Are we at an inflection point for the use of radiotherapy in renal cell carcinoma? Perhaps. Definitive, high-dose-per-fraction stereotactic radiation is having a sharp impact as an option for a growing population of patients. A review of the emerging data calls for guidelines for its use as an alternative to invasive approaches.
A new consensus is emerging for the treatment of a broad spectrum of renal cell tumors at multiple stages, including primary renal cell carcinoma (RCC), locally advanced RCC, central nervous system (CNS) RCC metastases, and extra cranial oligo-metastases. It is part of a significant evolution in thinking emphasizing the use of stereotactic ablative radiotherapy (SAbR) to deliver high ablative doses of radiation focally to the tumor to achieve local control in cases previously thought to be a radioresistant histology. SAbR is an emerging treatment that delivers a very high and ablative dose of radiation very precisely to any site within the body. SAbR has been implemented successfully in the definitive management of several cancers including primary lung and prostate,1-4 and is currently under investigation in many other sites including breast, pancreas and liver.5-9 SAbR has also been successfully implemented for the local control of metastatic lesions in multiple sites.5,10-12
Several lines of evidence have converged in recent years to largely debunk the long-held belief that radiotherapy is not well suited to the paradigm of treatment in kidney cancer. First, for early stage RCC (T1a) as the standard of care has shifted away from radical nephrectomy and toward more nephron-sparing approaches, the goals of treatment have also pivoted toward less invasive ablative treatments such as radiofrequency ablation or cryo-ablation. However, these modalities are also invasive, have attendant risks and limited to treatment on selective tumor locations within the kidney.1
RCC has traditionally been considered a radioresistant tumor.13 This conclusion was based entirely on a single study that examined the radiosensitivity of multiple human cancer cell lines in vitro14 and examined one human RCC cell line, which happened to be the most radioresistant among all tested cell lines when conventional low dose per fraction radiation was used. Since then, multiple in vitro and in vivo studies have demonstrated that RCC is indeed radiosensitive, particularly at higher doses per fraction such as are used for SAbR.15,16 Clinical experience mimics this conclusion with SABR showing efficacy ranges of 90-100% and 82-95% for RCC CNS and extra-CNS metastases respectively.17-23
Nomenclature is not always the same in the literature. Different terminology is often used to refer to SAbR. In some cases, it has been referred to as “stereotactic radiosurgery” or stereotactic body radiotherapy (SBRT). The significant advantage of SAbR is its ability to deliver high-dose radiotherapy to the tumor while minimizing dose to adjacent normal tissues.24 In their review of SAbR with respect to local control and toxicity outcomes, Siva et al25 delineate the reasons for the technique’s effectiveness. The very large hypofractionated doses used in SAbR can be given safely because:
- The treated volumes are small with tight margins (Figure 1) and
- The technique employs a large number of beams (8 or more) which individually contribute small dose along their path but together result in a much larger dose where they intersect and are summed at the locus of the cancer (Figure 2).
The utilization of volumetric modulated arc (VMAT) therapy, where the gantry delivering radiation rotates continuously around the tumor to deliver radiation and essentially utilizes an infinite number of beams, further reduces the fraction of doses in in the path of radiation, intensifying it to the tumor. With even more advancement of technology such as image guided radiation and appropriate tumor motion assessment and management, it is now possible to precisely target even a moving tumor in the kidney that exhibits respiratory motion with pin-point accuracy. As the experience grows with SAbR in various RCC settings—not just primary but metastatic as well—we need benchmark data regarding changes in size and rate of growth. There is now growing evidence supporting the use of this technique as it becomes more widely adapted clinically and its potential therapeutic benefit is realized.
Primary Renal Tumors:
Effect of SAbR on Growth Kinetics
From the histological evidence gathered in case reports to a meta-analysis on the use of SAbR in the treatment of primary renal tumors, there are numerous papers documenting favorable responses. Based on a review of re- cent literature, these trends have emerged:
- A systematic review5 reported a weighted rate of local control for the treatment of RCC with SAbR in 126 patients to be 93.9%.
- Reported toxicities after SAbR appear to be tolerable with severe toxicity of 3.8% and a weighted rate of minor toxicity of 21.4%.
- SAbR has been reported to provide local control with preservation of adequate renal function in solitary kidneys and in patients with preexisting chronic kidney disease.26
- The consensus of preliminary results supports a role of SAbR as an alternative treatment option for patients with primary RCC and comorbidities that exclude total or partial nephrectomy.27
Even in the setting of surgical candidacy, it makes sense to consider SAbR since in the rare event that the tumor progresses after SAbR, partial or radical nephrectomy may still be a possibility. Formation of scar tissue in the radiated field has been the concern for surgeons in performing surgery after radiation. However, with SAbR delivering extremely focused doses of radiation, the extent of scar tissue will be limited to regions immediately surrounding the tumor which may keep even the partial nephrectomy options option. Data are clearly lacking in these clinical settings.
The trends of SAbR treatment for primary RCC were delineated by Sun et al in their report on the effect of SAbR on the growth kinetics and enhancement pattern of primary renal tumors. Even though this is a retrospective study, the majority of the patients included in this study are from the phase I dose escalation study that escalated doses of 7Gy in 3 fractions all the way to 16Gy in 3 fractions designed by McBride et. al and first reported in the 2013 ASTRO conference.28 In their retrospective study of SAbR over a 5-year period involving 41 renal tumors from 40 patients they found that the mean pretreatment tumor growth rate of 0.68 cm/y decreased to -0.37 cm/y post treatment (P<0.0001), and the mean tumor volume growth rate of 21.2 cm3/per year before treatment decreased to -5.35 cm3/y after treatment (P=0.002). Local control defined as less than 5 mm of growth—was achieved in 38 of 41 tumors. Interestingly, the three failures in this study were already reported in the 2013 abstract 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 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.
With a 98% local tumor control rate after a median followup of 28 months, according to this report, SAbR seems to be more effective and certainly less invasive than thermal ablation. There was a measurable size reduction in 38 lesions, including complete remission in 19 while the renal function remained stable. The authors can only speculate on what their results might look like when patients are followed for the long term. However, even if renal function were to fail after a longer followup, the patients still would have experienced a prolonged period free from hemodialysis.
Ongoing Trials Seek to Extend Findings
Two ongoing trials are recruiting patients to continue investigations into the use of SAbR. One is being conducted at the University of Texas Southwestern Medical Center where patients with enlarging (>4mm growth within the past year) early renal cancers will undergo treatment of SAbR of 36Gy in 3 or 40Gy in 5 fractions. The primary endpoint of this single arm phase II trial is local control at 1 year which will be evaluated with radiographic scans and a tumor biopsy one year after treatment carefully evaluating the proliferative capability of baseline compared to post-treatment biopsy to confirm tumor non-viability. The estimated study completion date is December of 2018. The Clinical Trials.gov identifier is NCT021 41919.32
A second ongoing study, also phase II single arm, TROG 15.03 FASTRACKII,33 is being conduced in Australia, has an accrual target of 70 patients and is scheduled for completion in September of 2021. All participants will be assessed at regular intervals post treatment in order to estimate the activity and efficacy of the technique, tolerability, survival, distant failure rate, and change of renal function after SAbR. SAbR dose fractionation in this study depends on tumor size: fraction schedule 1: 26Gy in 1 fraction, for tumors of less than or equal to 4cm in size; fraction schedule 2: 42Gy in 3 fractions, for tumors of greater than 4cm in size (i.e. 14Gy per fraction, given in 3 fractions over a maximum of 3 weeks, each fraction given on non-consecutive days).
SAbR in Locally Advanced RCC:
A Bench to Bedside Case Report
The application of SAbR may find a role in a subset of kidney cancer patients—those who present with inferior vena cava (IVC) tumor thrombus (IVC-TT) and comprise up to 10% of RCC patients. Surgery is the only treatment with proven efficacy for this setting, but such resection is difficult, and mortality and morbidity is high. Until recently, the difficulty with surgery has left clinicians with no treatment options for recurrent or unresectable RCC IVC-TT which left untreated can lead to Budd-Chiari syndrome.
Our experience34 treating 2 RCC patients with Level IV IVC-TT, one with recurrent disease and the other unresectable—with SAbR —suggests how this modality may have utility in this difficult-to-treat setting. Our case report followed two elderly (75 years old and 83 years old) male patients both of whom had been refractory to systemic therapy. One received 50 Gy in 5 fractions and at 2 years of followup is doing well with a significant decrease in the enhancement and size of the IVC-TT. (Figures 3, 4) To view a larger version of Figure 3, click here).
The second patient survived 18 months post SAbR. None of the patients that underwent SAbR to IVC-TT experienced any treatment-related toxicity. The survival of 18 months and 24 months for these patients is comparable to the reported median survival of 20 months in similar groups of patients who underwent surgical resection.20
Despite the high surgical mortality (10%) and morbidity (up to 30%), majority of the patients return with systemic metastasis perhaps from the tumor emboli shed from the IVC-TT itself.35 Therefore, an intriguing hypothesis raised by our study is whether SAbR could have further application in the neoadjuvant setting and whether it might lower the likelihood of systemic metastases by making the tumor emboli non-viable. A safety lead-in phase 2 clinical trial is addressing this issue where level II or higher IVC-TT is being radiated to 40Gy in 5 treatments immediately prior to surgery and looking at relapse-free survival at one year as the primary outcome measure. The target enrollment is 30 patients and the estimated completion date is December of 2018 for this trial with a ClinicalTrials.gov identifier of NCT02 473536.36
SAbR for CNS RCC Metastases
Gamma knife surgery (GKS) for metastatic brain tumors from RCC has a long history since stereotaxis initially was invented and designed for intracranial lesions, beginning with the first report published more than 20 years ago. Recent studies, however, are not only building on the previous track record of successful results but elucidating additional benefits that may accrue from such radiosurgery, including improved tumor reduction and long-term survival. These reports are exploring some of the underappreciated nuances of GKS in this setting.
To what extent is GSK effective for growth control of metastatic tumors and what effect can it have on peritumoral edema control? This question was addressed in a retrospective report by Shuto et al studying 280 metastatic brain tumors—80 from RCC and others involving breast and lung. In addition, the authors included 11 patients with metastatic brain tumors from RCC who had direct surgery. After compiling the data, Shuto et al17 present a treatment algorithm with a recommended strategy depending on tumor size, toleration of general anesthesia, presence of symptomatic peritumoral edema, and number of tumors.
The retrospective findings suggested a tumor growth control rate of 84.3%. The key findings: The primary site (renal or not renal) and the delivered marginal dose (25 Gy or more) were significantly correlated with control of peritumoral edema; although peritumoral edema was extensive, it disappeared within 1-3 months. All tumors treated with direct surgery were 2 cm in maximum diameter.
Significant total tumor volume reduction at an early treatment seems to result in long-term survival, according to Kim et al, who proposed prognostic factors worth considering in determining outcomes. The median survival time for 46 patients in a study spanning 12 years was 18 months in the good response group, significantly longer than that observed in the poor response group (9 months. P=0.025). After treatment, local tumor control was achieved in 84.7% of the 85 tumors assessed.
Classification in the “good-response” group was the only independent prognostic factor for longer survival. Although the study did not specifically address the effect of total tumor volume reduction on quality of life, the authors suggest that such reduction can lead to improved neurologic symptoms and patients may be better able to undergo systemic therapy.
Spine Radiosurgery: Emerging Issues, Guidelines
Spine radiosurgery is an effective tool in managing patients with RCC. Although RT has little role in the treatment of primary disease, SRS does play an important role in the treatment of patients with spinal metastases, particularly those who received prior RT or instrumentation according to Taunk et al.37 It is known from multiple series that spine SRS for RCC has extremely high rates of durable local control and palliation. However, it demands high quality control, precision guidance, and careful patient selection in multi-modality consultations to be safely and effectively implemented.
SAbR requires several special techniques to deliver ablative RT safely and effectively, including (1) use of multiple conformal beams with intensity-modulation, (2) accuracy within millimeters, (3) image guidance with each treatment, and (4) custom immobilization. Multiple beams allow for shaping of highly conformal dose, particularly sparing the spinal cord, which is usually within millimeters of the target volume. Custom immobilization requires comfortable, reproducible patient positioning while securely immobilizing the shoulders, neck, abdomen, or pelvis, as needed. Image guidance uses daily on-board imaging, ideally with pretreatment cone-beam CT.38
Between 2004 and 2010, MSKCC treated 105 RCC metastases (59 spine lesions) with single-dose SRS or hypofractionated SRS. The overall 3-year actuarial local progression-free survival rate was 44%. In patients with disease treated in a single fraction and with a dose of 24 Gy or greater, the 3-year local progression-free survival rate was 88%. In contrast, patients receiving hypofractionated treatment in 3 or 5 fractions had a 3-year local control rate of 17%. Treatment delivered in a single fraction and with a dose of 24 Gy or greater significantly improved local control in multivariate analysis.20
The authors’ practice is to recommend SRS alone in patients with oligometastatic disease and mechanically stable spines. Operating in the NOMS (Neurologic, Oncologic, Mechanical instability, and Systemic disease) clinical framework, patients with spine lesions are assessed in a multidisciplinary clinic at MSKCC by a radiation oncologist, spine neurosurgeon, and neurointer- ventional radiologist. Careful patient selection is critical to identify those who may benefit the most from treatment, including patients for whom prior radiation treatment failed. Indicated procedures are performed for stabilization using implanted hardware or kyphoplasty before radiation. Patients with RCC who present with high-grade spinal cord compression often require surgical decompression and stabilization to separate the tumor from the spinal cord and facilitate delivery of SRS while remaining within spinal cord tolerance.
Stereotactic Radiotherapy for Extra-CNS Oligometastases
Although the evidence is relatively sparse compared to other treatment settings, data are growing and suggest compelling results for the use of SAbR in RCC extracranial 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 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 oligo-metastatic 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 ClinicalTrials.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.
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 systemic agents for RCC. The now well-known immune modulatory and antigen presenting properties of SAbR, which has not been elaborated and is beyond the scope of this review, may synergize with the approved and upcoming immunotherapies for RCC. While much is known about the local control, the impact of SAbR on PFS and eventually on extending patient survival is not known yet and careful design of prospective trials is clearly needed in this setting. With greater application of SAbR, the focus needs to be maintained on careful patient selection for the technique to be safely and effectively implemented and outcomes optimized, including long-term survival.
1. Boike TP, Lotan Y, Cho LC, Brindle J, DeRose P, Xie XJ, Yan J, Foster R, Pistenmaa D, Perkins A, Cooley S, Timmerman R. Phase I dose-escalation study of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer. J Clin Oncol. 2011;29(15):2020-6. Epub 2011/04/06. doi: 10.1200/JCO.2010.31.4377. PubMed PMID: 21464418; PMCID: 3138546.
2. Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, Fakiris A, Bezjak A, Videtic G, Johnstone D, Fowler J, Gore E, Choy H. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070-6.
3. King CR, Freeman D, Kaplan I, Fuller D, Bolzicco G, Collins S, Meier R, Wang J, Kupelian P, Steinberg M, Katz A. Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiotherapy and Oncology. 2013. doi: 10.1016/j.radonc.2013.08.030. PubMed PMID: 24060175.
4. Katz AJ, Santoro M, Diblasio F, Ashley R. Stereotactic body radiotherapy for localized prostate cancer: disease control and quality of life at 6 years. Radiat Oncol. 2013;8(1):118. doi: 10.1186/1748-717X-8-118. PubMed PMID: 23668632; PMCID: 3674983.
5. Timmerman RD, Kavanagh BD, Cho LC, Papiez L, Xing L. Stereotactic body radiation therapy in multiple organ sites. J Clin Oncol. 2007;25(8):947-52.
6. Berber B, Sanabria JR, Braun K, Yao M, Ellis RJ, Kunos CA, Sohn J, Machtay M, Teh BS, Huang Z, Mayr NA, Lo SS. Emerging role of stereotactic body radiotherapy in the treatment of pancreatic cancer. Expert Review of Anticancer Therapy. 2013;13(4):481-7.
7. Tao C, Yang LX. Improved radiotherapy for primary and secondary liver cancer: stereotactic body radiation therapy. Anticancer Research. 2012;32(2):649-55.
8. Kwon JH, Bae SH, Kim JY, Choi BO, Jang HS, Jang JW, Choi JY, Yoon SK, Chung KW. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic radiotherapy for liver cancer. BMC Cancer. 2010;10:475. doi: 10.1186/1471-2407-10-475. PubMed PMID: 20813065; PMCID: 2940809.
9. Bondiau PY, Courdi A, Bahadoran P, Chamorey E, Queille-Roussel C, Lallement M, Birtwisle-Peyrottes I, Chapellier C, Pacquelet-Cheli S, Ferrero JM. Phase 1 clinical trial of stereotactic body radiation therapy concomitant with neoadjuvant chemotherapy for breast cancer. Int J Rad Oncol Biol Phys. 2013;85 (5):1193-9.
10. Chang BK, Timmerman RD. Stereotactic body radiation therapy: a comprehensive review. American Journal of Clinical Oncology. 2007;30 (6):637-44.
11. Lo SS, Fakiris AJ, Teh BS, Cardenes HR, Henderson MA, Forquer JA, Papiez L, McGarry RC, Wang JZ, Li K, Mayr NA, Timmerman RD. Stereotactic body radiation therapy for oligometastases. Expert Review of Anticancer Therapy. 2009;9(5):621-35.
12. Lo SS, Fakiris AJ, Chang EL, Mayr NA, Wang JZ, Papiez L, Teh BS, McGarry RC, Cardenes HR, Timmerman RD. Stereotactic body radiation therapy: a novel treatment modality. Nature Reviews Clinical Oncology. 2010;7(1):44-54.
13. Bianco AI, The BS, Amato RJ. Role of radiation therapy in the management of renal cell carcinoma. Cancers. 2011;3:4010-4023.
14. Deschavanne PJ, Fertil B. A review of human cell radiosensitivity in vitro. Int J Radiat Oncol Biol Phys. 1996;34:251-266.
15.Ning S, Trisler K, Wessels BW, et al. Radiologic studies of radioimmunotherapy and external beam radiotherapy in vitro and in vivo in human renal cell carcinoma xenografts. Cancer. 1997;80:(Suppl) 2519-25288.
16.Walsh L, Stanfield JL, Cho LC, et al. Efficacy of ablative high-dose-per fraction radiation for implanted human renal cell cancer in a nude mouse model. Eur Urol. 2006;50:795-800.
17. Shuto T, Matsunaga S, Suenaga J, Inomori S, Fujino H. Treatment strategy for metastatic brain tumors from renal cell carcinoma: selection of gamma knife surgery or craniotomy for control of growth and peritumoral edema. Journal of Neuro-Oncology. 2010;98(2):169-75.
18. Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine. 2007;32(2):193-9.
19. Gerszten PC, Burton SA, Ozhasoglu C, Vogel WJ, Welch WC, Baar J, Friedland DM. Stereotactic radiosurgery for spinal metastases from renal cell carcinoma. Journal of Neurosurgery Spine. 2005;3(4):288-95.
20. Yamada Y, Bilsky MH, Lovelock DM, Venkatraman ES, Toner S, Johnson J, Zatcky J, Zelefsky MJ, Fuks Z. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. International Journal of Radiation Oncology, Biology, Physics. 2008; 71(2):484-90.
21. Nguyen QN, Shiu AS, Rhines LD, Wang H, Allen PK, Wang XS, Chang EL. Management of spinal metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Rad Oncol Biol Phys. 2010;76(4):1185-92.
22. Ranck MC, Golden DW, Corbin KS, Hasselle MD, Liauw SL, Stadler WM, Hahn OM, Weichselbaum RR, Salama JK. Stereotactic Body Radiotherapy for the Treatment of Oligometastatic Renal Cell Carcinoma. American Journal of Clinical Oncology. 2012. Epub 2012/08/08. doi:10. 1097/COC.0b013e31825d52b2. PubMed PMID: 22868242.
23. Wersall PJ, Blomgren H, Lax I, Kalkner KM, Linder C, Lundell G, Nilsson B, Nilsson S, Naslund I, Pisa P, Svedman C. Extracranial stereotactic radiotherapy for primary and meitastatic renal cell carcinoma. Radiotherapy and Oncology. 2005;77(1):88-95.
24. Adler JR, Chang SD, Murphy MJ, et al. The Cyberknife: a frameless robotic system for radiosurgery. Stereotact Funct Neurosurg. 1997;69:124-128.
25. Siva S, Pham D, Gill S, et al. A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma. BJU Int. 2012;110: E77377-E743.
26. Lo CH, Huang WY, Chao HL, et al. Novel application of stereotactic ablative radiotherapy using Cyberkife for early-stage renal cell carcinoma in patients with pre-existing chronic kidney disease: initial clinical experiences. Oncol Lett. 2014;8:355-360.
27. Sun MRM, Brook A, Powell MF, et al. Effect of stereotactic body radiotherapy on the growth kinetics and enhancement pattern of primary renal tumors. Am J Roent. 2016;544-553.
28. McBride SM, Warner AA, Kaplan ID. A phase 1 dose-escalation study of robotic radiosurgery in inoperable primary renal cell carcinoma. Int J Rad Oncol Biol Phys. 2013;87:S84.
29. Ponsky L, Lo SS, Zhang Y, et al. Phase I dose-escalation study of stereotactic body radiotherapy (SAbR) for poor surgical candidates with localized renal cell carcinoma. Radiother Oncol.2015;117:183-187.
30. Lo SS, Loblaw A, Chang EL, Mayr NA, Teh BS, Huang Z, et al. Emerging applications of stereotactic body radiotherapy. Future Oncol. 2014;10: 1299–310.
31. Staehler M, Bader M, Schlenker B, et al. Single fraction radiosurgery for the treatment of renal tumors. J Urol. 2015;193:771-775.
33. Focus ablative Stereotactic tadiosurgery for cancers of the kidney—a phase II clinical trial. TROG trial 15.03 on Australian Cancer Trials website.
34. Hannan R, Margulis V, Chun SG, et al. Stereotactic radiation therapy of renal cancer inferior vena cava tumor thrombus. Cancer Biology & Therapy. 2015;16:65-661.
35. Haddad AQ, Leibovich BC, Abel EJ, et al. Preoperative multivariable prognostic models for prediction of survival and major complications following survival resection of renal cell carcinoma with suprahepatic caval tumor thrombus. Urol Oncol. 2015;33;388:e1-9.
37. Taunk NK, Spratt DE, Bilsky M, et al. Spine radiosurgery in the management of renal cell carcinoma metastases. J Nat Compreh Can Network. 2015;13:801-809.
38. Taunk NK, Spratt DE, Bilsky M, et al. Spine radiosurgery in the management of renal cell carcinoma metastases. J Nat Compreh Can Network. 2015;13:801-809.
39. Alt AL1, Boorjian SA, Lohse CM, Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011; 117:2873-2882.
40. Svedman C, Sandstrom P, Pia P, et al. A prospective Phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma. Acta Oncologica. 2006;45:870-875.
41. Camphausen K, Moses MA, Menard C, Sproull M, Beecken WD, Folkman J, et al. Radiation abscopal antitumor effect is mediated through p53. Cancer Res. 2003;63(8):1990-1993.
42.Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequecning. N Engl J Med. 2012;36:883-892.
43. Straka C1, Kim DW, Timmerman RD, et al. Ablation of a site of progression with stereotactic body radiation therapy extends sunitinib treatment from 14 to 22 months. J Clin Oncol. 2013 Aug 10;31(23): e401-3.
44. CliicalTrials.gov. NCT020195766. KCJ
Keywords: Stereotactic ablative radiation, renal cell carcinoma, SBRT, primary RCC, metastatic, CNS metastases, oligometastases, spine.
Corresponding Author: Raquibul Hannan, MD, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390.