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.

Jeanne Erdmann | Contributors

On Guard: Gauging Aggressiveness of Prostate Cancer Aids Decision Making

What to Know Before You Go

Preparing for a Cancer-Related Emergency

Drug Reaction in the Family Tree

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