Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): Study protocol for a randomized phase III trial

Background: Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4-10 metastatic cancer lesions. Methods: One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. Discussion: This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4-10 oligometastatic lesions. Trial registration: Clinicaltrials.gov identifier: NCT03721341. Date of registration: October 26, 2018

Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial

<p>Abstract</p> <p>Background</p> <p>Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control. Survival outcomes for patients with oligometastatic disease treated with SABR appear promising, but conclusions are limited by patient selection, and the lack of adequate controls in most studies. The goal of this multicenter randomized phase II trial is to assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone.</p> <p>Methods</p> <p>After stratification by the number of metastases (1-3 vs. 4-5), patients will be randomized between Arm 1: current standard of care treatment, and Arm 2: standard of care treatment + SABR to all sites of known disease. Patients will be randomized in a 1:2 ratio to Arm 1:Arm 2, respectively. For patients receiving SABR, radiotherapy dose and fractionation depends on the site of metastasis and the proximity to critical normal structures. This study aims to accrue a total of 99 patients within four years. The primary endpoint is overall survival, and secondary endpoints include quality of life, toxicity, progression-free survival, lesion control rate, and number of cycles of further chemotherapy/systemic therapy.</p> <p>Discussion</p> <p>This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with oligometastatic disease, and will inform the design of a possible phase III study.</p> <p>Trial registration</p> <p>Clinicaltrials.gov identifier: NCT01446744</p

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p

Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence

To assess the capability of perfusion MRI to differentiate between necrosis and tumor recurrence in patients showing radiological progression of cerebral metastases treated with stereotactic radiosurgery (SRS). From 2004 to 2006 dynamic susceptibility-weighted contrast-enhanced perfusion MRI scans were performed on patients with cerebral metastasis showing radiological progression after SRS during follow-up. Several perfusion MRI characteristics were examined: a subjective visual score of the relative cerebral blood volume (rCBV) map and quantitative rCBV measurements of the contrast-enhanced areas of maximal perfusion. For a total of 34 lesions in 31 patients a perfusion MRI was performed. Diagnoses were based on histology, definite radiological decrease or a combination of radiological and clinical follow-up. The diagnosis of tumor recurrence was obtained in 20 of 34 lesions, and tumor necrosis in 14 of 34. Regression analyses for all measures proved statistically significant (χ2 = 11.6–21.6, P < 0.001–0.0001). Visual inspection of the rCBV map yielded a sensitivity and specificity of 70.0 respectively 92.9%. The optimal cutoff point for maximal tumor rCBV relative to white matter was 2.00 (improving the sensibility to 85.0%) and 1.85 relative to grey matter (GM), improving the specificity to 100%, with a corresponding sensitivity of 70.0%. Perfusion MRI seems to be a useful tool in the differentiation of necrosis and tumor recurrence after SRS. For the patients displaying a rCBV-GM greater than 1.85, the diagnosis of necrosis was excluded. Salvage treatment can be initiated for these patients in an attempt to prolong survival

Risk of benign meningioma after childhood cancer in the DCOG-LATER cohort:contributions of radiation dose, exposed cranial volume, and age

Pediatric cranial radiotherapy (CrRT) markedly increases risk of meningiomas. We studied meningioma risk factors with emphasis on independent and joint effects of CrRT dose, exposed cranial volume, exposure age, and chemotherapy. The Dutch Cancer Oncology GroupLong-Term Effects after Childhood Cancer (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 19632001. Histologically confirmed benign meningiomas were identified from the population-based Dutch Pathology Registry (PALGA; 19902015). We calculated cumulative meningioma incidence and used multivariable Cox regression and linear excess relative risk (ERR) modeling. Among 5843 CCSs (median follow-up: 23.3 y, range: 5.052.2 y), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volume CrRT. Compared with CrRT doses of 119 Gy, no CrRT was associated with a low meningioma risk (hazard ratio [HR] = 0.04, 95% CI: 0.010.15), while increased risks were observed for CrRT doses of 2039 Gy (HR = 1.66, 95% CI: 0.833.33) and 40+ Gy (HR = 2.81, 95% CI: 1.306.08). CCSs whose cancers were diagnosed before age 5 versus 1017 years showed significantly increased risks (HR = 2.38, 95% CI: 1.394.07). In this dose-adjusted model, volume was not significantly associated with increased risk (HR full vs partial = 1.66, 95% CI: 0.863.22). Overall, the ERR/Gy was 0.30 (95% CI: 0.03unknown). Dose effects did not vary significantly according to exposure age or CrRT volume. Cumulative incidence after any CrRT was 12.4% (95% CI: 9.8%15.2%) 40 years after primary cancer diagnosis. Among chemotherapy agents (including methotrexate and cisplatin), only carboplatin (HR = 3.55, 95% CI: 1.627.78) appeared associated with meningioma risk. However, we saw no carboplatin dose-response and all 9 exposed cases had high-dose CrRT. After CrRT 1 in 8 survivors developed late meningioma by age 40 years, associated with radiation dose and exposure age, relevant for future treatment protocols and awareness among survivors and physicians

Role of On-Table Plan Adaptation in MR-Guided Ablative Radiation Therapy for Central Lung Tumors

Purpose: As patients with centrally located lung tumors are at increased risk of toxicity with stereotactic ablative radiation therapy (SABR), we performed stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for such patients. We retrospectively analyzed the benefits of daily on-table plan adaptation. Methods and Materials: Twenty-five patients with central lung tumors underwent a total of 182 fractions of video-assisted, respiration-gated SMART on the MRIdian (ViewRay, Inc). Risk-adapted fractionation was used to deliver 60 Gy in 8 fractions (n = 20) or 55 Gy in 5 fractions (n = 5). For each fraction, daily MR-guided setup and on-table plan reoptimization, based on planning target volume (PTV) coverage and organ-at-risk (OAR) constraints, was performed. Gated breath-hold delivery was performed under continuous MR guidance. Benefits of daily plan reoptimization were studied by comparing 168 “predicted” plans, which are the calculated baseline plans on the anatomy of the day, with the reoptimized treatment plans. Results: The reoptimized plan was chosen for treatment in 92% of fractions. On-table plan adaptation improved PTV coverage in 61% of fractions by achieving superior coverage by the prescription dose (V 100% ) and a higher median dose (D 50% ). Mean increase in PTV V 100% was 4.6% (P <.01) with a median of 91.2% and 95.0% in predicted and reoptimized plans, respectively. The benefits of on-table adaptation persisted in an analysis restricted to fractions in which the PTV change was ≤1 cm 3 compared with baseline. On-table plan adaptation reduced the number of OAR planning constraint violations (P <.05). Maximum OAR doses remained mostly stable, with on-table reoptimization avoiding excessive OAR doses in selected cases. Conclusions: On-table plan reoptimization during breath-hold MR-guided SABR for central lung tumors improves target coverage while avoiding excessive OAR doses. The SMART approach may widen the therapeutic window of SABR in high-risk patients with central lung tumors