Stereotactic Radiation Strategies May Bolster RCC Multi-Modality Management Efforts

Tumor ablation using stereotactic radiation therapy represents a novel, tolerable approach to treating patients with locally advanced or metastatic renal cell carcinoma (RCC), although questions remain regarding optimal treatment sequencing of radiation with standard systemic therapies, according to Raquibul Hannan, MD, PhD.

In March 2023, Hannan and colleagues published findings from a phase 2 trial (NCT02141919) evaluating the efficacy of stereotactic ablative radiotherapy in patients with primary RCC. In total, 94% of patients (95% CI, 70%-100%) achieved radiographic local control at 1 year, all of whom had pathologic evidence of tumor response. Additionally, per RECIST v1.1 criteria, 100% of the tumor sites were progression free at 1 year.¹

Supported by these findings, the phase 3 SOAR trial (NCT05863351) will investigate the role of focused radiation compared with systemic therapy for patients with RCC with limited metastases.² The coprimary end points of this trial are overall survival (OS) and safety.

“Now that we have this new arsenal, the onus is on us to find the right application for stereotactic radiation and [determine] how to integrate it into the multi-modality management of kidney cancer,” Hannan said in an interview with OncLive® during the 2023 Kidney Cancer Research Summit (KCRS).

In the interview, Hannan discussed the benefits of using stereotactic radiation in patients with localized RCC who are unfit for surgery, research findings indicating improved outcomes in patients who received radiation for metastatic disease, and how this radiation technique may work in concert with systemic therapy.

Hannan is chief of the Genitourinary Radiation Oncology Service and a professor in the Departments of Radiation Oncology, Immunology, and Urology at UT Southwestern Medical Center in Dallas, Texas.

OncLive: What was the rationale behind refining stereotactic radiation strategies for patients with RCC?

Hannan: Radiation strategies for kidney cancer are an emerging field. We used to think radiation did not work well for kidney cancer. However, we learned recently that when we deliver high-focus doses of radiation to kidney tumors, they are sensitive to the radiation, and the local control or cure rates are high with minimal toxicity.

Since kidneys move with respiration, we needed to develop technology that could deliver those high ablative doses of radiation. Now that we have the technology, we can deliver high ablative doses with stereotactic radiation. With that, we are seeing good local control rates with minimal toxicity.

What are the benefits of using stereotactic radiation in patients with localized disease?

In the localized setting, for small renal masses, we have published several studies, including a phase 2 study, with rigorous end points of radiographic control and biopsy-confirmed control. We showed a control rate of 94% in primary kidney [cancer].

Some of the benefits of stereotactic radiation are that it is completely noninvasive. Patients who are elderly and are not surgical candidates can easily undergo this radiation. It has fewer limitations on location, unlike ablation. It also has fewer limitations on size. We can treat tumors 5 centimeters or larger. There are many advantages that make it a good modality to consider for patients with primary renal cancer.

Where might stereotactic radiation fit into the treatment of patients with IVC thrombus?

Moving on to the advanced setting, we have [used radiation] to control locally advanced tumors such as inferior vena cava [IVC] tumor thrombus. IVC tumor thrombus in kidney cancer is a complicated situation, and patients often need extensive vascular surgeries [and have high rates of] comorbidities.

We have applied stereotactic radiation in patients who are not surgical candidates to control IVC thrombus, and we found good success. We have now published a multi-institutional case report showing that 58% of patients responded and that all patients had palliative benefit.

One grave complication of venous thrombus is it produces venous congestion, or Budd-Chiari syndrome. We relieved that with stereotactic radiation. We are now investigating [radiation] in a clinical trial in the neoadjuvant setting where the goal is to try to improve local and systemic control and induce antigen presentation with radiation.

Another [radiation] application in the IVC thrombus setting could be that instead of a complicated surgery, we could just do a simple nephrectomy of the primary tumor and leave the thrombus to be treated by stereotactic radiation. That way, a complicated surgery could be reduced to a simpler surgery that the patient may be able to tolerate. This is another active area of research we are now investigating.

How might stereotactic radiation improve survival outcomes for patients with metastatic disease?

In the metastatic setting, we first see whether [a patient’s] metastatic kidney cancer can be controlled with stereotactic radiation. We have published results showing more than 90% local control with stereotactic radiation, with minimal toxicity for tumors that are metastatic to any part of the body. Often, patients have several metastases. How do we integrate stereotactic radiation for those patients? That’s the main question.

[One] place where we found an application for [stereotactic radiation] is in the oligometastatic setting. When patients with kidney cancer [have] metastases in only [1 to 5] sites, and their [disease] biology is not an aggressive biology [and is instead, for instance], International Metastatic RCC Database Consortium favorable- or intermediate-risk, [their disease] will not rapidly progress. In those patients, we had good success by administering focused radiation to all sites of visible metastases.

We are not curing these patients; other sites of metastasis are unseen or will grow, and the patients will eventually need systemic therapy. However, by giving radiation and controlling [the metastases] temporarily, we delay the start of systemic therapy and preserve the quality of life for these patients. Eventually, when the patients start systemic therapy, the efficacy of the systemic therapy may not be compromised.

We have published a retrospective study and a prospective, small, single-arm phase 2 trial confirming these findings. Now, we have designed a large, randomized phase 3 study. This is the SOAR trial, [opening soon], where we will randomly assign patients with oligometastatic RCC into 2 groups. [One group will receive] upfront stereotactic radiation [followed by] delayed systemic therapy [upon progression], [and the other group will receive] upfront systemic therapy.

[Since this is] a noninferiority trial, [we want to show that] the patients’ OS is not compromised by this method. Secondly, [we want to show that] grade 3 or higher toxicity is significantly less for patients who receive upfront stereotactic radiation. We’re excited about this trial, and we need help from other institutions to enroll and participate. This is a nationwide ECOG-ACRIN trial.

The second place in the metastatic setting where stereotactic radiation may find an application is in the setting of oligoprogression. These patients have metastatic disease all over and are on systemic therapy. [In these patients], systemic therapy is working for the most part, except 1 or 2 sites have become resistant. We see that frequently. The current strategy is to abandon the systemic therapy that was working for the most part and go on to the next line of systemic therapy. We don’t have many systemic therapies available for these patients, and if a patient is already tolerating 1 therapy, they may not tolerate the next therapy, because these therapies have significant adverse effects.

One of the strategies we have tried is to attack the resistant clones, or sites, with focal therapy, such as stereotactic radiation. That way, the patient can continue to receive the same systemic therapy. By these means, we showed that we can increase the efficacy of the systemic therapy by almost a year, which is significant. Interestingly, if the systemic therapy is an immunotherapy agent, [such as a] checkpoint inhibitor, the median extension [of the efficacy of this therapy] is almost 20 months. [This is an indication] that radiation may work synergistically with immunotherapy as well. This strategy is under investigation in a few phase 2 studies. We have published our own phase 2 study and retrospective study confirming this. We hope this will be another place where stereotactic radiation can be integrated into the multi-modality treatment of patients with kidney cancer.

What findings were you excited to see come out of KCRS 2023?

The Kidney Cancer Research Summit was excellent. I learned many things. [There is much] advancement coming along, and with that, many opportunities as well. We need to find out where [stereotactic radiation] is applicable and effective, how we can integrate it with the new therapies that have been discussed at KCRS, and how we can move the field forward to get the best benefits for our patients.

References

1. Hannan R, McLaughlin MF, Pop LM, et al. Phase 2 trial of stereotactic ablative radiotherapy for patients with primary renal cancer. Eur Urol. Published online March 8, 2023. doi:10.1016/j.eururo.2023.02.016
2. Focused radiation versus systemic therapy for kidney cancer patients with limited metastasis, SOAR study. ClinicalTrials.gov. Updated May 18, 2023. Accessed August 3, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05863351