Stereotactic Ablative Radiation Therapy for Pulmonary Metastases: Histology, Dose, and Indication Matter

doi:10.1016/j.ijrobp.2017.02.093

International Journal of Radiation OncologyBiologyPhysics

Volume 98, Issue 2, 1 June 2017, Pages 419-427

https://doi.org/10.1016/j.ijrobp.2017.02.093 Get rights and content

Purpose

To assess the association between colorectal cancer (CRC) histology, dose, and local failure (LF) after stereotactic ablative radiation therapy (SABR) for pulmonary metastases, and to describe subsequent cancer progression, change of systemic therapy (CST), survival, and their association with treatment indications.

Methods and Materials

From a prospective SABR cohort, 180 pulmonary metastases in 120 patients were identified. Treatment indications were single metastasis, oligometastases, oligoprogression, and dominant areas of progression. Doses of 48 to 52 Gy/4 to 5 fractions were delivered. Since 2010 the dose for peripheral CRC metastases was increased to 60 Gy/4 fractions. Cumulative incidence function (CIF) was used to report LF, progression probability, and CST. The Kaplan-Meier method estimated overall survival (OS). Univariate and multivariable analyses to assess variable associations were conducted.

Results

Median follow-up was 22 months (interquartile range, 14-33 months). At 24 months, the CIF of LF was 23.6% (95% confidence interval [CI] 15.1%-33.3%) and 8.3% (95% CI 2.6%-18.6%), respectively, for CRC and non-CRC metastases (P<.001). This association remained significant after adjusting for confounders (subdistribution hazard ratio [SHR] 13.6, 95% CI 4.2-44.1, P<.001). Among CRC metastases, 56 and 45 received <60 Gy and 60 Gy, respectively. Delivering 60 Gy was independently associated with a lower hazard of LF (SHR 0.271, 95% CI 0.078-0.940, P=.040). At 12 months the CIF of progression was 41.67% (95% CI 21.69%-60.56%), 42.51% (95% CI 29.09%-55.29%), 62.96% (95% CI 41.25%-78.53%), and 78.57% (95% CI 42.20%-93.48%), respectively, for patients treated for single metastasis, oligometastases, oligoprogression, and dominant area of progression (P<.001). A CST was observed, respectively, in 4 (17%), 17 (31%), 12 (44%), and 10 (71%) patients with a median time of 13.1, 11.1, 8.4, and 8.4 months.

Conclusion

Colorectal cancer lung metastases are associated with a higher hazard of LF and require higher SABR doses. Outcomes for patients with oligometastases and oligoprogression treated with SABR seem favorable. Prospective clinical trials are needed to confirm these benefits.

Introduction

The management of patients with distant metastases predominantly involves systemic therapy (ST). The role of radiation in such patients was limited to a palliative one. However, that paradigm is changing. There is growing interest in considering high-dose radiation therapy and/or surgery to eradicate tumors, especially when the metastases are limited.

New high-precision radiation therapy techniques have allowed for noninvasive ablation of metastases (1). Stereotactic ablative radiation therapy (SABR) enables the delivery of high doses to the tumor while restricting the doses to adjacent normal tissues to a minimum (2). There is mounting evidence suggesting the safety and efficacy of SABR in the setting of pulmonary metastases, with 2-year control rates ranging from 70% to 90% 3, 4, 5, 6. Nevertheless, prognostic data from prospective trials are limited. Previous retrospective reports have suggested that pulmonary metastases from colorectal adenocarcinoma (CRC) might have a higher rate of local failure (LF) compared with other primary histology and that there is an association between the dose delivered and LF 7, 8.

The use of SABR to treat pulmonary metastases is increasing despite no randomized evidence, particularly in the treatment of “oligometastases” (9). The oligometastatic state, first described by Hellman and Weichselbaum (10), refers to a state between local-regional and widespread metastatic disease in which metastases are limited in number and location. In such a scenario, eradication of all sites of visible disease may result in prolonged progression-free survival and perhaps “cure” in a small proportion of patients, as shown in nonrandomized studies documenting the efficacy of resecting oligometastatic tumors 11, 12.

Another emerging indication for SABR is in the situation termed “oligoprogression.” This refers to the scenario in which cancer progression occurs in a limited number of tumors while the majority of other metastases are responding or stable while on an ST strategy. Rather than changing ST, one approach is to use a local therapy, like SABR, to treat the progressing tumors while staying on the same ST strategy (13). Such an approach has been reported in patients who develop oligoprogression while receiving targeted agents for non-small cell lung cancer and kidney cancer 14, 15, 16. The goal of such a strategy is to delay change of ST (CST).

This study aims to review the clinical outcomes of pulmonary metastases and identify predictors of success. The primary hypothesis is that among patients treated with SABR for pulmonary metastases, CRC primary is associated with a higher hazard of LF after adjusting for potential confounders. The secondary hypotheses are that: (1) dose is an independent predictor of LF among patients with metastases from CRC primary; and (2) there is an association between treatment indication and progression, CST, and overall survival (OS).

Section snippets

Population

Consecutive pulmonary metastases treated with SABR between November 2008 and December 2013 were identified from a prospective SABR cohort. This study was approved by our institutional research ethics board. Pulmonary metastases in adult patients with any solid primary tumor were included. Indications for SABR were as follows: (1) Single metastasis and oligometastases, for which the goal was to irradiate all sites of disease (≤5 active metastases; tumors previously ablated surgically or by

Patient and tumor characteristics

One hundred eighty-four consecutive pulmonary metastases in 120 patients were treated with SABR; 101 and 83, respectively, from CRC and non-CRC primary. The median follow-up was 22 months (IQR, 14-33 months). No patients were excluded in this analysis. Patient and tumor characteristics in the entire cohort and by primary site (CRC vs non-CRC) are described in Table 1. Overall they were equally distributed between the 2 groups, except for SABR indication: oligometastases was the most common SABR

Discussion

This study reported on the outcomes of SABR for pulmonary metastases from a large single institution. Colorectal cancer metastases were more likely to fail locally when compared with non-CRC, suggesting an underlying difference in tumor biology and radioresistance. This is in line with previous findings from observational studies 7, 20, 21, 22, 23. Takeda et al (7) reported a 1-year LC of 80% and 94%, respectively, for 21 CRC and 23 non-CRC pulmonary metastases treated with SABR. Similarly a

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Radiotherapy in the management of lung oligometastases
2024, Cancer/Radiotherapie
In recent years, the development of both medical imaging and new systemic agents (targeted therapy and immunotherapy) have revolutionized the field of oncology, leading to a new entity: oligometastatic disease. Adding local treatment of oligometastases to systemic treatment could lead to prolonged survival with no significant impact on quality of life. Given the high prevalence of lung oligometastases and the new systemic agents coming with increased pulmonary toxicity, this article provides a comprehensive review of the current state-of-art for radiotherapy of lung oligometastases. After reviewing pretreatment workup, the authors define several radiotherapy regimen based on the localization and size of the oligometastases. A comment on the synergistic combination of medical treatment and radiotherapy is also made, projecting on future steps in this specific clinical setting.
Ces dernières années, le développement de l’imagerie médicale et de nouveaux agents ciblés ont révolutionné le domaine de l’oncologie, conduisant à une nouvelle entité : la maladie oligométastatique. L’ajout d’un traitement local des oligométastases à celui systémique pourrait conduire à des survies prolongées sans impact significatif sur la qualité de vie. Compte tenu de la prévalence élevée des oligométastases pulmonaires et de la toxicité pulmonaire accrue des nouveaux agents systémiques, cet article propose une revue complète de l’état actuel des connaissances sur la place de la radiothérapie pour les patients atteints d’oligométastases pulmonaires. Après avoir passé en revue le bilan préthérapeutique, les auteurs définissent plusieurs régimes de radiothérapie en fonction de la localisation et de la taille de l’oligométastase. Un commentaire sur la combinaison synergique du traitement médical et de la radiothérapie est également fait, ouvrant sur les étapes futures dans ce contexte clinique particulier.
Stereotactic Body Radiotherapy for Lung Oligo-metastases: Systematic Review and International Stereotactic Radiosurgery Society Practice Guidelines
2023, Lung Cancer
A systematic review of treatment characteristics, outcomes, and treatment-related toxicities of stereotactic body radiation therapy (SBRT) for pulmonary oligometastases served as the basis for development of this International Stereotactic Radiosurgery Society (ISRS) practice guideline.
In accordance with PRISMA guidelines, a systematic review was performed of retrospective series with ≥50 patients/lung metastases, prospective trials with ≥25 patients/lung metastases, analyses of specific high-risk situations, and all randomized trials published between 2012 and July 2022 in the MEDLINE or Embase database using the key words “lung oligometastases”, “lung metastases”, “pulmonary metastases”, “pulmonary oligometastases”, “stereotactic body radiation therapy (SBRT)” and “stereotactic ablative body radiotherapy (SBRT)”. Weighted random effects models were used to calculate pooled outcomes estimates.
Of the 1884 articles screened, 35 analyses (27 retrospective-, 5 prospective, and 3 randomized trials) reporting on treatment of >3600 patients and >4650 metastases were included. The median local control was 90 % (Range: 57–100 %) at 1 year and 79 % (R: 70–96 %) at 5 years. Acute toxicity ≥3 was reported for 0.5 % and late toxicity ≥3 for 1.8 % of patients. A total of 21 practice recommendations covering the areas of staging & patient selection (n = 10), SBRT treatment (n = 10), and follow-up (n = 1) were developed, with agreements rates of 100 %, except for recommendation 13 (83 %).
SBRT represents an effective definitive local treatment modality combining high local control rates with low risk of radiation-induced toxicities.
Stereotactic Body Radiation Therapy for Pulmonary Metastasis from Colorectal Adenocarcinoma: Biologically Effective Dose 150 Gy is Preferred for Tumour Control
2023, Clinical Oncology
To compare the local control rate of pulmonary metastatic lesions in colorectal adenocarcinoma treated with stereotactic body radiation therapy (SBRT) using a biologically effective dose with an α/β ratio of 10 (BED₁₀) of 150 Gy.
We analysed 231 pulmonary metastatic lesions from colorectal adenocarcinoma treated with SBRT in 135 patients. The patients were referred for the control of oligometastatic or oligoprogressive disease in the lungs. A dose of 40–60 Gy in three to eight fractions was delivered. The local control per tumour (LCpT) by BED₁₀ was evaluated. The local control per patient (LCpP), pulmonary progression-free survival (PPFS), any progression-free survival (APFS) and overall survival were also reported as clinical outcomes.
A significant difference was observed in the LCpT between the BED₁₀ groups (P < 0.001). The 1-, 2- and 3-year LCpT were 38.9%, 25.9% and 25.9% in BED₁₀ < 100 group; 84.1%, 62.6% and 60.4% in 100 ≤ BED₁₀ < 150 Gy group; and 97.3%, 94.9% and 85.2% in BED₁₀ ≥ 150 Gy group, respectively. BED₁₀ ≥ 150 Gy remained significant in the multivariate analysis of LCpT. The 3-year LCpP, PPFS, APFS and overall survival rates were 62.7%, 26.5%, 24.8% and 67.7%, respectively. Oligoprogression (versus oligometastasis), multiple pulmonary nodules and extrapulmonary metastasis were associated with a poor prognosis.
A BED₁₀ ≥ 150 Gy may be required to achieve sufficient local control. The indications for SBRT and the extent of metastatic disease should be assessed for proper estimation of the clinical outcomes.
Toxicity and Efficacy of Multitarget Thoracic Stereotactic Body Radiation Therapy
2023, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Assuming normal tissue constraints are achieved, this suggests that a single-isocenter approach is feasible in select cases and results in a modest increase in dose to the lungs. Colorectal histology was associated with a higher risk of LF after SBRT and, as indicated in multiple previous studies, this is thought to be due to the underlying differences in tumor biology and inherent radioresistance present in colorectal metastases.28-32 On univariate analysis, higher BED was found to be predictive of increased LF, which is contrary to the standard belief that higher dosing will improve local control.
With the increasing use of stereotactic body radiation therapy (SBRT) for primary and metastatic cancer, use of multitarget thoracic (MTT) SBRT is rising. Given the limited safety and efficacy data, we report the experience of this strategy from a large academic center.
Between 2012 and 2021, patients who received SBRT for ≥2 thoracic targets separated by ≤1 year were retrospectively reviewed. The primary endpoint was clinically significant radiation pneumonitis (CSRP) requiring steroids, oxygen, or intubation. Secondary endpoints included local failure (LF), initiation or change of systemic therapy (ICST), progression-free survival, and overall survival. Competing risk analysis was used to evaluate the cumulative incidence of CSRP, LF, and ICST. Univariate and multivariable analyses were performed to look for clinical and dosimetric predictive factors of CSRP and LF.
One hundred ninety patients (481 lesions) were treated with MTT SBRT with a median follow-up of 19.7 months. Indications for SBRT were oligometastases (n = 70; 36.8%), oligoprogression (n = 62; 32.6%), curative intent in patients with primary lung cancer (n = 37; 19.5%), and control of dominant areas of metastatic progression (n = 21; 11.0%). The number of irradiated tumors ranged from 2 to 7 and the majority of SBRT courses were delivered simultaneously (88.2%). Overall, 14 patients (7.4%) had CSRP, with 5 cases requiring oxygen. The cumulative incidence of CSRP at 6 and 12 months was 5.3% and 7.6%, respectively. The cumulative incidence of LF at 2 years was 10.5%. The cumulative incidence of ICST at 2 years was 41.1%. Median progression-free survival was 11.8 months and median overall survival was 51.3 months. On multivariable analysis, a higher lung V35_Gy (hazard ratio, 2.59; P = .02) was a statistically significant predictor of CSRP and colorectal histology predicted for higher LF (hazard ratio, 2.12; P = .02).
In one of the largest institutional series of MTT SBRT, rates of CSRP and LF were low. Optimizing plans to lower the lung V35_Gy may decrease the risk of CSRP.
Single-Fraction Stereotactic Ablative Body Radiotherapy to the Lung – The Knockout Punch
2022, Clinical Oncology
Citation Excerpt :
A German series with 94 lung metastases treated with single-fraction SABR (17–26 Gy, median 24 Gy) or multi-fraction SABR (20–60 Gy, median 45 Gy in two to twelve fractions) reported higher 1- and 2-year local control of 89% and 83% with single-fraction SABR compared with 75% and 59% with multi-fraction SABR (P = 0.026) [25]. This finding should be interpreted with caution, as the lesions receiving single-fraction SABR were significantly smaller (median 12 mm versus 16 mm), more peripheral (71.1% versus 42.4%) and had fewer CRC primaries (17.8% versus 42.9%) [25,26]. Conversely, a Dutch study with 327 lung metastases (57.3% CRC, 17.5% NSCLC, 5.3% melanoma) showed 30 Gy single-fraction SABR (BED10 = 120 Gy) to be associated with lower local control (hazard ratio 3.63, P < 0.001) compared with multi-fraction SABR with BED10> 100 Gy in three to five fractions in unadjusted univariable analysis; this was not significant in multivariable analysis adjusted for factors including CRC histology and chemotherapy [27].
This overview summarises the current evidence on efficacy and safety of single-fraction stereotactic ablative body radiotherapy (SABR) for primary lung cancers and lung metastases, in comparison with the more widely adapted multi-fraction SABR regimens. A literature search using the Medline database through PubMed was carried out using the following key words: (‘stereotactic’ or ‘sabr’ or ‘sbrt’), (‘radiotherapy’ or ‘radiation therapy’), (‘lung’ or ‘thorax’ or ‘thoracic’ or ‘chest’), (‘cancer’ or ‘metasta-’ or ‘oligometasta-’), alongside: (i) (‘single-fraction’ or ‘single-dose’) to identify trials and cohort studies with single-fraction SABR to lung malignant tumours and (ii) (‘fraction’ or ‘schedule’) limiting the search to ‘clinical trial’ and ‘randomized controlled trial’ to ensure thorough capture of lung SABR trials comparing different fractionations. The review discusses the radiobiological, technical and organ at risk considerations of single-fraction SABR to the lung.
Outcomes of extra-cranial stereotactic body radiotherapy for metastatic breast cancer: Treatment indication matters
2021, Radiotherapy and Oncology
To summarize the clinical outcomes of stereotactic body radiotherapy (SBRT) for metastatic breast cancer (mBC) from a large institution.
Patients with mBC who received extra-cranial SBRT to metastatic lesions from 2011 to 2017 were identified. Treatment indications were: oligometastases, oligoprogression, and local control of dominant tumor (CDT). Endpoints included overall survival (OS), progression-free survival (PFS), local control (LC) and cumulative incidence of starting/changing chemo or hormonal therapy (SCT). Univariate and multivariate analyses were used to identify predictive factors.
We analyzed 120 patients (193 treated metastatic lesions) with a median follow up of 15.25 months. 1-and 2-year LC rates were 89% and 86.6%, respectively. 1-and 2-year OS rates were 83.5% and 70%, respectively, with treatment indication and molecular subtype being the predictive factors on MVA. 1-year OS was 91.0%, 78.5% and 63.9% for oligometastases, oligoprogression and CDT, respectively (p = 0.003). The worst OS was seen in basal subtype with 1-and 2-year OS rates of 59.2% and 39.5% (p = 0.01). Treatment indication was found to be predictive for PFS and lower rates of SCT on MVA. 1-and 2-year PFS rates were 45% and 32%, respectively. The 1-year PFS for oligometastases, oligoprogression, and CDT was 66%, 19.6%, and 14.3%, respectively (p < 0.001). The cumulative incidence of SCT at 1-year was 12% for oligometastases, 39.7% for oligoprogression and 53.3% for CDT (p < 0.001).
Patients treated for oligometastases have better OS and PFS than those treated for oligoprogression or CDT. SBRT may delay SCT in mBC patients, particularly those with oligometastases. SBRT provided an excellent LC in mBC patients.

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Clinical InvestigationStereotactic Ablative Radiation Therapy for Pulmonary Metastases: Histology, Dose, and Indication Matter

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Population

Patient and tumor characteristics

Discussion

Int J Radiat Oncol Biol Phys

J Thorac Oncol

Radiother Oncol

Clin Oncol

J Thorac Oncol

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Clin Oncol (R Coll Radiol)

Radiother Oncol

Clin Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
Stereotactic Ablative Radiation Therapy for Pulmonary Metastases: Histology, Dose, and Indication Matter