Radiation therapy for oligoprogressive NSCLC

Oligoprogression is defined as limited metastatic areas that progress while on/off systemic therapy in the context of oligometastatic or polymetastatic disease. Individuals with non-small cell lung cancer (NSCLC) metastasis with oligoprogression may benefit from local ablative radiotherapy, also known as stereotactic body radiation therapy (SBRT), stereotactic ablative radiotherapy (SABR), or stereotactic radiosurgery (SRS).

Diversity of oligoprogressive state

When considering local treatment in the background of oligoprogressive disease, it is important to take into account the diverse nature of oligoprogression, which is underpinned by certain factors including:

·       Initial burden of the disease. Did this patient have multiple sites of disease at diagnosis?

·       Efficacy of systemic therapy. If a patient goes into a state of disease-free control with systemic therapy, can local treatment add further benefit?

·       Underlying biology driving the recurrence. Is there a druggable resistance mechanism driving the recurrence?

·       Characteristics of the lesion. Specific to ablative radiotherapy, the risk profile of a 1-cm lesion right next to the main stem bronchus is going to be different from a 4-cm lesion in the periphery of the lung.

With these considerations in mind, an assessment will have to be made for each individual patient regarding the potential risk versus benefit of any local treatment for oligoprogressive disease.


Figure 1: Diversity of oligoprogressive state

·        T-X: Diagnosis and treatment of primary cancer (black) in a nonmetastatic state
·        Under treatment with active systemic therapy
·        T0: First time diagnosis of new oligometastasis (green) >6 months after cancer diagnosis



·        T-X: Diagnosis of oligometastases followed by local or systemic treatment or both
·        Under treatment with active systemic therapy
·        T0: Diagnosis of new (blue) and growing or regrowing (green) oligometastases


·        T-X: Diagnosis of polymetastatic metastatic disease followed by systemic treatment with or without local treatment
·        Under treatment with active systemic therapy
·        T0: Diagnosis of new (blue) and growing or regrowing (green) oligometastases; possible residual non-progressive metastases (black)


[T-X=Any previous point in time; T0=At this current point of time; adapted from Lancet Oncol 2020;21:e18-e28]

The role of radiation therapy

With radiation therapy, the risk profile of treatments can be readily calibrated with different dose fractionations, while delivering the same biological effective dose. These dose fractionations will enable clinicians to strike a balance and optimize the therapeutic window such that patients are more likely to benefit from local treatment.

In a study presented at the 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting, high-dose radiation therapy conferred benefit for individuals with lung cancer after failure of systemic therapy in up to five disease sites. This is the first randomized study that evaluated SBRT for the treatment of oligoprogressive, metastatic lung and breast cancer. [ASTRO 2022, abstract LBA-07]

Among lung cancer patients who did not receive SBRT, median progression-free survival (PFS) was 9 weeks. Whereas for those who did receive SBRT, median PFS was about fivefold longer than that achieved without radiation therapy (44 weeks). A comparison between arms yielded a log-rank p-value of 0.001.

Compared with patients with breast cancer, it was primarily the lung cancer population who derived benefit from SBRT. Moreover, the addition of SBRT to systemic treatment did not lead to significant severe toxicities.

Synergy with immunotherapy

Another reason that accounts for the enthusiasm around adding radiotherapy to systemic treatment in the oligoprogressive state is the synergy between radiation and immunotherapy.

There are now several data corroborating the benefits of augmenting systemic therapy with radiotherapy. In a trial evaluating patients with early-stage (stage I/II) NSCLC, those who received both immunotherapy (nivolumab) and SBRT had a markedly better 4-year event-free survival than those on nivolumab only (hazard ratio [HR], 0.38; p=0.0056). [Lancet 2023;402:871-881]

These results aligned with that seen in studies involving patients with stage III NSCLC, as well as those with metastatic disease (stage IV). In a pooled analysis of two randomized studies, the addition of single-site RT to pembrolizumab in patients with stage IV disease more than doubled median PFS (9.0 vs 4.4 months) and overall survival (19.2 vs 8.7 months), yielding HRs of 0.67 for both outcomes. [Lancet Respir Med 2021;9:467-475]

Systemic therapy: Do we stop or continue?

Given these benefits, radiation therapy has been increasingly used in practice to obtain durable control of resistant metastases. However, a key question remains – whether patients should continue or interrupt their systemic therapy during radiotherapy.

In a study that looked at the effect of continuous vs interrupted targeted therapy during SBRT, the overall incidence of severe toxicity with combined SBRT and targeted therapy was rare and there were no significant differences in terms of survival and incidence of severe toxicities between the two groups. This implies that radiation therapy was just as safe and beneficial regardless of whether systemic therapy was continued or not. [Cancers (Basel) 2021;13:4780]

Nonetheless, this is a rapidly evolving space with new systemic agents coming into clinical practice and further data will be needed to guide our practice.

Red flags

When delivering SBRT in clinical practice, it is useful to consider patients who might be at higher risk of radiation related toxicities. This would include patients with:

1.    Tumour targets which are close to or abut the trachea and mainstem bronchi (also known as central or ultra-central tumours) [Ther Radiol Oncol 2019:3:18] Treating these lesions can raise the risk profile of the treatment and in these cases, a longer dose fractionation can be warranted.

2.    Ongoing systemic therapies such as antiangiogenics, anticoagulants, or patients who have demonstrated prior immune-related adverse events (irAEs). For instance, patients with prior irAEs have a higher risk of developing radiation pneumonitis. [Ann Oncol 2020;31:1719-1724]

3.    Interstitial lung disease (ILD), as patients with ILD tend to have worse prognoses and are also at higher risk of severe radiation related toxicities. [J Thorac Oncol 2020;15:902-913]

Key takeaways

Radiation therapy is a promising tool to improve disease control in oligoprogressive NSCLC. The delivery technique and risk assessment for radiotherapy is critical, and it is imperative to discuss local therapy for these patients in a multidisciplinary setting.

Two upcoming studies – the phase II/III HALT (UK) and phase II STOP (Canada) trials – will further evaluate the synergy between systemic treatment with tyrosine kinase inhibitors and local therapy with SBRT in NSCLC patients with ≤5 oligoprogressive sites.