Radiation Oncology/Kidney

Epidemiology Less than 3% of all malignancies. 36,000 cases/yr in 2005. 12,660 deaths. 80% have localized disease at presentation. Renal cell carcinoma makes up 85% of kidney cancer. 25% present with advanced disease. Pathology Adenocarcinoma. Conventional (clear cell) renal carcinoma - 80%. Papillary renal carcinoma - 12%. Others: chromophobe -4%, oncocytoma (benign), collecting duct, unclassified. Papillary has 5-yr OS of 90%, 5:1 male predominance. Metastasizes less frequently than does clear cell. Oncocytomas are benign, but often a kidney is resected for suspected RCC. Collecting duct RCC is aggressive. VHL gene mutation in 60% of sporadic clear cell RCC. Syndromes Von-Hippel Lindau disease (retinal angiomas, CNS hemangioblastoma, pheochromocytoma, clear cell renal carcinoma) -- see Radiation Oncology:Cancer Syndromes. Staging AJCC 7th Edition (2009) Primary Tumor: T1 - 7 cm or less, limited to the kidney T1a - 4 cm or less T1b - 4-7 cm T2 - > 7 cm, limited to the kidney T2a - >7 but ≤10 cm T2b - >10 cm T3 - extends into major veins or perinephric tissues but not into ipsilateral adrenal gland and not beyond Gerota's fascia T3a - extends into renal vein or invades perirenal and/or renal sinus fat but not beyond Gerota's fascia T3b - extends into the vena cava below the diaphragm T3c - extends into vena cava above the diaphragm or invades the wall of the vena cava T4 - invades beyond Gerota's fascia (including contiguous extension into the adrenal gland) Regional Lymph Nodes: Regional nodes - renal hilum, caval (para/pre/retrocaval), interaortocaval, aortic (para/pre/retroaortic) N0 - no N1 - yes Distant Metastases: M0 - no distant mets M1 - distant mets Stage Grouping: I - T1 N0 II - T2 N0 III - T3 or N1 IV - T4 or M1 Changes from 6th Edition: Subdivided T2 into T2a and T2b based on size Invasion of adrenal moved to T4 (was T3) Invasion of renal vein moved to T3a (was T3b) N-stage is N0 or N1 instead of N0-2 Stage grouping remains essentially the same Older staging systems AJCC 6th Edition (2002) Primary Tumor: T1 - 7 cm or less, limited to the kidney T1a - 4 cm or less T1b - 4-7 cm T2 - > 7 cm, limited to the kidney T3 - extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota's fascia T3a - invades adrenal gland or perirenal and/or renal sinus fat but not beyond Gerota's fascia T3b - grossly extends into renal vein or its segmental branches, or the vena cava below the diaphragm T3c - extends into vena cava above the diaphragm or invades the wall of the vena cava T4 - invades beyond Gerota's fascia Regional Lymph Nodes: N0 - no nodal mets N1 - single node N2 - more than one node Distant Metastases: M0 - no distant mets M1 - distant mets Stage Grouping: I - T1 N0 II - T2 N0 III - T3 or N1 IV - T4 or N2 or M1 Treatment Standard treatment for nonmetastatic RCC is complete resection of the tumor by either a radical or partial nephrectomy. Adjuvant therapy is not standard. Prognosis 30% of pts will relapse after surgery. Response rates for metastatic RCC are poor, only 15-25%. Adverse prognostic factors: nodal and venous involvement (Memorial Sloan Kettering) - 8270978 Relapse according to stage (including median time to relapse): Levy, M.D.Anderson - 9507823 T1 - 7%, 38 months T3 - 40%, 17 months especially poor prognosis for T3 with venous invasion Nomograms Memorial Sloan Kettering nomogram link 2001 11435824 -- "A postoperative prognostic nomogram for renal cell carcinoma." (Kattan MW, J Urol. 2001 Jul;166(1):63-7.) Survival 5-yr survival: Stage I - 95% Stage II - 88% Stage III - 59% Stage IV - 20%; median 13 months 2000 10737472 -- "Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria." (Tsui KH, J Urol 2000 Apr;163(4):1090-5.) Adjuvant treatment Neoadjuvant approach Preoperative embolization of the renal artery 10683065 (Zielinksi H et al 2000) Retrospective. 474 pts. 118 had embolization. All had radical nephrectomy or radical nephrectomy with embolization. 5 and 10-year OS 62% and 47% (embolization) vs 35% and 23% (surgery alone) Adjuvant hormonal therapy and chemotherapy medroxyprogesterone - similar relapse rate (2934557) VAU (vinblastine, doxorubicin, UFT (tegafur-uracil)) - Japanese study. Retrospective. Improved survival. (1394804) Immunotherapy Interferon alpha and IL-2 Used with success in metastatic setting ECOG Adjuvant Interferon Trial (12663707) 294 pts. Randomized after surgery to 12 weeks IFN-alpha or observation. Median f/u 10 years. No difference in recurrence or survival. Significant toxicities of treatment. IL-2 - also failed to show a benefit in the adjuvant setting Vaccines Jocham et al. Lancet 2004 Cell lysates incubated with gamma-IFN/tocopherol acetate. 558 pts. T2-3b N0/1. After nephrectomy, randomized to vaccine or observation. Improvement in tumor progression rate, but only for T3 tumors. Ongoing trials Heat shock protein vaccines - induces a stronger immunogenic reponse than with tumor antigen alone Thalidomide Adoptive immunotherapy - passive transfer of immuno cells LAK - lymphokine-activated killer cells TIL - tumor-infiltrating lymphocytes Use of radiotherapy Meta-Analysis Karachi; 2010 20139152 -- "Need for a new trial to evaluate postoperative radiotherapy in renal cell carcinoma: a meta-analysis of randomized controlled trials" (Tuni MA, Ann Oncol. 2010 Feb 5. [Epub ahead of print]) Meta-analysis. 7 RCT, 735 patients. Radical nephrectomy vs radical nephrectomy + post-op RT for localized RCC Outcome: Significant reduction in locoregional failure; no difference in DFS or OS Toxicity: Generally well tolerated Conclusion: PORT significantly reduces LRF, without impact on DFS or OS. However, poor accrual and older RT techniques Randomized Copenhagen Renal Cancer Study Group, 1987 (1979-84) - 3445125 — "A randomized trial of postoperative radiotherapy versus observation in stage II and III renal adenocarcinoma." Kjaer M et al. Scand J Urol Nephrol. 1987;21(4):285-9. 72 pts. Stage II-III. After nephrectomy, randomized to RT vs observation. RT was 50 Gy in 20 fx to kidney bed, ipsilateral and contralateral nodes No benefit for relapse rate or survival. Unacceptable toxicities from RT. Radiobiology Renal cell carcinoma cells were the most radiation-resistant cells among 694 cell lines (271 tumor-derived and 423 fibroblast-derived), with D = 4.8Gy (compared with for example melanoma D = 2.51Gy) Paris, 1996 (France) 12118559 -- "A review of human cell radiosensitivity in vitro." (Deschavanne PJ, Int J Radiat Oncol Biol Phys. 1996 Jan 1;34(1):251-66.) Stereotactic Radiotherapy Karolinska Sweden 1997-2003 15972239 -- Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma. (2005 Wersall PJ, Radiother Oncol. 2005 Oct;77(1):88-95.) Retrospective. 58 patients treated with SRT (8 Gy x4, 10 Gy x4, or 15 Gy x3) Response: 30% CR, 60% PR/SD; Local control 90-98% Mild side effects Conclusion: "Our use of SRT for patients with primary and metastatic RCC yielded a high local control rate with low toxicity. Patients with one to three metastases, local recurrences after nephrectomy or inoperable primary tumors benefited the most, i.e. had fewer distant recurrences (13/23) and longer survival times compared to patients with >3 metastases (24/27 recurrences)." Brain Mets Also please see the main brain metastases page Epidemiology Percentage of patients who develop brain mets: only 3-14% (but majority of these have multiple brain mets) Majority of patients with brain mets also have active disease elsewhere, typically lung Japan, 1995 (1981-1992) 7637246 -- "[Clinical study of renal cell carcinoma with brain metastasis]" - [Article in Japanese] (Yonese J, Nippon Hinyokika Gakkai Zasshi. 1995 Jul;86(7):1287-93.) Retrospective. 130 patients with renal cell CA, 10.6% developed brain mets (>90% of these had prior pulmonary mets) 1981 7272969 -- "Distant metastasis of renal adenocarcinoma." (Saitoh H, Cancer. 1981 Sep 15;48(6):1487-91.) Retrospective. 1451 autopsy cases. Brain mets ~10% Whole Brain RT WBRT results have historically been poor with standard fractionations, due to perceived radioresistance But, median survival of MD Anderson cohort (4.4 months) is the same as median survival in RTOG RPA meta-analysis 9128946 (4.4 months). The Cleveland Clinic cohort did worse, possibly since they had almost no RPA Class I patients (who were typically treated with WBRT + surgery or + SRS) There may be benefit for patients with multiple brain mets and with RPA Class I Germany, 2010 20488627 -- "Do Patients Receiving WBRT for Brain Metastases from RCC Benefit from Escalation of the Radiation Dose?" (Rades D, Int J Radiat Oncol Biol Phys. 2010 May 18.) Retrospective analysis of 60 pts receiving 30/10 vs 40/20 or 45/15. Majority of pts were RPA Class 2-3 (13% RPA 1, 42% RPA 2, 45% RPA 3). 30/10 used in 31 pts; higher dose in 29 pt (23 pt treated with 40/20, 6 pt with 45/15). 1 yr OS 13% vs 47% for low vs high dose (SS on MVA) 1 yr local control 7% vs 35% for low vs high dose (trend p=0.06 on MVA) Conclusion: Suggest escalation above 3 Gy x 10 improves outcomes in brain mets from RCC. Cleveland Clinic, 2004(1983-2000) 14697446 -- "Results of whole brain radiotherapy and recursive partitioning analysis in patients with brain metastases from renal cell carcinoma: a retrospective study." (Cannady SB, Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):253-8.) Retrospective. 46 patients with RCC treated with WBRT. Median RT 30/10. Median F/U 3 months Median OS: 3 months. RPA I 8.5 months (but only 2 patients!) vs. RPA Class II 3 months vs. RPA Class III 0.6 months RT: higher dose associated with better OS, but confounded by RPA Conclusion: despite poor prognosis, there is benefit to WBRT over supportive care MD Anderson 1997 (1976-1993) 9128947 -- "External radiation of brain metastases from renal carcinoma: a retrospective study of 119 patients from the M. D. Anderson Cancer Center." (Wronski M, Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):753-9.) Retrospective. 119 patients treated with WBRT only. Multiple tumors in 60% Survival: median 4.4 months. (single met 4.4 months, multiple mets 3.0 months). 76% neurologic cause of death, 16% systemic progression Conclusion: unsatisfactory results suggest more aggressive approaches 1988 (1968-1985) 2458823 -- "Palliative radiotherapy for brain metastases in renal carcinoma." (Maor MH, Cancer. 1988 Nov 1;62(9):1912-7.) Retrospective. 46 patients with RCC brain mets. Mostly WBRT 30/10 Median survival: 8 weeks. 10 patients improved after WBRT, median OS 17 weeks Conclusion: brain mets from renal cell usually unresponsive to conventional photon therapy Jefferson, 1985 (1956-1981) 2414257 -- "Radiation therapy in the treatment of metastatic renal cell carcinoma." (Onufrey V, Int J Radiat Oncol Biol Phys. 1985 Nov;11(11):2007-9.) Retrospective. 125 with metastatic lesions (12 brain mets). Total doses 20-60 Gy Response rate: 65% of TDF >70, 25% for TDF <70 Conclusion: kidney mets should be treated to higher doses 1983 (1965-1980) 6185207 -- "The role of radiation therapy in the management of metastatic renal cell carcinoma." (Halperin EC, Cancer. 1983 Feb 15;51(4):614-7.) Retrospective. 35 patients palliated for met renal CA, 60 sites (10 CNS) CNS: disappointing results. 30% response in brain and SC lesions SRS Patients treated with SRS appear to do better than patients treated with WBRT (as a historical comparison) Role of WBRT in addition to SRS is unclear. It probably improves local control; its effect on distant brain failure and survival is unclear based on several single-institution retrospective reviews Utah, 2006 link -- "Stereotactic radiosurgery as therapy for melanoma, renal carcinoma, and sarcoma brain metastases: Impact of added surgical resection and whole-brain radiotherapy." (Rao G, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4 Suppl):S20-5.) Retrospective. 68 patients with brain mets (melanoma 68%, RCC 28%, sarcoma) treated with SRS +/- WBRT or surgery. KPS >70 Median OS: 14.2 months WBRT: no difference in survival MD Anderson, 2005 (1991-2002) 15854241 -- "Outcome variation among "radioresistant" brain metastases treated with stereotactic radiosurgery." (Chang EL, Neurosurgery. 2005 May;56(5):936-45; discussion 936-45.) Retrospective. 189 patients with 264 brain mets (melanom 103, renal cell 77, sarcoma 9) treated with SRS. Median dose 18 Gy (10-24). Median F/U 7.4 months 1-year LC: renal cell 64% vs. melanoma 47% vs. sarcoma 0% (SS). Neurologic death renal cell 31% vs. melanoma 66% vs. sarcoma 60% (SS) 1-year OS: renal cell 40% vs. melanoma 25% vs. sarcoma 22% (SS) WBRT: Only 16 patients WBRT+SRS => no difference in LC, DBF, or OS ECOG E6397, 2004 (1998-2003) ASCO Abstract -- "Phase II trial of radiosurgery (RS) for 1 to 3 newly diagnosed brain metastases from renal cell, melanoma, and sarcoma: An Eastern Cooperative Oncology Group Study (E6397)." (Manon RR, Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 1507 Phase II. 32 patients with renal cell, melanoma, sarcoma brain mets, 1-3 mets, no prior cranial RT. RT 24 or 18 or 15 Gy based on size. Median F/U 25 months Median OS: 8.3 months, 32% died from CNS death. Local control: in-field failure 3 months 28%, 6 months 45%; out-of-field failure 4% and 17%. Conclusion: median survival better than WBRT alone; delaying WBRT may be appropriate for some subgroups. However, local failure rate comparable to surgery only in Patchell trial Pittsburgh 2003 12593621 -- "Radiosurgery in patients with renal cell carcinoma metastasis to the brain: long-term outcomes and prognostic factors influencing survival and local tumor control." (Sheehan JP, J Neurosurg. 2003 Feb;98(2):342-9.) Retrospective. 69 patients with 146 renal cell brain mets treated with SRS and other things Survival: median 15 months from brain met diagnosis (13 months from SRS for no active extracranial disease, 5 months for with active disease). 83% died of progression of extracranial disease Response: 63% decreased in size, 33% stable, 4% increased Predictors impacting survival: age, KPS, time from Dx to brain mets, dose to margin, total dose, and treatment isodose. Tumor resection, whole brain RT, chemotherapy, immunotherapy did not correlate with survival Conclusion: SRS provides effective control 1998 9669818 -- "Stereotactic radiosurgery for brain metastasis from renal cell carcinoma." (Mori Y, Cancer. 1998 Jul 15;83(2):344-53.) Retrospective. 35 patients with 52 brain mets treated with SRS. 28 also underwent WBRT. RT 17Gy (13-20) Median OS: 11 months after SRS. 8% died of progression of irradiated tumor LC: 90% (disappearance 21%, regression 44%, SD 26%). LR in 3 patients, DBF in 12 patients WBRT: local control: no failures in WBRT + SRS, DBF 46% vs. 50%, OS no difference Wayne State, 2002 12507083 -- "Gamma knife radiosurgery for renal cell carcinoma brain metastases." (Hernandez L, J Neurosurg. 2002 Dec;97(5 Suppl):489-93.) Retrospective. 29 patients with 92 brain mets treated with GKS. 48% WBRT prior GKS, 7% after GKS. Mean GKS dose to 50% isodose 16.8 Gy (13-30) Survival: RPA Class I - WBRT/GKS 18 months vs. WBRT 7.1 months, RPA Class II - WBRT/GKS 8.5 months vs. WBRT 4.2 months, RPA Class III - WBRT/GKS 5.3 months vs. 2.3 months Conclusion: WBRT combined with GKS may improve survival in all RPA classes Mayo Clinic, 2002 12188943 -- "Stereotactic radiosurgery for patients with "radioresistant" brain metastases." (Brown PD, Neurosurgery. 2002 Sep;51(3):656-65; discussion 665-7.) Retrospective. 41 patients with 83 mets (renal cell 16, melanoma 23, sarcoma 2). Survival: 14.2 months after SRS. RPA Class I survival 23.5 months, RPA Class II/III survival 10.5 months. Trend to better survival with renal cell (17.8 months) vs. melanoma (9.7 months). Control: 12% recurred locally, 54% distal brain failure. WBRT: improved local control (100% vs. 85%, SS), and decreased DBF (17% vs. 64%, SS), no impact on OS Cleveland Clinic, 2000 (1991-1998) 10863072 -- "The role of whole brain radiotherapy and stereotactic radiosurgery on brain metastases from renal cell carcinoma." (Goyal LK, Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):1007-12.) Retrospective. 29 patients with 66 tumors treated with SRS. Median RT 18 Gy to 60% isodose. Median F/U 12.5 months. Median OS: 10 months. Only 9% recurred locally. WBRT: no improvement on local control Distant brain failure: single met 23% (3/13), multiple mets 60% (6/10). Conclusion: SRS alone excellent control. Consider adding WBRT if multiple brain mets Saar, 1996 (Germany) 8840485 -- "Treatment of brain metastases from hypernephroma." (Nieder C, Urol Int. 1996;57(1):17-20.) Retrospective. 22 patients (7 surgery + RT, 2 fractionated SRT, 13 WBRT to 30 Gy) Best results surgery + RT. SRT alone better than WBRT (accelerated WBRT no difference from standard WBRT). Only 4/13 WBRT improved Conclusion: SRT and surgery superior but not always available. Higher WBRT should be investigated Bone mets See also: Bone metastases chapter Prospective trials: Princess Margaret, 2005 (1996-2002) 16177996 (Free full text) — "A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma." Lee J et al. Cancer. 2005 Nov 1;104(9):1894-900. Phase II. 31 pts. Symptomatic mets (25 pts with bone mets) from RCC treated with 30 Gy / 10 fx. 83% reported a decrease in pain; in 43% pain relief lasted until last f/u visit. 13% had complete relief of pain. Median f/u 4.3 mo. Retrospective: Jefferson, 1985 (1956-1981) 2414257 -- "Radiation therapy in the treatment of metastatic renal cell carcinoma." (Onufrey V, Int J Radiat Oncol Biol Phys. 1985 Nov;11(11):2007-9.) See details above at Brain Mets 86 pts with bone mets. 1983 (1965-1980) 6185207 (Free full text) -- "The role of radiation therapy in the management of metastatic renal cell carcinoma." (Halperin EC, Cancer. 1983 Feb 15;51(4):614-7.) See details above at Brain Mets 36 pts with bone mets. Varying doses given, taking dose and time factors into account as TDF (Time Dose Factor) Bone pain responded at 77% of the treated sites. No apparent dose effect (most bony sites received 45-85 TDF; this is a wide range of doses, corresponding to 30 Gy over 3 weeks to 50 Gy in 5 weeks).