When Howard Wolinsky, 72, received a prostate cancer diagnosis in 2010, the urologist at a community hospital wasted no time in presenting him with a range of treatment options: surgery, radiation and cryotherapy (freezing tissue to destroy it). The biopsy had revealed just a small lesion of low-grade cancer in one of 12 zones, or sectors, of the prostate gland, but Wolinsky’s doctor was among many at the time who did not yet recommend active surveillance as a less-invasive alternative for men with low-risk prostate cancer.

Fortunately, Wolinsky, a Chicago journalist, was well-informed and knew that the University of Chicago had an active surveillance program. Typically, men in these programs are monitored carefully through routine prostate-specific antigen (PSA) testing and periodic biopsies. PSA is a normal protein produced by the prostate gland, which is located below the bladder and makes some of the fluid found in semen. Levels of PSA are often elevated in men who have prostate cancer. Men in active surveillance do not undergo traditional treatment, such as surgery to remove the prostate or radiation, until it’s warranted — if ever. Wolinsky said that his urolo- gist called him “a poster boy for active surveillance” and he immediately signed on. Today, almost 10 years later, he is still in active surveillance. His cancer has not progressed.

Jim Cassell*, 72, of Silver Spring, Maryland, received a similar diagnosis in 2011. In early 2012, he was accepted into a clinical trial at the National Cancer Institute that was testing the diagnostic effectiveness of multiparametric MRI, which merges ultrasound with MRI to reveal details about anatomy and function. Although the MRI continued to show no cancer progression, a targeted biopsy conducted in 2016 found that Cassell’s cancer had spread to eight of the 14 prostate sectors tested, with some tumors classified as intermediate-risk disease. Cassell had little choice but to be treated, and he selected to have his prostate surgically removed. However, over the course of the following year, cancer cells were still detected, requiring radiation. Today, Cassell is cancer-free, but unlike Wolinsky, he lives with side effects from both surgery and radiation.

These two patients illustrate the promise and the limitations of active surveillance. Why did Wolinsky’s cancer remain indolent (slow growing), whereas Cassell’s progressed? Could additional screening tools have led to a different outcome for Cassell? Questions like these remain unanswered.

The good news is that ongoing research may better illuminate the biology of prostate cancer and the reasons for progression. What’s more, oncologists have become more aware of what variables require close attention when evaluating men for active surveillance. “Looking at the quality of the biopsy, the quality of the pathology report, the quality of the MRI and how it was read, as well as asking important questions, such as the man’s age, his overall health, his family history and his projected life span, are all important factors to take  into account,”says Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans. “By paying close attention to these nuances, we have a much better chance of selecting the right candidates.”

Active surveillance is a minimally invasive treatment method that the National Comprehensive Cancer Network (NCCN) recommends for men with low-risk prostate cancer who are expected to live at least 10 more years. However, men with local or regional prostate cancer who have a five-year survival rate of nearly 100% are generally considered good candidates for active surveillance, too. Those with low-risk disease but shorter anticipated life spans might instead be assigned to even less invasive watchful waiting, which isn’t meant to be curative and involves fewer tests, instead focusing on treating symptoms as they arise.

Active surveillance became more popular in response to a wave of overdiagnosis and overtreatment of prostate cancer. Because of routine PSA testing in older men, cancers that might have gone undetected without ever causing health problems were identified and treated. The test measures the amount of PSA in the blood, and it was widely thought that if the number rose above 4, a man could have cancer.

Typically, the next step involved taking 10 to 12 biopsies, or cores, each from a different one of the prostate’s 14 zones. During this invasive procedure, the physician takes tissue samples that can then be analyzed and assigned a grade from 1 to 5, with 1 indicating slightly abnormal cells and 5 indicating very abnormal cells with potential to grow aggressively. Adding the two grades that represent the largest portion of cancerous tissue generates a Gleason score. For instance, if the dominant pattern is 3 and the secondary pattern is also 3, the tumor is assigned a 3 + 3 = 6 score. The higher the score, the more aggressive the tumor. The highest it can be is 10.

PSA is currently the best marker for early detection of prostate cancer, but the test has numerous drawbacks. “For one thing, the test cannot distinguish between indolent and aggressive cancer,” says Dr. Richard Ablin, professor of pathology at the University of Arizona College of Medicine in Tucson and the pioneer who discovered PSA. “What’s more, there’s no level of PSA that’s truly diagnostic. A man can have a PSA of 11 and not have cancer, (whereas) another man with a PSA of 0.5 can have aggressive cancer.”

Nonetheless, the PSA test remains a key element of active surveillance that has gained traction over the past decade. According to data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), between 1990 and 2009, just 6.7% of men who received diagnoses of low-risk prostate cancer were on active surveillance; between 2010 and 2013, that number soared to 40.4%. This increase can be partly attributed to mounting evidence that there is little difference in overall survival rates between men with low-risk disease who are in active surveillance and those who receive more invasive treatment.

Case in point: The Prostate Cancer Intervention Versus Observation Trial (PIVOT). Published in the New England Journal of Medicine in 2017, the 20-year study followed 731 men with localized prostate cancer who were randomly assigned to either radical prostatectomy or observation.

The results showed no significant difference in mortality between the two groups. Disease progression, however, was higher in the observation group, pointing to one reason some men may opt for treatment immediately following diagnosis.

The reason the active surveillance rate among eligible men isn’t 100% may be related to the belief among some men and their partners that forgoing definitive treatment will breed constant worry. As a result, some choose more invasive treatment even when surveillance is an option. Those who do choose surveillance may find it desirable for an important reason: It delays, either temporarily or permanently, living with incontinence and erectile dysfunction, the main side effects of surgery and radiation.

With active surveillance now established as the gold standard for low-risk disease, the next challenge is determining what diagnostic tools to use. Most programs incorporate PSA testing every three to six months and a digital rectal exam, performed manually by a doctor, with similar frequency. The differences lie in whether MRI is part of the protocol and how often biopsies are done. Some may also recommend a 5-alpha-reductase inhibitor, which prevents testosterone from converting into the more potent androgen dihydrotestosterone and reduces prostate cancer risk. The physician’s personal preference also plays a role in how the program is executed.

The Johns Hopkins Hospital in Baltimore, a pioneer in active surveillance, has a reputation for running a rigorous program. The Hopkins program looks for patients with a Gleason score of 6 or lower and cancer in just one or two cores, with a small amount of cancer in each. The physicians also pay close attention to PSA density, determined by dividing the PSA by the volume of the prostate. This test adjusts for men with larger prostate glands, who tend to have higher PSA levels, giving a truer picture of their levels.

“We think density is a better measurement of risk than the PSA score alone,” says Dr. Jonathan Epstein, director of surgical pathology at Johns Hopkins and an early advocate for active surveillance. “The grade of the tumor is also a red flag. It correlates with the risk of the tumor spreading locally.”

Epstein adds that they do a biopsy each year during the early years, a practice in alignment with NCCN guidelines. Over time, however, biopsies are conducted less often, a recent adjustment to the program.

Dr. Greg Auffenberg, an assistant professor of urology at Northwestern Medicine in Chicago, also follows the NCCN guidelines, but he stresses the importance of a confirmatory biopsy after the initial diagnosis. Before Auffenberg does that, he often has his patient undergo an MRI.

“For the confirmatory biopsy, I’ll use MRI fusion technology, which overlays the ultrasound images in real time over the MRI,” Auffenberg explains. “If a patient has an area of concern usually not biopsied, I find this strategy helpful in targeting that area, ensuring that we’re evaluating the patient’s risk accurately.”

Auffenberg joins a growing field of urologists and oncologists who use MRI increasingly for both diagnosis and surveillance. “It’s a game changer,” Ablin says. “It enables urologists to go back to the same area biopsied previously so that they compare apples to apples instead of apples to oranges. It’s a very big deal.”

Sartor agrees but adds that, in his view, MRI enables physicians to forgo biopsies unless there are indications that they are necessary. “If you look at the MRI and it is stable from year to year, you’re looking at a small chance of finding significant cancer,” he says. “We think this approach saves unnecessary biopsies, especially since there’s a 3% to 4% risk of infections or other complications.”

But in Cassell’s case, the MRI missed the spread of cancer, which was revealed only by biopsy. In fact, the literature is mixed as to the percentage of false negatives and false positives that emerge from MRIs and the subsequent role of biopsies.

Patient selection is also very important. Sartor carefully assesses all available evidence before admitting men into his program. “I look at the number of cores, the percentage of involvement of each core, how big each core is and whether there is cancer on both sides of the prostate,” he says. “I also have numerous conversations with the patient and his family. I often find that spouses are reluctant to go along with active surveillance. Their feeling is that if their husband has cancer, it should be treated. In those instances, I gently remind the spouse what active surveillance is and why it works for prostate cancer.”

Sartor and Auffenberg both estimate that 30% of the men in their active surveillance programs experience disease progression and need treatment over a five- to 10-year period. Research corroborates that: A 2010 study by Dr. Laurence Klotz of Toronto, one of the leaders in the field, found that over about a seven-year period, 30% of 450 men in an active surveillance program progressed to definitive treatment.

IMPROVING ACCURACY OF ACTIVE SURVEILLANCE

Although active surveillance has come a long way, most physicians agree that there is room for improvement. Better tools are needed to, as Klotz says, “find the wolf in sheep’s clothing”: About 25% of men in active surveillance for low-risk cancer turn out to have hidden pockets of higher-grade disease.

In a paper published in Translational Andrology and Urology in 2018, Klotz writes: “Nomograms incorporating MRI and/or biomarker findings to predict the risk of co-existent higher-grade cancer are urgently needed.” Using complex math, nomograms predict risk based on data from a large number of men. An emerging field called radiogenomics is working on ways to combine data from genomic testing and multiparametric MRI on large numbers of patients followed for long periods to more accurately identify patients for active surveillance.

The role of the genomic markers currently available, however, is questionable. “I’m not convinced that genomic markers are helpful, except perhaps in further analyzing borderline cases,” Sartor says. “I don’t get genomics on every patient.”

Epstein agrees with that approach. “The tests are very expensive and are usually done at the request of a patient,” he adds.

Another ongoing debate in the field is whether active surveillance is a viable option for men with intermediate- risk disease (Gleason score of 3 + 4 = 7). “This is a controversial area,” Epstein acknowledges. “I would consider this more for older men, but for younger men with a longer life span, I wouldn’t recommend that route.”

Although he wasn’t able to remain on active surveillance, Cassell says he’s grateful he participated for a few years. “I only wish that the progression had been detected sooner,” he says, “through a biopsy done earlier.”

Wolinsky, by all accounts an active surveillance success story, says he feels lucky that he has what one of his doctors called a “lame cancer.” But over the years, he has felt like a pincushion, given how often his prostate has been probed during biopsies. An MRI, too, is not without consequences. He has tinnitus, a ringing or buzzing in the ears, from loud clanging during one of his first MRIs. Wolinsky adds that there is emerging concern about the safety of gadolinium, a contrast dye used during an MRI. Some studies suggest that it may stay in the body longer than previously thought, posing risks for people with impaired kidney function.

“Men should be aware that active surveillance is not a stroll in the park,” Wolinsky says. “It definitely has down- sides. But at this point, active surveillance should be on the table for all men diagnosed with low-risk prostate cancer.”

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Active surveillance has become the treatment of choice for low-risk prostate cancer, but new tools are needed to make it more precise.

Polishing the Gold Standard in Prostate Cancer

After receiving a cancer diagnosis, most patients feel compelled to take definitive action to get rid of the disease.

It seems the obvious choice, but when the diagnosis is low-risk prostate cancer, there’s another option: active surveillance. The concept took a long time to set in for both

patients and physicians. Although some details remain unresolved, this minimally invasive approach, which delays surgery or radiation while periodically testing for progression, is considered the gold standard for men with low-risk disease.

But why is that, and how can a man decide if it’s the right strategy for him? Our article in this issue of CURE® explores the supporting data behind active surveillance and unresolved questions about the program, as well as what the scientific community is doing to answer them.

A major benefit of active surveillance: It lets men avoid invasive treatment and the accompanying side effects, including incontinence and impotence. Carefully monitored, men on this program have outcomes as favorable as those of their counterparts who choose more invasive treatments.

In most cases in which the cancer progresses, surgery or radiation can be prescribed to control the disease. Doctors generally do well in determining the right moment for this, and their accuracy will only grow with continued understanding of the biology of the disease. In the meantime, patients can help delay the need for intensive treatment through lifestyle choices. One study showed that men who follow a Mediterranean diet — low in red meat and sugar; high in fruits, vegetables, legumes, fatty fish and grains &mdash; reduce their risk of aggressive prostate cancer. Another study showed that regular, vigorous physical activity also reduced risk.

For some, the biggest concern about active surveillance is that a very small portion of men assigned to this method may have unexpectedly aggressive prostate cancer that metastasizes before its progression is picked up by a test. In these cases, patients find out too late that potentially curative surgery or radiation would have been better options, although it still is not known if early treatment would have made a difference. Ideally, scientists will soon uncover a way to even more accurately identify the men who will never need invasive treatment. A clearer understanding of the genomics that drive prostate cancer will help sort this out.

Another barrier to active surveillance is concern that it will breed worry about unchecked disease progression. As a result, some who are eligible for active surveillance choose surgery or radiation instead.

In the medical community, we know that, at a population level, active surveillance is better for certain men with prostate cancer, so we believe the benefit weighs in their favor. We would like to offer men more certainty that surveillance can work for them and hope that, in the next few years, research will bring that to pass.

Editor's Page

Growing Knowledge Will Help Refine Decisions About Who Should Participate in Active Surveillance of Prostate Cancer

When it comes to treating advanced kidney cancer, more may be better.

Since the April 2018 approval of two immunotherapies given together for patients with advanced disease, additional combination strategies have emerged, further transforming treatment options.

Primarily, these involve combining immunotherapies known as checkpoint inhibitors with targeted drugs — agents that affect cell functions such as growth, invasion and cell death that are relevant to their malignant behavior.

In April of this year, the Food and Drug Administration (FDA) approved the combination of the immunotherapy Keytruda (pembrolizumab) and the targeted drug Inlyta (axitinib) for initial treatment of patients with advanced kidney cancer, also known as renal cell carcinoma (RCC). Earlier, in February, the agency granted an expedited review to the experimental combination of Inlyta and a different immunotherapy, Bavencio (avelumab), in these patients.

Checkpoint inhibitors disable proteins that normally keep the immune system in check; this allows the immune system to rev up so it can better recognize and kill cancer. Targeted drugs inhibit the activity of proteins, genes or their microenvironment that help a cancer grow and survive.

With these novel regimens come unique side effects, dosage schedules and administration methods, so it’s important to carefully match treatments to the patients most likely to benefit from them, according to Dr. Bradley McGregor, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston and senior physician and instructor in medicine at Harvard Medical School.

“The field of RCC is changing at a rapid rate, and there are lots of options for our patients,” McGregor said in an interview during the 2019 OncLive ® State of the Science SummitTM on Genitourinary Cancers. (OncLive® is a sister publication of CURE ®.) “Determining which option for which patients is going to involve a balanced discussion with the patient about side effects, convenience, (oral) versus intravenous (administration) and how they want to manage their care going forward.”

The spate of regimens approved in the past couple of years amounts to no less than “a revolution in the first-line (initial treatment) setting,” McGregor said.

The evolution started when the combination of the immu- notherapies Opdivo (nivolumab) and Yervoy (ipilimumab) generated an improvement in overall survival in patients with advanced-, poor- and intermediate-risk kidney cancer that had not been treated before. Rates of complete response — all the cancer disappeared &mdash; reached 10%, a previously unheard-of level in this population, and the responses were relatively long-lasting. McGregor cautioned that the regimen does not work for everyone; the overall response rate, which includes all complete and partial responses, is 40%.

Then came the pairing of targeted drugs such as tyrosine kinase inhibitors with immunotherapies. Using Keytruda plus Inlyta as initial treatment for advanced kidney cancer generated an overall response rate of close to 60% and more of a survival benefit than with Sutent (sunitinib), a targeted drug that is a standard treat- ment for these patients. Those results led to the FDA’s recent approval of the combination.

Another advantage of Keytruda/ Inlyta: Patients can benefit regard- less of the risk classification of their disease. That makes the combination a better standard of care than Sutent for patients with good-risk disease, McGregor said.

Meanwhile, a similar combination of Bavencio plus Inlyta looks promising in clinical trials. “What stands out is the tolerability,” McGregor said. “Only 11% of patients required

high-dose steroids (to ease side effects caused by the immune system attacking healthy organs). It seems to be a well-tolerated regimen, and so it certainly offers another potential option for our patients; it’s exciting to see the data mature.”

Doctors are still sorting out which patients should get which regimen, but McGregor follows some guidelines in his own practice.

If a patient experiences a crisis such as symptomatic liver or lung metastases and needs immediate help from an anticancer medication, McGregor favors tyrosine kinase inhibitor/immunotherapy combinations because of their 50% to 60% response rate.

On the other hand: “I might have a younger patient who has minimal, small-burden disease, but I want to do whatever has the best chance to get (them) off therapy in the future,” he said. “Based on what we know right now ... some of these patients (are) able to stop therapy with Opdivo/Yervoy and maintain their complete response."

With numerous regimens being investigated, there is no sign that the breakthroughs will slow down anytime soon.

An immunotherapy/targeted drug duo that generated promising results in clinical trials combines the checkpoint inhibitor Tecentriq (atezolizumab) with Avastin (bevacizumab), which kills the blood vessels that tumors rely on to survive.

“We have seen (Tecentriq/Avastin) data in the IMmotion150 and IMmotion151 studies compared with (Sutent),” McGregor said. “Again, responses were similar to what we see with (Opdivo/Yervoy) — right around 40%.

“The combination is certainly a well-tolerated regimen, and from my experience in non-clear cell RCC (a minority of kidney cancers that respond less to treatment), there seems to be activity. However, we are waiting for more data to see where the role is going to apply in kidney cancer going forward. It is being studied in combination with (the targeted drug) Cabometyx (cabozan- tinib) right now in the front-line setting, both in non-clear cell and clear cell RCC, so it continues to evolve.”

Cabometyx, which simultaneously disables several cancer-driving proteins, is a standard RCC treatment for advanced renal cell carcinoma. It may soon also be used as an initial treatment for that condition, McGregor said.

The drug is being investigated as a first treatment for patients who are ineligible for immunotherapy or have autoimmune disease. In these patients with intermediate- or poor-risk disease, data shows that Cabometyx delayed disease progression compared with Sutent, he said.

In addition, Cabometyx is being studied in combina- tion with novel drugs to treat kidney cancer. One trial pairs it with CB-839, a glutaminase inhibitor. “It is impressive that there is no increase in toxicities (when CB-839 is added), but there is a great disease control rate,” McGregor said. He added that a HIF-2 inhibitor has also been paired with Cabometyx in trials.

“What we really need are novel approaches,” he said. “Unfortunately, even with the great responses of these combi- nations in the front-line setting, there are still patients who don’t respond. We need novel agents and rational combinations. Looking for new targets to help those patients who don’t respond to what we have is going to be critical.”

Drug duos that hit kidney cancer with immunotherapy and targeted treatment offer a better alternative to single agents.

A One-Two Punch in Kidney Cancer

Treatment for cancer brings plenty of physical discomforts and countless things to worry about, making every good moment especially precious.

CURE® contributor Khevin Barnes pointed this out in a 

: “Surviving and living with cancer is a complicated endeavor, with chemotherapies, clinical trials, experimental drugs, invasive procedures and so much more. And while we wish for positive reports and encouraging news, when all is said and done, it is often our basic need for a simple, serene and pain-free day — just a single day &mdash; that takes center stage in our lives.”

Barnes, who had breast cancer, concludes: “This very day I’m living as a cancer survivor is the most important day of my life. And it will remain that way until tomorrow when, if I’m so fortunate, I’ll have another one to follow.”

In this special issue of CURE®, we delve into the topic of minimally invasive treatments for genitourinary cancers and point out that these therapies, as opposed to more invasive strategies such as open surgery, can make recovery quicker and less complicated. That means patients move through pain and other surgical side effects more swiftly, returning sooner to having comfortable days. In prostate cancer, these techniques may even reduce side effects long-term.

The article explores tactics such as laparoscopic and robot-assisted surgeries, which are accomplished through very small incisions; radiofrequency ablation and high-intensity focused ultrasound, which destroy cancer cells via heat; cryosurgery, which freezes the cells to death; and stereotactic body radiosurgery, a type of precision radiation. Readers will learn what to look for in a doctor who will perform these treatments.

Also within this realm, we highlight advances in the precision of active surveillance for low-risk prostate cancer and discuss the questions that scientists still need to answer.

Elsewhere in the issue, we offer overviews of recently approved and emerging medical treatments for kidney cancer. A number of targeted drugs and immunotherapies are being used and tested, with the latest efforts focused on intelligently combining these medications with each other and/or older treatments such as chemotherapies.

Finally, we look at standard multidisciplinary treatments for the rare penile carcinoma and provide guidance on how to recognize this disease before it progresses so that treatment can be less invasive.

We hope the information shared in these pages will be helpful to readers across the genitourinary cancer landscape, offering insights into the myriad treatments available and the issues to consider when choosing a therapeutic path.

From the Chairman

Minimally Invasive Treatments Let Patients Feel Better Faster

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.

“My approach has been to talk to everybody about this as much as possible,” says Edwards, who shares his message through exhibitions, talks and workshops in galleries, art centers and hospitals. Five of the professionals who treated him have since taken up an art form.

Stewart, also originally from the United Kingdom but now a longtime resident of the Atlanta suburbs, says his British sense of humor has helped him deal with the diagnosis. “It is very hard, but you have to look at it in a positive light,” he says. “I am still me.”

As an example, Stewart shares a story about a recent early morning trip to the bathroom, where years of habit led him to stand in front of the toilet. “The joke’s on me, because all of a sudden my feet are getting soaking wet,” Stewart says.

Like Edwards, Stewart keeps busy with activities he loves, like traveling and volunteering at a local hospice. “My advice for people going through this is to try not to get depressed,” Stewart says. “Surround yourself with upbeat people who don’t give sympathy but, instead, give you the support you need.”

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

Penile Cancer: Hitting Close to Home

There was a time when open surgery was a given for certain genitourinary (GU) cancers — those of the bladder, kidney, urinary tract and male reproductive system. Typically, a surgeon would make a large incision to remove the tumor, along with surrounding tissue and lymph nodes it may have affected.

In the past two decades, treatment has shifted. Today, more people with GU cancers are being treated with minimally invasive techniques such as laparoscopic surgery, robot-assisted surgery, tissue ablation and surgery done by endoscopy, a flexible tube equipped with a light and a camera that allows doctors to see the inside of the digestive tract. Other techniques, such as high-intensity focused ultrasound, continue to emerge as the treat- ment landscape evolves.

At the core of each of these techniques is precision, which often comes down to millimeters, as tumors and lesions are targeted and treated in place, signifi- cantly reducing tissue injury and healing time.

Urologists are very familiar with endoscopic approaches to the GU tract. “Through this access, they’re able to treat renal pelvic, ureteric, bladder, prostate and urethral problems,” says Dr. Thomas Keane, chairman of urology and chief of the Specialty Surgery Integrated Center of Clinical Excellence at Hollings Cancer Center at the Medical University of South Carolina in Charleston.

Perhaps the best-known minimally invasive technique is laparoscopic surgery. A surgeon inserts a laparoscope, a long thin tube fitted with a tiny camera, through a few small incisions in the patient’s body. Since the 1980s, when technological advances allowed images to be magnified and projected on screen during surgery, the technique has gained widespread acceptance. Laparoscopic surgery now treats a range of GU cancers.

“With a new generation of diagnostic tools including MRIs, computed tomography scans and novel tumor imaging techniques, we can now pretty accurately pinpoint where tumors are and see the nature of the tumor, such as whether it’s solid or cystic,” Keane says. “That allows us to treat the tumor only. The development of minimally inva- sive approaches allows us to do the same things through significantly smaller incisions. It’s remarkable what can be done today that couldn’t be done 20 years ago. However, when necessary, open approaches are still required.”

Laparoscopic surgery has led to the emergence of robotic, or robot-assisted, surgery, in which instruments are attached to a robot’s mechanical arms. The best-known system, the da Vinci surgical system, was approved by the Food and Drug Administration (FDA) in 2000. While seated, the surgeon controls the arms, including a camera arm, from a computer console near the operating table and maneuvers surgical instruments in the patient through a series of small incisions. It can allow for finer manipulation and visualization.

But is robotic surgery better than other procedures?

According to the article “Robotic vs. Standard Laparoscopic Technique — What Is Better?” in the May 2014 issue of Frontiers in Surgery, robotic surgery helps surgeons overcome some of the limitations of traditional laparoscopic surgery, including two-dimensional images and a restricted range of motion with surgical instruments. In other words, robotic surgery allows surgeons to not only see high-definition 3D images but also move the instruments in ways that are beyond the limits of their own two hands.

Advances in these techniques have led to increasing numbers of patients being treated with a minimally invasive approach. Still, it’s difficult to answer the question of whether robotic surgery is always the better choice. There are ongoing studies to assess this in specific situations, whereas in others, the comfort level of surgeons has advanced to the point where it has become the preferred approach.

In the case of minimally invasive radical hysterectomy for cervical cancer, patients were found to have higher recurrence and worse survival compared with open surgery (laparotomy). However, in the GU realm, “Minimally invasive laparoscopic or robotic surgery is now the state of the art for kidney and prostate cancer,” says Dr. Jeffrey Cadeddu, director of the University of Texas (UT) Southwestern Clinical Center for Minimally Invasive Treatment of Urologic Cancer in Dallas. “Generally, open surgery should be reserved for locally advanced invasive cancers that are too big for a minimally invasive surgery. In bladder cancer, it’s more arguable whether one should do laparoscopic surgery or open surgery.” That’s because some lesions in the bladder cannot be fully visualized or surgically treated this way, so it needs to be a case-by-case decision.

The care team drives the decision about which approach to take with a patient, Cadeddu says, adding that scientific literature over the past 15 years supports no difference in survival outcomes between minimally inva- sive and open surgery for prostate and kidney cancers. “If I want to do open surgery, I have to have a good reason,” he says. “I have to be able to explain it to my patient.”

Cadeddu’s patients include Bill Huber, 53, of Dallas. Huber received a diagnosis of stage 3 kidney cancer in November 2017 after a body scan at Cooper Clinic, where his employer sent him for an executive physical. A runner since high school, Huber considered himself in excellent shape but was curious about his cardiac health because his father had died at age 60 of cardiovascular disease.

Although Huber’s heart health was excellent, he was shocked to learn that he had a 6.5-centimeter tumor on his kidney.

He left that day with a referral to Cadeddu. Huber assumed he’d need open surgery to remove the entire kidney, but his conversations with Caddedu convinced him otherwise. “He told me he could remove the tumor and a portion of the kidney and that my odds for a longer life were better with one-and-a-half kidneys instead of just one,” the now-retired executive says.

On Dec. 17, 2017, Huber had robot-assisted laparoscopic surgery. The procedure, which took about four hours, included four half-inch incisions and one 3-inch incision, through which the tumor and part of his kidney were removed. He left the hospital a few days later, with no need for chemotherapy or radiation, and experienced only some post-operative discomfort as his digestive system returned to normal. “I have to believe my recovery was quicker because of the minimally invasive approach,” he says.

Long-term outcomes in prostate cancer are generally the same whether a patient has open or robotic surgery, according to Dr. Isaac Kim, chief of the division of urology at Rutgers Robert Wood Johnson Medical School and chief of urologic oncology and executive director of the prostate cancer program at Rutgers Cancer Institute of New Jersey in New Brunswick. But there are several differences between the approaches when it comes to potential immediate post-surgical impacts. With minimally invasive surgery, Rutgers sees significantly shorter hospital stays, less risk of blood loss and reduced need for blood transfusion, less post-surgical incontinence and lower risk of erectile dysfunction, though the latter depends on the patient’s baseline, Kim says.

In laparoscopic and robotic surgery, carbon dioxide is used to create space inside the patient for the surgeon to work. “This helps maintain a continuous pressure, almost like a gentle hand,” Kim says. “This pressure helps decrease bleeding during surgery. It also leads to a cleaner surgical field. When you can see better, you can do more precise surgery.” But laparoscopic and robotic surgeries aren’t without risk. Though rare, Kim says, carbon dioxide could form a dangerous bubble in a vein. Other risks include infection, bowel perforation and bleeding, as with all surgeries.

The need for chemotherapy or radiation after minimally invasive surgery depends on how advanced the disease is, Kim says. “For example, if a concurrent lymph node removal is done at the time of prostate cancer surgery and cancer is detected, I will refer the patient to a radiation oncologist and medical oncologist,” he says.

In most cases, these minimally invasive approaches are covered by insurance; patients and their doctors can ask health insurers to confirm.

GU cancer care has begun taking a team-based approach, according to Keane. “Urology used to be an isolated field,” he says. Now urologists work closely with other experts to identify tumor types and their genetic profiles, as well as tailored treatments ranging from minimally invasive surgery to targeted therapy, immunotherapy and radiation therapy.

One of the biggest advances in GU cancer care involves the development of multidisciplinary clinics, where teams of urologic oncologists, medical oncologists, radiation oncologists, pathologists and surgeons meet weekly to discuss each patient’s case and make recommendations, Keane says: “This approach offers the advantage of consensus rather than individual opinions.”

Not all treatments are appropriate for all patients, Keane cautions. “Someone will walk in and say, ‘My friend had this.’ But it might not be suitable for them,” he says. Contraindications for minimally invasive treatments can include the type, size and location of the tumor; patient size; past extensive surgical procedures in the area; and any adhesions or scar tissue.

Some bladder cancers can be treated minimally invasively using a cystoscope or resectoscope — a thin, tubelike instrument inserted into the urethra to allow surgery and fulguration (burning away the tumor and its surrounding location with an electric current). New options are emerging to treat bladder cancer, but as with many developing therapies, more research is needed, Keane says.

Other minimally invasive GU cancer treatments include radiofrequency ablation, in which a radiologist uses a thin needle to deliver high-frequency energy directly to a tumor, heating it and killing nearby cells. With cryosurgery, or cryotherapy, liquid nitrogen or argon gas freezes and kills cancerous tissue. These techniques are sometimes used to treat kidney and prostate cancers, typically when surgery is not an option.

For prostate cancer, another emerging treatment is high-intensity focused ultrasound, in which focused ultrasonic beams heat and destroy cancer cells. Studies are still evaluating whether the treatment is adequate and as effective as others. “That takes time,” Keane says. “Quite rightly, the FDA and other agencies demand a lot of evidence.”

Still, waiting can be difficult for someone with a cancer diagnosis. Mike Crosby, 59, of Edmond, Oklahoma, a former U.S. Navy pilot, was told by his Veterans Affairs (VA) care team that an annual blood test revealed an elevated level of prostate-specific antigen, a protein that can rise in men with prostate cancer. When Crosby faced excessive wait times and arranged a biopsy outside the VA system in 2015, he received a diagnosis of intermediate-risk prostate cancer. Told that his only option at the VA was open radical surgery, Crosby did his own research. He ultimately connected with the care team at Swedish Radiosurgery Center in Seattle, where he opted for treatment with stereo- tactic body radiation therapy through a system known as CyberKnife. No incisions are made; instead, using a robotic arm and cameras, focused radiation is delivered precisely to the affected area.

After an outpatient procedure in which four gold markers were inserted in his prostate as a reference point, Crosby returned to the hospital for outpatient treatment of one dose, or fraction, of radiation each day for five days. “I wore a sweatsuit and listened to jazz music for about 45 minutes,” he says. “It was an incredibly easy experience.”

Crosby says he was drawn to stereo-tactic body radiation therapy because it is noninvasive. He also had tremendous confidence in his radiation oncologists, Drs. Sandra Vermeulen and Robert Meier. “I felt comfortable because of the number of procedures Dr. Meier had accomplished,” says Crosby, a CyberKnife advocate who founded Veterans Prostate Cancer Awareness Inc., a nonprofit group that aims to educate veterans and caregivers about prostate cancer and the importance of regular screenings.

“Being treated by someone with the skill of Dr. Meier is like playing in a football game with Tom Brady as your quarterback.”

When it comes to minimally invasive techniques, experience is critical, says Cadeddu, who, according to UT Southwestern, was the first surgeon in Texas to perform ablation for kidney cancer. “In a big city, you should be able to find someone skilled in minimally invasive surgery,” he says. “In a small town, your resources might be fewer.”

Kim, who has performed more than 1,800 robotic prostate surgeries, emphasizes the importance of getting a surgeon referral from someone you trust. Friends and family members can be good sources, as can primary care physicians. He also recommends seeking care at centers that are engaged in clinical trials.

No matter which surgeon you select, ask about their experience, Cadeddu says: “The surgeon should be able to tell you the number of procedures they’ve done, and most will share that right away.” Typically, it’s a good idea to look for someone who’s done at least 200 to 300 over the past few years. That’s because surgeons get better with practice — and because technology is changing.

Kim is particularly excited about single-port robotic surgery. It requires just one small abdominal incision instead of the four needed with the current four-port robot and has the potential to further shorten hospital stays, he says.

“There’s not too much (of a) learning curve for an experi- enced robotic surgeon, as the surgical movement the surgeon uses is essentially the same,” he says. “But never in my wildest dreams did I think I’d see same-day prostate cancer surgery.”

A variety of minimally invasive techniques can remove genitourinary tumors.

Genitourinary Cancer Special Issue 2019 | CURE

Polishing the Gold Standard in Prostate Cancer

Growing Knowledge Will Help Refine Decisions About Who Should Participate in Active Surveillance of Prostate Cancer

A One-Two Punch in Kidney Cancer

Minimally Invasive Treatments Let Patients Feel Better Faster

Penile Cancer: Hitting Close to Home

Precision Incisions: Minimally Invasive Techniques in Genitourinary Cancer

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