home_v14n1_2_wp pic_figlin_okTrue or False: Chemotherapy and radiation are generally considered ineffective treatment approaches in renal cell carcinoma (RCC).  The knee-jerk response would be “true,” and if the question appeared on a CME post-test, for example, the response would no doubt be considered correct, since the prevailing opinion about these two modalities is that they are largely ineffective, certainly ineffective compared to the standard of care use of targeted agents. However, if the question were slightly reworded, “chemotherapy and radiation are being reconsidered as effective treatment options in RCC,” there would be reason to think again about how one responds. In this case, the correct response again might be “True,” contrary to conventional wisdom.

No one is saying that we are witnessing a tectonic shift in the treatment paradigm. This is far from the case. But there is an undercurrent in the literature that compels us to revisit our conventional views about chemotherapy and radiation in RCC. It is not that the modalities as monotherapy are generating new hypotheses but when used in combination with another agent or vehicle to deliver treatment, chemotherapy and radiation are getting a fresh look.

Consider one hypothesis from a recent report that serves as a cutting edge for reevaluating radiation. The authors suggest that stereotactic body radiotherapy (SBRT) and interleukin-2 therapy could provide potential benefit. The hypothesis is that radiation increases tumor antigen release and changes the tumor microenvironment such that the immune effects of IL-2 are significantly more effective in melanoma and RCC.

None of the studies suggest that radiotherapy has a role by itself (except in specific circumstances involving oligometastatic disease, its use in treating CNS metastasis, or for palliation). This is especially true in view of new data on immunotherapy using checkpoint inhibitors. As checkpoint blockade gets mainstream attention—due to striking and durable clinical responses in some patients with metastatic disease—there is more interest in the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy. The emphasis of studies so far continues to be on fractionated and not single dose radiotherapy. The report in this issue of the Kidney Cancer Journal  brings everyone up to date on intriguing results.

And what about chemotherapy? Its track record in RCC is largely disappointing. But that was before nanoparticle technology became more of a gleam in a researcher’s eye. Nanoparticle technology could potentially be used to deliver a payload of chemotherapy and a TKI to the tumor cell, bypassing normal cells. It is not a vision but a premise being investigated in a Phase 2 trial now fully accrued to study the effects of nanoparticle technology on tumor cell permeability. Expectations surrounding this trial are high in view of positive data gained in a Phase 1b/2 study in which the nanoparticle conjugate developed by Cerulean was also evaluated and showed promise for extending progression-free survival. The Phase 2 trial compares CRLX101 in combination with bevacizumab to investigator’s choice of standard of care (SOC) in patients with RCC who have received two or three prior lines of therapy. Results may not be available until 2017, but if the favorable results seen in preliminary investigations can be validated there could be one more option to improve the therapeutic ratio in RCC.

Robert A. Figlin, MD