Leah Lawrence

Darryl Elzy, 60, an Air Force retiree from North Carolina, has been living with prostate cancer for about 12 years and has been a participant in clinical trials almost as long.

“Every time they offered me a trial, I said, ‘Sign me up!’” Elzy says.

Earlier this year, Elzy completed a clinical trial — his third — testing PARP inhibitors, a class of drugs that is new to the treatment of prostate cancer. PARP is an enzyme in cells that helps repair DNA when it becomes damaged. The inhibitors can block PARP in cancer cells, keeping them from repairing their damaged DNA and causing them to die.

PARP inhibitors were first approved by the United States Food and Drug Administration (FDA) in 2014 to treat certain ovarian cancers and, more recently, to treat breast cancers. In May, two PARP inhibitors became the first in their class approved as therapies for certain metastatic prostate cancers, ushering in a new era of treatment with targeted drugs. 

While drugs that suppress the hormones that fuel metastatic prostate cancer are the mainstay of treatment, PARP inhibitors can help certain patients whose disease has become resistant to those medications.

In particular, the patients most likely to benefit from PARP inhibitors are those who have tumors with DNA repair defects. It is for those patients that Lynparza (olaparib) and Rubraca (rucaparib) are intended.

“Our bodies have mechanisms in place to repair damage that happens to our DNA,” explains Dr. Veda N. Giri, director of cancer risk assessment and clinical cancer genetics at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia. DNA damage happens on a daily basis and can be caused by things such as exposure to ultraviolet light, radiation, cell turnover or substances in the environment.

“DNA houses genes that act as the control center for our cells and tell the cells what to do,” Giri says. “If DNA is damaged in the region that houses those genes — called DNA repair deficiency — it can lead to improper signals and result in disease conditions such as cancer.”

Mutations in DNA repair genes can be acquired, meaning that the mutation develops in the tumor as it grows, or they can be inherited, meaning that the glitches are present throughout the body in all of a patient’s cells.

“Reports state that about 25% to 30% of men with metastatic prostate cancer have acquired, tumor-only DNA repair deficiency mutations, and about 12% to 17% of men have inherited mutations,” Giri says. “For men with earlier-stage prostate cancer, about 5% to 7% have inherited mutations.”

Among the most common DNA repair deficiency mutations are BRCA1 and BRCA2 gene mutations and a mutation in ATM, a “BRCA-like” gene also involved in DNA repair, Giri says.

DNA repair deficiencies affect signaling pathways, strings of chemical reactions that pass messages to a cell from its environment about how to behave. Pathways are associated with proteins encoded by specific genes.

When cancer cells have a DNA repair deficiency in the BRCA pathway, for example, the cells adapt and use an alternative pathway to repair themselves. PARP is one of those pathways. Using PARP inhibitors in patients who have an existing DNA repair deficiency delivers a one-two punch (known in scientific terms as “synthetic lethality”) to the cancer cells, which leads to cell death.

The exact percentage of men with DNA repair mutations who will benefit from these drugs is still being established, according to Dr. Joshua M. Lang, associate professor of hematology, medical oncology and palliative care at the University of Wisconsin School of Medicine and Public Health in Madison. That is because, for many years, it was thought that genetics were not as important in prostate cancer as in other cancers.

“Fundamentally, this is all a new area in prostate cancer,” Lang says. “In the last five years, we have become aware of genetic changes associated with prostate cancer not just in the tumor cells, but also in genes that can be inherited.”

Previously, the majority of genomic testing was done in samples taken during prostatectomy, meaning the surgical removal of the prostate, Lang explains. While inherited mutations can be found through tests of blood, saliva or tissue samples, experts are learning that acquired mutations — the ones that occur in the cancer as it grows — are not always present in the prostatectomy sample and may only appear later in biopsies taken from metastatic sites.

Elzy received a diagnosis of prostate cancer when he was 48. Although the average age at diagnosis is about 66, men found to have an inherited BRCA2 mutation are more than four times as likely than those without the mutation to receive a diagnosis before that age. Compared with men who don’t have the mutation, the risk of prostate cancer is more than eightfold higher for men who have the BRCA2 mutation and are 65 or older.

Elzy was initially treated with radiation and a prostatectomy to remove the tumor.

“My doctor realized that a portion of my cancer was outside of the margin of being able to remove it, so I knew that there was still the possibility of lingering tumor that we couldn’t reach,” Elzy says.

To address the lingering cancer cells, Elzy underwent chemotherapy, but his blood level of the protein prostate-specific antigen (PSA) — which often rises in response to the growth of prostate cancer — continued to increase. That is when his physician began to look for clinical trials.

“My first two trials both had good results to start, but all of a sudden the PSA would start rising again,” Elzy says.

Eventually, his doctor decided that Elzy should be sent for genetic testing. The National Comprehensive Cancer Center now recommends that all men with metastatic prostate cancer undergo blood tests to determine if they have inherited DNA repair deficiency. Testing can also be done on tumor samples to look for acquired mutations.

Elzy’s results revealed a BRCA2 mutation that his doctors suspect he inherited from his mother, who died of breast cancer in 1992. If genetic testing had been more advanced back then, Elzy, who has no siblings or children, likely would have been advised to undergo genetic testing to find out if he had inherited the mutation.

Dr. Maha Hussain, deputy director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University’s Feinberg School of Medicine in Chicago, noted that, at the moment, having information about inherited mutations does not change the initial approach to treating newly diagnosed prostate cancer. Similarly, knowing a patient is BRCA-negative when newly diagnosed does not eliminate the possibility that the tumor will acquire a mutation as it grows.

“This could all change as our knowledge improves,” Hussain says. However, in her practice, Hussain says she has begun to send tissue for testing in men with high-risk, 

hormone-sensitive disease or prostate cancer that has recently stopped responding to hormone-suppressing drugs. “Getting prepared and ahead of the game is the best approach,” she says. “Clearly, testing for germline has implications for blood relatives, and I offer patients the opportunity.”

In Elzy’s case, once he learned that he had an inherited mutation, he was quickly recruited into a clinical trial of a PARP inhibitor.

Lynparza and Rubraca are the only PARP inhibitors approved by the FDA so far for men with metastatic castration-resistant prostate cancer (mCRPC), meaning disease that has spread beyond the prostate and has progressed on hormone-suppressing treatments. Lynparza is approved to treat men with cancer that progressed after treatment with one of two hormone-based prostate cancer therapies, Xtandi (enzalutamide) or Zytiga (abiraterone). 

To be eligible, patients must have a mutation in one of the homologous recombination repair (HRR) genes, specifically BRCA1, BRCA2 or ATM, which constitutes a DNA repair deficiency. Patients can be selected as good candidates to receive the therapy based on the results of an FDA-approved companion diagnostic for Lynparza.

Rubraca is approved for men with mCRPC and a BRCA1 or BRCA2 mutation who have received treatment with androgen receptor-directed therapy and a taxane-based chemotherapy.

Lynparza was approved based on the results of a clinical trial comparing the drug against Xtandi or Zytiga. Men with BRCA1, BRCA2 or ATM mutations were assigned to treatment with Lynparza, while men with any of 12 other mutations associated with HRR were given Xtandi or Zytiga. Men treated with the PARP inhibitor went twice as long before experiencing disease progression (7.4 months versus 3.6 months), and early data showed that their overall survival was nearly five months longer than those in the group that received hormonal treatment (19.1 months versus 14.7 months). 

In patients who had tumors that could be measured, about one-third of those who received Lynparza saw their tumor respond to the drug compared with only 2% of men treated with the other drugs. When looking at all the men in the study, including those with mutations other than BRCA or ATM, a meaningful delay in disease progression was observed among those who took Lynparza compared with investigator’s choice of treatment (5.8 months versus
3.5 months).

Response to Lynparza also may vary depending on the type of mutation, with the phase 2 TOPARP-B study showing that 80% of patients with a BRCA1 or BRCA2 mutation responded to the treatment while 37% of patients with ATM mutations responded.

Rubraca was approved based on the results of a trial in which all patients received the PARP inhibitor and a hormone-suppressing drug. In this study, 42% of the men who participated saw their tumor respond to the drug. “There are many ways to assess response, including the rate of PSA decline, the shrinkage of tumors and delaying cancer progression,” Hussain said. 

“Based on the PROfound trial, the odds of response to Lynparza as measured by PSA decline of 50% or greater was seen in 43% who had BRCA1, 2 or ATM mutations compared with 8% (six of 77) in the patients who received Zytiga/prednisone or Xtandi. In the overall study population, a PSA response was confirmed in 30% in the Lynparza group compared with 10% in the control group. The data also show benefit in terms of significantly delaying pain progression, which is a critical point from a quality-of-life perspective.”

Patrick McGuire, 73, a retired scientist from Wisconsin, has benefited from PARP inhibitors. McGuire received a diagnosis of prostate cancer in October 2015. After under-going prostatectomy, he learned he had metastatic disease and began to participate in clinical trials. Like Elzy, he found that each trial led to only a temporary improvement in his disease.

Throughout his time in clinical trials, McGuire had been providing blood samples for testing, and after his cancer progressed during the first two trials, Lang had him undergo genetic testing, which revealed a BRCA2 mutation. McGuire did not disclose whether the mutation was acquired or inherited. Lang helped McGuire enroll in a clinical trial testing the combination of Zytiga and a PARP inhibitor.

“The drug that I am on now has helped me significantly,” McGuire says of the PARP inhibitor. “Before I took this drug, I was in a lot of pain and was regularly having to take oxycodone. On this drug, within about a month, the pain went away, and I was able to get off oxycodone.”

Prior to his cancer diagnosis, McGuire and his wife loved to travel, fish, hike and camp. For years, McGuire was no longer able to enjoy these activities, but treatment with the PARP inhibitor has allowed him to start participating again.

Like most cancer treatments, PARP inhibitors do cause some side effects. McGuire says he experiences shortness of breath, which was helped by a dose reduction; the drug also affected his red blood cell production. Other common side effects of these drugs include anemia, nausea, fatigue, decreased appetite, diarrhea, vomiting, cough, rash, constipation and low platelet levels.

It is important that patients discuss these side effects with their physicians, Hussain says.

“When I start someone on these drugs, I try to see them within a few weeks of initiating treatment,” she says. “I want to evaluate them and make sure there are no major side effects. If there are, the earlier we intervene the better the chance of sustainability of treatment.”

While on a PARP inhibitor, Elzy says, he experienced nearly no side effects. But unlike McGuire, who is still 

taking his PARP inhibitor, Elzy has moved on to his next treatment.

“It lowered my PSA level to about 0.3 and it stayed like that for maybe four to five months, but in the last three weeks, my PSA level started going upward bound,” Elzy says of the PARP inhibitor. “That is when the drug was stopped.”

Because PARP inhibitors are so new in the treatment of prostate cancer, many questions about the drugs are still being explored. For example, it is unknown if men without DNA repair mutations might benefit from the drugs. It is also unclear if men with inherited versus acquired mutations benefit more from one PARP inhibitor than another.

“Right now, it seems that some patients who have inherited mutations have cancers that are more sensitive to PARP inhibitors and see long-term response that potentially lasts more than a year,” Lang says. “For those patients whose mutation is only in the tumor, we still see a benefit for the majority of patients, but whether that is going to last for more than a year is less certain.”

While the trials that led to the approval of Lynparza and Rubraca showed significant improvements in survival, Lang and other researchers want to find out if they can do better. “We are just at the tip of the iceberg in terms of developing PARP inhibitors and other therapeutic strategies around this class of medications,” Lang says.

For example, researchers are looking into the possibility of combining PARP inhibitors and immunotherapy. There are also trials exploring combining PARP inhibitors with other treatments that target DNA damage repair, including radiation therapy.

“Combining treatments that target DNA in the cancer cell might be its own way to improve disease control and potentially knock aggressive cancers back for many years,” Lang says.

Another strategy being explored is the combination of PARP inhibitors with Zytiga as an initial treatment for mCRPC. The role of PARP inhibitors alone or in combination with other drugs is also being evaluated for use earlier in the disease, before the metastatic stage. Another question involves the role of platinum, a DNA-damaging agent used in some chemotherapies, as an alternative to PARP inhibitors, Hussain says. There are several case series suggesting potential benefit, though there are no data from a large, prospective clinical trial yet.

Finally, the whole field is faced with the challenge of ramping up testing for mutations in men with prostate cancer, some of whom may benefit from a referral to a genetic counselor to discuss familial risk.

“Now there are thousands and thousands of men who need testing, and it will take a lot of hard work to catch up,” Lang says. “We also face a national shortage of genetic counselors, so the field isn’t entirely prepared, but hopefully we will see improvements in the coming years.”

Experts agree that more genetic and genomic testing for men with advanced prostate cancer is likely taking place at major academic centers compared with community cancer centers. It is important that men are educated about genetic and tumor genomic testing, their implications, timing and whether they are eligible.

“Every patient with advanced prostate cancer, and particularly mCRPC, should discuss with their oncologist the role of tumor genomic testing and if they qualify for these treatments, the timing of treatment (and) what to expect in terms of side effects,” Hussain says. “Do not turn to the internet unless it is sources of information that are well-vetted.”

Throughout his treatment, McGuire turned to the Prostate Cancer Foundation, which was active in the funding of studies that helped reveal the role of inherited mutations in prostate cancer. Its website, pcf.org, offers information and resources about genetic testing.

FORCE (Facing Our Risk of Cancer Empowered) is an organization established to improve the lives of individuals and families affected by hereditary breast, ovarian and related cancers. This includes prostate cancer, and the organization’s website, facingourrisk.org, includes information on the disease and the genetic mutations that might increase someone’s risk of developing it.

Elzy and McGuire have faced their diagnoses with the steadfast help of their wives and with a positive attitude.

“I always say, ‘I have cancer, but cancer doesn’t have me,’” Elzy says. “I can’t let it consume me. When I was diagnosed in 2008, my first doctor told me to get my affairs in order, and I’m still here.”

They both credit participation in clinical trials for extending their lives.

“If you have metastatic cancer, I tell people to go find a doctor and a hospital you have confidence in and participate in clinical studies,” McGuire says. “In my view, these trials have basically saved my life.”

Articles

Primed to knock out cells vulnerable due to DNA-repair problems, PARP inhibitors are ushering in a targeted-drug era in prostate cancer treatment.

PARP Inhibitors Demonstrate the Value of Targeted Treatments in Prostate Cancer

When Honora Miller, 53, wondered how to explain her cancer-related fatigue to her son, a friend recommended using an analogy involving spoons. The spoon theory held that Miller would start each day with a certain number of the utensils, each one representing energy. Each daily activity cost a spoon.

“Let’s say I only have 10 spoons today, but I do more than I should, in a sense borrowing from tomorrow’s spoons. I know that tomorrow will have to be a rest day because I won’t have enough spoons,” Miller says she told her son. “It has become a shorthand for us. My 14-year-old understands that is why some days after I pick him up I have to go home and go to sleep.”

Miller has multiple myeloma, a cancer involving malignant plasma cells that grow abnormally in bone marrow, and has had to adapt to the day-to-day management of fatigue that accompanies the disease and its treatments. Cancer-related fatigue can be defined as a distressing, persistent sense of physical, emotional and/or mental tiredness or exhaustion related to cancer and/or its treatment that is out of proportion to recent activity and interferes with usual function. People with all kinds of cancer report this common side effect, and many surveys of patients with advanced cancer rank fatigue as the most disturbing symptom.

“Unlike other forms of fatigue or tiredness, cancer-related fatigue is not relieved by your typical rest,” says Dr. Carmen Escalante, professor and chair of the department of general internal medicine at The University of Texas MD Anderson Cancer Center in Houston. “These people do not wake up feeling refreshed after a good night’s sleep.”

Between 80% and 100% of people with cancer report experiencing fatigue, and sometimes the symptoms extend years into survivorship.

Experts such as Escalante do not yet know the exact cause or why certain patients experience more cancer-related fatigue than others. “There are a lot of factors to consider when evaluating for fatigue, including the cancer’s stage, the extent of the disease, and past and current treatments,” Escalante says. “Patients with more extensive disease and those who have undergone multimodality treatments, like combinations of chemotherapy, radiation, hormonal therapy and surgical treatments, do seem to have more cancer-related fatigue.”

Some study findings suggest that the number of markers in the blood that indicate inflammation, such as C-reactive protein or certain fatty acids, could also increase the risk of cancer-related fatigue.

Miller experienced debilitating fatigue before she knew she had cancer. She recalls taking her son to a museum and napping on a bench while he looked around; before that, she’d had enough energy to hike and bike for miles. Her inability to do what she normally could prompted her persistence to find out what was behind the fatigue. After receiving her diagnosis and starting treatment for myeloma, Miller discussed her fatigue with her specialists. Outside of clinical trials, doctors do not always administer specific questionnaires to diagnose cancer-related fatigue.

“Often, we start by looking at fatigue as a subjective experience,” says Leigh Kinczewski, a certified registered nurse practitioner in the supportive oncology and palliative care program at Fox Chase Cancer Center in Philadelphia. “It is something that is emotional, cognitive and germane to how the patient is feeling and is not well captured with bloodwork, imaging and other objective measures.”

In some cases, Kinczewski says, a simple numeric scale is used. “I may ask the patient to think back over their last seven days to capture how they have been feeling recently,” she says. “A response of 0-3 is mild fatigue; 4-6, moderate fatigue; and 7-10, severe fatigue.” Patients with moderate to severe fatigue may be asked follow-up questions to identify patterns or assess its duration.

Miller also underwent a thorough assessment with a palliative care team to determine if other factors were contributing to her fatigue. Cancer-related fatigue rarely occurs on its own and is often diagnosed along with symptoms such as pain, depression, anxiety, anemia and sleep disturbances.

“The consensus, almost without exception, is that depression is consistently associated with fatigue at an at least moderate level, but it is unclear whether being fatigued causes people to be depressed, if the depression is causing the fatigue or if they are occurring in different pathways,” Kinczewski says.

Treating the depression can sometimes lower the level of fatigue, Escalante says.

A thorough general medical history and review of recent treatments and medications can also reveal other sources of fatigue. For example, patients with under- lying conditions such as heart failure, past coronary disease, diabetes, kidney disease, thyroid disorders and anemia may experience fatigue.

“Many of our patients with cancer are 50 or older,” Escalante says. “Often, trying to understand the status of those other comorbidities can be helpful in deter- mining whether they are contributing to the overall level of fatigue.”

Fatigue can also stem from treatment for these conditions, with medications such as beta blockers, opioids, antidepressants, nausea drugs and some antihistamines, Kinczewski adds. “Oftentimes, if I have a patient with fatigue, I will look at their medication list and discuss with them and their providers alternative medications or dose reductions,” she says.

In Miller’s case, her health care team opted to manage her pain before addressing her fatigue. Prior to undergoing a stem cell transplant, a procedure that replaces damaged stem cells with healthy ones, Miller had received very high doses of a chemotherapy drug called melphalan. As a result, she dealt with significant joint pain. “It was really when we managed the pain that I was able to turn my attention to managing my fatigue,” Miller says.

For Charles Tucker, 60, cancer-related fatigue came on gradually as he got deeper into treatment. Like Miller, Tucker has multiple myeloma.

Prior to his 2016 diagnosis, Tucker was an active power walker, runner and long-distance cyclist. Once he began radiation therapy and then chemotherapy, he began to feel as though he was in a fog. “It is hard to describe, but every day, I was taking breaks and taking naps. I was lying down more,” Tucker recalls. “You feel like your body shouldn’t be moving, like it can’t move.”

The only thing that helped, he says, was to do the opposite of what his body told him to do. He got moving.

The many recommended or tested treatments for cancer-related fatigue mostly fall under two categories: pharmaceutical and nonpharmaceutical.

“For pharmaceutical options, there are two primary options we consider: corticosteroids and Ritalin (meth- ylphenidate),” Kinczewski says. “Corticosteroids can work well in certain circumstances but cause side effects such as increased blood pressure or muscle weakness, so we often only use them in short-term situations and for patients who are rather ill.”

Ritalin is a stimulant and classified as a psychotropic drug, as is another medication approved for narcolepsy, Provigil (modafinil). Whereas some evidence backs Ritalin’s effectiveness in alleviating cancer-related fatigue, the data supporting Provigil are less clear-cut.

“The National Comprehensive Cancer Network recommends using Ritalin cautiously,” Kinczewski says. “Provigil and other drugs like antidepressants are not recommended when the primary indication is cancer-related fatigue.”

Nonpharmaceutical options may bring more success. Findings from a study comparing types of treatment for cancer-related fatigue showed that psychological interventions, such as cognitive behavioral and psycho- educational therapy, and exercise improved symptoms but drugs did not.

“The research that has been done, especially in breast cancer but in other cancers too, has been consistent in showing that resistance training together with aerobic exercise is a very worthwhile strategy against cancer- related fatigue,” says Cornelia Ulrich, executive director of the Comprehensive Cancer Center at the University of Utah’s Huntsman Cancer Institute in Salt Lake City.

The frequency, amount and type of exercise vary by study, but everyone agrees that any exercise is better than nothing. “We know that exercise helps,” Escalante says.

After eventually undergoing a stem cell transplant, Tucker actively retrained his body. Initially, exercise meant a lap around the hospital ward. Weeks and months later, he was power walking four to five miles.

“I had to rebuild my body and push myself through times when I felt like what I would really like to do was sit down,” Tucker says. “That sensation is still there, but I realize now that when I do get moving, the value in terms of energy is pretty plain right away.”

Miller agrees that the payoff is almost immediate. “In particular, when I swim, I don’t feel as much pain, and when I am done, I have decent energy,” she says. “I may still have to nap later, but in the time around the swim, I have a boost of energy for the next couple of days.” When she takes a break from regular exercise, her energy declines, she says.

Although there are no specific recommendations regarding the amount of activity, many studies looking into the effects of exercise had participants engage in physical activity about three times a week, Ulrich says.

“What is encouraging, as well, is that the effect seems to be consistent across multiple types of cancer, whether it is breast, pancreatic or prostate,” she says. “Although this fatigue cannot exactly be prevented, what is critical is that these exercise regimens be implemented at the time when patients are experiencing the most fatigue.”

Miller has also tried several pharmacologic solutions. Provigil, she says, gave her the jitters and no energy. She also recently tried Vyvanse (lisdexamfetamine dimesylate), a stimulant for attention-deficit/hyperactivity disorder; it boosted her energy but also kept her awake at night.

“Exercise is what works best for me, but I have also spoken to others where Provigil is the thing that works for them, or Adderall (dextroamphetamine plus amphetamine),” she says. “Different people have different paths.”

A wide variety of other methods to relieve fatigue have been tested in clinical trials with moderate success. These approaches include yoga, massage, acupuncture and acupressure aimed at relaxation rather than stimulation, but Kinczewski notes that these methods are not accessible or appropriate for every patient.

Could diet play a role? Escalante says that there are no effective dietary strategies for cancer-related fatigue, but an individual’s diet can exacerbate symptoms. “If a patient is not eating well or not eating the right foods, I tell them that may be contributing,” she says.

The results of one randomized trial of American ginseng showed improvement, compared with placebo, among fatigued cancer survivors. No benefits have been seen with other supplements, including Coenzyme Q10 and L-carnitine.

Patients regularly have bloodwork done to look for imbalances in nutrients such as sodium, potassium, calcium, iron and magnesium, Kinczewski said. Taking supplements to correct known deficiencies may help patients feel more energetic. However, there is no routinely recommended dietary strategy, she said.

Miller and Tucker have more than myeloma in common. They both regularly attend Exercise for Energy and Exercise for Strength programs led by Joanna M. Losito, a nurse at Palo Alto Medical Foundation of Sutter Health in Mountain View and Sunnyvale, California.

“I met Joanna at the infusion center where she works, and she encouraged me to attend,” Tucker recalls. “Joanna’s class was so important to my journey because it was led by somebody who understands and specializes in cancer-related fatigue. It was incredibly valuable.”

Having a place to go where you feel understood and supported is very important, Miller agrees. A couple of years into her battle with myeloma, she was forced to leave a demanding but beloved career in social work. Miller choked up as she discussed having to accept that she can no longer work in her profession. “It is an ongoing process, coming to terms with that, with accepting these new realities,” Miller says.

Instead of focusing on that loss, she tries to turn her attention to what she can control. Regular exercise and dietary changes led to a desirable 80-pound weight loss in the last year. She strives to remain as healthy as possible for as long as possible and practices the art of being compassionate toward herself. “That takes a lot of intentionality,” Miller says. “My life looks different now.”

Both Miller and Tucker describe their myeloma as under control but continue to receive maintenance treatments. Additionally, both have been told by their physicians that much of their current fatigue is likely caused by treatments they received over the past few years to keep the disease in check.

“It was profound for me to realize that it was the treatment that was doing this to me and that I could get through it,” Tucker says.

Miller says she didn’t want to assign blame for how she felt but found it reassuring and helpful to understand that tradeoff.

“It is important for patients to hear that this is not just in their head and that it is a true challenge,” Ulrich says. “The biggest message I would give to people facing cancer-related fatigue is that once they get over that initial hump of getting up and getting started even when they don’t feel well, exercise can really make a difference in how they feel.”

People who have had cancer often contend with deep, pervasive exhaustion. The counterintuitive cure: exercise.

Outrunning Cancer-Related Fatigue

When Seana Roubinek, 52, learned in fall 2011 that she had ovarian cancer, her son, Jordan, was just 13 years old. She knew the statistics for her stage 3c diagnosis, but Roubinek’s goal was to survive long enough to see him graduate from high school.

Now, eight years later, she is a few months away from seeing him graduate from college. Roubinek is one of the more than 22,000 women each year who receive an ovarian cancer diagnosis in the United States and also one of the approximately 70% of patients who will experience disease recurrence.

Patients like Roubinek, who are surviving years from diagnosis are a reflection of the treatment advancements made in recent years, according to Dr. Stephen C. Rubin, chief of gynecologic oncology at Fox Chase Cancer Center in Philadelphia. “We have a lot of new and beneficial treatments to offer people that are extending how long they are able to live with ovarian cancer,” he says.

In 2006, Roubinek’s family practitioner advised her to undergo genetic testing because both sides of her family have a history of breast cancer. It was then that she learned she has a BRCA1 mutation. BRCA mutations put women at higher risk of developing breast and ovarian cancer and increase men’s risk of breast and prostate cancer. By age 80, about 72% of women with a BRCA1 mutation will develop breast cancer and about 44% will develop ovarian cancer.

Roubinek began getting regular mammograms and breast MRIs, alternating every six months, and was advised several years later to consider the removal of her ovaries and fallopian tubes through a surgery called salpingo-oophorectomy to help reduce her ovarian cancer risk. She elected to have the procedure, and the surgeon incidentally discovered ovarian cancer. She learned how advanced her disease was following debulking surgery to remove the cancer.

In its early stages, ovarian cancer doesn’t typically cause symptoms. But when it does common signs include bloating, abdominal pain and feeling the need to urinate urgently or often. Most women with the disease, including Roubinek, don’t experience those symptoms, which is why more than 70% of cases are diagnosed at an advanced stage.

“Hindsight being 20/20, though, I realized I had been complaining to my family practitioner about chronic fatigue and lower back pain for a couple of years,” says Roubinek, who lives in Rockport, Maine. “Both are symptoms of ovarian cancer, although less common ones.”

Roubinek had serous carcinoma, the most common type of ovarian cancer, which accounts for more than half of diagnoses. Less common types include clear cell, mucinous and endometrioid carcinoma. The rate of recurrence doesn’t vary greatly by disease subtype but rather by the stage.

“Patients with stage 1 disease have a 10% recurrence risk over five to 10 years,” says Dr. Robert L. Coleman, a professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center in Houston. “In contrast, patients diagnosed at stage 3 or 4 have an 80% chance for recurrence over the same time frame.”

How quickly the disease recurs depends on several factors, such as BRCA mutation status, tumor grade, how much of the tumor could be surgically removed and whether the tumor responds to a common class of initial treatments called platinums.

In 2016, Philadelphia native Lizbeth Brunswick found out her ovarian cancer had returned about two years after completing her initial treatment for stage 3 ovarian cancer at Fox Chase under the care of Rubin. Similar to Roubinek, Brunswick has a BRCA mutation. However, her mutation is somatic, meaning she did not inherit it. Women with somatic BRCA mutations tend to receive cancer diagnoses at an older age compared with those with inherited mutations.

“I really thought I would be the girl who would go into remission or whose cancer would go away, because I was always pretty fit and healthy,” says Brunswick, who is now 66. “But I know my body pretty well, and I could always tell when something wasn’t right.”

The current standard of care for patients who complete initial chemotherapy and go into remission is to undergo blood screening every three months to check levels of cancer antigen 125 (CA 125). This protein can be elevated in patients with ovarian cancer before they experience any physical signs, according to Dr. Ursula A. Matulonis, chief of the division of gynecologic oncology at the Dana-Farber Cancer Institute in Boston.

“Follow-up imaging with CT scans is not recommended to be done on a routine basis,” Matulonis says. “I order a baseline scan after chemotherapy has been completed, but for the most part, we are following the patient history, CA 125 level, how the patient is feeling and findings on physical exams.”

Brunswick’s intuition was correct. During a follow-up visit, Rubin told her that her CA 125 levels were rising and her cancer was back.

“There was a trial published several years ago that looked at CA 125 and showed that its early detection did not improve overall survival but instead increased patient distress,” Matulonis says. “However, as more effective treatments are becoming available, physicians should not be waiting until patients develop symptoms of their cancer recurrence to start treatment.”

Roubinek had a similar experience. She underwent initial treatment for her ovarian cancer as part of a clinical trial testing IV delivery of chemotherapy compared with intraperitoneal delivery, in which the drugs are adminis- tered directly into the area of the abdominal organs.

More importantly, everyone on the trial was treated with the drug Avastin (bevacizumab), which was not approved for ovarian cancer at that time. Avastin is designed to help cut off the tumor’s blood supply.

“The treatment worked beautifully, and I had very few side effects,” Roubinek says.

The regimen kept her cancer-free for two years. During that time, she continued working and even completed the Boston Marathon. About one month after the race, Roubinek went for her every-three-month examination and bloodwork, which showed elevated CA 125 levels. A CT scan confirmed the cancer’s return.

“One of the biggest unmet needs in ovarian cancer is coming up with effective therapies that can cure patients after disease recurrence,” Coleman says. “But that doesn’t mean that we haven’t made incredible progress in the last 15 years.”

One of the biggest improvements in care, he explains, is the growing specialization of gynecologic oncologists, who are trained in the use of surgery and chemotherapy for cancers of the reproductive organs. One study showed that women with ovarian cancer who live farther from a practicing gynecologic oncologist had significantly higher ovarian cancer death rates than nearby patients.

In the past, a second surgery may have been performed to remove as much cancer as possible before restarting chemotherapy. However, at least one large study showed that this additional surgery did not extend life for patients with recurrent disease.

Instead, chemotherapy or a targeted therapy is almost always the treatment of choice, says Rubin. Whether a patient receives additional chemotherapy often depends on length of remission, known in medical terms as “disease-free interval.”

“Our standard front-line drugs are typically carboplatin and Taxol (paclitaxel), with or without the addition of bevacizumab,” Rubin says. “If people go more than a year or

so in remission after these drugs, which is quite common, then they are very likely to respond again to re-treatment with carboplatin.”

Patient preference is also an important factor in chemotherapy selection, according to Matulonis. “You can use a lot of different drugs in combination with carboplatin,” she says. “Paclitaxel, for example, will lead to hair loss and/ or neuropathy. If your patient does not want to lose her hair again or already has neuropathy, you are probably going to want to stay away from paclitaxel and choose a different drug in combination with carboplatin.”

After recurrence, Avastin may also be combined with chemotherapy. Adding Avastin has been shown to extend progression-free survival by about four months compared with chemotherapy alone.

Many patients who respond to this second chemotherapy treatment will be advised to begin a PARP inhibitor as maintenance therapy, designed to keep the cancer away. “PARP inhibitors are oral agents that have considerable activity in ovarian cancer, particularly in women whose cancer occurred as a result of (a) BRCA mutation,” Rubin says.

About 50% of high-grade serous ovarian cancers have homologous recombination deficiency, a weakness in DNA repair. Its presence may predict response to PARP inhibitors. “We are learning more in the last year or two which patients are the best candidates,” says Rubin.

The Food and Drug Administration has approved three PARP inhibitors as maintenance therapy in ovarian cancer:

Zejula (niraparib), Lynparza (olaparib) and Rubraca (rucaparib). Rubraca is also approved for women whose cancer comes back a third or fourth time. All three drugs have been shown to extend a patient’s disease-free interval compared with no maintenance therapy.

Although PARP inhibitors are used only after disease recurrence, slowly mounting evidence suggests that they may be effective as an initial treatment for all patients with ovarian cancer.

After her recurrence in 2014, Roubinek re-treated her disease with carboplatin and liposomal doxorubicin, then enrolled in a clinical trial testing Lynparza as a maintenance therapy. The trial randomly assigned some patients to the PARP inhibitor and others to a placebo, but, based on her side effects, Roubinek is fairly confident she received Lynparza.

Gastrointestinal issues, nausea, fatigue and bone marrow suppression are the major side effects of PARP inhibitors, according to Coleman. At some higher doses, patients may experience anemia, low white blood cell counts or myelosuppression, a condition in which bone marrow activity is decreased.

“Some symptoms, like fatigue, can be mitigated with dose interruptions or reductions,” Coleman says. “Patients should be made aware ahead of time of what symptoms may be coming.”

Brunswick also re-treated her cancer with her front-line regimen, carboplatin plus Avastin, and then was given Zejula.

For maintenance therapy, Avastin also has benefit, but that benefit may be somewhat less than that seen with PARP inhibitors, Rubin explains.

Roubinek and Brunswick both had platinum-sensitive disease, meaning their cancer responded to treatment with platinum drugs. For women who are platinum-resistant, it’s a bigger challenge to determine the best second-line treatment. Some patients with platinum-resistant disease will undergo single-agent chemotherapy with a nonplatinum drug.

The common regimens include pegylated liposomal doxorubicin, Taxol, Gemzar (gemcitabine) and topotecan. In addition, treatment with Avastin combined with pegylated liposomal doxorubicin, Taxol or topotecan has some activity in women with platinum-resistant ovarian cancer recurrence. Finally, there is some evidence that women with platinum-resistant disease who have a BRCA mutation may respond to treatment with a PARP inhibitor.

Ultimately, finding the best option includes consideration of the patient’s treatment history, including side effects; convenience of treatment; cost; and patient preference.

Having each faced two recurrences, Roubinek and Brunswick say the disease has changed their lives. “The first (recurrence) really socks you in the gut,” Roubinek says. “Each time you hear it is back is horrible, but with my second recurrence, I wasn’t as surprised, and I was able to more quickly focus on what needed to be done.”

She credits her ability to do that on the support she received at the Dempsey Center, located in Lewiston, Maine, which offers free programs and support to people affected by cancer. Roubinek and her son took advantage of the services, and she found that her participation with the center and the Ovarian Cancer Research Alliance, an advocacy organization, made her a more informed patient.

“Becoming knowledgeable, at least for me, has made having this disease less stressful,” she says. “I learned to advocate for myself when it comes to my health and to put myself at the top of the list of things to take care of.”

In contrast, Brunswick reveals that she put her faith in Rubin and his team. She turned to family and friends for much of her support. “So many people ask me how I have gotten through this, and I really believe that you have to be positive and make the most out of your life,” she says. “I didn’t want to stop enjoying my life just because I had this cancer, so I have tried to continue to live as normal a life as possible.”

Women with ovarian cancer are living longer than ever, even those whose disease returns after initial treatment.
 

Managing Ovarian Cancer Recurrence

At 44, John D. Edwards was slowing down from what he describes as a life of sex, drugs and rock ’n’ roll when he received a diagnosis of penile cancer in 1996.

“I had just gotten divorced, my life had calmed down a bit and I started to look after myself a bit better,” says Edwards, now 67, an artist who lives and works outside London, England. “That is how I first noticed that I wasn’t feeling so good.”

During a bath one day, Edwards noticed a lump in his groin, which prompted him to see his general practitioner, who referred him to a specialist. A biopsy of the lump, which was a lymph node, revealed cancer, but its source remained a mystery.

“When I met with a specialist, he asked me if I had trouble pulling back the foreskin of my penis, and although I hadn’t really thought about it much before, I realized that, yes, I did,” Edwards recalls.

This condition, called phimosis, in which the foreskin becomes tight and difficult to retract, is a known risk factor for penile cancer. “With phimosis, the foreskin is stuck down over the head of the penis, and that contributes to a poor hygiene situation and the possible buildup of smegma, a substance that can develop under the foreskin,” says Dr. Kirsten L. Greene, a professor of clinical urology at the University of California, San Francisco.

Edwards’ specialist recommended that he undergo a partial circumcision to reveal the head, or glans, of the penis. The procedure revealed a tiny area of the skin that turned out to be penile cancer.

The presentation and diagnosis of Edwards’ cancer was typical of this rare disease type, which is identified in about 2,080 men in the United States each year.

“The population of men in whom it is most commonly diagnosed are men who are not circumcised,” Greene says. In countries where circumcision is more common, like the United States and Israel, rates of penile cancer are lower. In countries with economic disparity or low rates of circumcision, penile cancers can account for as many as 10% of cancers in men.

Human papillomavirus, commonly known as HPV, is also thought to contribute to about half of penile cancers. The 150 strains of the virus can cause different types of warts or growths. Men with penile cancer usually have HPV 16 and 18, types that can be prevented via vaccine and are associated with cervical and oropharyngeal cancers.

“Regrettably, because penile cancer is so uncommon, little research has been done on its associations with HPV compared with a cancer like cervical cancer,” says Dr. Viraj Master, professor of urology at Emory University School of Medicine in Atlanta.

The one unusual aspect of Edwards’ diagnosis was his age: early 40s. The average age of diagnosis is 68.

Other known risk factors include chronic inflammation, obesity, HIV/AIDS, tobacco use and light treatments for chronic psoriasis.

Just over half of penile cancers are diagnosed at stage 1, when the cancer is confined to the tissue just below the top layer of the skin and has not spread to nearby lymph nodes.

“Stage 1 is very curable, and patients tend to do very well,” Master says. About 85% of men who receive a diagnosis of stage 1 disease are alive five years later.

In stage 2 disease, the cancer has begun to spread to nearby blood vessels or nerves. In stage 3, it has reached nearby lymph nodes. Stage 4 disease involves nearby or distant tissues or lymph nodes.

“All too frequently, we see men with penile cancer present with late disease,” Master says. “Often, these men may be ashamed to show anyone their penis because of concerns that it will be viewed as abnormal. In other cases, men may have poor health literacy and are not aware that anything is wrong.”

Once the disease has spread to the lymph nodes, survival depends on aggressive treatment, says Dr. Lance C. Pagliaro, a medical oncologist with Mayo Clinic in Rochester, Minnesota. At these later stages, the treatment team expands beyond urologists like Greene and Master to include radiation or medical oncologists such as Pagliaro.

“What is distinctly uncommon in penile cancer, though, is that less than 3% of cases in the U.S. will be diagnosed after the disease has spread to other organs,” Pagliaro says.

Key to early diagnosis is knowing the signs and symptoms. According to Pagliaro, it is a misperception that these should be obvious to men or their partners. Penile cancer may present as a lump or an ulcer or as a change in the color or thickness of skin on the penis. Men may notice a rash, small bumps or flat, bluish-brown growths. “These can often be mistaken for a fungal infection, an injury or a local irritation,” Pagliaro says.

Men may also notice swelling of the penis, lumps in the groin area, or a smelly discharge or blood under the foreskin.

Patients with penile cancer who are interested in nonsurgical approaches may be able to undergo radiotherapy, according to Pagliaro. Although the medical community has been slow to adopt this option, Pagliaro says that centers with teams devoted to treating penile cancer may offer it as part of multidisciplinary therapy.

Ronald Stewart, 87, underwent a circumcision at age 70 to diagnose his penile cancer and was prescribed radiation. Between treatment for prior prostate cancer, its recurrence and his penile cancer, Stewart estimates that he has received close to 95 rounds of radiation. He says he has never experienced side effects: “I’ve had no pain from it whatsoever.”

Edwards says his experience with radiation was quite painful. “The skin was sort of burnt away, and then, incredibly, it came back like new,” he recalls.

In the years that followed, Edwards experienced ongoing issues, including extreme fatigue and the buildup of fluid in the lymph nodes in his groin. Called lymphedema, this is a common side effect of radiation.

Chemotherapy’s role has also been better defined during the past decade, but this treatment remains underused in penile cancer. Topical chemotherapy can be used in men who have cancer in just the top layers of the skin, called carcinoma in situ. Systemic chemotherapy, which travels throughout the body, is given for more advanced cancers that have spread to the lymph nodes or distant organs, Pagliaro says.

“There are chemotherapy combinations that succeed in reducing the size of lymph nodes and, when combined with surgery, can improve five-year survival rates,” Pagliaro says. “Chemotherapy at lower doses can be given at the same time as radiotherapy, and (although) there are no dedicated clinical trials showing the benefit of that approach, it is being increasingly employed at specialty and community centers.”

In some cases, systemic chemotherapy can be given in an attempt to shrink a tumor prior to surgery. Researchers are studying whether chemotherapy after surgery can help prevent recurrence and improve survival.

Surgery is the primary treatment for penile cancer at any stage but especially for large localized tumors, according to Greene. If the cancer is confined to the foreskin, circumcision might be all that is needed. In a simple excision, it may be possible to cut off just a small piece of the penis, such as the edge of the glans, and preserve function and anatomy, Greene says.

When Edwards’ penile cancer returned in 2012, his specialist recommended a glansectomy to get rid of the cancer’s primary source. This required removing a large amount of the skin on the head of the penis, followed by a skin graft to repair the area.

If the cancer has grown deeply inside the penis, a partial or total removal of the penis, called a penectomy, may be necessary. “Systemic chemotherapy can be used to try to shrink the cancer to allow us to do a partial penectomy,” Greene says. “With a partial penectomy procedure, only a part of the penis is removed, which can change the shape of the penis or the length.”

This procedure leaves sensation unchanged, Greene says. “Men can still have intercourse, orgasm and ejaculate normally, depending upon how much length is preserved,” he says. “The exception to this is skin grafts or flaps, which would have little to no sensation.”

When Stewart’s penile cancer returned about eight years after his radiation, he was referred to Master at Emory. When the recurrence showed signs of growth, Master scheduled Stewart for a minor surgery to remove the cancer.

“Between when the surgery was scheduled and the day of the surgery, the cancer became quite aggressive,” Stewart recalls. Master then explained that the best course of action was a total penectomy.

“With a penile amputation, for the patient, it is almost equivalent to having a limb amputated,” Master says. “Depending on the length of the phallus, the man may not have length left to support traditional sexual intercourse and will no longer be able to void urine in a standing position.”

With this procedure, the entire penis is removed, sometimes including roots located in the pelvis. A new opening to drain urine is created in the area behind the scrotum.

“When Dr. Master told me that they might have to take everything, my words to him were: ‘If it is ‘him’ or me, take ‘him,’” Stewart says. Stewart acknowledges that his age helped lessen the impact; a diagnosis earlier in his life would have been much more difficult.

Men who undergo partial or total penectomy do have options for reconstruction. “In some cases, a skin graft can be used to make the glans penis appear more natural,” Greene says. “Sometimes the suspensory ligament of the penis can be cut to gain extra length.”

Another possibility: penile reconstruction via phalloplasty, the technique used in people undergoing gender reassignment surgery. “Here, the idea would be to try to make it cosmetically look as though the penis is there, but it is not going to look exactly the same as a naturally derived penis,” Greene says. “The goal is more often to let men stand to urinate, and if a prosthesis is implanted, sexual intercourse could be possible, as well.”

Some centers also are looking at penile transplantation as an experimental option, Greene says. The world’s first penile transplant was performed in 2018, but the procedure is still highly experimental, Greene says. “In either case, we would want a man to be cancer-free for enough time to be certain that the cancer is gone before undertaking a complex reconstruction,” Greene says.

), Edwards continues to put his experience on canvas in a series of paintings depicting his life with cancer. He also wrote a book, “How Cancer Saved My Life,” which he plans to republish to include updates about his recurrence.

Edwards says he has tried to live with his cancer honestly and accept that there’s no going back to his old life. While the past two decades have been difficult, he says, he has no doubt about the power, value and joy that comes from externalizing his experience through his art.

Penile cancer can be a deeply personal and devastating disease, but catching it early can mean more tolerable treatment.

Author | Leah Lawrence

PARP Inhibitors Demonstrate the Value of Targeted Treatments in Prostate Cancer

Outrunning Cancer-Related Fatigue

Managing Ovarian Cancer Recurrence

Penile Cancer: Hitting Close to Home