During the annual meeting of the Large Urology Group Practice Association (LUGPA) in Chicago in November 2013, the organization’s president, Deepak A. Kapoor, MD, completed his 2-year term and handed the gavel to incoming president Juan A. Reyna, MD.

 sat down with both leaders to learn about the successes and challenges LUGPA experienced during Kapoor’s term in office and the issues expected to take center stage under Reyna’s direction.

Kapoor is chairman and CEO of Integrated Medical Professionals, PLLC, in Melville, New York, and Reyna is with Urology San Antonio.

Dr. Kapoor: Proud to Have Increased Organization’s Membership

UCC: What were the biggest issues you tackled during your term as LUGPA’s president?

: One of the things I’m most proud about is that, over my 2-year term, membership has grown by close to 30%. At this point, more than a quarter of all urologists in the United States are LUGPA members, and nearly one-third of independent practicing urologists are in groups that are members of LUGPA. The greatest challenge we’ve been facing is the profound uncertainties that exist around the future of health care. We’re trying to cope with the changes that the Affordable Care Act is going to bring, but so many of the changes are so vague. We also have the continual uncertainty associated with the Sustainable Growth Rate, or SGR issue.

As the private sector is trying to cope with the healthcare exchanges and the expansion of the Medicaid program, urologists have the additional burden of dealing with the myriad changes that are going to be coming down in the Medicare system; in the average urology practice, 45 to 55 percent of patients are covered by Medicare, with the exception of certain subgroups such as pediatric urology. As a consequence, some of the regulatory changes in the Medicare system are of real concern. But we’ve been extremely active in Washington to tell the story of what our member groups can bring, especially in terms of providing tremendous access on a community level in an affordable and high-quality venue. Getting that message out has been extremely important for us.

The other great challenge we’ve seen is the mischaracterization of integrated, comprehensive health care. Unfortunately, this has occurred because medicine is a zero-sum game: If urology practices are providing services [such as radiation therapy, imaging, and laboratory services], that means other people are no longer providing those services. For a urology practice, these business lines enable us to control the quality of services needed to provide care for our patients, but they are extensions of our core skills. For other specialties, that’s all they do, and in an attempt to protect their revenue streams, they’ve resorted to gross distortions to attempt to recapture lost market share via legislative fiat. In the course of that debate, we’ve needed to combat misinformation about our use of in-office ancillary services. Fortunately, physicians in both chambers of Congress have recognized the importance of preserving patient access to these services.

Your organization is composed mainly of large urology groups, and there seems to be a trend toward smaller groups across the country merging and growing. What will this trend mean to the independent practice of urology?

Regardless of practice milieu, every urologist fundamentally has more in common with any other urologist than with physicians practicing in other specialties; therefore, our needs are extremely similar to each other. These synergies enable us to develop group practices in which we can practice at a very high standard while simultaneously reducing overheads through shared economies of scale. When you look across the United States, anywhere in the country where there’s enough population density to support group practice integration, you have seen LUGPA groups develop, often becoming dominant players in their market. It’s very important that people understand that having a large share of the market is not a violation of any type of antitrust rules. In fact, if you’re behaving in a pro-competitive fashion, market share is something that can be very positive and productive. It enables you to deal with third-party payers to ensure that compensation is fair and reasonable, prevent predatory hospital systems from limiting access to genitourinary services, and, most importantly, standardize services across a region to ensure that our specialty is practiced in accordance with the highest medical and ethical standards.

It’s my profound conviction that, going forward, the integration of urologists into larger group practice is going to be the backbone that ensures the survival of the independent specialty of urology. I’m really very excited about where we are as a specialty and where we are going.

With the field facing a shortage of urologists, what can be done to increase the number of new doctors taking up this specialty? Can LUGPA be part of a solution?

Let’s take a look at some of the fundamentals about urology: 1) There are already not enough urologists in the United States; 2) The need for urological services is going to be expanding as the population ages; 3) The attrition rate for urologists to death and retirement exceeds the graduation rate from urology residencies; and 4) The average age of the urologist is 55, making it the second-oldest specialty after cardiothoracic surgery. What you see is a situation where the relative undersupply of urologists—already dramatic in more rural areas in the country&mdash;is actually going to become much more profound.

This requires the coordinated efforts of not just LUGPA, but every urological society. There’s a tremendous need to have increased resources devoted to residency funding. And that will require us to abandon the historical town-versus-gown differences that have separated us.

We’re seeing an era in which the differences between academic urology and independent urology are becoming profoundly blurred. Community urologists can provide very sophisticated clinical services and produce similar patient outcomes as academic centers; simultaneously, academic physicians are finding it more and more necessary to support their departments on their clinical productivity. The opportunity exists right now to put aside those historical differences and work together on issues that are common to us. Certainly, one cause we can all work together on is to ensure that adequate resources are in place for residency training going forward, because getting the best and brightest minds into urology serves all of our interests.

As you prepare to leave office, how do you see this year’s LUGPA meeting benefiting urologists?

What’s exciting about this particular meeting is that the people here are exclusively thought leaders. Everybody here leads a group and everybody here is responsible for understanding recent regulatory changes, and not only explaining that to their doctors but implementing policies and procedures so their practices can adapt.

Because the people who come here are extremely high-level decision makers, the meeting provides the opportunity to network with other individuals who face similar challenges. If you are coping with a predatory hospital system, if you’re dealing with third-party payers that won’t negotiate, if you’re having problems getting your own practitioners to comply with your policies, it’s guaranteed that there’s somebody else here who has faced those problems and come up with real-world solutions.

This is the only forum in the world where the individuals dealing with those problems are here all at one place and one time. So I’m excited about what this meeting offers to our members, and I think that, as we go forward, this ability to brainstorm and network with other individuals who are dealing with the same issues is only going to become more valuable.

Dr. Reyna: Opening Doors of Organization to Smaller Urology Groups

UCC: What are your top goals as LUGPA president?

My vision is a little different from where we’ve been as an organization for the past several years. During that time, we’ve been fighting a battle in Washington, DC, to retain our right as large groups to offer in-office ancillary services. We have a tremendous team doing advocacy for us on the hill and protecting those in-office ancillaries, and I in no way want to diminish those efforts. But I do want to increase our efforts this year to try to give back to the rest of our membership. A lot of our members don’t have the big radiation units and the big pathology units and the CT scanners that the big groups have, and my hope is to give back to all the groups in LUGPA by providing for them the services, information, and initiatives that will help them grow and become more successful.

We did some rebranding this year, and our new logo is "LUGPA: Integrated Practices, Comprehensive Care.’ ‘ "Large"is nowhere included in that rebranding. Our hope is to start reaching out to smaller groups, touch base with them, and get a two-way dialogue going between what they need and what we can provide—and really sometimes what we need, since they’ve had successes that we can learn from, as well.

There are a lot of less-than-kosher initiatives out there driving people to think that they have to be part of hospital systems. I’m not necessarily saying that hospital systems are a horrible way to practice, but if urologists want to maintain their independence, we are trying to provide ideas for them in terms of collaborative efforts and other revenue-producing efforts.

You mentioned that one of those efforts involves a men’s health initiative in which LUGPA’s member practices can participate. Can you tell us more about that?

Here’s an excellent way of bringing more work to your practice, increasing your revenue. It’s an initiative that Dr Peter Knapp [of Urology of Indiana] started, called "Your Numbers Matter,"that is being kicked off here at this meeting. The idea is that men need to know certain numbers that are very important to them—their PSAs, testosterones, cholesterols&mdash;and we are providing an entire marketing package to all practices within LUGPA, for free, that will help them communicate with patients about this issue. We will provide posters and flyers that practices can display in their offices, and there are letters made out to patients and letters dedicated to referring physicians. There are a number of things that will be done under this initiative that are quite unique, and all the heavy lifting is already done. It’s just a matter of practices tagging their logos onto this initiative and making it their own.

What do you hope attendees have gotten out of this annual meeting?

At every meeting, we try to highlight the newest of the therapies available. We don’t do presentations that are pro or anti any particular drug, but just provide solid information about the treatments out there. My hope is that, when people come to the meeting, they do learn clinical information. But even more so, I hope they will get information about how to thrive within the current healthcare changes.

There will be a tremendous number of changes starting very soon, and there’s no reason why we each have to learn how to do any given method of reimbursement, for example, over and over again. We can start to share what is working, and what isn’t, when it comes to newer reimbursement strategies. We’d like to serve as a clearinghouse for that kind of information, so groups can say, "Well, the guys in Indianapolis are doing a very unique thing with the medical home concept; maybe that’s where we want to go with our accountable care organization in our city."

Articles

During the annual meeting of the Large Urology Group Practice Association (LUGPA) in Chicago in November 2013, the organization's president, Deepak A. Kapoor, MD, completed his 2-year term and handed the gavel to incoming president Juan A. Reyna, MD.

LUGPA Aims to Help Practices Thrive: Leaders Discuss Progress and Goals

When I first entered practice in 1990, I was fortunate to have senior partners and colleagues who offered sage advice, much of it based on retrospective analysis of their own successes and failures over time.

Two of the most memorable really struck a chord:

1.Take time to watch your children grow up.

2.The only thing of value that you have and the government cannot tax is your free time.

Using that as my modus operandi, from day one of my new career I tried to take Thursday afternoons and be true to those core statements. It did allow me precious time with both my children during those formative years before they started school. Once they were enrolled, I was able to engage with friends and peers, often walking the golf course at our local club. Both have provided great memories that I will always cherish and never regret. One particular sweltering Thursday in the dead of summer, I was walking the number 3 fairway with a friend in the investment industry. He inquired if I was taking new patients, as he would like to make an appointment for a urologic issue. My response at the time was yes, I will always see new patients, but what did he know about me as a urologist? He promptly stated that I had taken care of many of our friends, as well as his mother, who actually had staghorn calculus in a solitary kidney (one of my partners and I did an anatrophic pyelolithotomy….oh, the good old days!). That was true, but what data did he have that justified his trust in me, besides my reputation? I said that if I were going to invest my money with him, I would like to know what his returns were over time, irrespective of our friendship; why did physicians not have to worry about providing outcome data, just like the rest of the world? (I did, by the way, end up doing his vasectomy.)

If you think about the mechanism by which patients have historically ended up in our offices, it has been due to relationships that we have forged over time. We may have overlapped with our referring physicians in medical school, residency, the golf course, the neighborhood, or our children’s school. They refer their patients and, to the best of our ability, we try to provide optimal care. The end result, we hope, is that more patients are referred, and that we establish reputations as caring and “good” physicians. I still believe in that fundamental. However, we are coming into a time where we will have to show that we are better, not just by reputation, but by providing outcome data that differentiate us from others. Otherwise, the ever-growing number of narrow networks, ACOs, etc, despite our perceived reputations, may not allow their insured to grace our offices.

So, what does good look like? I guess the simple answer is: It depends. If you ask that question to a payer or insurance company, it relates to how much, or little, money they have to pay out in claims. If you ask that to a government bureaucrat, their response may be one that actually measures a process, and compliance.

Did the patient get his or her beta blocker or antibiotic at the appropriate time during surgery? What is the patient’s cholesterol level or hemoglobin A1C? Was incentive spirometry ordered postoperatively? Did you ask the Medicare female patient that you are seeing in the office for a renal mass about incontinence? Easy to measure and get a number, but is that really the measure of quality? What IS good?

The real answer should be: Good is what is important to the patient. Do I live longer because you have treated my muscle invasive bladder cancer by removing my bladder? If so, what will be my quality of life? Will my continence or erectile function be maintained after this robotic-assisted prostatectomy? How long can I expect to stay dry and not wear pads after this sling procedure? How quickly can I return to work after surgery? Right now, we do not have the answers to any of these questions as individual surgeons, and we will not agree on what are the right questions to answer. We can cite population-based data, but very few of us know exactly how well we are doing across disease states.

Our concerns up to now have been about volume and profitability of services. Moving forward as payment reform shifts, we need to transform to a value-driven system that focuses on maximizing outcomes for our patients. In order to get there, however, we need to define the outcomes and know what our true costs are to achieve those endpoints. If we have better outcomes, the costs will ultimately decrease. That will make us more attractive to payers and our volumes will increase, as will our market share. We need to begin this process and not let an outside agency determine what the metrics are going to be. If we acknowledge that maximizing value for the patient is the new fundamental strategy, we as physicians are vital to the most important relationship that exists, and that is between us and our patients.

As I write this, I feel a little bit like Tom Cruise in the opening minutes of the movie “Jerry Maguire,” where, in a business of “more is better,” he was advocating quality, personal attention, and personal relationship. That movie was in 1996. We are only 20 years behind, but I hope that we can experience the same ending and be the Ambassadors of Kwan.

What Does Good Look Like?

Men with clinically localized prostate cancer who were treated with radiotherapy were more likely, over the subsequent 5 years, to be admitted to a hospital, undergo rectal, anal, or open surgical procedures, or develop secondary malignancies than men treated with radical prostatectomy, although those in the surgery group faced a higher risk for urological procedures, according to the results of a study published recently in the British Journal of Anaesthesia. Nam et al conducted the study as a means of helping these patients and their physicians to choose treatment options, since it is not yet clear whether survival is better with radiotherapy versus prostatectomy, and decisions are often made based on patient preference. “Patients want to know the frequencies and severities of various complications associated with different treatments,” the authors wrote.

The investigators did not look at the incidence of urinary incontinence or erectile dysfunction, saying that these potential side effects of surgery or radiotherapy have been the focus of many studies in the past. Instead, they considered complications including post-treatment urinary or rectal bleeding; infection in the urinary or lower gastrointestinal tract; recto-urethral fistulae; an increased prevalence of secondary malignancies; and other complications treated on an outpatient basis that might necessitate minimally invasive urological procedures (eg, cystoscopy) or other endoscopic procedures (eg, colonoscopy). Their study, they said, was the first to comprehensively assess these endpoints after radical prostatectomy or radiotherapy.

“Accurate knowledge of the incidence of such complications would enhance patient-centered decision making,” they wrote. In the population-based, retrospective cohort study, the authors included all men aged 18 years and older who underwent a radical prostatectomy or had radiotherapy for localized prostate cancer between January1, 2002, and December 31, 2009, in Ontario. They excluded patients who underwent laparoscopic or robotic prostatectomy, since the procedure was not routinely used in Ontario during the study period, and also those who underwent both radiation treatment and radical prostatectomy. A total of 3265 men, found in the records of Ontario’s government-operated healthcare system, were included in the study. Of these patients, 1570 underwent radical prostatectomy and 1695 had radiotherapy. The authors also identified a control group with no history of prostate cancer for comparison.

The study’s endpoints were the 5-year cumulative incidence of hospital admissions; urological, rectal, or anal procedures; open surgical procedures; and secondary malignancies.

The authors found that patients given radiotherapy had a higher incidence of hospital admissions, rectal or anal procedures, open surgical procedures, and secondary malignancies at 5 years than did those who underwent surgery (adjusted hazard ratios [HRs] 2.08—10.8, 

 <.0001). However, the number of urological procedures was lower in the radiotherapy than in the surgery group (adjusted hazard ratio 0.66, 95% CI 0.63—0.69; 

The investigators also looked at a subgroup of men in the targeted population who were admitted to the hospital and stayed more than 1 night, finding that was more likely in patients who had undergone radiotherapy (3.3%, 95% CI, 3.0—3.6) as opposed to surgery (1.5%, 1.3–1.7; 

 <.0001). The adjusted HR for hospital admission of longer than 1 day for patients who had radiotherapy compared with those who had surgery was 5.55 (95% CI, 3.55— 8.67, 

Most of the hospital admissions in the surgical group were for urinary obstruction, whereas hospital admissions in the radiotherapy group were largely due to radiation proctitis, the authors wrote. Open surgical procedures were the least frequent of all adverse outcomes, they noted.

In assessing the development of second malignancies from 5 to 9 years after treatment, the authors found a risk of 113 per 100,000 person-years in the surgery group and 309 per 100,000 person-years in the radiotherapy group. The cumulative incidence in years 5 to 9 was 4.5% in the radiotherapy group and 1.8% in the surgery group. The most common site of secondary malignancy was the gastrointestinal tract, and increased risk was also reported for lung, hematological, and genitourinary cancers. To establish whether the development of such cancers was associated with treatment, the authors compared results with the cancer incidence in the general population.

“Increasing age and comorbidity were associated with higher incidence of complications, but the type of treatment was the most important determinant,” the authors concluded. “Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy.”

Nam RK, Cheung P, Herschorn S, et al. Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radio-therapy for prostate cancer: a population-based cohort study. Lancet. Published online ahead of print, January 17, 2014. 

Men with clinically localized prostate cancer who were treated with radiotherapy were more likely, over the subsequent 5 years, to be admitted to a hospital, undergo rectal, anal, or open surgical procedures, or develop secondary malignancies than men treated with radical prostatectomy

Hospital Admissions and Rectal Procedures are More Common After Radiotherapy Than Prostatectomy

Brisk walking helps normalize the shape of vessels in prostate cancer tumors, which may make the tumors less aggressive and more responsive to anti-cancer therapies, a team of investigators reported at the AACRProstate Cancer Foundation Conference on Advances in Prostate Cancer Research, held January 18-21 in San Diego, California.

The study’s authors, van Blarigan et al, had demonstrated in a previous study that higher amounts of small, irregularly spaced vessels in human prostate tumors resulted in a greater risk for lethal disease. They embarked on the current investigation because of other previous data showing that exercise normalized tumor vasculature in mice with prostate cancer; in addition, the authors wrote, brisk walking and vigorous activity have been associated with a lower risk of prostate cancer recurrence and mortality in humans.

In the retrospective study, the team looked at prediagnostic physical activity and vessel morphology in 572 men who underwent radical prostatectomy or transurethral resection of the prostate. The men were all participants in the Health Professionals Follow-up Study, launched in 1986 to consider the effects of nutritional and lifestyle factors on the incidence of serious illnesses, such as cancer and heart disease. Every 2 years, participants fill out questionnaires that gauge whether they have diseases and what medications they take, as well as their involvement in activities such as smoking and exercise. The men fill out questionnaires about their dietary habits every 4 years.

Before being diagnosed, the men had filled out an average of nearly 5 questionnaires assessing their levels of total, vigorous, and nonvigorous activity, as well as their walking pace. Vessel morphology—including vessel size, regularity of the vessel lumen, and microvessel density&mdash;was assessed through the analysis of tumor-section images stained to detect the expression of the protein CD34. The team of investigators considered the relationship between the cohort’s level of physical activity and their vessel morphology.

They found that prediagnosis brisk walking was associated with more regularly shaped vessels in prostate tumors. Men who walked the fastest, from 3.3 to 4.5 miles per hour, had 8% more regularly shaped vessels than men who walked the most slowly, from 1.5 to 2.5 miles per hour (

 = .01). Brisk walking was also associated with larger vessels (

Walking pace did not demonstrate any effect on microvessel density, and the amount of time spent walking did not prove meaningful when it came to vessel morphology in general. The authors suggested that further studies should investigate whether increasing brisk walking after prostate cancer diagnosis will fuel positive changes in a man’s tumor vasculature.

van Blarigan EV, Gerstenberger J, Jones L, et al. Physical activity and tumor vessel morphology among men with prostate cancer. Presented at: the AACR-Prostate Cancer Foundation Conference on Advances in Prostate Cancer Research; January 18-21, 2014; San Diego, California. Abstract 275791_1. 

Brisk walking helps normalize the shape of vessels in prostate cancer tumors, which may make the tumors less aggressive and more responsive to anti-cancer therapies

Brisk Walking May Lower Prostate Cancer Aggressiveness

		Dana-Farber Cancer Institute/Lank Center for Genitourinary Oncology

Urothelial carcinoma is the most common histologic subtype of bladder cancer and accounts for 90% of all cases.

 In the United Sates, more than 72,000 new cases of bladder cancer and about 15,000 deaths were estimated in 2013.

In patients with muscle invasive bladder cancers (MIBC), pathologic stage and nodal status are the most important prognostic factors for progression and overall survival (OS).

 Radical cystectomy alone is associated with a 5-year survival rate of 80% for organ-confined disease without lymph node metastasis.

 However, patients with extravesical disease and patients with lymph node involvement have a 5-year survival rate of approximately 40-50% and 15-35%, respectively.

Contemporary management of patients with MIBC consists of a multimodality treatment including surgery, cytotoxic systemic chemotherapy, and, for selected patients, chemoradiation with the objective of bladder preservation. While chemotherapy is part of the standard of care in the neoadjuvant setting, studies show it is infrequently used, and while some of the benefits of cytotoxic therapy alternatively may be attained via adjuvant treatment, the effectiveness of that strategy is still under investigation.

Here, we review the data supporting the standard use of neoadjuvant and adjuvant chemotherapy for patients with MIBC.

Neoadjuvant Treatment Demonstrates Mild Benefit Neoadjuvant chemotherapy (NC) allows the in vivo assessment of the response in the primary tumor, indicating whether the individual’s tumor is responsive to a specific chemotherapy regimen. In addition, the magnitude of the chemotherapy response correlates with long-term remission or survival.

There can be some drawbacks to neoadjuvant chemotherapy use in this population. For patients without major responses to NC, the delay of definitive therapy may potentially increase the risk of disease progression. Furthermore, pre-surgical staging is not always correctly evaluated before radical cystectomy, and some low-risk patients may unnecessarily receive chemotherapy.

 However, several clinical trials have demonstrated that there is a role for NC in eligible patients with MIBC.

The Nordic I trial randomized 311 patients with cT1G3-T4NxM0 disease to two cycles of cisplatin and doxorubicin versus no chemotherapy. All patients received radiation therapy before radical cystectomy. There was no significant difference in OS and cancer-specific survival (CSS). However, the subgroup of patients who presented with pT3-T4 disease and received NC had a 15% absolute survival benefit.

 The Nordic Cystectomy-2 trial enrolled 309 patients who were randomized to receive three cycles of neoadjuvant cisplatin and methotrexate or surgery alone. No statistically significant differences in OS were found between the two groups (53% vs 46%)

While these two studies were underpowered and used what would now be considered suboptimal chemotherapy, a combined analysis of these two trials revealed a trend for better OS favoring NC (OS: 56% vs 48%; 

A large prospective trial (EORTC-MRC) evaluated 976 patients with cT2 grade 3-T4N0 MIBC. Patients were randomized to receive three cycles of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) or no therapy before local definitive therapy.

 In this trial, local therapy was radiotherapy in 42% of patients, radical cystectomy in 50%, and a combination of surgery and radiotherapy in 8%. Updated long-term follow-up of these patients showed a statistically significant benefit in OS (36% vs 30%; HR: 0.84; 

 Following NC, pathologic complete response (pCR) was observed in 32.5% compared with 12.3% with surgery alone.

Southwest Oncology Group (SWOG) 8710 was a prospective randomized controlled trial of 317 patients with cT2-T4aN0M0 MIBC to compare three cycles of MVAC chemotherapy (methotrexate,vinblastine, doxorubicin, and cisplatin) preceding radical cystectomy against cystectomy alone.

 The pCR rate with MVAC was 38% compared with 12% with surgery alone. Although NC did not provide a statistically significant benefit in OS (57% vs 43%; 

 = 0.06), the original planned analysis was defined with one-sided 

 < 0.05, and this goal was achieved. In addition, NC did not increase surgeryrelated complications, and median OS was poor for patients with residual muscle-invasive disease or lymph node-positive disease: 3.4 and 2.4 years, respectively.

Before the publication of the updated positive results of the EORTC-MRC trial,12 a meta-analysis of 11 randomized trials of NC included 3005 patients, and an absolute OS benefit of 5% (HR: 0.86; 95% CI, 0.77—0.95; 

 = .003) favoring platinum-based combinations was reported. Cisplatin was the platinum agent used in the vast majority of patients (>90%), with carboplatin used in 6-7% of patients. Additionally, platinum-based combinations appeared to be superior to platinum monotherapy.

	Adjuvant Treatment Benefit Suggested, but Not Definitive

Due to the low rates of adoption of neoadjuvant chemotherapy, clinicians are often faced with the decision of whether or not to recommend adjuvant chemotherapy (AC) for many moderate- to high-risk patients.

In a randomized trial, 140 patients were assigned to receive two neoadjuvant cycles followed by three adjuvant cycles after surgery compared to five adjuvant cycles of MVAC. This study was unable to demonstrate a survival difference, but there was a suggestion that NC may be more feasible than AC. Only 54 of 70 patients (77%) received two or more cycles of MVAC after surgery, whereas 68 of 70 (97%) received at least two cycles when assigned to initial neoadjuvant MVAC.

Larger but incomplete contemporary studies of AC have also failed to provide definitive supportive evidence for routinely recommending AC. The prospective Italian Multicenter Trial of 194 patients was underpowered to demonstrate a survival difference in patients receiving four cycles of adjuvant gemcitabine and cisplatin (GC) (

 The Spanish Oncology Genitourinary Group (SOGUG) trial was designed to randomize 340 patients with T3-T4 or node-positive disease to treatment using four cycles of paclitaxel, gemcitabine, and cisplatin (PGC) or observation. However, the trial was prematurely closed after only 142 patients were enrolled. At a median follow-up of 51 months, adjuvant PGC resulted in a significant increase in OS compared to no chemotherapy (60% versus 30%, HR: 0.44).

The largest study of AC was designed by EORTC to compare deferred therapy at the time of recurrence with adjuvant therapy according to physician choice of GC, MVAC, or dose-dense MVAC.

This trial had a goal of 660 patients but was closed after enrollment of only 242 due to slow accrual. Follow-up results are expected.

Meanwhile, an innovative biomarker-driven trial in patients with organ-confined disease (pT1-2, N0M0) randomized patients with altered p53 levels to three cycles of MVAC versus observation. There was no difference in relapse-free survival and no impact on any of the outcome measures based on p53 status.

Recently, an updated meta-analysis of nine randomized AC trials including 945 patients reported a disease-free survival (DFS) and OS benefit (HR: 0.77; CI, 0.59—0.99; 

 = .049) in MIBC patients who received adjuvant chemotherapy after radical cystectomy compared with those who underwent surgery alone.

 Additionally, lymph node-positive patients appear to have a greater DFS benefit than lymph node-negative patients. There is still insufficient evidence to support the routine use of adjuvant chemotherapy, and NC is the standard. Nonetheless, many physicians consider AC to be reasonable in patients who have not received NC, who have pathologic extravesical and/or node-positive disease, and who are eligible to receive cisplatin-based combination therapy.

Physicians are sometimes reluctant to pursue NC because they fear that it may increase the incidence of perioperative morbidity.

However, when neoadjuvant and adjuvant chemotherapy have been compared, NC did not increase perioperative morbidity.

Cisplatin-based NC is an established standard, improving overall survival in MIBC. However, less than 20% of patients undergoing radical cystectomy actually receive this modality of treatment, and its standard implementation needs to be pursued.

At the same time, we must look for ways to improve the efficacy of these treatments. Dose intensification of MVAC has been studied in several prospective studies with the aim of increasing pCR rates while minimizing local treatment delay and avoiding the shortcomings of a potential curative surgery in non-responders.

The addition of new agents to cisplatin-based chemotherapies may improve the pCR rate beyond the 30% observed in patients with cT2-4aN0M0 who are treated with cisplatin-based chemotherapy alone. Some attempts to add bevacizumab have been reported.

 However, it is still uncertain whether increasing complete response with dose intensification or the addition of targeted therapies will result in better long-term outcomes.

In the genomic era, understanding MIBC biology may lead to improvements in therapeutics. The Cancer Genome Atlas has allowed the molecular characterization of a large number of tumors, opening new avenues in the treatment of urothelial tumors. This may help us identify new targets for therapeutic interventions and biomarkers that can predict response to therapies, making it easier for us to appropriately select patients for the therapeutic strategies that are on the horizon.

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			Millikan R, Dinney C, Swanson D, et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant MVAC versus cystectomy with both preoperative and postoperative M-VAC. 

			Cognetti F, Ruggeri EM, Felici A, et al. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. 

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 

			L. G. Paz-Ares ES, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. Journal of Clinical Oncology - ASCO meeting abstratcs. 2010;Vol 28(No 18_suppl (June 20 Supplement), 2010: LBA4518).

			Stadler WM, Lerner SP, Groshen S, et al. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. 

			Leow JJ, Martin-Doyle W, Rajagopal PS, et al. Adjuvant Chemotherapy for Invasive Bladder Cancer: A 2013 Updated Systematic Review and Meta-Analysis of Randomized Trials. 

			Apolo AB, Grossman HB, Bajorin D, Steinberg G, Kamat AM. Practical use of perioperative chemotherapy for muscle-invasive bladder cancer: summary of session at the Society of Urologic Oncology annual meeting. Urologic oncology. Nov-Dec 2012;30(6):772-780.

			David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. 

			Toni K. Choueiri SJJ, Angela Q. Qu, Christopher Sweeney, Leonard Joseph Appleman, Christopher P.G. Tretter, Glenn J. Bubley, Aymen Elfiky, Rachel Park, Edward C. Stack, Sabina Signoretti, Meghara K. Walsh, Graeme Steele, Michelle S. Hirsch, Katherine Maragaret Krajewski, Mary-Ellen Taplin, Jonathan E. Rosenberg and Robert W. Ross. A phase II multicenter study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy with pegfilgrastim support in patients (pts) muscle-invasive urothelial cancer (MIUC): Safety, pathologic, radiologic, and molecular correlates. 

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			Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. 

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			Arlene O. Siefker-Radtke AMK, Paul G. Corn, Surena F. Matin, H. Barton Grossman, Randall E. Millikan, Colin P.N. Dinney. Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the M. D. Anderson Cancer Center. 

A review by AndrÃ© P. Fay, MD, on the data supporting the standard use of neoadjuvant and adjuvant chemotherapy for patients with muscle invasive bladder cancers.

Chemotherapy is Indicated, Yet Used Infrequently, in Patients With MIBC

Some patients with micropapillary urothelial carcinoma face a three-fold risk of cancer death because their disease amplifies HER2 and overexpresses its protein product, and there may be a role for treatment of the condition with HER2- targeted agent trastuzumab, which has vastly increased the odds of survival for eligible patients with breast cancer, according to the results of a recent study.

 late last year, Schneider et al compared a group of patients with micropapillary urothelial carcinoma against a cohort of patients with typical urothelial carcinoma, to test the frequency of amplification and protein expression and their effect on cancer-specific survival. All of the patients had undergone radical cystectomy at the Mayo Clinic between 1980 and 2008. The investigators assessed HER2 amplification via fluorescence in situ hybridization (FISH) and protein expression via immunohistochemistry.

They found HER2 amplification in 9 (15%) of 61 micropapillary carcinomas compared with 9 (9%) of 100 urothelial carcinomas. In patients with micropapillary carcinoma, HER2 amplification was associated with a nearly three-fold increased risk of cancer death, and on multivariate analysis, it remained associated with an increased risk of death from bladder cancer (hazard ratio 4.3; 

 = .0008). No association was found between HER2 amplification and cancer-specific survival in patients with typical urothelial carcinoma, the investigators wrote.

The researchers concluded that HER2 amplification is more frequent in micropapillary urothelial carcinoma than in typical urothelial carcinoma, and that patients with micropapillary carcinoma who have the amplification face worse cancer-specific survival than those who do not.

“Identification of [HER2] amplification in micropapillary carcinoma could provide important prognostic information and possibly provide a role for [HER2] targeted therapy,” they suggested.

“These findings show it is critical for pathologists to recognize this type of bladder cancer and that providers should be aware of and order the appropriate tests,” added John C. Cheville, MD, a Mayo Clinic pathologist and lead author of the study, in a written statement about the findings posted online by the institution. “This will be essential for any clinical trial examining the effectiveness of trastuzmab in treating MPUC.”

Some patients with micropapillary urothelial carcinoma face a three-fold risk of cancer death because their disease amplifies HER2 and overexpresses its protein product, and there may be a role for treatment of the condition with HER2- targeted agent trastuzumab, which has vastly increased the odds of survival for eligible patients with breast cancer.

Some With Micropapillary Urothelial Carcinoma May Benefit From HER2-Targeted Treatment

Long-term outcomes for patients with prostate cancer following radical prostatectomy were better when a spinal or epidural pain block was added to general anesthesia during the surgery, according to the results of a large, retrospective study published recently in the

Authors Scavonetto et al found that systemic tumor progression and all-cause mortality were lower in the group given the combined painmanagement strategy during surgery, compared with the group that got anesthesia only. One reason, they postulate, is that the patients given the combination strategy needed fewer perioperative opioids, which might suppress the immune system and thus promote tumor recurrence.

The authors embarked on the study because, in animals, spinal or epidural pain blocks have proven to decrease the need for systemic opioid administration, as well as two other factors that can impair the body’s defenses against cancer: the surgical stress response, and the use of volatile anesthetics.

The team sought to determine whether those dynamics hold true in humans, after smaller studies brought mixed results. Their own study was unique, they wrote, because it relied on the 23,000-patient Mayo Clinic Radical Prostatectomy Registry, one of the world’s largest.

Specifically, their study was designed to investigate whether adding spinal or epidural pain blocks to general anesthesia reduces cancer recurrence, systemic cancer progression, cancer mortality, and all-cause mortality.

Using the prostatectomy registry along with Mayo’s anesthesia database and electronic medical records, the investigators identified patients who had undergone radical prostatectomy for adenocarcinoma between January 1, 1991 and December 31, 2005.

A total of 1642 patients given the combined anesthesia strategy were matched 1:1 with patients who had received general anesthesia alone.

Of the patients given the dual anesthetic strategy, 83% got neuraxial analgesia in the form of a spinal block with morphine, and, less frequently, hydromorphone, the authors specified. Perioperative opioids included morphine, fentanyl, hydrocodone, hydromorphone, meperidine, oxycodone, oxymorphone, propoxyphene, and sufentanil.

“As expected, systemic opioid use was reduced in patients given general/neuraxial anaesthesia, although not entirely eliminated,” the authors wrote.

Follow-up occurred at a median 8.6 years for patients who received the dual anesthetic strategy and a median 9 years for patients given general anesthesia alone.

In a conclusion they deemed their most important, the investigators found that patients given anesthesia alone faced an increased risk of systemic cancer progression (hazard ratio [HR] = 2.73, 

 <.001). The authors also found that patients given anesthesia alone had a higher risk of prostate cancer mortality (HR = 2.43, 

 = .048) and greater overall mortality (HR = 1.35, 

“In our multivariable model that included covariates for individual comorbidities, positive surgical margins, and adjuvant treatment, systemic progression was greater in general anaesthesia- only patients [adjusted HR = 2.81, 

 = .008], as was overall mortality [adjusted HR = 1.32,

While there weren’t enough prostate cancer deaths to conduct the fully adjusted multivariable model, the study showed some evidence (though not statistically significant) that general anesthesia alone was associated with a higher rate of deaths from the disease (HR = 2.2, 

The team pointed out some limitations of their study.

“We are unable to attribute which component(s) of neuraxial anaesthesia improved oncological outcomes,” they wrote. “We hypothesize that a reduction in systemic opioids is an important potential component to improved outcome, but this assumption is speculative and other components may have played a role. For example, some local anaesthetics—notably lidocaine&mdash;have distinct systemic effects independent from their action on nerve conduction. Another possibility is that patients who received neuraxial anaesthesia would require lower concentration of volatile anaesthetic.”

Their results, they suggested, should be tested in prospective, randomized clinical trials.

Scavonetto F, Yeoh TY, Umbreit EC, et al. Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study. 

. Published online ahead of print, December 16, 2013. 

Long-term outcomes for patients with prostate cancer following radical prostatectomy were better when a spinal or epidural pain block was added to general anesthesia during the surgery.