Rare Kidney Tumors - Current Treatments

Non-clear cell renal cell cancer

Renal (kidney) cell cancer is the most common type of kidney cancer. Indeed, approximately 90% of diagnosed kidney cancers are renal cell carcinoma (RCC). Therefore, unless otherwise specified, kidney cancer should be understood to mean renal cell cancer. This type usually develops as a single tumor in the kidney. However, sometimes 2 or more tumors occur, and multiple tumors can even appear simultaneously in both kidneys.

Clear cell cancer accounts for 75% of renal cell cancers.

Non-clear cell cancers are rare. Non-clear cell kidney cancers comprise the following subtypes:

• Papillary renal cell cancer (15% of all kidney cancers)
• Chromophobe type (5%)
• Collecting duct (less than 5%)
• Sarcomatoid type (less than 5%)

The foundation of clear cell kidney cancer treatment consists of immunotherapies and targeted drugs [antiangiogenic agents (VEGF inhibitors) and mTOR inhibitors]. However, drug development options for non-clear cell kidney cancers are more limited because, for these rare tumors, suitable clinical trials for patients are often not designed.

Papillary renal cell cancers

This is the most common subtype of non-clear cell kidney cancer, and 2 types have been defined:

• Type-1 disease: often involves a mutation in the gene MET, a proto-oncogene .
• Type-2 disease: TFE3 fusion, silencing of the CDKN2A gene, and SETD2 and fumarate hydratase gene mutations

Previously, MET proto-oncogene mutations were detected in around 13% of papillary renal cell cancers. More recent studies, however, identified high MET gene expression and c-MET activation in almost all papillary kidney cancers, suggesting that c-MET-inhibiting targeted drugs may be a good option. An ongoing phase-2 clinical trial is testing foretinib, a new drug that inhibits both VEGF/MET pathways, in papillary kidney cancer. The overall response rate was 13%, and progression-free survival (the time disease remains controlled with treatment) was 9.3 months. Furthermore, foretinib was more effective in patients with germline MET mutations. However, drug development was stopped because the study did not achieve its initially targeted response rate of 25%.

Many retrospective studies assessed another VEGF pathway-targeted drug, sunitinib (Sutent), in papillary kidney cancer, but found a low response rate of 4.8%. A phase-2 study by the French Genitourinary Group found response rates in type-1 and type-2 papillary kidney cancer of 11% and 13%. Another phase-2 study, ESPN, compared treatment in 68 patients with non-clear cell kidney cancer using sunitinib and everolimus (Afinitor), finding no significant difference in progression-free survival (6.1 versus 4.1 months). The ASPEN study, in metastatic papillary, chromophobe and unclassified non-clear cell kidney cancer, compared sunitinib and everolimus in 108 patients. Progression-free survival significantly favored sunitinib (8.3 versus 5.8 months).

In RECORD-3, a larger prospective study of 471 patients, 238 received first-line everolimus followed by sunitinib, and 233 received first-line sunitinib followed by everolimus. Median progression-free survival was 7.9 months with first-line everolimus and 10.7 months with first-line sunitinib.

Other promising drugs being tested in clinical trials for this disease are crizotinib, bevacizumab and erlotinib. SWOG 1500, a phase-2 trial testing multityrosine kinase inhibitors (oral targeted drugs), has also recently begun. SWOG 1500 is testing cabozantinib, crizotinib, savolitinib and sunitinib in metastatic papillary kidney cancer. In SAVOIR, which compares savolitinib and sunitinib, genetic changes in the MET pathway are used as a patient selection criterion.

These studies will enable more precise treatment selection for metastatic papillary renal cell cancer.

Chromophobe renal cell cancers

This is another rare renal cell cancer. In ASPEN, chromophobe kidney cancers generally responded better to sunitinib than everolimus; however, of 6 patients receiving everolimus, 2 had a partial or complete radiological response. Furthermore, median progression-free survival in metastatic chromophobe disease was 11.4 months with everolimus and 5.5 months with sunitinib.

Another retrospective study of 36 patients with metastatic chromophobe kidney cancer treated with first-line sunitinib found a clinical benefit rate of 78%, median progression-free survival of 19 months and overall survival of 26 months. Thus, the chromophobe type may have better treatment responses and survival than other non-clear cell kidney cancers.

Sarcomatoid renal cell cancer

Renal cell cancer with sarcomatoid features often has an aggressive clinical course and poor outcomes. Many also classify the sarcomatoid type within clear cell kidney cancer and use the extent of the sarcomatoid component in the kidney tumor as a marker of aggressiveness. In ECOG 8802, 38 patients received doxorubicin plus gemcitabine as a two-drug chemotherapy regimen, and patients generally responded (median overall survival 8.8 months and progression-free survival 3.5 months). In another phase-2 study, 39 patients with sarcomatoid kidney cancer and 33 with high-risk kidney cancer received gemcitabine plus sunitinib. The study found better responses in those whose tumors contained less than 10% sarcomatoid tissue.

Collecting duct renal cell cancer

Also called Bellini duct carcinoma, this rare cancer often arises from the epithelial cells lining the kidney’s collecting ducts. Most patients are diagnosed with locally advanced or metastatic disease. Surgery is the main treatment for localized disease; advanced disease is treated like other genitourinary cancers (gemcitabine and cisplatin or gemcitabine and carboplatin chemotherapy). The only prospective study in this area found an objective response rate of 26% with gemcitabine plus cisplatin or carboplatin.

Conclusion

Rare genitourinary (kidney and urinary tract) cancers generally have a poor prognosis (disease outlook), and diagnosis and treatment are challenging. Identifying their distinctive characteristics and increasing physicians’ awareness will lead to better diagnosis and treatment.