Jeanne Erdmann

The story unfolds in a way familiar to many men: A routine blood test brings news of an elevated prostate-specific antigen (PSA) level. It’s nothing alarming, until infection and benign prostatic hyperplasia are ruled out. Then a biopsy reveals a small tumor that probably won’t endanger health in the long run, but it brings a long consultation with a urologist and a list of treatment options that carry a payload of worrisome long-term side effects.

That’s how Jim Cassell of Silver Spring, Md., learned of his prostate cancer. In 2011, his primary care physician noticed a rise in the level of PSA in Cassell’s blood compared with the previous year and suggested he have a follow-up PSA test. Subsequent levels measured over the next few months showed another increase, sending Cassell to a urologist, who ordered a biopsy. The results showed a very small tumor in one area of his prostate and undetermined “suspicious” activity in two other areas. Fortunately, Cassell was considered low-risk, meaning his cancer would be unlikely to shorten his life. Still, he says, “just the idea that you have cancer is kind of a blow.”

Diagnosed with a small, localized tumor in his prostate, Jim Cassell weighed numerous treatment options before choosing active surveillance. [Photo by Daniel Peck, Peck Studios]

He needed to make a decision. One urologist recommended brachytherapy, a type of internal radiation treatment. Cassell, 64 at the time, wanted to wait; his wife was less certain. He contacted the National Cancer Institute (NCI) about a clinical trial testing magnetic resonance imaging (MRI) scans as part of a surveillance program that keeps an eye on men who have low-risk cancers to help them stave off surgery, perhaps forever. Cassell liked the idea, but couldn’t get an appointment for months. He sought out another practitioner, a urologic oncologist at Johns Hopkins Hospital in Baltimore; this one suggested that surgery might be the best approach. Physicians worried that the rapid change in his PSA level — something called PSA velocity &mdash; might point to an aggressive tumor. Still, the tumor was small and confined to one area, so he did more research. “I put two and two together and thought, ‘This is cancer, and it’s not good news, but it’s not like I have to do something tomorrow.’”

A member of a local prostate cancer support group encouraged Cassell to pursue the NCI trial, even though there was a wait. Cassell did, and underwent an MRI scan and a biopsy, both of which confirmed a very small tumor in one section of his prostate. The areas previously deemed “suspicious” showed nothing.

Cassell has been participating in the active surveillance program at the NCI for several years. A yearly PSA test and a multiparametric, or extra-sensitive, MRI monitor his tumor. “My last MRI in early 2015 showed no change in the lesion from the previous year,” Cassell says.

American men face a 15.3 percent lifetime risk of developing prostate cancer, but the risk of dying from the disease is only 2.7 percent. Men with localized disease enjoy a nearly 100 percent survival rate over five years. In fact, a study published in 2012 in the 

 concluded that among men with localized cancer — most of whose cancers were diagnosed after PSA testing &mdash; removing the prostate made them no less likely to die from prostate cancer within 10 years than had they done nothing more than active surveillance. Prostate removal did benefit the subset of men who had aggressive disease.

The numbers are less encouraging, however, for men with aggressive disease based on the histological grade (Gleason score) and sites of spread. Once prostate cancer spreads, the five-year survival drops to 31.9 percent. Doctors have a growing number of tools that can help identify “advanced” cancers, which in turn can help them predict outcomes and offer patients an array of treatment alternatives. Yet the most widely used tool, the PSA test, is also the most controversial because of its high rate of false positives.

PSA levels can fluctuate, and levels that go up and down like a roller coaster don’t necessarily point to prostate cancer, explains Herbert Ballentine Carter, a professor of urology and oncology at Johns Hopkins University in Baltimore. But because rapidly rising PSA levels can flag an aggressive cancer after benign causes have been ruled out, doctors can use that PSA velocity to the patient’s advantage.

“I don’t think any urologist in the U.S. is going to ignore a PSA that’s exponentially increasing,” Carter says.

Other tests can be added to the PSA test to ensure a more accurate diagnosis. Researchers are working to find a noninvasive way to detect prostate cancer by looking for biomarkers in seminal fluid or urine. These biomarkers may help identify cancers that are less or more aggressive and, perhaps, eliminate the need for biopsies.

The Prostate Health Index is a blood test, approved by the FDA in 2012, that takes into account subtypes or variations of PSA to help determine whether biopsies are warranted in men with PSAs between 4 and 10 ng/mL. 4KScore is another system for checking blood to help determine which men with elevated PSAs, if biopsied, will turn out to have high-grade disease.

In 2012, the FDA also approved the PCA3 (prostate cancer gene 3) gene test. Prostate cancer cells overexpress PCA3 RNA, which can be detected with a urine test. The test can be used, for example, if the PSA level is high but a biopsy is negative. Another genetic test of urine carries the long name TMPRSS2:ERG. In some cancers, genetic material rearranges itself and then fuses together. The unhealthy combination of 

 genes wreak havoc in the prostate because they spark a cascade of events that lead to the development of prostate cancer. Yet even that test is imprecise.

Also available to help men discern whether they might benefit from repeat biopsies are ConfirmMDX, the Prostate Core Mitomic Test and the PTEN prognostic assay, which look differently at tissue collected in an initial biopsy.

Men can also get hung up on their numbers by thinking that a higher PSA level always means a worse cancer, but that’s a false assumption. “You can have a PSA of 50 from a bad prostate infection and a bad type of prostate cancer with a PSA of 1.5,” says Oliver Sartor, medical director of Tulane Cancer Center in New Orleans, adding that he gets his own PSA levels checked even though the test “is far from perfect.”

In recent years, there’s been a rise in the percentage of men with low-risk prostate cancer who initially opt for active surveillance.

Of men with low-risk disease tracked in two large U.S. databases, between 13 and 21 percent chose active surveillance in 2004; those percentages rose to between 20 and 32 percent in 2010.

Yet once a PSA test leads to a biopsy and then to a low-grade cancer diagnosis, some men want that cancer removed, and removing only part of the prostate is not an option.

“Men are not comfortable with doing nothing when faced with a cancer diagnosis,” says Richard Hoffman, a professor of internal medicine at the University of New Mexico in Albuquerque, which is why the phrase “watchful waiting” is problematic. “Patients don’t want to hear, ‘You have prostate cancer, but don’t worry. If it looks like it’s going to cause problems, we’ll do something to treat your symptoms,’” he adds. “‘Active surveillance’ seems more acceptable because we’re not ignoring the cancer.”

In response to the trend toward overdiagnosing and potentially unnecessarily treating some cancers, a working group of the NCI recently published recommendations on the definition of cancer. It suggested that many lesions detected during prostate cancer screenings should be referred to as “indolent lesions of epithelial origin,” not “cancer.”

Deciding whether to choose active surveillance is something doctors and patients should accomplish through a dialogue, suggests Mitchell C. Benson, the Herbert and Florence Irving Professor at Columbia University Medical Center, New York- Presbyterian Hospital.

He said he goes through a PowerPoint presentation with his patients to help them understand the factors in choosing active surveillance versus active treatment, including their biological and chronological age and the details of their disease. “Going on active surveillance is a risk assessment,” Benson says. “Active surveillance doesn’t mean no treatment ever. It just means no treatment now, and that’s an important thing for the patient to understand.”

Indeed, although they are not immediately treating cancer, active surveillance programs have the intent of still being able to cure the disease by providing treatment if necessary. Hoffman says sometimes the program is dubbed “proactive” to give men an even higher comfort level. The type and frequency of monitoring varies. In general, men are monitored via frequent PSA tests, perhaps every six months, possibly with MRIs and biopsies conducted every couple of years. A change for the worse in any of these tests can reclassify cancer to the intermediate or high-risk category. Even this treatment option comes with issues that need to be considered.

One criticism of active surveillance is that men might worry more between testing, knowing that the cancer is still there. Cassell hasn’t found that to be the case.

“I don’t dwell on it, but I do think about it,” he says. “Is there any certitude in life about anything? I have as much information as I can get at this point, given what we know about these things.”

If any of his test results worsen, Cassell says he will come out of active surveillance, and he’s emotionally ready for that, as well. “I’ll say, ‘We do what we’ve got to do here.’”

Another issue for men on active surveillance is that every biopsy raises the risk of serious infection because prostate tissue is sampled close to the anus. Men might have previously taken antibiotics, increasing the chances that bacteria in their stool have developed a resistance to a common antibiotic. Puncturing the prostate could then carry resistant bacteria into the gland, making the men sick enough to be hospitalized.

Because biopsies give a limited view of the prostate, some medical centers are using powerful MRIs to confirm or monitor the size of the tumor or for preoperative staging. An emerging trend is the use of multiparametric MRI, in which imaging is done in several sequences that allow physicians to see the prostate, blood flow and water movement, increasing the accuracy of the test and, ideally, reducing the number of false positives; this is the type of MRI Cassell receives when he’s screened by the NCI. Not all men have access to a medical center with that type of MRI scanner or to radiologists trained to interpret the images, but the technology is becoming available at more centers all the time.

As MRI techniques improve, calling for an MRI rather than a biopsy might be “the preferred way of evaluating a guy with elevated PSA,” says Gerald Andriole Jr., a urologic surgeon at Washington University School of Medicine in St. Louis.

Evaluating biopsy tissue for gene mutations might help physicians predict which tumors will spread. GenomeDx launched a new genetic test called Decipher. Other tumor genetic tests include Myriad Genetics’ Prolaris and the Oncotype DX test from Genomic Health. In addition, ProMark, which uses immunofluorescent imaging to classify tumors, entered the market in 2014. These tests analyze tissue from prostate biopsies for gene activity that points to how aggressive the cancer might be. Doctors can use the tests in several ways. For men on active surveillance, the tests might be able to help determine whether to keep a patient in a particular treatment program. The tests also can be used on prostate tissue following radical prostatectomy to help physicians evaluate the risk of whether the cancer will recur.

Out-of-pocket costs for such tests can range from $375 to around $3,800. Coverage depends on insurance plans, but companies offer assistance with appeals and also patient financial assistance. “It’s hopeful that these tests, if they show that cancer is aggressive, could be enough to switch a guy from active surveillance to treatment,” Andriole says. “If it confirms it’s not aggressive, then everybody sleeps a bit better knowing that we’re not undertreating the issue.”

The most important thing to remember about prostate cancer is to keep the disease in perspective, Carter says. “Prostate cancer is not the most common cause of death in men — it is below cardiovascular disease and diabetes,” he adds. “People are afraid when they hear the word ‘cancer’ because they think it’s automatically deadly and want aggressive treatment. So, we work with patients to help them make a careful decision.”

Articles

New ways to find prostate cancer and gauge its aggressiveness help patients make better choices.

On Guard: Gauging Aggressiveness of Prostate Cancer Aids Decision Making

	Some minor pains and aches can be safely ignored; others could land a patient in the intensive care unit, or worse. The best defense is to be prepared, beginning the day of the cancer diagnosis.

	When patients leave the hospital or doctor’s office after a cancer diagnosis is confirmed, they should have a written description of the type of cancer they have, the stage, the treatment and the monitoring plan. They should ask the doctor which signs and symptoms could signal complications from the cancer or the treatment that would warrant a trip to the emergency room, and how they differ from signals that the cancer is progressing. Patients should also ask how to reach the practice after hours, because it is always better to reach someone who knows their case or has access to their records.

	Once home, patients should make a one-page fact sheet listing the phone numbers of their care team, the name of the cancer, the type of treatment they’re receiving and where the cancer is being treated. They should also make certain that caregivers and family members have this information. If patients must visit the emergency room, it is preferable to have the on-call oncologist telephone in advance to provide ER personnel essential information and to help coordinate care. “This is just common sense, but it’s amazing when you’re in the midst of an emergency how hard it is to think of those kinds of things,” says Deborah Mayer, an advanced practice oncology nurse and researcher at the University of North Carolina in Chapel Hill.

[Preparing for a Cancer-Related Emergency]

	Caregivers need to be aware of possible issues because patients can miss the significance of certain symptoms, such as severe pain, weakness or delirium, which require immediate attention.

	In general, it’s better to be overcautious and report symptoms right away. Patients might need to be persistent, especially if they’re not getting the attention they need. “What we want to do is tell people if something is worrisome or bothersome, it’s a phone call away from either having their mind put at ease or to pick up a potentially serious problem earlier,” Mayer says. 

Be prepared, cautious and report certain symptoms to your medical team immediately.

What to Know Before You Go

	Carmen Gonzalez, an associate professor of emergency medicine at MD Anderson Cancer Center in Houston, still remembers a patient who came to the emergency room 15 years ago. An internist by training, she had just begun working at MD Anderson.

	The patient was a man in his 40s, a husband and father with sarcoma who was undergoing chemotherapy and had ignored a fever of more than 101 degrees Fahrenheit. The fever raged for one day, then two and then three. By the fourth day, he was so drowsy that his wife brought him to the ER. But it was too late. His cancer was survivable, but he died of sepsis, a severe blood infection that can result from a chemotherapy-induced low white blood cell count.

	Gonzalez could have saved the patient from this oncologic emergency with antibiotics and intravenous fluids if only he’d come for help earlier. “His wife had to live with the sorrow of thinking his death could have been prevented, and their children had to live without a father—just because they thought he would get better,” she says.

	Deborah Mayer, an advanced practice oncology nurse and researcher at the University of North Carolina in Chapel Hill, says oncologic emergencies fall into two categories: those that can be prevented or managed early and those that are urgent. Serious oncologic emergencies requiring immediate medical attention include uncontrolled pain or bleeding, seizures and delirium.

	Other symptoms may not warrant an immediate trip to the ER or a call to 911 but should be brought to the attention of healthcare providers to prevent a bad situation from becoming life-threatening. Basically, Mayer says, if symptoms are new or are getting worse, they should be brought to the attention of the patient’s cancer care team. “The real trick is to get the problem evaluated and let an oncology specialist decide the best approach,” she says. “If the patient doesn’t talk about the problems, it’s hard for the provider to guess.”

	Not everyone who has cancer is at risk for an oncologic emergency, but all patients and their caregivers need to be aware of and to prepare for such a possibility. In fact, preparing for an emergency ahead of time can save precious minutes when patients end up in an emergency room that’s not affiliated with their care team. Most hospitals in the U.S. are not linked together via electronic medical records, so emergency room physicians, such as Gonzalez, often work in fits and starts when patients come through the doors already critically ill as they wait for patient records.

	Gonzalez had a patient recently who came into the ER complaining of excruciating pain. She knew nothing about him other than his symptoms. The patient and family members could not tell her what diagnosis had been given, nor the treatment provided. They just knew he had “cancer.” But because he had jaundice and abnormal lab tests, he was sent to the intensive care unit. She says caring for him in the ER would have been much easier if she’d known right away what type of cancer he had and how the disease was being treated.

While symptoms such as pain and fever may be universal, oncologic emergencies can be cancer specific. Doctors evaluate and treat oncologic emergencies depending on many factors, including the type of cancer, the stage of the disease, the type of treatment, and whether the goal of treatment is curative, life extension or palliative.

For example, a cancer emergency will be handled differently for the patient who has a small tumor and expects to be cured than it will be for someone with advanced disease who may not have much longer to live, says Timothy Moynihan, an oncologist at the Mayo Clinic in Rochester, Minn. Although it’s difficult for doctors to foresee every scenario, Moynihan tells his patients a general set of rules. If they have mild symptoms, then they can probably wait a few days to call. For example, patients who develop symptoms of a cold when others in the household have colds might not be a cause for alarm. However, if symptoms worsen over time or if the patient is the only one in the household who is ill, it may be time to call the oncologist.

	A fever of 101 degrees Fahrenheit or higher should never be ignored in someone actively receiving chemotherapy, Moynihan says. Such a patient should have a blood count checked to determine the treatment and the urgency of this situation. A new headache can mean something different for a person with brain cancer or potential brain metastases than it could for a patient without a history of cancer. “There are a wide variety of issues, and we try and tailor them to what we might anticipate patients will have, based on underlying disease,” Moynihan adds.

	The key is for patients to bring any problems to their doctors’ attention right away, so the issue can be monitored. “If they wait and a family member calls and says the person is not responsive and the temperature is 103, that’s a problem,” Gonzalez says.

	Another problem for people with cancer is that they often have no idea of what to expect, Moynihan says. Patients generally fall somewhere in the middle of the worry spectrum, from being overly anxious to almost unemotional, he adds. “It’s hard to talk about cancer patients as the ‘worried well.’ Some patients call too often because they’re scared all the time. Then some patients are too stoic and don’t want to call and bother the doctor,” Moynihan says. “Those are the ones to whom you really want to say ‘please call me.’ ”

	Gonzalez says she hopes that emergency room physicians will learn to think more broadly about oncologic emergencies for patients with incurable cancer. “It’s very easy to quickly intubate a patient in the ER,” she says. “It takes five minutes for a patient who is short of breath.” But intubation may not reflect the wishes of certain patients or their families.

	For patients with end-stage disease, Moynihan emphasizes that the answers aren’t so simple. There comes a time when oncologists will tell family members or patients not to call 911. For example, when the cancer has progressed to its final stage and the patient experiences an oncologic emergency, it might be best to contact the hospice care team, he says.

	Gonzalez says it’s better to act with an abundance of caution. Chest pain might not have anything to do with the cancer, but it could be a sign of a heart attack. “Don’t ever assume,” Gonzalez says. “We can take care of your cancer, but you could die of a heart attack.”

	> Patients can prepare for oncologic emergencies by knowing detailed information about their cancer and treatment.

	> If mild symptoms worsen over time, it may be necessary to call the oncologist. 

Know which symptoms call for immediate action and which can be safely ignored.

Preparing for a Cancer-Related Emergency

The body’s ability to process drugs is influenced, like so many things, by our genes. Our genetic makeup controls how quickly or slowly the liver breaks down medications, as well as how effectively they’re transported throughout our body. Every step in the sequence determines how much of a drug our bodies absorb.

If we metabolize certain drugs too slowly, the medication will build up in the bloodstream. A standard drug dose might be too much for some patients, and the side effects magnified. On the flip side, people who metabolize medications too quickly may not benefit from a standard dose, says Richard Weinshilboum, a pharmacogeneticist at the Mayo Clinic in Rochester, Minnesota. 	

One of the earliest discoveries of gene-drug interactions came in 1989 when Weinshilboum discovered that reactions to certain drugs, called thiopurines, could be inherited (thiopurines are used to treat children with the most common type of leukemia). Children who can't metabolize these drugs may have an adverse reaction if they take them. 

"If your body can't metabolize the drug it's like getting an overdose," Weinshilboum says.	

Today, a laboratory test can tell doctors which patients should and should not take thiopurines. The field of pharmacogenomics uses all 22,000 genes or so to tailor a drug and its dose to an individual's genetic makeup. Such information can predict how patients will react to certain drugs, which can help minimize bad reactions and maximize a drug's effectiveness. 	Research has found that a gene called CYP2D6 plays a role in the way tamoxifen is metabolized in women with estrogen receptor-positive breast cancer. Doctors can use this information to identify women who might respond best to the hormone therapy, although its routine use is still controversial. However, most cancer drugs are still used without pharmacogenetic guidance.	

On the horizon are laboratory tests to predict which individuals will experience chemotherapy-induced long-term and late effects, such as hearing loss, cardiac toxicity and neuropathy. Eileen Dolan, a professor of medicine at the University of Chicago, is working to identify genetic markers to make such predictions. 

"These patients can have a poor quality of life, or may need their chemotherapy dose reduced, which could compromise outcome," Dolan says.

	She and her colleagues presented research at the annual meeting of the American Society of Human Genetics last October showing that similar genetic variants were associated with neuropathy after paclitaxel. Dolan's team hopes to use the information to identify new agents to treat or prevent neuropathy. Although using genetic markers to identify patients at risk for neuropathy is still unrealized, "the technology is advancing quickly," Dolan says.

The body’s ability to process drugs is influenced by our genes.

Drug Reaction in the Family Tree

	Mark Roll’s pulmonary doctor was so astonished to learn that his stubborn cough was due to lung cancer that he tracked Roll down on a warm June evening in 2012 to tell him right away. The call came on Roll’s mobile phone as he napped in the car, awaiting his wife and daughter, who were shopping. Roll had never smoked, and the doctor suspected his cough might have come from exposure to a fungus on a trip from the previous year. Roll wondered about that trip, as well: How could he have hiked 63 miles over 12 days in Cimarron, N.M., at an elevation of 12,000 feet with 50 pounds of gear and supplies in his backpack, yet apparently be so sick now.

	Not only did the diagnosis confirm Roll had lung cancer but scans found tumors in both of his lungs, his bones and in his brain. A special test of the tumor revealed something else: it contained a mutation in the EGFR gene, which happens more often than not in nonsmokers who develop lung cancer. Often, the results of these special tests can help in all stages of cancer treatment. In Roll’s case, his tumor’s EGFR mutation was a perfect target for Tarceva (erlotinib).

	Roll started on Tarceva as soon as his mutation was identified, and the treatment allowed him to put cancer in the rearview mirror for the time being. His brain tumors are dwindling, his right lung is clear, and the tumors in his left lung are stable. His stamina returning, the 53-year-old was able to dance for hours at his oldest daughter’s wedding. “Until that day they put me on oxygen I’m not going to worry about it,” Roll says.

	Biomarkers are changing the way doctors diagnose, treat and monitor cancer. Tests for biomarkers can find misbehaving genes or other telltale signs that can help with treatment decisions. These tests might be as simple as using a chemical detection method that stains certain proteins in cancer cells or as elaborate as genetic sequencing to determine a specific mutation unique to cancer cells but not found in healthy cells.

	Traditional chemotherapy has been more of a one-size-fits-all approach, with some patients responsive and others not. Now, instead of giving people a simple diagnosis of lung cancer or breast cancer, doctors often are able to provide much more detailed information. “Diagnosing and treating cancer this way is a whole new ballgame, and that’s the beauty of it,” says Mark Kris, chief of thoracic oncology at Memorial Sloan-Kettering Cancer Center in New York.

	In some types of cancer, treatments have been developed to target a mutation. For example, in non-small cell lung cancer, a mutation in the ALK gene makes an abnormal protein, which fuels the cancer. The drug Xalkori (crizotinib) is designed to block that protein. But if the cancer carries a mutation that is different from the drug’s intended target, there’s no reason to treat the patient with at drug that won’t work. In some cases, the presence of a mutation in a tumor may mean there are no effective targeted treatment options.

	Rick Ramos, 57, had already begun treatment for late-stage colon cancer in July 2012 when he learned that his tumor had a mutation in the KRAS (Kirsten rat sarcoma) gene. (The gene is named after Werner Kirsten, who discovered it in a cancer-causing virus in rats.) Ramos’ oncologist told him that having the mutation meant using two agents designed to target the epidermal growth factor receptor (EGFR), which makes a protein that’s essential to cell division, would be ineffective. Currently, there are no drugs to target KRAS mutations (although there is intensive research in that direction). At present, studies suggest that mutations in KRAS work together with other genes as part of cell networks, and that some of these other genes can be targeted by drugs.

	“Should these approaches be borne out in the clinic, there is hope that tumors with KRAS mutations may one day also be treated with targeted therapies,” says Daniel Haber, director of the Massachusetts General Hospital Cancer Center in Boston. “Even when a tumor responds dramatically to a targeted therapy, however, it can develop resistance to the treatment within a year.

	“Tumors adapt,” Haber explains. “And even the most effective therapies end up selecting for cancer cells that have developed mechanisms to overcome the drug. There are very specific ways in which cancer cells become resistant, often with additional mutations in the genes that were targeted in the first place and that prevent the drug from binding. As we begin to understand these, we can monitor for them and develop drugs that work against the resistant cancer cells.” Essentially, it becomes a race between the cancer’s ability to mutate and become resistant to treatment and the scientists’ ability to develop new drugs against the mutated genes.

	Ramos is taking a new regimen of Xeloda (capecitabine) and Avastin (bevacizumab) that, so far, is working. Xeloda is a chemotherapy that acts against fast-growing cells, and Avastin works against the signaling protein VEGF (vascular endothelial growth factor), which spurs blood vessel growth to the tumor.

	Biomarkers have not only changed the way cancer is diagnosed and treated but also the way doctors monitor a patient’s progress. During treatment, doctors can use biomarkers to learn if the cancer has developed drug resistance or if harmful side effects crop up. These telltale signs can show up as a protein in a blood test or a chemical reaction to chemotherapy.

	Kris says the best example of using biomarkers to choose and monitor treatment is chronic myeloid leukemia (CML). The drug Gleevec (imatinib) targets the weak spot in CML—the BCR-ABL fusion gene, which is the sole driver of the disease when it is in the “chronic” phase. As sometimes happens with cancer, the malignant cells develop drug resistance. With CML, researchers went back to the laboratory, Kris says, found the mutations that signaled resistance to treatment and developed new treatments. “We now have four or five drugs approved that can target those mutations,” he adds.

	While some biomarkers can point doctors to a definitive course of action, some are less definitive and can leave treatment decisions in a gray zone. For instance, breast cancer cells with extra copies of the HER2 gene make too much of the HER2 protein, a growth factor receptor that keeps cancer cells growing. However, additional factors to determine the impact of cancer response to HER2-targeted therapy are needed.

	In a study presented at last year’s annual meeting of the American Society of Clinical Oncology (ASCO), researchers found that a tumor’s response to HER2-targeted therapy Perjeta (pertuzumab) was linked to the actual amount of HER2 protein the cancer cells produced. A study by different researchers presented last year at the American Association for Cancer Research found that women with HER2-positive breast cancer, who also had a mutation in the PIK3CA gene did not respond as well to Perjeta, perhaps because the mutation overrides the HER2 overexpression. More validation is needed before these markers can be used to make risk/benefit decisions about the use of HER2-targeting therapies. Recently, mutations in the HER2 gene have been discovered in a variety of cancers, seen mostly in cases that do not overexpress HER2 and therefore test “negative” for HER2 and require gene sequencing to detect. In the laboratory, HER2 kinase inhibitors, such as neratinib, can block HER2 mutation-bearing cells, and clinical trials are now testing neratinib for several cancer types harboring this mutation. Phase I clinical trials (a test to determine dosing and safety) tested neratinib and another drug called temsirolimus and showed that diarrhea was the most common complaint.

	Even though advanced cancers eventually find their way around treatments aimed right at a tumor’s most vulnerable spot, there may or may not be effective alternative therapies once that happens. “I have known so many people who have survived their cancer because of advances in knowledge, advances in therapy, and in diagnostic tools,” Korc says. “People forget what happened in the 1970s, where no matter what we did for all kinds of cancers, some patients would be dead in a few months. Today many categories of cancer get diagnosed and treated successfully.”

When deciding on a cancer treatment&mdash;and determining its effectiveness&mdash;look for a biomarker.

Under the Microscope: Cancer Biomarkers

In 2010, while leading a focus group in Knoxville, Tenn., Joanne Buzaglo looked around the room and saw a group of people who appeared highly educated, well-dressed and comfortably middle class. She had been helping people with cancer cope with the social fallout of the disease for 20 years. By that time, she thought she’d seen and heard it all. But Buzaglo found herself speechless as, one by one, the people around the table described their struggles with one of cancer’s most toxic side effects: medical debt so crushing that it cost patients everything.

“It was the most poignant moment I’ve ever felt,” says Buzaglo, vice president of research and training for the Cancer Support Community. “People felt shame and worry, and they were often too overwhelmed to take action.” Buzaglo and her team convened similar groups across the country to update 

Frankly Speaking About Cancer: Coping with the Cost of Care

, a program aimed at helping people manage the cost of cancer treatment.

Health care is generally expensive, but cancer care tends to rack up the largest of medical bills—at precisely a time when people are least able to cope. Medical insurance cannot cover all the costs. Debt piles up quickly, and soon patients can find themselves fighting not only for their physical lives but for their fiscal lives, as well. To make matters worse, patients often have little or no control over the cost of services. Even when they are vigilant about choosing network providers, they soon learn that hospitals contract with providers who may be out of their network, triggering penalties on top of hefty expenses. And newly released data from the Centers for Medicare and Medicaid Services show that hospitals&mdash; even facilities in close vicinity&mdash;charge vastly different prices for the most common medical procedures. With so much out of a patient’s control, it’s more important than ever to craft a plan for managing debt from the cost of cancer care.

Early in their cancer experience, patients should develop an action plan for managing medical debt— one that includes evaluating their insurance and asking their healthcare providers if they provide financial assistance, discounts and extended payment plans, says Mark Rukavina, of Community Health Advisors. He urges patients to contact a social worker to get started identifying places that offer assistance, and then meet with a patient accounts representative and ask for help in assessing finances and applying for aid.

The worst thing anyone can do is to ignore a bill, Rukavina says, because it may be sent to a collection agency, triggering another set of complications, such as ruined credit. Reaching out to government leaders can sometimes help in identifying local, state or community services. “If people don’t ask for help, they’re not likely to get it,” Rukavina says.

Bob Kail and his wife, Patte, sought financial help following his diagnosis of late-stage colon peritoneal carcinomatosis in 2012. Four tumors in different areas brought extensive surgery, including the removal of his colon, and affected nearly every aspect of their lives, in addition to the lives of Patte Kail’s two children from a previous marriage. Because Kail had to use an ileostomy and couldn’t lift heavy objects, he could no longer work as a truck mechanic. The health insurance he received through his employer carried a $5,500 deductible, which Kail quickly met. But when his employer could no longer pay for Kail’s insurance, Kail had to obtain coverage via the Health Insurance Portability and Accountability Act, with premiums of nearly $700 a month.

People also need to scrutinize insurance statements for accuracy, and relentlessly pursue billing errors, says Karen Pollitz, a senior fellow at the Kaiser Family Foundation. In fact, the Commonwealth Fund’s 2012 Biennial Health Insurance Survey reported that in 2012, 4 percent of adults ages 19 to 64—an estimated 7 million people&mdash;were contacted by a collection agency because of an error on a medical bill.

Patients should ask a friend or family member for help in deciphering any charge that seems suspicious and figuring out what service may have been paid or denied incorrectly. Pollitz, who is also a survivor of cancer, recalls receiving insurance statements that were “cryptic and infuriatingly vague.” Many phone calls to the insurance company’s billing specialist, and many hours of persistence, may be necessary to track down exactly what services were rendered, especially when the insurance claim indicates something as indistinguishable as “medical services” or “laboratory services.” To obtain the proper information, patients may have to ask the insurer for every detail of a particular claim, the actual billing codes and the exact description of each service, as well as who ordered the service. Insurance companies are required by law to provide that information, Pollitz says.

Patients should follow up immediately with insurance companies, using the formal process of appealing a billing mistake or a treatment that’s been unfairly denied, and include all supporting documentation. “Don’t take the word of the customer service representative at the other end of an 800 number,” Rukavina says. “Pursue it formally and get a formal response. Copy the state attorney general or the state office of protection.”

“When you’re on Social Security, that’s 70 percent of your income,” Patte Kail says. “We worry. Bob especially worries, and he doesn’t need the extra stress. With Bob, I try not to discuss finances until I have to. We have a house with two and a half years left on a mortgage. I have a pre-teen and a teenager, and I still have to be able to give to them; this affects everyone.”

The Kails turned to their state representative for help but found none, so now they are seeking help from their U.S. representative in Washington, D.C. While awaiting Medicare eligibility, which typically takes two years, Kail applied for public assistance through the state of Pennsylvania, but his Social Security disability payments may mean that his income is too high. Many of Kail's out-of-pocket expenses aren’t covered, including 25 percent of the wound care supplies for his ileostomy and unhealed surgical incisions, as well as some of his home health care and a 50 percent share of ambulance bills.

The Kails are still paying a modest monthly amount toward four hospital bills and home health care from 2012, which they negotiated with the institutions. “They send you a bill for $1,500. You look at them and say, ‘Yeah, really,’” Patte Kail says. But help is available for those who qualify, she adds. She suggests seeking out a social worker for assistance with applications. A $10,000 grant from the CancerCare Co-Payment Assistance Foundation pays for Kail’s chemotherapy drugs but not for his steroids and antinausea medication. 

After Martha Jacobs of Chicago received diagnoses of breast and colon cancer between 2010 and 2012, she continued working through her chemotherapy and radiation treatments. But she lost her job—and her health insurance&mdash;in 2012, and had to obtain COBRA coverage. Jacobs had to deal with three different hospitals, calling each to set up an affordable payment plan.

“Each has been very helpful in taking what I can afford at the time of payment,” she says. “At a very stressful time, this has helped me in so many ways and has given me peace of mind and the ability to focus on what lies ahead.”

While a bill is in dispute, patients should call their doctor or hospital and inform the billing department of the dispute, explaining that they’re trying to sort it out and asking them to place the bill on hold. “Otherwise, the second they put the bill in the mail, a clock starts ticking, and often after 60 to 90 days, if the bill is not paid, it may be moved to delinquent status and sent to collection,” Rukavina says.

Another option: Patients can contact faith-based or other nonprofit organizations to ask if emergency funds might be available. Also, the federal government lists assistance programs at 

. Use the search terms “consumer assistance” to locate programs in individual states.

Additional potential funding sources for resolving medical debt include: 

> Viatical settlements (selling a life insurance policy to a third party) 

Some cancer patients choose to modify their mortgage by asking the lending institution to temporarily lower the interest rate and, thus, the monthly payments. Such a modification can still be added to a credit report and can negatively impact a credit rating, says Rodney Anderson, a mortgage lender in Dallas and author of 

. Plus, the fees and interest don’t go away but get added to the back of the loan.

With some clients, Anderson sees confusing medical bills going to collection agencies because patients believe they are not bills or that third party payers are handling them in total. “If you find an unpaid bill from a collection agency, call the agency and ask for a validation letter for the debt,” Anderson says. “But also ask the provider to remove the item from your credit report before you pay the bill, although by law they don’t have to.” Anderson is supporting two pieces of legislation under consideration in Congress: one would remove medical debt in collection from credit reports after the debt is fully paid or settled; the other would give a consumer 120 days to settle or dispute a medical debt with a debt collector before any adverse report is sent to a credit reporting agency.

Sometimes, regardless of how hard people try to resolve medical debts, bankruptcy remains the best option, or, as Anderson puts it, “losing the battle to win the war.” The authors of a recent study published in 

 analyzed a database of people who had received a cancer diagnosis in Washington state from 1995 to 2009 and found that they were “2.65 times more likely to go bankrupt than people without cancer.”

Bankruptcy may ruin your financial life, Anderson says, but bankruptcy isn’t the only thing that can ruin credit for years. Bankruptcy stays on credit reports for 10 years, but it can take seven years for a bad credit rating to be cleared, especially when the bills go to collection. Anderson cautions that credit agencies can sell unpaid debts to another collection agency, and then the seven years of bad credit starts over again. Personal bankruptcy avoids this action and can protect long-term assets, such as home equity and retirement funds.

People with cancer are sometimes reluctant to ask for help because they may not want to expose financial reserves, such as college and retirement funds. Rukavina tells them to face their biggest fears and ask themselves what they’re afraid of, and what they are afraid of losing.

“Weigh the money first, and understand where you are financially,” he says. “You have to be able to have an honest conversation. Sharing that information may be uncomfortable but necessary. Even ambulance companies will give people breaks.”

Editor’s Note: Bob Kail died on Nov. 26. 

Coping with cancer’s financial aftermath calls for creative solutions.

Debt Crisis: Coping with Cancer's Financial Aftermath

To steer clear of the avoidance trap, she suggests patients join a cancer support group, which can provide an encouraging environment in which they can feel safe enough to open up and learn how others in similar circumstances have managed. “Talking about feelings is easier than talking about money,” Buzaglo says.

She says patients should begin by setting up a spreadsheet detailing the date of service, the provider, the amount owed and whether the amount is in dispute. They should also keep a log of phone calls and never throw away anything. Many hospitals and physicians bill separately, so they will need to be contacted separately. As bills and insurance statements arrive in the mail, Buzaglo recommends putting them immediately into one place, even if patients aren’t in a position at the moment to sort and organize. Never ignore them. If patients have a friend or family member who is contacting insurance companies or providers on their behalf, it may be necessary to fill out forms giving them formal permission to speak on their behalf.

, provides information about how the healthcare reform legislation will impact cancer care, applying for various forms of government assistance, co-pay support and foundation programs, as well as multiple community resources. Download the book or order a print version from the Cancer Support Community website (

“I tell people that if they work with me, I will work with them, but people are so embarrassed,” says Rosalind Roberts, a clinical financial specialist at the Siteman Cancer Center in St. Louis. “These are the kind of people who have never asked for any kind of help. “Don’t be embarrassed,” she adds. “It’s not a stigma.”

The first and most important step people can take in developing a financial plan that deals with the financial toxicity of cancer care is to deal with avoidance, says the Cancer Support Community’s Joanne Buzaglo.

Frequently, people with health issues, such as cancer, will fret about the sorts of questions that might be asked by well-meaning colleagues, says Stephanie Smith, a licensed clinical psychologist who practices near Denver. “How much do I want to reveal to folks? How much do I want to keep private? How many times can I answer the same questions? It becomes a huge stressor.”

Patients should have a plan on tackling medical debt.

Crafting a Financial Plan

Children are often urged by well-meaning adults to eat plenty of fruits and vegetables. Well, that might also be the best advice for preventing certain types of cancer. Numerous epidemiological studies have shown that consuming fruits and vegetables is associated with a lower risk of cancer and 

During the past 20 years, many large clinical trials have tried to determine the cancer-fighting power of specific micronutrients (vitamins and minerals) in food by testing them in pill form in healthy men and women, in heavy smokers and in cancer survivors. Not only did large doses of micronutrients fail to prevent cancer, in some trials micronutrients increased the rate of the very cancer the trial was designed to prevent.

“The assumption that ‘oh, if a little is good, a lot can’t possibly hurt me’ has been proven incorrect,” says Susan Mayne, an epidemiologist at Yale University in New Haven, Conn.

People confuse the effect of micronutrients in a test tube and the effect of micronutrients in a body. They’re really different.

Micronutrients are trace substances found in food that help promote the growth of cells and tissues. Although the body needs only small amounts of micronutrients, their absence can produce serious health problems. For example, a lack of iron can cause iron-deficiency anemia, and a vitamin A deficiency can lead to blindness. People who don’t eat enough fruits and vegetables have a higher risk of developing some cancers. So it seemed reasonable for researchers to test whether micronutrient supplements offered the same protective benefits seen in whole foods. Recent data from several large trials proved otherwise.

A trial with the aim of preventing prostate cancer tested vitamin E and selenium in more than 35,000 healthy men. Results showed that men who took vitamin E alone had an increased risk of developing prostate cancer. A trial to test whether vitamin E and beta carotene could prevent lung cancer in 29,000 heavy smokers fared just as poorly. In participants receiving beta-carotene, the incidence of lung cancer increased.

Researchers administer high doses of supplements in clinical trials so they can be assured that those in the supplement group have notably higher nutrient status when compared with those in the control group. But “people confuse the effect of micronutrients in a test tube and the effect of micronutrients in a body,” says Alan Kristal, an epidemiologist at the Fred Hutchinson Cancer Center in Seattle. “They’re really different. It’s taken a while for people to appreciate that.”

Many researchers who specialize in micronutrients are offering a word of caution about micronutrient supplements, even for those who are survivors of cancer. Not only can they be expensive, but the Food and Drug Administration does not regulate supplements, and recent trials proved some supplements harmful. “I always have trouble with this because it’s so important for people to make their own choices, choose their own path and empower their own health. I don’t want to step on that but I don’t take vitamins, and I think it would be better if all cancer patients didn’t either,” says Tim Byers, a clinician and cancer epidemiologist at the University of Colorado in Aurora.

One large micronutrient prevention trial currently underway in the U.S. is testing whether vitamin D and omega-3 fatty acid might prevent colon cancer and heart disease. Vitamin D supplementation has been controversial because experts don’t agree about the health consequences of low vitamin D or whether low levels raise cancer risk or simply serve to identify people who are at higher risk due to other factors associated with low vitamin D.

“In the end it’s like Mom and apple pie,” Kristal says. “After decades, and after hundreds of millions of dollars of research, we discover you should eat an apple every day.”

Whole foods will always fare better than micronutrient supplements.


Whole Foods Help Against Cancer

Fruit juice can be refreshing and nutritious. Sometimes, though, certain ingredients in juice, particularly in grapefruit juice, can work against cancer therapies.

Natural doesn't always equal safe, says Mary Paine, a registered pharmacist and assistant professor at the University of North Carolina at Chapel Hill, N.C. More than 20 years ago, researchers discovered that grapefruit juice had compounds, called furanocoumarins, that could interact with certain medications.

Our bodies consider drugs as foreign substances and clear them away via enzymes called cytochromes, such as CYP3A4, which break down some oral medications, limiting the amount that reaches the bloodstream. Furanocoumarins block CYP3A4 in the intestine, preventing the enzyme from breaking down some anticancer agents. If CYP3A4 can’t work, too much medication might reach the bloodstream with potentially harmful consequences. High levels of a class of anticancer drugs (tyrosine kinase inhibitors) have the possibility to cause a heart rhythm so erratic that blood can no longer be pumped effectively to the body, causing cardiac arrest in some cases.

In addition to grapefruit juice, furanocoumarins can be found in pomelos (a cousin of grapefruits), limes and Seville oranges, which are used to make marmalade. David Bailey, a clinical pharmacologist at the Lawson Health Research Institute and professor emeritus at Western University in Ontario, Canada, discovered this interaction and emphasizes the need for education by a healthcare provider, such as a pharmacist or physician, before patients take a medication that interacts with grapefruit juice or foods that contain furanocoumarins.

Anticancer agents that could react negatively with grapefruit juice include: Xalkori (crizotinib), Sprycel (dasatinib), Tarceva (erlotinib), Afinitor (everolimus), Gleevec (imatinib), Tykerb (lapatinib), Tasigna (nilotinib), Votrient (pazopanib) and Sutent (sunitinib). Additional drugs that are being studied include cyclophosphamide, Nexavar (sorafenib), Capresla (vandetanib) and Zelboraf (vemurafenib).

There could be an upside to such interactions, however. One group of researchers is examining how to turn the negative action of grapefruit juice into a positive one by mixing grapefruit juice with susceptible anticancer agents, deliberately raising the blood levels of the drug. With more of the drug absorbed from one pill, the dose could be lowered and still be effective.

Taking less medication could ease gastrointestinal side effects and could potentially be less expensive, says Ezra Cohen, a cancer specialist at the University of Chicago. Cohen’s team recently published preliminary results of such an effort in Clinical Cancer Research. In the study, one group of people with incurable cancer drank a glass of grapefruit juice with Rapamune (sirolimus), an oral medication approved by the Food and Drug Administration to prevent rejection of organ transplantations. (The drug is not approved for cancer treatment.) The grapefruit juice boosted blood levels of Rapamune by 350 percent. Cohen’s group is working to extend their findings to larger trials.

It is not that grapefruit and related fruits or interacting drugs are bad. It's all about the circumstances of use.

But Bailey and Paine express concern that mixing grapefruit juice in such a manner would likely make blood levels of anticancer agents unpredictable, and there’s currently no simple test to forecast the intended response beforehand.

"It is not that grapefruit and related fruits or interacting drugs are bad," Bailey says. "It's all about the circumstances of use. Although these adverse interactions may occur in low frequency in the patient population, which we don’t currently know, the consequences [can be] dire and easily preventable. Caution is by far the wisest approach."

Grapefruit juice may interfere with some anticancer agents.

Grapefruit Juice: Forbidden Fruit?

So much of food’s appeal is wrapped up in the senses—sight, aroma and taste converge to make people hungry. One of the many injustices of some cancer treatments is that chemotherapy alters the senses to destroy appetite, which can weaken the body’s ability to fight disease. Some patients find the aroma of cooking so unappetizing they need to leave the kitchen. For others, fear of nausea can trigger anxiety over the sight of food. Chemotherapy can give food a metallic taste. Patients who aren’t hungry in the first place can find themselves eating less if food doesn’t taste good.

“Food is medicine. You have to eat to improve your chances of the treatment working,” says Gerald P. Miletello, MD, an oncologist at the Baton Rouge Clinic and co-author of 

Eating Well Through Cancer: Easy Recipes and Recommendations During & After Treatment

. “Patients and their families become obsessed with the fact that patients lose their appetites. It becomes a bone of contention between the patient and their caregiver. The constant nagging to eat makes one want to eat less.” 

A 2008 Swedish study found that of 518 patients, 75 percent self-reported taste and smell changes that were closely related to other chemotherapy side effects. Many chemotherapeutic agents can cause changes in taste. The reasons for these negative effects are unclear, but one possibility is that chemotherapy damages the cells in taste buds. Drugs or radiation to the head and neck can also stop saliva secretion, causing dry mouth, which also can make food less appealing. Worse, chemotherapy-induced changes in taste and smell can linger for weeks, with one small study showing recovery taking up to three months.

Because people undergoing chemotherapy are seldom driven by hunger, Miletello and Leni Javier, a registered dietitian at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, offer these suggestions to maintain good nutrition during and after treatment:

> Eat small amounts of food on a schedule throughout the day.

> Try sucking on a thin slice of lemon or mint hard candy prior to eating to stimulate taste buds (not recommended for patients with mouth sores or sore throat).

> Eat more at breakfast because the chance of being hungry is greatest at this time of the day. 

> If the aromas of cooking are bothersome, get help with food preparation and get out of the kitchen, or eat cold, non-fragrant foods, such as chicken salad, cheese or yogurt. 

> Make the dining experience as pleasant as possible. 

> Create distractions by turning on the TV, reading a newspaper or eating with friends who can provide good conversation. 

> To get rid of food’s metallic taste, use plastic utensils. If red meats taste bitter, eat chicken or other types of protein, or use marinades to enhance flavor.

> Consult with a registered clinical dietitian for a nutritional assessment and intervention during cancer therapy and for recovery.

One key to tolerating chemotherapy is maintaining enough reserves to deal with side effects. Weight is one measure of those reserves, says Joel Picus, MD, a medical oncologist at the Siteman Cancer Center. When patients lose weight, they lose muscle mass, and weakened bodies lack energy to do much. 

“If you are going to hike Mount Everest or run a marathon, you wouldn’t want to be weak and undernourished,” Picus says. “It’s not just weight, but also strength and ability to exercise.”

Coping with appetite changes from chemotherapy.