Some diagnoses are straightforward; others can take months or even years to pinpoint. That is why it is crucial for patients who know that something is not right to continue to follow up with their care team or seek out specialists.

Our feature story describes the experience of a woman who was not satisfied with her doctors’ answers regarding her abdominal pain and bloating. After pushing on through many visits with health care professionals, including specialists, she eventually received a diagnosis of late-stage appendix cancer. That persistence likely saved her life, because the disease tends to not show many symptoms until it is advanced. Once signs appear, diagnosis and treatment are crucial.

Self-advocacy does not stop there. Patients with rare cancers — or their parents or caregivers — should seek out a medical team that specializes in treating their disease. Finding clinical trials and physicians who treat rare diseases can lead to monumental breakthroughs, such as the first Food and Drug Administration approval for children with neurofibromatosis type 1.

, we hear from the researchers who contributed to the life-changing approval for a therapy for this condition; traditionally, only the symptoms, not the disease itself, could be treated.

Major advances do not only rely on patients and researchers but also result from organizations teaming up to gain better patient outcomes. For example, the Cholangiocarcinoma Foundation worked with health technology companies to gather data and improve patients’ access to top-notch care.

Many key players are moving the field of cancer forward, especially among the rarer malignancies. In this special issue, we highlight some of these people and their work, but remember: 

Articles

From the Chairman

While the rare cancer landscape is growing, progress is happening thanks to patients advocating for their care.

With Rare Cancers, Progress Starts With the Patients

In recent years,clinicians, particularly pathologists, have improved at identifying and treating salivary gland cancers, even when they pop up in unsuspecting places such as the breast, skin, cervix (in women) and prostate (in men).

For patients with this type of salivary gland cancer, called adenoid cystic carcinoma, genetic and

genomic testing is paramount, with the results determining the most effective treatment plan. For example, patients with HER2-positive disease may respond best to the monoclonal antibody Herceptin (trastuzumab), whereas others may do better with the targeted drug Vitrakvi (larotrectinib), approved in 2018 for patients with solid tumors that harbor fusions of the NTRK gene.

Thanks to the constantly evolving understanding of cancer genetics, as well as increased use of next-generation sequencing, more drugs are being investigated for use in cancers with certain molecular makeups, regardless of location. This is a landmark change for rare cancers that traditionally are understudied because of the small number of people with the disease.

® discusses My Pathway, a phase 2 clinical trial that matched patients with a diversity of cancers to one of six targeted therapies based on the genetics of their tumor. Although just 19 patients with salivary cancers were involved, most (63%) responded to their individualized treatment, eliminating the need for a larger, salivary gland cancer-specific trial, for which it likely would be difficult to find enough enrollees.

Advances in genetics continue to fuel breakthroughs for nearly all cancer types but perhaps hold special value for rare cancers, in which there are limited patients to join studies and few professionals who specialize in their treatment. Now, more than ever, it is crucial that patients with these diseases ask their treatment teams about the role of tumor genetics for their situation and clinical trials for which they might be eligible.

Editor's Page

The evolving understanding of cancer genetics is allowing for clinicians to look at how to move rare cancer treatments, and identifications, forward.

Genetics Remains Paramount for Moving Rare Cancers Forward

Elizabeth Ames knew something wasn’t right. Feeling increasingly bloated and full, the busy Atlanta attorney and mother of two figured she just needed to clean up her diet.

She was wrong. “It got to a point where it was noticeable and not normal,” Ames says. She visited her primary care doctor, and a preliminary exam and blood tests showed nothing out of the ordinary.

But Ames didn’t let it go. With a scheduled hernia surgery on the horizon, she wanted answers. She saw several specialists, starting with a gastrointestinal doctor, who suspected a bacterial overgrowth. Not satisfied with that explanation, Ames consulted her gynecologist, who did a sonogram and found fluid in her abdomen. Within an hour, Ames was in a surgeon’s office.

Still, definitive answers remained elusive. The surgeon was “95% sure” the fluid was related to her existing hernia, according to Ames, who asked, “How do we get to 100% sure?’”

A CT scan revealed the answer. “We did the scan and to his surprise, it was not a hernia,” Ames says. “It was cancer.”

At just 38, Ames received a diagnosis of stage 4 high- grade appendix cancer. Her type: adenocarcinoma with the pseudomyxoma peritonei syndrome.


Appendiceal cancers are rare, with 1,500 to 3,000 new cases each year in the United States, according to Dr. Kiran Turaga, a surgical oncologist at UChicago Medicine. “Appendix cancers have been poorly understood over many decades,” he says. “When we use the words ‘appendix cancer,’ that usually comprises a heterogeneous group of tumors.”

Broadly, appendix tumors, or masses, include neuroendocrine tumors, sometimes known as carcinoid tumors, are composed of malignant cells that sometimes produce hormones that can go throughout the body. About half of all tumors found in the appendix are neuroendocrine tumors, which tend to grow slowly and are typically removed successfully during surgery.

Adenocarcinomas grow in the epithelial tissue, or lining, of the appendix. According to Turaga, some of these tumors form glands and behave like colon and other types of cancer, sometimes spreading to lymph nodes and other parts of the body.

Within the appendix, epithelial cells produce mucin, a jellylike substance containing proteins that forms a barrier to protect the intestinal lining. Appendiceal epithelial neoplasms, or tumors, can prompt the cells to over- produce mucin, causing the appendix to become “like a little balloon,” Turaga says. When these tumors rupture, mucin fills the abdomen and can lead to a potentially fatal condition called pseudomyxoma peritonei, in which mucinous tumor cells fill the abdomen and pelvis and can coat and constrict organs.

Appendiceal adenocarcinomas are classified as either low, intermediate or high grade, depending on the histology, or how the tumor appears under a microscope, according to Dr. John Paul Shen, a physician scientist in the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

“All cancer looks different from normal cells under a microscope,” he says. “Cells that look reasonably similar to normal tissue are classified as low grade. These are cells that should form glands, and you can see that the cells are trying to do that. (Although) they’re abnormal, the cells are behaving in a lot of ways like the normal tissue they started from. We call that cancer well differentiated.”

High-grade, or poorly differentiated, cells are unlike the normal tissue. “They have lost all the normal signals that a cell would have. They tend to grow faster, and in appendix cancer, you have a worse prognosis,” Shen says.

Other types of highly aggressive appendix cancers include signet ring cell adenocarcinoma and ex-goblet cell adenocarcinoma (adenoneuroendocrine).

One of the challenges of diagnosing appendix cancer is its lack of symptoms. By the time symptoms appear from appendix cancer and pseudo- myxoma peritonei — in some cases, years after undetected growth — the condition can be quite advanced.

Appendix cancer is usually diagnosed incidentally, discovered while a person is being tested or treated for another condition, according to Dr. Charles Staley, chief of the division of surgical oncology at Emory University School of Medicine in Atlanta. “(For example,) you’re scanning somebody for a kidney stone and you find a mucinous mass in the appendix,” he says. Sometimes a pathology report after appendix surgery confirms cancer.

Doctors can’t count on CT scans, ultrasounds or MRI in diagnosing appendix cancer. “Unlike breast cancer or colon cancer, there’s no screening modality for it,” Turaga says. “And, when appendix tumors spread, they tend to spread along the lining of the belly cavity called the peritoneum. Think of it like a room with paint on the walls. There’s a lot of paint, but it’s very thin. When you have a CT scan, you can only see objects that have a big masslike discrimination, like the liver or the spleen — like a table or chair in the room.”

For many people, like Ames, bloating is the first sign that something is wrong. That was also the case for Jerry Lewandowski, 46, of Bethesda, Maryland, president of the Appendix Cancer Pseudomyxoma Peritonei Research Foundation. In late 2007, at age 33, he felt an unusual tightness in his belly. “When I leaned over to tie my shoes, I couldn’t do it without a lot of discomfort,” he says. His concern led him to the emergency department, where a sonogram showed liters of fluid in his abdomen. A CT scan and exploratory laparotomy — a surgical incision into the abdomen — confirmed a diagnosis of stage 4 low-grade mucinous neoplasm of the appendix.

Treatment depends on how the cancer is staged and graded, which can be challenging. “Staging of this disease is extremely archaic,” Staley says. “Any tumor that has ruptured is stage 4,” which is precisely the point at which many people are diagnosed.

Tumor volume can be staged during surgery using the peritoneal cancer index, Staley says: “Basically, we divide the abdomen into nine quadrants, like a tic-tac-toe board. Each square gets a score from zero to three, depending on whether there’s no tumor or the size of the biggest cancer nodule in that quadrant.” A similar method is used to score the small intestine.

“Your score can be anywhere from a zero to 39,” he says. “That’s how we score the volume and amount of cancer in people’s abdomens.”

Surgical removal of the tumor and some surrounding tissue is the most common treatment for appendix cancer. Surgery types include appendectomy, removing the appendix and local tissue; hemicolectomy, removing a small portion of the colon near the appendix, some- times with accompanying blood vessels and lymph nodes; and cytoreduction, also known as debulking, removing as much of the tumor(s) as possible.

Chemotherapy prior to surgery is rarely used for low- grade mucinous neoplasms because they typically don’t respond to it, according to Staley. “For people with high- grade tumors, we may give them some chemotherapy before surgery, anywhere from three to six months,” he says.

Ames received a three-month course of chemotherapy prior to what she calls a “whammy of a surgery.” Staley, her surgeon, removed her appendix along with half her colon, her gallbladder and spleen, three stomach arteries and her omentum. She also had a full hysterectomy. “Fortunately, my small intestine was not covered in tumors,” she says. “But everything else was.”

During the surgery, Ames also had hyperthermic intraperitoneal chemotherapy (HIPEC), in which chemotherapy agents heated to 108 degrees Fahrenheit are delivered to the abdominal cavity immediately following cytoreductive surgery. Chemotherapy circulates through the abdominal cavity in a closed system on a modified bypass machine.

Therapy for low-grade mucinous neoplasms has been the same for the last 20 years, according to Staley. “That’s complete cytoreduction, where you remove all the cancer you can visibly see throughout the peritoneal cavity, along with removing the appendix. Then we wash the abdominal cavity out with a hot chemotherapy agent to kill any microscopic tumor cells that are floating in the abdominal cavity,” he says.

When making treatment decisions, Turaga says, it’s important to consider both the patient and the disease. “I ask, ‘Who is the patient and what are their wishes? Are they healthy? Are they fit?’” he says. “Second is the disease itself. What really matters is the pathology. That’s why it’s so important that slides are reviewed by a pathologist who’s experienced in this. Because appendix cancer is so rare, many pathologists might see only one or two in their career.”

Doctors and patients agree that for rare cancers, an experienced team is critical. Lewandowski said his wife, Karolyn — they were dating when he was diagnosed — researched not only treatment options but also doctors. He had a peritoneal cancer index score of 39 (out of 39) and was treated with surgery and HIPEC in January 2008, followed by another surgery with HIPEC after a recurrence a year later. His pathology showed a mix of low- and high-grade cancer, so he was treated with systemic chemotherapy following his second surgery. In March 2010, Lewandowski had a third recurrence, with another surgery and HIPEC.

“It’s really important to get the right treatment from an appendix cancer specialist and get it early in the process,” he says. “And it’s important to be engaged in the process to find the right specialist.”

Carolyn Langlie-Lesnik of Crown Point, Indiana, founder of the Appendix Cancer Connection, Inc., received a diagnosis of stage 4 signet ring cell appendix cancer 19 years ago, at age 41, after her appendix ruptured. “I tell people who are newly diagnosed that the No. 1 thing they need to do is find a specialist who knows appendix cancer,” she says.

An expert also can help you access clinical trials and preclinical research. Shen is involved in research looking at potential targetable mutations in appendix cancer. “In low-grade appendix cancer, we know that one of the most commonly mutated genes is called GNAS. Right now, we don’t have any drugs against that, but we think it’s a potential candidate,” he says. “We’re also looking at how that gene signals, so if we can’t target a drug against the gene itself, there are a lot of other links in that chain that we could hit with drugs. That’s something we are actively testing in the lab.”

Repurposing existing drugs in the fight against appendix cancer is a research focus, according to Shen.

“We’re looking at trying medicines in the taxane family,” he says. “They’re commonly used in breast cancer and have been shown to work in small bowel cancer. Because appendix cancer tends to be more similar to a small bowel cancer, these drugs could work in appendix cancer.”

Lewandowski’s second surgery and HIPEC included the use of heated melphalan, a drug commonly used for multiple myeloma treatment and for which many specialists have seen positive results with appendix cancer.

Staley says molecular gene testing may be done in patients with higher-grade tumors like signet rings and adenocarcinomas, but that’s a smaller group. For most appendix cancers, there is no targeted therapy.

As knowledge grows, treatment and management of appendix cancers is evolving. A multidisciplinary working group released the Chicago Consensus on Peritoneal Malignancies: Management of Appendiceal Neoplasms, published in April 2020 in two journals simultaneously, 

. “These are new treatment guide- lines and protocols that are a good framework,” Turaga says.

Ultimately, Ames says, it’s critical to be your own advocate. “The rarer the disease, the more important it is to find an expert,” she says. “Ask those hard questions of your doctor. Ask how many of these surgeries they’ve done and how many times they’ve seen this type of cancer. Make them sell you that they’re the right doctor. This is your life.”

Feature

Often uncovered by accident, appendiceal cancers trigger few symptoms until they’re advanced and can be difficult to detect and treat.

Appendix Cancer: An Elusive Diagnosis

It wasn’t the first time Sharon Haber found a lump in her neck. She’d had them twice before – the last one 10 years prior. Both times, they were benign. Still, she knew she had to get it checked out.

Haber’s primary care doctor in Encino, California, agreed that the small lump in her neck, under her left ear, most likely was nothing. But he ordered a CT scan, just in case. When the scan came back, the doctor still believed the lump was benign. Out of an abundance of caution, he sent her to a head and neck specialist for a second look. The specialist biopsied the lump, which he also expected to be benign.

“A couple of days later, when I got the call that I have cancer, that was probably the scariest moment of my life,” Haber says. The 69-year-old retired marriage and family counselor now has been cancer free for more than six years.

Haber had three lesions on her parotid gland — one of the three major salivary glands and the most common one on which tumors can form. The majority of growths that develop on this gland are benign. In fact, salivary gland cancers are extremely rare. In the U.S., they make up less than 1% of all cancers diagnosed each year.

“And that’s cases spread throughout the U.S., so, of course, a lot of people haven’t even heard of it,” says Dr. Maie St. John, chair of head and neck surgery at Ronald Reagan UCLA Medical Center in Los Angeles.

There are dozens of types of salivary gland cancers — nearly as many as there are types of cells that compose the salivary glands. Most of the time, these can be treated with single modality surgery, depending on the anatomic location, and patients can have a very good outcome. Doctors usually recommend radiation after surgery to ensure no cancer cells are left behind and to lower the risk of recurrence. But for some people surgery is not possible or doesn’t completely remove the cancer. In some cases, the cancer returns. Clinical trials underway are exploring the roles that chemotherapy and targeted drugs can play in treating this rare disease.

Cancerous tumors can arise in the three major salivary glands or any of the thousands of minor glands that line the mouth and extend into the nose and pharynx, the cavity that connects the nose and mouth to the esophagus.

The three pairs of major salivary glands are the parotid, sublingual and submandibular glands. The parotid, the largest of these glands, occupies the side of the face between the ear and the back molars. It extends to the height of the upper and lower jaws. The sublingual gland sits in the floor of the mouth under the tongue. The submandibular is located under the lower jaw.

Doctors grade cancers from low to high based on how abnormal the cells look under a microscope. Low-grade cancer cells look the most like normal cells and tend to be slower growing and less aggressive. These cancers are usually easier to treat and have better long-term survival rates. High-grade cancers, on the other hand, look very different from normal cells and grow and spread faster than lower grade cases.

Salivary gland cancers are as diverse as they are rare.

“There are many differences in salivary gland cancers,” says Dr. Ashok Shaha, the Jatin P. Shah Chair in Head and Neck Surgery and Oncology at Memorial Sloan Kettering Cancer Center in New York. “The greatest variation in human cancers is probably in salivary gland tumors. And the more we look into the basic differentiation of these cells, the more different names for them keep coming up.”

Mucoepidermoid carcinomas are the most common salivary gland cancers. They most often arise in the parotid gland but can appear in the other major glands, as well. These are usually low-grade cancers, but intermediate- and high-grade cases do occur.

Adenoid cystic carcinomas are slow growing, low- grade cancers, but they spread along nerves. “Even if you go in and remove everything you can see and feel, there still could be a few cells that run along the nerve. Those cells spread by using the nerve like a little highway, and this would predispose patients to recurrence,” St. John says. This type of cancer can recur many years after the initial treatment.

Adenocarcinoma is a general term to describe cancers of the gland cells. Salivary adenocarcinoma describes numerous subtypes of both low- and high-grade cancers, some of them quite rare.

A common symptom of salivary gland cancers, particularly those that arise in the parotid gland, is a lump in the side of the face or neck like Haber had.

“Something I hear from my male patients is ‘I was shaving, and I felt this lump,’” says Dr. Theodoros Teknos, president and scientific director of the UH Seidman Cancer Center and a head and neck oncologist at University Hospitals Cleveland Medical Center.

A painless lump could be an early sign of cancer. As the disease progresses, depending on the location of the tumor, it can cause earaches, trouble swallowing or difficulty opening the mouth.

Numbness and pain can develop in the face, as well. It’s not a sudden paralysis such as Bell’s palsy. The gradual numbness may start with one lip, then include another, and eventually spread to other parts of the mouth or face.

Mark Fetterman, a 59-year-old construction foreman in Olmstead Falls, Ohio, started having pain and numbness on one side of his face in 2016. A neurologist told him he had trigeminal neuropathy. This disorder affects the trigeminal nerve, which controls facial sensation and movement. Imaging tests didn’t find any cause for the condition. The doctor prescribed medications, but over the next two years, the pain and numbness became worse. In 2018, Fetterman found a lump in the roof of his mouth. A biopsy found that it was salivary duct carcinoma, a rare, high-grade adenocarcinoma.

“The [physician] said that the cancer was all along the trigeminal nerve going up to his brain, but not in his brain, and that it might have been this all along,” says Fetterman’s wife, Lori.

For almost everyone with salivary gland cancer, surgery is the first treatment. Depending on the tumor’s location and size, the surgeon may be able to remove the cancer completely. But, because tumors may be near the eyes, in the mouth or nose, near the brain, or in the face on crucial nerves or blood vessels, the surgery comes with risks of adverse effects. It can cause temporary or permanent loss of movement in the face. But surgeons make every effort to avoid this.

“We do parotid surgery with a nerve monitor so you can monitor and preserve the nerve,” St. John says. “We do not sacrifice the facial nerve unless the cancer is just wrapped around it and it has to be taken in order to clear the cancer. Otherwise, we dissect around it.”

Haber’s tumor was on her facial nerve. She knew going into it that surgery came with the risk of partial paralysis. “All I could think about was my grandkids,” she recalls.

“I didn’t want to look scary to them.” But after an 11-hour surgery performed by St. John, Haber says, “she not only got all the cancer, and took out all the lymph nodes around it, but she did not hit that nerve. She saved my face – and my life.”

Doctors often recommend following surgery with radiation therapy to address residual microscopic cancer cells. If a tumor is inoperable, radiation — sometimes in combination with chemotherapy — may be the main treatment.

Chemotherapy isn’t a first-line treatment for salivary gland cancers. “Salivary gland cancers are considered relatively chemo-resistant tumors,” says Shaha. “If a patient has a poor prognosis or if they have [had a recurrence], then we would add chemotherapy.”

Investigators are exploring through clinical trials whether chemotherapy, which is not typically used for salivary gland treatment, might improve outcomes when added to surgery and radiation.

In general, systemic treatments — medications that travel through the bloodstream as opposed to procedures that target the tumor directly — for salivary gland cancers are considered experimental. Patients with recurring or metastatic cancers may receive these treatments in clinical trials.

“In a salivary gland cancer that’s metastasized, we typically (gene) sequence the tumor, look at the muta- tions, and try to provide targeted therapies for the specific tumor,” Teknos says.

In salivary duct carcinomas, for example, the HER2 gene is often overactive. The gene’s hyperactivity can help the tumor grow and thrive. In HER2-positive tumors, the blockbuster breast cancer drug Herceptin (trastuzumab) blocks that gene’s activity and may slow or stop tumor growth.

Fetterman is still taking Herceptin. He receives an IV transfusion of the drug every three weeks. “On the last CT scan, the cancer was unchanged. It hadn’t grown or shrunk. So I will continue to take it, and they will just keep monitoring it,” he says.

People with this type of cancer also may be candidates for androgen receptor inhibitors, drugs commonly used to treat prostate cancer. Androgen receptors, which by some estimates, are present in up to 98% of salivary duct carcinomas, support the growth of tumors that thrive on androgen hormones. These drugs can block the receptors and deprive the tumor of the hormone. In a clinical trial, this treatment led to higher response rates than chemotherapy in metastatic or recurrent disease.

In other clinical trials, investigators are exploring other genetic targets in salivary gland tumors that might align with existing targeted drugs. In the phase 2 MyPathway trial (NCT02091141), researchers matched patients with targeted drugs based on the tumor’s genetic profile. Because salivary cancers are so rare, the trial included only 19 people. Twelve of them (63%) responded to the personalized treatments they received.

Numerous other trials are in progress. In cases of metastatic or recurring salivary gland cancers, clinical trials may be the only remaining treatment options.

Because salivary gland cancers are so rare, doctors recommend that patients find a hospital with a track record. “You don’t need to go to another state,” Shaha says, “but you need to go to a center where head and neck surgery is very common and there are recognized experts in salivary gland tumors.”

But it’s not just the surgeon that matters. Salivary gland cancers can affect facial appearance and function and psychological well-being. Treatment can require a team. Reconstructive surgeons help maintain or restore facial appearance. Physical and speech therapists work with patients to maintain function. Radiologists and medical oncologists collaborate on nonsurgical aspects of care. Mental health professionals provide support for coping with life changes brought about by the cancer.

“It is what we call a multidisciplinary team,” Shaha says. “You need a good surgeon. You need a good radiologist. You need a medical oncologist. You need a radiation therapist or radiation oncologist, and a good pathologist. If you have that team, that’s a real place where you want to be treated.”

Salivary cancer is a rare disease that has some of the greatest variances of all types of cancer.

Salivary Gland Cancer: As Rare As It Is Diverse

During the two years after Nelda Blair turned 50, her gynecologist urged her to get her first colonoscopy, and she finally agreed. After the test, her gastroenterologist told her she had a rare tumor on her anus and referred her to an oncologist.

Blair and her gynecologist had thought the growth was a hemorrhoid, even though it wasn’t red or painful. It turned out to be stage 2 anal cancer, most likely caused by the human papillomavirus (HPV).

“I had no symptoms,” says Blair, a married stepmother and lawyer who lives and works in The Woodlands, a Houston suburb. “When (the gastroenterologist) went to do the colonoscopy, the tumor was right there. It’s not hard to see. My gynecologist didn’t know what it was.”

Although anal cancer is rare, the number of people developing and dying from it has steadily increased since 2001, according to a study published in November 2019 in the Journal of the National Cancer Institute. From 2001 to 2015, the incidence of anal cancer, or squamous cell carcinoma of the anus, rose by 2.7% per year, making it one of the nation’s fastest-growing cancers.

Over the years, the disease has also become more likely to be diagnosed at later stages, when it is more difficult to cure. If the cancer is caught early, survival is likely; nearly half of patients receive their diagnoses at this point, and 82% are alive five years later. For those with metastatic disease, which has spread further into the body, the five-year survival rate is 32%.

Because a higher proportion of patients are receiving diagnoses of advanced disease, the associated death rate jumped by 3.1% in each year of the study, the authors found.

The main culprit behind this trend is HPV, a sexually transmitted infection that causes more than 91% of anal cancers. Nearly all adults encounter HPV at some point; it can spread through skin-to-skin contact, including deep kissing, oral sex, hand-to-genital contact and intercourse.

When the anal cancers now being tracked began to develop, years or even decades before they were diagnosed, little could be done about the HPV that sparked them. Now, however, there is a way to stem the tide for future generations.

This opportunity lies in the HPV vaccine, which can prevent anal, cervical, oropharyngeal (throat, mouth or tongue), vulvar, vaginal and penile cancers throughout life in the eligible children and young adults who receive it.

Anal cancer became preventable when the Food and Drug Administration (FDA) approved the HPV vaccine Gardasil in 2006. The goal in giving the vaccine is to inoculate people against HPV before they are exposed to it. Initially, the Advisory Committee on Immunization Practices (ACIP) within the Centers for Disease Control and Prevention (CDC) recommended the vaccine for girls and women ages 9 to 26, but in 2011 it added boys and men ages 9 to 26. Although young adults may already have encountered some strains of HPV, the vaccine can help them avoid others.

The inoculation program evolved further in 2014, when the FDA replaced the vaccine with Gardasil 9, which protects against the same four strains as the original, plus another five. Although the HPV vaccine was approved for use in adults up to age 45 in June 2019, it’s not routinely recommended for those older than 26; the ACIP recommends that patients consult their doctors to determine if vaccination is likely to be beneficial. Possible candidates in the older age group would be those who have not had sex or are recently widowed or divorced, and thus may not previously have contracted HPV, Dr. Mona Saraiya, an epidemiologist with the CDC, says.

Although there are more than 100 strains of HPV, Gardasil 9 specifically prevents infection from the strains that cause most of the cancers — HPV-16, HPV-18 and five others, as well as two known to cause 90% of genital warts.

The HPV vaccine has been administered to millions of patients and proved safe and effective, Saraiya says. New data show that in the youngest populations, genital warts and precancerous conditions have decreased, she says.

Study findings show that HPV vaccinations provide lasting protection when given prior to HPV infection, reduce precancerous lesions and likely result in fewer cancers. If vaccination rates reached the federal government’s goal uptake of 80% of children by age 13, the incidence of anal and cervical cancers could be reduced enormously, and cancer-causing strains of HPV would virtually disappear due to herd immunity, meaning that so many people would be vaccinated that it would be difficult for HPV to infect the unvaccinated.

Yet, in the United States, only about 51% of those eligible are up to date with their HPV vaccines. Among the primary reasons cited for the relatively low level: When the vaccine was first introduced, pediatricians emphasized its role in preventing a sexually transmitted infection. Some parents feared that this would give their children a false sense of protection and encourage promiscuity. Multiple studies have disproved that concern.

Some parents questioned the vaccine’s safety. “Anti-vaxxers are very passionate about their position, but it’s based on no science,” says Dr. Joel Palefsky, a professor of medicine and an infectious disease specialist at the University of California, San Francisco. “We feel they cause a lot of harm by influencing others.”

Other studies showed that, instead of presenting the shot as one more routine childhood vaccine to be given during the annual physical, doctors introduced it as something parents could think about and return for later.

Educating physicians and parents about cancer- prevention aspects for girls and boys has improved vaccination rates, especially among Blacks and Hispanics, says Sherrie Flynt Wallington, an assistant professor of health disparities and oncology at The George Washington University School of Nursing at the Milken Institute School of Public Health. Although these two populations have high rates of seeking out vaccines, their rates for completing the HPV two- or-three- shot series are still low, she says. Vaccination rates remain low among whites and in rural areas.

“We need to do more work educating the physicians about the complete story of HPV from a biological standpoint (and why they need to be) holding those conversations with parents,” Wallington says. “You’re seeing a shift now, from parental hesitancy to provider hesitancy.”
In the United Kingdom and Australia, where children get vaccines at school, 90% of the eligible population is vaccinated.

In the U.S., four jurisdictions require that students receive the HPV vaccine to attend school: Rhode Island, Virginia, the District of Columbia and Puerto Rico. Virginia requires the vaccine only for girls.

Do mandates work? The CDC doesn’t take a position, Saraiya says. According to the National HPV Vaccination Roundtable, a coalition of 70 organizations, early studies found that these orders do not promote increased vaccination uptake because parents are able to opt out.

“Parents don’t think the government should usurp decisions made about their children. What really works is educating parents so they can make an informed decision and equipping providers with the knowledge and skills to make strong HPV recommendations. Providers are the key,” Wallington says.

One recent study credited Rhode Island’s school-entry requirement with an 11% increase in HPV vaccination rates for boys but not girls. Washington, D.C., has a 78% HPV vaccination rate and Virginia has a 59% rate, but the Roundtable reports that it’s unknown whether this uptake is linked to school-entry mandates.

The HPV connection explains a lot about some of the groups most affected by the rise in anal cancer — people who are immunocompromised and less likely to be able to fight off HPV.

Those with HIV or AIDS are at higher risk of developing anal cancer, and, in a related statistic, Black men born in the mid-1980s receive five times as many diagnoses as black men born in the mid-1940s.

“Our speculation was that the rise in incidence (in young Black men) was due to the fact that HIV infections are higher,” says Ashish Deshmukh, assistant professor of medicine at The University of Texas Health School of Public Health in Houston and lead author of the 

Journal of the National Cancer Institute 

article on the rising incidence of anal cancer. “It’s very hard to speculate why it’s increasing in women,” he added.

Women may be more at risk than men because of anatomical differences and the “HPV field effect,” Saraiya says: If the virus is in or around the cervix, it can easily spread to the anus.

Others at risk of anal cancer include women who have had an irregular Pap test or cervical or vulvar cancer, people who have had organ transplants and those with autoimmune diseases, says Dr. Van Morris, assistant professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center (MD Anderson) in Houston. Middle-aged and elderly people also are experiencing a greater incidence of anal cancer, Deshmukh says. The rate of increase has been smaller for Hispanic people, and there were very few cases in Asian people, Deshmukh says.

The average age of those diagnosed with anal cancer is 62. Each year in the United States, an estimated 8,590 adults — 5,900 women and 2,690 men — will receive the diagnosis.

Anal cancer is highly curable when caught early, but there are no official guidelines for screening, says Dr. James M. Cleary, a gastrointestinal medical oncologist at Dana- Farber Cancer Institute. Experts recommend screening for those who are HIV positive and for men who have sex with men, who also face a higher risk of anal cancer, making up 10% of the population that has the disease. However, there’s disagreement within the medical community about screening men who have sex with men, partly because demand would exceed the supply of doctors who know how to perform the screening, say Morris and Palefsky.

The current screening practice isn’t great, Morris says: “There’s a need for increased vigilance among providers.”

To improve screening, the ongoing NCI-funded ANCHOR clinical trial involving HIV-positive men and women ages 35 and older seeks to find an anal cancer equivalent of the Pap test, which detects cervical cancer and has slashed deaths from the disease. In this test, doctors swab the anal lining and look at the cells under a microscope for signs of cancer or precancerous cellular changes.

In the study taking place at 17 sites across the country, people are screened for precancerous anal lesions. Those with lesions are enrolled and randomized to either receive treatment or be monitored every six months.

Although imperfect, Palefsky would like another method known as the digital anal rectal exam (DARE) to become a routine part of the annual physical for men and women. The more common digital rectal exam (DRE) is designed to look for tumors in the rectum, which is different from the anus. In both tests, doctors use their fingers to feel for lumps.

“We found that practitioners were not paying that much attention to the anus. We want them to feel more carefully for tumors in the anus,” Palefsky says. “If someone does it and feels something hard, the earlier you catch an anal cancer, the better the survival.” One condition that might be found is anal intraepithelial neoplasia, or precancerous lesions. There is no one standard of care for these lesions, which can be burned away with a low-voltage probe, cut out surgically or treated with a cancer-fighting topical cream version of the drug imiquimod or fluorouracil.

Gastrointestinal oncologists advise people to know the signs of anal cancer and see a physician as soon as they experience symptoms. These include a new growth, thinning of stools, incomplete evacuation, rectal or anal pain or itching, rectal bleeding, or discomfort during a bowel movement.

In 2004, Michael McKnight, 64, of Scottsdale, Arizona, noticed anal pain and bowel movement discomfort and changes. A few weeks later he saw a doctor, who told him it was probably an anal fissure and would heal itself. McKnight, who is gay and married, knew it wasn’t that simple. He called his primary care advanced practice registered nurse, who referred him to a proctologist. The proctologist examined the area with a scope and did a biopsy.

“It came back as anal cancer, stage 0,” says McKnight, who is retired after selling his advertising and marketing business. He underwent five surgeries within a month to remove the tumor and get margins that showed no sign of cancer, he says. He continued to go for follow-up visits, and in 2010, he received another diagnosis of anal cancer, classified as stage 2. The surgeon removed the growth, and McKnight received simultaneous chemotherapy and radiation treatment, called chemoradiation.

In fact, chemoradiation — sometimes after surgery to remove cancerous tissue — is the standard of care for anal cancer in stages 1 through 3. Most cancer treat- ment centers use a combination of two chemotherapy drugs: 5-fluorouracil and mitomycin C, Morris says. His institution uses the chemotherapy cisplatin instead of mitomycin C: “We believe it’s equally effective and less toxic for patients,” he says.

If chemoradiation doesn’t rid the patient of cancer permanently, abdominal perineal resection, which involves removing the whole rectum, can be done, Cleary says. Although the surgical procedure saves lives, it results in the need for a colostomy.

If anal cancer spreads to areas such as the lungs, bones, liver or brain, it can’t be cured, but doctors can try to halt or slow the progression with 5-fluorouracil and cisplatin and sometimes radiation. Surgery also might be an option.

Until recently, there weren’t many options for those with metastatic, or stage 4, anal cancer. An MD Anderson team led a study of immunotherapy treatments offered to patients at 10 U.S. academic centers. Early results involving 37 patients showed that 24% responded favorably to treatment with Opdivo (nivolumab), an inhibitor of the protein PD-1 that activates the immune system to attack tumors, according to findings published in 

“We’re extremely excited about this, but we still have a lot of work to do,” says Cleary, who is involved with this research. “The group that was being ignored was the metastatic patients. Fortunately, that’s changed with the PD-1 immunotherapy. ... We’re trying to figure out what to do with the 80% of patients in whom it doesn’t work.”

When anal cancer is caught early, most, like Blair and McKnight, return to their normal lives. “Don’t stop your life and do cancer,” says Blair, who continued to work through her treatment, walking around with a chemotherapy bag tucked into a black-fringed, leopard-print purse.

“My new normal is different,” she says, because her colon doesn’t work like it did before. “I no longer gain weight. Nothing stays in me very long.”

But Blair sees the silver lining: “I’m a big chocolate lover. Now I can eat a chocolate chip cookie every day if I want to.”

To halt the rise of anal cancer, everyone eligible needs to be vaccinated against HPV, which causes most cases of the disease.

Anal Cancer: Locking Out an Intruder

I learned I have a very rare, aggressive form of soft-tissue sarcoma that metastasized after treatment. Phyllodes tumor is so rare that half the oncologists, surgeons and doctors I’ve seen have disagreed about exactly what category of tumor it is, what treatments are available and whether it can even be considered a breast cancer. (The consensus among my oncologists: It is a cancer in the breast but not of the breast.)

Phyllodes tumor is so rare that when I received my diagnosis, all the scientific literature agreed on just one thing: If it metastasizes, the prognosis is “universally fatal within three years.” When the first biopsy showed that that tumor was benign, pathology after surgery revealed it as high-grade malignant and then I faced metastasis within a matter of months, a lot of people seemed surprised that I laughed and joked through the entire experience.

My family had to get used to my dark jokes about my own death and mangled body after surgeries and treat- ments that may or may not work. My oncologists seemed relieved that I could still laugh and look to the future. My primary care provider was concerned that I might not be processing my emotions. My nurses smiled and told me that “attitude is everything.”

Here’s the thing about my diagnosis: Yes, it was shocking and dismaying and daunting at times. But it was also an opportunity to acknowledge the absurdity of life in general and really learn about letting go. It became a wonderful opportunity to remind myself to laugh, because whether I have a week left or three years or, miraculously, even longer, I don’t intend to have that amount of time pass in misery, fear and stress. I intend for my time to be filled with joy and stupid jokes. I intend to see this time as the ultimate lesson in how ridiculous life can be, and I’m going to embrace that. Because let me tell you, life is ridiculous.

In the span of one year, I went from being an athletic dancer and model to having body parts cut out of me and wondering what music I would want played at my funeral. I went from “thank goodness it’s benign” to “oh dang, looks like we’re at ‘universally fatal’ status.” I went from being relieved at finding out AIM chemotherapy — Adriamycin (doxorubicin), ifosfamide, and mesna — was actually working on my metastasis to being told we couldn’t continue chemo because my body wasn’t rebounding fast enough. I went from healing from additional surgery and chemotherapy to finally having a chance to rebuild my life ... straight into lockdown for COVID-19.

Did I mention that life is ridiculous? The week my blood counts were finally recovering adequately from chemo and I was about to go back to work, dance and my other activities is the same week that COVID-19 emerged in the United States, in my state, in my region. I went from self-quarantine and wearing a face mask everywhere straight into ... self-quarantine and wearing a face mask everywhere.

I like to joke that “A Series of Unfortunate Events” was supposed to be a cute fiction, not an accurate description of my life. When people compliment me that I don’t “look sick,” I joke that it’s because I’m dying on the inside, not the outside. I love jokes and dark humor because while I’m laughing, I know I’m still living.

We can’t control everything that happens to us, but there is one thing we can control: how we react to it. And I intend to laugh. I’m going to laugh in the face of death, and I’m going to laugh as long as I live. We can’t always know when we are going to die, so we might as well smile until it happens.

If we’re really lucky, we might even be smiling when it happens.

Voices

Life can be ridiculous, one survivor writes.

Laughing in the Face of Cancer and Death

In the middle of the night, in October 2018, Kelly Fosso Rodenberg awoke to what felt like lightning bolts running through the fingers on her left hand. Given that she had worked on a computer for 35 years, she thought it might be a pinched nerve.

But in the days that followed, Rodenberg noticed some oddities, such as typing mistakes and a twitch in her hand. Then, while slicing an apple for her breakfast, she cut her thumb but didn’t feel it.

Rodenberg called a clinic in Minneapolis but couldn’t get in for two weeks. A nurse recommended that, based on her symptoms, she go to a walk-in clinic. From there she was sent to a neurologist.

Within 10 days, Rodenberg received a diagnosis of stage 4 glioblastoma (GBM), a rare and aggressive type of brain cancer. Although devastated, Rodenberg relied on her sense of humor to help her through surgery, radiation and chemotherapy.

Channeling her experience as a patient and caregiver for her husband, who has a rare blood disorder called POEMS syndrome, she wrote a book, “There’s Something Going On Upstairs: Learning to Laugh My Way through a Cancerous Brain Tumor, One Chemo Cycle at a Time.”

®, she details her diagnosis and biggest challenges and reveals who keeps her laughing.

®: How quickly did the neurologist know that something wasn’t right?

It took the neurologist 30 minutes to say, “I think there’s something going on upstairs.” We tried to get an appointment for an MRI, which didn’t happen because it was late in the day on a Friday. He said, “I’m so sorry. We’ll have to send you home, but if you have any other symptoms over the weekend, I want you to go to the emergency room.” I got up Saturday morning and my balance was completely off. So we went to the ER and 45 minutes later they’re showing me a golf ball-size brain tumor above my right ear.

My husband and I made the decision to get a second opinion. They were telling me in Minneapolis that there was a 50-50 chance after surgery that my entire left side was going to be paralyzed. We didn’t like that option. 

So that’s when we decided to go to Mayo Clinic, and that surgeon said, “I think I can input a pinpoint insertion from underneath your tumor, so I don’t affect your motor bands and your sensory bands. And if that’s the case, I give you about a 5% chance that your movement will be any different.” Today, my hand is the same after surgery as it was before, which is a blessing. I’ve done a little bit of therapy, but it hasn’t helped a whole lot, so I still type with one hand.

What has been the most challenging aspect of dealing with your cancer?

The fatigue was just terrible. There were a couple of months when I was in bed for 12 days straight and thought, “Seriously, I have to go brush my teeth today?” But almost equally — and again, I’ve been a caretaker for my husband and now I’m the patient — it’s challenging to ask for help. It’s been a learning curve to be patient with myself. Not everything happens the way it

used to, so you have to step back and find a different way to do daily things. I laugh because I told my oncologist, “Well, my husband was able to keep me both busy and quiet for a solid 45 minutes when he asked me to take a twist-tie off a bag.” Because you have one hand. Or folding a load of clothes — you have one hand, so it takes twice as long.

In between the bouts of radiation and chemotherapy, it’s easy to pull a blanket over your head and get very depressed. I learned early on that I needed to find light in this whole situation. That’s when the writing of this book came to be. It started out as a journal for myself, but the more I typed, the better I felt. And I thought, “This could actually help somebody along the way — having both the caregiver and now the patient experience.”

Can readers expect a lesson from “There’s Something Going On Upstairs”?

It’s not always easy. It’s not always fun. But the way you react ... It doesn’t do anybody any good — yourself, your caregiver, your spouse — to bury your head. Try to have a sunnier disposition and make the best out of a bad situation. I think the turning point for me was when I saw and heard how I was helping people get through their struggles. That is a complete motivator.

Do you look back on any moments since the diagnosis that stand out as humorous?



I enjoy poking fun of myself, and one of my greatest joys is that my brothers and nephews still poke fun at me at family get-togethers. I joke that I have an official “brain tumor card” and I can use it anytime. It’s something I have for medical reasons, but it’s also a way to poke fun, and it helps people know that you still enjoy a laugh.

Bookshelf

After receiving a stage 4 glioblastoma diagnosis, one woman taps into her sense of humor — and turns that into a book.

Laughing In The Face of A Brain Tumor

Running a mile in under four minutes was believed to be humanly unachievable. Roger Bannister was the first to do it in 1954. Within a year, another runner did it. And soon, many others had as well.

In cancer, these paradigm shifts seem to occur in a similar manner with advancements in treatment often coming in quick succession. Determining the catalyst for this progress is difficult, as changes take years of development. Could collaboration be a catalyst for changing the landscape for rare cancers?

One small rare cancer foundation thinks it is and is leading the way through innovative partnerships. The Cholangiocarcinoma Foundation was founded in 2006 by a family desperate to understand the rare cancer diagnosis that they had just received. Cholangiocarcinoma was not only difficult to pronounce, but also extremely challenging to research. There was not much easily understood information available and there were no resources for patients.

Rare cancers present significant challenges for patients, doctors and scientists. Patients may find it difficult to find a specialist who regularly sees patients with cholangiocarcinoma and has access to the latest research and clinical trial opportunities. Doctors may not treat this cancer, and often may not know experts with whom they can consult or make a referral. Science follows money, and rare cancers are often the least funded, which slows down the discovery and availability of viable treatment options.

Enter the Clements family. Mark Clements was a fit, active, 38-year-old father of three with a fourth on the way when he learned he had an inoperable, incurable cancer. Desperate to find hope, his family began an intensive 15 months of research, networking and connection.

Sadly, the family lost Mark. However, his sister, Stacie Lindsey, and her family were doggedly determined to make sure others could benefit from the growing community and base of knowledge they had begun to create. Focused on the principles of patients first, collaboration, and always maintaining a sense of urgency, the Cholangiocarcinoma Foundation was born. These core values still drive the work of the foundation to this day.

Less than 15 years later, with robust collaborations in place with other nonprofits, regulatory bodies, industry partners, medical start-ups and corporations, the drive for a cure is gaining momentum. In spring of 2020, the community celebrated the Food and Drug Administration (FDA) approval of the first targeted therapy for cholangiocarcinoma. The development of effective treatments takes many years and the contributions of innumerable people and organizations. Closely following are several other treatment options which are currently being developed in the pipeline.

Common to the progress of these developments is deep meaningful, multilevel collaborations. So, could collaboration be the key? True collaboration involves much more than organizations or individuals working together toward a common goal. It is defined by convening partners who each bring unique and specific contributions to the table. Through partnership, organizations can leverage assets to accomplish more than they could on their own.

The Cholangiocarcinoma Foundation has been successful in creating a culture of collaboration in what is, very often, an intensely competitive environment.

Two such partnerships have the potential to be game changing in the rare cancer space. Citizen is a consumer health technology company that has a platform to enable patients to collect, organize and share their medical records digitally. They have developed a user-friendly interface to facilitate the expedited gathering of records from multiple health care facilities into a central, searchable database. Patients are then able to have complete control of their health data. It empowers them to coordinate their care with teams from multiple healthcare providers, to more easily get second opinions and to understand trial eligibility.

Additionally, patients can make their records available to provide clinically validated data to researchers to help develop therapies and options for the rare cancer community. Ciitizen uses the HIPAA Patient’s Rights of Access laws to give them the control over their own Protected Health Information.

Partnering with Komodo Health has helped patients with cholangiocarcinoma access specialists around the country by leveraging their unique intelligence platform which combines de-identified data from over 500 sources capturing more than 320 million Americans’ health care journeys. With this data, the Cholangiocarcinoma Foundation can connect patients with the best care possible through the cholangiocarcinoma specialist map. The map incorporates both clinical and scientific activity for providers across the nation to find the most active clinicians and researchers. The map leads patients and their caregivers to find the top specialists in their area, in hopes of a better chance of survival. The specialist map has had a significant impact on patient lives.

These collaborations could be game-changing because each helps to put power in the hands of the patients. This is especially important in rare cancers where many viable treatment options are often found only at major cancer centers and academic institutions.

The Cholangiocarcinoma Foundation is committed to maximizing partnerships to benefit patients. The Foundation is determined that, through collaboration, they can accomplish what was once believed unachievable, the cure for cholangiocarcinoma.

The Advocate

Could paradigm shifts in cancer research help find a cure for cholangiocarcinoma? Experts discuss.

2020 Rare Cancers Special Issue | CURE