Within the past 7 years, seven new agents have been approved for the treatment of mRCC. Five of these targeted therapies are specifically focused on anti-angiogenesis, targeting the vascular endothelial growth factor (VEGF)-mediated pathway and impeding new blood vessel growth by the tumor. The interest in anti-angiogenesis treatment and mRCC is predicated on the highly vascular nature of these tumors and the inactivation of von Hippel-Lindau (vHL) gene in the majority of patients with clear cell RCC, with resultant elevated levels of hypoxia-inducible factors (HIFs) and VEGF. Therefore, this seemed the most likely tumor to prove the concept of an antitumor effect of inhibition of VEGF. While this approach on the surface would also appear to be most effective in clear cell mRCC with its associated up-regulation of HIF proteins, there is also definite activity in the non–clear cell subtypes of mRCC. The two additional approved agents for mRCC are directed toward inhibition of the mammalian target of rapamycin (mTOR) and have a multitude of downstream effects, including anti-angiogenesis, antimetabolism, and impairment of protein synthesis.
These seven agents are all administered as outpatient therapies, and five are oral agents. While they target similar pathways, there are also drug-specific effects, so distinguishing between the different agents and developing algorithms of treatment has become complicated. There are questions regarding sequencing of these drugs and their role, if any, in combination therapy or combined with immunotherapy.
The initial anti-angiogenesis study by Yang using bevacizumab(Drug information on bevacizumab) (Avastin) in mRCC showed marked decline in rates of tumor growth, and even tumor shrinkage. Two subsequent phase III studies, one in Europe (AVOREN [Avastin and Roferon in Renal Cell Carcinoma]) and one in the United States (CALGB [Cancer and Leukemia Group B]) compared bevacizumab plus interferon alfa to interferon alfa alone. The overall response rate (ORR) doubled with the addition of bevacizumab, with ORRs of 31% vs 13% and 25% vs 13%, respectively; there was also a significant improvement in progression-free survival (PFS) with the combination (with PFS results of 10.2 vs 5.4 months and 8.5 vs 5.2 months, P < .0001, respectively). The oral anti-angiogenesis agents have also demonstrated antitumor activity in mRCC in terms of improved PFS following cytokines (sorafenib [Nexavar], sunitinib [Sutent], pazopanib [Votrient]), in comparison with interferon in previously untreated patients (sunitinib, bevacizumab), and following treatment with other anti-angiogenesis tyrosine kinase inhibitors (TKIs; axitinib [Inlyta]).[41-46] The mTOR inhibitors have been shown to have activity in poor-risk mRCC patients, in non–clear cell mRCC (temsirolimus [Torisel]), and following treatment with anti-angiogenesis TKIs (everolimus [Afinitor]).[47,48] All of these agents produce a plateau of PFS, and when given as single agents sequentially, they appear to extend overall survival (OS) for patients with mRCC. The median survival of mRCC patients with intermediate risk, entered into recent trials in which crossover to other active agents is permitted, is now approaching 24 months (compared with 10 months prior to the availability of multiple agents). Table 5 summarizes phase III data from trials of new approved agents for mRCC.
Non–Clear Cell Renal Cell Carcinoma
Non–clear cell RCC includes a broad spectrum of histologies, from adenocarcinomas with papillary and chromophobe histology, to tumors arising more distally, such as collecting duct and medullary renal cell carcinoma. Additionally the translocation RCC found in young people seems to be a distinct entity, with a distinct Xp translocation. There is also sarcomatoid de-differentiation that is seen arising from clear cell or papillary RCC.
There have been substantial investigations in recent years of the different subtypes of renal cancer, initially by histologic appearance—that is, clear cell, papillary, chromophobe, or collecting duct tumors—and more recently by recognition of molecular and gene expression profiles characteristic of different subtypes, which perhaps will eventually direct therapy.[49,50] The distinction between clear cell and non–clear cell types of renal cancer lead to the observation that clear cell renal cancer is more likely to be responsive to immunotherapy than non–clear cell. This is the most definitive distinction with an impact on current treatment choices.
Non–clear cell RCC in general is not thought to be sensitive to immunotherapy, although anecdotal responses are reported in patients with papillary and chromophobe subtypes. In addition, the initial clinical trials of anti-angiogenesis agents were restricted to patients with clear cell carcinoma. However, in the expanded-access trials of sorafenib(Drug information on sorafenib) and sunitinib that were opened to allow broader patient access prior to commercial availability, the eligibility criteria were greatly expanded. Approximately 10% of patients in these trials of 5000 patients each had non–clear cell histologies.[52,53] While strict response evaluation was not completed due to the rapid availability of the commercial drug, the overall impression was that there was no difference in outcome for those with non–clear cell histologies, in terms of response or toxicity. Additionally, in the phase III trial of temsirolimus vs interferon, about 10% of the RCC patients had non–clear cell histologies, mainly papillary histology, reported by the treating institutions. In a specific analysis, patients with non–clear cell RCC did as well—or better—with temsirolimus as they did with interferon (due in part to the lack of efficacy of interferon in this RCC subtype). These data, therefore, have led to the use of targeted therapies in mRCC of non–clear cell histologies, albeit with no further formal study.
At the other end of the spectrum, collecting duct and medullary RCC are very aggressive subtypes, are more similar to urothelial cancers, and on the basis of anecdotal evidence are treated with chemotherapy regimens used for urothelial cancers, but with no specific regimen identified as optimal. Reports of treatment for these subtypes include therapy with taxanes, cisplatin(Drug information on cisplatin), carboplatin(Drug information on carboplatin), and gemcitabine(Drug information on gemcitabine) (Gemzar). These variants are so uncommon that clinical trials have not been accomplished. Medullary RCC is associated with sickle cell trait; is seen in younger patients; usually presents with widespread metastatic disease; and is treated with chemotherapy or targeted agents, with limited success. RCC with a large component of sarcomatoid features is the most aggressive classification, with very rapid growth of metastatic disease. We have reported some success with a chemotherapy regimen of doxorubicin(Drug information on doxorubicin) and gemcitabine, including complete responses, some of which have been durable. An ongoing Eastern Cooperative Oncology Group study is evaluating sunitinib alone compared with sunitinib plus gemcitabine in patients with tumors that have sarcomatoid features. The Cleveland Clinic has reported some success with anti-VEGF targeted therapies in this variant, but with responses seen only in patients who have clear cell RCC with less than 20% sarcomatoid features.
The treatment of RCC has been enhanced in recent years. Several newer agents have been introduced, generally targeting the angiogenesis pathways; these have significant antitumor effects and have become part of the routine care of this disease, resulting in improved disease control and survival. Immunotherapy continues to play an important role and can induce long-term remissions. In addition, although conventional RT continues to play a role, particularly in bone metastases, SBRT appears superior to conventional treatment in the metastatic setting and should be considered when feasible. Finally, use of stereotactic techniques to treat the primary RCC tumor is under study and may come to play an important role in the management of RCC in the future.
Financial Disclosure: Dr. Dutcher is a consultant for Pfizer, Novartis, Prometheus, and Bristol Myers-Squibb. Dr. Ennis and Dr. Mourad have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.