More personalized approaches are being developed to treat patients with metastatic disease.
I decided that as long as I was alive, I needed to be a voice for this disease. We don’t blame victims for their disease — we help them.
— MICHELE LONGABAUGH, patient - PHOTO BY JENNY MYERS
As she edged closer to 50, Michele Longabaugh resolved to take better care of her health and scheduled a well visit with her doctor. The 47-year-old resident of Wichita, Kansas, told him that the main thing bothering her was what she assumed to be a painful and persistent hemorrhoid.
“The color drained from his face, and I knew then that this was something more serious,” recalls Longabaugh, now 54, a registered nurse who works in industry. “But a diagnosis of anal cancer was definitely not on my radar.”
While anal cancer is fairly rare and much less common than colon or rectal cancer, the number of new cases in the United States has been on the rise for several decades. For 2017, the American Cancer Society estimates about 8,200 new cases and 1,100 deaths due to anal cancer. It occurs in the anal canal, the opening at the end of the rectum, and is found mainly in older adults, with the average age being in the early 60s. Also, the risk of being diagnosed is slightly higher for women than men.
After multiple biopsies and an MRI, Longabaugh’s oncologist diagnosed her with metastatic stage 4 anal cancer in February 2010. She had ignored the symptoms for months, but during that time, a large tumor had been growing out of her sacrum — the large, triangular bone at the base of the spine. Her prognosis was grim, a mere three years even if she sought treatment. First-line treatment for anal cancer that has not spread typically includes a combination of chemotherapy and radiation therapy, chemoradiation, which can often cure the patient without the need for surgery. This is most often used for nonmetastatic cases. Choice of treatment plan depends on the location, type and stage of tumor, along with the patient’s age, general state of health and personal preferences.
However, no consensus treatment approach exists for the treatment of metastatic disease. In the last few decades, immunotherapy has helped fight certain types of cancer such as lung, bladder and kidney, by stimulating a patient’s immune system to attack cancer cells. Only recently has immunotherapy started to make headway in anal cancer treatment, bolstered by last year’s promising results from a multicenter, phase 2 trial investigating Opdivo (nivolumab). Opdivo works by blocking the activity of PD-1, a protein that prevents the body’s T cells from attacking cancer cells.
The clinical trial marks the first prospective study investigating the use of immunotherapy in patients with anal cancer. The results, published in The Lancet Oncology in 2017, showed a 24.3 percent objective response rate in 37 patients with metastatic anal cancer. Two patients had a complete response, while seven patients had a partial response.
Shoshana Bitner, 49, had suffered through the harsh side effects of chemoradiation for multiple recurrences before participating in the Opdivo trial. After experiencing pain and bleeding from her bowels over a decade ago, she was diagnosed with stage 3 anal cancer at only 38 years old.
In 2015, she and her husband decided to fly to MD Anderson Cancer Center in Houston to try a new treatment plan. Cathy Eng, M.D., professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, fortunately had been looking for patients with treatment-refractory metastatic anal cancer for the Opdivo clinical trial at the time. She was given Opdivo every two weeks through intravenous injection.
“There were only 37 slots for the trial, so I was very lucky to participate. That treatment really spoiled me because the immunotherapy was very gentle,” says Bitner, who responded to Opdivo but was not cured. “I’ve been in and out of chemotherapy for 12 years, and it by far beat any chemotherapy I had ever received.”
Who Is at Risk?
The majority of anal cancers consist of squamous cell carcinomas — where tumors originate from the squamous cells that line the anal canal and anal margin — and have been linked to human papilloma virus (HPV) infection. Because viral proteins expressed by the tumor cells are “foreign” and therefore activate the immune system more, immunotherapy may be a highly effective treatment option for patients. HPV is a group of more than 150 related viruses, with the subtype HPV-16 being most likely to cause anal cancer. Other subtypes carry a high risk of cervical, vaginal, vulvar, penile and throat cancers.
“More than 90 percent of anal cancer cases are linked to HPV, so utilizing immune therapies is very reasonable especially given the early data suggesting benefit for other squamous cell cancers,” Eng says.
The virus spreads through skin-to-skin contact with an infected area of the body. For men, being uncircumcised or having a high number of sexual partners can increase the risk of HPV infection. Women commonly contract the virus at a young age — under 30 years old — and certain types of sexual behavior can heighten their risk. For instance, having sex at an early age or with many partners.
Women who have had cancer of the cervix, vagina or vulva are more likely to get anal cancer, along with individuals, both men and women, who have contracted HIV. Other vulnerable populations include men who have sex with men, people who engage in receptive anal intercourse, people with a history of anal warts, current smokers and those with lowered immunity.
However, not all individuals with anal cancer possess a prominent risk factor.
Longabaugh, for instance, found herself in shock after hearing her diagnosis because she lacked any red flags for possibly getting the disease. “I had none of the risk factors for anal cancer. I never had a positive HPV test, and I didn’t engage in high-risk activities,” she says. “My doctors couldn’t explain it, but I just had it.”
As Longabaugh did, many people who have symptoms of anal cancer assume they are caused by hemorrhoids. These symptoms include bleeding, itching, pain, abnormal discharge, a lump or mass at the anal opening, and the narrowing of stool or other changes in bowel movements. Other anal cancers, such as those that begin higher up in the anal canal, are less likely to cause symptoms and be found early.
While not commonly done, screening for anal cancer could benefit people at increased risk including men who have sex with men, women who have had cervical or vulvar cancer, HIV-positive individuals and those who have lowered immunity due to organ transplant. Every one to three years, some experts recommend these populations to get a digital rectal exam (DRE), which involves a doctor feeling around for unusual growths, and an anal cytology test, also known as an anal Pap smear. During a cytology test, a doctor swabs the anal lining to detect any abnormal cells.
In the past, treatment involved surgery as the first — and oftentimes, only — option for patients. Today, chemoradiation often eliminates the need for surgery. But in some cases, local resection is used to treat small cancers of the anal margin that have not spread to nearby tissues or lymph nodes.
An extensive procedure that removes the anus and rectum, called abdominoperineal resection, is only used for refractory disease.
The main treatment for anal cancer typically includes external beam radiation, which uses a focused beam of radiation from a machine outside the body, and a combination of two chemotherapy drugs. Most often, 5-fluorouracil (5-FU) and mitomycin are used for initial treatment.
Survival rates for anal cancer depend on stage and type, with rates being better for squamous cell versus non-squamous cell disease.
“The response rate for newly diagnosed anal cancer to chemotherapy and radiation therapy is actually very high,” says Lei Zheng, M.D., Ph.D., associate professor of oncology at Johns Hopkins School of Medicine in Baltimore. “However, we do not have any effective treatment for anal cancer after it has recurred. Therefore, we have very limited options for refractory anal cancer.”
After having surgery to remove her tumor, Longabaugh went through a grueling treatment of chemoradiation with side effects that included uncontrolled diarrhea, pain, hair loss, nausea, vomiting and a feeling of uneasiness.
The treatment worked for a while, but then the cancer came back in her lung. Bitner’s disease recurred multiple times, with doctors finding cancer first in her liver and then upper rib. Both women found themselves back on chemoradiation — a treatment typically used for local disease — only two years after their initial treatment.
The lack of effective treatment options for metastatic, treatment-refractory anal cancer has led to the emergence of clinical trials exploring immunotherapy drugs. The phase 2 study for Opdivo enrolled all subjects within 5 months of opening which demonstrates an unmet need in this area, according to Eng.
“This trial was in the setting of metastatic anal cancer, where there is no standard of care,” says Eng. “There is no standard of care for both frontline and recurrence, and meanwhile it has been rising in incidence by about 2 percent per year.”
Opdivo showed limited toxicity in the trial and was mostly well-tolerated by patients. Grade 3 toxicities occurred in five patients and included anemia, fatigue, rash and hypothyroidism. Eng stresses that immunotherapy does have its own set of side effects and is not toxicity-free.
Overall, Zheng thinks the trial findings show promise and predicts that Opdivo will soon get approval by the Food and Drug Administration (FDA).
“I have to point out that this is still a small study — there were only 37 patients, and I definitely think the results need to be validated in a larger study,” he says. “But based on the results, and also the rareness of the disease, I don’t think the FDA will require a randomized trial to prove this treatment.”
A larger study would also help determine which patients would be the best candidates for immunotherapy. As of now, it remains unknown if any particular patient factor is associated with a good response.
Meanwhile, other immunotherapy clinical trials are in the works. Lakshmi Rajdev, M.B.B.S., associate professor of clinical medicine at Albert Einstein College of Medicine in the Bronx, New York, will head a study testing Opdivo after chemoradiation in patients with high-risk anal cancer. These include individuals with tumors larger than 5 centimeters, cancer that has spread to other organs or node-positive cancer. One hundred and eighty patients will be randomized to chemoradiation plus Opdivo or chemoradiation alone.
“The trial will be testing the benefit of adding Opdivo for six months following chemoradiation in patients with highrisk anal cancers in the hopes of curing more patients, since cure rates are on the order of 50 to 60 percent in this group,” says Rajdev.
A Voice for the Disease
Being a rare disease, anal cancer faces a financial barrier to new research studies. But it also carries with it a certain amount of shame and stigma due to its associations with sexual promiscuity, anal intercourse and HPV/HIV infection.
“People are not familiar with anal carcinoma, but in 2017, it’s supposed to affect 8,000 people in the U.S. Internationally, it will affect 20,000 to 27,000 individuals,” says Eng. “A lot of people refuse to pay attention to it because of the stigma.” Organizations such as The HPV and Anal Cancer Foundation have been established to inform the public about the disease, increase research funding and provide support for patients. The foundation encourages survivors and patients to tell their stories openly on the website as one way to diminish the stigma.
Longabaugh aims to raise awareness for anal cancer through outreach and her blog. Although she had one recurrence in 2012, she went into remission a year later and has remained cancer-free since.
“There’s a huge stigma that goes with ‘below the belt’ cancers, and after my diagnosis, I felt the shame instantly,” Longabaugh says. “But then I decided that as long as I was alive, I needed to be a voice for this disease. We don’t blame victims for their disease — we help them.”