Renal Carcinoma: Causes, Symptoms, and Treatments

The number of individuals diagnosed with cancer steadily increases each year. Data from the National Cancer Institute suggest that 23.6 million new cases will be diagnosed by 2030.¹

Renal carcinomas account for about 3.5% of cancer diagnoses in the United States (see Figure). In 2018, an estimated 65,000 newly diagnosed cases of kidney cancer will result in the death of about 23% of those patients.² The kidneys are a vital aspect of human homeostasis, producing hormones that stimulate erythropoiesis, filtering the blood’s extraneous materials, maintaining critical electrolyte balances, and regulating blood pressure.³ When abnormal pathologies, such as kidney cancer arise, integrity and organ function are compromised, resulting in detrimental outcomes. Although renal carcinomas can be treated, the level of intervention depends on the complexity of the cellular subtype. Clear cell carcinoma is a histological subtype of kidney cancer considered to encompass 70% of all renal neoplasms.^4,5 However, clear cell carcinoma cases are unresponsive to usual chemotherapeutic regimens, making them increasingly difficult to treat with traditional chemotherapeutics, such as capecitabine, 5-fluorouracil, and gemcitabine.⁶ Therefore, the need to produce therapies and develop innovative approaches to treating renal neoplasms is critical.

Epidemiology

Renal cell carcinomas (RCCs) of all subtypes and variations are dispersed nationwide. The incidence and number of kidney cancer cases is not geographically specific. African Americans, Alaska Natives, and Native Americans are at an increased risk for developing kidney and renal pelvis cancers. Gender-based analysis has produced data indicating that men are twice as likely to develop renal cancers than women.⁸ The development of renal cancers largely correlates to those with both at-risk ethnic backgrounds and predisposing risk factors to carcinogenesis.⁹

Risk Factors

Individuals are predisposed to an increased risk of developing RCCs depending on the number of environmental, hereditary, and personal health-related comorbidities (see Table 1).^10-15 Prognosis is related to increased age, overall health, and the stage of disease. Early detection typically increases survival rates. Occupational exposure to chemicals such as asbestos, benzene, cadmium, and trichloroethylene has been associated with an increase in the incidence of RCCs. Individuals who are employed in the agricultural industry, commercial painting, dry cleaning, jewelry production, and welding are frequently exposed to the chemical compounds implicated in renal neoplasms.^10,11 Smoking cigarettes has been found to increase the risk of developing kidney cancer by 50%.¹² Patients with a history of hypertension may have as much as a two-thirds increased risk of developing renal carcinomas.¹³ Modifying risk factors, such as blood pressure maintenance, healthy diet adherence, smoking cessation, and weight loss may reduce a patient’s overall lifetime risk.¹⁴ However, there are genetic conditions that cannot be modified by patient intervention. Familial diseases, which include Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, and von Hippel-Lindau syndrome, can predispose a patient to developing severe forms of nephrological neoplasms.¹⁵

Signs and Symptoms

Generally, RCC is not detected based on specific signs or symptoms. Most patients tend to be asymptomatic in the early stages.¹⁶ This cancer is generally detected when patients present with unrelated complaints or during routine imaging exams. Patients may present with symptoms such as fatigue, fever of unknown origin, flank pain, hematuria, and weight loss (see Table 2^16-18).¹⁷ More subtle signs indicative of disease progression include adenopathy, bone pain, coughing, and shortness of breath.¹⁸ Unfortunately, data concerning the frequency of the signs and symptoms are scarce and not well defined. Many of the observable manifestations of disease are specific to each patient.

Pathology

Most RCCs originate in the epithelial cells of the proximal convoluted tubule.¹⁹ The site of origination depends on whether the carcinoma is from hereditary or sporadic causes. Hereditary renal cell tumors are usually associated with bilateral RCCs, whereas nonfamilial causes are usually unilateral. As the tumor progresses, malignant cells have the potential to penetrate through the renal vein and migrate through the vena cava to susceptible tissues. Common sites of metastasis include the adrenal glands, bones, brain, liver, lungs, and lymph nodes (see Table 3).²⁰ The lungs and bronchial tissues are the most susceptible to malignant renal cells when establishing a secondary site.⁵

Staging and Treatment Algorithm

Staging is based on the size of the primary tumor, growth into nearby areas, spread to lymph nodes, and metastasis to distant organs. Surgical excision is considered the first-line treatment option for RCC in all stages, unless the cancer is surgically unresectable.²¹ Primary tumor subtype 1a (pT1a) is defined as a stage 1 tumor that is less than or equal to 4 cm and has not metastasized. Tumors between 4 and 7 cm are classified as a primary tumor subtype 1b (pT1b). For pT1a or pT1b tumors, treatment methods rely on either removal of the tumor or ablation therapy in patients who do not qualify for surgery.^22,23 However, as RCC progresses and the cancer metastasizes, a patient’s prognosis becomes increasingly poor and the necessity for chemotherapeutic agents becomes a crucial piece of the treatment algorithm. Because of the highly resistant nature of RCC toward traditional antineoplastic drugs, biologics become first-line agents in advanced-stage and metastatic kidney cancer.^4,5 Clinicians reserve the option to use certain biologics according to patient-based criteria in conjunction with supportive care. Worsened prognoses in the later stages could be attributed to high plasma levels of calcium, lactate dehydrogenase, and anemia.²³ The following algorithm (Table 4) outlines renal carcinoma treatment based on staging and ideal procedures to increase survival rates and reduce complications.^21-23

Therapy Options

Traditional approaches to cancer treatment include a combination of surgery and radiation or monotherapy with biologics based on the stage of disease progression (see Table 5).^6,24 When treating kidney cancers and most of its subtypes, the typical treatment begins with either a partial or radical nephrectomy. Radiation therapy is neither desired or used because of its low efficacy and potential to damage healthy renal tissue.²³ Most patients can function with a unilateral kidney.

Table 5. Targeted Therapy^6,24

Tyrosine kinase inhibitors

Sorafenib (Nexavar)

Sunitinib (Sutent)

Pazopanib (Votrient)

Axitinib (Inlyta)

mTOR kinase inhibitors

Temsirolimus (Torisel)

Everolimus (Afinitor)

VEGF inhibitors

Bevacizumab (Avastin)

Tyrosine kinase inhibitors / VEGF inhibitors

Cabozantinib (Cabometyx)

Lenvatinib (Lenvima)

Immunotherapy⁶

Cytokines

Interleukin-2

Interferon-α

Checkpoint Inhibitors

Nivolumab (Opdivo)

CTLA-4 Inhibitors

Ipilimumab (Yervoy)

^{mTOR indicates mammalian target of rapamycin; VEGF, vascular endothelial growth factor.}

Clinician Place in Therapy

Clinicians play a vital role in managing and monitoring dose adjustments, drug interactions, patient adherence, and treatment-related toxicities. Prevention programs, such as lifestyle management and smoking cessation, should be continually promoted to reduce the risk of renal cell carcinoma. Empowering patients to make these changes early is the key.

Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, are clinical pharmacists in Pensacola, Florida.Matthew Bailey and Amanda Boyer, are PharmD candidates at Auburn University in Alabama.

References

• National Cancer Institute. Cancer statistics. NCI website. cancer.gov/about-cancer/understanding/statistics. Updated April 27, 2018. Accessed May 19, 2018.
• National Cancer Institute. Kidney (renal cell) cancer — patient version. NCI website. cancer.gov/types/kidney. Accessed May 19, 2018.
• Kidney overview. Healthline website. healthline.com/human-body-maps/kidney. Accessed May 21, 2018.
• Kidney cancer: introduction. Cancer.net website. cancer.net/cancer-types/kidney-cancer/introduction. Published August 2017. Accessed May 19, 2018.
• Low G, Huang G, Fu W, Moloo Z, Girgis S. Review of renal cell carcinoma and its common subtypes in radiology. World J Radiol. 2016:8(5):484-500. doi: 10.4329/wjr.v8.i5.484.
• Kidney cancer: treatment options. Cancer.net website. cancer.net/cancer-types/kidney-cancer/treatment-options. Published August 2017.Accessed May 19, 2018.
• United States cancer statistics (USCS). CDC website. cdc.gov/uscs. Updated July 13, 2018. Accessed July 27, 2018.
• National Cancer Institute. Cancer stat facts: kidney and renal pelvis cancer. NCI website. seer.cancer.gov/statfacts/html/kidrp.html. Accessed May 19, 2018.
• US Cancer Statistics Working Group. United States Cancer Statistics: data visualizations. CDC website. gis.cdc.gov/grasp/USCS/DataViz.html. Accessed May 19, 2018.
• Kabaria R, Klaassen Z, Terris MK. Renal cell carcinoma: links and risks. Int J Renovasc Dis. 2016;9:45-52. doi:10.2147/IJNRD.S75916.
• Karami S, Colt JS, Schwartz K, et al. A case-control study of occupation/industry and renal cell carcinoma risk. BMC Cancer. 2012;12:344. doi:10.1186/1471-2407-12-344.
• Kidney cancer. Cancer Research UK. cancerresearchuk.org/about-cancer/kidney-cancer/risks-causes. Updated January 13, 2016. Accessed July 27, 2018.
• Hidayat K, Du X, Zou SY, Shi BM. Blood pressure and kidney cancer risk: meta-analysis of prospective studies. Journal Hypertens. 2017;35(7):1333-1344. doi: 10.1097/HJH.0000000000001286.
• Kidney cancer: risk factors and prevention. Cancer.net website. cancer.net/cancer-types/kidney-cancer/risk-factors-and-prevention. Published August 2017. Accessed May 21, 2018.
• National Cancer Institute. Renal cell cancer treatment (PDQ) — patient version. NCI website. cancer.gov/types/kidney/patient/kidney-treatment-pdq. Updated May 11, 2018. Accessed May 20, 2018.
• UCLA Health. Kidney cancer symptoms and risk factors. UCLA Health website. urology.ucla.edu/kidney-cancer-symptoms. Accessed May 22, 2018.
• 7 symptoms of renal cell carcinoma. Healthline website. healthline.com/health/renal-cell-carcinoma-symptoms#outlook. Accessed May 20, 2018.
• Nordqvist C. What you need to know about kidney cancer. MedicalNewsToday. January 22, 2018. medicalnewstoday.com/articles/164659.php. Accessed May 22, 2018.
• Renal cell carcinoma. AMBOSS website. amboss.com/us/knowledge/Renal_cell_carcinoma. Accessed May 21, 2018
• Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol. 2012;23(4):973-980. doi: 10.1093/annonc/mdr362.
• Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017:15(6):804-834. doi: 10.6004/jnccn.2017.0100.
• Sachdeva K. Renal cell carcinoma staging. Medscape. emedicine.medscape.com/article/2006851-overview. Published May 5, 2017. Accessed May 18, 2018.
• Vandever LA. What’s the connection between kidney cancer stage and five-year survival rates? Healthline website. healthline.com/health/kidney-cancer/kidney-cancer-prognosis-stage#risk-factors. Published February 26, 2018. Accessed May 22, 2018.
• Biologic therapy drugs. Cancer Research UK. cancerresearchuk.org/about-cancer/kidney-cancer/advanced/biological-therapy/drugs. Accessed May 22, 2018.