Smoking History, Obesity Increase Risk for Renal Cell Carcinoma in Veterans

While toxic exposures such as contaminated water at Camp Lejeune increase the likelihood of developing renal cell carcinoma (RCC), veterans have higher risks for the cancer even beyond those unusual events. A history of cigarette smoking and obesity—both of which are more common in veterans than the general population—raises the risk for RCC, which is twice as common in men than women.

By Annette M. Boyle

AUGUSTA, GA—Effective this March, the VA officially added renal cell carcinoma and seven other cancers to the list of diseases considered to be presumptively service-connected for certain veterans, former reservists and former National Guard members who served at Camp Lejeune from 1953 to 1987.

The Camp Lejeune exposure stands out as a specific risk for kidney cancer for former military servicemembers, many of whom have several other factors that might increase their risk.

“The risk factors for kidney cancer are smoking tobacco, exposure to toxins such as asbestos and/or cadmium, being on dialysis, obesity and some inherited syndromes that run in families,” said Martha K. Terris, MD, urology physician at the Augusta (GA) VAMC and co-author of a recent review article on the risks for renal cell carcinoma published in the International Journal of Nephrology and Renovascular Diseases. High blood pressure also increases risk.1

The new ruling on presumptive service connection “relates kidney cancer to two water wells on base that were contaminated with trichlorethylene, percholorethylene, benzene, vinyl chloride and other compounds,” Terris said.

Each year, about 1,300 veterans develop kidney and urothelial renal pelvis cancer, which account for 3.3% of all cancers in veterans. The American Cancer Society estimates that 40,610 men and 23,380 women will develop kidney cancer this year.  Of those, 85% to 90% of cases will be renal cell carcinoma (RCC). 2

Renal cell carcinoma and other related cancers occur twice as often in men as in women. The majority of cases arise in individuals between the ages of 55 and 74 and are more common in African-Americans, American Indians and Alaska Native populations, noted Terris and her co-authors.

Veterans have higher rates of two major risk factors for RCC: a history of cigarette smoking and obesity. Veterans who have ever smoked have 40% greater risk of RCC than those who never smoked. Risk increases with the number of cigarettes smoked per day, with 40 or more cigarettes a day doubling risk compared to nonsmokers. Each pack-year of smoking also raises the risk 1%. Quitting smoking reduces risk of developing RCC, but a history of smoking remains associated with more-aggressive RCC and worse survival rates, according to the authors.

Military service has historically been associated with higher rates of cigarette smoking, but both the DoD and the VA have aggressively implemented smoking cessation programs to bring down smoking rates. While current servicemembers are about 20% more likely to be smokers than their civilian counterparts (24% vs 20%), veterans have a similar rate of current cigarette smoking as nonveterans today. Still, in the general U.S. population, about 57% of people say they have never smoked cigarettes, compared to only 32% of veterans who receive care through the VA.

Obesity also is more common in veterans than in the general population, at 41% compared to 36.5%. The risk of RCC rises with body mass index, with patients who have a BMI greater than 35 at 71% greater risk of RCC than individuals with BMIs between 18 and 25. The association between obesity and survival, however, appears more complicated, with two studies indicating that underweight patients have quadruple the mortality rate of normal weight patients and several Japanese studies suggesting that high visceral fat provides cancer-specific and overall survival benefit in RCC, according to the authors.

Hypertension also increases the risk of RCC in a dose-dependent fashion, with systolic pressure above 150 mmHg doubling the risk. Patients who lower their blood pressure, though, reduce their risk over time, Terris and colleagues noted.

“Since the vast majority of kidney cancers are what we call ‘spontaneous’ or due to no obvious cause, there are not many things veterans can do to change risk.” Terris told U.S. Medicine. “However, quitting smoking, watching weight and controlling blood pressure are steps that veterans can employ to help decrease their risk of RCC as well as the risk of stroke, heart attack and many other diseases.”

No specific screening test is recommended for kidney cancer, but Terris said that the urine sample taken during patient health maintenance examinations might show blood in the urine, which may be an indicator for renal cell carcinoma cancer, among other conditions.

For veterans diagnosed with renal cell carcinoma, 75% to 85% will have clear cell RCC. While surgical resection continues to be the only curative treatment for localized RCC, 30% of patients who have surgery experience local or metastatic recurrence, and another 35% receive their initial diagnosis at an advanced stage.4

The standard treatment for advanced RCC relies on immunomodulatory and targeted therapies, along with surgery, when possible, as standard chemotherapy has shown little efficacy in most types of metastatic RCC. Interleukin (IL)-2 and interferon-a have been the primary treatments for years and produce durable, complete responses in 7% to 10% of patients, but both have serious toxicity issues.5

The treatment landscape for this type of cancer has changed dramatically in the last two years with three new second-line medications—nivolumab, cabozantinib and a combination of lenvatinib and everolimus—gaining approval by the U.S. Food and Drug Administration (FDA). Sunitinib, pazopanib, temsirolimus and bevacizumab combined with interferon-a are approved for first-line use in metastatic clear cell RCC, while the new agents join sorafinib and axitinib for subsequent treatment. Sunitinib has been the standard of care for advanced RCC for the last decade.

The three new therapies have all demonstrated an overall survival benefit for RCC patients, have higher rates of objective tumor response and extend progression-free survival substantially beyond that seen with previous treatments, according to Thomas A. Hutson, DO, PharmD, co-author of the Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma and director of the Genitourinary Oncology Program, Charles A. Sammons Cancer Center at Baylor University Medical Center in Dallas. The lenvatinib plus everolimus therapy, for instance, has a median progression free survival of 14.6 months compared to 5.5 months with everolimus monotherapy.

With so many options now available, Hutson urged individualization of therapy to a patient’s particular situation. In an interview with OncLive, he noted that mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus should be avoided in diabetics, and patients with rheumatoid arthritis might not be good candidates for an immunotherapy.

  1. Kabaria R, Klaassen Z, Terris MK. Renal cell carcinoma: links and risks. Int J Nephrol Renovasc Dis. 2016 Mar 7;9:45-52. doi: 10.2147/IJNRD.S75916. eCollection 2016. Review.
  2. Zullig LL, Jackson GL, Dorn RA, Provenzale DT, McNeil R, Thomas CM, Kelley MJ. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System. Mil Med. 2012 Jun;177(6):693-701.
  3. Breland JY, Phibbs CS, Hoggatt KJ, Washington DL, Lee J, Haskell S, Uchendu US, Saechao FS, Zephyrin LC, Frayne SM. The Obesity Epidemic in the Veterans Health Administration: Prevalence Among Key Populations of Women and Men Veterans. J Gen Intern Med. 2017 Apr;32(Suppl 1):11-17. doi:10.1007/s11606-016-3962-1.
  4. Venur VA, Joshi M, Nepple KG, Zakharia Y. Spotlight on nivolumab in the treatment of renal cell carcinoma: design, development, and place in therapy. Drug Des Devel Ther. 2017 Apr 11;11:1175-1182. doi: 10.2147/DDDT.S110209. eCollection 2017. Review.
  5. Raman R, Vaena D. Immunotherapy in metastatic renal cell carcinoma: A comprehensive review. BioMed Research Int. 2015 Mar; article ID:367354, 8 pages, 2015. doi:10.1155/2015/367354.
  6. Choueiri TK, Halabi S, Sanford BL, et al: Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Study. J Clin Oncol. November 14, 2016 (early release online).

 

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