A predictive model of polymetastatic disease from a multicenter large retrospectIve database on colorectal lung metastases treated with stereotactic ablative radiotherapy: The RED LaIT-SABR study.

Aim: Stereotactic ablative radiotherapy (SABR) showed increasing survival in oligometastatic patients. Few studies actually depicted oligometastatic disease (OMD) evolution and which patient will remain disease-free and which will rapidly develop a polymetastatic disease (PMD) after SABR. Therefore, apart from the number of active metastases, there are no clues on which proven factor should be considered for prescribing local treatment in OMD. The study aims to identify predictive factors of polymetastatic evolution in lung oligometastatic colorectal cancer patients. Methods: This international Ethical Committee approved trial (Prot. Negrar 2019-ZT) involved 23 Centers and 450 lung oligometastatic patients. Primary end-point was time to the polymetastatic conversion (tPMC). Additionally, oligometastases number and cumulative gross tumor volume (cumGTV) were used as combined predictive factors of tPMC. Oligometastases number was stratified as 1, 2-3, and 4-5; cumGTV was dichotomized to the value of 10 cc. Results: The median tPMC in the overall population was 26 months. Population was classified in the following tPMC risk classes: low-risk (1-3 oligometastases and cumGTV ≤ 10 cc) with median tPMC of 35.1 months; intermediate-risk (1-3 oligometastases and cumGTV > 10 cc), with median tPMC of 13.9 months, and high-risk (4-5 oligometastases, any cumGTV) with median tPMC of 9.4 months (p = 0.000). Conclusion: The present study identified predictive factors of polymetastatic evolution after SABR in lung oligometastatic colorectal cancer. The results demonstrated that the sole metastases number is not sufficient to define the OMD since patients defined oligometastatic from a numerical point of view might rapidly progress to PMD when the cumulative tumor volume is high. A tailored approach in SABR prescription should be pursued considering the expected disease evolution after SABR, with the aim to avoid unnecessary treatment and toxicity in those at high risk of polymetastatic spread, and maximize local treatment in those with a favorable disease evolution.

Stereotactic radiotherapy for adrenal oligometastases.

Approximately 50% of melanomas, 30-40% of lung and breast cancers and 10-20% of renal and gastrointestinal tumors metastasize to the adrenal gland. Metastatic adrenal involvement is diagnosed by computed tomography (CT ) with contrast medium, ultrasound (which does not explore the left adrenal gland well), magnetic resonance imaging (MRI) with contrast medium and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18FDGPET-CT ) which also evaluates lesion uptake. The simulation CT should be performed with contrast medium; an oral bolus of contrast medium is useful, given adrenal gland proximity to the duodenum. The simulation CT may be merged with PET-CT images with 18FDG in order to evaluate uptaking areas. In contouring, the radiologically visible and/or uptaking lesion provides the gross tumor volume (GTV ). Appropriate techniques are needed to overcome target motion. Single fraction stereotactic radiotherapy (SRT ) with median doses of 16-23 Gy is rarely used. More common are doses of 25-48 Gy in 3-10 fractions although 3 or 5 fractions are preferred. Local control at 1 and 2 years ranges from 44 to 100% and from 27 to 100%, respectively. The local control rate is as high as 90%, remaining stable during follow-up when BED10Gy is equal to or greater than 100 Gy. SRT-related toxicity is mild, consisting mainly of gastrointestinal disorders, local pain and fatigue. Adrenal insufficiency is rare.

Stereotactic radiotherapy for lung oligometastases.

30-60% of cancer patients develop lung metastases, mostly from primary tumors in the colon-rectum, lung, head and neck area, breast and kidney. Nowadays, stereotactic radiotherapy (SRT ) is considered the ideal modality for treating pulmonary metastases. When lung metastases are suspected, complete disease staging includes a total body computed tomography (CT ) and/or positron emission tomography-computed tomography (PET -CT ) scan. PET -CT has higher specificity and sensitivity than a CT scan when investigating mediastinal lymph nodes, diagnosing a solitary lung lesion and detecting distant metastases. For treatment planning, a multi-detector planning CT scan of the entire chest is usually performed, with or without intravenous contrast media or esophageal lumen opacification, especially when central lesions have to be irradiated. Respiratory management is recommended in lung SRT, taking the breath cycle into account in planning and delivery. For contouring, co-registration and/or matching planning CT and diagnostic images (as provided by contrast enhanced CT or PET-CT ) are useful, particularly for central tumors. Doses and fractionation schedules are heterogeneous, ranging from 33 to 60 Gy in 3-6 fractions. Independently of fractionation schedule, a BED10 > 100 Gy is recommended for high local control rates. Single fraction SRT (ranges 15-30 Gy) is occasionally administered, particularly for small lesions. SRT provides tumor control rates of up to 91% at 3 years, with limited toxicities. The present overview focuses on technical and clinical aspects related to treatment planning, dose constraints, outcome and toxicity of SRT for lung metastases.

Stereotactic radiotherapy for liver oligometastases.

The liver is the first metastatic site in 15-25% of colorectal cancer patients and one of the first metastatic sites for lung and breast cancer patients. A computed tomography (CT ) scan with contrast medium is a standard procedure for assessing liver lesions but magnetic resonance imaging (MRI) characterizes small lesions better thanks to its high soft-tissue contrast. Positron emission tomography with computed tomography (PET-CT ) plays a complementary role in the diagnosis of liver metastases. Triphasic (arterial, venous and time-delayed) acquisition of contrast-medium CT images is the first step in treatment planning. Since the liver exhibits a relatively wide mobility due to respiratory movements and bowel filling, appropriate techniques are needed for target identification and motion management. Contouring requires precise recognition of target lesion edges. Information from contrast MRI and/or PET-CT is crucial as they best visualize metastatic disease in the parenchyma. Even though different fractionation schedules were reported, doses and fractionation schedules for liver stereotactic radiotherapy (SRT ) have not yet been established. The best local control rates were obtained with BED10 values over 100 Gy. Local control rates from most retrospective studies, which were limited by short follow-ups and included different primary tumors with intrinsic heterogeneity, ranged from 60% to 90% at 1 and 2 years. The most common SRT-related toxicities are increases in liver enzymes, hyperbilirubinemia and hypoalbuminemia. Overall, late toxicity is mild even in long-term follow-ups.

Stereotactic body radiation therapy for the treatment of pleural metastases in patients with thymoma: a retrospective review of 22 patients.

BACKGROUND: Thymomas can benefit of cytoreductive surgery even if a complete resection is not feasible. The pleural cavity is the most common site of progression and the resection of pleural metastases can be performed in selected patients. We evaluated the results of stereotactic body radiation therapy for the treatment of pleural metastases in patients not eligible for surgery. METHODS: We retrospectively selected 22 patients treated with stereotactic body radiation therapy for pleural metastases between 2013 and 2019. According to RECIST criteria 1.1 modified for thymic epithelial tumors, time to local failure and progression free survival were calculated using Kaplan-Meier method. RESULTS: The median age was 40 years (range, 29-73 years). There were 1 A, 3 AB, 3 B1, 3 B2, 3 B2/B3 and 9 B3 thymomas. Pleural metastases and primary tumor were synchronous in 8 patients. Five patients had a single pleural metastatic site and 17 presented multiple localizations. Sixteen patients received stereotactic body radiation therapy on multiple sites of pleural metastases. The median dose of radiation was 30 Gy (range, 24-40 Gy). With a median follow-up of 33.2 months (95% CI: 13.1-53.3 months), ten patients experienced disease progression with a median progression free survival was 20.4 months (95% CI: 10.7-30.0 months). The disease control rate was 79% and 41% after 1 and 2 years, respectively. Local disease control rate was 92% and 78% after 1 and 2 years, respectively. There were not significant differences in progression free survival between patients diagnosed with synchronous and metachronous metastases (P=0.477), across those treated or not with chemotherapy (P=0.189) and between those who received or not a previous surgical resection of the pleural metastases (P=0.871). There were not grade 3-4 toxicities related to the treatment. CONCLUSIONS: Stereotactic body radiation therapy of pleural metastases is feasible and offers a promising local control of diseases. The impact of this treatment on patients' survival is hardly predictable because of the heterogeneous clinical behavior of thymomas.

Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis.

UNLABELLED: The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials. PATIENT SUMMARY: This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.

Stereotactic radiotherapy for adrenal gland metastases: university of Florence experience.

PURPOSE: To evaluate a retrospective single-institution outcome after hypofractionated stereotactic body radiotherapy (SBRT) for adrenal metastases. METHODS AND MATERIALS: Between February 2002 and December 2009, we treated 48 patients with SBRT for adrenal metastases. The median age of the patient population was 62.7 years (range, 43-77 years). In the majority of patients, the prescription dose was 36 Gy in 3 fractions (70% isodose, 17.14 Gy per fraction at the isocenter). Eight patients were treated with single-fraction stereotactic radiosurgery and forty patients with multi-fraction stereotactic radiotherapy. RESULTS: Overall, the series of patients was followed up for a median of 16.2 months (range, 3-63 months). At the time of analysis, 20 patients were alive and 28 patients were dead. The 1- and 2-year actuarial overall survival rates were 39.7% and 14.5%, respectively. We recorded 48 distant failures and 2 local failures, with a median interval to local failure of 4.9 months. The actuarial 1-year disease control rate was 9%; the actuarial 1- and 2-year local control rate was 90%. CONCLUSION: Our retrospective study indicated that SBRT for the treatment of adrenal metastases represents a safe and effective option with a control rate of 90% at 2 years.

Efficacy of eradicative radiotherapy for limited nodal metastases detected with choline PET scan in prostate cancer patients.

AIMS AND BACKGROUND: In patients with recurrent prostate cancer, discriminating local or systemic recurrence is critical to decide second-line treatment. We investigated the capability of stereotactic body radiotherapy to treat limited nodal recurrences, detected using choline PET scan. METHODS AND STUDY DESIGN: Seventy-one patients with biochemical failure were studied after prostate cancer treatment: prostatectomy (28), radiotherapy (15) or both (28). Following computed tomography and choline PET imaging, stereotactic body radiotherapy was delivered on pathological lymphatic areas by 6 MV Linac, using dynamic micromultileaf collimation and intensity-modulated arc therapy optimization. Sixty days post-treatment, choline PET/CT imaging was carried out. RESULTS: Median follow-up was 29 months (range, 14.4-48). Choline PET detected recurrences in 39 of 71 patients. Median PSA velocity was 0.40 ng/ml/year in PET-negative patients and 2.88 ng/ml/year in PET-positive subjects (P < 0.05). Twenty-five patients with limited nodal recurrences, out of the 71 submitted to choline PET, received eradicative radiotherapy. Persistent regression was recorded in 13; early spread to bone was found in 2 cases; lymph node recurrences in 8, all in sites outside the irradiated areas; 2 patients were lost to follow-up. At the 3-year follow-up, overall survival, disease-free survival and local control rates were 92%, 17% and 90%, respectively. In patients with a complete regression, PSA fell from 5.65 to 1.40 ng/ml (median). PSA nadir value (median 1.06 ng/ml) was maintained for 5.6 months (median). CONCLUSIONS: Stereotactic body radiotherapy was effective in disease eradication of limited nodal recurrences from prostate cancer, saving patients from, or at least postponing, systemic treatments.

Unresectable locally advanced pancreatic cancer: a multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration.

BACKGROUND: Pancreatic cancer accounts for approximately 3% of cancer deaths in Europe. Locally advanced pancreatic cancer (LAPC) involves vascular structures, and resectability is low, with a median survival time of 6 to 11 months. We conducted a prospective, nonrandomized study of patients with LAPC to assess the effect of stereotactic body radiotherapy (SBRT) on local response, pain control, and quality of life (QOL). METHODS: Twenty-three patients with histologically confirmed LAPC underwent SBRT. Radiotherapy (30 Gy) was delivered in three fractions, and treatment toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE v. 3.0). All patients received also gemcitabine chemotherapy and were followed up until death. Local control was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, pain control was assessed with a visual analog scale, and QOL was assessed with the SF-36 instrument (Italian v. 1.6). RESULTS: No grade 2 or higher acute or late toxicity was observed. The overall local response ratio was 82.6% (14 partial response, 2 complete response, 3 stable disease). SBRT showed a good short-term efficacy in controlling both pain and QOL. Median survival was 10.6 months, with a median follow-up of 9 months. The LAPC became resectable in 8% of the patients. Median time to progression of disease was 7.3 months. Six patients developed early metastatic disease. CONCLUSIONS: The SBRT method is a promising treatment for LAPC. Local control rates, even compared to historical data from conventional radiotherapy, can be achieved with minimal toxicity. Resectability can also be achieved.

Image-guided robotic stereotactic radiosurgery for unresectable liver metastases: preliminary results.

The aim of this study was to evaluate the usefulness of image-guided robotic stereotactic radiosurgery for the local control of unresectable liver metastases from colorectal and non-colorectal cancer. Twenty-seven consecutive patients (median age 62 years, range 47-80 years) with liver metastases considered unsuitable for surgery were enrolled in the study. The diagnosis was colorectal cancer liver metastasis in 11 (41%) and other secondary malignancies in 16 (59%) patients. The patients were treated with 25 to 60 Gy (median 36 Gy) delivered in 3 consecutive fractions, and the isodose value covering the planning target volume was 80% of the prescribed dose. Overall, the mean tumour volume was 81.6+/-35.9 ml. Inhibition of growth or a reduction in size was obtained in 20 (74.1%) patients: 7 with complete response and 13 with partial response. There was a local complete response with other single lesions appearing in 3 (11.1%) patients and progressive disease in 4 (14.8%). The median post-treatment volume of the tumour was 24 ml (range 0-54 ml) among the responders. Mild or moderate transient hepatic dysfunction was evident in 9 patients and minor complications in five. Two patients with progressive disease died of liver failure. In conclusion, in patients with liver metastases unsuitable for surgery, stereotactic radiosurgery achieves high rates of local disease control, representing an acceptable alternative therapy, but should be further studied in larger series.

On-line image guidance for frameless stereotactic radiotherapy of lung malignancies by cone beam CT: comparison between target localization and alignment on bony anatomy.

INTRODUCTION: Free-breathing stereotactic radiotherapy for lung malignancies requires reliable prediction of respiratory motion and accurate target localization. A protocol was adopted for reproducibility and reduction of respiratory motion and for target localization by CBCT image guidance. Tumor respiratory displacements and tumor positioning errors relative to bony anatomy alignment are analyzed. MATERIALS AND METHOD: Image guided SRT was performed for 99 lung malignancies. Two groups of patients were considered: group A did not perform any breathing control; group B controlled visually their respiratory cycle and volumes on an Active Breathing Coordinator (ABC) monitor during the acquisition of simulation CT and CBCT, and treatment delivery. GTV on end inhale and exhale CT data sets were fused in an ITV and the extent of tumor motion evaluated between these 2 phases. A pre-treatment CBCT was acquired and aligned to the reference CT using bony anatomy; for tumor positioning the ITV contour on the reference CT was matched to the visible tumor on CBCT. Interobserver variability of tumor positioning was evaluated. ITV and CBCT tumor dimensions were compared. RESULTS: 3D tumor breathing displacement (mean+/-SD) was significantly higher for group A (14.7+/-9.9 mm) than for group B (4.7+/-3.1 mm). The detected differences between tumor and bony structure alignment below 3 mm were 68% for group B and 45% for group A, reaching statistical significance. Interobserver variability was 1.7+/-1.1 mm (mean+/-SD). Dimensions of tumor image on CBCT were consistent with ITV dimensions for group B (max difference 14%). CONCLUSIONS: The adopted protocol seems effective in reducing respiratory internal movements and margin. Tumor positioning errors relative to bony anatomy are also reduced. However bony anatomy as a surrogate of the target may still lead to some relevant positioning errors. Target visualization on CBCT is essential for an accurate localization in lung SRT.

Cone beam CT image guidance for intracranial stereotactic treatments: comparison with a frame guided set-up.

PURPOSE: An analysis is performed of the setup errors measured by a kV cone beam computed tomography (CBCT) for intracranial stereotactic radiotherapy (SRT) patients immobilized by a thermoplastic mask and a bite-block and positioned using stereotactic coordinates. We evaluated the overall positioning precision and accuracy of the immobilizing and localizing systems. The potential of image-guided radiotherapy to replace stereotactic methods is discussed. METHODS AND MATERIALS: Fifty-seven patients received brain SRT. After a frame-guided setup, before each fraction (131 fractions), a CBCT was acquired and the detected displacements corrected online. Translational and rotational errors were analyzed calculating overall mean and standard deviation. A separate analysis was performed for bite-block (in conjunction with mask) and for simple thermoplastic mask. Interobserver variability for CBCT three-dimensional registration was assessed. The residual error after correction and intrafractional motion were calculated. RESULTS: The mean module of the three-dimensional displacement vector was 3.0 +/- 1.4 mm. Setup errors for bite block and mask were smaller (2.9 +/- 1.3 mm) than those for thermoplastic mask alone (3.2 +/- 1.5 mm), but statistical significance was not reached (p = 0.15). Interobserver variability was negligible. The maximum margin calculated for residual errors and intra fraction motion was small but not negligible (1.57 mm). CONCLUSIONS: Considering the detected setup errors, daily image guidance is essential for the efficacy of SRT treatments when mask immobilization is used, and even when a bite-block is used in conjunction. The frame setup is still used as a starting point for the opportunity of rotational corrections. Residual margins after on-line corrections must be evaluated.

Relevance of biologically equivalent dose values in outcome evaluation of stereotactic radiotherapy for lung nodules.

PURPOSE: Different biologically equivalent dose (BED) values associated with stereotactic radiotherapy (SRT) of patients with primary and metastatic pulmonary nodules were studied. The BED values were calculated for tumoral tissue and low alpha/beta ratio, assuming that better local response could be obtained by using stereotactic high-BED treatment. METHODS AND MATERIALS: Fifty-eight patients with T1-T3 N0 non-small-cell lung cancer and 46 patients with metastatic lung nodules were treated with SRT. The BED was calculated for alpha/beta ratios of 3 and 10. Overall survival (OS) was assessed according to Kaplan-Meier and appraised as a function of three BED levels: low (30-50 Gy), medium (50-70 Gy), and high (70-98 Gy; alpha/beta = 10). RESULTS: The OS rates for all 104 patients at 12, 24, and 36 months were 73%, 48.3%, and 35.8%, respectively. Local response greater than 50% for low, medium, and high BED values was observed in 54%, 47%, and 73%, respectively. In the high-BED treated group, OS rates at 12, 24, and 36 months (80.9%, 70%, and 53.6%, respectively) were significantly improved compared with low- (69%, 46.1%, and 30.7%, respectively) and medium-BED (67%, 28%, and 21%, respectively) treated patients. Results are also discussed in terms of BED calculated on alpha/beta 3 Gy characteristic of the microcapillary bed. No acute toxicity higher than Grade 1 was observed. CONCLUSIONS: Radioablation of pulmonary neoplastic nodules may be achieved with SRT delivered by using a high-dose fraction with high BED value.

Stereotactic interstitial radiosurgery with a miniature X-ray device in the minimally invasive treatment of selected tumors in the thalamus and the basal Ganglia.

The aim of this study was to evaluate the role of interstitial radiosurgery (IR) using the photon radiosurgery system (PRS) in the treatment of selected tumors within the thalamus and the basal ganglia. The PRS is a miniature X-ray generator that was developed for interstitial irradiation. This series included 14 patients (5 with glioblastomas, 4 with low-grade astrocytomas and 5 with metastases) harboring spheroidal lesions with dimensions ranging from 13 to 42 mm (mean 30 mm). After stereotactic biopsy, a radiation dose ranging from 6 to 15.4 Gy (mean 11.3 Gy) was delivered at the target volume margins. Follow-up varied from 3 to 26 months (mean 10.2 months). In the group of glioblastomas, 3 patients died (3-12 months after the procedure) because of tumor progression, while the remaining had tumor control. Two patients with metastases died from systemic disease (4-9 months after the treatment), and 3 were alive and well at the end of the study. Local control was achieved in all metastases. Patients with low-grade astrocytomas were well and imaging studies showed tumor control PRS IR is a minimally invasive procedure for the treatment of selected glial or secondary brain tumors. Compared to conventional radiosurgery (brachytherapy and external radiosurgery), PRS IR presents dose delivery characteristics useful for the treatment of tumors in the thalamus and basal ganglia, without inconveniences such as handling radioisotopes, the need of expensive facilities and radiation protection measures. Although the clinical value needs further investigations, PRS IR seems to be effective in metastases while it provides less benefit in malignant gliomas. PRS IR could have a major role in the treatment of low-grade astrocytomas.