stract to be on the 7Gy and 9Gy x3 dose fractionations and no failures were observed when >10Gy in three fractions were used. Authors made an intriguing observation in this study. They noticed that even in the setting of good local control, SAbR did not have an impact on the enhancement of the residual mass. Physicians treating renal tumors with ablative technique are reassured when enhancement is lost since the technique inherently disrupts the treated tissue leading to loss of tumor vasculature and lack of contrast dye uptake. However, SAbR primarily kills tumor cells by DNA damage leading to mitotic catastrophe or a loss of their proliferative ability with minimal damage to the vasculature. As a result, it is not surprising that local control is seen in the setting of continued contrast enhancement. Despite these promising results, there are unresolved issues concerning the tolerability of escalating doses of SAbR for primary treatment of localized RCC in poor surgical candidates.29 For example, the dose regimens used in earlier studies from 2005 to 2007 ranged from 16-48 Gy in 3-5 fractions but no consensus emerged regarding the optimal dose regimen for RCC.30 The phase 1 dose-escalation study by Ponsky et al offers insights as it explores data on achieving the maximum tolerated dose for SAbR. It highlights concerns with the delivery of ablative doses of radiation. These concerns are related to tumor motion with respiration and the close proximity to various organs at risk, including the small bowel. Ponsky et al used a robotic radiosurgery system with tumor tracking capability to deliver the radiation requiring a smaller margin around the gross tumor volume (GTV) to create a target planning volume (PTV). This enabled the authors to treat a smaller amount of ipsilateral normal kidney and other organs at risk. A stepwise dose escalation regimen was followed and 48 Gy in 4 fractions was reached without causing dose-limiting toxicity. One patient experienced an acute and late grade 4 duodenal ulcer. Interestingly, while none of the 15 evaluable patients developed progression at a median follow up of 13.67 months, 7 of the 11 tumors biopsied post-SAbR showed “viable” tumor. The efficacy of radiation (or chemotherapy for that matter) in controlling tumor cells in vitro comes from cell survival curves from clonogenic assays where after a certain dose of radiation the tumor cell’s ability to form colonies are measured and reported as surviving fraction. In reality, the surviving fraction is not reporting on whether the cells are alive or dead, they are merely reporting on whether the cells are able to divide and form colonies. In essence, a cancer cell that has lost its ability to divide, is perhaps not a cancer anymore. In the context of no progression, a “viable” reading from H&E staining on a biopsy that did not perform any tests of proliferation is certainly inconclusive and the authors address this in the discussion and agrees to add proliferative indices in the future patients. Therefore, while the dose escalation design and primary endpoint of this study is robust, the secondary endpoint of local control 74 Kidney Cancer Journal Figure 2. SAbR setup and beam arraignment for kidney lesion. The setup for SAbR abdominal treatment includes a vacuum bag for accurate reproducibility and a body frame that allows the stereotaxy. Multiple beams in non-coplanar arrangements are typically used to produce the focal dose distribution. definition (loss of enhancement and biopsy) is flawed. As a result, with the goal of further improving local control, the investigators are enrolling patients for a starting dose of 48 Gy in 3 fractions. If the acute toxicity is acceptable, then the next 4 patients will be escalated to 54 Gy in 3 fractions. And then, if a dose limit has not been reached at that point, the last group of 4 patients will be treated to 60 Gy in 3 fractions. Based on all the other reported doses and local control rates for primary and metastatic RCC, one might argue that a dose escalation to this extent is likely unnecessary. Nonetheless, the reported study remains to be an important and the first prospective dose escalation study on SAbR for primary RCC. Corroborative evidence of safety and efficacy for SAbR appeared in a European study by Staehler et al31 who reported on renal tumors treated with single fraction radiosurgery. This study demonstrated the short-term benefits of the technique in 40 patients who had an indication for nephrectomy and subsequent hemodilation. The phase 2 study devised an aggressive treatment approach delivering 25Gy in a single fraction with fiducial placement and respiratory motion tracking using the CyberKnife system. The study overcame the challenges seen with conventional radiation: even when lesions were close to or in the ureter, a measure that is not possible with ablative techniques, the authors achieved complete tumor control without functional impairment. A high dose of radiation could be applied precisely with 1 mm accuracy to the renal tumor, thus avoiding collateral damage to surrounding healthy tissue. The disadvantage of this set-up is the dependency on fiducial placement which is a (minimally) invasive procedure. Utilizing image guidance technology, it is now possible to administer the same dose without the need for fiducials making SAbR completely non-invasive.
30114GA
To see the actual publication please follow the link above