Treatment review: Non-clear cell renal carcinoma

The incidence of kidney cancer doubled between 1990 and 2013 and while most of these are characterized as clear cell renal cell carcinomas (ccRCC), nearly 25% are of non-clear cell histology. These are a mixed bag of multiple types of tumors originating in the kidney with distinct molecular and genetic characteristics that are very different from ccRCC.

Currently, there is no treatment specifically approved for non-clear cell renal carcinomas (ncRCC) in the US by the Food and Drug Administration (FDA). Therapies evaluated in clinical trials are typically conducted in ccRCC, but the FDA approval covers all types of renal cancers. Although less frequent in incidence, ncRCC are often incurable and fatal in advanced stages which contributes to the morbidity and mortality of the disease.

Ulka Vaishampayan, MD, from the Karmanos Cancer Institute at Wayne State University in Detroit, MI, feels that due to the rare incidence, advances in ncRCC need clinical trials with adequate number of patients requiring the cooperation of many facilities. She reviewed the evolving treatment models in ncRCC, taking into account the recent advances in molecular and tumor genomic testing. Her review was published in Current Treatment Options in Oncology.

Types of ncRCC along with clinical, histologic, and genetic characteristics, as well as management recommendations, are summarized as follows:

Type of ncRCC	Clinical Characteristics	Genetic Mutations	Management
Papillary Type 1	Localized, with metastases unlikely	Familial: 100% MET mutations Sporadic: 13% MET mutations	Trials of MET inhibitors preferable (cabozantinib has MET inhibitory effects)
Papillary Type 2	Usually high grade and metastatic	Familial: often fumarate hydratase gene mutation  Sporadic: no specific gene mutations	Consider anti-VEGF therapies (sunitinib, pazopanib, cabozantinib)
Chromophobe	Varied clinical course	Familial: 96% folliculin gene mutation Sporadic: unknown	This subgroup may benefit from front-line everolimus
Sarcomatoid	Aggressive, usually metastatic presentation	Familial: none Sporadic: 32% biallelic TP53 mutations	Chemotherapy with doxorubicin and gemcitabine combo or cisplatin-based, nivolumab has shown some promise
Translocation Type	Frequently metastatic and incurable	Renal/melanoma syndrome: germline mutations of MiTF Sporadic: TFE3 and TFEB	Same therapy as for ccRCC
Medullary	Rapidly progressing, metastatic at presentation	Usually sickle cell trait association Others: FH gene mutation, VHL mutation, HIF-1 alpha	Chemotherapy: cisplatin- or doxorubicin-based
Collecting Duct	Rapidly progressing, metastatic at presentation	No specific gene mutations noted	Chemotherapy: cisplatin or doxorubicin-based
Unclassified	Rapidly progressing, metastatic at presentation, fatal	No specific gene mutations noted	Chemotherapy: consider anti-VEGF therapies (sunitinib, pazopanib, cabozantinib)

Specific genetic or familial syndromes have been reported for ncRCC, including hereditary papillary renal carcinoma, Birt-Hogg-Dubé, hereditary leiomyomatosis renal cell carcinoma, succinate dehydrogenase kidney cancer, tuberous sclerosis complex (TSC), and Cowden's disease.

Treatment of ncRCC

Due to suboptimal systemic therapy, cytoreductive nephrectomy (CN) in ncRCC is important. Although the studies of CN were done in patients with ccRCC, the principle of impacting survival by debulking surgery applies to localized and metastatic ncRCC as well.

Evidence indicates that there is no benefit with adjuvant systemic therapy post-nephrectomy. Results of the EVEREST trial, in which patients (including ncRCC) were randomized to adjuvant everolimus or placebo, are forthcoming.

In high-risk patients with sarcomatoid, medullary, or collecting duct carcinoma, adjuvant chemotherapy with doxorubicin and gemcitabine or cisplatin and gemcitabine should be considered.

In metastatic disease, CN should be performed if the patient demonstrates adequate performance status with symptomatic large primary or minimally symptomatic non-bulky metastases.

Local therapy should be considered in the management of ncRCC, if feasible. Metastasectomy to render complete remission is an important strategy, especially in a disease with suboptimal systemic therapy outcomes. Non-invasive therapies like stereotactic radiation therapy (SRT), cryotherapy, and other ablation techniques should be considered in patients with oligometastatic disease. There is evidence that durable remissions in metastatic disease can be achieved with local therapy alone.

Systemic treatment options for ncRCC depend on histology; however, randomized studies have demonstrated that anti-vascular endothelial growth factor (VEGF) therapy with sunitinib results in better outcomes than everolimus. Two studies in patients with ncRCC reported improved progression-free survival (PFS) and overall survival (OS) with front-line sunitinib therapy.

A phase 2 trial of pazopanib in ncRCC reported an 81% disease control rate and partial response in 27% of patients.

In papillary RCC, which is the most common histology of ncRCC, c-MET inhibition has been extensively tested in phase 2 trials. The results of these and other studies may have the potential to change current standard therapy of front-line sunitinib for metastatic papillary RCC.

High-dose interleukin-2 should not be considered in ncRCC due to lack of demonstrated efficacy. Immune checkpoint inhibitors have not been specifically studied in ncRCC, but can be used because they are approved for treatment of advanced kidney cancer.

Unfortunately, the advent of targeted therapies based on next-generation sequencing has been slow in kidney cancer, due primarily to the heterogeneity of RCC. Targets detected are not predictive of therapeutic efficacy. Despite a number of small studies and case reports in sarcomatoid, translocation type, collecting duct, unclassified, and medullary histologies, no specific therapeutic recommendations can be made within the limitations of the current level of evidence.

"Due to the rare incidence, any advances in ncRCC continue to require accrual from multiple institutions or cooperative group trial efforts. Recognizing this, priority should be given for rational drug development trials in ncRCC in a collaborative effort," concluded the author.

To read more about this study, click here.