Multidisciplinary Collaboration in Metastatic Hormone-Refractory Prostate Cancer Featured Expert NEAL D. SHORE, MD, FACS Director, Certified Physician Investigator (CPI) Carolina Urologic Research Center Managing Partner Atlantic Urology Clinics Myrtle Beach, South Carolina Neal D. Shore, MD, FACS, is the medical director for the Carolina Urologic Research Center and managing partner for Atlantic Urology Clinics in Myrtle Beach, South Carolina. Dr Shore has conducted more than 175 clinical trials, focusing mainly on prostate and bladder disease, and he serves on the boards of several academic and advocacy networks. He has contributed to numerous peer-reviewed journals and has lectured extensively on the treatment of prostate and bladder cancers. •A  multidisciplinary, collaborative approach to the treatment of patients with metastatic hormonerefractory prostate cancer (mHRPC) can help identify opportunities that lead to improved patient outcomes − the ultimate goal of caring for patients with mHRPC.1 •R  eferral to a medical oncologist provides the potential to provide appropriate therapy to these patients at earlier stages of metastatic disease, yet approximately 1 in 5 men with mHRPC are not referred to a medical oncologist for care.2 •W  hile a multidisciplinary approach may be challenging for some clinicians who practice in the community setting, strategies can be implemented to maximize collaboration and communication, with a resulting benefit to the patient.

Featured Expert DANIEL J. GEORGE, MD Associate Professor of Medicine and Surgery Divisions of Medical Oncology and Urology Director, Genitourinary Oncology Duke Cancer Institute Duke University Medical Center Durham, North Carolina Daniel J. George, MD, is an associate professor of medicine and surgery in the Divisions of Medical Oncology and Urology and Director of Genitourinary Oncology in the Duke Cancer Institute at Duke University Medical Center in Durham, North Carolina. Dr George’s research efforts in prostate cancer have focused on growth factors as prognostic markers, molecular targets, and surrogate measures of response. In addition, Dr George is a principal investigator for Duke on the Department of Defense Prostate Cancer Clinical Trials Consortium Grant, which focuses on early-phase drug development in prostate cancer. •A  s current treatment options for mHRPC continue to expand, the terminal phase of the disease has been extended, making it increasingly important to individualize treatment decisions.3,4 •A  multidisciplinary approach to care, utilizing a team of healthcare professionals whose focus is treating the patient with mHRPC in each stage of disease, can help identify opportunities for appropriate therapy at earlier stages of disease and maximize synergies of patient care.1,5 •P  atients with HRPC may harbor unsuspected metastases. It is, therefore, crucial to actively monitor and screen these patients, so as to identify metastatic disease early and optimize the use and timing of available treatment options. • F ollowing referral to a medical oncologist, it is important that the urologist continues to see the patient and remains involved with patient care.

1

ClinTopics

Question & Answer NEAL D. SHORE, MD, FACS Director, Certified Physician Investigator (CPI) Carolina Urologic Research Center Managing Partner Atlantic Urology Clinics Myrtle Beach, South Carolina While mortality rates for prostate cancer have been decreasing, nearly 1 of 3 patients will progress to mHRPC. What are unmet medical needs related to the treatment of mHRPC? Despite steadily declining rates of prostate cancer mortality over the past 2 decades, prostate cancer remains the second leading cause of cancer death in men in the United States.6,7 In fact, it is estimated that more than 33,000 American men will have died from prostate cancer in 2011.7 National Comprehensive Cancer Network® NCCN Guidelines™ note that there is a high risk of progression to mHRPC, with approximately 30% of patients progressing to mHRPC regardless of initial treatment with intent to cure.8 Interestingly, a 2010 market research study involving 100 medical oncologists/hematologists and 75 urologists found that approximately 1 in 5 men with mHRPC were not referred to a medical oncologist by their urologist. Additional findings from the same market research study showed that, while 2/3 of locally advanced patients referred to oncologists were considered eligible for chemotherapy, only 66% of them actually began therapy (Figure 1).2 These findings indicate that there is a treatment gap, or unmet need, in the treatment of mHRPC. Specialists who care for patients with mHRPC, including urologists, medical oncologists, and radiation oncologists, are often challenged in their effort to communicate with one another and establish a collaborative approach to patient care. These challenges vary depending on the geographic location and practice settings. Physicians are encouraged to implement strategies to surmount these challenges because coordinated management and multidisciplinary collaboration can help identify opportunities for appropriate therapy at earlier stages of metastatic disease and may lead to improved patient outcomes − the ultimate goal of caring for patients with mHRPC.1

2

Figure 1: Locally Advanced Patients Referred to Oncologists: Eligibility for Chemotherapy2

2/3 are considered eligible for chemotherapy

34% 66%

34% 22%

44%

Eligible for chemotherapy Not eligible for chemotherapy

Of those patients eligible for chemotherapy, 2/3 actually begin it Not eligible for chemotherapy Begin chemotherapy Do not begin chemotherapy

DANIEL J. GEORGE, MD Associate Professor of Medicine and Surgery Divisions of Medical Oncology and Urology Director, Genitourinary Oncology Duke Cancer Institute Duke University Medical Center Durham, North Carolina How is disease progression assessed in mHRPC, and why is it important to carefully monitor disease progression? What is the role of symptomatology in measuring disease progression? Disease progression may be assessed using a variety of methodologies, as is shown in Table 1. However, as no one measure is sensitive or specific enough to be used alone, physicians should rely on a composite of findings to assess progression. Careful monitoring of disease progression is important, particularly since many patients who progress to mHRPC are asymptomatic or mildly symptomatic.9-13 An analysis of the baseline patient characteristics from various mHRPC clinical studies showed that 19% to 45% of patients had rising prostate-specific antigen (PSA) as sole evidence of metastatic disease progression.9,10 Additionally, 27% to 67% of the patients

reported no pain or mild pain at study entry.9-14 Patients with HRPC may harbor unsuspected metastases, and the metastatic burden in early disease is likely underestimated. For instance, an analysis of patients who failed screening for enrollment into a clinical trial revealed that 30% of patients who were presumed to have nonmetastatic HRPC actually had asymptomatic metastatic disease that was identified using bone and computed tomography (CT)/ magnetic resonance imaging (MRI) scans.15 In other words, 1 out of 3 cases of mHRPC may be missed using predictors that clinicians would typically use to identify progression to metastatic disease. In my opinion, and considering the above data, it is important to perform radiologic studies early, despite what may seem to be nonmetastatic disease based on other clinical indicators. It is also important to remember that disease progression of mHRPC is rapid and that median bone metastasis-free survival is approximately 30 months.16,17

Table 1: Methods Used to Assess Disease Progression17-19 Radiographic

Bone metastases, soft tissue (lymph nodes), CT, MRI

Clinical

Pain, anemia, fatigue, weight loss

Biochemical

PSA, PSADT, lactate dehydrogenase (LDH), alkaline phosphatase, hemoglobin

Pathologic

Prior Gleason score

Cellulara

CTCs

PSADT=PSA doubling time; CTCs=circulating tumor cells. a

Research shows that CTCs may assist in the earlier discontinuation of an ineffective treatment. However, the use of CTCs has not yet transitioned to the clinical setting.19

Medical oncologists may classify patients with mHRPC in 1 of the 4 categories shown in Table 2. These 4 categories capture the evolution of the tumor burden, radiologic changes, and symptoms in patients with mHRPC. A key treatment goal is preventing the patient from progressing to M1, moderate to severe symptomatic; a stage characterized by debilitating pain and symptoms that require the use of narcotics. Once this stage is reached, it is very difficult to reverse disease progression. It is vital that treatment options be used as early as possible in patients with mHRPC, to help improve patient outcome. Historically, and partly due to the limited treatment options available, there has been a more conservative approach toward screening for metastatic disease in patients considered M0. However, the treatment landscape for these patients has significantly changed. It is, therefore, imperative for the caregiver at the M0 stage, typically the urologist, to actively screen for metastases so that they can be identified early, allowing the use and timing of available treatment options to be optimized.

Table 2: 4 Categories of Patients With mHRPC20,21 Category 1. M0, with rising PSA only

20,21

2. M1, asymptomatic 21 3. M1, minimally symptomatic21 4. M1, moderately to severely symptomatic21 3

What are triggers for initiating treatment for patients with mHRPC? Patients present with different profiles of mHRPC. For example, PSA levels may be elevated in some patients with mHRPC and remain low in others. Medical oncologists need to consider each patient’s unique disease presentation and develop a treatment plan accordingly. Triggers used to initiate treatment for patients with mHRPC may be considered in 2 groups: measurable and nonmeasurable disease triggers. Measurable disease triggers include measurement of tumor lesions and malignant lymph nodes. Tumor lesions must be accurately measured in at least 1 dimension with a minimum size of 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). Malignant lymph nodes are typically ≥15 mm by CT scan (CT scan slide thickness no greater than 5 mm) to be considered measurable. At baseline, when more than 1 measurable lesion is present, all lesions up to a maximum of 5 lesions (and a maximum of 2 lesions per organ) representative of all involved organs should be identified as target lesions.22 Examples of nonmeasurable disease triggers include PSA progression, the appearance of new lesions, lesions requiring irradiation, and pain.23 Both measurable and nonmeasurable types of triggers are useful; neither is more important than the other. Identifying patients with poor prognostic factors is crucial. Nomograms have been created from phase 3 studies and metaanalyses that have identified several prognostic factors, including performance status, PSA, alkaline phosphatase, LDH, and hemoglobin level, as well as the original Gleason score.24 What treatment options currently exist for mHRPC, and how is this landscape changing to extend the terminal phase? Why is it increasingly important to individualize treatment plans for these patients? Treatment options for mHRPC continue to expand; they include androgen deprivation therapy and second-line hormonal therapy, chemotherapy, immunotherapy, isotope therapy/ radiation therapy, and antiresorptive therapy.3,8 In some cases, patients may benefit from combinations of these treatments.8 The treatment landscape for mHRPC is changing, mainly because of factors such as earlier diagnosis, stage migration, and changes in practice patterns. The expansion of available treatment options, combined with changes in the treatment landscape, have helped improve outcomes in patients with mHRPC.3 Many patients may have preconceptions regarding prostate cancer treatments. Consequently, I believe that the role of the oncologist is to help educate patients on the rationale, benefits, and risks associated with each treatment option, so that patients can make an informed decision on what is best for their overall situation. In my opinion, patients benefit if urologists stay involved in their care at this point and participate in this conversation. This collaborative approach between oncologists and urologists helps to ensure that there is consistency in how patient care is managed and what is communicated to patients. With the variety of treatment options available for patients with mHRPC, it is now even more important to individualize treatment decisions based on disease-related and patientspecific factors (Table 3).4 Physicians need to assess patient expectations and goals for their treatment plan. I prefer to proactively pursue this discussion early in disease. I find that it helps to prepare patients for all the steps moving forward, and helps guide a treatment plan that will maximize achievement of the patient’s goals.

Table 3: Patient-Specific Factors

4

Comorbid conditions4

Patient lifestyle

Concomitant medications4

Family support at home

Performance status4

Travel plans

Quality of life4

Activities and hobbies

Patient commitment to duration of treatment How are treatment switch points identified throughout disease progression to ensure that patients receive maximum benefit from therapy? Prostate cancer is typically diagnosed, and initially managed, under the care of the urologist. The involvement of medical oncologists generally comes later in the disease and tends to be more of a switch point for the primary management of the patient. However, it is advisable that the urologist remain involved with patient care from a collaborative perspective and to assist with the management of urological complications that the patient may experience. Diagnostic tools can be used to identify treatment switch points throughout disease progression to help ensure that patients have the opportunity to receive all appropriate therapies during their periods of optimal efficacy. The clinical goal is to strive for maximal survival and quality of life by prescribing the right therapy to the right patient at the right time.18 The first step is being able to identify patients who are at risk. Disease progression factors can be used to guide not only the decision of whether to refer or not to refer the patient to a medical oncologist, but also the timing of the referral. The timing of the referral to the medical oncologist depends on the individual urology practice. At Duke University, the institution where I practice, urologists tend to make the referral to medical oncologists early, when patients are just beginning to exhibit HRPC biology. Referral at this time in the disease process is key because, even in the best case scenarios, this point is when the time course of the disease shortens; survival time is typically measured over a few years, not a decade or more. Consequently, follow-up, intervention, and treatment switch points all need to happen much more rapidly. As previously stated, I think it is critical that urologists continue to see their patients. In early and less aggressive disease, urologists may maintain primary management as long as they continue to screen for metastases and provide supportive care. When the decision is made to switch primary management of patients to medical oncologists, it is important for urologists to work with medical oncologists, and possibly primary care physicians, to help coordinate care and ensure that the transition is as seamless as possible for patients. In general, what value has been shown with multidisciplinary collaboration in managing patients with cancer, including the improvement of patient outcomes when treating mHRPC? The ideal situation is for patients with mHRPC to feel that every member of the medical team has their best interests at heart. Multidisciplinary collaboration helps maximize synergies of patient care across all the specialties involved with their care and offers many benefits to patients and providers. In fact, patients report improved patient satisfaction and psychological benefits.5 Multidisciplinary collaboration improves provider-patient 4

communication throughout the entire course of patient survivorship and improves the efficiency and integration of care for institutions and healthcare providers.1,5 As treatment options for patients with mHRPC increase, a multidisciplinary approach to patient care is becoming even more important.1 A complete multidisciplinary team includes not just a urologist, medical oncologist, and radiation oncologist, but can also include a nurse, primary care physician, and support services (Figure 2).1,5,25 Other key members can include nutritionists, mental health professionals, pain management experts, and other professionals whose focus is treating the patient in each stage of disease to support timely and appropriate care.1,5

Figure 2: A Complete Multidisciplinary Team1,5,25

Urologist

Nurse

Radiation oncologist

PATIENT WITH PROSTATE CANCER Support services

Medical oncologist

Primary care physician

Studies have shown that multidisciplinary collaboration may lead to improved patient outcomes. A study conducted at Thomas Jefferson University (TJU), which utilizes a multidisciplinary care approach for mHRPC, showed that there were significant improvements in TJU 10-year survival rates when compared with Surveillance Epidemiology and End Results prostate cancer outcomes data, especially in high-risk locally advanced patients.1 A second study at the University of Colorado, a multidisciplinary “center of excellence,” showed that 5-year survival rates for prostate cancer patients exceeded the survival rates from across the state and region.26,27 From a medical oncologist’s perspective, how do you feel that this type of multidisciplinary approach can help improve individualized treatment plans and treatment outcomes for patients? I believe the medical oncologist, urologist, and any other physicians caring for the patient need to be consistent in their message and how they manage the care of the patient. Based on my personal experience, the best way to have a consistent and transparent approach is to have regular interactions, such as phone discussions, or, if clinicians practice in the same building or clinic, tumor board/case review sessions or meetings. Medical documentation alone cannot solely achieve this level of communication. I have found that both oncologists and urologists can benefit from understanding each other’s practice patterns, thought processes, and management style. This type of collaboration ultimately creates the greatest patient satisfaction, patient trust, and the best support for patient decisions regarding their primary goals and individual care. I also think as healthcare, payor, and reimbursement changes occur in the future, this collaborative group will be in the best position to adapt and continue to provide optimal patient care.

(cont’d on page 5)

Question & Answer NEAL D. SHORE, MD, FACS Director, Certified Physician Investigator (CPI) Carolina Urologic Research Center Managing Partner Atlantic Urology Clinics Myrtle Beach, South Carolina From a urologist’s perspective, what are your thoughts on how urologists can collaborate with oncologists to improve patient care and treatment outcomes? Achieving multidisciplinary collaboration in the community setting is much different than in an academic or institutional setting. I think it is important to look within your community and identify opportunities to create multidisciplinary communication team building that fits your practice environment. Given the advantages of modern technology, such as e-mail and other methods for oral and written communication, collaboration is possible even in small rural communities. For remote community practices with geographical distance between specialists, I believe there needs to be dedicated time for the referring physicians to meet and discuss real-world patient cases to share their thought processes and management approach for each patient. Table 4 includes examples of some questions that may be useful in facilitating such a discussion.

(cont’d from page 4)

I have found that most patients are pleased and willing to have additional office appointments when they feel that there is a collaborative team approach supervising and overlooking their care. To that effect, the conversation between urologists and patients at the time of referral to medical oncologists, or other specialists, is crucial; patients need to feel that they are not “being passed on” or “abandoned” by their urologist. As it is usually the urologist who first diagnosed the patient and has treated him for several years, patients often develop a level of comfort and trust with their urologist and his/her entire staff. At the time of referral, I may explain to my patient that “although he has done well under my care, he has reached a point in his disease where I want to reach out to a colleague with additional experience with specific systemic oncology therapies that are available to help him in order to better combat his advancing disease.” I also think it is important to explain to patients that they will continue to see their urologist and that he or she will still be involved with their care, for example, in areas of nutritional support, hormonal therapy, and/or bone health, skeletal-related event prevention, etc. This direct communication at the time of referral will help allay fears of abandonment and give them an understanding of the ongoing team approach for their care moving forward. Ultimately, the collaborative approach should assure the patient not only that he is receiving all appropriate clinical options, but also that he will maximize his quality of life and clinical progress.

Table 4: Questions to Facilitate Discussions on a Multidisciplinary Approach to Patient Care What are the triggers for ordering further tests to decide when a patient may convert from radiological negative to positive (eg, M0 to M1)? What are the treatment options during that interval of time when the patient is still androgen sensitive, through progression to M0, and then M1? What are the diagnostic triggers for ordering further evaluation? What is the frequency of evaluation? What are the treatment options? How does the approach to a patient with high tumor burden differ from the approach to a patient with low tumor burden? What are the options once a patient becomes symptomatic?

5

ClinTopics

References 1. Gomella LG, Lin J, Hoffman-Censits J, et al. Enhancing prostate cancer care through the multidisciplinary clinic approach: a 15-year experience. J Oncol Pract. 2010;6(6):e5-e10. 2. Data on File. sanofi-aventis U.S. LLC. 3. Antonarakis ES, Eisenberger MA. Expanding treatment options for metastatic prostate cancer. N Engl J Med. 2011;364(21):2055-2058. 4. Fitzpatrick JM, Sternberg CN, Saad F, et al. Treatment decisions for advanced genitourinary cancers: from symptoms to risk assessment. Eur Urol Suppl. 2009;8(9):738-746. 5. Look Hong NJ, Wright FC, Gagliardi AR, Paszat LF. Examining the potential relationship between multidisciplinary cancer care and patient survival: an international literature review. J Surg Oncol. 2010;102(2):125-134. 6. American Society of Clinical Oncologists (ASCO). Progress against cancer. http://www.cancer.net/patient/Publications%20and%20Resources/Progress%20Against%20Cancer/Progress_Against_Cancer_Timeline.pdf. Accessed January 2, 2012. 7. American Cancer Society. Cancer facts & figures 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/ documents/document/acspc-029771.pdf. Accessed January 2, 2012. 8. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™. Prostate Cancer. V.4.2011. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed January 2, 2012. 9. Hamberg P, Verhagen PC, de Wit R. When to start cytotoxic therapy in asymptomatic patients with hormone refractory prostate cancer? Eur J Cancer. 2008;44(9):1193-1197. 10. Sternberg CN, Petrylak DP, Sartor O, et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castraterefractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009;27(32):5431-5438. 11. Saad F, Eastham J. Zoledronic acid improves clinical outcomes when administered before onset of bone pain in patients with prostate cancer. Urology. 2010;76(5):1175-1181. 12. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422. 13. Shore ND, Smith MR, Jievaltas M, et al. J Clin Oncol. 2011;29(suppl). Abstract 4533. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_ detail_view&confID=102&abstractID=78458. Accessed January 2, 2012.14. Logothetis C, de Bono JS, Molina A, et al. Effect of abiraterone acetate on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer post docetaxel: results from the COU-AA-301 phase 3 study. Presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. 15. Yu EY, Nathan FE, Higano CS. Detection of metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetatstatic castration-resistant prostate cancer. J Clin Oncol. 2011;29(15)(suppl). Abstract 4655. http://meeting.ascopubs.org/cgi/content/abstract/29/15_suppl/4655?sid=042b8512-b7f2-4236-9d44057232bd7030. Accessed January 2, 2012. 16. Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918-2925.17. Smith MR, Cook R, Lee K-A, Nelson JB. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer. 2011;117(10):2077-2085. 18. Scher HI, Halabi S, Tannock I, et al; for the Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-1159. 19. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302-6309. 20. Potvin K, Winquist E. Hormone-refractory prostate cancer: a primer for the primary care physician. Can J Urol. 2008;(suppl 1):1420. 21. Bellmunt J, Carles J, Albanell J. Predictive modelling in hormone-refractory prostate cancer (HRPC). Clin Transl Oncol. 2009;11(2):82-85. 22. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 23. Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res. 2010;16(1):203-211. 24. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003;21(7):1232-1237. 25. Sternberg CN, Krainer M, Oh WK, et al. The medical management of prostate cancer: a multidisciplinary team approach. BJU Int. 2007;99(1):22-27. 26. University of Colorado Hospital. Cancer Outcomes 2010. http://www. uch.edu/pdf/Cancer_Outcomes_Book.pdf. Accessed January 2, 2012. 27. University of Colorado Hospital Web site. http://www.uch.edu/conditions/cancer. Accessed January 2, 2012.

This promotional program was developed based on interviews with Neal D. Shore, MD, FACS, and Daniel J. George, MD, in conjunction with and funded by sanofi-aventis U.S. LLC. Dr Shore and Dr George each received a fee for participation in this project. ClinTopics® is a registered trademark of BioPharm Communications, LLC. ©2012 sanofi-aventis U.S. LLC.

6

All rights reserved.

Printed in USA.

February 2012

US.CAB.12.02.042