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Consensus statement from the International Radiosurgery Oncology Consortium for Kidney for primary renal cell carcinoma Shankar Siva*,1, Rodney J Ellis2, Lee Ponsky2, Bin S Teh3, Anand Mahadevan4, Alexander Muacevic5, Michael Staehler5, Hiroshi Onishi6, Peter Wersall7, Takuma Nomiya8 & Simon S Lo2 Aim: To provide a multi-institutional consensus document for stereotactic body radiotherapy of primary renal cell carcinoma. Materials & methods: Eight international institutions completed a 65-item survey covering patient selection, planning/treatment aspects and response evaluation. Results: All centers treat patients with pre-existing hypertension and solitary kidneys. Five institutions apply size constraints of 5–8 cm. The total planning target volume expansion is 3–10 mm. All institutions perform pretreatment imaging verification, while seven institutions perform some form of intrafractional monitoring. Number of fractions used are 1–12 to a total dose of 25 Gy–80 GyE. Imaging follow-up for local tumor response includes computed tomography (n = 8), PET-computed tomography (n = 1) and MRI (n = 5). Follow-up frequency is 3–6 months for the first 2 years and 3–12 months for subsequent 3 years. Conclusion: Key methods for safe implementation and practice for stereotactic body radiotherapy kidney have been identified and may aid standardization of treatment delivery. First draft submitted: 26 October 2015; Accepted for publication: 6 January 2016; Published online: 3 February 2016 Renal cell carcinoma (RCC) is one of the top ten most common malignancies in the developed world [1] . According to the American Cancer Society, kidney cancer incidence rates increased by 4.1% per year in men and 3.3% per year in women between 2004 and 2008 [2] . It affects predominantly the older population with a median age at diagnosis of 65 years, with a slight male preponderance. Surgery is the standard of care for primary RCC, however, many patients in this population have medical comorbidities that may preclude them from extirpative therapies. Patients undergoing partial or radical nephrectomy for renal cancer experience postoperative nephron loss, which may result in de novo chronic kidney disease or advancement of pre-existing renal dysfunction [2–5] . Nonsurgical definitive treatment options for this population of patients are limited. Radiofrequency ablation (RFA) and cryotherapy are two alternative ablative therapies available for patients with inoperable disease. RFA is a treatment technique that involves percutaneous insertion of electrodes to achieve thermal ablation of a renal tumor. Cryotherapy is based Division of Radiation Oncology & Cancer Imaging, Peter MacCallum Cancer Center, East Melbourne, Australia University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Cleveland, OH, USA 3 Houston Methodist Hospital, Weil Cornell Medical College, Houston, TX, USA 4 Beth Israel Deaconess Medical Center, Boston, MA, USA 5 University of Munich Hospitals, Munich, Germany 6 Department of Radiology, University of Yamanashi, Yamanashi, Japan, 7 Karolinska University Hospital / Karolinska Institute, Stockholm, Sweden, 8 National Institute of Radiological Sciences, Chiba, Japan *Author for correspondence: Tel.: +61 3 9656 1111; Fax: +61 3 9656 1424;
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Keywords
• ablation • kidney cancer • patterns of practice • radiotherapy • SABR • SBRT • stereotactic
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10.2217/fon.16.2 © 2016 Future Medicine Ltd
Future Oncol. (Epub ahead of print)
part of
ISSN 1479-6694
Consensus Statement Siva, Ellis, Ponsky et al. on a series of freezing and thawing cycles to achieve cell kill within a cancer. Supercooled liquid is introduced into a probe, either inserted percutaneously or laparoscopically, in order to achieve thermal ablation of the tumor. A meta-analysis by Kunkle and Uzzo [6] demonstrated local tumor progression rates of 5.2% after renal cryoablation and 12.9% after RFA. The use of RFA is limited to treating smaller tumors as well as those away from the ureter and renal pelvis due to the risk of heat sink effects, stricture and/or fistula developing [7] . Cryotherapy use is limited by cost, availability and ability only to treat smaller tumors. With larger tumors treated there is a significant risk of hemorrhage, which can require a nephrectomy to control. Both of these techniques are invasive, with access to the kidney through incisions in the skin, which can be problematic in the increasing numbers of patients who may have a number of contraindications such as anticoagulative medications. By contrast, stereotactic body radiotherapy (SBRT) is an emerging noninvasive treatment option for patients with inoperable primary RCC. SBRT does not necessitate in-patient hospital admission, is delivered in a single or few treatment sessions, and is typically associated with a low toxicity and excellent local control rates in a variety of malignancies [8] . By comparison to RFA and cryotherapy for primary RCC early results from SBRT compare favorably with local progression rates of 6.1% [9] , with modern reports indicating very infrequent severe treatment related toxicities [10,11] . Specifically, a systematic review in 2012 revealed 126 patients were reported in the literature at that time with local control rates ranging from 84 to 100% with weighted grade 3 or higher toxicity rates of 3.8% [9] . More recently, studies have reported local radiographic control rates of 87% in 15 patients [12] , 95% in 19 patients [13] and 100% in 30 patients [10] , all with rates of grade 3 or higher toxicities of less than 5%. Unlike RFA or cryotherapy, SBRT does not have specific limitations relating to tumor size or position relative to pelvic calyceal structures. However, tumor biopsy confirmation is not achieved at the time of treatment delivery and must be obtained at a separate time to the treatment session. As yet there is no international consensus as to patient selection, technical approaches or follow-up in the setting of SBRT to primary RCC. Several institutions have independently
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Future Oncol. (Epub ahead of print)
developed expertise in the treatment approach having completed early phase clinical trials and/or published clinical evidence. These groups were invited to form an international consortium in order to formulate a consensus statement for the treatment of primary kidney cancer with SBRT. The purpose of this study was to evaluate patterns of practice, treatment strategies and expert opinion in order to establish treatment guidelines for implementation of a SBRT primary RCC program. Materials & methods Eight international institutions that have completed Phase I clinical trials and/or published clinical evidence in the field of SBRT were invited to participate in the formulation of this practice consensus statement. These institutions were located in the Australia, Germany, Japan, Sweden and the USA and form the International Radiosurgery Oncology Consortium for Kidney (IROCK). All eight of the institutions were academic hospitals. Listed alphabetically, these institutions were the Beth Israel Deaconess Medical Center (BIDMC; Boston, MA, USA), European Cyberknife Center (ECC; Munich, Germany), Houston Methodist Hospital (HMH; Houston, TX, USA), Karolinska Institute (KI; Stockholm, Sweden), National Institute of Radiological Sciences (NIRS; Chiba prefecture, Japan), Peter MacCallum Cancer Center (PMCC; Melbourne, Australia), University Hospitals Seidman Cancer Center (UHSCC; OH, USA) and University of Yamanashi (UY; Yamanashi prefecture, Japan). The cumulative experience of the consortium comprised of 285 patients at the time of survey response. Each institution completed a comprehensive survey consisting of 65 questions covering major aspects of patient selection, planning/treatment aspects and response evaluation (Supplementary Materials) . The questions were divided into ten focus areas as follows; patient eligibility, indications for treatment, use of systemic agents, imaging for staging and simulation, target definition, organ at risk (OAR) dose constraints, treatment modality, dose/fractionation schedule, image guidance and follow-up/response evaluation. An additional module of questions was directed at future opportunities in the field. All participants completed the survey between the periods of November 2014 to January 2015. Consensus recommendations for OAR dose constraints were formulated. Results were compiled,
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Consensus statement from the IROCK for primary renal cell carcinoma synthesized and reviewed by all members prior to publications. Results ●●Patient eligibility, indications for
treatment & use of systemic agents
Patient selection was largely consistent within all eight participating institutions. No institution had an upper age limit for treatment or an exclusion criterion based on location of the tumor within the kidney. All centers would treat patients with pre-existing hypertension and patients who were asymptomatic from disease. Six centers required a minimum performance status (Eastern Cooperative Oncology Group performance status 0–1 or Karnofsky performance status ≥70). All institutions would recommend SBRT for patients who were medically inoperable, patients unsuitable for ablation and patients with operable RCC but are at risk for dialysis after surgery. Six of the institutions would recommend SBRT in patients in all patients not recommended for surgery, including those suitable for alternative ablative techniques. All and five centers would treat primary RCC in patients with solitary kidneys and bilateral primary RCC with SBRT, respectively. Seven centers would still treat the primary RCC despite the presence of limited distant metastatic disease. Of these seven, four would not treat the primary in the presence of intracranial metastases. Seven institutions considered SBRT immunostimulatory in the setting of RCC, and were interested in exploring combinations of immunotherapy and SBRT in the primary setting. There were differences in some patient selection criteria amongst institutions. Four centers required pathologic confirmation prior to SBRT. Three centers would set a lower limit on creatinine clearance of 25–30 ml/min. Contraindications included prior high-dose radiotherapy to the upper abdomen (n = 7), inflammatory bowel disease (n = 1), connective tissue disease (n = 3) and diverticular disease (n = 1). Four centers would consider a tyrosine kinase inhibitor (TKI) for cytoreduction of the primary prior to SBRT and two of these would administer both agents concurrently. The other two centers would interrupt delivery of TKIs 2–7 days either side of the SBRT. Within the experience reported by the consortium, 80–100% of patients treated had primary RCC 3
1
1
>3
>3
2
>3
25 Gy in 1 fraction
40–50 Gy in 26 Gy in 40–70 Gy in 5 fractions 1 fraction 10 fractions 42 Gy in 3 fractions 80–90% 80% 80–90%
1 day
36 Gy in 3 fractions 64–80 GyE in 54 Gy in 48 Gy in 3 fractions 12 fractions 3 fractions
Objective 67% prescription isodose Days between Consecutive fractions
100%
75%
70%
45 Gy in 3 fractions 50 Gy in 5 fractions 50 Gy in 10 fractions 56 Gy in 8 fractions 67%
Consecutive
1 day
NA
2 days
n/a or 1 day
1 day
BIDMC: Beth Israel Deaconess Medical Center; ECC: European Cyberknife Center; HMH: Houston Methodist Hospital; ITV: Internal target volume; KI: Karolinska Institute; NIRS: National Institute of Radiological Sciences; OAR: Organ at risk; PMCC: Peter MacCallum Cancer Center; PTV: Planning target volume; UHSCC: University Hospitals Seidman Cancer Center; UY: University of Yamanashi. ●●Organ at risk definition, doses
& fractionation, dose constraints
Consensus recommendations for dose constraints for varying fractionation schedules can be found in Table 3. The most common OAR delineated was the small bowel, with all eight institutions contouring this structure. Seven institutions contoured spinal cord as an OAR, followed by large bowel in six institutions. The major dose-limiting organ was stated to be small bowel in seven of the institutions, whereas one stated that the dose to ipsilateral kidney was the major limiting factor. ●●Future directions
All of the institutions stated willingness to randomized clinical trials in the context of SBRT for primary RCC. The consortium participants were presented with four options for clinical trials: a) randomized versus RFA or cryotherapy for small renal masses; b) randomized versus surgery for definitive treatment; c) randomized versus nephrectomy in the setting of metastatic disease with intact primary; d) and SBRT to the primary and TKI randomized versus TKI alone in the setting of metastatic disease. Four institutions selected option a), both Japanese centers selected option b), and one further institution selected each of c) and d). Discussion Among the IROCK members there were several clinically significant areas of consensus that result in key recommendations from this evaluation. Previous high-dose abdominal radiotherapy should be a contraindication to SBRT. Pre-existing hypertension and the presence of
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a primary RCC in a functionally solitary kidney should not be contraindications to therapy. Pretreatment diagnostic and fusion imaging should include CT, and where possible, CT with contrast and MRI. Consensus OAR constraints are provided in Table 3. Pretreatment image guidance should include soft-tissue imaging with CBCT and/or stereoscopic kV imaging of fiducial surrogates. Post-treatment follow-up should include a CT of the chest and abdomen, at a frequency of 3–6 monthly for the first 2 years and 3–12 months for the subsequent 3 years for all centers. Key areas of inconsistency that warrant further investigation include the acceptable lower limit of renal function prior to SBRT, optimal dose/fractionation and prescription methodology and expansions to account for microscopic disease, organ motion and setup errors. These variances in technical delivery methodologies indicate that multi-institutional standardization through clinical trials is required. Whilst there is little clinical evidence available to support the approach, the group consensus was that SBRT to the primary could be considered in patients in spite of the presence of limited metastatic disease. This approach is analogous in intent to that of cytoreductive nephrectomy in the setting of medically operable patients, which has demonstrated a survival benefit in the setting of interleukin immunotherapy [16] . In the era of systemic targeted agents, the role of cytoreductive nephrectomy is presently being assessed through the SURTIME [17] and CARMENA [18] randomized clinical trials. While using first principles, it may be that SBRT could be used for the primary in inoperable patients receiving tyrosine
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10.2217/fon.16.2
Consensus Statement Siva, Ellis, Ponsky et al. Table 3. List of dose/fractionation schedules and suggested dose constraints. Organ at risk constraint Spinal cord Small bowel
Fractionation schedule 1 fraction
3 fractions
5 fractions
Carbon ions (10fractions)
