Neoadjuvant dose-dense gemcitabine and cisplatin for bladder cancer

	This single-arm phase II study will test the use of neoadjuvant dose-dense gemcitabine and cisplatin in patients with muscle-invasive bladder cancer who plan to undergo cystectomy with curative intent. An initial transurethral biopsy tissue may be obtained at an outside institution but must be confirmed by pathologic review at a study site. Patients will undergo radiographic staging before the start of chemotherapy and after the completion of chemotherapy and surgery. Patients will continue on surveillance follow-up per National Comprehensive Cancer Network guidelines following surgery for a total of 5 years from study enrollment or until death. Treatment with 3 cycles of dose-dense gemcitabine and cisplatin will be administered on an inpatient or outpatient basis. The primary outcome measure is the rate of complete response at cystectomy. Secondary outcome measures include treatment tolerability, overall survival (OS), and relapse-free survival. The investigators will also analyze molecular markers of chemotherapy resistance in tissue specimens from cystectomy and transurethral resection of bladder tumor specimens, when available, in order to gauge their predictability for chemotherapy efficacy and survival.	

 section is intended to stimulate discussion about ongoing clinical trials and to promote collaboration across the urology community. 

 presents summaries of ongoing research relating to a variety of urologic cancers.

Docetaxel and lapatinib for metastatic transitional cell carcinoma of the bladder

 University of Southern California/Norris Comprehensive Cancer Center

This phase II study will assess the efficacy of 1250 mg of lapatinib ditosylate combined with docetaxel in patients with metastatic, previously treated transitional cell carcinoma of the bladder. Individuals are eligible provided they have locally recurrent or advanced, nonresectable or stage IV transitional cell carcinoma and have undergone prior platinum salt-based chemotherapy for their disease. Patients are also required to have tumor tissue available for evaluation for epidermal growth factor receptor and human epidermal growth factor receptor 2/neu status. Study participants will receive docetaxel IV over one hour on day 1 and lapatinib ditosylate PO daily for 21 days; the regimen is repeated every 21 days until disease progression or unacceptable toxicity. The primary outcome measure is progression-free survival (PFS). Secondary outcome measures include objective response rate (ORR), OS, and treatment safety and tolerability.

Cabazitaxel versus standard treatment for metastatic castration-resistant prostate cancer

This phase III study will test whether first-line cabazitaxel in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) is superior to docetaxel. Both treatment groups will receive concurrent prednisone. Cabazitaxel is a novel taxane active in D-sensitive and -resistant tumor models. Docetaxel/prednisone as first-line chemotherapy in patients with mCRPC is the current standard of care; however, treatment is not curative, and D-resistant disease typically develops. Patients with ECOG performance status of 0-2, histologically/cytologically confirmed metastatic prostate adenocarcinoma with no prior chemotherapy, and with disease progression following medical or surgical castration are eligible. The primary endpoint is OS. Secondary endpoints include PFS, radiologic PFS, tumor response in measurable disease, prostate-specific antigen (PSA) response and PSA PFS, pain response and pain PFS, time to occurrence of any skeletal-related events, safety profile, and health-related quality of life. Cabazitaxel pharmacokinetics and pharmacogenomics will be assessed in patient subgroups.

 Medivation, Inc and Astellas Pharma, Inc

This phase II study will test the effect of neoadjuvant androgen receptor (AR) blockade with AR inhibition alone using MDV3100 or combined with maximal suppression of androgens involving MDV3100 plus leuprolide and dutasteride. MDV3100 is a potent AR-signaling inhibitor (ARSI) that inhibits AR signaling via three mechanisms: inhibition of androgen binding to AR, inhibition of AR nuclear translocation, and inhibition of nuclear AR-DNA binding. The study population includes men with treatment-naïve, localized prostate cancer who are candidates for radical prostatectomy and have either a PSA greater than 10 ng/mL or Gleason score of 7 (4 + 3) or higher with 3 or more cores containing tumor and no evidence of metastatic/nodal disease. All patients receive MDV3100 (160 mg/day orally); those randomized to MDV3100 plus leuprolide and dutasteride therapy also receive leuprolide (22.5 mg IM every 3 months) and dutasteride (0.5 mg/day orally). The primary efficacy endpoint is pathological complete response rate at the time of radical prostatectomy.

This phase III study will compare the investigational agent orteronel (TAK-700) plus prednisone versus placebo plus prednisone in patients with mCRPC that has progressed during or following docetaxelbased therapy. Orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In order to be eligible, patients must have evidence of disease progression during or after receiving a total of 360 mg/m

 docetaxel or more within a 6-month period. Patients who cannot tolerate docetaxel or who have progressive disease before receiving 360 mg/m

 or more are also eligible if they have received at least 225 mg/m

 of docetaxel within a 6-month period and satisfy the other inclusion criteria, which include radiographically documented metastatic disease and baseline testosterone level lower than 50 ng/dL following surgical or medical castration. The primary endpoint is OS. Secondary endpoints include radiographic PFS, PSA decrease of 50% or greater at 12 weeks, pain response at 12 weeks, safety, time to PSA progression, ORR by RECIST, circulating tumor cell and endocrine marker changes, and patientreported outcomes. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity.

Hormone therapy, radiation therapy, and TAK-700 for prostate cancer

This phase III study will compare standard treatment involving androgen-deprivation therapy with radiotherapy versus standard treatment with the addition of 24 months of steroid 17alpha-monooxygenase TAK- 700 in men with clinically localized prostate cancer with unfavorable prognostic features. TAK-700 (orteronel) is a novel, selective, and potent inhibitor of 17,20-lyase. In order to be eligible, patients must have a histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to enrollment with a high risk of recurrence as determined by one of the following combinations: Gleason Score (GS) ≥ 9, PSA ≤ 150 ng/mL, any T stage; GS ≥ 8, PSA < 20 ng/mL, T stage ≥ T2; GS ≥ 8, PSA ≥ 20-150 ng/mL, any T stage; or GS ≥ 7, PSA ≥ 20-150 ng/mL, any T stage. The primary outcome measure is OS. Investigators intend to recruit 900 patients.

Everolimus alternating with sunitinib for renal cancer

This phase II study is aiming to determine the activity and safety of an alternating regimen of two therapies with different targets (sunitinib and everolimus) in patients with advanced renal cell carcinoma (RCC). Individuals are eligible provided they have RCC with a clear-cell component, metastatic or locally advanced disease not suitable for resection, ECOG performance status of 0-1, and low or intermediate Memorial Sloan-Kettering Cancer Center prognostic score. Treatment is administered in 12-week cycles consisting of 4 weeks of sunitinib 50 mg daily followed by 2 weeks rest, followed by 5 weeks of everolimus (10 mg daily), followed by 1 week rest. The primary endpoint is the status of being alive and progression-free by RECIST 1.1 criteria 6 months after enrollment. Participants who stop one drug because of toxicity or disease progression on or before the 6-month assessment will continue the other drug until subsequent progression or unacceptable toxicity on the second drug.

Everolimus after surgery for renal cancer

This phase III study will evaluate everolimus in patients with RCC who have undergone radical or partial nephrectomy, including removal of all clinically positive nodes. Study participants will be stratified according to pathologic stage (intermediate high risk vs very high risk), histologic subtype (clear cell vs non-clear cell), and performance status (0 vs 1), and then randomized to 1 of 2 treatment arms. One group of patients will receive oral everolimus once daily on days 1 though 42, and treatment is repeated every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity. The other group of patients will receive oral placebo once daily on days 1 through 42, and treatment is repeated every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity. The primary endpoint is recurrence-free survival. Secondary endpoints include OS and toxicity. After the end of treatment, patients are followed up every 6 months for 2 years, and then annually for 8 years.

Articles

Urologists in Cancer Care presents summaries of ongoing research relating to a variety of urologic cancers.

November 2012: Clinical Trials in Progress for Urologic Cancers

	In a mission statement, the Large Urology Group Practice Association (LUGPA) states its aim to provide urological surgeons “…the means to access resources, technology and management tools… to care for patients with acute and chronic illnesses of the genitourinary system in an efficient, cost effective, and clinically superior manner.”

	Urology San Antonio has transformed itself into a model reflective of these expanded group practice goals, part of a nascent trend in large urology group practices to provide cancer care where before patients would be referred out to oncologists. In this interview for 

, Daniel R. Saltzstein, MD, director of Clinical Research, describes steps Urology San Antonio has taken toward creation of such a comprehensive urologic care practice, including establishment of a bone health clinic and an advanced prostate cancer clinic. Saltzstein looks ahead to new therapies that will continue to expand the options for advanced prostate cancer and the management of bone metastasis, and comments on the controversial recent US Preventive Services Task Force (USPSTF) statement on PSA screening.

: Could you speak about your practice’s decision to start a bone health clinic? What provided the impetus, and what challenges did Urology San Antonio face in its early development?

 We realized a number of years ago, as more literature was being published, that androgen-deprivation therapy (ADT) was associated with a lot of potential side effects, and that as a specialty, we were not addressing those needs. It was difficult in our setting to change this. We had fragmented care. Among a group of 25 physicians, we had six offices and were addressing bone health and the various ADT side effects differently. As a group, we decided that we wanted to develop “centers of excellence” in standardized care. We thought it would be best if we managed this goal in one location, with a model that included “physician champions” and “physician extenders.” Within approximately one year we had instituted two clinics under the guise of our centers of excellence concept. One was a bone health clinic and one an advanced prostate cancer clinic.

How do you manage the delivery of the complex services you added to the practice with the launch of these clinics? 

	We manage with established protocols and the help of a physician assistant (PA). Each patient who comes to the clinic receives similar care. When a patient comes to the clinic for bone health issues arising from treatment with an androgen-deprivation therapy, we determine their status with DEXA scans. The PAs check compliance with calcium and vitamin D and exercise. Because androgen-deprivation therapy has side effects other than those relating to bone health, we check weight, cholesterol, diabetes status, and we inquire about symptoms such as hot flashes. If patients need a dental evaluation because we are worried about the side effects of some of the medicines, we take care of that.

	The value of having a clinic like this is emphasized in light of new evidence for an improvement in survival with continuous androgen-deprivation therapy, meaning that patients may be taking it longer.

 This suggests that we will be dealing more and more with the side effects of these medicines.

Your large group practice also instituted an advanced prostate cancer clinic. Could you describe the rationale for that initiative? 

	We established an advanced prostate cancer clinic for reasons similar to those that resulted in the bone health clinic at Urology San Antonio—as a move toward a center of excellence concept, where all advanced prostate cancer care is provided in one setting.

	Urologists now have a number of different products in our quiver (eg, sipuleucel-T, abiraterone, enzalutamide) that are “urology-friendly.” Urologists are very comfortable giving these medications in the office versus referring patients out to oncologists for advanced chemotherapeutic care.

	Also, Urology San Antonio and a number of other large urology group practices throughout the country are starting to form alliances with oncologists to offer a “one-stop shopping” option for prostate cancer patients.

What involvement does your organization have in clinical trials, and how does your organizational structure support this activity along with rendering patient care? 

	We have an active clinical trials research division and have been involved in clinical trials for 12 to 15 years. Urology San Antonio Research, of which I am director, has been involved in clinical trials for many agents that have come out for the treatment of bone health and for advanced prostate cancer care.

	We are currently involved in five to six prostate cancer trials for agents in different stages of development and also with studies of biomarkers which may complement PSA in the future. We are involved in a number of advanced prostate cancer trials, some of which involve the chemotherapeutic agent Taxotere. We are participating in early prostate cancer trials for patients who have failed early therapy, and we are also doing trials in prostate cancer pre-radical prostatectomy to see whether patients will respond to certain antioxidants.

	Mutually beneficial alliances help to make possible the goal of Urology San Antonio to offer the full continuum of cancer care all in one setting and to participate in studies to advance treatment options. In one mutually beneficial alliance, an oncologist leases space in our radiation center, allowing us to give our patients chemotherapy. Patients with castrate-resistant prostate cancer who come into the office, for example, are managed by me and the physician extender. We make sure that each patient is given the opportunity to get involved in some of these new cancer treatments, whether or not they are on study.

	Our radiation oncologist is a partner in Urology San Antonio. Physician extenders, who spend more time with patients, help to make sure that all “I’s” are dotted and “Ts” are crossed and that patients are compliant with vitamin D and calcium, and are working side-by-side successfully with the oncologists.

What trial results or new agents can you identify that may soon be an important part of the care of patients with urological cancer? 

	The biggest news in prostate cancer care is the recent FDA approval of enzalutamide, an oral androgen receptor inhibitor. Preliminary data in the post-chemotherapy space has shown an improvement of more than four months in survival with very little toxicity. It’s a drug that urologists are very familiar with because it is basically a sister drug to bicalutamide with a better survival profile. So this newly approved agent has a potentially huge impact on urologists’ practices.

	The other one is abiraterone, which has been available for a while and is approved in chemotherapy failures, but is moving into the pre-chemotherapy space.

	A new radiation product, radium-223, is a first alpha-pharmaceutical, with a short-range of penetration resulting in less penetration into the bone marrow, less bone marrow suppression, and better tolerance. A recently reported phase III study in patients with castrate-resistant prostate cancer and bone metastases showed a significant improvement in overall survival and a delay to time to first skeletal-related event, and less bone pain. This is a very exciting product still in clinical study.

	Galeterone (TOK-001), an androgen biosynthesis inhibitor, received fast-track status by the FDA in June. This agent will compete with abiraterone. One of the challenges with abiraterone is that you need to give it with prednisone to prevent the side effects such as hypertension and fluid retention. Orteronel (TAK-700) is in a phase III clinical study in Japan. Because it is not necessary to give orteronel with prednisone, it will be more user-friendly for urologists who are not comfortable giving corticosteroids.

Do you have a sense, or have you assessed, whether patients like this new model of care? 

	For numerous reasons, patients like this model. Many of these patients have been receiving care under our auspices for 10 to 15 years, and over time they have developed close relationships with our staff. They may have had a radical prostatectomy, and it has failed. Maybe their PSAs are rising, and hormone therapy has failed. Patients may receive second-line hormone therapy, and now they are failing that. The model that we have created involves an enduring alliance between the urologist and a physician champion over the long term.

	Patients feel almost abandoned if we send them off—refer them out.

Does the model you are describing—of providing care across the entire range of treatments and types of care for cancer and other patients for the long term, and in one physical setting&mdash;represent a national trend in urology group practices? 

	I think this kind of model is gaining momentum. I was just in Dallas with board members of LUGPA. There is a push by LUGPA to maintain the care of the prostate cancer patient within the urology clinic, and along with it a big push to educate urologists and LUGPA partners on how to implement this kind of model within their practices. Geographically it is a challenge, with different practice situations in different cities and locales. But it is starting to gain momentum. Whether the San Antonio model will be adopted by other large urology practices remains to be seen. This is a challenge, because every community has its own political, geographical, and logistical challenges.

Many professional and patient-interest and advocacy groups, including the American Urological Association, LUGPA, the American Association of Clinical Urologists, the Project to End Prostate Cancer (ZERO), the Men’s Health Network, and more, have issued strongly worded releases rejecting the recent USPSTF’s “D” recommendation against PSA screening. How would you comment on this action and the way in which it may affect decisions urologists make with their patients? 

	In a general sense, urologists are very upset, perhaps in the way gynecologists and oncologists were upset when the Task Force came out with the statement regarding no routine mammograms for women between the ages of 40 and 49 years. We understand, from a societal point of view, the cost issue: that the cost of curing one patient is too expensive, and that you have to screen 100 patients for one cure. It’s a dollar-and-cents issue in a country that is bankrupt and trying to allocate scarce healthcare dollars.

	What bothers urologists is that there has been anywhere from a 40% to 45% improvement in prostate cancer-related survival in the PSA era. We get the fact that you have to screen 100 men to benefit seven men. Who is going to bear the cost of the other 93? But how can we discard the PSA test when we don’t have something to replace it, knowing that it has truly revolutionized prostate cancer care?

	What the Task Force was saying is that: (1) we overdiagnose prostate cancer, and (2) we overtreat it, and that this is misusing the PSA and potentially causing a lot of morbidity in a lot of people who do not need to be exposed to morbidity.

	The urologists’ comeback to that argument would be that we are told that the national average of positive prostate biopsies is probably about 25% to 28%. At Urology San Antonio, the prostate biopsy-positive rate, which is based on 1700 biopsies per year, is around 48%. So, according to their records we are under-biopsying people.

	The other argument urologists make is that we are very good stewards of prostate cancer care. We are not overtreating prostate cancer. When we tracked our treatment paradigms in San Antonio we found that 30% of patients get surgery, 30% get radiation, 30% get some form of active surveillance, and maybe 10% get some form of hormone therapy. A 72-year-old man who is not very healthy, with a PSA of 8 and a positive biopsy, may go on to active surveillance and not suffer the potential morbidities of treatment. But a 68-year-old man with bad prostate cancer and a PSA of 4 and a Gleason score of 7-8 needs therapy. We know which men need therapy and which ones don’t.

	The thought process of urologists is that until we have a better test than the PSA, appropriate men need to be screened. Trust us to make the right decisions for patients. In time, as newer molecular tests are developed, patients and urologists will be better able to select appropriate prostate cancer therapies.

	1. Hussain M, Tangen CM, Higano CS, et al. Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients: results of S9346 (INT-0162), an international phase III trial.

Daniel R. Saltzstein, MD, describes steps Urology San Antonio has taken toward creation of a comprehensive urologic care practice, including establishment of a bone health clinic and an advanced prostate cancer clinic.

Urology Practices Organize to Deliver Comprehensive Cancer Care: An Interview With Daniel R. Saltzstein, MD

Just ten years ago, almost all patients using “specialty” pharmaceuticals were being treated in infusion centers or hospitals. Today, the opposite is true, and single-specialty or large multispecialty practices are more likely to be managing patients who need novel biologics, oncolytics, and immunosuppressant therapies. Just as new technologies supported the migration of urologic procedures from inpatient to office settings, novel formulations of specialty drugs have shifted the treatment of patients taking oncologic and biologic agents from infusion centers to the doctor’s office.

	An oral oncology drug, abiraterone acetate (Zytiga, Janssen Biotech, Inc), for men with advanced, metastasized prostate cancer, is one example of this shift of care into urology offices. Another is the introduction of home-administered “self-injectable” biologics used by patients with rheumatoid arthritis and multiple sclerosis. Specialty pharmacy providers (SPPs) deliver prefilled syringes or other injection devices to community pharmacies, prescribers’ offices, or directly to patients. Even patients who need infused drugs often receive treatment at home from a visiting infusion service, which is also supplied by specialty pharmacies.

	Certainly the easiest way to get drug therapy is to swallow a pill, and manufacturers of biologic therapies are moving as many agents as possible into oral tablet formulations. In 2011, SPPs reported that 58% of the cancer prescriptions they handled were oral agents.

 Generally, patients and their doctors agree that the shift from hospital-administered therapies is a positive change. First, it is much more convenient for the patient. In addition, it lowers the risk of infection associated with inpatient care and it lowers the cost of drug administration. In fact, an average 6% of oral oncology drugs and 12% of self-injectables that are covered by insurance are distributed by SPPs to physician offices, where they are administered to patients.

	Managing Patients Who Take Biologic Therapies

	While distribution of orals or self-injectables may be fairly easy for a practice, managing a patient’s use of such specialty drugs can be daunting. Zytiga again illustrates the point. The drug manufacturer has filed applications in the United States and Europe for a new indication: treatment of prostate cancer patients who have never had chemotherapy. The current indication is more limited, for treatment of metastatic castration-resistant prostate cancer that has progressed after treatment with chemotherapy. Zytiga prescriptions are likely to triple if the earlier-use indication is approved.

 Urologists will be managing more prostate cancer patients spanning a broader disease-progression period.

	By definition, biologic therapies, even in pill form, are both complex and costly. Consequently, patient monitoring is often intensified, and comprehensive treatment may include management of difficult side effects and the careful avoidance of drug-drug interactions common among patients being treated for serious diseases. Managing use of a biologic regimen puts pressure on patients, doctors, and the entire clinical team.

	Helping patients obtain ongoing coverage or financial assistance for such therapy is also time-consuming and is a task that often falls to the practice administrator. So, meeting the needs of these patients takes more time, different resources, more information, better data tracking, smoother transitions of care—more of just about everything.

	Thomas Paivanas, MHSA, the executive director of the CUSP Group, offered a view of how urologists have responded to the changing treatment advances in their field. The CUSP Group is a “provider-centric” uro-oncology trials management organization composed of 15 large, integrated urology practices. Their organization was formed, explained Paivanas, “to collect clinical, operational, and cost data that support a ‘systemic urology therapy’ approach to patient care across the full progression of disease.”

	“Everything is changing in the uro-oncology field,” Paivanas said, “including guidelines that support a standard of care, treatment pathways that insurers use to predict cost of treatment for specific conditions, and the way urology practices are defragmenting the delivery of care by integrating complete treatment services in large practices.”

		According to the National Cancer Institute, a biologic drug is a substance that is made from a living organism or its products and is used in the prevention, diagnosis, or treatment of cancer and other diseases.

		URAC, the leading healthcare accreditation organization for specialty pharmacy companies, concedes that definitions of a specialty drug vary, but that most would agree that specialty drugs are expensive and complex.

 URAC also reported that the specialty drugs segment of the industry represented 17% of total pharmaceutical revenues in 2011, a percentage that would more than double by 2020.

		The Centers for Medicare & Medicaid Services defines drugs that cost more than $600 per month as specialty drugs, while other health plans put the threshold at $1200 per month.

		The Foundation for Managed Care Pharmacy investigated the question of what defined a specialty drug by surveying pharmaceutical management companies to submit their own criteria for defining and including drugs on specialty drug lists.

					Specialty drugs typically cost $500 or more per dose or $6000 or more per year, and have one or more of the following characteristics:

					Specialized patient training and coordination of care required prior to therapy initiation or during therapy

					Unique patient compliance and safety monitoring requirements

					Unique requirements for handling, shipping, and storage

					Potential for significant waste due to the high cost of the drug

				National Cancer Institute at the National Institutes of Health. Available at: 

http://www.cancer.gov/dictionary?cdrid=426407

				URAC. Specialty Pharmacy White Paper. Washington, DC: URAC. October 6, 2011. Available at: 

https://www.urac.org/press/cmsDocument.aSPx?id=771

	Practices such as the CUSP Group usually have evolved to include internal subspecialists who manage patients with advanced or complex conditions, such as cancer. Patients whose disease has progressed beyond standard initial treatment are often referred internally to a subgroup of physicians who conduct research and make use of the most progressive therapies. Paivanas suggests that it is usually these physicians who tend to drive practice-wide change, such as new product adoption.

	As practices have taken on the management of patients who need biologic therapies, such as prostate cancer patients, they may also have entered new business relationships with SPPs. Paivanas believes that it is likely to be the physician-researchers within an integrated urology practice who “will drive a new collaborative model in partnership with SPPs.”

	Certainly SPPs have become a major presence in oncology practices. Some aspects of these relationships have been helpful to physicians and their patients. Others—most notably the erosion of oncologists’ direct purchasing of oncology drugs&mdash;have caused deep contention. Nevertheless, interactions between SPPs and specialist practices are likely to expand because specialty products now account for 21% of the total US pharmaceutical market revenue, and that percentage is expected to grow to 25% by 2014.

	For the present, in urology practices, most patients taking specialty drugs have cancer. Urology practices care for patients with prostate, kidney, testicular, and bladder cancers—four fairly common types. Also, the national patient population is aging, and cancer risk increases with age. Older age is associated with an especially high risk for prostate cancer.

 Currently recommended biologic agents for the cancer patients managed in urology practices include not only oncology drugs but also hormonal agents and immunologics.

	Paivanas estimates that from 10% to 25% of urology practices in the United States have begun to adopt a “true systemic therapeutic approach to treatment.” In this practice model, as he describes it, “once a patient is diagnosed with cancer, all subsequent therapeutic needs of that patient can be addressed by the practice. Care is truly integrated in the most efficient and effective manner possible.”

	Maintaining the level of care that Paivanas describes has historically proven to be a tall expectation for any specialty practice, and most use outside services to support the practice in some ways, such as for data collection, in which SPPs have a natural position as the keeper of pharmacy data.

	A less well-known reason that use of SPPs by urology practice partners may increase is that drug pipelines are laden with new biologic therapies, and an estimated 72% of specialty drugs are distributed by SPPs.

 The role of SPPs has expanded as the number of specialty drugs has expanded. In 2010, 887 of the more than 3000 medicines and vaccines under development in the United States were for treatment of cancer: lung (98), prostate (80), colorectal (55), solid tumors (240), and all others (323).

 It is expected that by 2016, biologic drugs treating cancer will be among the top 10 selling pharmaceuticals in the country.

	Specialty drug distribution has long been an integral part of delivering oncology agents. As these agents entered the market, SPP companies were the obvious choice for distribution, and their service base has rapidly expanded through patient and drug management services that ease the introduction of fragile, costly, and toxic agents into the marketplace.

	SPPs have carved out a secure space in the market because their services are not only useful to manufacturers, but also to insurers, and increasingly to physicians and patients. At the least, an SPP tracks the business of drug distribution to doctors, institutions, and patients, as well as the purchase and reimbursement data as determined by contract. Their distribution streams include mail order, and delivery to homes, offices, and community pharmacies.

	In fact, the diversity of their services presented a challenge to the Centers for Medicare & Medicaid Services (CMS) to define what constitutes a “specialty pharmacy.” The criteria for the definition is important because the CMS requires pharmaceutical industry groups to include drug sales to “specialty pharmacies” in its calculations of Medicaid’s average manufacturer price (AMP), which is used for insurance reimbursement. CMS opted to delay both the definition and the directive until 2013. If it takes on the challenge then, it will be the first time that 

	Almost all SPPs have assumed clinical management roles, which muddies definitional waters but may be serving to clarify what kind of attention to patients works best. SPPs document encounters and interventions with specific patients, supplied through their disease management and case management services.

	However, SPPs rarely contract directly with clinical organizations. Their contracts are with drug manufacturers and insurers, both of which have a stake in making sure biologic agents are used correctly and by the right patients. Like with many specialty drugs, Zytiga was launched with a list of specialty pharmacies that had contracts to distribute the drug and to provide a patient support program called “ZytigaOne.”

 The opt-in program is selected through an enrollment form that is provided to physicians to distribute to their patients.

	SPP contracts with manufacturers and insurers affect not only the price of the drug, but also have the ability to affect overall costs of specialty therapy because these contracts seek to ensure quality of care and safety. Although many services are available, the core contracted services are listed below.

		Distribution or volume guarantees affecting inventory availability

		Reporting responsibility to meet FDA Risk Evaluation and Mitigation Strategy (REMS) requirements

		Assistance with prior authorization and physician documentation

		Assistance with obtaining financial help for patients

	To tighten control further, “limited drug distribution” contracts are common. Such agreements sometimes name only a few specific SPPs for distribution to clinical networks, which affects downstream purchases by hospitals, physician practices, other care facilities, and patients. However, manufacturers want to support a reasonable regional coverage, especially for distribution of oral agents that are usually dispensed directly to patients through community pharmacies. Zytiga was launched with 16 SPP distributors.

	Some physician practices welcome patient support services for their patients and work cooperatively with the SPP vendor. Others see the patient-based services as an intrusion in the physician-patient relationship and the therapeutic process. As an industry, SPPs have adopted a long-term business focus on building therapeutic expertise, which may conceivably make them more valuable as a clinical extension of the physician practice: performing tests that monitor effects of therapy, recommending dosing changes, and monitoring physician use of clinical guidelines.

 The question for the practice is, “What aspects of patient management do we want to hang on to, and which are we better off letting go of?” The answer is never simple.

	Oncology practice managers report that they dedicate countless hours arranging prior authorizations and financial assistance for patients who cannot afford prescribed therapies.

 Infectious disease practices found themselves almost swamped by patient management needs when new, genetically targeted agents for hepatitis B and C were introduced in 2011. Managing growing numbers of patients on complex regimens usually requires careful record keeping and higher levels of information technology within the practice. And, there are no measures of how much harder it will be to keep up with therapeutic education. Information overload is a constant challenge for all doctors.

	Paivanas also commented on the need for information. “There is such a cascade of data arising from genetic research, it’s like trying to drink from a fire hose. We all have to adapt and become facile with these new tools and information.” He predicts that as more biologic therapies become available, the early adopters in the urology field will pursue combinations and sequencing of therapies in order to provide optimal treatment to the patient over the full course of disease. Because the burden of education about new biologic therapies usually falls to the manufacturers, and by delegation, to the contracted specialty pharmacy group, this could also become a benefit of collaboration with SPPs.

	How the physician practice and a specialty pharmacy can or will interact is far from predictable. Practices and SPPs vary endlessly. However, considering the market and the linchpin-like spot SPPs occupy in the distribution of biologic drugs, urology practices may see an opportunity to use SPPs in achieving a common goal: a successful therapeutic outcome for the patient.

The 2012 Genentech Oncology Trend Report: Perspectives From Managed Care, Specialty Pharmacy Providers, Oncologists, Practice Managers, and Employers.

 4th ed. South San Francisco, CA: Genentech; 2011.

			Staton T. Bigger Zytiga market a step closer with J&J’s approval filings. June 18, 2012. Available at 

http://www.fiercepharma.com/story/bigger-zytiga-marketstep-closer-jjs-approval-filings/2012-06-18

Specialty Pharmacy Management: Industry Overview and Assessment of Leading SPM Companies.

 Health Strategies Group. Lambertville, NJ; May 2011.

. Atlanta, GA: American Cancer Society; 2012:1-62.

			American Society of Clinical Oncology. Oncologist-approved cancer information from the American Society of Clinical Oncology. Cancer Types. Available at 

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http://www.phrma.org/sites/default/files/1000/medicinesindevelopmentcancer2011_0.pdf

			Correia R. Oral oncology therapies: specialty pharmacy’s newest challenge. Pharmacy Times. Available at: 

http://www.pharmacytimes.com/publications/issue/2011/May2011/Oral-Oncology-Therapies-Specialty-Pharmacys-Newest-Challenge-

			Steinke S. Manufacturers seek CMS definition of “specialty pharmacy.” 

http://www.zytiga.com/support_and_resources

Novel formulations of specialty drugs have shifted the treatment of patients taking oncologic and biologic agents from infusion centers to the doctor's office.

Urology Practices Form Collaborative Partnerships With Specialty Pharmacy Providers

	ï»¿I have always found the summer to be an interesting time, especially as I walk through the doors of the hospital to make my rounds. It conjures up memories of my first few months as a general surgical intern at Vanderbilt Hospital in 1984, wondering why I was driving with the traffic lights still blinking in Nashville to start rounds at 4:30 in the morning, knowing that I would not return to the comforts of my apartment until sometime the following night. Many of you probably remember putting on the standard hospital-issue attire—white pants and short lab coat, looking as if we had just finished working a shift at the ice cream shop. (And we wonder why many of our colleagues possess peculiar sartorial tastes.)

	The routine was the same, irrespective of your location or what teaching hospital you were affiliated with: Make rounds, meet with senior residents to be assigned cases (for which you would then be the primary object of verbal abuse), round again and make sure everything was checked off your scut list, hopefully grab a meal in the bowels of the hospital cafeteria (not a food court with multiple options!), and then start the evening grind of preparing patients for surgery the following day. There was no such entity as early-morning admissions or 23-hour stays. I checked pre-op labs and x-rays, made sure that operative permits were signed (whoever heard of informed consent?), and still managed the 20 or so patients on my service, without the benefit of a nutritional support team, IV therapy, or in-house hospitalist. I believe back then they were called your “friends” on other services. This pattern would repeat itself every other day for the next two years. Who would believe that I voluntarily asked for this schedule?

	Many of you would agree, however, that despite this grueling and insane way of life, the learning curve was exponential, and our ability to take care of and manage the acutely ill patient served us well as we became attendings. More important, the friendships forged as a result of those shared efforts will last forever. I personally look back on those times and would not trade the experience for anything.

	Times have certainly changed for residents and house officers (can we still call them that?). The Libby Zion law has limited the number of hours that they can spend in patient care on a continued basis. The support at most hospitals is far superior compared with what was previously available. Technology has driven the market to a more minimally invasive/robotics-assisted world. I have had the distinct pleasure, despite being in “private practice,” to work daily with the Vanderbilt Urology residents as a part of their training for the past 22 years. I am not saying that the residency system is better or worse. It is simply different.

	Now we are certainly entering into a changing system in the healthcare environment. It is, and certainly will be in the future, different. As you know, the Patient Protection and Affordable Care Act (ACA) has been upheld by the United States Supreme Court. Dr Deepak Kapoor, current president of the Large Urology Group Practice Association (LUGPA), has written a very thoughtful piece in this edition of 

, discussing the potential effects of this legislative action on urology groups in the United States. (

The Affordable Care Act: An Analysis of Its Impact on Urology Practices

	Many out there do not want to accept the fact that traditional fee-for-service is going away. As with most industries where outcome metrics are crucial for continued success, the government is wanting physicians to deliver care that is outcome- and evidence-based, which will hopefully result in lower costs. Payment will be based on the ability to implement such a system. This will be a very daunting process, to say the least, but one that is clearly critical to long-term success and viability.

	The management of the urologic cancer patient may well be a great starting point. As many of you are keenly aware, we are often on point for the early management of these patients. Now, with new therapies being introduced and fast-tracked for approval, we need to begin to develop integrated models within our existing practices that will allow us to continue to direct patient care well past the immediate postoperative period. We need to venture outside of our traditional surgical toolbox in order to survive in this changing environment. Generally, we physicians are resistant to change and prefer the status quo. It won’t be easy for most of us, but it will be worth it. (A bit like trying to change your golf swing: If it seems simple, you probably haven’t really changed anything.)

	Because we are in the middle of an election year, and depending on the November result, the battle over the ACA likely will not commence until 2014. Now is the time for us to look forward and be proactive in our efforts to effect change. As my good friend, Sandy Siegel, MD, (of Chesapeake Urology Associates, Baltimore, MD) says, doctors usually do not know they are drowning until the water is up to their chins. The waters are rising rapidly. Let’s put on the life vests now before it’s too late.

As with most industries where outcome metrics are crucial for continued success, the government is wanting physicians to deliver care that is outcome- and evidence-based.

Are Physicians Drowning?

Chairman and CEO, Integrated Medical Professionals, PLLC

		President, Large Urology Group Practice Association.

	It has been two months since the Supreme Court of the United States effectively upheld the constitutionality of the Patient Protection and Affordable Care Act of 2010 (ACA). Since that time, opponents of the bill have been analyzing legislative activity to delay or thwart the ACA’s implementation, while the administration and the bill’s supporters have been working to expedite development of the massive government infrastructure required for the provisions of the bill to function. Unfortunately, the ultimate outcome of this political conflict hinges on the outcome of the upcoming general election; thus, the Supreme Court decision does not provide the finality needed for any sector of the healthcare industry to be on solid ground in terms of long-term strategic planning.

	For those of us with administrative responsibilities in large urology groups, the dilemma is amplified by the fact that we are affected not only as providers of care but as employers. The overwhelming majority of our practices have greater than 50 employees; those who do not provide “creditable coverage” will face a $2000 per employee penalty. Presently, this minimum (known as “bronze coverage”) will provide for certain essential health benefits (

) and cover 60% of the benefit costs of the plan, with an out-of-pocket limit equal to the Health Savings Account (HSA) current law limit ($5950 for individuals and $11,900 for families in 2010). Depending on the policies adopted by an individual state, many of us will be faced with the same uncomfortable decision as other small businesses: It may be economically advantageous for us to cease offering health insurance as an employee benefit and pay the penalty, effectively forcing our staff into Medicaid-run state insurance exchanges.

		Table 1. Essential Health Benefits as Presently Defined

	Furthermore, there is absolutely no question that surgical specialists, urologists in particular, do not fare well under the provisions of the ACA. For hospitals and insurance companies, reductions in premiums and/or reimbursements are to be offset by decreases in the number of uninsured patients; insurance companies will have more customers, and hospitals will presumably have to provide less indigent care. As there is approximately $700 billion to be cut from the Medicare program under the ACA, any specialty with a high percentage of Medicare beneficiaries will be disproportionately adversely affected by these changes. As most large urology groups have Medicare populations that account for 45% to 55% of their total patients, these cuts have a potentially drastic negative impact on reimbursements. To be fair, those practices with a high percentage of uninsured patients will obtain some relief, but this is unlikely to offset the losses in Medicare reimbursements. Furthermore, primary care physicians participating in Medicaid-run insurance exchanges are afforded protection under the ACA, as certain codes referable to their specialty are guaranteed enhanced reimbursement; urologists are afforded no such assurances.

	Another profound change that affects large groups is the development of Accountable Care Organizations (ACOs). Simply put, an ACO is an organization that, through a variety of criteria (

), internally manages utilization and outcomes for a given subset of Medicare beneficiaries. In return, the ACO is eligible to receive a portion of any cost savings realized by the Medicare program, and ultimately will be penalized for any cost overruns. Although modifications in the ACO regulations now permit specialists to participate in multiple ACOs, there is no question that the design of the regulations significantly favors hospitals and multispecialty groups that incorporate primary care physicians; an inherent risk to this model is the development of healthcare oligarchies that will ultimately stifle competition and increase costs. On the other hand, one collateral benefit of the ACO initiative is the recognition that it is necessary for any organization that assumes risk to control both the quality and utilization of a variety of ancillary services, which extends to specialty organizations that may be able to provide case rates or episodes of care to ACOs. This has reduced the legislative and regulatory appetite for expansion of Federal Stark self-referral legislation, as at-risk entities control costs of ancillary services by internally referring these services. Recognition of this led the Medicare Payment Advisory Commission (MedPAC) to acknowledge in its March 2010 

 that integrated medical practices “could be well-positioned to succeed under a new payment model.” As the regulatory infrastructure governing the behavior of ACOs is murky at best, it remains to be seen whether these potential advantages will outweigh the risks associated with widespread consolidation of medical services.

		Table 2. Requirements of an Accountable Care Organization as Delineated in the ACA

					Assume accountability for the quality, cost, and overall care of the Medicare fee-for-service beneficiaries assigned to it.

					Enter into an agreement with the Secretary to participate for no less than three years

					Have a formal legal structure that would allow the organization to receive and distribute payments for shared savings to participating providers of services and suppliers.

					Include primary care ACO professionals that are sufficient for the number of Medicare fee-for-service beneficiaries assigned to the ACO under subsection					

							In order to be eligible to participate in the ACO program, the ACO shall have at least 5000 beneficiaries assigned to it.

					Provide the Secretary with information regarding professionals participating in the ACO as the Secretary determines necessary to support the assignment of Medicare fee-for-service beneficiaries to an ACO, the implementation of quality and other reporting, and the determination of payments for shared savings. The ACO shall have in place a leadership and management structure that includes clinical and administrative systems.

					The ACO shall define processes to promote evidence-based medicine and patient engagement, report on quality and cost measures, and coordinate care, such as through the use of telehealth, remote patient monitoring, and other such enabling technologies.

					The ACO shall demonstrate to the Secretary that it meets patientcenteredness criteria specified by the Secretary, such as the use of patient and caregiver assessments or the use of individualized care plans.

	The impact of the many regulatory changes will vary in different markets depending on the population density, the demographics of the population, the number of hospitals, and the availability of specialists. One component of the ACA that has profound and potentially devastating impact on a national level is the activity of the Independent Payment Advisory Board (IPAB). This panel consists of 15 members, all of whom must be full-time (no practicing physician need apply), and only a minority of whom (by statute) can be healthcare providers. As the specific language of the bill prohibits IPAB from recommending healthcare rationing, changes in Medicare benefits, or revision of eligibility standards, its only tool is to reduce payments to providers. There are two components to IPAB that are particularly dangerous: (1) IPAB has the ability to create Medicare payment policy around arbitrarily determined budgetary guidelines that have the potential to automatically become law without the possibility of administrative or judicial review; and (2) hospitals and certain other entities such as nursing homes are exempt from IPAB recommendations until 2019 (implemented 2020); thus, 

100% of all Medicare reimbursement cuts for 5 years are to physicians, pharmaceutical companies, and device manufacturers

! In addition, the regulations governing IPAB make repealing this provision very difficult because it draws its resources directly from Medicare trust funds—even the traditional method of Congress starving an agency’s budget won’t work. Without question, because of the disproportionate financial burden placed on providers, IPAB is the component of the ACA that poses the greatest threat to urology group practices, and on a broader note, the independent practice of medicine in general.

	Regardless of the outcome of the debate surrounding the implementation or repeal of the ACA, one thing is certain: The historical practice of medicine as we once knew it will soon cease to exist. There is a clear push away from traditional fee-for-service medicine toward models that require significant infrastructure to deliver; thus, healthcare ultimately will be delivered by fewer, larger providers. When these pressures are added to the byzantine regulations and unfunded mandates that accompany implementation of a bill that governs onesixth of the US gross domestic product, it is doubtful that individual or even small group practices will long be able to survive.

	However, given the nature of urology as a specialty, large integrated urology group practices may find a niche in the market by providing comprehensive specialty services to a number of larger providers, as well as directly contracting with the government and other thirdparty payers. In addition, as large urology groups generally have welldeveloped central management, the opportunity exists to provide such services to physicians of other specialties that are seeking an alternative to hospital employment. By developing innovative, comprehensive care models that enhance access, improve outcomes, and reduce costs, large integrated urology groups are uniquely positioned to not only survive, but to thrive in the brave new healthcare world.

For those of us with administrative responsibilities in large urology groups, the dilemma is amplified by the fact that we are affected not only as providers of care but as employers.

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Urology Practices Form Collaborative Partnerships With Specialty Pharmacy Providers

Are Physicians Drowning?

The Affordable Care Act: An Analysis of Its Impact on Urology Practices