Radiation for Localized Renal Cell Carcinoma

Kidney cancer is the third most commonly diagnosed genitourinary malignancy in the United States, and it is estimated that the disease will cause nearly 14,000 cancer-related mortalities in 2022.^1,2 Most of these patients will have renal cell carcinoma (RCC), primarily with either clear cell (80%-85%) or non–clear cell histology (papillary, chromophobe, oncocytoma).³ Surgery via radical or partial nephrectomy remains the primary treatment modality for patients with localized RCC; however, up to 40% of these patients will ultimately develop metastatic disease even after treatment.

Early identification and treatment are essential to reduce this risk. The role of radiation therapy in the management of RCC has traditionally been thought of as minimal due to the inherent radio resistance exhibited by RCC. Several studies have demonstrated this phenomenon, although the exact mechanisms for RCC’s molecular resistance to radiation remain unclear. In a study comparing radiation sensitivity of 76 human cell types (in vitro), Deschavanne and Fertil demonstrated that RCC cells are some of the most resistant types of oncologic cells.⁴

Benefits of Stereotactic Body Radiotherapy

According to major guidelines, including those from the American Urological Association (AUA) and the European Association of Urology (EAU), the role for radiation in managing localized RCC is minimal at best. Techniques for primary therapy such as partial nephrectomy and radical nephrectomy provide the best oncologic outcomes, but for patients who are poor surgical candidates, other options are often used. Ablative techniques such as radiofrequency ablation or cryotherapy may be offered to these patients, but such techniques have limitations in the size of lesions that can be treated and result in higher rates of recurrence compared to surgical therapy.⁵

Stereotactic body radiotherapy (SBRT), also referred to as stereotactic ablative therapy (SABR), is thought to provide potential benefit for patients who are deemed unfit for surgical therapy and have lesions that cannot be treated with other modalities. Most SBRT protocols deliver 24 to 40 Gy of radiation in 1 to 5 fractions (hypofractionation) in an effort to provide a high, targeted dose of radiation in a noninvasive manner.⁶ Because delivery of SBRT requires extreme precision, various techniques, including immobilization devices and placement of fiducial markers, have been developed.⁶

Although there is a paucity of phase 3 randomized trial data on the use of SBRT in the localized RCC setting, several authors have published smaller series of data demonstrating the significant potential for SBRT. In 2015, Staehler et al demonstrated the use of SBRT for local tumor control in a series of 40 patients.⁷ After treatment of 45 total lesions, including 29 RCC lesions, they reported a 98% rate of local tumor control, minimal reduction in renal function, and an overall low rate of treatment-related toxicity. More recently, a meta-analysis conducted by Siva et al comparing single-fraction with multifraction SBRT also demonstrated a favorable therapeutic profile.⁸ At 4 years in a total series of 223 patients, the authors reported a local control rate of 97.8%, a cancer-specific survival rate of 91.9%, and a progression-free survival rate of 65.4%.⁸

The toxicity profile of SBRT is also promising. Preservation of renal function is always of paramount concern regardless of the modality used to manage localized RCC. In the series by Staehler et al, patients had a median creatinine clearance of 76.8 mL/min/1.73 m² before receiving SBRT that declined only slightly after therapy to a median of 70.3 mL/min/1.73 m². Siva et al reported a similar result, noting a mean estimated glomerular filtration rate (eGFR) of 59.9 mL/min, which declined by 5.5 mL/min after treatment.⁸

SBRT may also be a viable option for patients with preexisting chronic kidney disease at high risk for requiring dialysis after therapy, although the data in this context are limited. In a series of 21 patients with preexisting renal dysfunction, a mean tumor size of 4.8 cm and mean eGFR of 52 mL/ min, the authors demonstrated an exponential dose decline curve of renal function.⁹ At the end of treatment, all patients remained off dialysis support with an end treatment mean eGFR of 43 mL/min. Although promising, the limited data from small series in this patient population are insufficient to widely recommend SBRT in patients with preexisting renal dysfunction.

Adverse effects of SBRT that have been reported include fatigue, gross hematuria, and erythrodermia, all of which were self-limited. In summary, the current role of SBRT in the localized RCC setting will remain investigational until prospective randomized trials are performed, and results become available. At present, SBRT should be reserved as an option for patients who are poor operative candidates and cannot undergo percutaneous ablation.

Survival With Radiation Therapy

The history of radiation therapy in the adjuvant and neoadjuvant settings of localized RCC has also been explored and is worth reviewing. In the neoadjuvant setting, 2 trials published in the 1970s illustrate the lack of utility of radiation in localized RCC. The first trial, published in 1973 by van der Werf-Messing et al, reported on a series of 126 patients with localized RCC randomized to neoadjuvant radiation followed by nephrectomy or upfront nephrectomy.¹⁰

Patients in the neoadjuvant radiation arm received a total of 30 Gy of radiation prior to nephrectomy, and the results demonstrated no benefit to overall survival at 5 years between the 2 arms.¹⁰ The second major trial demonstrating no significant benefit in the neoadjuvant setting was published in the late 1970s by Juusela et al, in which the authors randomized patients to neoadjuvant radiation of 33 Gy followed by nephrectomy or upfront nephrectomy.¹¹ They reported that the 5-year survival was superior for patients in the upfront nephrectomy arm at 63% compared with 47% for those in the experimental arm.¹¹ The results of these trials solidified the lack of a role for radiation in the neoadjuvant setting.

The use of adjuvant therapy has also been explored in historical trials. Kjaer et al published data in 1986 on the role of postnephrectomy adjuvant radiation therapy.¹² They randomized 72 patients after surgical therapy to either radiation therapy (50 Gy in 20 fractions) or observation. In nearly half of the radiation cohort (44%) patients experienced post radiation complications in the stomach, duodenum, and liver, and 19% eventually experienced post radiation complication–related mortality.¹²

As the population continues to age and rates of RCC diagnosis increase with the use of imaging, advancing alternative treatment modalities such as SBRT in the localized setting may be paramount to expanding our treatment repertoire. Until the data surrounding SBRT in the localized setting mature, surgery will remain the primary workhorse approach to managing localized RCC.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

 

References

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