Marijke Vroomen Durning, RN

When Cindy Stemple of Westerville, Ohio, noticed a sore on her tongue, the last thing she imagined was that she may have head and neck cancer. After all, she was only 27 years old.

She finally went to see her dentist when the sore wouldn’t heal. Since Stemple 

CINDY STEMPLE was only 27 years old when she received her diagnosis of stage 3 oral squamous cell carcinoma.

didn’t have any known risk factors for head and neck cancer, the dentist didn’t expect cancer either. After trying several treatments, they decided it was time for a biopsy. Stemple still wasn’t concerned.

“It wasn’t even in the realm of possible things,” she says. “I didn’t even take anybody to the appointment when I got the results and found out it was cancer because it was the furthest thing from my mind.”

She received a diagnosis of stage 3 oral squamous cell carcinoma — which is a cancer that occurs in the mouth and/or throat.

Tremendous Change in Head and Neck Cancer

Historically, head and neck cancer, the seventh most common cancer globally, was predominantly diagnosed in older individuals and was often linked to tobacco and alcohol use. As smoking rates began to decline, so did tobacco- and alcohol-related cases among older individuals.

But head and neck cancer rates began rising in another group — younger and middle-aged adults — driven by HPV infections, predominantly HPV type 16, which has been shown to be a clear risk factor for head and neck cancer as well as cervical cancer.

HPV-positive oropharyngeal cancers in the United States increased from 16.3% of head and neck cancers in the 1980s to more than 70% in the 2000s. Researchers, however, expect an eventual decrease as the effects of the HPV vaccine take hold, but it may take up to three decades to get to that point.

“I’ve been in the field for about 25 years, and it has changed tremendously,” says Adena Dacy, associate director of health care services in speech-language pathology at the American Speech-Language-Hearing Association in Rockville, Maryland. “Most of my patients tended to be older, usually with a long history of tobacco or alcohol use. Today we still see some of that, but we are seeing much younger patients, often (those who are) tobacco- or alcohol-free.”

Improving Survival While Increasing Quality of Life

In most cases, different treatment approaches are used for the two groups. For instance, since many patients with tobacco- or alcohol-related head and neck cancer are often older and have other comorbidities, treatment options are limited.

On the other hand, patients who are younger and healthier are likely better able to tolerate side effects and extended treatment regimens, if deemed necessary. Additionally, HPV-related head and neck cancers are more likely to respond better to treatments, meaning less aggressive therapy may be used.

Initially, the primary treatment of head and neck cancer revolved around removing as much of the tumor as possible to extend life.

But surgeries often left patients disfigured, and high doses of radiation destroyed healthy tissues along with the tumors. These issues led to a significantly diminished quality of life for many patients, including not wanting to appear in public and being unable to enjoy a meal with friends and family.

In the early 1990s, researchers investigated a combination of chemotherapy and radiation aimed at better organ preservation. New drugs were also approved, such as Salagen (pilocarpine) to increase saliva production, which in turn reduced complications caused by dry mouth.

Food and Drug Administration approved Opdivo (nivolumab)

 after clinical trials showed that the drug doubled one-year survival (the percentage of patients who remained alive from diagnosis or start of treatment) for recurrent or advanced head and neck cancers and caused fewer severe side effects, compared with standard-of-care chemotherapy.

The earlier the disease is detected, the better the survival rate. In fact, some estimates suggest that patients with locally advanced HPV-related head and neck cancer have up to an 80% long-term survival rate. 

These results, according to researchers, depict how harsh treatments can have a long- lasting effect on a patient’s quality of life.

“Over the past 20 years, we’ve seen more of an emphasis on organ preservation and less aggressive surgical intervention,” Dacy says. “(For) 70% of the people who came in years ago with cancer of the throat or larynx, the gold standard was that they would have a total laryngectomy.”

Now, surgical treatment is less invasive and more focused on improving quality of life, according to Dacy.

“Twenty or 30 years ago, the only focus was on a cure,” says Dr. Scott Roof, a head and neck oncologic and reconstructive surgeon at Mount Sinai Health System in New York. 

“Now it’s somewhat shifted to (asking), ‘Not only can we cure patients, but how are we going to leave them with the best functional outcomes?’ Speech and swallowing are integral to what we do in our everyday life and how we interact with people.”

The location of the cancer also plays a role in long-term recovery, according to Roof.

“The head and neck involve everything from your lips all the way down to your esophagus,” he explains. “If you have cancer in your mouth, the side effects are different than if it’s in the larynx, or voice box.”

The location of the tumor also affects the type of long-term rehabilitation required after treatment.

Dr. Theodoros (Ted) Teknos, president and scientific director for the University Hospitals Seidman Cancer Center at University Hospitals Cleveland Medical Center and deputy director of the Case Comprehensive Cancer Center, explained that some head and neck cancers result in more extensive deficiencies than others because of tumor location.

Despite the widespread adoption of advanced reconstructive surgery, according to Teknos, cancers of the tongue base, jaw and throat often leave patients with both functional and cosmetic abnormalities, which require extensive rehabilitation.

In general, there are many possible side effects from head and neck cancer treatment. Surgery may lead to difficulties with chewing and swallowing, affecting not only nutritional status but socialization. Speech may be difficult or impossible for some patients. And if the surgery involves removing the larynx, cutting into nerves or removing lymph nodes, patients may be left with weakness in the shoulder and neck muscles.

Radiation alone or in combination with other treatments may also cause short-term sores and pain in the mouth, difficulty swallowing, changes in taste, nausea and even difficulty opening the mouth as wide as before treatment.

But even if these side effects don’t occur or resolve over time, radiation treatment may lead to the development of radiation fibrosis syndrome (injury to the skin, connective tissues, muscles and more) weeks or even years after treatment.

“Functional deficits can arise many years after the initial treatment,” Teknos explains. “Patients (with HPV-related cancers) are typically treated with chemo and radiation therapy. And while those are highly effective treatments typically delivered to younger patients, as the patient ages, their ability to compensate for the damage caused by therapy decreases and they start developing swallowing and musculoskeletal deficits many years after their treatment.”

Teknos also mentions that about a quarter of patients develop significant hearing loss, which may require hearing aids.

But as treatments improve, these long-term effects occur less frequently.

Dacy notes that she has seen a reduction in the effect of radiation fibrosis syndrome on patients’ quality of life compared with when she started working with this patient group. The reason, she says, is because of lower dose regimens, newer delivery methods and preventive habilitation techniques.

Mike Jirousek, from Hamden, Ohio, received a diagnosis of head and neck squamous cell carcinoma four years ago at the age of 59. After noticing a rapidly growing lump in his throat, he went to a local urgent care clinic.

The attending physician was so concerned that Jirousek was immediately transported to the hospital by ambulance.

“They were afraid of (the lump) closing off my airway,” he says.

After a CT scan, Jirousek was rushed to the UH Seidman Cancer Center in Cleveland.

“I was admitted to the hospital that day, and things began to move very quickly,” he says.

The treatment plan was to remove the tumor and then start chemotherapy and radiation. But his treatment didn’t stop there, as Jirousek met with several other care professionals.

According to Teknos, a team approach is necessary for the recovery of patients with head and neck cancer. 

He notes that this multidisciplinary team includes speech pathologists, audiologists, physical medicine/ rehab experts, physical therapists and nutritionists, along with specialists in dentistry, prosthodontics and anaplastology (the use of removable facial and ocular prosthetics).

Over time, there was a shift toward preparing patients for the aftereffects of surgery and other debilitating treatments.

Although MIKE JIROUSEK remains on a feeding tube, he has maintained the ability to speak. 

“We used to get (other health care professionals) involved on the back end, once patients had gone through their treatments and were dealing with some of the functions afterward,” Roof recalls. “We’ve realized this is not as good, so there’s a big push to have patients work with people like speech and language pathologists pre-treatment, during treatment and then post-treatment.”

If scarring develops, Roof mentions, patients need to counteract the side effect by regularly using the muscles and structures to prevent stiffening of the area.

He likened it to the notion of if you don’t use it, you lose it.

Now, patients are also encouraged to swallow, eat, drink and speak during treatment. Actively participating in these activities may help retain some of those functions after treatment has stopped.

“We learned that if you can encourage patients to learn to swallow, eat, drink and speak throughout their treatment, they’re more likely to preserve (these functions) after treatment,” says Roof.

Jirousek says his first head and neck cancer diagnosis and treatment happened so fast that he was ineligible for prehabilitation, but he notes
he met with therapists when his treatment began.

“I met with the oncologists, radiation specialist, and then the nutritional experts and rehabilitation as well,” he recalls.

The therapists helped Jirousek prepare for potential difficulties with swallowing and limited nerve function in his neck and shoulder.

“During my first time, I was convinced that I would be able to keep eating and swallowing, and I was able to,” he says.

Unfortunately, Jirousek’s disease returned 18 months later, and his treatment was more invasive. He underwent a radical neck dissection — a notable surgery that consists of a significant removal of muscle, tissue and lymph nodes from the collarbone to the jaw — followed by chemotherapy and radiation.

As a result, Jirousek needed a feeding tube, and although he remains on the feeding tube, he is still able to speak.

Feeding tubes are not uncommon among patients treated for head and neck cancer. Data from a study published in 2017 in the journal 

 demonstrated that more than 50% of patients with head and neck cancer required a feeding tube.

Of note, in many cases feeding tubes are temporarily placed during and after treatment. But they are often removed later as a patient’s swallowing function returns.

Stemple, whose disease returned five years ago, says that she didn’t see rehabilitation therapists before treatment for her primary diagnosis. She only recalls seeing them briefly during her radiation treatment.

It was after her treatment was completed that she received extensive therapy.

“I would definitely have been open to doing other therapies before treatment,” she says. “It wasn’t really presented to me as an option at the time.”

For more news on cancer updates, research and education, don’t forget to 

Articles

Years ago, the goal of head and neck cancer treatment was strictly focused on a cure. Now, there has been a slight change in approach to improve survival rates while preserving quality of life.

A Shift in Focus for Head and Neck Cancer Treatment

For many people with cancer, getting the best care means getting to a large city. A major barrier to this: the cost of travel. Although health insurance usually covers the costs associated with the care itself, each patient foots the bill for gas, flights, lodging and food.

Average cost of one night in a U.S. hotel room: $120.72. Factor in dining out and transportation and the price tag can be overwhelming, especially for patients who face months of treatment. The reality of traveling for cancer care may make them think twice, no matter how highly recommended the treatment.

Some hotels offer medical-stay discounts to help ease the burden, but despite the lower rates, patients may have a difficult time paying the bills. Amie Sanders, a stay-at-home mom who has breast cancer, underwent treatment at Roper Hospital in Charleston, South Carolina, a two-hour drive from her home in Barnwell. She used a medical discount of $120 per night the first two times she stayed in Charleston, where the average nightly cost of a hotel room runs from about $150 to $300-plus.

“After that, we had pretty much blown all the money we had,” Sanders says. Searching for affordable options so she could continue treatment led her and her husband, Gibby, to Hotel Keys of Hope.

Hotel Keys of Hope offers patients with cancer deeply discounted or free hotel rooms close to the treatment center where they will receive care. Extended Stay America created the program in 2013 to support the American Cancer Society’s (ACS) Hope Lodge program. More than 30 Hope Lodges throughout the country provide free accommodations for patients but have a limited number of rooms. That is where Hotel Keys of Hope steps in.

“One of the options that has dramatically increased the number of solutions we’re able to provide is the Hotel Keys of Hope program and our partnership with Extended Stay America,” says Richard Wender, M.D., chief cancer control officer of the ACS.

Extended Stay America has a tiered fee structure based on patient need. Someone who can afford a modest fee will get a 25 percent discount. If that amount is tight, they can get a room for $19. If that is still too much, they are offered rooms for free.

“The key to surviving cancer is getting access to treatment,” says Terry Atkins, vice president of marketing communications at Extended Stay America. “Probably one of the biggest barriers to getting access to treatment is the cost associated with it. You find people who are already potentially financially insecure, and then they may have lost their job because of the illness, can’t work or whatever the case may be. They’re in a really dire situation.”

Shane Caldwell understands this well. He lives in Columbia, South Carolina, and frequently travels the 230 miles to Duke University Cancer Center in Durham, North Carolina, for lung cancer treatment. He and his wife, Renay, appreciate the choices in the tiered system.

“We made the decision not to accept the room for free because we feel there is always someone else who needs that rate more than we do, but we do appreciate the significantly reduced rate,” says Renay. “Our rate is $19 per night, and that’s what we’re comfortable with.”

Extended Stay America, which has properties in 44 states, welcomes children under age 18 who are accompanied by an adult. The hotels are pet-friendly, too. “A lot of people find comfort in bringing their dog or cat,” Atkins says.

The rooms offer basic kitchen facilities — a fridge, microwave, dishwasher, small appliances and kitchen necessities. This amenity allowed Sanders to bring her two children, who were 6 and 8 years old when she started treatment, and was especially appreciated because her son has food allergies. “Eating breakfast out is very tricky. He is allergic to wheat, eggs and oats &mdash; pretty much all of your traditional breakfast foods &mdash; so it was nice to be able to take a gallon of milk and a box of cereal or have little things for them to eat,” she says. “My husband is diabetic, so keeping sugar-free drinks and bottles of water &mdash; those are big deals for us.”

Having a kitchen is also important for patients who have low tolerance for the smells of certain foods — a side effect of some cancer treatments that can make restaurant outings challenging, says Pam Daniels, whose husband, Jerry, traveled to Emory University in Atlanta to undergo treatment for diffuse large B-cell lymphoma and non-Hodgkin lymphoma. “You can make what you know doesn’t make the person sick and doesn’t have an odor that is irritating to them. It’s so easy to get malnourished at this time,” she says.

Patients and their families also can save money by making meals in the room rather than dining out for every meal. That becomes especially important for patients whose stay time lasts as long as several months.

William Sampson took advantage of the program while undergoing 30-plus treatments for prostate cancer at the Radiotherapy Cancer Institute in Duluth, Georgia, staying Monday through Friday each time. “They took good care of me,” he recalls. “Whatever I asked for, they accommodated me, and staying there took the burden off me and my family. It helped a lot.” Sanders quickly learned that having three specialists on your team can create a challenging schedule. Her plastic surgeon could see her only on Tuesdays or Thursday; her breast surgeon was available only on Wednesdays and Fridays; and her oncologist, on Thursdays or Fridays.

“It takes a good tank of gas to get to Charleston and back, so it was such a help to be able to go there and stay,” Sanders says. “It really did make a difference when we began to stay over. The first time we stayed, the nurses said, ‘Oh, my gosh, your blood pressure is so much better this morning. What’s the difference?’ It was that we didn’t just drive for two hours in horrible Charleston traffic.”

Although Extended Stay America offers the hotel rooms, it does not administer the program. All registration is handled through the ACS’s National Cancer Information Center (800-227-2345). This central system eliminates the need for patients to call individual hotels to book rooms and, at the same time, vets patients to ensure their eligibility.

Eligible patients must have a permanent address, be traveling for a cancer-related medical appointment and be in need of lodging near their treatment center. They also must be able to take care of their personal needs or travel with a companion who can assist them.

According to the ACS, patients often learn about Hotel Keys of Hope through a health care professional, such as a nurse or social worker. They also can find details on Cancer.org.

The assistance goes beyond booking rooms. “There may be other ways we can help,” says Elaine Mathis, senior program manager at the ACS. “Our representatives will talk with them not only about lodging but [also about] other resources, such as transportation or cancer information.”

In 2017, Extended Stay America donated 10,000 free rooms, 10,000 rooms at $19 a night and 20,000 at a 25 percent discount. The program allowed thousands of people with cancer to get access to treatment and saved them close to $5.5 million dollars in hotel costs, according to Extended Stay America.

“This is a financial burden for anybody,” Daniels says. “When you add on top of that what you’re going through physically, anything like the Extended Stay that removes some or part of that and gives you a place to stay for a little longer time rather than just one night — that’s a big benefit to myself and any other patient with cancer.”

Sanders couldn’t agree more. “I would not have gotten the treatment I needed without that program — I really wouldn’t have,” she says. “We could not have made the same decisions. I would not be where I am at now.”

Hotel Keys of Hope offers patients discounted or free hotel rooms to ease travel for cancer care.

A Home Away From Home

OUR HAIR IS A large part of our identity. When asked to describe someone, their hair is usually one of the first descriptors we use. Losing our hair can be traumatic regardless of the cause, and for people who have cancer, alopecia (hair loss) can trigger feelings of lack of control in an already overwhelming situation.

Until recently, there hasn’t been much to offer for the treatment of alopecia. For those who want to prevent hair loss while undergoing chemotherapy, scalp cooling caps that chill hair follicles, protecting them from chemotherapy damage, are becoming more widely available. And taking Biotin, or vitamin B7, during chemotherapy may help to preserve hair if the anticancer drug tends to cause only partial hair loss.

But now there’s also promising news for some who have already lost hair. Over the past few years, evidence has been accumulating that a class of medications called Janus kinase (JAK) inhibitors — used to help treat myeloproliferative disorders such as polycythemia vera, as well as other conditions &mdash; can also help resolve alopecia areata (AA), hair loss caused by an immune system malfunction. This condition affects some people treated for cancer, but also many others.

The last two-and-a-half years have revolutionized treatment for this form of hair loss, which can cause people enormous despair, says Brett Andrew King, M.D., Ph.D., assistant professor of dermatology and medical director of Yale Dermatology-Middlebury in Connecticut, in an interview with 

“Alopecia areata affects (at least) 3 to 5 million Americans and 100 million people worldwide,” he says. “Three years ago, there (were few) treatments for severe disease, and now there’s increasing acceptance that a relatively new class of medications will effectively treat the condition.”

Experts reiterate, though, that JAK inhibitors won’t treat all types of alopecia. “It’s important to note that, so far, we know that the JAK inhibitors are only useful for those types of hair loss that are mediated by inflammation,” says Mario E. Lacouture, M.D., director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center in New York City. This type of hair loss occurs in 1 to 2 percent of the population, he explains, including many patients who have received chemotherapies. In addition, some cancer treatments, such as the new immunotherapies, result in this type of hair loss in one out of 50 people. “The JAK inhibitors would have a potential benefit in some cancer patients and survivors,” Lacouture says. However, they are not expected to work in cases where chemotherapy is the direct cause of hair loss.

 There’s a reason the drugs work specifically in those with AA.

“In alopecia areata, the hair follicle sends out a message that calls the body’s immune system to attack the hair,” King explained. “When a patient takes a JAK inhibitor, this message to the immune system is interrupted, allowing the hair to grow. And because the hair follicle was not damaged, the hair grows as it should, as long as the patient takes the medication. This is unlike male- or female-pattern baldness, in which the hair follicle atrophies and stops growing hair. In that case, JAK inhibitors cannot help.”

In fact, unlike in AA, experts “don’t know exactly what causes male-pattern baldness or female-pattern baldness,” King continues. However, they do know of one strategy that has proved helpful for that condition over the past few years: Rogaine, a topical form of minoxidil, which is a blood pressure medication. In pattern baldness, he says, “Rogaine seems to rejuvenate some hair follicles.” Rogaine may also work for those with mild AA.

Both Rogaine and Xeljanz were found to have an effect on alopecia accidentally, as people taking the drugs experienced renewed hair growth. However, taking JAK inhibitors to treat alopecia would not be expected to confer any protections against cancer, as no studies have been done that demonstrate such an association, King says.

Besides Rogaine, more typical treatments for AA include steroids, the psoriasis medication Dritho-Scalp (anthralin), topical immunotherapy and photochemotherapy (which involves the patient taking a light-sensitive drug and then exposing the scalp to ultraviolet light).

JAK inhibitors have been approved by the Food and Drug Administration (FDA) to treat people with blood and autoimmune diseases. In the cancer arena, Jakafi (ruxolitinib) is approved to treat myelofibrosis and polycythemia vera. Meanwhile, Xeljanz (tofacitinib) is approved to treat rheumatoid arthritis, and Apoquel (oclacitinib) to treat dermatitis and associated issues. Many other JAK inhibitors are being tested in clinical trials.

JAK inhibitors interfere with the body’s ability to generate enzymes called cytokines, which stimulate growth signaling pathways. If unchecked in polycythemia vera, for instance, these growth factors stimulate cells to grow and divide excessively in the bone marrow, causing blood to thicken, increase in volume and have problems flowing through vessels.

Recently, King and his colleagues published the results of studies that tested JAK inhibitors as treatments for AA.

 In February 2017, “we published a study of 90 adults who were treated with tofacitinib,” King said. “At the same time, we published a study of 13 adolescents, between the ages of 12 and 17 years, treated with the same medication, and before that, in November, the results of a clinical trial involving 66 adult patients.” King and his colleagues also published the results of a single teenage patient’s experimental use of Jakafi, which the researchers had compounded so it could be applied to the skin, rather than taken orally. The results of all the studies have been promising.

In the larger study of Xeljanz (40 men and 50 women), 77 percent of the 65 patients who were thought to be potential responders experienced hair regrowth; 58 percent of them experienced an improvement of 50 percent or more. In the clinical trial involving 66 subjects (31 men and 35 women), 32 percent had a brisk response to the medication over three months. And in the study of 13 adolescents, nine experienced complete hair regrowth, one participant whose hair started to regrow subsequently lost it again and three did not respond.

These medications must be taken continuously for their effects to continue. Discontinuing treatment results in a return of hair loss within a few months. As with all medications, JAK inhibitors may cause side effects. In the rheumatoid arthritis clinical trials, side effects reported with Xeljanz included fungal, bacterial and viral infections; diarrhea; headache; nasal congestion; sore throat; runny nose; and, rarely, cancer. The recently published studies in AA have shown that Xeljanz was well-tolerated among both adults and adolescents, though the numbers of patients in these studies were very small compared to the larger studies that will be necessary to determine safety.

The patient treated with Jakafi cream did not report any adverse effects. Side effects from the oral formulation, when used to treat blood cancers, include dizziness, weight gain, headache and gas; more serious side effects can include fatigue, bruising and a reduced ability to fight infection. Less is known about long-term side effects, as these drugs are relatively new to the market.

In the studies that used Xeljanz to treat AA, starting the dose was 5 mg twice daily by mouth. In some studies, depending on the response at three months, dosage was increased up to 10 mg twice daily, or it was given in conjunction with 300 mg of pulsed prednisone (a steroid), once monthly for three doses.

While JAK inhibitors are currently available only in oral form, they can be compounded into creams by specialty pharmacies. King tested a topical formulation of Jakafi on a 17-year-old female who had alopecia universalis, an advanced form of AA. The patient applied the cream twice a day to her scalp and eyebrows for 12 weeks. Her eyebrows were restored and she had partial growth of the hair on her scalp. She then switched to the oral medication and grew a full head of hair. The results indicate that the cream version of the medication was just as useful as the oral version, King has said.

 Because topical formulations are not the norm, their use can be met with obstacles. “We have to use a specialty pharmacy that will compound (the medication), and many times we have issues with this being covered by insurance,” Lacouture says. “I hope that, in the future, we have many different vehicles in which we can use these medications topically, which will minimize the risk for side effects and provide as much benefit as the oral tablets.”

JAK inhibitors are quite expensive, and it’s not yet clear whether cosmetic formulations would be less costly, or whether they would be covered by health insurance, the doctors said.

There has been speculation that cyclindependent kinase (CDK) inhibitors and Wnt inhibitors may also be promising treatments for alopecia. One CDK inhibitor, Ibrance (palbociclib), has been approved by the FDA to treat breast cancer; Wnt inhibitors are still experimental.

According to King, there is evidence of the Wnt pathway being involved in male- and female-pattern baldness, but that observation is not likely to lead to a new treatment any time soon. “There is some evidence that the CDK signaling pathway may be important in chemotherapy- induced baldness, but that observation, too, is not likely something that is on the edge of practical application,” he says.

Researchers are continuing their work to find solutions for people who live with alopecia.

“Patients who have hair conditions, including oncology patients and survivors, should not feel that they have to suffer or live with these conditions for the rest of their lives,” Lacouture said. “There are many options right now to treat or minimize hair problems that they may face as a result of their chemotherapy, immunotherapies, radiation or surgical procedures.”

JAK inhibitors, used to treat blood and autoimmune disorders, also reverse one type of hair loss.

Right on the Head: JAK Inhibitors May Reverse Hair Loss

Whenever 60-year-old Catherine Messinger experienced pain in her side, she would chalk it up to diverticulitis, a condition that had plagued her for many years. But in April 2013, her intense pain signaled something else. Messinger, whose doctor initially suspected a kidney stone, had a tumor on her kidney and was diagnosed with stage 4 renal cell carcinoma (RCC), or kidney cancer.

After Messinger underwent several months of scans to monitor her progress, a new tumor was found in her spine and, in January 2014, despite initial treatment, her doctors found that the tumor had spread to her abdomen. Messinger needed innovative treatment, and, luckily, she qualified for the one spot her oncologist, Elizabeth Plimack, M.D., M.S., had in an immunotherapy trial at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“The trial sounded really promising, so I agreed to do it,” Messinger says of the ongoing phase 1 study, which is considering the best dosing for the immunotherapy Opdivo (nivolumab) when it’s combined with targeted drugs Sutent (sunitinib) or Votrient (pazopanib), as well as the effectiveness of Opdivo given with either Sutent, Votrient or another immunotherapy, Yervoy (ipilimumab). Two- and-a-half years later, Messinger is still taking her immunotherapy regimen.

Yervoy is an immune checkpoint inhibitor, which blocks the protein CTLA-4 on T cells. The job of CTLA-4 is to help hold the body’s immune system in check; blocking its activity frees up a patient’s immune system to work more powerfully to kill cancer cells. Opdivo is another checkpoint inhibitor that works on the same principle, but targets a different protein, PD-1. These drugs can slow tumor growth or even shrink tumors.

Messinger, who goes to the clinic for assessment and treatment every two weeks, is experiencing a few side effects from her treatment, but nothing that makes her feel she needs to discontinue it.

“I’m really tired and, just lately, my joints and bones have started hurting. They don’t know if it’s the nivo or because I’m 60,” she says. “I get nauseated now and then, but for the most part, it’s really not been a bad ride at all.”

Both Yervoy and Opdivo have been approved for at least a couple of years to treat other cancers, but it was only recently that Opdivo was given the green light by the U.S. Food and Drug Administration (FDA) for use in patients with advanced RCC. That happened in November 2015, based on findings from a phase 3 trial, which showed longer overall survival and fewer serious side effects with Opdivo than with another newer treatment, the targeted drug Afinitor (everolimus). Opdivo can cause side effects including fatigue, itching, rash, upper respiratory problems, swelling of the hands and feet, gastrointestinal disturbances, muscle pain, fever, and abdominal, chest or joint pain.

“This drug works by stimulating the body’s immune system in a much more specific fashion than previous generations of such treatments, to elicit an immune response,” says Sumanta Kumar Pal, M.D., assistant clinical professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope in Duarte, California. “When you look at the older classes of immune- based treatments, like IL-2 (interleukin-2) and interferon, these were incredibly toxic. There were many toxicities that ultimately might lead to death. This is far different with the targeted, immune- based therapies that we have now in the clinic. By and large, I’ve found that patients are able to maintain their quality of life. It always helps to have tight oversight by a physician who is knowledgeable of these medications. If you do have that, then certainly, you can still enjoy excellent quality of life while extending survival.”

It’s an improvement that’s a sign of the times. The treatment landscape for advanced RCC has changed drastically over the past few years, with several targeted drugs that are not immunotherapies also approved by the FDA. These include Cabometyx (cabozantinib) and Lenvima (lenvatinib), which target and disable cell enzymes known as tyrosine kinases that help drive some cancers. There’s also a regimen that combines two kinase inhibitors, Afinitor and Lenvima. As a group, these therapies have the potential to further reduce RCC’s already dropping mortality rate.

Until about 10 years ago, a diagnosis of kidney cancer was grim. If the cancer was caught early enough, surgery to remove the kidney and tumor may have been sufficient treatment, but anything beyond complete removal rarely had a good outcome. Unfortunately, detecting early kidney cancer, which tends to be asymptomatic, is not easy.

“We don’t have any screening techniques for kidney cancer as it stands now,” says Pal. “With kidney cancer, often times we catch it at a much more advanced stage because of the lack of appropriate screening.”

Traditional chemotherapies, called cytotoxic chemotherapies, can sometimes be successful in treating other cancers, such as breast cancer or lung cancer, but are not effective for kidney cancer.

For a while, biological therapy, or immunotherapy, was the only hope for many patients with advanced RCC. Researchers found in 1985 that interleukin-2 (IL-2) could use a patient’s own immune system to shrink tumors in the kidney. The FDA approved its use to treat advanced kidney cancer in 1992. However, few patients responded well to the treatment, and the side effects were quite serious, often requiring patients to be admitted to intensive care units. While the treatment was potentially curative for those who responded to it, the drug produced responses in only about 10 percent of patients.

The newer targeted therapies, meanwhile, such as Cabometyx and Lenvima block cancer cells from getting the nutrition they need in order to develop new blood vessels and grow (angiogenesis), and/ or block proteins that help the cancer cells survive. “One of the principle molecules that we think drives kidney cancer growth is a molecule called VEGF,” Pal says. There are now, in practice, more than half a dozen drugs that target that particular molecule. Besides Cabometyx, these include Nexavar (sorafenib), Sutent and Avastin (bevacizumab). Nexavar was approved for treatment of advanced RCC in 2005, Sutent in 2006 and Avastin in 2009. In addition, VEGF inhibitors Votrient and Inlyta (axitinib) were approved in 2009 and 2012, respectively. “We also have two drugs that target a molecule that’s downstream from VEGF called mTOR,” Pal says; these are Torisel (temsirolimus) and Afinitor, approved in 2007 and 2009, respectively.

One of Pal’s patients, 65-year-old David Pasternak, a lawyer in Los Angeles, California, was diagnosed with advanced RCC in April 2014, after tumors were found in his lungs. Two months after his diagnosis, Pasternak entered a phase 1 clinical trial, taking Avastin and the new checkpoint inhibitor Tecentriq (atezolizumab) every three weeks. It’s one of a number of trials to combine targeted drugs with immunotherapies or with each other, a strategy experts believe may further improve the effectiveness of RCC treatment. “I was the first patient at City of Hope on this trial, and it was terrific for over a year,” Pasternak says. “The tumors in my lungs were shrinking, although recently they have been growing a little bit.” Pasternak has since been switched to Cabometyx.

The newest drug available to treat advanced RCC, Cabometyx targets not only VEGF, but a combination of other proteins at the cell surface that drive kidney cancer growth. Approved in 2016, as was Lenvima, Cabometyx got the green light based on results from the phase 3 METEOR trial, which compared it with Afinitor. The findings showed that Cabometyx offered patients longer progression-free survival. The most common side effects of Cabometyx include gastric system disturbances and fatigue. Lenvima’s approval was based on a phase 2 trial that compared Lenvima plus Afinitor, Lenvima alone and Afinitor alone. In this study, Lenvima plus Afinitor and Lenvima alone both resulted in longer progression-free survival than did Afinitor alone.

Lenvima can cause high blood pressure, diarrhea, joint pain, fatigue, nausea, mouth inflammation, headache, and swelling and/or pain in the hands and feet. Afinitor’s side effects can include nausea, vomiting, diarrhea or constipation, an unusual taste in the mouth, itching or skin rash, nosebleeds, mouth sores, high blood sugar, lung inflammation and headache and other cold symptoms. In the trial of Lenvima and Afinitor, both regimens containing Lenvima sparked more serious or severe side effects in patients, mainly diarrhea and the presence of extra protein in the urine, which can indicate kidney damage.

Pasternak says that his quality of life has remained positive while participating in the trial of Avastin and Tecentriq. “I have been working full-time, have had a full social life, almost completed a year as president of the California State Bar, and had much travel within the state of California this year, flying to northern California about 25 times,” he says.

The newer treatments were approved as second-line therapies, to be used for patients whose cancer had returned following treatment, or whose cancer did not respond to treatment. Cabometyx, Opdivo and Lenvima were each approved for patients who had previously received treatment with anti-angiogenics, such as Avastin. Afinitor was approved for use in patients whose cancer had returned or progressed after they take Sutent or Nexavar.

“Right now, we don’t necessarily know which factors drive benefit with one drug over the other,” Pal says. “I tend to favor cabozantinib in second-line treatment because, with this drug, it’s really the first time we’ve seen a benefit in this setting for progression-free survival, response rates and overall survival.”

According to Thomas E. Hutson, D.O., Pharm.D., director of the GU Oncology Program at the Charles A. Sammons Cancer Center at Baylor University Medical Center in Dallas, Texas, therapy with VEGF inhibitors (Sutent or Votrient) is what most people should get first. The COMPARES trial, published in the New England Journal of Medicine two years ago, compared Sutent versus Votrient and showed that Votrient was not superior to Sutent, so patients generally receive either drug as their first therapy, he says.

Afinitor is no longer the first choice for second-line treatment, Hutson notes, with better options being Opdivo, Cabometyx, Lenvima plus Afinitor, or Inlyta. “To be honest, you probably want to give all four of those therapies at some point,” he says. “What we don’t know is what the sequence should be. You can’t give them all second, so you have to choose, and we don’t have comparative trials that show us which is the best therapy. Unfortunately, we don’t really have the data yet to tell us, without a doubt, that one drug should be given over the other. I think we’re waiting on future trials to help guide us as to what the optimal order should be.”

Taking the precision medicine approach is also important, meaning that doctors should know which targetable mutations, if any, are driving a patient’s cancer, says Toni Choueiri, M.D., director of the Lank Center for Genitourinary Oncology and the Kidney Cancer Center at the Dana-Farber Cancer Institute in Boston, Massachusetts. Taking into account each patient’s variability (genes, environment and lifestyle) should also play a role in choosing treatment. “I look at drugs that are more tolerable. I look at the side effect profile of each drug and at the patients,” he explains. “If a patient has an established autoimmune disease on therapy, this person should not have novel immunotherapy. If you have a patient who struggled with severe hypertension and intolerable tyrosine kinase inhibitor side effects even after dose reduction, maybe I wouldn’t move to one that has a similar side effect profile.”

Finding an effective treatment means also finding therapies that patients can take without impacting their quality of life so much that they will discontinue their regimen. This was a problem faced by many patients who were treated with IL-2, which could cause flu-like symptoms; rapid heartbeat; low blood pressure; swelling of the hands, face, and feet; and difficulty breathing, to name a few. IL-2 is given in the hospital, often in the intensive care unit, because all or nearly all patients experience serious side effects and may need medical support. A 2015 review that looked at a variety of studies done on the side effects of IL-2 indicated that low blood pressure was perhaps the most common side effect; one study found that it occurred in 92.6 percent of enrolled patients taking low-dose IL-2.

“The side effects associated with low-dose (720,000 IU/kg) intravenous treatment were not trivial,” the review states. “More than half of the treatment courses were discontinued due to intolerable side effects.” As a result, Hutson says, IL-2 has “fallen out of favor,” and is mostly not given to patients with advanced RCC anymore.

The side-effect profiles of the newer treatments are significantly less severe. For example, results of the phase 3 METEOR trial show that serious or severe side effects affected 39 percent of patients who took Cabometyx, and 40 percent who took Afinitor. Twelve percent of the first group stopped treatment, and 11 percent of the second group. The most common side effects from Cabometyx were diarrhea, fatigue, nausea and decreased appetite.

Messinger, for one, has been satisfied with her experience on the newer drugs. They’re allowing her to look forward, she says, to watching her grandchildren grow. “I have a new one on the way, and a 3-year-old,” she says. “I think I’ll be around awhile. I will keep fighting.”

Given the new research and what is coming down the pipeline, oncologists experienced in treating advanced RCC are encouraging patients like Messinger to be hopeful. “The future is actually bright,” Choueiri says.

“This is a positive thing in 2016 compared to what we had in 2005 and even in 2010,” Choueiri says. “Patient survival is more prolonged. People are living two, three and four times longer. The future is brighter and brighter.”

The treatment landscape for advanced kidney cancer has changed dramatically over the past few years, with several targeted drugs and an immunotherapy approved by the FDA.

Marijke Vroomen Durning, RN

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