Total tumor volume as a predictor of survival in patients with multiple oligometastases treated with stereotactic ablative radiotherapy (SABR).

BACKGROUND: Delivering stereotactic ablative radiotherapy (SABR) in patients with multiple oligometastases represents a challenge for clinical and technical reasons. We aimed to evaluate the outcome of patients affected by multiple oligometastases treated with SABR and the impact of tumor volume on survival. MATERIALS AND METHODS: We included all the patients treated with single course SABR for 3 to 5 extracranial oligometastases. All patients were treated with the volumetric modulated arc therapy (VMAT) technique with ablative intent. End-points of the analysis were overall survival (OS), progression free survival (PFS), local control (LC) and toxicity. RESULTS: 136 patients were treated from 2012 to 2020 on 451 oligometastases. Most common primary tumor was colorectal cancer (44.1%) followed by lung cancer (11.8%). A total of 3, 4 and 5 lesions were simultaneously treated in 102 (75.0%), 26 (19.1%), and 8 (5.9%) patients, respectively. Median total tumor volume (TTV) was 19.1 cc (range 0.6-245.1). With a median follow-up of 25.0 months, OS at 1 and 3 years was 88.4% and 50.2%, respectively. Increasing TTV was independent predictive factor of worse OS (HR 2.37, 95% CI 1.18-4.78, p = 0.014) and PFS (HR 1.63, 95% CI 1.05-2.54; p = 0.028). Median OS was 80.6 months if tumor volume was ≤ 10 cc (1 and 3 years OS rate 93.6% and 77.5%, respectively), and 31.1 months if TTV was higher than 10 cc (1 and 3 years OS rate 86.7% and 42.3%, respectively). Rates of LC at 1 and 3 years were 89.3% and 76.5%. In terms of toxicity, no grade 3 or higher toxicity was reported both in the acute and late settings. CONCLUSION: We demonstrated the impact of tumor volume on survival and disease control of patients affected by multiple oligometastases treated with single course SABR.

Multimodal Treatments for Brain Metastases from Renal Cell Carcinoma: Results of a Multicentric Retrospective Study.

The aim of this study was to evaluate the clinical outcomes of a large series of brain metastatic renal cell carcinoma (BMRCC) patients treated in three Italian centers. METHODS: A total of 120 BMRCC patients with a total of 176 lesions treated were evaluated. Patients received surgery plus postoperative HSRS, single-fraction SRS, or hypofractionated SRS (HSRS). Local control (LC), brain distant failure (BDF), overall survival (OS), toxicities, and prognostic factors were assessed. RESULTS: The median follow-up time was 77 months (range 16-235 months). Surgery plus HSRS was performed in 23 (19.2%) cases, along with SRS in 82 (68.3%) and HSRS in 15 (12.5%). Seventy-seven (64.2%) patients received systemic therapy. The main total dose and fractionation used were 20-24 Gy in single fraction or 32-30 Gy in 4-5 daily fractions. Median LC time and 6 month and 1, 2 and 3 year LC rates were nr, 100%, 95.7% ± 1.8%, 93.4% ± 2.4%, and 93.4% ± 2.4%. Median BDF time and 6 month and 1, 2 and 3 year BDF rates were n.r., 11.9% ± 3.1%, 25.1% ± 4.5%, 38.7% ± 5.5%, and 44.4% ± 6.3%, respectively. Median OS time and 6 month and 1, 2 and 3 year OS rates were 16 months (95% CI: 12-22), 80% ± 3.6%, 58.3% ± 4.5%, 30.9% ± 4.3%, and 16.9% ± 3.6, respectively. No severe neurological toxicities occurred. Patients with a favorable/intermediate IMDC score, a higher RCC-GPA score, an early occurrence of BMs from primary diagnosis, absence of EC metastases, and a combined local treatment (surgery plus adjuvant HSRS) had a better outcome. CONCLUSIONS: SRS/HSRS is proven to be an effective local treatment for BMRCC. A careful evaluation of prognostic factors is a valid step to manage the optimal therapeutic strategy for BMRCC patients.

The impact of stereotactic ablative radiotherapy on oligoprogressive metastases from renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) represents 80-90% of all kidney tumors and about 15-25% of patients will develop distant metastases. Systemic therapy represents the standard of care for metastatic patients, but stereotactic ablative radiotherapy (SABR) may play a relevant role in the oligoprogressive setting, defined as the progression of few metastases during an ongoing systemic therapy on a background of otherwise stable disease. Aim of the present study was to analyze the outcome of RCC patients treated with SABR on oligoprogressive metastases. MATERIALS AND METHODS: In this monocenter study, we analyzed patients affected by RCC treated with SABR on a maximum of 5 cranial or extracranial oligoprogressive sites of disease. Endpoints were overall survival (OS), progression-free survival (PFS), and toxicity. RESULTS: We included 74 oligoprogressions (26 intracranial and 48 extracranial) and 57 SABR treatments in 44 patients. Most common concomitant treatments were sunitinib (28, 49.1%), pazopanib (12, 21.0%) and nivolumab (11, 19.3%). Median follow-up was 19.0 months, and 1- and 2-year OS rates were 79.2% and 57.3%, respectively. Repeated SABR was a positive predictive factor for OS (p = 0.034). Median PFS was 9.8 months, with 1- and 2-year rates of 43.2% and 25.8%. At multivariable analysis, disease-free interval (p = 0.022) and number of treated metastases (p = 0.007) were significant for PFS. About 80% of patients continued the ongoing systemic therapy 1- and 2-years after SABR with no grade 3 or 4 toxicities. CONCLUSIONS: we confirmed the efficacy and safety of SABR for oligoprogression from RCC, with the potential to ablate resistant metastases and to prolong the ongoing systemic therapy.

Stereotactic Body Radiation Therapy for Lung and Liver Oligometastases from Breast Cancer: Toxicity Data of a Prospective Non-Randomized Phase II Trial.

AIMS: We report the mature toxicity data of a phase II non-randomized trial on the use of SBRT for lung and liver oligometastases. METHODS: Oligometastatic patients from breast cancer were treated with SBRT for up to five lung and/or liver lesions. Inclusion criteria were: age > 18 years, ECOG 0-2, diagnosis of breast cancer, less than five lung/liver lesions (with a maximum diameter <5 cm), metastatic disease confined to the lungs and liver or extrapulmonary or extrahepatic disease stable or responding to systemic therapy. Various dose-fractionation schedules were used. Then, a 4D-CT scan and FDG-CTPET were acquired for simulation and fused for target definition. RESULTS: From 2015 to 2021, 64 patients and a total of 90 lesions were irradiated. Treatment was well tolerated, with no G 3-4 toxicities. No grade ≥3 toxicities were registered and the coprimary endpoint of the study was met. Median follow-up was 19.4 months (range 2.6-73.1). CONCLUSIONS: The co-primary endpoint of this phase II trial was met, showing excellent tolerability of SBRT for lung and liver oligometastatic in breast cancer patients. Until efficacy data will mature with longer follow-up, SBRT should be regarded as an opportunity for oligometastatic breast cancer patients.

Training and validation of a knowledge-based dose-volume histogram predictive model in the optimisation of intensity-modulated proton and volumetric modulated arc photon plans for pleural mesothelioma patients.

BACKGROUND: To investigate the performance of a narrow-scope knowledge-based RapidPlan (RP) model for optimisation of intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) plans applied to patients with pleural mesothelioma. Second, estimate the potential benefit of IMPT versus VMAT for this class of patients. METHODS: A cohort of 82 patients was retrospectively selected; 60 were used to "train" a dose-volume histogram predictive model; the remaining 22 provided independent validation. The performance of the RP models was benchmarked, comparing predicted versus achieved mean and near-to-maximum dose for all organs at risk (OARs) in the training set and by quantitative assessment of some dose-volume metrics in the comparison of the validation RP-based data versus the manually optimised training datasets. Treatment plans were designed for a prescription dose of 44 Gy in 22 fractions (proton doses account for a fixed relative biological effectiveness RBE = 1.1). RESULTS: Training and validation RP-based plans resulted dosimetrically similar for both VMAT and IMPT groups, and the clinical planning aims were met for all structures. The IMPT plans outperformed the VMAT ones for all OARs for the contra-lateral and the mean and low dose regions for the ipsilateral OARs. Concerning the prediction performance of the RP models, the linear regression for the near-to-maximum dose resulted in Dachieved = 1.03Dpredicted + 0.58 and Dachieved = 1.02Dpredicted + 1.46 for VMAT and IMPT, respectively. For the mean dose it resulted: Dachieved = 0.99Dpredicted + 0.34 and Dachieved = 1.05Dpredicted + 0.27 respectively. In both cases, the linear correlation between prediction and achievement is granted with an angular coefficient deviating from unity for less than 5%. Concerning the dosimetric comparison between manual plans in the training cohort and RP-based plans in the validation cohort, no clinical differences were observed for the target volumes in both the VMAT and IMPT groups. Similar consistency was observed for the dose-volume metrics analysed for the OAR. This proves the possibility of achieving the same quality of plans with manual procedures (the training set) or with automated RP-based methods (the validation set). CONCLUSION: Two models were trained and validated for VMAT and IMPT plans for pleural mesothelioma. The RP model performance resulted satisfactory as measured by the agreement between predicted and achieved (after full optimisation) dose-volume metrics. The IMPT plans outperformed the VMAT plans for all the OARs (with different intensities for contra- or ipsilateral structures). RP-based planning enabled the automation of part of the optimisation and the harmonisation of the dose-volume results between training and validation. The IMPT data showed a systematic significant dosimetric advantage over VMAT. In general, using an RP-based approach can simplify the optimisation workflow in these complex treatment indications without impacting the quality of plans.

Stereotactic Body Radiation Therapy for Lung Metastases From Sarcoma in Oligometastatic Patients: A Phase 2 Study.

PURPOSE: The lung is the most frequent site of metastasis in patients with sarcoma. Pulmonary metastasectomy is the most common treatment performed. Stereotactic body radiation therapy (SBRT) has proven to be a potential alternative to resection. This prospective phase 2 study aimed to assess the role of SBRT for patients with lung metastases. METHODS AND MATERIALS: Adult patients with up to 4 lung metastases (LMs) ≤5 cm in diameter and unsuitable for surgery were included. Dose prescription was based on site and size: 30 Gy/1 fraction for peripheral lesions ≤10 mm, 60 Gy/3 fractions for peripheral lesions 11 to 20 mm, 48 Gy/4 fractions for peripheral lesions >20 mm, and 60 Gy/8 fractions for central lesions. The primary endpoint was the proportion of treated lesions free from progression at 12 months. Secondary endpoints were disease-free survival (DFS), overall survival (OS), and toxicity. RESULTS: Between March 2015 and December 2020, 44 patients with a total of 71 LMs were enrolled. Twelve-month local control was 98.5% ± 1.4%, reaching the primary aim; the median DFS time was 12 months (95% CI, 8-16 months), and the 1-, 2-, 3-, 4-, and 5-year PFS rates were 50% ± 7.5%, 19.5% ± 6.6%, 11.7% ± 5.8%, 11.7% ± 5.8%, and 11.7% ± 5.8%, respectively. The median OS time was 49 months (95% CI, 24-49 months), and the 1-, 2-, 3-, 4-, and 5-year OS rates were 88.6% ± 4.7%, 66.7 ± 7.6%, 56.8% ± 8.4%, 53.0% ± 8.6%, and 48.2% ± 9.1%, respectively. Prognostic factors recorded as significantly affecting survival were age, grade of primary sarcoma, interval time from diagnosis to occurrence of LMs, and number of LMs. No severe pulmonary toxicity (grade 3-4) occurred. CONCLUSIONS: The study found a local control of LMs in almost all patients treated, with negligible toxicity. Survival was also highly satisfactory. Well-designed randomized trials comparing surgery with SBRT for patients with metastatic lung sarcoma are needed to confirm these preliminary data.

Locally Advanced Non-Small Cell Lung Cancer: Clinical Outcome, Toxicity and Predictive Factors in Patients Treated with Hypofractionated Sequential or Exclusive Radiotherapy.

BACKGROUND: This study evaluated the outcome, toxicity and predictive factors in patients unfit for concurrent chemo-radiotherapy (CT-RT) treated with hypofractionated sequential CT-RT or exclusive radiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: We included patients affected by LA-NSCLC (stage IIA-IVA) treated with a total dose of 50-60 Gy in 20 fractions. The primary outcomes were local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS). Univariate analysis was used to correlate outcomes with prognostic factors. RESULTS: Between 2011 and 2019, 210 patients were treated, 113 (53.8%) with sequential CT-RT and 97 (46.2%) with exclusive RT. After a median follow-up of 15.3 months, 74 patients (35.2%) had a local progression and 133 (63.3%) had a distant progression. The one-, two- and five-year LC were 73.6%, 55.3% and 47.9%, respectively. At the time of analysis, 167 patients (79.5%) died. The one-, two- and five-year OS were 64.7%, 36% and 20%, respectively. PTV volume correlated with PFS (p = 0.001) and LC (p = 0.005). Acute and late toxicity occurred in 82% and 26% of patients. CONCLUSIONS: Albeit with the known limitations of a retrospective and heterogeneous study, our work shows that hypofractionated sequential CT-RT or exclusive RT offer a good local control and toxicity profile and a promising survival rate in LA-NSCLC patients unfit for the concurrent CT-RT scheme.

Oligoprogressive castration-resistant prostate cancer treated with metastases-directed stereotactic body radiation therapy: predictive factors for patients' selection.

Oligoprogression is defined as limited metastatic clone resistant to on-going systemic treatment that grows in a background of stable or responding systemic disease. Aim of the present study was to analyze oligoprogressive prostate cancer (PC) patients treated with stereotactic body radiation therapy (SBRT) during systemic treatment to identify predictive factors and improve patients' selection. We included PC patients treated with SBRT on a maximum of 3 sites of oligoprogression during systemic therapy. Endpoints were freedom from polymetastatic progression (FPP), local control (LC), distant progression free survival (DPFS), overall survival (OS), and next systemic therapy free survival (NEST-FS). Fifty-three patients were treated on 85 oligoprogressive metastases. Lymph nodes were the most common sites (56.47%), followed by bone (39.29%). Median follow-up was 24.9 months. Rates of FPP at 1- and 2-year were 80.1% and 68.9%, respectively. Median time to polymetastatic progression was 33.7 months. Disease free interval (p = 0.004), site of metastases (p = 0.011), and type of systemic therapy (p = 0.003) were significant for FPP. Switch or intensification of systemic therapy after SBRT was observed in 29 (54.72%) patients with a median NEST-FS of 15.2 months. LC at 1- and 2-year was 94.0% and 92.0%, with PSA doubling time resulted to be significantly associated (p = 0.047). Median DPFS was 8.93 months and median OS was 50.6 months. In conclusion, we confirmed the efficacy of SBRT for oligoprogression from PC, with the potential to prolong the on-going systemic therapy and interrupt the metastatic cascade.