Jan/February 2016- War on Cancer: An Update

Jan/February 2016

Doctors Metro MetroDoctors THE JOURNAL OF THE TWIN CITIES MEDICAL SOCIETY

War on Cancer: An Update

In This Issue: • • • •

Working Together to Reduce Cancer Burden What’s New in Cancer Care Charles Bolles Bolles-Rogers Award Luminary of Twin Cities Medicine

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CONTENTS VOLUME 18, NO.1

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JANUARY/FEBRUARY 2016

IN THIS ISSUE

Cancer — The Current Frontier

By Peter J. Dehnel, M.D.

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PRESIDENT’S MESSAGE

Physician Satisfaction

By Carolyn A. McClain, M.D.

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TCMS IN ACTION

By Sue Schettle, CEO

Page 32

Page 6

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CANCER UPDATE

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Colleague Interview: A Conversation with Thomas P. Flynn, M.D.

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•

Minnesota Cancer Alliance: Working Together

By Jeanne R. Steele, Ph.D.

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Milestones in the Discovery of the HER2 Biomarker and Related Diagnostic Tests

By Franklin Pass, M.D.

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Advances in the Treatment of Pediatric CNS Tumors

By Anne Bendel, M.D.

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Colon Cancer: Some Good News

By Ann Lowry, M.D.

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Prostate Cancer Update: 2016

By Todd Brandt, M.D. and Basir Tareen, M.D.

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SPONSORED CONTENT:

Exploiting the Immune Response to Treat Patients With Cancer

By Jeffrey Miller, M.D.

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•

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David J. Dries, M.D. Receives 2015 Charles Bolles Bolles-Rogers Award

Traditional and Novel Treatments for Melanoma

By Charles E. Crutchfield III, M.D.

In Memoriam Page 28

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Caring Hearts for Homeless People Supply Drive New Members Career Opportunities

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LUMINARY OF TWIN CITIES MEDICINE

John H. Kersey, M.D.

Page 5 MetroDoctors

The Journal of the Twin Cities Medical Society

On the Cover: New and exciting developments in the care and treatment of cancer. Articles begin on page 6.

January/February 2016

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Doctors MetroDoctors THE JOURNAL OF THE TWIN CITIES MEDICAL SOCIETY

Physician Co-editor Peter J. Dehnel, M.D. Physician Co-editor Robert R. Neal, Jr., M.D. Physician Co-editor Marvin S. Segal, M.D. Physician Co-editor Richard R. Sturgeon, M.D. Physician Co-editor Charles G. Terzian, M.D. Medical Student Co-editor Katherine Weir Managing Editor Nancy K. Bauer TCMS CEO Sue A. Schettle Production Manager Sheila A. Hatcher Advertising Representative Betsy Pierre Cover Design by Andrea Westmoreland MetroDoctors (ISSN 1526-4262) is published bi-monthly by the Twin Cities Medical Society, 1300 Godward Street NE, Broadway Place West, Suite 2000, Minneapolis, MN 55413. Periodical postage paid at St. Paul, Minnesota. Postmaster: Send address changes to MetroDoctors, Twin Cities Medical Society, 1300 Godward Street NE, Broadway Place West, Suite 2000, Minneapolis, MN 55413.

To promote its objectives and services, the Twin Cities Medical Society prints information in MetroDoctors regarding activities and interests of the society. Responsibility is not assumed for opinions expressed or implied in signed articles, and because of the freedom given to contributors, opinions may not necessarily reflect the official position of TCMS. Send letters and other materials for consideration to MetroDoctors, Twin Cities Medical Society, 1300 Godward Street NE, Broadway Place West, Suite 2000, Minneapolis, MN 55413. E-mail: nbauer@metrodoctors.com.

January/February Index to Advertisers TCMS Officers

President: Carolyn A. McClain, M.D. President-elect: Matthew A. Hunt, M.D. Secretary: Thomas E. Kottke, M.D. Treasurer: Nicholas J. Meyer, M.D. Past President: Kenneth N. Kephart, M.D. TCMS Executive Staff

Sue A. Schettle, Chief Executive Officer (612) 362-3799; sschettle@metrodoctors.com Nancy K. Bauer, Associate Director, and Managing Editor, MetroDoctors (612) 623-2893; nbauer@metrodoctors.com Karen Peterson, BSN Executive Director, Honoring Choices Minnesota (612) 362-3704; kpeterson@metrodoctors.com Lynn Betzold, Program Coordinator, Honoring Choices Minnesota (612) 362-3703; lbetzold@metrodoctors.com Emily Larsen, Marketing and Communications Coordinator (612) 623-2885; ejohnson@metrodoctors.com Helen Nelson, Administrative Assistant, Honoring Choices Minnesota (612) 362-3705; hnelson@metrodoctors.com Ellie Parker, Project Coordinator Physician Advocacy Network (612) 362-3706; eparker@metrodoctors.com

Audiology Concepts ...........Inside Back Cover Coldwell Banker Burnet....Inside Back Cover Classified Ad .......................................................23 Crutchfield Dermatology.................................. 2 Entira Family Clinics .......................................30 Fairview Health Services .................................31 Healthcare Billing Resources, Inc. ...............20 Lakeview Clinic .................................................31 M Health .............................................................12 Minnesota Epilepsy Group, PA .........................

Inside Front Cover MN Prostate Cancer Coalition .....................22 Olmsted Medical Center.................................30 PrairieCare PAL .................................................20 Sage Screening Program .. Inside Front Cover Sage Screening Program ..................................19 Saint Therese.......................................................23 Senior LinkAge Line.........................................17 St. Cloud VA Medical Center ............................

Outside Back Cover St. David’s Center .............................................11 Uptown Dermatology & SkinSpa................11 U.S. Navy Recruiting .......................................29 Wapiti Medical Group .....................................31

Crutchfield Dermatology “Remarkable patient satisfaction from quality service, convenience and excellent results”

Exceptional Care for All Skin Problems

For advertising rates and space reservations, contact: Betsy Pierre 2318 Eastwood Circle Monticello, MN 55362 phone: (763) 295-5420 fax: (763) 295-2550 e-mail: betsy@pierreproductions.com MetroDoctors reserves the right to reject any article or advertising copy not in accordance with editorial policy. Advertisements published in MetroDoctors do not imply endorsement or sponsorship by TCMS. Non-members may subscribe to MetroDoctors at a cost of $15 per year or $3 per issue, if extra copies are available. For subscription information, contact Andrea Farina at (612) 623-2885.

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January/February 2016

Charles E. Crutchfield III, M.D.

Board Certified Dermatologist

Psoriasis & Acne Specialist 1185 Town Centre Drive Suite 101 Eagan, MN 55123

Your Patients will Look Good & Feel Great with Beautiful Skin.

Appointments 651-209-3600

www.CrutchfieldDermatology.com

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At your request, we have same day appointments available for your patients with acute skin care needs.

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IN THIS ISSUE...

Cancer — The Current Frontier

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o hear a physician give the diagnosis of “cancer” to you, a family member or close friend is a universally devastating event. That is where the ability to listen to more information usually stops and people are not able to hear anything else for the remainder of that life-changing conversation. With a little time and very patient explanation, the diagnosis sinks in and questions about type, extent of the disease, treatment options and, most importantly, prognosis usually begins.

It is because of cancer’s very significant and dreaded impact on individuals that I am very pleased to introduce this edition of MetroDoctors. For those of us who have been in the delivery of health care for more than a few years, it has been remarkable to see the progress that has been made in earlier detection, effective treatment options, reduction of treatment-related complications and increases in life expectancy after diagnosis for the majority of cancer types. Even more remarkable has been the increased understanding of cancer at a molecular level, and how that understanding is leading to development of treatment strategies that may actually lead to long-term cures of cancer currently thought of as incurable.

Thomas Flynn, M.D., former president of Minnesota Oncology Hematology, PA, starts off this subject with our traditional “Colleague Interview.” He has spent years at the forefront of the delivery of oncology treatment and shares some great perspectives on this very important topic. He also provides some guidance in how to approach some of the more controversial topics in this area to help guide clinical decision-making.

Jeanne Steele, Ph.D., provides some important information for all of us about the Minnesota Cancer Alliance. Its overall goal is to provide a means by which a number of interested individuals can work collaboratively to reduce the burden of cancer in Minnesota. It is an effort that was born out of the “Cancer Plan Minnesota 2005-2010.”

The story of the development of the HER2 marker is outlined by one of the principal investigators — Franklin Pass, M.D. Biomarkers are, of course, rapidly expanding in their role to better characterize certain cancers as well as direct specific therapies — or, conversely — preclude some therapies. This is a remarkable story of a local company, and the role the investigators are playing to enhance our treatment armamentarium.

Pediatric brain and other CNS tumors are a life-altering

By Peter J. Dehnel, M.D. Member, MetroDoctors Editorial Board

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The Journal of the Twin Cities Medical Society

diagnosis for children and their parents. There are also significant future neurodevelopmental implications of these diseases. Anne Bendel, M.D., guides us through the current state of this area. New developments are promising better long-term outcomes with less treatment-related morbidity — a great accomplishment for these very challenging conditions.

Two very common cancers — colon cancer and prostate cancer — are covered by Ann Lowry, M.D. for colon cancer and Todd Brandt, M.D. and Basir Tareen, M.D. for prostate cancer.

Dr. Lowry highlights the progress made in improved survival for people with colon cancer, and the very important role screening continues to play in early detection and/or treatment at the earliest possible point of diagnosis. Drs. Brandt and Tareen highlight some of the controversies in screening for prostate cancer as well as treatment of early disease. Progress in treatment options for more advanced disease continues to evolve as well.

Charles Crutchfield, M.D., gives us a look at the current state of the art for treatment of melanoma. While being the most dreaded of the skin-based cancer, there is exciting news in terms of new treatments for metastatic disease. This is giving hope to patients with advanced disease who did not have a lot of great treatment options until recently.

A new feature in this edition reflects MetroDoctors’ efforts to reach out to, and partner with, the larger health systems in the Twin Cities area. Jeffery Miller, M.D., from M Health, enlightens us with recent developments in better recruiting the body’s immune system to better fight the invading foreign cells — cancer cells — that are proliferating without restraint. He highlights the specific work with natural killers cells to become “cancer scavengers.”

Finally, Marv Segal, M.D. highlights the life and career of John Kersey, M.D., in another of his literary offerings of “Luminary of Twin Cities Medicine.” Marv has again in a very succinct and well-written way provided a snapshot of this most remarkable GIANT from the University of Minnesota Medical Center.

I hope you thoroughly enjoy this edition of MetroDoctors.

As always, if you have comments, questions or responses, please contact Nancy Bauer at nbauer@metrodoctors.com.

January/February 2016

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President’s Message

Physician Satisfaction CAROLYN A. McCLAIN, M.D.

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he most recent Physician Lifestyle report stated that all specialties are at a burnout rate of higher than 40 percent. My specialty, Emergency Medicine, is second only to Critical Care Medicine in rates of burnout, with Family Practice, General Surgery and Internal Medicine close behind with rates of over 50 percent. Why are we burnt out? The survey, which had prepopulated boxes to check, indicated increased paperwork, frustration with the EHR, the ACA and increased pressure to see more patients. Although these reasons are certainly credible, what about all of the unrealistic expectations the public has for their doctors — or all the unrealistic expectations we have for ourselves?

Recently, I watched a rerun of Grey’s Anatomy. I normally don’t do this because it is incredibly frustrating to watch. Let’s be honest, who looked that good in residency, much less a surgical residency? Shoot, in residency, I went up, not one, but two scrub sizes. Yep. Anyway, Patrick Dempsey, who is a neurosurgeon on the show, came down to the ED and reattached a hand. Seriously, right there in the ED, in about 5 minutes. My take home — why have I been calling Orthopedics all this time for amputations? The public may realize this is television, however, in the collective unconscious, they expect doctors to do miraculous things.

We should thank network television for these unrealistic but heroic expectations because they balance out what the mainstream media is saying about us. Just a brief Google search pulls up recent headlines “greedy doctors prey on the needy,” or “it’s Physician pay, stupid!” But it’s not just our salaries that are attacked, it is also our motivations. We are accused of ordering tests to line our pockets. We are measured by patient satisfaction surveys where patients are asked, “Did the physician treat your pain?” Then we are skewered in the media for creating an opiate epidemic. Even with two physicians running for President this year, the public continues to get mixed messages about physicians’ motivations.

Both Rand Paul and Ben Carson stated in a recent debate that the vaccine schedule is inappropriate. Really? Pediatricians push vaccines to drive up Autism rates? Just sayin’.

A recent study out of UC Berkeley showed that patients see their physicians as “empty vessels” devoid of an inner life. In fact, the more important their doctor was to their health, the less personal characteristics the patients perceived in their physician. But as anyone who has lost a patient knows, we are not empty. Sometimes, after a tough shift in the Emergency Department, I am so rattled that I really don’t feel safe to drive home. All of us, every day, are “filled” with our patients. The EHR, the prior authorization paperwork, the ACA and the recent push for complete patient satisfaction are just metaphors for this lack of connection we feel to the patients we have committed our lives to and results in the crisis of physician burnout and some of the highest suicide rates of any profession.

This is why we need to organize. This is why TCMS and the MMA are so important. It is our opportunity, as physicians, to connect with our community and drive health care changes where we know they matter most, in lifestyle changes. Through Honoring Choices, TCMS has shown that connecting with communities can help people have hard discussions about end-of-life care and we can then “honor” those choices. We have pushed legislation that created the Indoor Clean Air Act which has decreased exposure to second-hand smoke. We are educating about e-cigarettes. And yes, we do have an agenda — get vaccinated, start exercising, lose weight. Our agenda is to make our communities healthy.

As President of the Twin Cities Medical Society I ask that you make yourself happy. Join organized medicine. You are some of the smartest people this country has produced. You are repaying mountains of debt to have the privilege of truly connecting with another human being. But if we don’t get involved in the process, if we don’t have a clear message for the public, we are left with Network television and Dr. Oz. When we come together through organizations like TCMS and the MMA we remind not only the public but ourselves that physicians are the solution to a healthier society.

Please reach out to me with your ideas and suggestions. This is your organization. Let’s work together for our patients and our profession.

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January/February 2016

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The Journal of the Twin Cities Medical Society

TCMS IN ACTION SUE A. SCHETTLE, CEO

Board News

Medical Students

The TCMS Board of Directors adopted a five year strategic plan at their November meeting, placing an emphasis on three goals: 1) Advocate for sustainable practices and a focus on physician well-being; 2) Advocate for public policy initiatives important to Twin Cities physicians; and 3) Advocate for equity in health and wellbeing. Staff has been researching opportunities to embrace these goals and ways to partner with existing initiatives. Watch for more information as formalized plans are put into action.

Two Lunch ’n Learn sessions were held at the University of Minnesota with first and second-year medical students. On October 22, Peter Dehnel, M.D. and Ellie Parker, Program Coordinator, Physician Advocacy Network (PAN), discussed “Up in Smoke: E-cigarettes and Other Tobacco Products.”

And, on November 3, James Struve, M.D. and Karen Peterson, Honoring Choices Executive Director, presented: “Advance Care Planning: What Physicians Need to Know.”

Senior Physician Association

The City of Richfield updated their tobacco ordinance on November 10. The new ordinance increases the minimum prices of cigars, prohibits the “sampling” of tobacco products, including e-cigarettes, in any new tobacco retail shop, and prohibits the use of e-cigarettes in public parks. The vote passed unanimously.

The St. Paul City Council voted December 2 to restrict the sale of all flavored (other than menthol), non-cigarette tobacco products to adult-only tobacco shops.

The ordinance also increases the price of cheap cigars and cigarillos. The ordinance is similar to what Minneapolis passed earlier this year. The final vote will take place in January. Thank you to all who wrote letters of support and a special thanks to Dr. Tom Kottke for his testimony at the public hearing on November 18.

Ellie Parker and Pete Dehnel, M.D. were recent guests of MDH Commissioner Ed Ehlinger, M.D. on “A Public Health Journal” to discuss e-cigarettes and recommendations for providers to address these new tobacco products with patients. To view this Public Health Journal presentation go to: https://www.youtube.com/ watch?v=DpvrJXsdnrs.

The 2016 Senior Physician Association officers were appointed at the October 27 meeting: Drs. Marilyn Joseph, President; Martin Lipschultz, Vice-President; and Stuart Hanson, Past-President. The following physicians will serve as at-large members on the Executive Committee: Drs. Robert Geist, Paul Hamann, Miriam McCreary, Eugene Ollila, Richard Pfohl, and Richard Woellner.

Supporters of City of Richfield tobacco ordinance updates.

Honoring Choices Minnesota

I am pleased to report that HCM was the recipient of a $250,000 grant from MDH to expand the ACP reach throughout the state of Minnesota. To accomplish this additional work, two new staff members have joined our HCM team. Please join me in welcoming Helen Nelson, Administrative Assistant, and Lynn Betzold, Program Coordinator.

TCMS Foundation

Staying true to its mission to improve the health and wellbeing of the community through strategic initiatives, the Foundation distributed $22,700 to seven community projects at its November meeting. Your generous contributions to the Foundation help to make these allocations possible.

Charles Bolles Bolles-Rogers Award

Congratulations to David Dries, M.D., recipient of the 2015 Charles Bolles Bolles-Rogers Award. Nominated by his colleagues at Regions Hospital, Dr. Dries exemplifies the criteria of an outstanding physician as a highly accomplished physician and surgeon, academician and researcher. (See related story on page 28.)

MetroDoctors

Physician Advocacy Network

Lunch 'n Learn presenters: Ellie Parker, PAN program coordinator, (Top) and Dr. James Struve and Karen Peterson, Executive Director, Honoring Choices.

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January/February 2016

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Cancer Update

Colleague Interview: A Conversation with Thomas P. Flynn, M.D.

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homas P. Flynn, M.D. is a board certified Hematologist/Oncologist and serves as Medical Director and Chairman, National Policy Board, The US Oncology Network. He received his medical degree from the University of Minnesota Medical School; completed an internship at Barnes Hospital, Washington University School of Medicine (St. Louis, MO); and residency at Barnes Hospital, St. Louis, MO and the University of Minnesota. A Hematology-Oncology fellowship was also completed at the University of Minnesota. Dr. Flynn was the President of Minnesota Oncology Hematology, PA from 2001-April 2013.

You have a rich historical perspective of changes in treatment over your career. What change, new treatment or transition stands out?

There have been two developments that stand out. The first is understanding and defining the cancer cell at the molecular level.

While we have known the basic characteristics that make a cell behave as a cancer cell for some time — unrestrained growth and replication along with the ability to invade and metastasize — defining at a molecular level the receptors and pathways within the cell that control its behavior has made possible a host of targeted therapies that can inhibit the malignant behavior. Dozens of therapies have been developed to target these receptors and pathways in the past 10 or 15 years. The second major advance, which is coming to the fore just in the last few years, is based on understanding again at a cellular and molecular level how cancer cells can inhibit the patient’s immune system to prevent themselves from being attacked. Several agents and approaches have been and are being developed that can unleash the immune system to attack a cancer, some of which are already showing remarkable benefit.

With the ever-advancing methods of detecting cancers that before would have gone untreated, how do we reconcile options for treatment with quality of life?

With costs? In particular, the evidence against PSA 6

January/February 2016

screening and the movement toward active surveillance for DCIS; are patients and doctors ready to accept the idea of living with cancer as a chronic disease instead of eliminating it?

Given scientific evidence and well designed clinical studies, oncologists will adapt their approach to conditions such as low grade prostate cancers and DCIS, including active surveillance rather than treatments that might generate unnecessary costs. The more difficult challenge is convincing patients to accept such an approach. It may require a change in terminology and removing the word “cancer” from the designation of some of these lesions.

Have some established prevention/screening programs become unnecessary or perhaps negative?

Certainly prevention and screening programs for colorectal and cervical cancers are effective in reducing morbidity and mortality.

While numerous studies have demonstrated that mammography saves lives, the controversies center around finding the most effective utilization regarding frequency and age to begin its use. PSA screening for prostate cancer is perhaps the most controversial area. We are doing better at separating out (based on tumor grade and patient age) those tumors where the patient will benefit from treatment from those for whom observation is most appropriate.

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Will one of the cancer research areas prevail or will all have a place?

Basic science research and drug development will and needs to continue as the foundation for discovering new therapies. In the area of clinical research, particularly with the new “targeted” therapies directed at specific mutations, the shift will be to smaller trials focused on particular subsets of patients. We will no longer see the randomized trials involving thousands of patients in broad categories, e.g. stage II breast cancer, comparing two chemotherapy regimens.

How would you suggest approaching the topic of value in oncology treatment? How can we best approach the rapidly increasing costs of cancer treatment, when health care in general is so expensive?

Value based care is a topic that is receiving a great deal of attention these days in the oncology world. One of the driving forces is the recent development by CMS of the “Oncology Care Model” which will reimburse for cancer care in a way that promotes value, rather than the traditional fee for service model. Other payers are pursuing and testing similar programs, and CMS has set out a goal that 50 percent of the reimbursement they provide by 2018 will be value based. A number of approaches show promise in improving value in oncology care. The use of clinical pathways for chemotherapy has been shown to result in lower costs with equivalent outcomes. Another opportunity is to reduce waste by limiting the use of low value testing such as serum tumor markers and imaging for surveillance in patients with a low risk of recurrence. Avoiding ER visits and hospitalizations for the management of treatment side effects when these things can be effectively handled in the outpatient setting can reduce cost of care significantly. The new value based reimbursement models will be increasingly implemented in the next few years, and I expect the approach will at least slow the rate of growth in costs. The other major challenge is the cost of new therapies. Many new cancer therapies today cost a breathtaking $10,000 per month. Some system of price control, such as is employed in other countries, needs to be looked at. Cost versus benefit also needs to be a part of the discussion we have with patients when a curative outcome is not possible.

Regarding the significant positive strides occurring in cancer care, please comment on the current and future implications (morbidity, mortality, financial implication, etc.) of biotherapy/immunotherapy and the treatment impact of individualized genetic prescriptions for patients and the specialty of oncology.

Immuno-oncology is the hottest topic in cancer care today. While harnessing the immune system to treat cancer has been a topic of research for many decades, and some agents have been developed MetroDoctors

The Journal of the Twin Cities Medical Society

in this regard such as the interferons, it has only been in the past few years that this approach has come into its own. We now have a number of agents, with many more in development, that allow immune cells, specifically T-cells, to destroy cancer cells.

These treatments are able to significantly extend the survival of patients with advanced melanoma and lung cancer, as well as Hodgkin’s Lymphoma. Active research continues in many tumor types including hematologic malignancies, and I expect we will see a number of new indications for these agents in the next few years. Some are even predicting that they will eventually replace cytotoxic chemotherapy to a large degree over the next 10-15 years. On the topic of individualized genetic prescriptions, or what is often call “precision medicine” there is also great excitement. New drugs in this category, it seems, are being approved every few weeks or so, and in certain settings can have a profound impact on care, providing extended survival and reduced side effects — for example in the case of lung cancers with the ALK mutation. The expanding knowledge of genetic mutations in a variety of cancer cell types, and the development of drugs designed to attack these mutations, is providing new, more effective treatment options for many patients. Another effect is the potential that we will change our overall thinking in oncology to categorize cancers and determine treatment based on the genetic mutations in the tumor cells, rather than our current approach that is based almost entirely on the cell of origin such as breast, lung, or colon. Because of the inordinate cost of many of the targeted agents, we will need to be attentive to cost and value as we apply these treatments.

Where or in what clinical areas should research resources be concentrated or directed? Comment on ethics issues in research trials.

The future focus of research in oncology was discussed under the fourth question. The majority of clinical trials have been, and likely will continue to be, conducted primarily in community oncology practices. Therefore, resources should continue to be focused on this setting. Ethical issues in clinical cancer research are carefully addressed through the Institutional Review Board mechanism used for both National Cancer Institute and industry funded trials to assure that patients who enroll in a trial are not going to receive substandard therapy or be placed at undue risk of adverse effects. In addition, any physician participating in the trials and enrolling patients is required to complete annual training regarding their responsibilities in conducting research trials in an ethical manner respectful of patient privacy. I think cancer patients should be confident that treatment on a clinical trial is a good approach, and sometimes the best approach to their care.

(Continued on page 8)

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Cancer Update Colleague Interview (Continued from page 7)

Are today’s oncology treatment options and resource requirements too complex for solo or small independent practices?

With the ever-expanding treatment options and increasingly complex therapies available, it is very difficult for an oncologist in solo practice or a small group to keep abreast of the latest knowledge in all tumor types. Larger groups are able to have oncologists sub-specialize in a few tumor types in order to have sufficient experience and keep up with the literature. Add to that the resources required to meet all of the regulatory requirements, EMR implementation and meaningful use requirements, as well as new programs such as ICD-10 coding and one quickly sees the challenges, both financial and organizational, becoming overwhelming for a very small practice. The other financial challenge is in providing these very expensive new treatments for patients under the “buy and bill” system imposed on oncology practices

by Medicare decades ago. If the practice isn’t reimbursed for a treatment costing $10,000 per month, the strain on cash flow quickly becomes severe. For these reasons we have seen a significant steady trend of small independent practices either merging into larger groups or being acquired by hospitals and health systems.

Once the practice becomes part of a hospital or health system, the cost of care to the patient and payer actually increases because of differences in reimbursement rates, which is counter to efforts to reduce the cost of cancer care.

What are the financial incentives that oncologists need to be aware of when they are recommending a certain course of therapy?

Under the “buy and bill” system for chemotherapy alluded to above, an oncology practice or a hospital purchases chemotherapy drugs and then bills the patient/payer once they are administered. Higher cost drugs, which may or may not be more effective than a lower cost alternative, provide a larger margin in absolute dollars. Some generic chemotherapy drugs are actually sometimes reimbursed at less than the cost of the drug, resulting in a financial loss for whoever is providing the therapy. One can see that there could be a financial incentive to prescribe a more expensive treatment, when there is a choice among treatments.

The move to value-based reimbursement with bundles of care will help to remove that incentive. In our practice we have for decades employed clinical pathways that are designed to identify treatment choices that are evidence based for a given tumor and stage. When there is a choice between equally effective regimens, the lower cost regimen is included preferentially in the pathway, removing the financial incentive. This approach is now available nationally in what are called Value Pathways powered by NCCN, 8

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which are incorporated into the guidelines of the National Comprehensive Cancer Network (NCCN) used by most oncologists in the country to guide treatment.

Is the FDA too slow, too careful, or do they have it about right?

I think the FDA has it about right. New cancer therapies are being approved at a rapid rate, based on very current clinical trial data, making the latest and greatest treatments available to patients. The FDA is charged with assuring that drugs are safe and effective. The demonstration of effectiveness is sometimes more straightforward than the safety component, as adverse effects may show up only after a drug is used extensively in a large number of patients. There will always be the tension between those who want to make new treatments available quickly and those who want to assure the drug is safe for all.

Please offer any additional (summary) thoughts on your career/experiences as an oncologist.

Since 1981, I have had what has truly been a privilege to make a difference in people’s lives as a medical oncologist and hematologist. I feel so fortunate to have had the opportunity to treat many wonderful patients over the years, and I am thankful to all who have entrusted me with their care. I have seen tremendous advances in cancer care over three decades. Starting out we had not much more than a handful of chemotherapy drugs, and there were many patients for whom we could not alter the course of their disease in any way. It has been very gratifying to see the advances we’ve made in understanding cancer at the cellular and molecular level and seeing how that knowledge has been translated into new treatment approaches. Cancer survivals overall have gone from less than 50 percent to now two-thirds of patients surviving beyond five years. I am confident that advances will continue and survivals will continue to improve. This will require considerable ongoing investment by society and participation in clinical trials by patients, who are the true heroes in our war on cancer. One of the most important lessons I have learned in life has been from my patients…and that is how to face challenges with incredible courage and grace. I am most thankful for the honor of having served in the role of a cancer care provider.

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Minnesota Cancer Alliance: Working Together

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he Minnesota Cancer Alliance is a voluntary association of organizations and individuals dedicated to reducing the burden of cancer by working together on shared objectives. Founded a decade ago, the Alliance is an independent, non-profit membership organization that works to nurture partnerships, reduce duplication, and advocate for policies and systems that attack cancer from multiple angles. It relies on the state cancer plan to set its agenda and on its members to do the work. Funding comes from sponsorships and registration fees for major events such as the several Cancer Summits the Alliance has sponsored, and from in-kind donations of staff time and resources from member organizations.

Imagine What is Possible When Organizations Combine Forces

In a sense, Cancer Plan Minnesota 20052010 gave birth to the Alliance. The plan was the culmination of work done by hundreds of Minnesotans who volunteered time and energy over a 12-month period to serve on committees and work groups, provided input at community forums, and identified objectives and set priorities that would reduce cancer’s impact on Minnesotans. A smaller group of movers and shakers, many of them physicians and researchers who had trained or worked together at the University of Minnesota, deserves credit for setting things in motion years earlier. They were assisted by staff from the Minnesota Department of Health and the American Cancer Society along with a planning grant from the Centers for Disease Control and Prevention. CDC

By Jeanne R. Steele, Ph.D. MetroDoctors

continues to provide funding to MDH for comprehensive cancer control activities, and ACS dedicates a percentage of staff time to support Alliance activities.

This core group of professionals and advocates was motivated by what they perceived as a troubling disconnect. On the one hand, Minnesota had, and still does have, a wealth of resources and programs dedicated to cancer prevention and control, including two National Cancer Institute-designated comprehensive Cancer Centers (the University of Minnesota’s Masonic Cancer Center and the Mayo Clinic Cancer Center), a top-ranked medical school and school of public health, nationally-recognized cancer researchers, a highly-trained health care workforce, and numerous community-based and serviceoriented organizations working to meet the needs of cancer patients and their families. Yet, on the other hand, there was a lack of communication and coordination among these organizations and individuals that resulted in missed opportunities for collaboration and a lack of synergy. In essence, the sum of resources that could be put to work against cancer was less than the rich promise of its parts.

The Minnesota Cancer Alliance came together to change this. Its vision was for Minnesota to be a place where: • Preventable cancers do not occur.

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•

People who develop cancer are diagnosed in the earliest stage possible.

• People with cancer are given the highest quality, state-of-the-art care available to maximize their chances of survival and quality of life.

• Preventable disparities in the prevention of cancer, and in the quality, experience, and outcomes of care for patients with cancer, are eliminated.

CancerPlan Minnesota 2005-2010 was written to help achieve this vision. It identified five overarching goals and 24 objectives along with specific strategies for achieving each one. Where available, baseline data were reported and targeted improvements were specified. Cancer Plan Minnesota 2011- 2016 followed suit: five overarching goals, 23 objectives in this second plan, with specific strategies and indicators spelled out. From the start, the Alliance’s goal was to implement as many of the cancer plan strategies as it could and to do so as efficiently and effectively as possible by working collectively across disciplines, specialties, programs and sectors. Its theme was working together.

Guided by a 22-member Steering Committee, the Alliance looks to its members to find opportunities for collective action. Although the Steering Committee (Continued on page 10)

January/February 2016

9

Cancer Update Minnesota Cancer Alliance (Continued from page 9)

historically identifies a handful of priorities on which to focus during a given year, its primary role has been that of supporting actor. It works as a convener, agenda setter, motivator and match-maker. With the support of MDH and ACS staff, it provides the infrastructure for networks that bring together people for information-sharing, relationship-building and problem-solving. Currently, there are three Alliance networks: MN Commission on Cancer Network, the Colon Cancer Network, and the Cancer Health Equity Network. Members also serve as volunteers on standing and ad hoc committees, and they can request Alliance endorsement of projects they are working on, provided the project involves two or more member organizations and directly links to cancer plan objectives and strategies. Information

about all of these opportunities for getting involved can be found on the Minnesota Cancer Alliance website (mncanceralliance.org).

A Record of Accomplishment, But Plenty of Work Remains

Well aware that it was impossible to tackle 24 (or subsequently 23) objectives at once, the Alliance identified four priorities on which to focus during its first few years: 1. Reducing tobacco use and exposure by increasing taxes on tobacco and expanding clean indoor air policies; 2. Reducing disparities in cancer screening and treatment; 3. Improving access to information about locally available services for cancer patients and their families; 4. Increasing colorectal cancer screening.

Significant progress has been made on all four of these fronts, including passage

Guiding Principles that Shaped the State’s First Cancer Plan

1. We believe that by seeking and acting on opportunities for collaboration we can accomplish more together than we can accomplish alone to reduce the burden of cancer in Minnesota.

2. We support science-based and evidence-informed approaches to address cancer control across the continuum of cancer care.

3. We value reaching out to and engaging all Minnesotans, regardless of age, race, ethnicity, gender, geography, education, language, sexual orientation, and socioeconomic status.

4. We respect cultural wellness practices and traditions and support the delivery of cancer services to all Minnesotans within a context of cultural values.

5. We believe that patients and their families must be empowered to make decisions based on information presented and shared in a manner they can understand.

6. We support equal access to cancer services for all Minnesotans.

7. We support the elimination of fragmented care for cancer patients.

8. We support efforts to more effectively and equitably use public and private resources to continuously, transparently, and measurably decrease suffering from cancer.

9. We believe in using population-based approaches, system changes, and interventions directed at individuals’ behavior to help reduce the burden of cancer.

10. We believe that moving this plan to action will require strong leadership, adequate resources, and broad-based commitment.

—Cancer Plan Minnesota Steering Committee—

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January/February 2016

of Freedom to Breathe; several cigarette and other tobacco tax increases; foster care, multi-unit housing and local tobacco control policy and regulatory initiatives; the expanded reach of both public and private breast, cervical and colon cancer screening programs; improvement in colon cancer screening rates; and several well-attended Cancer Summits and topic-specific conferences, to name just a few.

Another example of the power of partnerships is the track record of the Alliance’s policy committee launched in 2012 to support cancer-related initiatives, especially those that reduce risk. In just three years, the Alliance has contributed to passage of Minnesota’s tan-free teens and radon laws, helped increase momentum for hospitals to phase-out sugar-sweetened beverages on their premises, and added its voice in support of local efforts to curtail the sale of flavored tobacco products and e-cigarettes.

For the past two years, Sue Schettle, CEO of Twin Cities Medical Society, has chaired the Cancer Alliance’s Advance Care Planning workgroup formed to accelerate use of ACP. Schettle, backed by the support of the Alliance’s policy committee and many others, convinced the 2015 Minnesota Legislature to appropriate a quarter of a million dollars to expand community-based efforts that encourage individuals, families, caregivers and health care providers to engage in conversations about end-of-life choices.

Cancer Plan Update Underway

In November, the Alliance kicked off a year-long process to update the state’s 2011-2016 cancer plan. This time the goal is to identify objectives that can serve as a framework for action over the next decade, until 2025. Although the timeframe is longer, the five overarching goals that led to creation of the Cancer Alliance — Prevention, Detection, Treatment, Quality of Life, and Equity for everyone touched by cancer across the entire spectrum of cancer control — continue to guide the work.

Through February 2016, the Alliance is soliciting input from stakeholders statewide via on-line and in-person “listening sessions.” TCMS members are encouraged to participate by either hosting a listening session or expressing their views in person MetroDoctors

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or online. By listening, the Alliance hopes to learn what people think is working well, what is not working so well, and most importantly, what can be done better to reduce the burden of cancer in Minnesota.

No special expertise is required. Please contact communications@mncanceralliance.org if you’d like to help shape the next plan.

Concurrently, the Alliance plans to recruit workgroups of experts to help review the latest research, identify new trends and areas of concern, and frame data-driven objectives and strategies that are realistic and potentially achievable within the projected timeframe. Donna McDuffie, new director of the Comprehensive Cancer Control Program at MDH, is committed to developing a plan that brings communities into the Alliance infrastructure so that they can work collectively with traditional partner organizations to achieve shared goals and speak with one, consistent voice about health risks and winnable battles.

As one who has worked for years to narrow gaps between “have’s” and “havenot’s,” McDuffie sees the cancer planning process as an opportunity to look at the “wicked problem that is cancer” in new ways. She sees it as one of a host of diseases linked to the social determinants of health.

“How can I talk about inequities in cancer and not think about diabetes, heart disease and stroke,” she asks, acknowledging there are no easy answers. One thing is sure, however. The Alliance is committed to working collaboratively with organizations like the Twin Cities Medical Society as it searches for answers and crafts a plan for the next decade.

YOU

belong HERE.

MAKE A REFERRAL Early Childhood Education • Autism Services • Children’s Mental Health Pediatric Occupational, Speech and Music Therapy • Special Needs Support Services

952.548.8700 stdavidscenter.org

Jeanne Steele, Ph.D., joined the Minnesota Department of Health, Comprehensive Cancer Control Program, in 2007 after completing a post-doc in Pediatric Cancer Epidemiology at the University of Minnesota.

Before completing her doctorate at the University of North Carolina –Chapel Hill, she worked as a foreign service officer, newspaper reporter, public information officer, and education and health care marketing consultant.

To learn more about the Minnesota Cancer Alliance, visit www.mncanceralliance.org.

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January/February 2016

11

is for Innovation.

University of Minnesota Health Cancer Care specializes in translating innovative research into life-changing patient care. From pioneering minimally invasive surgical techniques to developing targeted cancer therapies, our physicians and researchers are working to improve cancer patients’ outcomes.

Recently, our team has had success with an early-stage clinical trial for patients with lymphoma and leukemia. This promising new immunotoxin therapy, using the diphtheria bacteria, targets cancer cells while limiting exposure to surrounding healthy cells.

A bold idea with life-changing results.

Learn more about our expert, innovative care at mhealth.org/cancercare

The University of Minnesota Health brand represents a collaboration between University of Minnesota Physicians and University of Minnesota Medical Center. Š 2016 University of Minnesota Physicians and University of Minnesota Medical Center

Milestones in the Discovery of the HER2 Biomarker and Related Diagnostic Tests One evening in 2008, two friends were dining at a restaurant on the campus of the University of Pennsylvania. The men shared a common heritage dating back to their childhood spent in Winnipeg, Manitoba and Duluth, Minnesota. Both were physicians. One was a prominent Ivy League molecular biologist and crystallographer, the other a serial entrepreneur in the biotechnology world. The dialogue proceeded something like this: “You know, my Penn lab has two new protein detection technologies.” “I know. My wife is a breast cancer survivor, and I think your recent discoveries can go a long way to managing the fear and uncertainty generated by the inefficiency and cost of breast cancer care. So let’s stick to HER2 diagnosis, and possibly therapy. You’re the world’s expert on HER2, and many believe your early research qualifies you as the Father of Precision Medicine.” “OK. You organize the company and recruit a management team.”

After so many years, it’s difficult to pinpoint who made the initial discovery, but 1978 is a good birth date for the emergence of what soon became known as erbB tumor biomarkers. This group of four related cell proteins function in a way that causes breast and other cancers. Half of each protein molecule sticks up outside the cell waving in the breeze, while the other half is an inactive enzyme inside the cell. If the cell starts making too many of these molecules (in breast the magic number is 500,000 per cell, up from a normal 40,000) the outside portions begin

By Franklin Pass, M.D. MetroDoctors

to cling together. When they touch, the enzyme portion is activated and cell proliferation, movement and invasion begins.

The second protein in this family of four bears the common designation HER2.

HER2 was originally isolated in the labs of Robert Weinberg (MIT) and Mark I. Greene (Harvard) and was called neu, after its origin in brain tumors. By 1986, Greene had demonstrated that monoclonal antibodies directed against HER2 caused HER2 tumor cells in tissue culture to revert to normal — the birth of precision (personalized) medicine. HER2 was recognized as an important “driver” of breast cancer, and a handful of clinical investigators working with the biotechnology company Genentech developed and brought to market the drug Herceptin™, a human version of Greene’s earlier discovery, for the management of breast cancer. Herceptin™ was the first therapeutic antibody targeted at a cancer-related molecular marker to receive FDA approval (1998).

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There are now three FDA approved monoclonal antibody drugs that do their thing by preventing HER2 proteins to clump outside the cell. There are three more FDA approved small molecule drugs that act on the enzyme portion of HER2 protein inside the cell. These drugs are most often less toxic than traditional cytotoxic chemotherapy. Thanks to HER2 drugs, and other very important therapeutic advances, women with metastatic breast cancer are living longer and better.

But we have not materially changed the mortality rate — what we’ve done is change breast and several other cancers from an acute disease to a chronic disease.

It is important to recognize that parallel investigations were occurring with HER1 (EGFR), leading to what we now know as targeted drugs for colon and lung cancer. In fact, what we call triple-negative breast cancer is most often HER1 driven.

HER3 is less well understood but plays at least a minor role in growth enzyme activation, while the function of HER4 remains obscure. What has resulted is an alphabet of receptors, cell growth enzymes, known mutations and precision drugs.

That’s the HER2 and related drug story. But only a minority (20-30 percent) of women with early stage breast cancer have HER2 driven tumors. How, then, do we identify erbB tumors? Enter the related field of diagnostic tests, and new terminology: theranostics and companion diagnostics.

During the 1990s, another group of researchers and a small number of diagnostics companies were developing assays (Continued on page 14)

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Cancer Update HER2 Biomarker and Related Diagnostic Tests (Continued from page 13)

to identify HER2, either by measuring overproduction of HER2 protein molecules on the surface of tumor cells by immunohistochemistry (IHC) or by measuring activity of HER2 DNA inside cells (FISH). A positive tissue test using IHC and/or FISH soon became and remains a requirement for targeted drug administration. Newer, more refined tissue assays look at RNA production or clumping, and are becoming more commonplace, names like OncotypeDx™ and HERmark™.

These tissue assays are performed on formalin-fixed, paraffin embedded tissue, most often only at the time of the original biopsy or surgery. Wouldn’t it be helpful to have a blood test that could monitor women during treatment and identify the recurrence of a HER2 tumor? Monitoring assumes added relevance since we now know that from inception, breast tumors may be pleomorphic, i.e., of more than one cell type. Isolated colonies of HER2 cells may be missed at biopsy. Furthermore, not uncommonly, only the metastatic tumor will be predominantly HER2, thus effecting a shift of metastatic disease that all of a sudden becomes amenable to better, targeted drug treatment.

In the mid-80s, scientists at Dupont began to identify and measure the outside portion of HER2 floating in the blood serum. The outside protein is broken off by blood enzymes and the concentration rises with the appearance and growth of a HER2 tumor. Walter Carney, working first from Dupont, configured a quantitative serum ELISA immunoassay and collaborated with many clinical researchers to define the role of circulating HER2 protein.

Soon after, Carney and the test wound up

as a separate business, Oncogene Science.

In 1998, the test received a 510(k) FDA clearance and soon after, a CPT reimbursement code. Carney recently moved on, but after several changes in ownership, HER2 ELISA kits continue to be manufactured and sold to reference labs. In parallel, a version of the test is sold to reference labs

by Siemens for use in their automated immune-analyzer. Both versions of the test provide near identical results.

The data from several research groups show serum HER2 rising and falling in lockstep with progression and remission, and acting as a bellwether of early recurrence. Unfortunately, controversy emerged, and no sooner than reaching the market, the serum assay fell out of favor and has remained largely unknown.

Clinical researchers continue to study serum HER2 but publish largely in less prominent international journals. The test has not engendered the “champions” or luminary advocates in the U.S. medical oncology community needed to popularize serum HER2 monitoring. Nevertheless, the need is there; other chronic diseases like diabetes and AIDS benefit enormously from serum monitoring.

We all gravitate toward new ideas and technology, and precision medicine is no exception. That includes an expanded focus on new biomarkers — stay tuned for tissue and serum tests of tumor immunity checkpoints, a new and very promising cancer therapeutic area. Machines capable of detecting circulating tumor cells (CTC) have arrived, and at least one company proposes to detect HER2 CTC. Circulating tumor DNA assays are on the way.

We’ve yet to master cancer diagnosis and treatment, but we can be confident that advances in diagnosis and treatment will continue to flow.

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January/February 2016

“It’s been seven years since we first came to this restaurant. That night we discussed opening a serum HER2 reference lab in Minnesota. The lab is well established now in Roseville. We’ve got a great management team in place and working relationships with a national reference lab, our Boston kit manufacturer and a couple of very good hospital labs. Meanwhile, I see that the dual administration of Herceptin™ and Perjeta™, something you first described over 20 years ago, is now standard practice. From your recent article in the journal Cell, I get the impression that you are re-defining the role of tumor immunity in breast cancer treatment, and we can expect the roll-out of new therapeutics.” “True. I see the accomplishments of the ’10s to be as important and exciting as the ’80s. And, we’re only halfway through the decade!”

Franklin Pass, M.D., is Chairman and CEO of Martell Diagnostic Laboratories, Inc., a cancer diagnostics CLIA reference laboratory, located in Roseville, Minnesota. Dr. Pass graduated from the University of Minnesota and University of Minnesota Medical School and then trained at Oregon Health Sciences University as a dermatologist. Following a dermatology residency and military service, he joined the faculty of Albert Einstein College of Medicine. At Einstein, he spent six years in an immunochemistry and molecular virology laboratory. He organized and led the residency training program in dermatology and collaborated in early human papilloma virus research. He returned to the faculty of the University of Minnesota Medical School in 1973 to continue his HPV research, which ultimately resulted in the formation of Molecular Genetics, Inc. in 1979. Since 1979, Dr. Pass has organized a handful of companies working in the field of agriculture, drug discovery-delivery and diagnostics. He is co-founder of Martell Diagnostic Laboratories (monitoring blood markers of certain cancers) and serves as a Director of PepTx (developing targeted therapeutics) and TerraMax (agricultural biotechnology). He lives in rural western Wisconsin and can be reached at fpass@martelldiagnosic.com or (651) 927-7970.

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Advances in the Treatment of Pediatric CNS Tumors

E

ach year in the United States, approximately 4,600 children ages 0-19 years will be diagnosed with a central nervous system (CNS) tumor.1 Pediatric CNS tumors are the second most common pediatric cancer; with leukemia being the most common.2 Overall, the outcome is relatively good for pediatric CNS tumors, with a 5-year survival rate of 73 percent.1 Despite the excellent cure rate, CNS tumors are the leading cause of cancer-related deaths in the 0-14 year age group,3 and survivors of childhood CNS tumors often suffer long-term side effects from the treatment.4 The goal, therefore, is to find treatments that provide the best chance of cure with the least short- and long-term side effects.

Surgery is an essential tool for the diagnosis and treatment of pediatric CNS tumors. Surgery provides tissue for histological confirmation of the diagnosis, and removes as much of the tumor as possible without causing significant irreversible neurological deficits. Complete tumor resection directly correlates with improvement in overall survival in most pediatric CNS tumors. In children who have deep-seated tumors located in the thalamus, basal ganglia, pineal region, optic pathway, hypothalamus, and brainstem, surgery is usually limited to a stereotactic or open biopsy solely to confirm the diagnosis, because any degree of surgical resection in these areas will typically result in neurological deficits.

Over the last decade there have been many technical advances in the field of neurosurgery, which aid the neurosurgeon

By Anne Bendel, M.D. MetroDoctors

in resecting as much of the tumor as possible and minimizing harm to the surrounding normal brain. Preoperative studies using different imaging tools — 3T MRI, functional MRI (fMRI), magnetic source imaging (MSI) or magnetoencephalogram (MEG) — not only precisely identify the location of the tumor, but also map out the nerve fibers as they travel through or around the tumor, define the function of the brain surrounding the tumor (i.e. language, memory, movement and sensation), and localize any seizure foci. Use of intraoperative neuronavigation (Stealth or Brainlab) during surgery is helpful in localizing the tumor and the surrounding key structures that may be at risk during surgery. Intraoperative MRI, located within the operating suite, allows for an MRI to be performed during the surgical procedure to confirm the extent of surgical resection or to define any complications. Endoscopic neurosurgery is a minimally invasive technique, which

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utilizes an endoscope placed through a small opening in the skull to visualize and remove tumors located near or within the ventricles, the surface of the brain, the skull base or spinal cord.5 Laser interstitial thermotherapy (LITT),6 another minimally invasive surgical tool, uses a laser placed directly into the center of the brain tumor through a small hole in the skull.

The laser is heated to a temperature that will destroy tumor tissues, while an MRI measures the temperature of the tissues in real time, assuring maximal ablation of the tumor and minimal heating of the surrounding normal tissue. LITT may allow surgical ablation of brain tumors that are difficult or impossible to access with conventional craniotomy. Both LITT and endoscopic neurosurgery result in quicker recovery time and fewer complications compared to those seen with conventional open craniotomy.

Radiation is key to improving longterm survival in many pediatric CNS tumors. Radiation can also be used as an alternative to surgery, if complete surgical resection has a high risk for neurological injury. Unfortunately, radiation therapy is known to have a high incidence of irreversible long-term side effects on the developing brain (cognitive impairment, vasculopathy, endocrinopathy, and secondary malignancy), which directly correlates with the total dose and volume of radiation delivered and inversely correlates with the age of the patient.4 The goal is to minimize radiation to the growing brain by either avoiding radiation or minimizing the volume and dose of radiation. Radiation (Continued on page 16)

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Cancer Update Advances in the Treatment of Pediatric CNS Tumors (Continued from page 15)

therapy uses high-energy irradiation to create free radicals that preferentially damage tumor DNA, because tumor cells do not effectively repair DNA. Conventional radiation therapy uses photon radiation, which delivers radiation to the entire prescribed field, but includes an entrance and exit dose delivered to the normal brain tissue. Proton radiation has the ability to lose energy at the edge of the target area, resulting in a decreased dose of radiation to the surrounding normal brain tissue.7 Radiosurgery (Gamma Knife, CyberKnife, LINAC based radiosurgery) involves delivery of multiple tiny beams of radiation focused on a small tumor target.7 Although each low-dose beam has very little effect on the brain tissue it passes through, a strong dose of radiation is delivered to the site where the beams meet. The precision of radiosurgery results in minimal damage to the healthy tissues surrounding the target.

There is concern, however, that its target is so precise that the microscopic “fingers” of tumors seen in many pediatric brain tumors might not be sufficiently treated.

Chemotherapy is essential to improving the cure rate for most malignant and some non-malignant pediatric brain tumors. Chemotherapy can also be used to reduce the dose or volume of radiation, or omit radiation, thus decreasing the long-term risks of radiation therapy on the developing brain. Limitations to chemotherapy include indiscriminate toxicity to all the cells of the body causing both short-term and long-term side effects. In addition, the presence of a blood brain barrier limits penetration of some chemotherapy drugs into the brain. There are multiple experimental techniques attempting to overcome the blood brain barrier such as Blood Brain Barrier Disruption, intra-arterial injection of chemotherapy, and convection enhanced delivery of chemotherapy.

Recent advances in genomic analysis have unveiled key molecular pathways involved in the promotion and maintenance of tumor growth in the majority of pediatric brain tumors. Mutations that activate specific molecular pathways can be predictive of the behavior of some tumors; therefore this data can be used to tailor treatment for each “molecular subtype” of a given tumor. For example, genomic data has determined that medulloblastoma is a heterogeneous cancer consisting of four “molecular subtypes”: WNT, SHH, group 3 and group 4 (table below).8 All patients with WNT subtype and infants with SHH subtype have an excellent prognosis, and can be treated with less aggressive therapy, including omission of radiation in some patients. On the other hand, group 3 medulloblastoma, especially if MYC or MYCN amplification is present, has a poor outcome from standard treatment and would benefit from new innovative treatments. Another advantage of

Molecular Subgroups of Medulloblastoma (Adapted from Taylor MD et al, Acta Neuropathol 123: 465-72, 2012)

Genetics

WNT (10%)

SHH (30%)

CTNNB1 mutation PTCH1/SMO/SUFU Monosomy 6 mutation MYCN amplification GLI2 amplification Gene Expression

Group 3 (25%)

Group 4 (35%)

MYC amplification i17q

CDK6 amplification i17q MYCN amplification

WNT signaling

SHH signaling PI3K signaling

Photoreceptor/GABAergic Neuronal/Glutamatergic signaling signaling

3-17 years (median 9.5 years)

Bimodal <3 years and >16 years

1-10 years (median 5 years)

2-36 years (median 9 years)

M=F

M=F

M>F

M>F

Histology

Classic

Desmoplastic/nodular

Classic, large cell anaplastic

Classic, Large cell anaplastic

Metastasis

Rare M+

Uncommon M+

Very frequent M+

Frequent M+

Prognosis

5 yr OS 94%

5 yr OS 87%

5 yr OS 32%

5 yr OS 76%

Demographic Age Gender Clinical Features

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January/February 2016

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identifying the specific molecular pathway driving a tumor is the potential to target that tumor with drugs aimed at inhibiting the active pathway. This not only allows for “targeted or personalized treatment” but it also results in less injury to healthy cells.

An example of successful targeted therapy is the use of everolimus to treat Subependymal Giant Cell Astrocytoma (SEGA) of the brain and angiomyolipoma (AML) of the kidney, which occur in Tuberous Sclerosis (TS), an inherited condition due to a germline mutation in the TSC1 or TSC2 gene. The function of TSC1 and TSC2 is to suppress tumor growth by inhibiting m-TOR, a protein involved in regulating the cell cycle. If the TSC1 or TSC2 gene is defective, as seen in TS, m-TOR is not suppressed resulting in the development of SEGAs and AMLs. Administration of everolimus, a drug that specifically inhibits m-TOR, results in shrinkage of both SEGAs and AMLs.9 Immunotherapy is a novel approach for the treatment of pediatric CNS tumors. Immunotherapy acts by stimulating

the immune system to reject or destroy tumor cells. Current investigational immunotherapies for pediatric CNS tumors include cancer vaccines, oncolytic virus therapy, adoptive cell therapy, immune boosters, and monoclonal antibodies.10 In summary, the field of pediatric neuro-oncology is more exciting than ever due to advances in treatment that are expected to increase survival rates and decrease long-term side effects, thereby promising to improve the quality of life seen in our pediatric CNS tumor survivors.

Anne Bendel, M.D. is the director of Pediatric Neuro-oncology in the Cancer and Blood Disorders Clinic at Children’s Hospitals and Clinics of Minnesota where she has worked for 21 years. She is also an active member of the CNS Tumor Committee of the International Children’s Oncology Group (COG).

Dr. Bendel can be contacted at (612) 8135940 or anne.bendel@childrensmn.org for any questions related to pediatric CNS tumors.

References: 1.

Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol. 2014; 16(s5):iv1-iv63.

2.

Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics. 2014.

CA Cancer J Clin. 2014; 64(2):83-103.

3.

Ostrom QT, de Blank PM, Kruchko C, et al.

Alex’s Lemonade Stand Foundation infant and childhood primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-Oncol. 2015; 17: x1-x35.

4.

Roddy E, Mueller S. Late effects of treatment of pediatric central nervous system tumors. J Child Neurol. 2015; Jun 4.

5.

Choudhri O, Feroze AH, Nathan J, et al. Ventricular endoscopy in the pediatric population: review of indications. Childs Nerv Syst. 2014; 30(10): 1625-43.

6.

Missios S, Bekelis K, Barnett GH. Renaissance of laser interstitial thermal ablation. Neurosurg Focus. 2015; 38(3):E13.

7.

Bindra RS, Wolden SL. Advances in radiation therapy in pediatric neuro-oncology. J Child Neurol. 2015: Aug 13.

8.

Taylor MD, Northcott PA, Korshunov A, et al.

Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012; 123(4):465-72.

9.

Franz DN, Agricola K, Mays M, et al. Everolimus for subependymal giant cell astrocytoma: 5 year final analysis. Ann Neurol. 2015;Sept 18.

10. Reardon DA, Gilbert MR, Wick W, et al. Immunotherapy for neurooncology: the critical rationale for combinatorial therapy. Neuro Oncol. 2015; 17 Suppl 7:vii32-vii40.

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Cancer Update

Colon Cancer: Some Good News

C

olorectal cancer is the third most commonly diagnosed cancer in American men and women.

However there is good news. The incidence and mortality rates have declined up to 30 percent in people over 50 years of age with the largest decrease in people 65 or older; that decline is attributed to increased rates of screening â&#x20AC;&#x201D; particularly colonoscopy. Identification and removal of adenomatous polyps has been shown to decrease the incidence of colon cancer.

Based upon that experience, the American Cancer Society along with other organizations set a goal of screening 80 percent of the eligible population by 2018.

Recommended screening options include stool tests for blood or DNA, flexible sigmoidoscopy, colonoscopy, barium enemas and CT colonography. Each test has advantages and disadvantages. Stool tests for blood may be better accepted by patients, are done at home, are relatively inexpensive and pose no risk to the patient.

If fecal immunochemical test (FIT) is used, dietary restrictions are not necessary. Data shows a reduction in colon cancer when stools tests are done annually with colonoscopy follow up of positive tests. However, the tests may miss many polyps and some cancers, may have false positive results and should be done annually. Stool tests for DNA are a newer option with similar advantages as stool tests for blood. From the limited data available, it appears to be accurate for cancer detection but less accurate for polyp detection. At present it should be considered a cancer detection rather than cancer prevention test. That

By Ann Lowry, M.D.

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January/February 2016

could change when data from longitudinal studies with serial testing is available. Flexible sigmoidoscopy is an office procedure requiring only enema prep and has limited risk, but only checks one-third of the colon. It is recommended every five years.

Colonoscopy usually allows viewing of the whole colon and offers the potential for identification and removal of polyps but it does require full bowel prep and carries a small risk of bleeding and perforation.

It is recommended every 10 years after a normal examination in an average risk patient. Both double contrast barium enemas and CT colonography usually view the whole colon and require bowel prep; they are recommended every five years.

While safe, since a double contrast barium enema involves radiation exposure, can be uncomfortable, has a higher risk of missing a polyp than colonoscopy and does not allow for polyp removal; it is rarely recommended. CT colonography has many of

the same disadvantages but is more comfortable although more expensive. Because insurance coverage is limited, it is most often used to check the proximal colon after an incomplete colonoscopy.

The current guidelines recommend screening of average risk persons between the ages of 50 and 75 years old and against screening in adults over 75 years old.

One of the challenges in clinical practice, however, is deciding at what age to stop.

Based upon the polyp to cancer sequence of typically 5-7 years, one could argue that anyone with a life expectancy of 10 years should be screened. For patients with significant medical illnesses, one might recommend stopping before 70 years old. On the other hand, for 75-year-old patients with no medical issues, their predicted life expectancy may warrant continued screening.

Another factor is the personâ&#x20AC;&#x2122;s risk of colon cancer based upon their personal and family history. One microsimulation model found that screening should stop at 66 years old in low risk, healthy patients with a negative colonoscopy. But in healthy, high risk patients, colonoscopy is warranted until age 86 years old. Screening guidelines may soon become more specific and personalized. On-line tools for risk assessment and screening recommendations are being developed.

Revised recommendations by the U.S. Preventative Task Force are available now for public comment. The recommendations for adults aged 50-75 and over 85 years old remain the same. However there is a shift in adults between 76-85 years old suggesting that screening may be of benefit for adults in that age group who

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have never been screened, assuming their general health is good.

While the positive impact of screening is very good news, the data also provides a word of caution. Historically the incidence of colorectal cancer occurring in people under 50 years old has been 10 percent. However, the overall incidence in that age group is rising by 1-2 percent per year and the incidence of rectal cancer is rising by 3.6 percent per year. Models predict a 27 percent increased incidence in people between 35-49 years old and a 90 percent increased incidence in people 20-34 years old with even higher rates for rectal cancer. The rates are higher in diabetic and obese patients. Some investigators attribute this increase to modifiable lifestyle factors, adding to the argument for promotion of healthy diets and exercise. To date, the screening recommendations are not changing for average risk patients but awareness of this rising incidence should remind all clinicians that symptoms such as a persistent change in bowel habits or bleeding should be investigated rather

than automatically attributed to benign anorectal conditions.

Family history is an important factor in screening recommendations. Identification of inherited cancer syndromes such as familial adenomatous polyposis and Lynch syndrome is critical in prevention of colon and other associated cancers. A careful family history of polyps and colon cancer must be routine. In addition to the known inherited syndromes, there are familial colon cancers. The general screening guidelines for those patients is to start at age 40 or 10 years younger than the youngest family member with either adenomatous polyps or colon cancer.

The primary treatment for colorectal cancer remains surgery. Minimally invasive techniques, usually laparoscopy for colon cancer and either laparoscopy or robotics for rectal cancer shorten the patient’s hospitalization and recovery. Large randomized studies of laparoscopic resections for colon cancer proved oncologic equivalence. More studies are needed for minimally invasive resection of rectal cancer.

New techniques have reduced the need for a permanent colostomy in patients with rectal cancer.

Patients with locally extensive disease or positive lymph nodes may require adjuvant treatment. For patients with colon cancer, chemotherapy may be recommended. Molecular genetics has changed chemotherapy recommendations and more research is being done. Colorectal cancer is now classified into two pathways: one with microsatellite instability (MSI) caused by defective DNA mismatch repair genes and a more common one with microsatellite stability but chromosomal instability. MSI tumors may be hereditary or sporadic and carry a favorable prognosis. Chromosomal unstable tumors are heterogeneous in their clinical course. Further work identified changes in oncogenes, tumor suppressor genes as well as other pathways. Research has already shown that certain subtypes benefit more from a given chemotherapeutic agent than others; indeed some (Continued on page 20)

Tell your patients there’s a better way to screen for colorectal cancer.

• Help them decide which screening test is best for them.

• Assist them in scheduling their test.

• If they’ll incur out-of-pocket costs, Sage Scopes may be able to help. Call 1-888-643-2584.

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January/February 2016

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Cancer Update Colon Cancer: Some Good News (Continued from page 19)

Your Link to Mental Health Resources

chemotherapy may have a negative effect in patients with certain subtypes. Testing for MSI status and certain mutations is becoming routine before treatment planning and recruitment to research studies.

The goal is a more personalized, targeted approach to therapy.

For rectal cancer both chemotherapy and radiation may be utilized. Pre-operative chemoradiation therapy reduces local recurrence rates and may improve survival in certain rectal cancer patients. However side effects are frequent. More accurate imaging techniques are being developed with the goal of more accurately identifying which patients will benefit from that treatment. Finally, a subset of patients have a complete response to chemoradiation and theoretically would not need surgery if they could be reliably identified; various modalities are being evaluated for that purpose.

Unfortunately the incidence and mortality rates for colorectal cancer remain high but there are reasons to be optimistic. Screening is reducing the incidence.

Surgical techniques are being refined and molecular genetics research is helping to personalize and target therapy. Providers must remain persistent about screening recommendations and evaluation of unexplained bowel symptoms even in young people to ensure that improvement continues.

Ann Lowry, M.D. practices colon and rectal surgery as a member of Colon and Rectal Surgery Associates. She is also a Clinical Professor of Surgery at the University of Minnesota.

Her career has been a combination of clinical practice, surgical education, and clinical research. Involved in colon and rectal surgery training for her entire career, she was the program director of the University of Minnesota colon and rectal surgery residency for over ten years. Currently she is President and CEO of Colon and Rectal Surgery Associates (CRSAL). She can be reached at alowry@ colonrectal.org.

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The Journal of the Twin Cities Medical Society

Prostate Cancer Update: 2016

P

rostate cancer is the most common non-cutaneous malignancy diagnosed in men. Last year in the U.S. an estimated 240,000 men were diagnosed with the disease, and 29,000 died because of prostate cancer. Approximately one in six men will be diagnosed with prostate cancer in their lifetime.

Over the last five to 10 years we have seen dramatic changes in the way prostate cancers are detected and treated. Traditionally, prostate cancer was detected using PSA testing and digital rectal exam with the primary treatments being surgery and/ or radiation. For metastatic disease patients were treated with hormonal therapy and cytotoxic chemotherapy. In this article we will discuss what’s new in prostate cancer screening, diagnosis, and treatment of localized and metastatic disease.

Screening

The PSA (prostate specific antigen) blood test is the most widely used screening test for prostate cancer since it first came into use in 1994. Men who are screened for prostate cancer using PSA are more likely to find their cancers earlier and have a higher chance of cancer cure. It is, however, not a perfect test, and many patients and physicians question its role in prostate cancer screening.

First, a PSA test can give both falsepositive and false-negative readings. Men with normal PSA readings may have prostate cancer, a false negative. More commonly, men with high PSA readings do not have cancer, a false positive. Men

By Todd Brandt, M.D. and Basir Tareen, M.D.

MetroDoctors

Todd Brandt, M.D.

Basir Tareen, M.D.

with high readings but without cancer go through unnecessary prostate biopsies and follow-up testing.

Second, prostate cancer in many men is indolent. PSA screening detects nonlethal as well as lethal cancers. One of the key challenges is differentiating those cancers which can be followed via active surveillance and those potentially aggressive cancers that will lead to significant morbidity and mortality. Most experts agree that not every prostate cancer needs to be treated. A significant trend clinically has been the acceptance by patients that not all cancers need immediate, aggressive treatment.

Controversy regarding PSA testing increased substantially after the U.S. Preventative Services Task Force came out with its position statement in 2010, giving the PSA blood test a “D” rating as a screening tool. Although many urologists and oncologists were critical of the rating, many practitioners at the primary care

level drastically changed their discussion with patients and practice patterns regarding PSA testing. Patients also became more critical of the test after heavy publicity of the USPSTF rating.

In 2013, the American Urologic Association established its own guidelines.

The AUA does not support the USPSTF position on PSA screening. The AUA recommends the omission of PSA screening for men with a life expectancy less than 10 years or those under 40. For all other men the AUA advocates shared decisionmaking for men and their physician regarding PSA testing — especially those men between ages 55-70 or those with a strong family history of disease.

Shared decision-making relies heavily on the guidance of a medical practitioner looking out for the best interest of the patient. We would encourage you to review the AUA guidelines at: https:// www.auanet.org/education/guidelines/

The Journal of the Twin Cities Medical Society

(Continued on page 22)

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Cancer Update Prostate Cancer Update (Continued from page 21)

prostate-cancer-detection.cfm. As urologists we strongly advocate for prostate cancer screening. In 2015 the current standard is the PSA test; in the future we hope a more cancer-specific test will emerge.

Diagnosis

The PSA is a basic screening test. It is often a starting point with patients as we discuss whether to perform a prostate biopsy, and, if a cancer is found, whether treatment or surveillance is most appropriate. Here we have also seen advances.

There are new genetic and biomarker studies which have added to our ability to find prostate cancers. Examples include the PHI (Prostate Health Index) or a 4Kscore — measures 3 or 4 different types of PSA kallikreins in the blood, and the PCA3 — a urine test that looks for a protein that is produced by prostate cancer cells. These tests are used to predict risk of high grade cancer prior to a patient having a biopsy. Advances in genetic testing

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allow us to better determine which cancers should be treated. Examples of this include the Oncotype DX and Prolaris — genetic tests run on a biopsy specimen to help determine if the biopsy sample represents low or higher risk disease.

Recent advances in MRI of the prostate have improved our ability to identify prostate cancers and, in some cases, differentiating indolent from aggressive tumors.

Urologists traditionally use trans-rectal ultrasound as a guide during a prostate biopsy, but the ultrasound is a low-resolution image. We now have software that can fuse a fixed MRI image with real-time ultrasonography. The radiologists reading the MRI will draw out specific areas requiring biopsy; the urologist can “fuse” that image with the ultrasound and insure that those specific areas are biopsied. This sequence creates a more targeted biopsy, detecting cancers we may have otherwise missed.

Treatment of Localized Disease

There is an increasing interest in active surveillance for low-grade prostate cancers.

Active surveillance is a close monitoring process that typically involves frequent PSA testing and rectal exams, repeat prostate biopsies, and imaging studies such as MRI to try to detect progression of disease.

While active surveillance is gaining traction, the gold standard for treatment of prostate cancer remains radical prostatectomy. Over the last decade daVinci robotic radical prostatectomy has emerged as the preferred surgical approach in the overwhelming majority of hospitals and centers of excellence. Robotic prostatectomy has shortened recovery times, decreased blood loss and, in experienced hands, improved outcomes.

Radiation, brachytherapy seed placement, cryotherapy (freezing), and a recently FDA approved treatment, highintensity focused ultrasound (HIFU), are also options for treatment of localized prostate cancer. Traditionally we treat or remove the entire prostate, even the benign tissue.

A different and developing strategy is focal therapy. Using some of the newer

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autologous infusion of patient’s own blood cells after they are exposed to the prostate cancer antigen in a lab. It has been shown to extend overall survival as well.

Radium 223 (Xofigo) is a radioactive agent used to target bone metastases. It is especially useful for men with late stage, painful bony metastatic disease.

Conclusion

Uronav biopsy.

technology such as HIFU or cryotherapy we can ablate only the cancerous lesion while leaving the normal prostate intact.

While focal therapy is not yet considered standard of care, improving imaging with MRI and other means of identifying tumor location within the prostate will likely make focal therapy a more common and standard option in the near future.

The landscape of prostate cancer diagnosis and treatment continues to evolve and improve. We believe this will help the lives of the many men diagnosed with prostate cancer. As urologists who are part of a larger practice, Metro Urology, that focuses on prostate cancer we see the benefit of adopting and employing these new technologies. We are excited about the future of prostate cancer care.

Todd Brandt, M.D., has practiced with Metro Urology for the past 15 years, focusing on prostate cancer and men’s health.

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Treatment of Advanced Disease

Prostate cancer is hormone sensitive and creating castrate levels of testosterone can help control the disease. Androgen deprivation therapy (ADT) uses either surgical castration, medical castration, and/or combined androgen blockade with the use of anti-androgens.

Despite initial tumor response to ADT, most cases will become resistant over time. Historically once the cancer became castrate resistant (CRPC) the only options were cytotoxic chemotherapy. Newer treatments have shown improved survival.

Abiraterone acetate (Zytiga) and Enzalutamide (Xtandi) are second-line inhibitors of androgen activity in the body, either by reducing production (Zytiga) or by androgen receptor blockage (Xtandi).

Both are being used commonly by urologists and oncologists for treatment after failure of initial ADT. Both show very good response and extension of survival.

Sipuleucel-T (Provenge) was a first of its kind cancer vaccine. It involves the

Basir Tareen, M.D., is a fellowship trained urologic oncologist. He has practiced with Metro Urology for 5 years.

Contact info: www.metro-urology.co; (651) 999-6800; tbrandt@metro-urology. com.

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January/February 2016

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Sponsored Content

Exploiting the Immune Response to Treat Patients With Cancer University of Minnesota Health physician-researchers keep improving the use of natural killer cells in the fight against cancer Contributed by Jeffrey Miller, M.D. The success of allogeneic (using donor cells) bone marrow transplant is dependent on three factors: • Chemotherapy and radiation therapy • Engraftment of new bone marrow stem cells from the donor • Permanent immune differences between the donor and recipient such that reconstituted donor lymphocytes help fight recipient cancer recurrence (a process referred to as a “graft-versus-leukemia” or GvL effect) The third factor is perhaps the oldest and best-established strategy to prove the power of the immune response in cancer therapy. This form of immunotherapy is mediated by donor immune lymphocytes and has been a platform to dissect immune components to develop better cancer therapies.

All humans, healthy or not, have cells called “natural killers” that help make up our immune systems. These white blood cells make up 10-15 percent of lymphocytes and are very different from T or B-cell lymphocytes. When cells become damaged, infected, or cancerous, NK cells recognize changes on those cells and kill them. They naturally mediate this function without activation or prior immunization.

So, for people with cancer that continues to grow, why don’t NK cells destroy the tumors? The answer is complicated because when tumors start to grow, they suppress the immune system. There’s no way to know how many times NK cells protect someone from cancer. We only know when they fail and cancer cells grow large enough to become symptomatic.

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At the Masonic Cancer Center, University of Minnesota, we’re studying NK cells and how best to use them in cancer therapies and have recently discovered new ways NK cells can be activated and directed to seek and destroy tumor cells.

In the past nearly 25 years, we have been exploring what capacity NK cells have to become cancer scavengers. We’ve treated more than 300 patients in clinical trials since then and have definitely had success. We started these investigations in 1994 treating lymphoma and breast cancer patients after autologous (using the patient’s own stem cells) bone marrow transplant. We gave these patients drugs called interleukins (IL-2) to expand NK cells in the body in hopes of preventing relapse, which occurs in the 25 percent of patients undergoing this procedure.

We found that IL-2 alone was ineffective to fully activate NK cells to kill cancer.

This led to our first cell therapeutic trial where autologous NK cells were taken out of the body and activated with high

concentrations of IL-2. Even though we could induce better immune function in the body, we were still not happy with outcomes and relapses continued to occur.

It was not until the late 1990s that we also discovered that patient NK cells are suppressed by their own tumor through special receptors that recognize “self ” molecules and turn off NK cell function.

Therefore, NK cells from a related donor can overcome this inhibition and more effectively kill cancer cells. In 2000, this biologic breakthrough led us to start using donor NK cells from family members.

NK cells are given to patients after what is called “lymphodepleting chemotherapy regimen” that makes space for new cells and alters the endogenous cytokine milieu (promotes interleukins in the body) to promote the survival of NK cells and their expansion in the body after donor NK cell infusion. In one clinical trial, for instance, we infused patients afflicted with resistant or relapsed acute myeloid leukemia (AML), a setting where salvage

What’s the Appeal of Natural Killer Cells?

While cancer treatments like chemotherapy and radiation damage cells indiscriminately, natural killer (NK) cells target only cancerous cells, leaving normal cells unharmed. NK cells can be collected from a donor’s blood, or they can be made in greater quantities from pluripotent stem cells. We also like that NK cell therapies don’t require as close of a genetic match between the recipient and donor as some other immunotherapies.

There’s also potential to manipulate them to target certain types of tumors. Today NK cells are good at killing blood cancers such as leukemia, but adding specific receptors to the cells could help them work better against solid tumors as well.

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chemotherapy only works <10 percent of the time, with NK cells from a healthy donor and saw a 30-40 percent remission rate — definitely a positive outcome.

We also have ongoing studies in patients with advanced lymphoma and late stage ovarian cancer. What we know is that we can put stubborn cases of various cancers into remission, and now we’re trying to re-purpose different receptors on the NK cells to get a higher percentage of patients into longer-lasting remission.

We currently have an open clinical trial for women who have ovarian cancer which involves infusing donor NK cells directly into the patients’ abdominal cavities instead of into the bloodstream as we did with leukemia.

We’re hoping we can improve the outcomes by putting NK cells into close proximity to the cancer. The goal for the study is to find the donor NK cells in the patient’s blood after seven or 14 days. If we can detect them in a blood test, we know the infused NK cells have expanded successfully.

Like most clinical trials, the ovarian cancer study is expensive, so right now the team is starting with one infusion per patient. But if the results indicate that it’s a successful therapy for ovarian cancer, future plans may involve infusions every three months for the first year of treatment.

Team Science

What we’ve built at the University is a “team science” approach: developing a critical mass of investigators focused on one area of research. We have a team of 20-plus researchers, including University of Minnesota Medical School faculty and staff, laboratory workers, students and postdoctoral fellows focused on immunotherapies. To make sure everyone stays abreast of work going on in other labs, we hold regular meetings and present clinical trial results to keep the lab team excited about what it’s doing. It is the talent of the collective group that keeps us on top of a very complicated field.

It’s important to build on our expertise to bring something meaningful to the cancer community. NK cell research is one of the Masonic Cancer Center’s specialties.

MetroDoctors

Jeffrey Miller, M.D., is a University of Minnesota Health blood and marrow transplant physician as well as deputy director of the Masonic Cancer Center, University of Minnesota and director of its Cancer Experimental Therapeutics Initiative (CETI). Dr. Miller is internationally recognized for his pioneering research on NK cells and immunotherapy for treating cancer.

Photo by Scott Streble.

Under that NK cell research umbrella, the scientists investigate separate but related projects. Major projects underway include the use of donor NK cells, typically from a half-matched family member, and studying the roles of different receptors on NK cells. Another project involves the cultivation of NK cells from human pluripotent stem cells, where our researchers developed a more efficient, cost-effective process for deriving NK cells from stem cells, which could pave the way for a larger-scale production effort.

Fine-Tuning the Formula

We have made exciting new discoveries in lab and have learned from 20 years of experience using NK cells to treat patients with cancer. We are focused on two major themes, which will drive our efforts for the next several years.

• BiKEs and TriKEs: The first path is based on the goal of making NK cells specific to recognize different tumors.

In collaboration with basic scientist Daniel Vallera, we have been able to produce Bi- or Tri-specific Killer Engagers (we call them BiKEs and TriKEs), which juxtapose NK cells and cancer targets to enhance clinical efficacy and overcome tumor inhibition.

The Journal of the Twin Cities Medical Society

Virus activation to induce “adaptive NK cells” with specialized function: The second area of focus is to make better NK cell infusions by building on a new discovery that viruses (such as cytomegalovirus) can prime NK cells and induce them to acquire properties of immunologic memory.

In bone marrow transplant patients, having high numbers of these “adaptive NK cells” leads to less relapse.

Our goal is to grow these cells for infusion into patients with cancer and we hope to test a new cell product by 2017.

With each new discovery, our team develops a better understanding of how NK cells can be manipulated to attack and kill cancer cells; then we tinker with the formula and try again.

To see a list of current open clinical trials at the University of Minnesota, including the trials mentioned in this article, visit z.umn.edu/cancertrials. You can also subscribe to our M Health Cancer Care quarterly physician newsletter to keep informed about program updates, new treatments and clinical trials. Visit mhealth. org/consult.

•

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Cancer Update

Traditional and Novel Treatments for Melanoma Treatment of Primary Melanoma

The preferred treatment for primary cutaneous melanoma of any thickness is surgical excision with histologically clear margins. Lesions of less than 0.7mm have an excellent prognosis and should be managed with surgical excision with appropriate (0.5-1.0 cm) margins, followed annually with liver function studies and chest x-rays, and comprehensive skin exams every six months. For lesions that are more than 0.7mm thick, a sentinel node biopsy is commonly performed to evaluate for metastasis. The surgical margins for invasive melanoma should be between 1.0 and 2.0 cm. If metastasis has occurred, other organ systems need to be evaluated along with imaging studies to detect small metastasis, and systemic oncologic therapy should be initiated.

The exact treatment of Melanoma is predicated on its stage. For brevity, there are sub-stages that will not be included in the following discussion.

Melanoma in-situ.

Stage 0 In Stage 0 melanoma, the melanoma is confined to the epidermis. There is no additional involvement. This stage is also called, “in-situ.” The definitive treatment of stage 0 melanoma is surgical excision with clear surgical margins.

By Charles E. Crutchfield III, M.D.

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Stage I Stage I melanoma is a non-ulcerated melanoma up to 2 cm thick. If the thickness is greater than 0.7 mm, then sentinel lymph node biopsy should be conducted. Stage I represents no lymph node involvement or metastases. The treatment of Stage I is the surgical excision with a 1 cm clear margin.

Moh’s micrographic surgery for the excision of cutaneous melanoma is controversial. The rapid freeze artifact associated with melanocytes can make microscopic evaluation difficult. Additionally, on sun damaged skin, there can be additional lentigos, making it difficult to determine where one melanocytic lesion ends and another begins. For these reasons, many Moh’s surgeons prefer not to use Moh’s micrographic surgery to excise melanomas.

Stage II Stage II melanomas are melanomas that are ulcerated but do not have lymph node involvement or metastases. The standard of treatment for Stage II melanoma is surgical resection and, dependent on Breslow thickness, sentinel lymph node biopsy, immunotherapy, and clinical trials.

Stage III Stage III melanomas are tumors that have spread to adjacent lymph nodes. There may also be local metastasis known as “intransit” or “satellite involvement.” There is no evidence of distant metastasis. The treatment for Stage III melanoma may include surgery, lymph node dissection, targeted therapies, immunotherapies, and clinical trials.

Stage IV In Stage IV, the melanoma has moved beyond the regional lymph nodes and metastasized to distant areas of the body.

Commonly this includes lymph nodes, liver, lungs, bone, skin, and brain. The standard of treatment of Stage IV melanoma can include surgery, radiation therapy, chemotherapy immunotherapies, targeted therapies, and clinical trials.

Non-Surgical Treatments for Melanoma

Chemotherapy Dacarbazine (DTIC) is a chemotherapy drug, specifically an alkylating agent which interferes with the growth of cancer cells. Currently, Dacarbazine is the only FDA-approved chemotherapy drug for the treatment of metastatic melanoma.

Dacarbazine is frequently used ‘off-label’ in combination with other chemotherapeutic drugs.

Radiation Therapy Radiation therapy is most effectively used to control the pain associated with bone metastases, spinal cord compression, and brain metastases. It is also used to treat broad-based superficial cutaneous melanoma.

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Immunotherapies Immunotherapy is based on the belief that the immune system can fight cancer. By enhancing the immune system’s attack on a malignancy, there is a better chance for remission and cure.

Talimogene laherparepvec “T-Vec” (Imlygic) Talimogene laherparepvec is a genetically modified live herpes virus treatment. It is used to treat melanoma lesions that cannot be resected surgically. T-Vec is injected directly into the melanoma lesions, where the virus causes the melanoma cells to rupture and die.

High-dose interferon alfa-2b (Intron A) High-dose interferon alfa-2b is a signaling protein that is released by cells under stress, enhances the ability of the immune system to destroy melanoma cells. The exact mechanism is poorly understood, but it has a role in fighting both cancer and viral infections. It is FDA approved for Stage III patients who are melanoma free but are at a high risk of the disease returning. It may also be administered to patients with a tumor with Breslow thickness of greater than 4mm.

Pembrolizumab (Keytruda) Pembrolizumab is a humanized monoclonal antibody that works by blocking the interaction of PD-1 and its ligands PD-L1 and PD-L2. As a result, it enhances the ability of T-cells to attack the melanoma.

It is FDA approved for patients with unresectable Stage III melanoma or metastatic disease with a BRAF mutation who have failed other medications or a BRAF inhibitor. This is the medication President Jimmy Carter received recently and produced a remission when he had brain metastases, Stage IV melanoma.

Nivolumab (Opdivo) Nivolumab is FDA-approved to treat unresectable metastatic melanoma. It is known as a medicine that affects the “immune checkpoint blockade.” It actually blocks a negative regulator (PD-L1) of cytotoxic T-Cells activity allowing the Tcell/immune system to attack cancer cells.

A combination therapy was approved to treat unresectable or metastatic melanoma MetroDoctors

in November of 2015. The combination includes Cobimetinib, kinase inhibitor in combination with vemurafenib (Zelboraf ), a B-Raf kinase inhibitor. Vemurafenib will be discussed below.

Interleukin-2 (Proleukin / Il-2) Interleukin-2 is a recombinant form of the cytokine interleukin-2 (IL-2). Interleukin-2 is a cytokine that activates cytotoxic/ natural killer T-cells to destroy cancer. Interleukin-2 is approved for the treatment of advanced metastatic melanoma in patients with normal lung, kidney, liver and heart status.

Peginterferon alfa-2b (Sylatron) Peginterferon alfa-2b is a signaling protein that enhances an immune response to fight off both malignancy and infections. The exact mechanism is poorly understood. It may also have a role in blocking angiogenesis. This form of interferon has a longer half life so lower doses can be administered and are better tolerated.

Peginterferon alfa-2b is FDA approved for patients with lymph node involvement within 84 days of surgical resection.

Ipilimumab (Yervoy) Ipilimumab is a human monoclonal antibody that blocks the activity of a molecule, CTLA-4, a protein that downregulates the immune system’s attack of malignant cells.

When Ipilimumab blocks CTLA-4, it effectively “removes the stop-sign from the immune system” and allows T-cells to activate and proliferate and destroy malignant cells. Ipilimumab is approved for patients with Stage III or Stage IV melanoma.

Targeted Treatments

Trametinib (Mekinist) Trametinib is a protein kinase inhibitor that, in BRAF positive malignancies, blocks the activity of the V600E or V600K mutations, which when present, allow uncontrolled cell growth. It should not be used in patients who have failed other BRAF inhibitors. About 50 percent of patients with melanoma have BRAF mutations.

Trametinib (Mekinist)and Dabrafenib (Tafinlar) in combination Tafinlar is an inhibitor of some mutated

The Journal of the Twin Cities Medical Society

BRAF kinases. Mekinist is an inhibitor of some MEK protein kinases. These kinases both help to maintain uncontrolled cell grow.

Dabrafenib (Tafinlar) Tafinlar is a protein kinase inhibitor that, in BRAF positive malignancies, blocks the activity of the V600E mutations which, when present, allow uncontrolled cell growth. Tafinlar is FDA-approved for adult patients who have the BRAF V600E mutation and who also have had unresectable Stage III melanoma or Stage IV melanoma.

Vemurafenib (Zelboraf ) Zelboraf is a protein kinase inhibitor that blocks the activity of BRAF with a V600E mutation. It is FDA-approved for adult patients who have the BRAF V600E mutation and who also have had unresectable Stage III melanoma or Stage IV melanoma.

Vemurafenib (Zelboraf ) and Cobimetinib (Cotellic) used in combination were approved by the FDA in November of 2015.

Prognosis

Approximately 85 percent of skin cancer deaths are from melanoma. Melanoma has a 99 percent five-year survival rate if detected and treated before it spreads to the lymph nodes. The five-year survival rate for regional lymph node involvement is 65 percent, and distant melanoma involvement (other organs/lymph node metastasis = stage III/IV) is 15 percent.

Prevention and early detection are key to successful management and to decrease the incidence and mortality associated with melanoma. If caught early, most melanomas can be cured.

Fortunately, with the advent of some of the novel immunotherapies and treatments that block the pathways of malignant transformation and maintenance, the prognosis for patients with late stage melanoma looks better and better.

Charles E. Crutchfield III, M.D., Clinical Professor of Dermatology, University of Minnesota Medical School, and Medical Director Crutchfield Dermatology.

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David J. Dries, M.D. Receives 2015 Charles Bolles Bolles-Rogers Award

T

he Twin Cities Medical Society Foundation has the unique honor of selecting and presenting the Charles Bolles Bolles-Rogers Award. The award (a bowl) is named after Mr. Charles Bolles BollesRogers, an “aristocratic” gentleman who lived in the Minneapolis area for 37 years and was especially interested in the health and hospital needs of the city. He served on the (former) St. Barnabas Hospital Board of Trustees and was president of that board for many years. Prior to his death he made provision for the Charles Bolles BollesRogers Award to be given annually to an outstanding physician.

David J. Dries, MSE, M.D., FACS, FCCP, MCCM, a trauma surgeon and critical care specialist in St. Paul, MN was selected as the recipient of the 2015 Charles Bolles Bolles-Rogers Award. Chris Johnson, M.D., Chair, Twin Cities Medical Society Foundation, presented the award on Tuesday, November 10, 2015, at the Regions Hospital Medical Staff 2015 Annual Meeting and Dinner. Dr. Dries was nominated by his colleagues at Regions Hospital.

The Charles Bolles Bolles-Rogers Award is given to a physician who, in the opinion of the members of the TCMSF selection committee, by reason of his/ her professional contribution to medical research, achievement or leadership, has become the outstanding physician of this and other years.

Dr. Dries is a highly accomplished and dedicated physician and surgeon and a consummate role model for physicians.

As an academician, Dr. Dries is widely recognized for his research and skills, particularly in the field of critical care.

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His numerous and impressive publicaUniversity of Minnesota; and Surgical tions span the themes of trauma, critiDirector, Pediatric Intensive Care Unit, cal care, pulmonary medicine and burns.

Gillette Children’s Hospital.

His achievements reflect an overwhelming Above all, Dr. Dries is respected depth and quality of work, both in his by patients and peers as an outstanding clinical practice and to the greater disciteacher, leader, researcher, and caregiver. plines of medicine and surgery.

The Twin Cities Medical Society and its Foundation are honored to award David J. As a leader, Dr. Dries holds the posiDries, M.D. with the 2015 Charles Bolles tion of John F. Perry, Jr., Professor of Surgery, University of Minnesota; Assistant Bolles-Rogers Award.

Medical Director, Surgical Care, HealthPartners Medical Group; Division Head: Surgery, Regions Hospital; Director: Academic Programs, Department of Surgery, Regions Hospital; Adjunct Professor of Clinical Emergency Medicine, University of Minnesota; Professor of Anesthesiology, The Charles Bolles Bolles-Rogers Award is presented to Dr. David Dries (left center) by Drs. Michael McGonagal (l), Chris Johnson (right center), and Bret Haacke (r).

In Memoriam THOMAS WILSON, M.D., passed away in September 2015. Dr. Wilson received his medical degree from the University of Pennsylvania School of Medicine and completed a neurology residency at Mayo Clinic. He joined Midwestern Neurologic and Psychiatric Consultants in Minneapolis. He then served two years in the U.S. Air Force as a medical doctor stationed in the Philippines, before returning to Minneapolis to complete his career.

C. CAMAK BAKER, M.D., passed away in November 2015. Dr. Baker was a neurologist and headache specialist, practicing first at Minneapolis Clinic of Psychiatry and Neurology, and then as a founder of the Headache Institute of Minnesota.

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Will Your Organization Share With Those Less Fortunate The Caring Hearts for Homeless People drive collects health and hygiene supplies and over-the-counter medications for homeless adults and children. Donated items will be sorted and distributed to the homeless through the following east metro programs: Health Care for the Homeless, Listening House of St. Paul, and SafeZone Drop-In Center.

Please consider putting out a collection box at your office and encouraging employees to donate. Many clinics and hospitals are involved in this drive year after year.

Please call Nancy Bauer, TCMS Foundation at (612) 623-2893 or email her at nbauer@metrodoctors.com if your organization would like to participate. You will

receive posters and lists of suggested items to donate. The drive runs throughout the month of February. Please drop off your donation box at St John’s Hospital, St Joseph’s Hospital or Woodwinds Health Campus by Sunday, February 28.

23rd Annual Supply Drive February 2016

CAREER OPPORTUNITIES

See Additional Career Opportunities on page 30.

New Members Joseph P. Amberg, M.D. Allina Palliative and Senior Care Transitions Internal Medicine Britt W. Ehlert, M.D. Allina Health – Bloomington Internal Medicine Erika E. Reid, M.D. Dermatology Specialists Dermatology Jeffrey S. Schiff, M.D. Minnesota Department of Health Pediatrics Justin M. Wudel, M.D. Address Unspecified Otolaryngology

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CAREER OPPORTUNITIES

See Additional Career Opportunities on page 31.

Olmsted Medical Center, a 220-clinician multi-specialty clinic with 10 outlying branch clinics and a 61-bed hospital, continues to experience significant growth. Olmsted Medical Center provides an excellent opportunity to practice quality medicine in a family oriented atmosphere. The Rochester community provides numerous cultural, educational, and recreational opportunities. Olmsted Medical Center offers a competitive salary and comprehensive benefit package.

Opportunities available in the following specialties: Anesthesiologist Hospital

ENT Rochester Southeast Clinic

Family Medicine

Psychiatrist

Sleep Medicine

Rochester Clinics

Rochester Southeast Clinic

Rochester Northwest Clinic

Pain Medicine

Psychiatrist– Child & Adolescence

Urology

Rochester Northwest Clinic

Hospital

Rochester Southeast Clinic

Send CV to: Olmsted Medical Center Human Resources/Clinician Recruitment 210 Ninth Street SE, Rochester, MN 55904 email: dcardille@olmmed.org • Phone: 507.529.6748 • Fax: 507.529.6622

www.olmstedmedicalcenter.org

30

January/February 2016

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The Journal of the Twin Cities Medical Society

CAREER OPPORTUNITIES

Please also visit www.metrodoctors.com

BEYOND TREATING, THERE’S CARING W E L L A N D BE YO N D Fairview Health Services seeks physicians with an unwavering focus on delivering the best clinical care and a passion for providing outstanding patient experience.

Be part of a collaborative team that puts patients at the center and is transforming health care for today and tomorrow.

We currently have opportunities in the following areas: • • • • • •

Allergy Dermatology Emergency Medicine Family Medicine General Surgery Geriatric Services

• • • • • •

Hospitalist Internal Medicine Med/Peds Neurology OB/GYN Orthopedic Surgery

• • • • • •

Pain Medicine Pediatrics Psychiatry Sports Medicine Urology Vascular Surgery

To learn more, visit fairview.org/physicians, call 800-842-6469 or email recruit1@ fairview.org fairview.org/physicians TTY 612- 672-7300 EEO/AA Employer Sorry,

no J1 opportunities.

Recruit With

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Rates starting as low as $175—call today!

Options for website listings available as well. www.metrodoctors.com

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The Journal of the Twin Cities Medical Society

January/February 2016

31

LUMINARY of Twin Cities Medicine

By Marvin S. Segal, M.D.

JOHN H. KERSEY, M.D.

M

uch has been written about the days of GIANTS at our U of M Medical School. Included in most historical catalogs, as examples of superb faculty leaders, are the names of Wangensteen, Watson and Good.

Other physicians certainly deserve such a heralded designation, and notable among them is our current Luminary — a GIANT of a physician scientist, and a GIANT of a person.

Dr. John Kersey was born and raised in Minneapolis, graduated from Dartmouth College, and received his M.D. and post graduate training at the U of M. His academic appointment progression at his alma mater was meteoric, attaining Professorships in the Departments of Laboratory Medicine, Pathology, Pediatrics and Therapeutic Radiology. He was the Director of the U’s Bone Marrow Transplantation program for over 20 years and the Founding Director of the U of M Cancer Center for another nearly 20 years.

His superb scientific accomplishments — early-on notably marked by leading the team who performed the first successful curative bone marrow transplant for malignant lymphoma — were numerous and profound: nearly 500 published medical literature contributions, 60 invited lectureships literally spanning the globe, and seeds of his knowledge virtually sown in many leading U.S. and international medical centers via the mentoring of 20+ doctoral level trainees. John’s achievement honors and awards were both plentiful and appropriately meaningful, and his leadership capabilities were robust and profound as demonstrated by Presidencies of the International Society for Experimental Hematology and the American Society for Blood and Marrow Transplantation.

Much is known of the documented objective aspects of his sterling professional career, though much less is recognized regarding the personal subjective facets of this modestly complex physician who remained quite active until his untimely passing in 2013 at the age of 74. By relating some of those attributes and experiences, we might appreciate Dr. Kersey even more.

Colleagues uniformly describe John as being passionate in his work, driven by an insatiable curiosity, and the best listener ever. He chose to care for sick children — really sick children — with an assertive risk-taking aptitude, knowing full well that he would probably make patients sicker with the hardships of chemotherapy and the complications of transplants before 32

January/February 2016

he made them better. He gently exerted a contagious enthusiasm to those around him as he translated preclinical science to bedside care.

The world’s first successful transplant patient, some 40 years later at the age of 56 recently stated, “If it wasn’t for Dr. Kersey, I wouldn’t be here.” Curing a patient of what had been an incurable disease is an immense gratification, and he was willing to make the tough decisions necessary to accomplish that. Interestingly, he modestly attributed his clinical successes to “sharp needles and the dedicated talents of nurses.”

John was a regular guy, never losing contact with his Washburn High School classmates, as his life-long buddies have attested. His deep loyalty to the U of M was demonstrated when he decided to stay there rather than be recruited to other renowned medical centers — including an offer to join his most valued mentor, Dr. Robert Good, at Sloan Kettering.

This man — who once traveled to Greenland to personally document the effects of climate changes on glaciers — was comfortably at home guiding, canoeing and fly-fishing in the lakes and streams of northern Minnesota and Alaska. He shepherded his beloved wife and three children to many corners of the earth while exploring those fascinating reaches beyond his cherished Minnesota. . . . and so we have it, a marvelous blend of pure science and humanity — Dr. John, a humble, brilliant and warm man for all seasons. Yes, and a GIANT. This last page series is intended to honor esteemed colleagues who have contributed significantly to Twin Cities medicine.

Please forward names of physicians you would like considered for this recognition to Nancy Bauer, managing editor, nbauer@metrodoctors.com.

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The Journal of the Twin Cities Medical Society

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