The evolving role of radiotherapy in advanced non-small cell lung cancer: beyond symptom control

Introduction

Lung cancer is the leading cause of cancer death in the UK, with at least 70% of patients being diagnosed with locally advanced or metastatic disease (1,2). Non-small cell lung cancer (NSCLC) accounts for the majority of cases of lung cancer. Only 60% of fit patients [performance status (PS) 0–1] in England with stage IIIB–IV NSCLC receive systemic anticancer therapy (SACT) for their cancer, with the remainder presumably electing for radiotherapy, best supportive care or initial surveillance (3). Of those diagnosed with stage III disease, a significant proportion (>20%) are unfit for curative treatment and thus palliative treatment makes up a significant proportion of active treatment for patients with NSCLC (4).

Radiotherapy technology has increased significantly in a short period of time in terms of treatment complexity, on-treatment imaging and indications. The vast majority of radiotherapy is delivered as external beam radiotherapy (EBRT) with high-dose megavoltage photons (X-rays), and there is a standard planning process. Low-dose palliative radiotherapy involves a computerised tomography (CT) scan, field placement, treatment calculation and then treatment. Higher dose treatment (including radical/curative treatment) involves a CT scan that accounts for organ motion (four-dimensional CT), followed by identification of the tumour and organs at risk by a clinician, development of a unique radiotherapy plan by the planning/physics team and then daily treatment. High-dose radiotherapy for lung cancer is usually given as daily doses over 4–6 weeks. New techniques such as intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) have allowed radiotherapy to shape the dose more conformally to avoid organs at risk (5). In early-stage lung cancer, stereotactic ablative body radiotherapy (SABR) allows higher doses of radiotherapy to be given in fewer treatments. In eligible patients, SABR produces similar outcomes to surgery. It has less toxicity and is likely more efficacious than standard radical radiotherapy for lung cancer. It is now recommended in European Society for Medical Oncology (ESMO) guidelines for inoperable peripheral tumours (6-12).

In parallel with these changes, the staging for lung cancer has now changed. It is recognised that outcomes with oligometastatic NSCLC are improved compared to those with more widespread metastatic disease. Oligometastatic disease (OMD) was first described in the 1990s as an intermediate state between localised disease and disseminated metastatic cancer (13). This identifies patients who might benefit from a local therapy, such as radiotherapy, either in addition to or instead of drug treatment.

Our review aims to discuss the evolving uses for radiotherapy in advanced NSCLC. Traditionally, low-dose palliative radiotherapy in NSCLC is a routinely used, as standard treatment to reduce symptom burden, for example for painful bony metastases. It is highly efficacious and easy to deliver. A single dose of radiotherapy for bone pain has a response rate of up to 80%. However, the evolving technology has led to the use of radiotherapy to provide disease control, both through the use of conventional radiotherapy and SABR. There are increasing indications for radiotherapy in the context of the rapidly changing landscape of drug treatment for lung cancer.

EBRT

Thoracic radiotherapy

Low-dose thoracic EBRT is integral to managing advanced lung cancer. Current guidelines by the Royal College of Radiologists recommend that patients with a lower PS of 3–4 receive lower-dose regimes of palliative radiotherapy such as 10 Gy in 1 fraction or 17 Gy in 2 fractions (14). Higher-dose regimens of 39 Gy in 13 fractions or 36 Gy in 12 fractions are reserved for patients with a better PS (0–2) (14). Low-dose radiotherapy is often used for symptom control, whereas higher-dose EBRT is usually aiming at disease control (see Table 1).

The majority of trials investigating palliative thoracic EBRT were undertaken over 30 years ago prior to the use of modern SACT, and sought to find optimal fractionation regimes. Palliative radiotherapy appears to improve thoracic symptoms. Studies have shown that multi fraction treatment is better than a single fraction. Thirty Gy in 10 fractions improves symptoms such as haemoptysis (79%), pain (52–60%), and cough (48%) (27). Erridge et al. showed a higher resolution of symptoms with a higher dose (30 Gy in 10 fractions vs. 8 Gy single fraction, 23% vs. 5%, P<0.001), but no significant difference in survival (17). Bezjak et al. showed a significant improvement in cancer-related symptoms (P=0.009), quality of life (QoL) (P=0.04) and survival compared to those receiving a single fraction of radiotherapy (16). Higher doses such as 39 Gy in 13 fractions may also improve survival in fitter patients not suitable for radical radiotherapy, but patients in these studies were not routinely positron emission tomography (PET) staged (15).

Currently, the dose/fractionation selected is likely to balance patient fitness, treatment toxicity, ease of accessing palliative radiotherapy (e.g., distance travelled) and likely prognosis. A systematic review of 13 randomised controlled trials comparing lower and higher-dose palliative radiotherapy showed a greater likelihood of symptom improvement and a survival advantage with dose escalation, but were associated with higher rates of toxicity (28). However, a 2015 Cochrane review argued that the survival benefit for higher-dose regimens was not supported by strong evidence and that there was no benefit for patients with lower PS (29). Low-dose palliative radiotherapy still has an important role in this context particularly in those not fit for SACT. It also has an important role in resource limited health care settings internationally, where complex radiotherapy treatments and expensive systemic therapy are less available.

To further investigate the role of palliative radiotherapy in NSCLC, the Thoracic Umbrella Radiotherapy Study in stage IV NSCLC (TOURIST) trial has been set up in the UK. This is an umbrella study with two trials currently open within it: the QUARTZ study and the PRINCE study. The QUARTZ study will assess the impact of thoracic radiotherapy before it is routinely indicated in patients who are unsuitable for systemic therapy with stage IIIB–IV NSCLC. These patients will be randomised to receive either low-dose palliative radiotherapy or no radiotherapy. The primary outcome is QoL (23). The PRINCE study aims to assess the role of high-dose palliative radiotherapy alongside modern SACT. All participants in this study receive standard-of-care first-line systemic therapy, with the treatment group also receiving high-dose palliative radiotherapy.

In summary, low-dose thoracic radiotherapy is beneficial in patients with respiratory symptoms. Dose-escalated radiotherapy is thought to have a role in improving survival for thoracic disease. This can be used as consolidation radiotherapy after SACT, or as an alternative to SACT, usually in low-volume metastatic NSCLC, oligometastatic NSCLC or where patients will not tolerate radical radiotherapy.

Bone metastases

Bone metastases are the most common cause of cancer-related pain (30). Approximately 20–30% of patients with NSCLC present with bone metastases at diagnosis, and between 35% and 60% will develop them during their disease course (31). Palliative radiotherapy is a mainstay of treatment for this group of patients. A meta-analysis has shown that typically 60% of patients report a significant reduction in pain following radiotherapy to bone disease; although it must be noted that the different studies used varying methods of assessing pain and defining what a significant decrease is (32). As for low dose thoracic radiotherapy, radiotherapy for bone metastases can be delivered in either a single fraction or multiple fraction regimens; multiple systematic reviews have shown no difference in response rates between single and multifractionated regimens, as well as similar rates of acute toxicities (30,32). It is generally accepted that retreatment rates are higher if using single fraction regimes.

Brain metastases

During the course of their disease, 25% to 50% of patients with lung cancer will develop brain metastases. The risk of brain metastases is higher in those with certain oncogene drivers, such as those with ALK rearrangements and ROS1 mutations (33).

Historically, brain metastases from NSCLC have been treated with surgical resection, stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) (34). The treatment landscape is evolving in light of new evidence. The QUARTZ trial found that omitting WBRT in patients with multiple brain metastases caused very little difference in survival and QoL outcomes (18). This study led to a significant change in clinical practice as WBRT was previously routine. In addition, increased use of magnetic resonance imaging results in smaller lesions being identified when compared to CT imaging. Some drugs, such as lorlatinib in ALK-positive NSCLC, have high intra-cranial response rates, meaning radiotherapy is not required upfront. Sadly, survival outcomes for patients with multiple brain metastases remain poor particularly in mutation negative NSCLC. Standard practice is now best supportive care with steroids when indicated for multiple brain metastases in these patients.

Stereotactic radiotherapy

SRS is a way of delivering highly targeted, high doses of radiotherapy with fewer treatments.

SRS was initially developed to deliver a radical treatment to low volume brain metastases. These strategies were then applied to visceral lesions, using SABR. SABR differs from conventional radiotherapy in its use of fewer, higher doses of radiotherapy to smaller and more highly focused areas. Standard radical radiotherapy delivers a relatively flat dose across the treatment volume, whereas SABR is delivered with a peaked dose at the centre of the treatment area, allowing for more rapid dose fall off. Treatment in fewer, bigger doses allows for a greater biological effect while minimising toxicity.

Use of SRS for intra-cranial oligometastatic cancer

As noted, the QUARTZ trial has shown that WBRT does not have a role for the majority of patients with multiple brain metastases from NSCLC. For low-volume brain metastases, the standard is to use SRS, which has randomised prospective data supporting its use alone for up to 4 brain metastases and prospective observational data for use in up to 10 brain metastases (14,35). There is no definitive trial proving the use of SRS in lung cancer. One trial found a higher rate of local recurrence for patients treated with SRS compared to WBRT, but as this did not translate into a difference in overall survival (OS) and WBRT had a lower QoL, they still recommended for SRS to be the standard treatment following surgical resection (36). Further work is required to understand the optimal role of local brain radiotherapy for patients with NSCLC, particularly in patients with mutation driven NSCLC. SRS is associated with lower rates of cognitive decline than WBRT, but there is no difference in OS between patients who undergo postoperative WBRT compared to SRS (37).

Most SRS is delivered in a single treatment; however, treatment can be fractionated if there is a significant risk of high toxicity to adjacent tissues or the lesion is larger, e.g., 2–3 cm (38). Furthermore, there is a role for the use of SRS post-operatively following the resection of brain metastases in the place of WBRT.

Use of SABR in non-intracranial oligometastatic cancer

SABR is the standard of care (SOC) for early-stage, medically inoperable lung cancers (39). Over the last decade, it has also begun to play a growing role in the treatment of oligometastatic NSCLC.

Two trials changed the landscape of managing oligometastatic lung cancer. The first was SABR-COMET, which randomised 99 patients 2:1 to SABR for 1–5 metastases vs. palliative SOC treatment. SABR-COMET included a range of solid tumours, including NSCLC. The SABR arm showed a marked benefit in OS (27.2% vs. 13.6% at 8 years, P=0.008). No patient receiving SOC survived beyond 5 years without progression or recurrence. Although there were more severe (grade 2 or above) toxicities in the SABR arm, there was no significant difference in QoL between the two groups (40-42). It is likely that the difference in the arms was maintained, as further SABR was delivered as appropriate in those randomised to SABR. Although the results of this trial are impressive, limitations include a small sample size and heterogeneity of tumour types. There has been a criticism that the SABR arm contained a greater proportion of patients with prostate cancer. However, it was always intended that SABR-COMET would be followed by a confirmatory phase III study.

SABR-COMET-3 (1–3 metastases) and SABR-COMET-10 (4–10 metastases) are randomised phase III trials building on the findings of SABR-COMET. They will compare SOC palliative-intent treatments to SOC and SABR to sites of all known disease. Both COMET-3 and COMET-10 have completed recruitment. Patients receive a radical SABR dose in COMET-3, but a lower-dose in COMET-10. The primary endpoint for both studies is OS, but they will also assess progression-free survival (PFS), time to development of new metastases, QoL, cost-effectiveness and toxicity (20,26). Both studies include multiple tumour types, including NSCLC, but are likely to be practice changing if positive.

The second landmark study specifically selected patients with NSCLC who had three or fewer metastatic sites, who had not progressed after induction palliative systemic therapy. Patients were randomly assigned to receive either maintenance therapy/observation or local consolidative therapy (LCT) in the form of surgery, radiotherapy or both to ablate all residual disease. The trial was closed early following a pre-planned assessment due to results indicating that the local therapy group had a significantly better median PFS of 37.6 vs. 9.4 months (P=0.03), and OS of 41.2 vs. 17.0 months (P=0.02) (19,43). The study was limited by its small sample size and the inclusion of a range of systemic regimens as first-line therapy. Very few patients received immunotherapy, which would now be SOC 1^st treatment for non-mutation driver lung cancer.

In contrast to these two studies, LU002 was a negative study. Patients with 1–3 synchronous metastases were randomised to SOC vs. SOC and LCT. It was a non-significant study, with hazard ratio 0.93 (95% confidence interval: 0.66–1.31). More than 90% of patients received immunotherapy in this study.

The American Society of Radiation Oncology (ASTRO) and European Society for Radiotherapy and Oncology (ESTRO) have developed a clinical guideline for the treatment of oligometastatic NSCLC. They strongly recommended a multidisciplinary, patient centred approach for all decision-making regarding potential treatment, due to the lack of significant randomised phase III trials. They recommend the use of LCT only if it is clinically safe and feasible for all disease sites, and only for patients with up to 5 extracranial metastases (21).

The role of SABR in OMD is likely to extend as further evidence accrues. The SARON trial has completed recruitment and is assessing the effect of SABR LCT following induction SACT in patients with synchronous OMD. The primary outcome is OS (24). Patients in the LCT group received radical radiotherapy to all sites of disease, followed by maintenance SACT as appropriate.

A further step in delineating the use of SABR for the treatment of OMD is finding optimal dose regimens. The SAFRON II trial has shown that there is no difference in treating lung metastases with multiple or single doses of SABR (44). The SIMPLIFY-SABR-COMET trial will compare single versus multi-fraction SABR to oligometastases, with the primary objective of determining treatment toxicity (45).

There is evidence that SABR has a role for oligoprogressive NSCLC. This means treating only enlarging lesions on a background of widespread metastatic disease. Data from TRACERx suggests that metastases seed from other metastases as well as from the primary tumour; therefore, ablating resistant metastases could prevent further seeding and prolong the use of a systemic therapy that is successfully controlling the majority of disease sites (46). The CURB study recruited patients with breast or lung cancer who had 1–5 progressive metastatic sites following one or more lines of systemic therapy and compared SOC with SOC and SABR to all progressive lesions. A total of 114 targets were treated across 55 patients in the SABR arm. Patients with NSCLC had a four-fold increase in PFS with SABR in comparison to the SOC arm; median PFS was 2.2 months in the SOC group and 10 months in the SABR group (P=0.004). In contrast, the cohort of patients with breast cancer had no benefit with the addition of SABR (22). CURB is limited by its small sample size and inclusion of multiple tumour types. Currently, NSCLC is the only type of cancer with randomised data to support the use of SABR in oligoprogressive cancer (47). Most patients in CURB had lung cancer without an actionable mutation. This data is being built upon by the HALT trial, which is assessing the use of SABR in mutation-positive NSCLC that progresses following tyrosine kinase inhibitor (TKI) therapy (25).

SABR for symptom benefit

The main palliative use of SABR outside of LCT for OMD is in the management of bone and brain metastases. A systematic review of 10 studies comparing SABR with conventional radiotherapy in bone metastases has shown that SABR is associated with higher pain relief rates, as it allows a higher dose of radiotherapy to be delivered to target areas while remaining within safe limits of doses delivered to surrounding healthy tissue (48).

Integration of radiotherapy with modern systemic therapies

Systemic therapies for NSCLC have evolved rapidly in recent years, with significant advancements in targeted therapies, immunotherapy, and combination regimens transforming the treatment landscape. Systemic regimes are broadly divided into those for patients whose cancers have actionable genetic mutations (up to 40–50% of patients, varying significantly between populations) and those without (49). Targeted drugs, or TKIs, now exist for the following genetic mutations: EGFR, ALK, ROS1, RET, MET, KRAS G12C, BRAF, HER-2 and NTRK (50-55). With the exception of KRAS and HER-2 mutations, targeted therapies are used first line for cancers with actionable genetic alterations (56). These patients often benefit from improved survival than those with non-mutation-driven lung cancer. For example, the CROWN study demonstrated a PFS of more than 5 years for patients receiving lorlatinib for ALK-positive metastatic NSCLC (57).

The majority of patients in the UK lack an actionable mutation suitable for first-line treatment. Immune checkpoint (PD-1/PD-L1, CTLA-4) inhibitors, otherwise known as immunotherapy, have been transformational in improving treatment outcomes, particularly in patients with high PD-L1 expression (defined as PD-L1 >50%). The KEYNOTE-024 study demonstrated that in this cohort, 32% of patients were alive 5 years after treatment, compared to 16% of those who received chemotherapy (58). When used in combination with chemotherapy, regardless of PD-L1 expression, 5-year survival was 19% vs. 11% (immunotherapy with chemotherapy vs. chemotherapy alone) (59). Consequently, patients now have access to potentially multiple lines of palliative SACT for NSCLC.

These new systemic agents are frequently used alongside radiotherapy, which raises concerns regarding increased toxicity. Toxicity data for treatment regimens combining radiotherapy and SACT is often scarce and based on retrospective data. This is because many clinical trials for the approval of systemic agents typically do not allow the use of concurrent radiotherapy (60). With regards to this, ESMO-ESTRO have recently published consensus statements highlighting potential risks when combining radiotherapy with SACT (61). For example, chemotherapy, including those commonly used to treat lung cancer (e.g., carboplatin, cisplatin, etoposide), may require radiotherapy dose or field adaptations to reduce acute toxicity, with consideration of pausing/stopping chemotherapy if significant toxicity occurs. TKIs with radiotherapy can enhance specific toxicities, e.g., sorafenib alongside liver radiotherapy resulting in severe hepatotoxicity. The HALT trial will help clarify the safety of concurrent TKIs with SABR (25). Immunotherapies present uncertainties due to their long half-life and immunologic impact, and may have organ-specific toxicity in relation to radiotherapy, e.g., increased risk of pneumonitis with thoracic radiotherapy. The SARON trial will help clarify toxicity of sequential immunotherapy and high-dose thoracic radiotherapy (24).

Conclusions

Palliative radiotherapy remains a core component of the treatment of incurable NSCLC, but its current use has developed hugely from the original fractionation studies of the 1990s that make up the majority of our data. There has been a marked shift toward using higher-dose techniques, such as SABR and consolidative EBRT, with the goal of modifying disease progression and improving survival outcomes. In particular, several trials such as SABR-COMET and the study by Gomez et al. (19) have highlighted the potential role for radiotherapy in achieving improved disease control in oligometastatic NSCLC. Large contemporary RCTs, including the TOURIST umbrella study, are underway to update the evidence base in the context of modern systemic therapies. However, further research is essential to determine which patients derive the greatest benefit from these approaches and to define how new radiotherapy techniques can be most effectively integrated into current systemic treatment paradigms while avoiding increased toxicity to patients.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-103/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-103/coif). I.F. reports that he has received support to attend unrelated meetings on gastrointestinal cancer by Servier and Takeda, pharmaceutical companies that also produce systemic treatments for non-small cell lung cancer. Both I.F. and I.P. serve as unpaid committee members of the trial management group in QUARTZ lung trial. I.P is supported by the National Health Service (NHS) Scotland Research career researcher clinician award. K.P. was supported by an NHS Education Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship (PCL/23/04). The other 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/.

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