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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.
The oligometastatic disease state was first defined in 1995 and refers to an stage of disease where cancer has spread beyond the site of origin, but is not yet widely metastatic . In such a state of limited metastatic disease burden, it is hypothesized that eradication of all sites of metastatic disease could result in long-term survival, or even cure, in a subgroup of patients . Ablation of metastatic deposits can be achieved surgically, or through stereotactic ablative radiotherapy (SABR), a new radiotherapy technology that delivers very large, hypofractionated doses of radiotherapy with high precision to small tumor targets, with high rates of local control.
Randomized trials are therefore necessary to establish the utility of ablative treatment of oligometastatic disease [10, 12], but such randomized trials are rare. One such completed randomized trial, Radiation Therapy and Oncology Group Trial 9508, compared whole brain radiotherapy (WBRT) with WBRT + stereotactic treatment for patients with 1-3 brain metastases, and found an overall survival advantage only in patients with a single metastasis and those patients in the most favorable baseline recursive partitioning analysis (RPA) prognostic group . Patients with inferior baseline prognostic factors did not achieve a survival benefit from stereotactic treatment. At least one other randomized trial investigating the oligometastatic paradigm has recently opened: in 2010, the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) trial was launched, comparing metastatectomy with best supportive care in patients with pulmonary metastases from colorectal cancer .
It is unclear if all patients with oligometastatic disease benefit from SABR, in terms of improved local control, improved survival or improved quality of life. Although SABR generally results in ablation of each metastatic target, patients remain at high risk of further metastatic progression. Results from SABR for treatment of oligometastases in published studies appears promising, but these promising results may be due to patient selection, rather than treatment intervention, and are based on comparisons with historical controls. The benefit of comprehensive treatment of oligometastases can only be demonstrated conclusively in the context of a randomized trial.
The randomized phase II design is required for 3 reasons: First, the randomization will provide an appropriate control group to serve as a comparator for the experimental arm. Historical or contemporaneous non-randomized controls would not be appropriate due to the multitude of biases that could be introduced by patient selection and other confounders. Second, a small sample size will allow for adequate power to assess for an early overall survival difference, quality of life, and to evaluate toxicity in the SABR arm. Third, the results will allow for a decision as to whether a multi-institutional phase III trial is warranted, and inform the design of such a trial.
Prior chemotherapy allowed but no chemotherapy (cytotoxic or molecularly targeted agents) therapy 4 weeks prior to first fraction of radiotherapy, during radiotherapy, or for two weeks after last fraction. Hormonal therapy is allowed.
For Arm 2, all treatments in this study are based on current protocols in clinical use at the LRCP and VUmc for treatment of lung , liver , brain [19, 20], and spinal column  metastases. The guiding principle for radiotherapy is to achieve disease control but to minimize any potential adverse impact on quality of life. Concurrent chemotherapy or targeted therapy at the time of radiotherapy is not permitted within the 4 weeks prior to SABR. Hormone therapy is permitted.
It is strongly recommended that dose constraints not be exceeded. If a dose constraint cannot be achieved due to overlap of the target with an organ at risk, the fractionation can be increased or the target coverage compromised in order to meet the constraint. It is strongly recommended that in cases where the target coverage is compromised in order to meet the constraint, the mean dose delivered to the GTV should be at least 80% of the nominal dose in Table 1. All such cases of dose reduction or target coverage compromise must be approved by the local PI prior to treatment. For vertebral tumors, an adequate PRV of 2 mm must be added to the spinal cord, and the dose constraints apply to this PRV.
For lung or liver metastases, each metastasis can be treated with a separate isocenter if metastases are well-separated. Since most metastases are treated every other day (Table 1), when two metastases are treated, these can be done on alternating days to reduce the daily time required on the linear accelerator (e.g. Monday/Wed/Friday for one target, and Tues/Thurs/Mon for another). For brain metastases, all the metastases should be treated at the same time. For bone metastases, if multiple metastases can be imaged and localized at the same time, they can be treated at the same time, otherwise, they can be treated on alternate days.
All radiotherapy plans must meet target dose levels for organs at risk (Tables 2). Prior to plan approval, the dose to each organ at risk must be verified by the physicist or treating physician. It is strongly recommended that dose constraints not be exceeded.
Patients treated with prior chemotherapy are eligible for this study, however, no chemotherapy agents (cytotoxic, or molecularly targeted agents) are allowed within the period of time commencing 4 weeks prior to radiotherapy (conventional or SABR) lasting until 2 weeks after the last fraction. Hormonal therapy is allowed. Use of chemotherapy schemes containing potent enhancers of radiation damage (e.g. gemcitabine, adriamycin) are discouraged within the first month after SABR.
Overall survival will be measured as time until death from any cause, and progression-free survival as time to either progression or death, whichever occurs first. Lesion response will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee ( ). The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.
There will be a 1:2 randomization between Arm 1 and Arm 2. In order to detect a 6-month improvement in median survival from 9 months to 15 months with SABR, a total of 93 patients (31 in Arm 1 and 62 in Arm 2) will be needed. Assuming a 5% rate of loss to follow-up, a total of 99 patients will be accrued (33 in Arm 1 and 66 in Arm 2). The study projects accrual over 48 months with 12 months of additional follow-up. Accrual targets are as follows: 20 patients in year 1, and 25-30 patients in years 2, 3, and 4.
The DSMC will meet annually after study initiation and after 50 patients are accrued to review toxicity outcomes. If any grade 3-5 toxicity is reported, the DSMC will review the case notes to determine if such toxicity is related to treatment. If the DSMC deems that toxicity rates are excessive (>25% grade 3 toxicity, or >5% grade 4 or 5 toxicity), then the DSMC can, at its discretion, recommend cessation of the trial, dose adjustment, or exclusion of certain treatment sites that are deemed as high-risk for complications. 350c69d7ab