J. Brantley Thrasher, MD

Dr. Thrasher, a Urology Times editorial consultant, is professor and chair of urology at the University of Kansas Medical Center, Kansas City.

 Editorial Consultant, is executive director of the American Board of Urology, Charlottesville, Virginia.

Androgen deprivation therapy (ADT) has been a mainstay of treatment for advanced prostate cancer for decades and has been shown to provide long-term disease control and improve symptoms. However, there is evidence that ADT increases cardiovascular (CV) risk, especially in men with preexisting CV disease.

 Additional concerns for gonadotropin-releasing hormone (GnRH) agonists are delayed castrate levels of testosterone and the need for intermittent injections, among many others.

The recent results of a phase 3 randomized controlled trial investigating relugolix, an oral GnRH antagonist, vs leuprolide may change the landscape in the treatment of advanced prostate cancer (see article, page 8). HERO (NCT03085095) was a multinational, open-label trial that randomized 934 men 2:1 to treatment with relugolix (360 mg on day 1, then 120 mg po qd) or subcutaneous leuprolide injection 22.5 mg (11.25 mg in Japan and Taiwan) every 3 months. Eligible men had confirmed advanced prostate cancer defined as biochemical or clinical relapse, metastatic disease, or advanced localized disease. Additionally, the men had to have serum testosterone levels of 150 ng/dL or greater, serum prostate-specific antigen above 2 ng/mL, and require at least 1 year of ADT. Men with a history of ADT for more than 18 months, active liver disease, or significant CV risk were excluded. The primary end point for the study was sustained castrate levels of testosterone
(< 50 ng/dL) through the 48-week study.

The 2 groups were well balanced in their clinical characteristics. In addition, both arms met the primary end point with 96.7% of relugolix patients and 88.8% of leuprolide patients achieving sustained suppression of testosterone.

Key differences in secondary end points were a much quicker suppression to castrate levels (56% vs 0%, at day 4) and a quicker return to normal by day 90 (54% vs 3%) in the relugolix vs leuprolide arms, respectively. As expected, it took approximately 1 month for the leuprolide-treated patients to reach castrate levels. Known adverse events (AEs) such as hot flushes and fatigue were very similar in both groups, with more grade 1 or 2 diarrhea in the relugolix arm, but this did not result in study discontinuation. Major adverse cardiovascular events (MACE) were 2.9% in the relugolix-treated patients and 6.2% in the leuprolide-treated patients. The authors performed a Kaplan-Meier analysis of cumulative MACE incidence over the study period and found a 54% risk reduction in the relugolix group.

If further studies confirm the efficacy and lower CV adverse effects with this new oral GnRH antagonist, this could make a substantial impact on most urologists’ practices. Patients could avoid an injection, initial testosterone surge would be alleviated, and a significant reduction in CV events would be realized. However, several questions remain to be answered, among them the following: 1. What will be the cost of this new oral therapy? 2. Will third-party payers reimburse for the therapy with currently available injectables already on the market? 3. Will the quicker testosterone recovery make this a more appealing option for intermittent therapy? 4. Might we see more gastrointestinal AEs in a larger trial? 5. What will the AE profile look like when this drug is given in conjunction with nonsteroidal antiandrogens such as bicalutamide?

Although there remain several unanswered questions about this new drug, the initial report is very promising. This new therapy could change the landscape for the treatment of advanced prostate cancer.

1. Van Hemelrijck M, Garmo H, Holmberg L, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the population-based PCBaSe Sweden. J Clin Oncol. 2010;28(21):3448-3456. doi:10.1200/JCO.2010.29.1567

Articles

"This new therapy could change the landscape for the treatment of advanced prostate cancer," Thrasher writes.

Are phase 3 HERO results a game-changer for urologists?

	Active surveillance (AS) continues to gain traction as a management strategy for low-risk prostate cancer in the United States. However, barriers still exist and challenges remain for both the treating urologist and the patient.

	Marzouk et al evaluated 463 patients enrolled in AS from March 2000 through January 2016. A total of 413 patients completed a prostate cancer quality of life survey as part of the follow-up. Questions related to the anxiety associated with their prostate cancer. Estimating equations were used to test the association between the risk of anxiety and age, marital status, PSA, Gleason sum, number of positive cores, family history, overall state of health, and length of time on AS.

	The authors found that the risk of anxiety decreased over time, and those reporting high overall health scores had lower anxiety levels throughout their duration on AS. They conclude that although moderate levels of anxiety exist in patients on AS, it significantly decreases over time and this should be taken into consideration when counseling men.

	This study adds to a growing body of information on how men perceive AS, its effect on their emotional well-being, and reasons they might consider leaving an AS protocol. Berger et al interviewed a small sample of the 1,159 men on the Johns Hopkins AS program who self-elected to leave 

 The authors noted that those electing to leave the program had higher baseline PSA levels and younger age. They also noted that this subset of men continued to feel anxious about their cancer and viewed AS as a way to delay treatment rather than avoid it. Additionally, the attitudes and worries of family members and loved ones were potential influences on the decision to leave the AS program.

	The take-home for all of us who treat low-risk prostate cancer and use AS protocols is that we need to tailor our counseling to consider many of these factors. Family members and loved ones should be included, when possible, in the counseling session. Detailed counseling regarding the very slow growth rates of low-grade prostate cancer, the protocol for follow-up, and trigger points for further decisions/intervention should be covered and questions answered to minimize anxiety.

	However, further studies are needed in this patient population to answer numerous questions: What should a standard AS protocol look like? How should contemporary imaging and genetic testing be incorporated? Should older men or those with multiple comorbidities be counseled differently than younger, healthy men? And finally, how should family members and loved ones be integrated into AS protocols?

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“Active surveillance continues to gain traction as a management strategy for low-risk prostate cancer in the United States. However, barriers still exist and challenges remain for both the treating urologist and the patient,” writes J. Brantley Thrasher, MD.

Challenges remain for active surveillance in low-risk PCa

The role of biopsy in renal masses is evolving. For large renal masses in particular, new data suggest biopsy may change the management of patients with certain high-risk features, according to 

 assistant professor of urology at the University of Wisconsin School of Medicine and Public Health Madison. Dr. Abel discusses biopsy’s role in small and large renal masses, associated risks, and when patients can be safely observed. Dr. Abel was interviewed by 

 Editorial Consultant J. Brantley Thrasher, MD, professor and chair of urology at the University of Kansas Medical Center, Kansas City.

Let’s start by discussing the small renal tumor. In the past, conventional wisdom was that a biopsy doesn’t add very much information. If you’ve already decided that a tumor needs treatment based on imaging, then doing a biopsy will only potentially cause a complication or lead to an indeterminate result. In your mind, which patients should be offered percutaneous biopsy for small renal masses today?  

	That’s an excellent question. I do think we should at least discuss renal mass biopsy with the vast majority of patients who have small renal masses. The biopsy informs patients and improves the decision-making process for treatment. Biopsy ultimately provides more information that allows the surgeon to provide better informed consent for treatment.

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	Given that about 20% of small renal tumors are benign in almost all surgical series, it’s difficult to make the argument that you can decide if a patient needs treatment based on imaging alone. Simply, biopsy allows identification of some patients with benign tumors, who may be spared unnecessary treatment. Biopsy is especially valuable for older patients with comorbidities or for patients who are poor candidates for nephron-sparing techniques.

	Finally, serious complications from percutaneous biopsy are rare in experienced centers, especially when compared to the possible complications from treatment.

Next: "Imaging has certainly improved the detection of lipid-poor angiomyolipomas but is not perfect."

Doesn’t improved imaging give us a better idea of whether a tumor might be an oncocytoma or angiomyolipoma, most of which are not renal cell cancers in the first place? Or do you still think there are places where we might benefit from biopsy for identifying benign versus cancerous masses?

	Lipid-poor angiomyolipomas and oncocytomas are two tumors that comprise the majority of benign tumors in surgical series. Imaging has certainly improved the detection of lipid-poor angiomyolipomas but is not perfect. If we can identify lipid-poor angiomyolipomas or oncocytomas from biopsy, contemporary studies have demonstrated that treatment can usually be avoided for these benign tumors. However, in younger patients with larger tumors, most experts would agree there’s less of a role for biopsy.

	Large renal masses demonstrate significant heterogeneity in radiological appearance. A multiquadrant technique samples cores from multiple enhancing areas in tumors, whereas standard technique obtains tissue from asingle location. (Source: Reprinted from the Journal of Urology, Vol. 194, page 887, Copyright 2015, with permission from Elsevier.)

How about women in childbearing years? Would you limit biopsy in those cases too?

	Biopsy is not appropriate for everyone and the decision should be made for each patient individually. However, I think it’s important to realize that biopsy is one way to avoid the morbidity associated with overtreatment of small renal masses. Overtreatment is associated with a decrease in renal function and increased cost of treatment. The potential risks associated with biopsy are very small, and it does provide more information to help patients make decisions.

What are those risks? When you’re doing informed consent with patients, what do you tell them?

	The risk is probably dependent on the institutional experience. In our last 700 patients, we’ve had less than 1% incidence of Clavien III complications-those requiring additional treatment. Most complications are related to bleeding and less than 1% of patients will require blood transfusion or angioemobolization.

Next: "The practice of urologists performing biopsies is encouraging."

Practicing urologists may be concerned about sending a patient to interventional radiology to do the biopsy and have the urologist take care of the complication. There’s also a concern about the radiologist doing cryotherapy or a percutaneous treatment right in the suite. Does this remain in our purview as urologists?

	Definitely. At our institution, we have a close relationship with our radiology department and communicate about patients frequently. Improving future patient outcomes is really dependent on cooperation across disciplines. However, it’s important that urologists continue to maintain ownership of these patients because we are trained to understand the tumor biology of kidney cancer and we follow these patients for years to observe the natural history of renal masses. The practice of urologists performing biopsies is encouraging.

	A gross pathology specimen demonstrates distinct pathologic diagnoses among different regions of large renal cell carcinoma. (Source: Reprinted from the Journal of Urology, Vol. 194, page 889, Copyright 2015, with permission from Elsevier.)

If you believe by imaging that you’re looking at a small, percutaneous tumor, how does biopsy help you risk-stratify patients?

	For the patient who has a very limited life expectancy and a very small tumor, it’s probably not helpful to identify whether or not a tumor is cancerous since it will not likely affect their life expectancy. In very young patients, biopsy is also probably not as helpful.

	But there are a lot of gray areas, since most patients with renal cell cancer are in their 60s or 70s and are healthy but have some comorbidities or borderline renal function. Patients may choose different treatments if they know that they have a benign tumor or a malignancy. If patients understand that they have cancer, some would feel more comfortable consenting to surgery.

Next: "I have had many patients in their 70s ask if a mass can be just followed instead of treating it. What do you tell them?"

I’ve had a few older patients who are not in great shape say that if they have cancer, they need to identify that for their cancer insurance policy; that’s one of the reasons to do a biopsy. Also, I have had many patients in their 70s ask if a mass can be just followed instead of treating it. What do you tell them?

	The minority of small renal masses will be aggressive tumors. But if you identify an aggressive tumor in an older patient, you may be more likely to treat it. If you identify a grade 4 or sarcomatoid tumor, even when it’s 2 or 3 centimeters, you may offer aggressive treatment to an older comorbid patient.

Patients also tell me they’ve read that aggressive cancer can actually spread cancer along the needle tract. What do you tell them?

	That is a very rare, almost theoretical risk with modern techniques. We struggle sometimes with explaining rare events because we can’t define the exact risk. We have not seen tumor seeding our institution in the last 20 years, and there have been very limited reports of it. It’s a theoretical concern, but we know that biopsy tract seeding is a rare event for any cancer that involves doing a biopsy, such as prostate cancer.

When you have an upper pole or lower pole tumor that may be extending into a calix or coming from the calix, do you use an endoscopic approach first before placing needles in those tumors?

	Yes. More central tumors and those we suspect are urothelial cancers are approached ureteroscopically rather than percutaneously.

Next: How do you see percutaneous biopsy fitting into the large heterogeneous class of renal masses?

How do you see percutaneous biopsy fitting into the large heterogeneous class of renal masses?

	In the management of locally advanced and metastatic renal cell cancer, there is not a lot of data to guide us how to use biopsy. For large, locally advanced but non-metastatic tumors, extended lymph node dissection certainly benefits some patients but may also be associated with increased morbidity.

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	Several groups have identified poor prognostic factors for patients who harbor lymph node metastases, including advanced clinical stage, high Fuhrman grade, clear cell renal cell cancer, necrosis in the specimen, and sarcomatoid features. If the primary tumor demonstrates these high-risk features from biopsy, the surgeon has that information prior to surgery, and you can discuss more aggressive surgery preoperatively with the patient.

	We know these large heterogeneous renal tumors frequently have areas with different tumor grades and rare aggressive pathologic features, such as sarcomatoid de-differentiation. Prior studies of large renal mass using a standard biopsy technique to obtain multiple cores from a single site may be prone to error from sampling. We presented data at the 2015 AUA annual meeting using a novel multiquadrant technique that obtains multiple samples from different sites in large tumors. Using this technique, we demonstrated a higher detection rate of sarcomatoid features, increasing sensitivity from 11% in prior studies to about 85%, and we had no higher rate of complications with this technique.

In patients with advanced disease, the medical oncologists are asking us to debulk the tumor before immunotherapy. In those cases, is there any reason to proceed with a biopsy?

	Even with newer therapies, there’s certainly a role for cytoreductive nephrectomy in many patients. However, we know from population-based studies that less than half of patients with metastatic disease undergo a cytoreductive nephrectomy; biopsy definitely has a role in identifying metastatic disease in those patients. Subtyping and getting those patients into appropriate treatment is important because some of the treatments work better than others for clear cell carcinoma.

	In patients with metastatic disease, renal mass biopsy using a multiquadrant technique demonstrated fewer non-diagnostic biopsies.

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	In the future, biopsy may be increasingly utilized to identify metastatic renal cell cancer patients who are unlikely to benefit from nephrectomy. For example, metastatic renal cell cancer patients with sarcomatoid de-differentiation in the primary tumor are known to have exceptionally poor survival and may not benefit from cytoreductive surgery.

Next: "I think we need to continue to be aggressive with cytoreductive surgery."

At our institution, medical oncologists often question whether a patient is a good candidate for cytoreductive nephrectomy simply because their tumor is advancing so quickly. They advise watching it for another 3 to 6 months. Is biopsy helpful in those cases, or are you simply watching the biological growth of such a tumor?

	In metastatic patients, biopsy establishes a diagnosis for histologic subtype of renal cell cancer. In patients with non-clear cell subtypes for whom there are not great systemic treatments, surgery remains a viable option. I think we need to continue to be aggressive with cytoreductive surgery, including nephrectomy, metastasectomy, and lymph node dissection. Despite the development of newer and better systemic therapies, most patients continue to have very poor outcomes, and surgery will be important for the foreseeable future in the treatment of metastatic renal cell cancer.

One other argument against biopsying large masses is that, in many cases, it leads to non-diagnostic results. How often does that happen in your series?

	We presented another study at the 2015 AUA annual meeting evaluating patient and tumor characteristics that were predictive of non-diagnostic findings from biopsy. Factors that may increase non-diagnostic rate are: tumor size, radiologic enhancement, the presence of cystic features, and the distance from the tumor to the skin. We reported a non-diagnostic rate of about 15%, which is similar or less than other large series.

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	The lack of consensus definitions for “non-diagnostic” biopsy is a source of considerable variability in reported biopsy diagnostic rates. It is important to note that the definition of non-diagnostic should also include biopsies that have only normal renal tissue and have likely “missed the target.” These findings should not be interpreted as benign.

	In large renal masses with a standard biopsy technique (multiple cores from one site), approximately 10% to 11% of biopsies are non-diagnostic. Using the multi-quadrant technique to sample several sites within large tumors decreased the non-diagnostic rate to 0% in our experience.

Next: "I think biopsy is relevant to anyone who sees patients with incidental renal masses."

You work at a major institution where people are doing this a lot. How is this relevant to the average private practitioner in a community hospital?

	I think biopsy is relevant to anyone who sees patients with incidental renal masses, although experience is definitely helpful to get the best results. To maintain good quality of care, discussing the approach to renal mass biopsy with your abdominal or interventional radiologist is important. If the urologist is performing a biopsy in the office, I think it’s important to carefully plan the procedure and begin with less anatomically complex lesions. It’s certainly reasonable to expect good results with renal mass biopsy, just as we do with other complex office procedures.

We know that partial nephrectomies for small renal masses are not done very often by private practitioners. They’re simply doing a radical nephrectomy. If you’re going to approach that surgery laparoscopically, would there be a reason to do a biopsy at the time and potentially avoid a nephrectomy?

	I think we should always use nephron-sparing and minimally invasive approaches when feasible. If a urologist sees a patient with a small central renal tumor and feels that the patient will need a radical nephrectomy for treatment, biopsy can be especially helpful. In most patients with benign masses such as oncocytoma, active surveillance is a better choice compared to radical nephrectomy.

Next: "We really believe it’s an advantage to have the pathologic diagnosis before the procedure."

The average urologist might consider doing a biopsy laparoscopically prior to definitive treatment. Would you recommend that approach?

	We really believe it’s an advantage to have the pathologic diagnosis before the procedure. Unfortunately, frozen pathology is not always reliable and establishing the diagnosis in patients treated with ablation is critical so that we know how to follow patients afterward. Historically, many patients were treated with thermal ablation without a biopsy, which makes it difficult to follow these patients clinically afterward.

I’ve looked at some of the cryotherapy series and some radiofrequency ablation (RFA) series. It appears that results with cryo might be a little better than with RFA, but our interventional radiologists are doing RFA in their suite. Do you favor one or the other at your institution?

	It’s a difficult question because we don’t have head-to-head, prospective, randomized studies. We actually do a lot of microwave ablation. Microwave is similar to radiofrequency ablation, but it’s a little bit more powerful and it provides a bit of a coagulation effect. Institutionally, we favor microwave ablation and we have good results. Patients who are young with no medical comorbidities are not generally selected for ablation.

Next: "If you do ablation, how are you following those patients afterwards?"

If you do ablation, how are you following those patients afterwards?

	We do MRIs post ablation in most patients. Especially in younger patients, there’s a concern about limiting radiation exposure. There’s not high-quality, evidence-driven data guiding us on the best methods to follow patients post ablation, but we generally obtain abdominal MRI or CT, and obtain labs/chest imaging similar to patients after surgery.

If you have some rim enhancement in that lesion, are you going back and doing biopsies or just following?

	To ensure there is no viable tumor present after ablation, we may biopsy the ablation bed at about 9 months. With no viable tumor, we can extend the interval between surveillance MRI or CT. Another approach is to follow with serial imaging at shorter intervals.

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In this interview, E. Jason Abel, MD, discusses biopsy’s role in small and large renal masses, associated risks, and when patients can be safely observed.

Renal biopsy may alter management in high-risk patients

Dr. BelldegrunCancer immunotherapy offers myriad advantages, including specificity and durability of response, but questions remain about its cost and what role the urologist should play in treatment. In this interview, Arie Belldegrun, MD, discusses the benefits of immunotherapy, the importance of a multidisciplinary treatment approach, and what the future holds for this treatment. Dr. Belldegrun is professor of urology, The Roy and Carol Doumani Chair in Urologic Oncology, and director of the UCLA Institute of Urologic Oncology at the David Geffen School of Medicine at UCLA. He is founder and CEO of Kite Pharma, a biopharmaceutical company dedicated to the development of immune-based and engineered autologous T-cell therapies.

Please provide an overview of cancer immunotherapy and how urologists are using it.

	Cancer immunotherapy, named as the 2013 “Breakthrough of the Year” by 

 magazine, is a treatment modality that harnesses the power of the immune system to fight and reject the patient’s own cancer. Urologists were among the first to apply the power of immunotherapy in the clinic by using instillation of bacillus Calmette-Guérin (BCG) into the bladder for the treatment of superficial bladder cancer, and BCG is all about local immunotherapy.

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	Two decades later, in 1985, interleukin-2 (IL-2), the first immunotherapy capable of mediating complete tumor regression of metastatic tumor deposits, was described. Urologists became familiar with IL-2 after its historic approval in 1992 for the treatment of patients with metastatic kidney cancer. It then remained the only approved drug for advanced renal cancer for the next 15 years, until the emergence of targeted therapy.

	In 2010, patients with hormone-refractory 

 who received an immune cancer vaccine called 

 demonstrated improved survival over placebo; sipuleucel-T was approved by the FDA later that year. At the same time, a huge step forward in the field of cancer immunotherapy was achieved when clinical evidence emerged that the administration of an antibody targeting inhibitory T-cell costimulatory molecules CTLA-4 and/or PD-1 could generate significant regressions of metastatic cancer in patients, including kidney and bladder cancers. This gave birth to a new field of clinical investigation called checkpoint modulators or inhibitors.

	Urologists have therefore been deeply entrenched in immunotherapy for over 5 decades now. The last several years, however, have witnessed a huge revolution in the field with dramatic clinical advances yet to come.

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You’ve alluded to one advantage of immunotherapy, which is that it’s very targeted. What are some other advantages it has over other systemic treatments?

	Specificity is the most important characteristic; immunotherapy attacks the cancer cells and spares normal cells. Durability is next: T-cell memory cells continue to circulate in the blood for many years and once they identify new cancer cells in the body, even in the form of mutated cancer cells, they will launch an attack and destroy these newly formed cancer cells. Third, although cancer’s heterogeneity evolves over time, the immune system still recognizes the cancer as foreign. Heterogeneity creates a problem for targeted cancer therapy since these treatments are directed against a specific target; immunotherapy overcomes this issue.

	What is most impressive with immunotherapy is that once a complete response has been achieved, it sustains for many years. In my personal experience, it is very rare for these patients to have cancer recurrence; I have patients who have had metastatic kidney cancer for two decades and are still responding to their original immunotherapy. Unfortunately, these success cases are still in the minority and therefore the question is how to increase that percentage of patients.

What do you consider the most exciting area now where immunotherapy would be most effective?

	That’s a very timely question. For years, metastatic kidney tumors were considered the best responders to immunotherapy among the urologic cancers. In addition, there’s the superficial bladder tumor, which can be treated with BCG.

	However, at the 2014 American Society of Clinical Oncology annual meeting, much-anticipated data was presented about a new immunotherapy agent called anti-PD-L1. It is a monoclonal antibody, a member of the checkpoint modulators growing family, that has demonstrated impressive clinical activity against advanced bladder cancer. It was a small study, with only about 40 patients, but it showed, for the first time, the power of immunotherapy to eradicate metastatic bladder cancer in patients who previously failed chemotherapy. Seventy-one percent of these patients had failed two prior treatments. The response rate was quite astounding at about 50%, with one complete responder and nine partial responders.

	Eventually, if it pans out the way this small study showed, we’ll see immunotherapy replacing chemotherapy as first-line therapy for bladder cancer in the very near future.

Next: The importance of multi-disciplinary clinics

As a urologist, these kinds of treatments raise some questions and concerns. How will these treatments be delivered, and by whom? Will the patient need to travel to an infusion center and, if so, will a medical oncologist be then in charge of the patient’s care? Is there any change in the delivery of immunotherapy that might be more practical to the urologist?

	That’s a very good question. Urologists must face the fact that most of the new generation of selective anti-cancer therapies are not going to come in the form of an oral pill that is easy to prescribe. Delivery might be more complex and require a different type of training. In my mind, as those new therapies will make their way to first-line treatments, multidisciplinary clinics will be the only way for the urologist to stay involved in the care of the patient and help in the decision-making process.

	At UCLA, we have separate clinics for kidney, bladder, and prostate cancers all under one roof of the Institute of Urologic Oncology. The joint clinics include urologists, medical oncologists, and radiation therapists working together and making joint recommendations regarding surgery, immunotherapy, chemotherapy, or radiation, including the sequence of these therapies. In such a way, the urologist maintains full control on his part of the patient’s care. In any other format, urologists will start losing control of the patient and decisions to delay surgery will be done without him. We are already witnessing this trend in the management of kidney cancer in the community.

	The role of, and the need for, surgery in the management of urologic cancers in the era of these new immunotherapies and targeted therapies is currently being redefined. Urologists must take a seat at the table where these critical decisions are being made. This will also require the urologists to participate in the design of meaningful clinical trials. Without clear and well-defined surgical endpoints for these new combination therapies, urologists will be left out and new practice guidelines will be created that will defer many of our mainstream surgical cancer procedures.

	We are already witnessing it in the need for, and timing of, radical nephrectomies in patients with advanced kidney cancer. The role of radical cystectomy in invasive bladder cancer will come next. For example, radical cystectomy is still the Holy Grail for the management of muscle-invasive bladder cancer. But if early anti-PD-L1 data is confirmed in larger studies, it can become first-line therapy with or without surgery. Urologists must be involved in these clinical decisions.

Next: Immunotherapy in the next 5 to 10 years

Where do you see immunotherapy in the next 5 to 10 years? Do you see other cancers and other disease sites where this might be appropriate?

	My prediction is that in the next 5 years, at least half of all oncologic cases will be managed by, or in combination with, immunotherapy. Immunotherapy will replace many existing treatments. Chemotherapy will be relegated to salvage therapy. Cancer therapy will be managed by immunotherapy, hormonal therapy, and targeted cancer therapy. How surgery will be incorporated in this treatment paradigm is yet to be defined and therefore, again, urologists must be active participants in the process.

	As for the second part of your question, hundreds of clinical trials are currently exploring other potential avenues for immunotherapy. Undoubtedly, the utility of immunotherapy will expand beyond our current thinking. One example is sarcoma, a very aggressive type of cancer. For years, at the National Cancer Institute, we tried immunotherapy with interleukin-2, and other types of therapy with very poor responses. However, at the 2014 American Association for Cancer Research annual meeting, Dr. Steven Rosenberg presented data showing that two-thirds of the sarcoma patients he treated with a new form of adoptive cell therapy called engineered TCR experienced significant responses, some of which lasted for several years. This therapy requires only a single infusion of activated T-cells engineered to express a tumor antigen called NY-ESO-1.

 the same group was able to successfully treat a patient with cholangiocarcinoma, a rare type of cancer, using autologous T-cells directed against a specific mutation that occurred in this particular tumor. These examples highlight the great potential for new versions of personalized immunotherapy that are currently being investigated for multiple cancer indications.

Next: "I personally believe that tumor volume will play an important role in response to immunotherapy"

Do you think that tumor volume is going to be an important factor in the delivery of immunotherapy? Will surgery play a part at least in de-bulking some of these tumors?

	I personally believe that tumor volume will play an important role in response to immunotherapy, and I can see the utility for de-bulking ahead of immunotherapy onset. The evidence, however, will have to be established in controlled clinical trials. I recommend starting to ask these questions now; otherwise therapies like anti-PD-1, PD-L1, anti CTLA-4, and others will be advanced to earlier and earlier disease stages without ever fully understanding the role of de-bulking.

	A decade ago, as IL-2 and interferon were introduced for the therapy of advanced kidney cancer, Dr. Robert Flanigan and others conducted an important study investigating the role of cytoreductive nephrectomy for these patients. The data, published in the 

 established the rationale for performing radical nephrectomy before immunotherapy; this became standard of care for many years. The same questions will need to be addressed for the newer forms of immunotherapy.

In immunotherapy with vaccines, you have to have a boost. Is that true with cancer immunotherapy as well?

	Checkpoint inhibitors are monoclonal antibodies that need to be given repetitively every 2 to 3 weeks by IV administration. The newer immunotherapies, in the form of engineered activated T-cells, are currently being tested as single-infusion therapy with no need for additional therapy. These T-cells continue to proliferate in the body and retain memory for many years. Therefore, unlike with vaccines, this is a living treatment that does not require any additional boost. In the future, however, as the field continues to evolve, I can foresee the introduction of combination immunotherapy with intermittent administration of cancer vaccines as boosts. Again, this will have to be tested in clinical trials.

One of the arguments against immunotherapies is the high cost. Are these treatments going to be sustainable from a cost standpoint?

	Yes, these treatments are expensive. But even the best targeted therapies have to be taken chronically and rarely lead to complete cancer remission. With the newer types of immunotherapy, we are facing a growing population of patients with complete response that do not need continuous therapy. Engineered T-cells are given once as a single infusion. So the cost proposition makes more sense as you start to think about the annualized cost of therapy. I also believe as the process is further optimized and automated, the cost will be reduced dramatically over time.

Next: "What’s most important is for young urologists to get involved"

Do you have anything else that you’d like to add?

	What’s most important is for young urologists to get involved. Twenty-seven years ago, I was a fellow at the National Cancer Institute and started to work on immunotherapy. At that time, we talked about mouse experiments; there was no human data. Flashing forward, 

 named cancer immunotherapy its 2013 “Breakthrough of the Year.”

	So we’ve come a long way, but the progress continues to accelerate and the field will keep evolving. This is the most exciting time in my academic career and I’m witnessing rapid changes on almost a daily basis. After many years of basic and molecular research, we are finally equipped with all the right tools to create new therapies and for the first time, we are starting to talk about cancer cures rather than just persistent long remission. The bottom line is this is one of the hottest areas in urology, and young urologists should get involved.

It sounds like we will need to have more postgraduate courses and instructional courses on immunotherapy and practical deliveries of targeted immunotherapy.

	Yes, we will and the Society of Urologic Oncology should take the lead in conducting clinical trials, integrating surgery with other forms of therapy, and educating the members and practicing urologists of all the new developments in the field.

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In this interview, Arie Belldegrun, MD, discusses the benefits of cancer immunotherapy, the importance of a multidisciplinary treatment approach, and what the future holds for this treatment.

Author | J. Brantley Thrasher, MD

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