Renal cell carcinoma (RCC) is the 14th most common cancer in the world and the 7th most common cancer in high-income countries.1 According to the 2019 National Comprehensive Cancer Network (NCCN) and American Society for Clinical Oncology (ASCO),2,3 surgical resection is the standard of care for patients with localized kidney cancer, which typically involves removal of either the entire kidney and surrounding tissues (i.e., a radical nephrectomy) or tumor plus margin (i.e., a partial nephrectomy). In the US, more than 3 of 4 surgeries are radical nephrectomies. Even for T1a disease, 49% of patients treated between 2006 and 2011 underwent radical nephrectomy and approximately 10% of patients undergoing PN required conversion to RN. 4

The median age of diagnosis is 65;5 therefore, a subset of patients are unable to tolerate surgery because of advanced age or medical comorbidities. Moreover, a significant proportion of patients who undergo either partial or radical nephrectomy experience postoperative nephron loss that may result in renal function decline.6 Thus, there is interest to develop nephron-sparing or non-invasive therapies for the treatment of RCC.

Stereotactic radiotherapy vs conventionally fractionated radiotherapy for RCC

Historically, radiotherapy (RT) has not been an accepted modality for RCC, because RCC has been considered a radioresistant tumor. This is because RCC cells do not die easily from conventional radiotherapy of 1.8-2 Gy fractions. Since 2003, stereotactic ablative radiation therapy (SABR), also termed stereotactic body radiation therapy (SBRT), has been gaining popularity in the treatment of primary RCC and oligometastatic cancer. The American Society for Therapeutic Radiation Oncology7 defines SABR as a treatment that couples a high degree of anatomic targeting precision and reproducibility with very high doses (i.e., > 8 Gy/fraction) of externally generated, ionizing RT. This highly accurate, ablative RT thereby maximizes the cell-killing effect on the target(s), while minimizing radiation-related injury in adjacent tissues. Typically, SABR is delivered in non-invasive, outpatient sessions typically lasting up to 45 minutes per day, for up to five treatments over approximately 2 weeks. In the United States, SABR is a billing term and must be delivered in ≤ 5 fractions (e.g., 50 Gy/5 fractions). In other parts of the world, it can sometimes be delivered in more fractions (e.g., 60 Gy/8 fractions).

From a radiobiological perspective, conventionally fractionated RT (i.e., < 1.8-2 Gy/fraction for 25 to 40 fractions) has not been known to improve outcomes of patients with primary RCC;8 moreover, repeat fractions of conventionally fractionated RT may inadvertently kill tumor-infiltrating lymphocytes that may have otherwise conducted immune-mediated killing of the treated tumor.9

Phenotypic and microenvironmental changes in tumors elicited by radiotherapy

Figure: Phenotypic and microenvironmental changes in tumors elicited by radiotherapy. Adapted from: Kwilas et al. In the field: exploiting the untapped potential of immunogenic modulation by radiation in combination with immunotherapy for the treatment of cancer. Frontiers in Oncology. 2012.

In contrast, SABR allows high-dose radiation that can overcome the perceived radioresistance of RCC by delivering an RT dose that is more radiobiological effective in the context of RCC.10 Additionally, SABR promotes tumor neoantigen expression and activation of antitumor T cells, an effect dependent on type I interferon induction in the irradiated tumor.11-13 Thus, SABR appears to be immunostimulatory for historically radioresistant cancers such as RCC, possibly explaining the dramatically improved efficacy of radiation in this context.

Stereotactic ablative radiotherapy for primary RCC

SABR has been used in the treatment of cancer metastatic to the kidney.14 However, there has been a reluctance to use SABR for RCC; in 2013, the NCCN guidelines did not propose RT as a treatment option for RCC. These guidelines continue to evolve from the publication of several studies.

2013 NCCN guidelines discussion of radiotherapy.png

Figure. 2013 NCCN guidelines discussion of radiotherapy.

SBRT for lung cancer metastastic to the kidney.png

Figure. SBRT for lung cancer metastatic to the kidney. From Verma and Simone. Stereotactic body radiation therapy for metastases to the kidney in patients with non-small cell lung cancer: a new treatment paradigm for durable palliation. Ann Palliat Med 2017;6(2):96-103 

In 2018, the International Radiosurgery Oncology Consortium for Kidney (IROCK) group published a pooled analysis of SABR for RCC.15 The objectives of the IROCK analysis were to assess safety, efficacy, and survival in a multi-institutional setting, and to compare outcomes of single- versus multi-fraction SABR. IROCK included 223 patients from nine international institutions treated with SABR. Among the 223 patients, the mean patient age was 72, 70% were men, and 87% had an ECOG score of 0 or 1. Of all patients, 118 received single-fraction SABR (median dose 26 Gy, range 14 to 26 Gy), and 105 received multi-fraction SABR (median dose 40 Gy, range 24 to 70 Gy, in 2 to 10 fractions).

In 2019 Correa et al 16 performed an international systematic review and meta-analysis on SABR for primary RCC. The authors included 26 studies, with 372 patients, and 383 tumors. The most common fractionation regimen was 40 Gy in 5 fractions, followed by 26 Gy in 1 fraction, and 48 Gy in 3 fractions. Local control was excellent at 97%, and significant toxicity was limited at <2%. Importantly, the impact on kidney function was limited: the difference in estimated glomerular filtration (eGFR) rate pre versus post-treatment was on average 7.7 ml/minute. Although direct comparison of renal function outcomes with surgical or thermal ablation is difficult, these results are comparable with a previously reported large systematic review and meta-analysis comparing partial nephrectomy with thermal ablation, where median changes in eGFR (range) were –6.2 (–18 to +4.1) and –4.9 (–8.0 to +1.5) ml/min, respectively.17

SBRT for primary RCC Figure. SBRT for primary RCC has a high rate (97%) of local control and a low risk (<2%) of significant toxicity

 impact on estimated glomerular filtration rate.pngFigure. SBRT for primary RCC has minor impact on estimated glomerular filtration rate, pre vs post different of < 8 ml/min

Future direction

As of 2019, the principal patients eligible for ablative techniques, based on the NCCN guidelines, are those with small stage I primary tumors and advanced age or competing for medical risks. While not specified as an ablative option for primary RCC, the guidelines describe that patients may benefit from SABR as an option for ablation of oligometastatic disease. Importantly, most of the studies to date describing SABR for primary RCC involve treatment of larger tumors, typically T1b. These tumors are typically not suitable for thermal ablation due to higher local recurrence risk for this modality with increasing tumor size. This is particularly pertinent as the option of active surveillance is increasingly adopted in medically inoperable patients with small renal masses. Therefore, in medically inoperable patients with larger renal tumors, SABR could be the ideal treatment alternative in a cohort with few curative options. Additionally, there is excitement about combination SABR and immune checkpoint inhibitors. SABR enhances systematic responses to anti-CTLA-4 antibodies in preclinical studies and clinical studies of historically radioresistant cancers.18,19 Immune checkpoint inhibitors induce systemic antitumor T cells in cancer, and concurrent immune checkpoint inhibitors with SABR appear to be superior to sequential therapy.20,21 In RCC specifically, SABR targeting the primary tumor induces the release of tumor-associated antigens and tumor-infiltrating T-lymphocytes, thereby demonstrating its potential immunomodulatory effect in RCC.22 Thus, SABR appears to have important synergistic effects when combined with immune checkpoint inhibitors, and future trials of SABR for RCC will explore the safety and efficacy of these approaches.

Written by: Nicholas G Zaorsky, MD, MS, Assistant Professor, Radiation Oncologist, Penn State Cancer Institute, Rohann JM Correa, MD, Ph.D., London Health Sciences Centre, Department of Oncology; and Shankar Siva, MD, Ph.D., Associate Professor, Radiation Oncologist, NHMRC fellow, Peter MacCallum Cancer Centre

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