metastases. Theoretical basis for this approach comes from the surgical metastasectomy data that showed overall survival benefit for oligo-metastatic RCC patients when all site of metastases were resected.39 SAbR offers a non-invasive technique for metastasectomy that can be applied to multiple sites of metastases throughout the body. The earlier reports on extracranial applications highlight how patient selection may be a key factor in whether SAbR is successful. Svedman et al,40 for example, suggest that SAbR can be considered as an option to surgery when there are a limited number of metastases, as local treatment in RCC with an indolent presentation or as a method of reducing tumor burden prior to medical treatment. One of the intriguing suggestions from this study is whether high-dose radiotherapy triggers regression of untreated metastases. Support for this hypothesis comes from other authors who speculate that this effect could be due to radiation induced immune response.41 From the same institution, the report from Wersäll et al23 also explored the extent to which certain patients may benefit more than others from SAbR, thus highlighting how patient selection could be used to greater advantage. For example, retrospective results in 58 patients in this Swedish study indicated that patients with one to three metastases and patients with inoperable primary tumors or local recurrence benefited more from this treatment than those with four or more metastases. The majority of patients were treated for metastases in the lungs. In a detailed analysis of our institutional experience for treatment of extracranial mRCC,24 we provide guidelines with dosimetric data and new insights on clinical factors affecting local control. Until recently, little has been known definitively about these factors. In the largest published experience of 175 metastatic lesions from 84 patients, we observed no failures when SAbR regimens of 24 Gy, 12 Gy, or 8 Gy in 1, 3, or 5 fractions were used with at least 95% PTV coverage. Overall local control rates were 91.2% at a one year. The most critical factors affecting local control of mRCC were adequate radiation dose and appropriate target coverage. Late toxicities were low and less than 3% were high grade. Interestingly, previous use of >1 systemic therapy came out to be an independent predictor of local failure in multi-variate analysis suggesting that higher radiation doses may be required to achieve the same local control in these patients. In one of the subgroups analyzed in this retrospective study are patients that are showing progression on limited sites of disease on systemic therapy that received SAbR to delay the switching of systemic therapy or essentially to extend the progression free survival (PFS) of the ongoing systemic therapy. The benefits of treating oligo-progressive RCC metastases with SAbR could be many folds: 1) owing to the tumor genetic heterogeneity between primary and metastatic sites as described elegantly by Gerlinger et al.42 It is possible that a majority of metastases in a patient are responding and only 1-2 sites are progressing. Therefore, SAbR allows continuation of a 78 Kidney Cancer Journal therapy that is otherwise effective and being tolerated by the patient. 2) By allowing effective continuation of the current therapy, SAbR may be preserving more lines of systemic therapy for a patient thereby possibly extending survival (OS). In a case report published by the same institution. Straka et. al. demonstrated extending the PFS of sunitinib from 14 months to 22 months by the use of SAbR for oligo-progressive disease.43 While the reported local control of SAbR for RCC is high, the question remains as to who truly benefits from the local control. It may be intuitive to treat oligometastatic RCC patients with SAbR either with a curative intent in the setting of metachronous metastasis or with the intent of preserving quality of live by delaying the initiation of systemic therapy. However, the most important question is whether by delaying systemic therapy, is the OS is being compromised? Data is lacking in this arena as to the effect of SAbR in PFS and OS, a few intriguing ongoing clinical trials are expected to provide insight to these settings. In one of these clinical trials begin conducted at UT Southwestern, oligo-metastatic RCC patients are being randomized to receive SAbR or standard of care systemic therapy in a phase II randomized trial. The accrual goal is 18 patients in each arm. The primary endpoint is the PFS on first line systemic therapy and essentially the study is measuring how long SAbR is able to extend the PFS on first line therapy. In addition to comparing OS, an important secondary endpoint is quality of life which is expected to be better in the SAbR arm that delayed the initiation of systemic therapy. The Clinical- Trials.gov. identifier is NCT02956798. A second clinical trial being conducted at multiple locations in Canada by Georg Bjernason is evaluating how well SAbR can destroy kidney cancer metastases no longer controlled by sunitinib. Only oligo-progressive patients on sunitinib with up to 5 sits of progression will be enrolled. The primary endpoint is local control while the secondary endpoint is PFS. This study will seek an enrollment of 68 patients with an estimated completion date of December 2019.44 The ClinicalTrials.gov. identifier is NCT020195766. Conclusion SAbR is becoming a more widely accepted modality for the treatment of a broad spectrum of renal tumors, including primary RCC, CNS RCC metastases, and extra- CNS oligometastases. It may also have potential application as neoadjuvant therapy. Renal tumors consistently show a very high (>85%) rate of local control in these settings after treatment with SAbR. The pivotal factor in optimizing the effectiveness of SAbR is appropriate dose selection. While additional clinical trials and longer-term follow ups are required to establish guidelines on the optimal dose in controlling RCC, the focus now is on how and when to integrate an effective local control modality such as SAbR with the growing armament of approved systemic agents for RCC. Treatment of oligo-progressive RCC metastasis may be a strategy to improve PFS of sys
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