# Radiation Oncology/Kidney

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## 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) - PMID 8270978
Relapse according to stage (including median time to relapse):
* Levy, M.D.Anderson - PMID 9507823
* T1 - 7%, 38 months
* T3 - 40%, 17 months
** especially poor prognosis for T3 with venous invasion

## Nomograms

* Memorial Sloan Kettering
** nomogram link
** 2001 PMID 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 PMID 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
** PMID 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 (PMID 2934557)
* VAU (vinblastine, doxorubicin, UFT (tegafur-uracil)) - Japanese study. Retrospective. Improved survival. (PMID 1394804)

### Immunotherapy

* Interferon alpha and IL-2
** Used with success in metastatic setting
* ECOG Adjuvant Interferon Trial (PMID 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 PMID 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) - PMID 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) PMID 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 PMID 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) PMID 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 PMID 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 PMID 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 PMID 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) PMID 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) PMID 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) PMID 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) PMID 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) PMID 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 No PMID 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) PMID 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 PMID 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 PMID 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 PMID 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 PMID 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) PMID 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) PMID 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)
** PMID 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) PMID 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) PMID 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).