‘Surging Burden’ of Anal Cancer Requires More Investigation, Education

Anal cancer accounts for less than 3% of gastrointestinal malignancies and 0.5% of all new cancer diagnoses in the United States.

However, the incidence rate has more than doubled in the past 3 decades, according to SEER statistics.

The trend appears driven primarily by sharp increases in anal squamous cell carcinoma, a subtype almost always caused by HPV infection.

Radiation therapy combined with chemotherapy are effective for anal cancer.

However, delayed diagnosis dramatically reduces the likelihood of survival. This can be problematic due to a lack of awareness about early warning signs, as well as societal taboos regarding the anatomical site of the cancer and its association with sexual behavior.

In addition, due to the rarity of the disease, the clinical community’s understanding of the disease — as well as treatment options — are limited. There also is no consensus on screening, even for high-risk individuals.

Photo courtesy of The University of Texas MD Anderson Cancer Center.

“Although incidence is still relatively small compared with other cancer types — such as breast cancer and lung cancer — there is a very clear rise,” Cathy Eng, MD, professor in the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, said.

“This is a sign that we need to educate the population about the symptoms of the disease, as well as preventive measures that can be taken,” Eng added. “We also need more data to reduce mortality from anal cancer — a cancer that has an unfortunate stigma associated with it.”

Healio Gastroenterology spoke with clinicians and researchers about the increased incidence of anal cancer, the risk factors that contribute to this largely preventable disease, the potential need for screening recommendations and the evolving treatment landscape.

‘Often Neglected’

An estimated 8,080 Americans are diagnosed each year with anal cancer.

It ranks as the 26th most common malignancy in the country. For context, 30 Americans are diagnosed with breast cancer for every one diagnosed with anal cancer.

However, incidence is on the rise.

The raw number of cases has doubled since 2003. The rate of new cases increased from 0.8 per 100,000 people in 1986 to 1.9 per 100,000 people in 2013, according to SEER data.

Farhad Islami, MD, PhD, strategic director of cancer surveillance research at American Cancer Society, and colleagues used data from the Cancer Incidence in Five Continents series, compiled by the International Agency for Cancer Research, to calculate age-standardized incidence rates for two subtypes: anal squamous cell carcinoma and anal adenocarcinoma.

Their results — published last year in International Journal of Epidemiology — revealed an annual percentage change in anal squamous cell carcinoma of 4.6% (95% CI, 2.8-6.4) among white women in the United States between 1996 and 2012.

Analyses of data from 1975 through 2012 revealed annual percentage changes of 4.2% (95% CI, 2.9-5.4) among black men; 3.3% (95% CI, 2.7-3.8) among white men; and 1.4% (95% CI, 0.5-2.4) among black women.

“As anal cancer is a relatively rare cancer, it is often neglected,” Islami told Healio Gastroenterology. “Knowing the trends in incidence of a cancer is important for setting priorities for cancer prevention and care, as well as monitoring progress against cancer.”

Researchers reported similar steady increases over the past 3 to 4 decades in other developed nations, such as Canada (4.5% per year among men and 4.9% per year among women), Denmark (4.3% among men and 4.7% among women), Italy (5.1% among men and 5.8% among women), the Netherlands (6.3% among men and 6.1% among women) and the United Kingdom (3.3% among men and 4.5% among women).

“Population-based preventive measures — including HPV vaccination and advocacy for safe sexual behaviors — may contribute to curbing the surging burden of disease,” Islami and colleagues wrote.

Role of HPV

Epidemiological studies have identified several risk factors that support the role of sexually transmitted infections in anal cancer carcinogenesis.

Frisch and colleagues conducted telephone interviews with 417 adults (77% women) in Denmark and Sweden diagnosed with invasive or in situ anal cancer. Researchers also interviewed 534 controls with adenocarcinoma of the rectum, as well as 554 population controls.

Investigators performed polymerase chain reaction to test anal cancer tissue and rectal adenocarcinoma samples for HPV DNA.

Their findings — published in The New England Journal of Medicine — revealed significant associations between sexual promiscuity measures and anal cancer risk among men and women.

Researchers reported “a significant trend toward an association” between anal cancer and increased numbers of partners of the opposite sex in men (P < .05) and women (P < .001).

Among women, receptive anal intercourse (OR = 3.4) — especially prior to age 30 years — and venereal infections in the partner (OR = 2.4) appeared associated with increased risk. Fifteen percent of men with anal cancer indicated they had homosexual contact, compared with none of the controls (P < .001).

Eighty-four percent of anal cancer specimens evaluated included high-risk HPV types, but all rectal adenocarcinoma samples tested negative for HPV.

The presence of high-risk types of HPV, notably HPV 16, in the majority of anal cancer tissue specimens lends support to the belief that most anal cancers are potentially preventable, Frisch and colleagues wrote.

Christopher Willett, MD, professor and chairman of the department of radiation oncology at Duke University, agreed.

“The HPV vaccine truly does have a lot of promise as a preventive tool in specific groups of at-risk patients by minimizing the risk for acquiring precursors of anal carcinoma lesions,” Willett told Healio Gastroenterology.

In a subinvestigation of a large, double blind study, Palefsky and colleagues randomly assigned 602 men who have sex with men to receive the quadrivalent HPV vaccine (Gardasil, Merck) or placebo. The safety and efficacy of the vaccine against anal intraepithelial neoplasia associated with four HPV types — 6, 11, 16 and 18 — served as the primary outcome measure.

Study participants ranged in age from 16 to 26 years.

The results, published in The New England Journal of Medicine, showed efficacy rates against neoplasia associated with the four specified HPV types of 50.3% (95% CI, 25.7-67.2) in the intention-to-treat cohort and 77.5% (95% CI, 39.6-93.3) in the per-protocol efficacy population.

Efficacy against anal intraepithelial neoplasia associated with any HPV type was 25.7% (95% CI, –1.1 to 45.6) in the intention-to-treat cohort and 54.9% (95% CI, 8.4-79.1) in the per-protocol efficacy population.

Researchers reported a 54.2% (95% CI, 18-75.3) reduction in the rate of grade 2 or grade 3 anal intraepithelial neoplasia associated with the four specified HPV types in the intention-to-treat cohort and a 74.9% (95% CI, 8.8-95.4) reduction in the per-protocol efficacy population.

No serious vaccine-associated adverse events occurred.

Given data that suggest the HPV vaccine can prevent nearly all anal, oropharyngeal, cervical and other genital cancers, clinicians are baffled why vaccine uptake remains low. Approximately 42% of eligible girls and 28% of eligible boys in the United States have completed the recommended HPV vaccine series.

“The association between HPV and anal cancer is between 80% and 90%, which is comparable to the association between HPV and cervical cancer,” Eng said. “Yet, the vaccine is completely underutilized here. As an oncologist, I no longer want to see patients with a preventable cancer. ... The HPV vaccine prevents cancer — this is the reality.”

HIV and Other Risk Factors

Anal cancer incidence among men who have sex with men and adult males with HIV/AIDS is 10 to 50 times higher than in the general population.

Among women, invasive anal cancer incidence is seven to 28 times higher among those with HIV/AIDS than the general population.

“HIV–infected persons have a much longer survival with effective treatment with highly active antiretroviral therapy. Because these patients are living longer, they are, therefore, more likely to go on to develop anal cancer,” Al B. Benson III, MD, FACP, FASCO, professor of medicine and associate director for cooperative groups at Robert H. Lurie Comprehensive Cancer Center at Northwestern University, said.

Anal cancer is one of the most common excess malignancies among those living with HIV, according to a study by Robbins and colleagues published in 2015 in Journal of the National Cancer Institute.

Researchers analyzed linked HIV and cancer registry data, as well as SEER data, and identified 7,760 cancer cases among HIV–infected people in 2010. Of these, approximately half (n = 3,920) were in excess of expected incidence.

The most common excess cancers were non-Hodgkin lymphoma (n = 1,440; 88% excess), Kaposi sarcoma (n = 910; 100% excess), anal cancer (n = 740; 97% excess) and lung cancer (n = 440; 52% excess).

The majority (83%) of excess anal cancer cases occurred in men who have sex with men, and 71% were reported in those living 5 years or more since the onset of AIDS.

“The excess cancer burden in the U.S. HIV population is substantial, and patterns across groups highlight opportunities for cancer control initiatives targeted to HIV–infected people,” Benson and colleagues wrote.

Yanik and colleagues examined the combined effects of aging and HIV. They pooled data from SEER registries to assess absolute cancer risk among people with HIV aged 65 years and older.

They determined 10.1% of individuals with HIV developed cancer during a 5-year period. The association between HIV and anal cancer incidence (adjusted HR = 34.2; 95% CI, 23.9-49) was second only to the association between HIV and Kaposi sarcoma (adjusted HR = 94.4; 95% CI, 54.6-163).

Other risk factors associated with increased anal cancer incidence include cigarette smoking and chronic immunosuppression in those who have undergone transplant.

Race and sex also appear to play a role, as highlighted in the study by Islami and colleagues.

“The million-dollar question is why black men and white women specifically are at high risk,” Nicholas J. Petrelli, MD, FACS, medical director at Helen F. Graham Cancer Center and Research Institute at Christiana Health Care System, said in an interview. “The etiologies for these disparities are not clear. However, this is not a cop-out. We do need answers. We need to know the factors driving these disparities at the patient and physician levels, and we need more research to focus on this.”

Screening Inconsistencies

Some specialists support annual screening for all high-risk individuals, as the use of anal cytology — essentially an anal Pap test — can lead to earlier diagnosis of anal high-grade squamous intraepithelial lesions and reduce a person’s risk for developing anal cancer.

However, no formal national or international guidelines exist.

“Let’s face it: We cannot even come to a clear consensus on screening for some of the other more common cancer types — such as breast or prostate cancers — so it is not surprising there is no clear consensus on screening for anal cancer,” Petrelli said.

Consequently, inconsistencies abound in practice.

“Screening is very heterogeneous across the country,” Willett said.

An analysis by Wells and colleagues — published in 2014 in AIDS Patient Care and STDs — identified seven state-, national- and international-based reports that suggested screening may help reduce anal cancer incidence among HIV–infected individuals.

However, they found no randomized controlled trials that provided strong evidence to support the effectiveness of anal cancer screening.

“This review highlights the paucity of screening-related research and is an area of need to provide clear direction and to define standard of care for anal cancer screening in HIV–infected persons,” Wells and colleagues wrote.

A study by Gaisa and colleagues — published last year in Clinical Infectious Diseases — indicated the few screening recommendations that are in place may not go far enough.

In 2007, the New York State Department of Health recommended three specific groups — HIV–infected men who have sex with men, HIV–infected individuals with a history of anogenital condylomata, and HIV–infected women with abnormal vulvar/cervical histology — undergo annual anal cytology screening.

In 2013, the HIV Medical Association endorsed that guideline and added another group to the list: HIV–infected women with a history of receptive anal intercourse.

Gaisa and colleagues — based at Mount Sinai Medical Center, which in 2009 began offering anal cytology screening to all HIV–infected individuals regardless of risk — screened 745 HIV–infected women between April 2009 and July 2014.

Results showed 21% of those who underwent initial screening were found to have high-grade squamous intraepithelial lesions on biopsy, as did another 10% who underwent secondary screening.

“Substantial numbers of high-grade squamous intraepithelial lesions would have been missed by strictly adhering to existing anal cancer screening guidelines,” Gaisa and colleagues wrote. “These results support routine screening of all HIV–infected women, regardless of HPV history or sexual practices.”

Beyond HIV diagnosis, a confirmed HPV infection is “red flag” that warrants screening, Petrelli said. Other potentially high-risk groups include men who have sex with men, women who have a history of cervical or vulvar cancer, and organ transplant recipients.

However, a lack of awareness of the disease — among both patients and clinicians — may limit screening uptake and contribute to delayed diagnosis.

Chiu and colleagues retrospectively surveyed 26 patients in Canada with newly diagnosed anal cancer.

Results, published in 2015 in Canadian Family Physician, indicated nearly half (46%) of respondents did not undergo a rectal examination during their first visit after symptom onset. Twenty-seven percent received a diagnosis of hemorrhoids, and only 54% were ordered to undergo further investigation.

A mean 3.2 months elapsed between the first visit to a physician and anal cancer diagnosis.

“Because anal cancer is so rare, primary care physicians may not consider the possibility of anal cancer, but instead may mistakenly diagnose the patient with hemorrhoids,” Theodore S. Hong, MD, associate professor of radiation oncology at Harvard Medical School and director of gastrointestinal service in radiation oncology at Massachusetts General Hospital Cancer Center, said in an interview. “The lack of screening can lead to more advanced-stage disease, which we know is a problem with any cancer.”

Treatment Landscape

Nonmetastatic anal cancer can be cured with concurrent chemoradiation.

For nearly 4 decades, standard treatment for early-stage anal cancer has consisted of radiation therapy plus fluorouracil (5-FU) and mitomycin, with surgery reserved for salvage.

“We do have effective therapies,” Petrelli said. “Prior to multimodality treatment for anal canal cancer, the standard was surgery requiring abdominal perineal resection, which results in a colostomy.”

Chemoradiation eliminated surgery as the initial treatment for primary anal canal cancer. Now, surgical therapy is utilized for patients with recurrent or persistent disease after chemoradiation. These patients can achieve long-term survival with abdominal perineal resection.

“The optimal time for assessment of persistent disease is controversial,” Petrelli said. “Some have performed this assessment at 6 or 12 weeks after chemoradiation, whereas there is a suggestion in the literature that tumor regression after chemoradiation continues for up to 26 weeks.”

Prophylactic inguinal lymphadenectomy is not recommended after initial chemoradiation for patients with known inguinal lymph node metastases, Petrelli added.

“Inguinal lymphadenectomy is generally reserved for persistent or recurrent disease in the inguinal nodes; however, rates of distant metastases are high and the morbidity from the procedure can result in a poor quality of life, especially when one takes into account previous radiation to the inguinal regions,” he said. “The bottom line is that management should be with a multidisciplinary experienced team with careful patient selection and shared decision-making for the best patient outcomes.”

About two-thirds (66.4%) of Americans diagnosed with anal cancer survive 5 years, according to SEER statistics.

However, survival depends greatly on disease stage. Five-year relative survival rates are 80.7% for those with localized disease, 60.8% for those with regional disease and 30.4% for those with distant disease.

“Patients with metastatic disease do not have an established paradigm of care,” Eng said. “We need to make an impact on treatment for patients with metastatic disease, as well as those with early-stage disease.”

‘Provocative Information’

Investigators are intensifying their efforts to determine whether anal cancers — because of their association with HPV infection — may be susceptible to recognition of an immune response.

“Immunotherapy is big in anal cancer right now because viral-mediated cancers are more likely to respond to treatment,” Hong said.

Ott and colleagues evaluated the anti–PD-1 therapy pembrolizumab (Keytruda, Merck) in 25 heavily pretreated patients with PD-1-expressing advanced anal cancers.

They reported a 20% overall response rate (duration range, 0.1+ months to 9.2+ months) for all comers with anal cancer — not just those with squamous cell — and a 64% disease control rate (duration range, 1.8+ to 11+). About one-third (31.6%) of patients were progression free at 6 months, and 19.7% were progression free at 1 year. Final data are pending.

Grade 3 or grade 4 treatment-related adverse events included one case each of thyroid-stimulating hormone increase, colitis, diarrhea and general physical health deterioration. Immune-mediated adverse events included hypothyroidism (n = 3) and colitis (n = 1). No treatment-related deaths occurred.

Eng and colleagues conducted a multi-institutional phase 2 study to assess nivolumab (Opdivo, Bristol-Myers Squibb) — a fully human IgG4 anti–PD-1 monoclonal antibody — in 37 patients, two of whom were HIV positive, who underwent one prior therapy for metastatic disease. Increased PD-1 expression was not required.

“We knew there was no standard of care for second- and third-line therapy patients with anal cancer, so we wanted to focus on this patient population,” Eng said.

Researchers calculated a 24% overall response rate, including two complete responses and seven partial responses. Minimal grade 3 toxicities were noted; no grade 4 toxicities occurred.

The study has been accepted for publication in The Lancet Oncology, and researchers plan to move on to a randomized extension study that will assess combination therapy with nivolumab and ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 immune checkpoint inhibitor.

“Given the unmet need for this patient population, nivolumab demonstrated both safety/tolerability and efficacy generating optimism for introducing novel immunotherapy approaches into the clinics,” Eng and Van Morris, MD, assistant professor of department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, wrote last year in Surgical Oncology Clinics of North America.

External-beam radiation therapy is the most common form of radiation used to treat anal cancer.

Researchers have investigated whether use of intensity-modulated radiation therapy — which allows for higher doses of radiation to be delivered to tumors while limiting the dose that reaches surrounding healthy tissue — can help reduce acute or chronic treatment-related toxicities.

De Francesco and colleagues assessed clinical outcomes and late toxicity in 27 patients treated with concomitant chemoradiotherapy with pelvic IMRT. All patients completed at least 1 year of follow-up, and some were followed for as long as 3.5 years.

Results, published last year in Clinical Oncology, showed treatment affected quality of life/sexual function in two of 21 female patients, as well as three of six male patients.

Data suggested good bowel continence after treatment for most patients. Patient-reported incontinent scores remained stable or improved over time, with no progressive change in function. Researchers reported no insufficiency fractures, and bone marrow function remained stable throughout follow-up.

“IMRT is not a standard of care for anal cancer, but I would encourage individuals to [consider it],” Eng said. “We also are much more cognizant of how pretreatment staging with diagnostic imaging is with regard to appropriate radiation fields and how it impacts the patient.”

Researchers also are examining the potential role of genetic sequencing for informing treatment decisions for patients who are refractory to chemotherapy.

In a study published in 2014 in PLoS One, Gardini and colleagues determined that patients with anal squamous cell carcinoma may potentially respond to anti–EGFR therapy.

In addition, their results indicated PIK3CA mutations may contribute to carcinogenesis in some patients. Use of tyrosine kinase inhibitors for the estimated 15% of patients with metastatic anal cancer who harbor PIK3CA mutations is now a research focus, Hong said.

“There is not a lot in the literature about targeting specific genetic mutations in patients with anal cancer,” Petrelli said. “However ... Gardini and colleagues observed clinically relevant genomic alterations and genes involved in DNA repair in about one-third of patients studied.

“We have provocative information here that needs further investigation,” Petrelli added. “This information could potentially lead to novel therapeutic and preventive strategies, but it really is too early to tell until we have more research.” – by Jennifer Southall

Click here to read the , “Should planned surgery be considered for large, localized anal cancers?”

• References:
• Chiu S, et al. Can Fam Physician. 2015;61:e509-e516.
• De Francesco I, et al. Clin Oncol (R Coll Radiol). 2016;doi:10.1016/j.clon.2016.04.039.
• Eng C, et al. Abstract 573. Presented at: Gastrointestinal Cancers Symposium; Jan. 21-23, 2016; San Francisco.
• Frisch M, et al. N Engl J Med. 199;337:1350-1358.
• Gaisa M, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw729.
• Gardini AC, et al. PLoS One. 2014;doi:10.1371/journal.pone.0092071.
• Hessol NA, et al. AIDS. 2009;doi:10.1097/QAD.0b013e32831cc101.
• Islami F, et al. Int J Epidemiol. 2016;doi:10.1093/ije/dyw276.
• Morris V and Eng C. Surg Oncol Clin N Am. 2017;doi:10.1016/j.soc.2016.07.008.
• NCI. Cancer stat facts: Anal cancer. Available at: seer.cancer.gov/statfacts/html/anus.html. Accessed on Feb. 7, 2017.
• Ortoski RA and Kell CS. J Am Osteopath Assoc. 2011;S35-S43.
• Ott PA, et al. Abstract #500. Presented at: European Cancer Congress; Sept. 25-29, 2015; Vienna.
• Palefsky JM, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1010971.
• Robbins HA, et al. J Natl Cancer Inst. 2015;doi:10.1093/jnci/dju503.
• Shiels MS, et al. J Natl Cancer Inst. 2012;doi:10.1093/jnci/djs371.
• Siegel RL, et al. CA Cancer J Clin. 2015;doi:10.3322/caac.21254.
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• Yanik EL, et al. AIDS. 2016;doi:10.1097/QAD.0000000000001077.

• For more information:
• Al B. Benson III, MD, FACP, FASCO, can be reached at a-benson@northwestern.edu.
• Cathy Eng, MD, can be reached at ceng@mdanderson.org.
• Theodore S. Hong, MD, can be reached at tshong1@mgh.harvard.edu.
• Nicholas J. Petrelli, MD, FACS, can be reached at npetrelli@christianacare.org.
• Christopher Willett, MD, can be reached at christopher.willett@duke.edu.

Disclosures: Benson, Eng, Hong, Petrelli and Willett report no relevant financial disclosures.