Stereotactic body radiotherapy takes on Lung Oligometastases: Latest breakthroughs

3.1 Oligometastases origin

Tumors that arise from different primary tissues often exhibit different sensitivities to radiotherapy.^{2, 9} Ahmed's prospective study also confirmed significant differences in radiation sensitivity among lung metastases from different organizations (P = 0.002).²² Even oligometastases from the same primary tissue can have distinct tumor microenvironments compared to the primary tumor, leading to altered effects on radiosensitivity.²³ For instance, lung oligometastases stemming from primary colorectal cancer exhibit reduced sensitivity to SBRT in contrast to non-colorectal cancer lung oligometastases, leading to a decreased duration of PFS.^24-26 In Osti's retrospective study, it was found that the three-year local recurrence rates for lung oligometastases were 64.8% and 86.3% for colorectal cancer and non-colorectal cancer, respectively (P = 0.01). The rates of local progression at three years were 12.1% and 41.9%, respectively (P = 0.03).²⁷ And cervical cancer demonstrates higher radiation sensitivity compared to sarcoma, colorectal cancer, kidney cancer, and NSCLC.²⁸ Currently, it is unclear whether different doses of SBRT are administered to these lung oligometastases with different radiosensitivities.⁴ Several ongoing studies, including European Society for Radiotherapy and Oncology - European Organization for Research and Treatment of Cancer RADiotherapy InfrAstrucTure for Europe (E²-RADIatE), NCT02759783 and SABR-COMET 10 are evaluating whether the addition of SBRT improves clinical outcomes in patients with different tumor types.

3.2 The size and number of oligometastasis

Oligometastases are the intermediate states between localized and widespread metastases. Each clinical trial investigating SBRT for the treatment of oligometastatic cancer has employed a distinct screening methodology tailored to identify patients with oligometastatic diseases. Typically, oligometastatic disease is characterized by ≤ 5 metastatic lesions within three organs.^{18, 29, 30} The American Radium Society Lung Cancer Panel defines oligometastatic disease as ≤ 3 metastatic lesions.³¹ Both NCT02759783 and SABR-COMET 3 trials included patients with ≤ 3 metastases, while NRG BR002 required ≤ 4 metastases for inclusion in patients with lung metastases. In contrast, the SABR-COMET 10 study investigated the impact of adding SBRT to standard-of-care treatment on OS, oncologic outcomes, and quality of life in patients with 4–10 metastatic lesions; primary completion is expected in 2029. Kevin's³² retrospective study indicated that for patients with oligometastatic lung cancer, the number of metastases, whether singular or multiple, does not affect the efficacy or safety of SBRT. The size of pulmonary oligometastases is closely associated with LC, OS, and PFS in SBRT.² Nicosia²³ indicated that when the diameter of metastatic tumors exceeds 20 mm, the risk of local progression significantly increases and survival rates decrease. The 2-year local PFS for pulmonary metastases with maximum diameters of ≤10 mm, 10–20 mm, and >20 mm are 79.7%, 77.1%, and 66.6%, respectively. The corresponding 2-year survival rates were 61.7%, 57%, and 41.6%, respectively. Sharma³³ also identifies a smaller pulmonary metastatic tumor diameter (< 3 cm) as an independent factor for improved OS rates. However, the ISRS proposes that SBRT has demonstrated favorable safety and efficacy for single peripheral pulmonary metastases with a maximum diameter of 5 cm.² Currently, there is currently no uniform standard for determining the size of pulmonary metastases in patients undergoing SBRT.

3.3 Characteristic markers of lung oligometastases

Recently, the emergence of CT-based radiomics and specific biological markers for oligometastases has revitalized the prediction of treatment efficacy in patients with oligometastasis by injecting fresh impetus into the precision of SBRT therapy.^{5, 30, 34-38}

One project aimed to develop a comprehensive system to characterize and classify oligometastases. However, further validation is necessary to assess its effectiveness in clinical practice and relevance to prognosis. This validation will be conducted through the E ²-RADIatE clinical trial.³⁰ Lussier³⁹ is actively engaged in identifying specific biological markers for oligometastatic tumors and has identified a preliminary candidate in the form of an miRNA family. The SABR-COMET 3 study is currently investigating the correlation between the candidate biomarkers of oligometastatic diseases derived from blood samples and oncological outcomes. NCT02364557 aims to explore and validate independent prognostic biomarkers that can enhance PFS and OS in patients with oligometastatic breast cancer. This is achieved by collecting circulating tumor cells (CTCs), circulating tumor deoxyribonucleic acid (ctDNA), and circulating miRNAs.

Radiomics has the potential to provide reliable prognostications on cancer outcomes by depicting histology and genetic characteristics, as well as capturing intratumoral tumor heterogeneity.^{5, 34, 35} In a prospective study, Cilla analyzed CT images of 80 lung metastases from 56 patients undergoing SBRT and identified four radiomic features associated with complete response: surface-to-volume ratio (SVR; P = 0.003), skewness (Skew; P = 0.027), correlation (Corr; P = 0.024), and grey normalized level uniformity (GNLU; P = 0.015).³⁶ Fodor⁵ analyzed clinical data from 38 patients, encompassing 70 instances of colorectal cancer lung metastases undergoing SBRT, and demonstrated that four radiomic features were significantly associated with local progression: Statistical Variance (P = 0.002), Statistical Range (P = 0.013), Grey Level Size Zone Matrix (GLSZM)_zoneSizeNonUniformity (P = 0.022), and Grey Level Dependence Zone Matrix (GLDZM)_zoneDistanceEntropy (P = 0.026). Cheung³⁴ suggested that skewness and root mean square were predictive factors for response to radiation therapy, achieving an accuracy of 74.8%. Although most published studies were from a single institution, larger studies are necessary to validate these findings. Nonetheless, these studies provide valuable evaluation criteria for accurately screening patients for lung oligometastases that are best suited for SBRT therapy.

4.1 Robotic SBRT

With the continuous advancements in radiation therapy techniques, robotic stereotactic body radiation therapy (rSBRT) has emerged as a more precise, safe, and effective treatment modality for pulmonary metastases. rSBRT is a modern variant of SBRT and offers the ability to deliver treatments with true robotic precision and integrated AI-driven real-time motion synchronization. It provides organ protection by rapidly reducing the dose at the periphery of the target, even in irregularly shaped lesions.^{7, 40} For instance, the CyberKnife® system (Accuray, Sunnyvale, CA, USA) exemplifies the use of a robotically positioned linear accelerator to deliver real-time image-guided SBRT, while also enabling continuous monitoring of respiratory motion.^{36-38, 40, 41} Utilizing irradiation from multiple angles has been demonstrated to create sharp dose gradients, allowing for a higher central dose to be administered to the gross tumor volume (GTV) without a corresponding increase in the marginal dose to the planning target volume (PTV). This technique enables more precise administration of radiation therapy while reducing the risk of damage to the surrounding healthy tissues.

Several hospitals have used rSBRT for cancer treatment. Johannes⁷ conducted a comprehensive retrospective analysis of all patients with lung metastases who underwent rSBRT at the Medicine and University Hospital of Cologne between 2012 and 2019. The prescribed doses varied from 25 to 60 Gy, were administered in 1–8 fractions, and included a 62–80% isodose contour that covered the PTV. The observed toxicity rate was slightly lower than that of non-robotic SBRT for lung metastases. Similarly, Hayashi's⁴² retrospective analysis of the clinical application of rSBRT in the treatment of lung metastases indicated two-year rates for LC, PFS, and OS rates of 89.1%, 37.1%, and 71.3%, respectively. Among the patients, grade ≥ 2 toxicities were observed in two cases: one patient experienced grade 2 radiation pneumonitis, and another patient had grade 3 toxicity. Notably, no grade ≥ 2 toxicities were observed in patients with exclusive metastasis limited to one lung. Several studies have investigated the efficacy of rSBRT for the treatment of lung metastases. However, definitive evidence regarding the factors influencing the therapeutic effectiveness is still lacking. These factors include the biologically effective dose (BED) with thresholds of <100 Gy and ≥100 Gy (P = 0.002), as well as histology, specifically colorectal carcinoma compared to other histological types (P<0.001).⁷ Furthermore, it remains uncertain whether these factors can be regarded as independent predictors of the safety and effectiveness of rSBRT.

4.2 The optimal dose fractionation pattern of SBRT

The dose fractionation scheme of SBRT is usually related to the location, size, patient factors, and the experience of radiation oncologists in treating lung oligometastases.⁴³ Recent randomized clinical trials investigating lung metastases have yielded findings indicating that single-fraction SBRT is comparable to multiple-fractionation in terms of toxicity, efficacy, survival, and quality of life outcomes.^44-46 In a prospective phase II clinical trial conducted by Shankar,⁴⁴ the multi-fractionated group exhibited OS rates of 93% and 67% at 1 and 3 years respectively, while the single-fraction group showed 95% and 81%. Nicosia's retrospective approach also found that single-fractionation therapy was more effective.²³ A retrospective approach in Nicosia also found that the efficacy of single-fraction SBRT is slightly better than that of multiple. The updated NCCN guidelines have removed tumor size and a 2 cm distance from the chest wall as limiting factors for single-fraction SBRT.⁴ However, other scholars hold the opposite view, arguing that single-fractionated radiotherapy is associated with a worse LC rate.^{25, 38} The majority of experiments were conducted using varying fractionated doses. For example, SABR-COMET 3 recommends administering a dose of either 48 Gy/12 Gy/4 f or 54 Gy/18 Gy/3 f for peripheral lesions and 60 Gy/7 Gy/8 f for those within 2 cm of the mediastinum. In addition, SABR-COMET 10 provides doses of 20 Gy in one fraction, 30 Gy in three fractions, and 35 Gy in five fractions.

4.3 The relationship between BED and the efficacy of SBRT

The BED is a crucial concept in radiobiology and is based on a linear-quadratic model of the radiation effect. This model takes into account the radiosensitivity of irradiated tissues, the total dose, and the dose per fraction.⁴⁷ The BED is closely related to the efficacy of SBRT.^{47, 48} Previous experience in treating NSCLC led to the belief that a BED exceeding 100 Gy was necessary to ensure the effectiveness of SBRT.^{21, 48} Somasundaram⁴⁹ suggested that a BED greater than 95 Gy provides significant LC benefits for SBRT in metastatic sarcoma. A study by Aparicio on SBRT for lung metastases demonstrated that higher BED values, with BED_99% > 85 Gy and BED_50% > 100 Gy, resulted in better LC rates than lower BED values (P = 0.001).⁵⁰ In cases where tumors show radiation resistance, increasing the BED₁₀ may be necessary to achieve efficacy.²³ In Klement's retrospective study,⁵¹ BED emerged as a pivotal factor in achieving effective LC of lung metastatic cancer. Within the cohort of patients receiving SBRT for lung metastases, with BED₁₀ values spanning from 39.4 to 309.4 Gy, individuals with a history of chemotherapy necessitated a higher BED₁₀ (211 ± 19 Gy) to sustain a 2-year 90% LC rate. However, some prospective studies have indicated that for lung oligometastases accompanied by effective systemic anticancer therapy, it might be appropriate to reduce SBRT doses to levels below 100 Gy BED₁₀.^{12, 52} There is ongoing controversy regarding the necessity of such a high BED₁₀ for hypercentral metastatic cancer, and some scholars have suggested that lowering the BED₁₀ to less than 75 Gy in these patients could help preserve the surrounding normal tissue.⁵³ Further research is needed to investigate this matter.

The precise SBRT regimen for individuals afflicted with lung oligometastases continues to be a subject of persistent contention within the medical domain. The determination of the number of fractions, dose per fraction, and effective biological dose, whether in single- or multiple-fractionation modes, should be individualized based on the specific clinical scenario of each patient. A treatment strategy that prioritizes the preservation of the surrounding normal tissues while effectively targeting metastatic cancer is deemed a favorable option, provided that the radiotherapy plan can be executed safely and efficiently. For instance, in cases of ultracentral lung oligometastatic cancer, administering a single high-dose SBRT may pose the risk of damaging nearby structures, such as large blood vessels and bronchi. In such scenarios, adjusting the fraction dose relative to the surrounding metastatic tumors, increasing the number of fractions, or opting for a slightly lower BED are considered viable strategies for ensuring treatment efficacy. In cases in which metastatic tumors demonstrate resistance to radiotherapy, escalating the effective dose or BED is imperative to enhance the local control rate. The emergence of proton radiotherapy heralds a new era of SBRT, potentially leading to transformative advancements in this field. However, further, extensive prospective studies are warranted to validate these approaches and facilitate stratified research.