Gy/12 fractions in combination with chemotherapy and PD-1 inhibitors, resulting in a 1-year OS rate of 94.4% without reaching the maximum tolerated fractionated dose (MTFD) (99) Several phase III trials, such as DUART and NRG LU-004, are currently investigating the synergistic effects of hypofractionated radiotherapy in combination with duvarizumab (100). However, it is important to note dose toxicity to prevent excessive damage to immune cells, with an example being EDIC >6 Gy (59).

Overall, the available evidence on the benefits of accelerated hypofractionated radiotherapy compared to conventional radiotherapy remains limited. Patients who have large tumors that are centrally situated are especially vulnerable to experiencing toxicity, which is a major concern. In the future, it is crucial for relevant clinical trials and promotional efforts to address the challenge of balancing efficacy and toxicity. One potential new direction to overcome this bottleneck is exploring the combination of immunotherapy with radiotherapy.

Immunotherapy

There exists a clear synergistic effect between radiotherapy and immunotherapy, which primarily stems from the following multiple complementary biological mechanisms: First, RT can induce immunogenic cell death, prompting tumor cells to release damage-associated molecular patterns such as ATP, HMGB1, and calreticulin, thereby functioning as an “in situ vaccine” to effectively activate dendritic cells and initiate T-cell responses (101). Second, DNA damage induced by RT triggers the activation of the cGAS-STING pathway, driving the production of type I interferons—a process that serves as a critical bridge connecting innate immunity to adaptive anti-tumor immunity (102,103). Finally, RT profoundly remodels the tumor microenvironment by upregulating MHC-I molecule expression on tumor cells to enhance antigen presentation capacity, while simultaneously stimulating tumor and stromal cells to release chemokines such as CXCL9 and CXCL10, thereby promoting T-cell infiltration and converting immunologically “cold” tumors into “hot” tumors (104,105).

The landmark PACIFIC trial and its long-term follow-up data have successfully translated the synergistic effect between radiotherapy and immunotherapy from a theoretical concept into clinical practice, shifting the research focus from “whether to combine” to “how to optimize” (37) (a summary of these clinical trials is provided in Table 4). Aspects related to radiation dose and technique have been discussed in preceding sections. Current research priorities center on optimizing treatment timing, primarily exploring the initiation timing and duration of immunotherapy. An exploratory analysis of the PACIFIC study suggested that earlier initiation of durvalumab consolidation therapy (within ≤14 days) following CCRT might provide additional clinical benefit to patients. Regarding the duration of immunotherapy consolidation, the GEMSTONE-301 trial demonstrated that two-year consolidation therapy is similarly effective (106). A meta-analysis further revealed that the 24-month overall survival rate reached 77.4% in patients receiving two-year consolidation therapy, significantly superior to the 60.7% observed in the one-year group, with comparable incidence of grade ≥3 pneumonitis between the two groups. These findings suggest that extending consolidation therapy duration may provide additional survival benefit without increasing toxicity However, current evidence regarding two-year immunotherapy consolidation remains limited, and additional clinical trials are required to establish the optimal duration of consolidation therapy (108).

Regarding the timing of immunotherapy initiation, the recent phase III PACIFIC-2 study results demonstrated that combining durvalumab concurrently from the initiation of CRT followed by continued consolidation therapy, compared with the placebo-after-CRT regimen, did not significantly improve PFS (HR 0.85, 95% CI: 0.65–1.12; P=0.247) or OS (HR 1.03, 95% CI: 0.78–1.39; P=0.823) (107). These findings further consolidate the current standard treatment paradigm—utilizing durvalumab consolidation after completing definitive CCRT—while suggesting that extending the consolidation therapy duration to two years may represent a more advantageous treatment strategy.

While establishing optimal treatment sequencing, addressing associated safety concerns—particularly the management of RP in the era of durvalumab consolidation—has become a central issue in clinical practice. Real-world studies consistently report a higher incidence of RP following consolidative immunotherapy than that observed in the PACIFIC trial, prompting the reevaluation of traditional dosimetric parameters for risk prediction (109). Available evidence indicates that although some studies have questioned the predictive value of V20 (110), most large-scale clinical investigations continue to support V20 and mean lung dose (MLD) as essential references for risk assessment (111-113). Furthermore, several studies have reported associations between other dosimetric parameters—such as V5, V10, and V40—and the risk of RP (114).

Conclusions

Although significant strides have been made in radiotherapy for inoperable LA-NSCLC over recent decades, several challenges persist. Key issues to address include local recurrence and toxicity concerns. Future research should focus on precision radiotherapy techniques, personalized treatment approaches, and combining therapy with immunotherapy. One promising approach is interstitial afterloading radiotherapy, which has the potential to deliver effective doses to target areas while sparing normal tissues. This method can also address targeting uncertainties and setup errors caused by motion. Adaptive radiotherapy, with real-time imaging guidance, offers promise for adjusting treatment plans to account for respiratory motion and tumor changes. Exploring biomarkers can help tailor therapy to individual patients, such as identifying those sensitive to radiation through monitoring ctDNA in blood or optimizing immunotherapy duration based on immune response. These advancements require more clinical trials and data analysis to improve survival rates and quality of life for inoperable LA-NSCLC patients

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1396/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1396/coif). The authors have 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. J Saller J. Boyle TA. Molecular Pathology of Lung Cancer. Cold Spring Harb Perspect Med 2022;12:a037812. [Crossref] [PubMed]
3. Rodrigues G, Higgins KA, Rimner A, et al. American Radium Society Appropriate Use Criteria for Unresectable Locally Advanced Non-Small Cell Lung Cancer. JAMA Oncol 2024;10:799-806. [Crossref] [PubMed]
4. Bradley JD, Hu C, Komaki RR, et al. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol 2020;38:706-14. [Crossref] [PubMed]
5. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
6. Machtay M, Paulus R, Moughan J, et al. Defining local-regional control and its importance in locally advanced non-small cell lung carcinoma. J Thorac Oncol 2012;7:716-22. [Crossref] [PubMed]
7. Consonni D, Pierobon M, Gail MH, et al. Lung cancer prognosis before and after recurrence in a population-based setting. J Natl Cancer Inst 2015;107:djv059. [Crossref] [PubMed]
8. Grills IS, Yan D, Martinez AA, et al. Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys 2003;57:875-90. [Crossref] [PubMed]
9. Tang C, Liao Z, Gomez D, et al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys 2014;89:1084-91. [Crossref] [PubMed]
10. Schwarz M, Van der Geer J, Van Herk M, et al. Impact of geometrical uncertainties on 3D CRT and IMRT dose distributions for lung cancer treatment. Int J Radiat Oncol Biol Phys 2006;65:1260-9. [Crossref] [PubMed]
11. Chun SG, Hu C, Choy H, et al. Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial. J Clin Oncol 2017;35:56-62. [Crossref] [PubMed]
12. Chun SG, Hu C, Komaki RU, et al. Long-Term Prospective Outcomes of Intensity Modulated Radiotherapy for Locally Advanced Lung Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 2024;10:1111-5. [Crossref] [PubMed]
13. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-99. [Crossref] [PubMed]
14. Dess RT, Sun Y, Muenz DG, et al. Cardiac Dose in Locally Advanced Lung Cancer: Results From a Statewide Consortium. Pract Radiat Oncol 2020;10:e27-36. [Crossref] [PubMed]
15. Sura S, Gupta V, Yorke E, et al. Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol 2008;87:17-23. [Crossref] [PubMed]
16. Le Roy T, Wallet J, Barthoulot M, et al. IMRT in the treatment of locally advanced or inoperable NSCLC in the pre-durvalumab era: clinical outcomes and pattern of relapses, experience from the Oscar Lambret Center. Front Oncol 2023;13:1236361. [Crossref] [PubMed]
17. Chen AB, Li L, Cronin A, et al. Comparative effectiveness of intensity-modulated versus 3D conformal radiation therapy among medicare patients with stage III lung cancer. J Thorac Oncol 2014;9:1788-95. [Crossref] [PubMed]
18. Harris JP, Murphy JD, Hanlon AL, et al. A population-based comparative effectiveness study of radiation therapy techniques in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014;88:872-84. [Crossref] [PubMed]
19. Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2007;68:94-102. [Crossref] [PubMed]
20. Liao ZX, Komaki RR, Thames HD Jr, et al. Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2010;76:775-81. [Crossref] [PubMed]
21. Tsukita Y, Yamamoto T, Mayahara H, et al. Intensity-modulated radiation therapy with concurrent chemotherapy followed by durvalumab for stage III non-small cell lung cancer: A multi-center retrospective study. Radiother Oncol 2021;160:266-72. [Crossref] [PubMed]
22. Masuo M, Shinohara E, Kitano M, et al. A comparison of the incidence of ≥ grade 2 radiation pneumonitis between intensity-modulated radiotherapy and three-dimensional conformal radiotherapy in patients with unresectable non-small cell lung cancer treated with durvalumab after concurrent chemoradiotherapy. Jpn J Clin Oncol 2024;54:312-8. [Crossref] [PubMed]
23. Sanuki N, Takeda A, Eriguchi T, et al. Local control correlates with overall survival in radiotherapy for early-stage non-small cell lung cancer: A systematic review. Radiother Oncol 2023;183:109664. [Crossref] [PubMed]
24. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol 2019;20:494-503. [Crossref] [PubMed]
25. Asai K, Shioyama Y, Nakamura K, et al. Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy: risk factors and dose-volume relationship. Int J Radiat Oncol Biol Phys 2012;84:768-73. [Crossref] [PubMed]
26. Liu L, Fei Z, Li J, et al. Impact of respiratory motion on dose distribution in SIB-SBRT for lung cancer. J Appl Clin Med Phys 2025;26:e70136. [Crossref] [PubMed]
27. Feddock J, Arnold SM, Shelton BJ, et al. Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 2013;85:1325-31. [Crossref] [PubMed]
28. Karam SD, Horne ZD, Hong RL, et al. Dose escalation with stereotactic body radiation therapy boost for locally advanced non small cell lung cancer. Radiat Oncol 2013;8:179. [Crossref] [PubMed]
29. Kumar S, Feddock J, Li X, et al. Update of a Prospective Study of Stereotactic Body Radiation Therapy for Post-Chemoradiation Residual Disease in Stage II/III Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2017;99:652-9. [Crossref] [PubMed]
30. Hepel JT, Leonard KL, Safran H, et al. Stereotactic Body Radiation Therapy Boost After Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Dose Escalation Study. Int J Radiat Oncol Biol Phys 2016;96:1021-7. [Crossref] [PubMed]
31. Higgins KA, Pillai RN, Chen Z, et al. Concomitant Chemotherapy and Radiotherapy with SBRT Boost for Unresectable Stage III Non-Small Cell Lung Cancer: A Phase I Study. J Thorac Oncol 2017;12:1687-95. [Crossref] [PubMed]
32. Doyen J, Poudenx M, Gal J, et al. Stereotactic ablative radiotherapy after concomitant chemoradiotherapy in non-small cell lung cancer: A TITE-CRM phase 1 trial. Radiother Oncol 2018;127:239-45. [Crossref] [PubMed]
33. Wu TC, Luterstein E, Neilsen BK, et al. Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial. JAMA Oncol 2024;10:352-9. [Crossref] [PubMed]
34. Williams TM, Miller E, Welliver M, et al. A Phase 2 Trial of Primary Tumor Stereotactic Body Radiation Therapy Boost Before Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2024;120:681-94. [Crossref] [PubMed]
35. Kim YJ, Kim SS, Song SY, et al. Feasibility of stereotactic radiotherapy for lung lesions and conventional radiotherapy for nodal areas in primary lung malignancies. Radiat Oncol 2018;13:127. [Crossref] [PubMed]
36. Heinzerling JH, Mileham KF, Robinson MM, et al. Primary lung tumour stereotactic body radiotherapy followed by concurrent mediastinal chemoradiotherapy and adjuvant immunotherapy for locally advanced non-small-cell lung cancer: a multicentre, single-arm, phase 2 trial. Lancet Oncol 2025;26:85-97. [Crossref] [PubMed]
37. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol 2022;40:1301-11. [Crossref] [PubMed]
38. Simone CB. II, et al. NRG LU008: Phase III Prospective Randomized Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed by Concurrent Mediastinal Chemoradiation for Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC). International Journal of Radiation Oncology, Biology, Physics 2024;120:e63. [Crossref]
39. Grassberger C, Ellsworth SG, Wilks MQ, et al. Assessing the interactions between radiotherapy and antitumour immunity. Nat Rev Clin Oncol 2019;16:729-45. [Crossref] [PubMed]
40. Heinzerling JH, Pen OV, Robinson M, et al. Full Dose SBRT in Combination With Mediastinal Chemoradiation for Locally Advanced, Non-Small Cell Lung Cancer: A Practical Guide for Planning, Dosimetric Results From a Phase 2 Study, and a Treatment Planning Guide for the Phase 3 NRG Oncology LU-008 Trial. Pract Radiat Oncol 2023;13:531-9. [Crossref] [PubMed]
41. Durante M, Orecchia R, Loeffler JS. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat Rev Clin Oncol 2017;14:483-95. [Crossref] [PubMed]
42. Salem PP, Chami P, Daou R, et al. Proton Radiation Therapy: A Systematic Review of Treatment-Related Side Effects and Toxicities. Int J Mol Sci 2024;25:10969. [Crossref] [PubMed]
43. Paganetti H. Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer. Phys Med Biol 2014;59:R419-72. [Crossref] [PubMed]
44. Teoh S, Fiorini F, George B, et al. Proton vs photon: A model-based approach to patient selection for reduction of cardiac toxicity in locally advanced lung cancer. Radiother Oncol 2020;152:151-62. [Crossref] [PubMed]
45. Liao Z, Lee JJ, Komaki R, et al. Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36:1813-22. [Crossref] [PubMed]
46. Li Y, Fan X, Yu Q, et al. Proton and Carbon Ion Radiation Therapy Decreased Severe Lymphopenia by Reducing Thoracic Vertebra and Aortic Doses in Non-Small Cell Lung Cancer Versus Intensity Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys 2023;116:579-89. [Crossref] [PubMed]
47. Zhao L, Sandison GA, Farr JB, et al. Dosimetric impact of intrafraction motion for compensator-based proton therapy of lung cancer. Phys Med Biol 2008;53:3343-64. [Crossref] [PubMed]
48. Peeters A, Grutters JP, Pijls-Johannesma M, et al. How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons. Radiother Oncol 2010;95:45-53. [Crossref] [PubMed]
49. Iwata H, Akita K, Yamaba Y, et al. Concurrent Chemo-Proton Therapy Using Adaptive Planning for Unresectable Stage 3 Non-Small Cell Lung Cancer: A Phase 2 Study. Int J Radiat Oncol Biol Phys 2021;109:1359-67. [Crossref] [PubMed]
50. Oshiro Y, Mizumoto M, Okumura T, et al. Results of proton beam therapy without concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer. J Thorac Oncol 2012;7:370-5. [Crossref] [PubMed]
51. Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer 2011;117:4707-13. [Crossref] [PubMed]
52. Chang JY, Verma V, Li M, et al. Proton Beam Radiotherapy and Concurrent Chemotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: Final Results of a Phase 2 Study. JAMA Oncol 2017;3:e172032. [Crossref] [PubMed]
53. Nguyen QN, Ly NB, Komaki R, et al. Long-term outcomes after proton therapy, with concurrent chemotherapy, for stage II-III inoperable non-small cell lung cancer. Radiother Oncol 2015;115:367-72. [Crossref] [PubMed]
54. Higgins KA, O’Connell K, Liu Y, et al. National Cancer Database Analysis of Proton Versus Photon Radiation Therapy in Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2017;97:128-37. [Crossref] [PubMed]
55. Gjyshi O, Xu T, Elhammali A, et al. Toxicity and Survival After Intensity-Modulated Proton Therapy Versus Passive Scattering Proton Therapy for NSCLC. J Thorac Oncol 2021;16:269-77. [Crossref] [PubMed]
56. Yu NY, DeWees TA, Liu C, et al. Early Outcomes of Patients With Locally Advanced Non-small Cell Lung Cancer Treated With Intensity-Modulated Proton Therapy Versus Intensity-Modulated Radiation Therapy: The Mayo Clinic Experience. Adv Radiat Oncol 2020;5:450-8. [Crossref] [PubMed]
57. Yu NY, DeWees TA, Voss MM, et al. Cardiopulmonary Toxicity Following Intensity-Modulated Proton Therapy (IMPT) Versus Intensity-Modulated Radiation Therapy (IMRT) for Stage III Non-Small Cell Lung Cancer. Clin Lung Cancer 2022;23:e526-35. [Crossref] [PubMed]
58. Patel JS, McCall NS, Thomas M, et al. Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC. Int J Part Ther 2024;12:100016. [Crossref] [PubMed]
59. McCall NS, McGinnis HS, Janopaul-Naylor JR, et al. Impact of radiation dose to the immune cells in unresectable or stage III non-small cell lung cancer in the durvalumab era. Radiother Oncol 2022;174:133-40. [Crossref] [PubMed]
60. Iocolano M, Yegya-Raman N, Friedes C, et al. Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era. Cancer 2024;130:2031-41. [Crossref] [PubMed]
61. Kanai T, Matsufuji N, Miyamoto T, et al. Examination of GyE system for HIMAC carbon therapy. Int J Radiat Oncol Biol Phys 2006;64:650-6. [Crossref] [PubMed]
62. Oike T, Niimi A, Okonogi N, et al. Visualization of complex DNA double-strand breaks in a tumor treated with carbon ion radiotherapy. Sci Rep 2016;6:22275. [Crossref] [PubMed]
63. Kamada T, Tsujii H, Blakely EA, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol 2015;16:e93-e100. [Crossref] [PubMed]
64. Okazaki S, Shibuya K, Takura T, et al. Cost-effectiveness of carbon-ion radiotherapy versus stereotactic body radiotherapy for non-small-cell lung cancer. Cancer Sci 2022;113:674-83. [Crossref] [PubMed]
65. Kubo N, Suefuji H, Nakajima M, et al. Five-Year Survival Outcomes After Carbon-Ion Radiotherapy for Operable Stage I NSCLC: A Japanese National Registry Study (J-CROS-LUNG). J Thorac Oncol 2024;19:491-9. [Crossref] [PubMed]
66. Yamamoto N, Miyamoto T, Nakajima M, et al. A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non-Small Cell Lung Cancer. J Thorac Oncol 2017;12:673-80. [Crossref] [PubMed]
67. Takahashi W, Nakajima M, Yamamoto N, et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC). Cancer 2015;121:1321-7. [Crossref] [PubMed]
68. Nakajima M, Yamamoto N, Hayashi K, et al. Carbon-ion radiotherapy for non-small cell lung cancer with interstitial lung disease: a retrospective analysis. Radiat Oncol 2017;12:144. [Crossref] [PubMed]
69. Hayashi K, Yamamoto N, Nakajima M, et al. Clinical outcomes of carbon-ion radiotherapy for locally advanced non-small-cell lung cancer. Cancer Sci 2019;110:734-41. [Crossref] [PubMed]
70. Hayashi K, Yamamoto N, Nakajima M, et al. Carbon-ion radiotherapy for octogenarians with locally advanced non-small-cell lung cancer. Jpn J Radiol 2021;39:703-9. [Crossref] [PubMed]
71. Chargari C, Deutsch E, Blanchard P, et al. Brachytherapy: An overview for clinicians. CA Cancer J Clin 2019;69:386-401. [Crossref] [PubMed]
72. Qiu B, Jiang P, Ji Z, et al. Brachytherapy for lung cancer. Brachytherapy 2021;20:454-66. [Crossref] [PubMed]
73. Chatzikonstantinou G, Zamboglou N, Baltas D, et al. Image-guided interstitial high-dose-rate brachytherapy for dose escalation in the radiotherapy treatment of locally advanced lung cancer: A single-institute experience. Brachytherapy 2019;18:829-34. [Crossref] [PubMed]
74. Cui R, Wang XL, Cao J. Implantation of computed tomography-guided high-dose-rate 192Ir brachytherapy in oldest old patients with advanced non-small cell lung cancer: A case report and literature review. Medicine (Baltimore) 2022;101:e32450. [Crossref] [PubMed]
75. Xiang L, Zhang JW, Lin S, et al. Computed Tomography-Guided Interstitial High-Dose-Rate Brachytherapy in Combination With Regional Positive Lymph Node Intensity-Modulated Radiation Therapy in Locally Advanced Peripheral Non-Small Cell Lung Cancer: A Phase 1 Clinical Trial. Int J Radiat Oncol Biol Phys 2015;92:1027-34. [Crossref] [PubMed]
76. Xiang L, Ren PR, Li HX, et al. Effect of 3-Dimensional Interstitial High-Dose-Rate Brachytherapy With Regional Metastatic Lymph Node Intensity-Modulated Radiation Therapy in Locally Advanced Peripheral Non-Small Cell Lung Cancer: 5-Year Follow-up of a Phase 2 Clinical Trial. Int J Radiat Oncol Biol Phys 2023;115:347-55. [Crossref] [PubMed]
77. Li X, Zhou H, Mou K, et al. Risk Factors for Operation Complications of High Dose Rate 3-Dimensional Interstitial Brachytherapy for Lung Cancer. Clin Lung Cancer 2023;24:e187-94. [Crossref] [PubMed]
78. Yu X, Li J, Zhong X, et al. Combination of Iodine-125 brachytherapy and chemotherapy for locally recurrent stage III non-small cell lung cancer after concurrent chemoradiotherapy. BMC Cancer 2015;15:656. [Crossref] [PubMed]
79. Wang ZM, Lu J, Liu T, et al. CT-guided interstitial brachytherapy of inoperable non-small cell lung cancer. Lung Cancer 2011;74:253-7. [Crossref] [PubMed]
80. Tian LJ, Liu HZ, Zhang Q, et al. Efficacy and Safety Aiming at the Combined-Modality Therapy of External Beam Radiotherapy (40Gy) and Iodine-125 Seed Implantation for Locally Advanced NSCLC in the Elderly. Cancer Manag Res 2021;13:5457-66. [Crossref] [PubMed]
81. Sur R, Pond G, Falkson C, et al. BRACHY: A Randomized Trial to Evaluate Symptom Improvement in Advanced Non-Small Cell Lung Cancer Treated With External Beam Radiation With or Without High-Dose-Rate Intraluminal Brachytherapy. Int J Radiat Oncol Biol Phys 2023;116:601-10. [Crossref] [PubMed]
82. Sui A, Song H, Yu H, et al. Clinical Application of Iodine-125 Seed Brachytherapy Combined with Anti-PD-1 Antibodies in the Treatment of Lung Cancer. Clin Ther 2020;42:1612-6. [Crossref] [PubMed]
83. Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2012;82:425-34. [Crossref] [PubMed]
84. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290-6. [Crossref] [PubMed]
85. Brower JV, Amini A, Chen S, et al. Improved survival with dose-escalated radiotherapy in stage III non-small-cell lung cancer: analysis of the National Cancer Database. Ann Oncol 2016;27:1887-94. [Crossref] [PubMed]
86. Mehta M, Scrimger R, Mackie R, et al. A new approach to dose escalation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2001;49:23-33. [Crossref] [PubMed]
87. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 1997;350:161-5. [Crossref] [PubMed]
88. Mauguen A, Le Péchoux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788-97. [Crossref] [PubMed]
89. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011;100:76-85. [Crossref] [PubMed]
90. Belani CP, Wang W, Johnson DHPhase III study of the Eastern Cooperative Oncology Group, et al. (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 2005;23:3760-7. [Crossref] [PubMed]
91. Hoppe BS, Nichols RC, Flampouri S, et al. Hypofractionated Proton Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial from the University of Florida and Proton Collaborative Group. Int J Radiat Oncol Biol Phys 2020;107:455-61. [Crossref] [PubMed]
92. Glinski K, Socha J, Wasilewska-Tesluk E, et al. Accelerated hypofractionated radiotherapy with concurrent full dose chemotherapy for locally advanced non-small cell lung cancer: A phase I/II study. Radiother Oncol 2020;148:174-80. [Crossref] [PubMed]
93. Katsuta T, Matsuura K, Kashiwado K, et al. Phase II Study: The Outcome of Hypofractionated Involved-Field Radiation Therapy With Concurrent Chemotherapy for the Treatment of Locally Advanced Non-small Cell Lung Cancer. Pract Radiat Oncol 2021;11:35-43. [Crossref] [PubMed]
94. Qiu B, Xiong M, Luo Y, et al. Hypofractionated Intensity Modulated Radiation Therapy With Concurrent Chemotherapy in Locally Advanced Non-Small Cell Lung Cancer: A Phase II Prospective Clinical Trial (GASTO1011). Pract Radiat Oncol 2021;11:374-83. [Crossref] [PubMed]
95. Iyengar P, Zhang-Velten E, Court L, et al. Accelerated Hypofractionated Image-Guided vs Conventional Radiotherapy for Patients With Stage II/III Non-Small Cell Lung Cancer and Poor Performance Status: A Randomized Clinical Trial. JAMA Oncol 2021;7:1497-505. [Crossref] [PubMed]
96. Hoppe BS, Nichols RC, Flampouri S, et al. Chemoradiation with Hypofractionated Proton Therapy in Stage II-III Non-Small Cell Lung Cancer: A Proton Collaborative Group Phase 2 Trial. Int J Radiat Oncol Biol Phys 2022;113:732-41. [Crossref] [PubMed]
97. Said BI, Geng Y, Badiyan SN, et al. Accelerated Hypofractionated Radiotherapy for Locally Advanced NSCLC: A Systematic Review From the International Association for the Study of Lung Cancer Advanced Radiation Technology Subcommittee. J Thorac Oncol 2025;20:39-51. [Crossref] [PubMed]
98. Morisada M, Clavijo PE, Moore E, et al. PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. Oncoimmunology 2018;7:e1395996. [Crossref] [PubMed]
99. Zhou R, Liu F, Zhang H, et al. Fraction Dose Escalation of Hypofractionated Radiotherapy with Concurrent Chemotherapy and Subsequent Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer: A Phase I Study. Clin Cancer Res 2024;30:2719-28. [Crossref] [PubMed]
100. Filippi AR, Dziadziuszko R, García Campelo MR, et al. DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Future Oncol 2021;17:4657-63. [Crossref] [PubMed]
101. Pointer KB, Pitroda SP, Weichselbaum RR. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer 2022;8:9-20. [Crossref] [PubMed]
102. Yang C, Liang Y, Liu N, et al. Role of the cGAS-STING pathway in radiotherapy for non-small cell lung cancer. Radiat Oncol 2023;18:145. [Crossref] [PubMed]
103. Liang Y, Hannan R, Fu YX. Type I IFN Activating Type I Dendritic Cells for Antitumor Immunity. Clin Cancer Res 2021;27:3818-24. [Crossref] [PubMed]
104. McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer 2020;20:203-17. [Crossref] [PubMed]
105. Charpentier M, Spada S, Van Nest SJ, et al. Radiation therapy-induced remodeling of the tumor immune microenvironment. Semin Cancer Biol 2022;86:737-47. [Crossref] [PubMed]
106. Zhou Q, Chen M, Jiang O, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2022;23:209-19. [Crossref] [PubMed]
107. Bradley JD, Sugawara S, Lee KH, et al. Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non-Small Cell Lung Cancer: The Phase III PACIFIC-2 Study. J Clin Oncol 2025;43:3610-21. [Crossref] [PubMed]
108. Li Y, Deng G, Liang N, et al. Chemoradiotherapy Combined with Immunotherapy in Stage III Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Efficacy and Safety Outcomes. Oncology 2024;102:382-98. [Crossref] [PubMed]
109. Girard N, Bar J, Garrido P, et al. Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study. J Thorac Oncol 2023;18:181-93. [Crossref] [PubMed]
110. Inoue H, Ono A, Kawabata T, et al. Clinical and radiation dose-volume factors related to pneumonitis after treatment with radiation and durvalumab in locally advanced non-small cell lung cancer. Invest New Drugs 2020;38:1612-7. [Crossref] [PubMed]
111. Lim CA, Ghosh S, Morrison H, et al. Durvalumab-Associated Pneumonitis in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Real-World Population Study. Curr Oncol 2023;30:10396-407. [Crossref] [PubMed]
112. Saito G, Oya Y, Taniguchi Y, et al. Real-world survey of pneumonitis and its impact on durvalumab consolidation therapy in patients with non-small cell lung cancer who received chemoradiotherapy after durvalumab approval (HOPE-005/CRIMSON). Lung Cancer 2021;161:86-93. [Crossref] [PubMed]
113. Oshiro Y, Mizumoto M, Sekino Y, et al. Risk factor of pneumonitis on dose-volume relationship for chemoradiotherapy with durvalumab: Multi-institutional research in Japan. Clin Transl Radiat Oncol 2021;29:54-9. [Crossref] [PubMed]
114. Gao RW, Day CN, Yu NY, et al. Dosimetric predictors of pneumonitis in locally advanced non-small cell lung cancer patients treated with chemoradiation followed by durvalumab. Lung Cancer 2022;170:58-64. [Crossref] [PubMed]