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RESEARCH
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© sm
a CNE-accredited Cancer Nursing Conference
Update on Current Therapies and Issues in Oncology Nursing
PROGRAM GUIDE
Saturday, October 20, 2012
New York, New York
Sponsored by:
Accredited by:
& The Herbert Irving Comprehensive Cancer Center
Tuition has been underwritten through educational grants from:
Astellas Pharma US, Inc • Bristol-Myers Squibb Company • Celgene Corporation
Millennium Pharmaceuticals • Novartis Pharmaceuticals • Onyx Pharmaceuticals
Table of Contents
Page
Purpose
1
Learning Objectives
1
Accreditation Statement
1
Educational Grantors
2
Agenda
4
Faculty Affiliations
5
Disclosure Information
6
External Review
7
Unlabeled/Investigational Uses
8
Faculty Biographies
9
Abstracts and Presentations
Clinical Updates in Breast Cancer Management
Maureen Major Campos, RN, MS, AOCN
19
Advances in Treating CRC & HCC
Stuart M. Lichtman, MD
21
Alphabet of NSCLC
Ann E. Culkin, RN, OCN
39
Advances in the Treatment of Prostate Cancer
Colleen A. DeBoer, RN, MSN, ANP-BC
49
Table of Contents (continued)
Page
Updates & Nursing Implications in the Treatment of Melanoma
Anna Skripnik, RN
71
Therapeutic Options in Multiple Myeloma
Denise G. O’Dea, ARNP-BC, OCN
81
Evolving Strategies for Chronic Myelogenous Leukemia
Joseph G. Jurcic, MD
93
Keynote Address:
New Horizons in Oncology: How Biology Will Change the
Course of Treatment & Survivorship
Robert C. Arceci, MD, PhD
109
© 2012 Letters & Sciences. All rights reserved. This audience guide is protected by copyright. No part may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording,
or utilizing any information storage or retrieval system, without permission from the copyright owner.
Purpose
This CNE conference, accredited by Letters & Sciences and presented by Columbia
University Medical Center & The Herbert Irving Comprehensive Cancer Center and
NewYork-Presbyterian – The University Hospital of Columbia and Cornell, will provide
nurses and other healthcare professionals involved in the treatment of cancer patients
with the opportunity to learn about new agents, modalities, procedures, developments,
and current trials in oncology.
Learning Objectives
At the conclusion of this activity, participants should be able to:
•
Identify current best practices and new agents that may be employed in the
treatment of solid and hematologic malignancies;
•
Summarize clinical efficacy and tolerability data from pivotal trials that impact
and change treatment paradigms for cancer care in 2012;
•
Discuss new data and strategies to assist nurses in managing side effects of
cytotoxic agents and novel therapies;
•
Review emerging novel targeted therapies and discuss nursing implications for
patient monitoring;
•
Describe a patient care plan for delivering and managing hormonal, cytotoxic, and
molecular therapies;
•
Discuss how advances in science and genetics allow clinicians to customize
therapy.
Accreditation
Continuing Nursing Education & Credit Designation
Letters & Sciences is accredited as a provider of continuing nursing education by the
American Nurses Credentialing Center’s Commission on Accreditation.
This activity has been designated for 5.6 contact hours.
1
Educational Grantors
This activity is supported by educational grants from:
•
•
•
•
•
•
Astellas Pharma US, Inc.
Bristol-Myers Squibb Company
Celgene Corporation
Millennium Pharmaceuticals
Novartis Pharmaceuticals
Onyx Pharmaceuticals
Learner’s Bill of Rights
Letters & Sciences recognizes that as a life-long learner, you have chosen to participate
in continuing education to fill a gap in knowledge, skill, or performance. In fulfilling our
responsibility to you as a learner, you have the right to expect that your continuing
nursing education experience includes content that:
•
•
•
•
•
•
•
Encourages improvements and quality in nursing care;
Is valid, reliable, and accurate;
Offers fair-balanced and scientifically rigorous presentations that are free of
commercial bias;
Is subject to a critical appraisal process that resolves any conflicts of interests of
faculty or planners;
Is based on educational needs and gaps in learning;
Addresses the stated learning objectives; and
Is evaluated and measured for its effectiveness in fulfilling the identified
educational needs.
3
Agenda
11:30 am – Noon
Registration and Luncheon
Noon – 12:20 pm
Welcome on Behalf of Columbia University
Sarah Sheets Cook, DNP, RN-CS
Columbia University School of Nursing
12:20 pm – 1:00 pm
Clinical Updates in Breast Cancer Management
Maureen Major Campos, RN, MS, AOCN (Chair)
Smilow Cancer Hospital at Yale-New Haven Hospital
1:00 pm – 1:40 pm
Colorectal & Hepatocellular Cancer: Focus on the Older Patient
Stuart M. Lichtman, MD, FACP
Memorial Sloan-Kettering Cancer Center
1:40 pm – 2:20 pm
The Alphabet of Non-Small Cell Lung Cancer
Ann E. Culkin, RN, OCN
Memorial Sloan-Kettering Cancer Center
2:20 pm – 3:00 pm
Advances in the Treatment of Prostate Cancer
Colleen A. DeBoer, RN, MSN, ANP-BC
Tisch Cancer Institute, Mount Sinai Medical Center
3:00 pm – 3:20 pm
Refreshment Break
3:20 pm – 4:00 pm
Updates & Nursing Implications in the Treatment of Melanoma
Anna Skripnik, RN
Memorial Sloan-Kettering Cancer Center
4:00 pm – 4:40 pm
Therapeutic Options in Multiple Myeloma
Denise G. O’Dea, ARNP-BC, OCN
NYU Cancer Institute, NYU Langone Medical Center
4:40 pm – 5:20 pm
Evolving Strategies for Chronic Myelogenous Leukemia
Joseph G. Jurcic, MD
Memorial Sloan-Kettering Cancer Center
5:20 pm – 6:00 pm
Carolyn Jaffe Memorial Lecture.
Keynote Address: New Horizons in Oncology: How Biology Will
Change the Course of Treatment & Survivorship
Robert C. Arceci, MD, PhD
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Children Cancer Center
6:00 pm – 7:30 pm
“Meet the Professors” Reception
Ram Café Atrium
Faculty Affiliations
Chair
Maureen Major Campos, RN, MS
Program Manager, Womens Oncology Services
Smilow Cancer Hospital at Yale-New Haven
New Haven, CT
Distinguished Faculty
Robert C. Arceci, MD, PhD
Director, Pediatric Oncology
Co-Director, Michael Garil Leukemia
Survivors Program
King Fahd Professor, Pediatric Oncology
Johns Hopkins Children Cancer Center
Sidney Kimmel Cancer Center
Baltimore, MD
Sarah Sheets Cook, DNP, RN-CS
Dorothy M. Rogers Professor of
Clinical Nursing
Vice-Dean, Columbia University
School of Nursing
New York, NY
Ann E. Culkin, RN, OCN®
Clinical Nurse III
Memorial Sloan-Kettering Cancer Center
New York, NY
Colleen A. DeBoer, RN, MSN, ANP-BC
Adult Nurse Practitioner
Tisch Cancer Institute
Mount Sinai Medical Center
New York, NY
Joseph G. Jurcic, MD
Attending Physician
Leukemia Service
Memorial Sloan-Kettering Cancer Center
New York, NY
Stuart M. Lichtman, MD, FACP
Attending Physician
Leader of the Geriatric Clinical Program
Memorial Sloan-Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York City
Denise G. O’Dea, ARNP-BC, OCN
Adult Nurse Practitioner
Multiple Myeloma Program
NYU Cancer Institute
NYU Langone Medical Center
New York, NY
Anna Skripnik, RN
Clinical Nurse, Dermatology Department
Memorial Sloan-Kettering Cancer Center
New York, NY
Nonendorsement of Products
The audience is advised that the educational content contained herein was developed by
and reflect the opinions of the presenters and faculty, and do not necessarily reflect the
opinions or recommendations of Letters & Sciences. Accredited status does not imply
endorsement by Letters and Sciences or American Nurses Credentialing Center’s
Commission of any commercial products discussed/displayed in conjunction with the
educational activity.
The contributing faculty developed the content independently. All materials are included with
permission. The opinions expressed are those of the faculty and are not to be construed as those
of the educational sponsor or grantors.
5
Disclosure Information
It is the policy of Letters & Sciences to ensure balance, independence, objectivity, and scientific
rigor in all sponsored educational activities. All faculty participating in sponsored programs are
expected to disclose to the program audience any real or perceived conflicts of interest related to
the content of their presentations or to their financial and professional relationships. Letters &
Sciences is committed to stringent enforcement of full disclosure in the planning and execution of
all sponsored activities and resolution of any perceived conflicts. Pursuant to regulatory
guidelines, Letters & Sciences complies with those protocols established by professional,
scientific, and governmental oversight, and expects the faculty to adhere to the same, in order to
help ensure the integrity of both scientific content and professional conduct. It is not assumed that
these financial interests or affiliations will have an adverse impact on the faculty presentations.
They simply are noted here to fully inform course participants. Further, an independent third
party has reviewed the presentations and has determined that no commercial bias exists.
Faculty Disclosures
The faculty has disclosed the following:
Robert C. Arceci, MD, PhD
Has indicated that he has nothing to disclose
Stuart M. Lichtman, MD, FACP
Has indicated that he has nothing to disclose
Sarah Sheets Cook, DNP, RN-CS
Has indicated that she has nothing to
disclose
Maureen Major Campos, RN, MS
Has received honorarium from Amgen
BioOncology, Novartis
Ann E. Culkin, RN, OCN®
Has indicated that she has nothing to
disclose
Denise G. O’Dea, ARNP-BC, OCN
Has served on the speakers bureau for
Amgen
Has served on the speakers bureau for
Celgene Corporation
Colleen A. DeBoer, RN, MSN, ANP-BC
Has indicated that she has nothing to
disclose
Joseph Jurcic, MD
Has indicated that he has nothing to disclose
Anna Skripnik, RN
Has indicated that she has nothing to
disclose
Activity Staff Disclosures
The planners, reviewers, editors, staff, CNE committee, or other members at Letters & Sciences
who control content have no relevant financial relationships to disclose.
External Review
In accordance with Letters & Sciences policy and ANCC standards to identify and
resolve any potential conflicts of interest, to assure fair balance, independence and
objectivity, and to instill scientific rigor in all CNE activities, all presentations, with any
potential for conflict of interest, have been reviewed by two external reviewers. These
external reviewers, who have no potential conflicts of interest, have determined that no
bias exists in these presentations. These external reviewers are:
Susan Goodin, PharmD, FCCP, BCOP
Associate Director for Clinical Science
Professor of Medicine, UMDNJ-Robert
Wood Johnson Medical School
Cancer Institute of New Jersey
New Brunswick, New Jersey
Michelle Magiera, PharmD
Pharmacy Consultant
Private Practice
Raritan, New Jersey
7
Unlabeled Uses/Investigational Uses/Not Yet Approved
Commercial Products
The audience is advised that one or more sections in this CNE activity may contain
references to unlabeled or unapproved uses of drugs. Not all agents and/or protocols
described in the presentations may be approved by the US Food and Drug Administration
(FDA). Nurses should note that the use of these agents outside current approved labeling
is considered experimental and are advised to consult current prescribing information for
these products. The faculty is required to disclose their discussion of drugs or medical
devices that are unlabeled, investigational, or not approved for the use that is being
discussed.
Faculty members have disclosed the following:
Robert C. Arceci, MD, PhD
Will not be discussing off-label uses
Sarah Sheets Cook, DNP, RN-CS
Will not be discussing off-label uses
Ann E. Culkin, RN, OCN®
Will not be discussing off-label uses
Colleen A. DeBoer, RN, MSN, ANP-BC
Will not be discussing off-label uses
Joseph Jurcic, MD
Will be discussing investigational agents in TKI-resistant CML
Stuart M. Lichtman, MD, FACP
Will not be discussing off-label uses
Maureen Major Campos, RN, MS, AOCN
Will be discussing unlabeled/unapproved uses of agents in metastatic breast cancer
Denise G. O’Dea, ARNP-BC, OCN
Will not be discussing off-label uses
Anna Skripnik, RN
Will not be discussing off-label uses
Faculty Biographies
Robert J. Arceci, MD, PhD graduated from Trinity College in Hartford, Connecticut.
He received his PhD in molecular and developmental biology and his MD from the
University of Rochester, in Rochester, New York, and then pursued a residency in
pediatrics and a fellowship in pediatric hematology/oncology at the Boston Children’s
Hospital. Following faculty appointments at Harvard Medical School, the Dana Farber
Cancer Institute and Boston Children’s Hospital, Dr. Arceci was appointed Director of
Pediatric Hematology/Oncology at Cincinnati Children’s Hospital. In 2000, he was
named Director of Pediatric Oncology at the Johns Hopkins Medical Institutes. Currently,
he is Co-Director of the Michael Garil Leukemia Survivors Program and King Fahd
Professor of Pediatric Oncology there.
Dr. Arceci is a member of numerous scientific and medical societies, and has received
several prestigious honors and awards, including election as a Fellow of AAAS, an honor
bestowed upon members by their peers. AAAS Fellows are recognized for meritorious
efforts to advance science or its applications.
An international authority in many challenging areas of clinical pediatric oncology
including the diagnosis and treatment of leukemia and histiocytic disorders, Dr. Arceci is
Editor-in-Chief of Pediatric Blood and Cancer and editor of several textbooks, including,
Pediatric Hematology. He originated the Emmy award-winning documentary on
childhood cancer, A Lion in the House, directed and produced by filmmakers Steven
Bognar and Julia Reichert.
9
Faculty Biographies
Sarah Sheets Cook, DNP, RN-CS is the Dorothy M. Rogers Professor of Clinical
Nursing at Columbia University School of Nursing. After completing a Bachelor’s degree
in clinical nursing at the University of Michigan, Dr. Cook pursued a Master’s degree in
maternal child health at the Columbia University Teachers College. Her credentials
expanded with certification as a maternal child health nurse, a lactation specialist, and a
perinatal nurse. Five years ago, she completed a Doctorate in nursing at Columbia
University.
Dr. Cook was the first faculty member of the Columbia University School of Nursing to
have a contributory faculty practice, and pioneered the role of “attending nurse,” taking
students to her practice while providing care to patients. This later became the basis for
the Columbia University School of Nursing’s universal faculty practice plan.
In 1997, she was named Vice Dean, a role in which she is an active member in the
legislative networks of numerous nursing, public health, medical and university
organizations. She also acts as Administrative Director of the School of Nursing World
Health Organization Collaborating Center for International Development of Advanced
Practice, helping to initiate, develop and maintain international nursing student and
faculty projects.
Her interest in competency-based education has led to the development of self-paced,
outcomes oriented courses in pediatric and obstetrical nursing, maternal and infant
nutrition, human growth and development, promotion of health and prevention of illness
through the life cycle, and genetics. Dr. Cook’s scholarly interests are many, including
assessing the healthcare needs of women, providing interventions that yield positive
outcomes, and determining methods to assure or improve outcomes. Several innovative
clinical research projects have evolved from her practice including methods of prenatal
education to promote breastfeeding and weight gain in pregnancy, teaching inner city
residents to become paraprofessional parent education liaisons, and identifying a role and
curriculum in genetics for advanced practice nurses, among other investigations.
She has published articles in nursing journals resulting from her practice and research
about nursing education, children’s and families’ responses to illness and death, and
patient education materials tailored to the needs of the clients in her practice.
Faculty Biographies
Ann Culkin, RN, OCN® is a clinical nurse in a collaborative office-practice setting who
has been practicing oncology nursing for more than two decades. She was educated at
Marymount Manhattan College in New York City, Indiana University-Purdue University
at Indianapolis, Indiana, and Mercy Hospital School of Nursing in Scranton,
Pennsylvania. She has worked in a variety of oncology specialties including gynecologic
oncology, bone marrow transplantation, and for the past twenty years at Memorial SloanKettering Cancer Center in New York, as a specialist in thoracic oncology.
Ms. Culkin is a member of the National Oncology Nursing Society, and Past President of
the New York City Chapter of the Oncology Nursing Society, where she remains an
active member. She has authored or co-authored numerous abstracts and publications
covering a variety of clinical subjects related to lung cancer, and has lectured at
nationally and internationally.
Other professional activities have included participation in the “Lung Cancer Awareness
Campaign” with annual appearances on the NBC Today Show and since 2006, United
Against Lung Cancer Foundation and Cancer Care®. She is the recipient of the 2007
Samuel and May Rudin Award at Memorial Sloan-Kettering Cancer Center for
excellence in Nursing Practice and the 2011 New York City Healthcare Chaplaincy
Wholeness of Life Award with her colleague Mark Kris, MD.
11
Faculty Biographies
Colleen A. DeBoer, RN, MSN, ANP-BC is a Senior Nurse Practitioner in the
Genitourinary Medical Oncology Program at Mt. Sinai Medical Center in New York
City. She received her Bachelor of Science degree from Wagner College, Staten Island,
NY; a Masters’ of Science degree in Nursing from Hunter College, New York City,
graduating Magna Cum Laude. She pursued a Post Masters’ Advanced Certificate
degree as a Nursing Practitioner, Adult Primary Care from New York University.
Ms. De Boer began her nursing career as a Registered Nurse at Memorial Sloan-Kettering
Cancer Center (MSKCC) in 1984. She practiced on the Inpatient Hematology and
Medical Oncology Service for 6 years before working as Nurse Clinician for the inpatient
service in Breast Medical Oncology for 3 years. After completing her Master’s degree
with honors, Ms. DeBoer was promoted to Inpatient Clinical Nurse Specialist for
Genitourinary/Head and Neck Medical Oncology services where she practiced for 5
years.
In 1998, Ms. De Boer left the inpatient oncology arena at MSKCC to begin her first nurse
practitioner position in pre-admission testing there. Eight years later, she joined
MSKCC’s Nurse Practitioner led Survivorship Program to develop the Breast Surgical
Survivorship Program.
In 2010, Ms. De Boer was recruited to Mount Sinai Medical Center for an opportunity to
provide direct care to genitourinary patients in an ambulatory setting. Her current role
includes direct care and management for patients in phases I, II and III clinical trials and
service as a preceptor for advanced nursing colleagues.
Ms. De Boer is a regularly published author for Lippincott. She has held an appointment
as Clinical Associate Faculty at Pace University, and has shared her clinical experience
with both professional and community audiences as a respected speaker in a variety of
forums.
Faculty Biographies
Joseph G. Jurcic, MD is an Attending Physician on the Leukemia Service of Memorial
Sloan-Kettering Cancer Center in New York City, and is an Associate Professor of
Medicine at the Weill Cornell Medical College. He is board certified in internal
medicine, hematology, and medical oncology, and specializes in the treatment of patients
with leukemia.
A graduate of the University of Pennsylvania School of Medicine in Philadelphia, he
completed an internship and residency in internal medicine at Barnes Hospital,
Washington University School of Medicine in St. Louis, and received fellowship training
at Memorial Sloan-Kettering Cancer Center. He joined the faculty of Memorial SloanKettering Cancer Center in 1994. In 2001, he received the Louis and Allston Boyer
Young Investigator Award for Distinguished Achievement in Biomedical Research.
Dr. Jurcic’s research interests have focused on antibody-based therapies to harness the
body's immune system to kill leukemia cells and to deliver radiation treatment directly to
leukemia cells. Most recently, he has concentrated on the use of radioimmunotherapy
using targeted alpha particle-emitting radionuclides for the eradication of minimal
disease.
A contributor to the oncology literature, Dr. Jurcic also serves as a Leukemia Section
Editor for The Oncologist.
13
Faculty Biographies
Stuart M. Lichtman, MD is an Associate Clinical Member, Associate Attending, and
Leader of the Geriatric Clinical Program at the Memorial Sloan Kettering Cancer Center
in New York City and Commack, NY. He is board certified in internal medicine, medical
oncology, hematology, and geriatric medicine. His main interest is clinical research
emphasizing cancer and aging. For the past 25 years, he has been actively involved in the
treatment of older patients with cancer.
Dr. Lichtman earned a Bachelor of Science degree in chemistry from Rensselaer
Polytechnic Institute in Troy, NY, and a Medical degree from the Mount Sinai School of
Medicine in New York City. His residency and fellowship training took place at the
North Shore University Hospital–Cornell University Medical College, Manhasset, NY.
He was an attending physician at North Shore University Hospital from 1986 to 2004,
where he was also Director of Geriatric Oncology.
Active in a number of research organizations, Dr. Lichtman’s involvement has included
involvement in the Cancer and Leukemia Group B (CALGB) Committee on
Pharmacology & Experimental Therapeutics and the Committee on Cancer in the Elderly.
He has served on the Scientific Advisory Board of the Geriatric Oncology Consortium,
the International Society of Geriatric Oncology (SIOG) and its Taskforces on Geriatric
Assessment, Renal Dysfunction, Chemotherapy and Gynecologic Oncology. His
involvement in the American Society of Clinical Oncology (ASCO) leadership has been
extensive, including managing the Program Committee for the 2005, 2006 Annual
Meetings, and the Patient Care Tract. Dr. Lichtman has been reappointed for 2012-2014,
as well as the ASCO Special Interest Group in Geriatric Oncology. In 2008 and 2010, he
was a faculty member of the ASCO Educational Session devoted to the pharmacology of
chemotherapy and assessment in older patients. In addition, he has have been a faculty
member for the Vail ASCO/AACR Clinical Trials Workshop (2004-2009) and in 2011,
was the Scientific Chair of the 11th International Society of Geriatric Oncology (SIOG)
Meeting.
Currently, Dr. Lichtman is a member of the Board of Directors and the Elderly Taskforce
of the Gynecologic Oncology Group, and also serves on the External Advisory
Committee of the Holden Comprehensive Cancer Center of the University of Iowa. He is
editing a textbook on the Management of Gynecologic Cancers in Older Women that will
be published this year.
Faculty Biographies
Maureen Major Campos, MS, RN is the Program Manager for the Breast Service at the
Smilow Cancer Center at Yale-New Haven Hospital. Prior to her appointment to this
position, she worked as a Breast Center Manager at the Smilow Family Breast Health
Center at Norwalk Hospital, and was at Memorial Sloan-Kettering Cancer Center in New
York for nearly 15 years. She has also acted as Oncology Program Manager for
Caremark, Inc., and as the nurse manager for an adoptive immunotherapy clinical
research trial of interleukin 2 at New York Hospital, Cornell Medical Center.
Ms. Major received her bachelor of science in nursing from Villanova University in
Villanova, Pennsylvania, and her master’s of science in nursing from Columbia
University in New York City. She has lectured nationally on timely topics including
novel approaches to breast cancer management and effective Internet use for health care
professionals. She was the editor of the Interactive Breast Cancer Web Site, developed in
collaboration with the Alleghany Health Care Systems and the Department of Defense,
and the associate editor of Homecare Management of the Bone Marrow Transplant
Patient. She is also the Co-editor of a wide range of nursing educational materials
including the book Breast Matters: Care of the Patient with Breast Cancer.
15
Faculty Biographies
Denise G. O’Dea, ARNP-BC, OCN is a nurse practitioner on the Multiple Myeloma
Team at NYU Langone Medical Center, Cancer Institute in New York City. She was
educated at Niagara University in Lewiston, NY, and then pursued a Master of Arts
degree at New York University as an Adult Nurse Practitioner.
Ms. O’Dea began her nursing career as a registered nurse in inpatient and outpatient
services at Memorial Sloan-Kettering Cancer Center (MSKCC) in Manhattan. She
practiced at MSKCC for 7 years before becoming a nurse practitioner. Her first nurse
practitioner position was at St. Vincent’s Comprehensive Cancer Center (SVCCC) in
New York City. There she began a 5-year commitment to caring for patients in the GI
Medical Oncology Department, before moving to surgical practice and breast imaging.
While at SVCCC, Ms. O’Dea practiced for 3 years in the Multiple Myeloma Transplant
Program. Five years later, a transition to Mount Sinai Medical Center presented her with
the opportunity to provide direct care to adult multiple myeloma patients in ambulatory
and inpatient settings. After 2 years, Ms. O’Dea moved to her current position at NYU
Cancer Institute. In this position, Ms. O’Dea performs clinical assessments, and
interprets diagnostic and therapeutic tests toward the development of plans of care, in
collaboration with the medical attendings and the interdisciplinary team. Her role also
includes direct care and management for patients in phases I, II and III clinical trials, and
serving as a preceptor for advanced practice nursing colleagues.
An ONS Oncology Certified Nurse, Ms. O’Dea is active in her local ONS NYC chapter.
She is also board certified by the American Nurses Credentialing Center (ANCC) as an
adult nurse practitioner.
Ms. O’Dea is widely published as a primary and contributing author and educator in
peer-reviewed and educational publications. For nearly a decade, she has been sharing
her clinical insights and experience with professional audiences as a highly respected
speaker at state, regional and national forums.
Faculty Biographies
Anna Skripnik BSN, is a Clinical Nurse in the Dermatology Department of Memorial
Sloan-Kettering Cancer Center (MSKCC) where she focuses on dermatologic
oncological disease and lymphoproliferative disorders. Her clinical role focuses on
quality of life improvements, disease management and preventative care, early melanoma
detection, wellness and health management.
Ms. Skripnik matriculated a Bachelor of Science degree in pre-med biology from Pace
University, and subsequently, received a BSN degree in Nursing from Concordia
College. After receiving her BSN and before joining MSKCC, Ms. Skripnik worked at
the Columbia University Medical Center in the Cutaneous Oncology Surgical Unit.
She demonstrated leadership skills early on in her nursing career by establishing the first
chapter of the Nursing Student Association at Concordia College. Later, in 2010, she
worked there as a clinical instructor demonstrating nursing skills, assessments and
priority actions, and subsequently winning the annual Nursing Leadership Award. More
recently, Ms. Skripnik served on a Pace University panel, encouraging students to enter
the nursing profession.
Her passion for caring for oncology patients is inspired daily through encounters with the
patients she manages. The specialized care required for each patient has taught her to
plan, implement, and evaluate effectively in a fast-paced environment. She especially
appreciates the opportunities to teach patients at risk about protection and prevention of
skin cancer, emphasizing monthly skin self-exams and the application of sunscreens and
sun-protective clothing.
17
Clinical Updates in Breast Cancer Management
Maureen Major Campos, RN, MS, AOCN
Smilow Cancer Hospital at Yale-New Haven
19
Lichtman - CRC & HCC
Colorectal Cancer and Hepatocellular Carcinoma: Focus on the Older Patient
Stuart M. Lichtman, MD, FACP
Attending Physician
65+ Clinical Geriatrics Program
Memorial Sloan‐Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
October 2012
Disclosure Information
• Has indicated that he has nothing to disclose
• Will not be discussing off‐label uses
Learning Objectives
• Identify problem of CRC in the elderly
• Discuss role of adjuvant therapy in elderly CRC patients
• Review issue of HCC as a major contributor of cancer‐related mortality • Highlight benefit of targeted novel therapies for HCC
21
% US Population 65 and older
Life Expectancy: Woman
Life Expectancy (years)
Age
Healthy
Average
Sick
65
20.0
18.5
9.7
70
15.8
14.8
8.6
75
12.1
11.5
7.3
80
8.8
8.4
5.9
85
6.1
5.9
4.5
Lichtman - CRC & HCC
Age‐Specific SEER Incidence Rates by Sex
For Colon and Rectum Cancer, All Races
SEER 13 Registries for 1998‐2002
• From 1998‐2002, the median age at diagnosis for cancer of the colon and rectum was 72 years of age. • Approximately 29.2% between 75 and 84; and 12.6% 85+ years of age.
5‐year Survival by Stage for Patients with Colon Cancer
Percentage of Patients
100
P<.001
93
85
83
72
80
64
60
44
40
20
8
0
Stage I
(T1-2N0)
Stage IIA Stage IIB Stage IIIA
(T3N0)
(T4N0)
(T1-2N1)
Stage
IIIB
Stage
IIIC
Stage IV
(T3-4N1)
(TanyN2)
(M1)
.
23
Adjuvant Therapy
Recurrence of Colon Cancer Following Resection of Stage II or III Disease
Recurrence Rate (%)
8
7
6
74% in 3 years
5
4
3
2
1
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
Years
MOSAIC Study: Adjuvant FOLFOX4 vs 5‐FU/LV in Stage II and III Colon Cancer Multicenter International Study of Oxaliplatin/5‐Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer
André et al. N Engl J Med. 2004;350:2343.
Please see accompanying full prescribing information, including Boxed WARNING.
Lichtman - CRC & HCC
MOSAIC Phase III Trial
n=1123
Surgery
≤7 weeks
N=2246
FOLFOX4
Randomization
Colon cancer
• Stage II (~40%)
• Stage III (~60%)
•
Primary end point: disease-free survival (DFS)
•
Secondary end points: overall survival (OS), safety
LV5FU2
n=1123
Please see accompanying full prescribing information, including Boxed WARNING.
MOSAIC: Patient Characteristics
FOLFOX4
(n=1123)
LV5FU2
(n=1123)
Sex (%)
Male
56.1
52.4
Female
43.9
47.6
61.0
60.0
Median age (y)
Karnofsky PS (%)
100
29.7
30.5
90
52.2
53.9
80
4.4
3.3
70
≤60
13.2
0.6
11.9
0.4
Please see accompanying full prescribing information, including Boxed WARNING.
MOSAIC: DFS by Treatment Arm
for Overall Population
Proportion Disease-Free
1.0
0.9
P=.0008
0.8
0.7
0.6
0.5
0.4
FOLFOX4 (Overall)
LV5FU2 (Overall)
4-year DFS, FOLFOX4 = 75.9% vs LV5FU2 = 69.1%
0.3
0.2
0.1
Hazard ratio: 0.76 (95% CI, 0.65-0.90)
0
0
10
20
30
40
50
60
Months
CI = confidence interval.
Please see accompanying full prescribing information, including Boxed WARNING.
25
Median age: 62
Chemotherapy
Colon Cancer
Fluoropyrimidines
Lichtman - CRC & HCC
5FU Toxicity and Aging
Association of toxicity with increasing age of the
patient seen in the GISTG study [Stein, et al, 1995]
5FU Toxicity Increased in Elderly?
• Toxicity dependent on:
– Performance status
– Schedule: bolus (Roswell v. Mayo), infusion
– Age >70 and female predicted for severe toxicity and for treatment related deaths primarily with daily bolus Capecitabine • Indicated: breast, colon
• Three step activation
– Carboxylesterase
– Cytidine deaminase
– Thymidine phosphorylase (intratumoral)
27
Capecitabine • Oral therapy convenient
• Compliance (over or under)
• Pharmacology is not significantly affected by:
– age, gender, body surface area, hepatic dysfunction
– may need dose adjustment with reduced creatinine clearance (~25%)
– drug interaction with coumadin
• Dose often a moving target
• Favorable comparisons to bolus LV/5FU
• No randomized trial vs. infusion
Oxaliplatin
Oxaliplatin
• Less nephrotoxicity than cisplatin
• Less hematologic toxicity than carboplatin
• Transient peripheral neuropathy triggered or enhanced by exposure to cold. • Oxaliplatin could be administered safely in patients with impaired renal function without dose adjustment or hydration
• Dose adjustments necessary with severe renal dysfunction (CrCl <30)
• Meta‐analysis shows no increased toxicity
Lichtman - CRC & HCC
FOLFOX in > 70 Year Olds
•
•
•
•
•
3700 patients in 4 trials
493 older than age 70
No difference in overall survival
No difference in toxicity including neuropathy
No difference in 3rd and 6th cycle dose intensity
Sargent, et al. World Congress of GI Cancer, 2005
Questions
1. Do older patients receive adjuvant
chemotherapy?
2. Do older patients benefit from adjuvant
therapy?
Questions
1. Do older patients receive adjuvant
chemotherapy?
2. Do older patients benefit from adjuvant
therapy?
29
Age and Adjuvant Chemotherapy Use After Surgery for
Stage III Colon Cancer
Age, years
65-69
70-74
75-79
80-84
85-89
>90
% treated
78
74
58
34
11
2
Odds ratio
1.0
.76
.37
.14
.04
.01
Schrag, et al. JNCI 2001
Colon Cancer
• Older patients
– Have fewer nodes resected (Baxter, 2005)
– Receive less chemotherapy when adjuvant
therapy is administered (Dobie, 2006)
– Fewer referrals to oncologist (Davidoff,
2008)
Questions
1. Do older patients receive adjuvant
chemotherapy?
2. Do older patients benefit from adjuvant
therapy?
Lichtman - CRC & HCC
Colon Cancer-Adjuvant
Sargent, et al. NEJM 2001
Colon Cancer-Adjuvant
Age NOT A Factor
Survival
Sargent, et al.
NEJM 2001
Recurrence
Efficacy by Age with Oxaliplatin
PFS/DFS
Goldberg, JCO, 2006
31
Older Patients
MOSAIC Follow‐up
Survival and Stage
Age and Efficacy
Andre, et al. 2009; results similar to C-07: Kuebler, et al. 2007
Meta‐analysis
Summary
• No benefit of newer drugs in older patients
• Included irinotecan which has no efficacy as adjuvant
Hubbard, et al, 2011
Older Patients
• SEER Database: Patients over 65 years
– Oxaliplatin based therapy was associated with improved survival (HR 0.566; p=0.0087) compared with LV5FU alone
• Potential biases of database and retrospective analysis
• Healthier patients more likely to receive oxaliplatin
Hubbard, et al, 2011
Lichtman - CRC & HCC
Should Older Patients Receive Oxaliplatin?
• Stage II
– Low risk; no adjuvant therapy
– High risk: LV5FU2
• Benefit no greater than 5% (NCCN guidelines)
• Stage III
– Folfox: Good performance status and functional status; minimal comorbidity
– 5FU/LV or capecitabine: others
Tournigand, et al. 2012
Adjuvant Regimens
• FOLFOX
• LV/5FU permutations
– Roswell
– Mayo
– Quasar
– deGramont
• capecitabine
A Study of the Cancer and Aging Research Group
33
Predictors of Toxicity
Age
Tumor/
Treatment
Variables
¾Age ≥ 73 years
¾GI/GU Cancer
¾Standard Dose
¾Polychemotherapy
¾Hemoglobin (male: <11, female: <10)
Labs
¾Creatinine Clearance (Jelliffe-ideal wt <34)
¾Fall(s) in last 6 months
¾Hearing impairment (fair or worse)
¾Limited in walking 1 block (MOS)
¾Assistance required in medication intake (IADL)
Geriatric
Assessment
Variables
¾Decreased social activity (MOS)
Risk Stratification vs. KPS
Conclusion‐Adjuvant Stage III
• In an older patient with PS=0 who is working therefore probably excellent functional status would use:
– FOLFOX or FLOX
• If patient refuses infusion or contraindication to oxaliplatin
– Capecitabine as per X‐ACT trial
– LV/5FU regimen
Lichtman - CRC & HCC
Hepatocellular Carcinoma
Cancer Deaths Worldwide
•
•
•
•
•
•
lung (1.37 million deaths)
stomach (736 000 deaths) liver (695 000 deaths)
colorectal (608 000 deaths) breast (458 000 deaths) cervical cancer (275 000 deaths)
Mortality and Survival
35
Risk Factors
Trichopoulos, et al. JNCI 2011
Geographic Variation
Treatment
• Curative
– Surgical resection
– Transplant
• Palliative
– Sorafenib
• Oral small molecular inhibitor of several tyrosine protein kinases
– chemotherapy
Lichtman - CRC & HCC
Sorafenib
Abou-Alfa, et al, JCO 2006
Sorafenib
Llovet, et al. NEJM 2008
Conclusion
• Society has treated the elderly poorly even when curative therapy exists
– Less surgery
– Lower use of chemotherapy
– Less chemotherapy
•
•
•
•
•
•
Older patients can tolerate standard therapy
No significant age related changes in PK
Toxicity differences exist
Under treatment results in lower benefit
Need to provide better supportive care
Improvements in patient assessment needed
37
Conclusion
• Older patients benefit from chemotherapy
• Individualization is important
• Options are available for a patients with a variety of comorbidities and functional status
• Older patients should not be denied therapy—
surgery, chemotherapy and radiation‐‐‐ based on age alone
Culkin - Alphabet of NSCLC
The Alphabet of Nonsmall Cell Lung Cancer
2012
Ann Culkin, RN, OCN®
Disclosure Information
• Has indicated that she has nothing to disclose
• Will not be discussing off‐label uses
Learning Objectives
• Review considerations for 1st line treatment
• Discuss role of histologic assessment and molecular testing
• Identify novel treatments and role of oncology nurse in patient management
39
Lung Cancer
2012
New cases: 226,160
Deaths: Deaths: 160,340
Lung Adenocarcinomas 2012
Considerations for First‐Line Treatment Selection
• Drug regimen with the highest likelihood of benefit
with toxicity deemed acceptable according to both
the physician and the patient should be selected as
initial therapy
• Disease stage, weight loss, PS, and sex predict survival
• Unfit patients (PS 3‐4) at any age do not benefit from cytotoxic treatment, except erlotinib for EGFR
mutation–positive patients
1. NCCN Clinical Practice Guidelines in Oncology. Non‐Small Cell Lung Cancer. V.2.2012. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 2, 2012. Culkin - Alphabet of NSCLC
Why Is Molecular Profiling of Lung Tumors Important? • Molecular profiling can explain heterogeneity of lung adenocarcinoma and define targets for therapy
EML4‐ALK Gene Fusion in Lung Adenocarcinoma1‐3
ALK: anaplastic lymphoma kinase.
1. Chiarle R et al. Nat Rev Cancer. 2008;8:11‐12. 2. Mossé YP et al. Clin Cancer Res. 2009;15:5609‐5614. 3. Soda M et al. Nature. 2007;448:561‐566. Selection of First‐Line NSCLC Therapy Based on Results of Molecular Testing
NCCN recommendations1
Adenocarcinoma, large cell, NSCLC NOS Æ
mutation testing Æ EGFR mutation positive
EGFR mutation discovered prior to 1st‐line CT
Erlotinib
EGFR mutation discovered during 1st‐line CT
Switch to erlotinib or
add erlotinib to current CT
Adenocarcinoma, large cell, NSCLC NOS Æ mutation testing Æ ALK
positive
Crizotinib
ASCO Clinical Opinion on EGFR
Testing for Pts With NSCLC:
Considering First-Line Therapy2
Provisional Clinical Opinion: On
the basis of the results of five phase
3 randomized controlled trials, pts
with NSCLC who are being
considered for 1st-line therapy with
an EGFR TKI (ie, pts who have not
previously received chemotherapy or
an EGFR TKI) should have their
tumor tested for EGFR mutations to
determine whether an EGFR TKI or
chemotherapy is the appropriate 1stline therapy.
CT: chemotherapy.
1. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Non‐Small Cell Lung Cancer. V.2.2012. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 2, 2012. 2. Keedy VL et al. J Clin Oncol. 2011;59:2121‐2127.
41
Discussion of Histopathologic and Molecular Testing: Recommendations and Controversies
• Key recommendations/take aways
− Biospecimen collection and processing Æ accurate testing Æ
implications for clinical decision‐making
− Effective coordination and communication among specialists (oncologist, surgeon, pathologist, etc) necessary
• What information about histopathologic and molecular testing should be provided to patients, and by whom?
• Is broad‐screen genotyping ready for more widespread use—in academic and larger centers vs community setting? • Looking ahead: “CAP‐IASLC‐AMP Molecular Testing Guidelines for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors”—
expected in mid‐2012
2004
2012
Here's my sequence...
Which Patients Are Good Candidates for EML4‐ALK Testing?
• ~ 5% of patients with lung adenocarcinoma harbor fusion oncogene composed of 5’ portion of EML4 gene and the 3’
portion of the ALK gene1
• EML4‐ALK is more common in the following subgroups1‐3:
– Patients with wild‐type EGFR and KRAS; mutually exclusive of EGFR and KRAS mutations
– Never‐smokers or former light smokers – Patients with adenocarcinoma histology
1. Sasaki T et al. Eur J Cancer. 2010;46:1773‐1780. 2. Inamura K et al. J Thorac Oncol. 2008;3:13‐17. 3. Shaw AT et al. J Clin Oncol. 2009;27:4247‐4253. Culkin - Alphabet of NSCLC
Crizotinib
On August 26, 2011, the U. S. Food and
Drug Administration granted accelerated
approval to crizotinib (XALKORI Capsules,
Pfizer Inc.) for the treatment of patients with
locally advanced or metastatic non-small
cell lung cancer (NSCLC) that is anaplastic
lymphoma kinase (ALK)-positive as
detected by an FDA-approved test. The
FDA approved the Vysis ALK Break-Apart
FISH Probe Kit (Abbott Molecular, Inc.)
concurrently with the crizotinib approval.
This companion diagnostic test is designed
to detect rearrangements of the anaplastic
lymphoma kinase (ALK) gene in NSCLC.
Crizotinib
PRINCIPAL ADVERSE EFFECTS
Hematologic: Infrequent neutropenia and lymphopenia Neurologic: Dizziness, motor neuropathy, peripheral neuropathy, headache, dysgeusia Cardiovascular: QT prolongation, bradycardia
Pulmonary: Rare severe pneumonitis
Gastrointestinal: Nausea, vomiting, diarrhea, constipation, mild esophageal irritation Hepatic Elevated bilirubin, ALT Miscellaneous: Vision disorder, edema, fatigue, Low Testosterone in men
Role of the Oncology Nurse
43
Role of the Oncology Nurse
• Listen to your patients
– Histories and subjective experiences are key components to decision‐making
– Comprehensive symptom management of side effects leads to prolonged treatment
• Instruct patient and caregiver on Safe Handling and Storage of chemotherapy at home
• Relationship‐based care provides for optimal conversation and improved outcomes with side‐effect management and treatment adherence
PATIENTS ARE LIVING LONGER
Association of KRAS and EGFR mutations
with survival in patients with advanced lung
adenocarcinomas
Median Survival Reported in Months
Women 28.4 vs Men 19.3
EGFR (+)=33.7
KRAS (+) 16.3
Never-smoker=30.4 vs
current/former smoker=22.1
JOHNSON, M. L., SIMA, C. S., CHAFT, J., PAIK, P. K., PAO, W., KRIS, M. G., LADANYI, M. AND RIELY, G. J. (2012), ASSOCIATION OF KRAS AND EGFR MUTATIONS WITH SURVIVAL IN PATIENTS WITH ADVANCED LUNG ADENOCARCINOMAS. CANCER. DOI: 10.1002/CNCR.27730
Patient Education
• Histology Influences Treatment Selection
– Nurse is often at the helm navigating patients and caregivers in the process of diagnosis
• Tissue collection
– A pathologist is looking for changes (mutations) in the DNA make‐up of the tumor
– Looking for specific proteins present in the tumor
• Wait time
• Understanding Genotyping
Culkin - Alphabet of NSCLC
Education About Treatment
• Medication: Erlotinib – Take at the same time every day
– Take 1 hour prior to eating or 2 hours after eating
– Side‐effect management
» Rash
» Diarrhea Dermatologic
ErlotinibÆDay 22
Images provided courtesy of Ann Culkin, RN, OCN.
Other Adverse Effects Associated With Erlotinib
Paronychia Trichomegaly
Images provided courtesy of Ann Culkin, RN, OCN.
45
Safety and Adherence Safe Handling of Chemotherapy and Biotherapy at Home
Handling the medication
• Wash your hands before and after touching the medicine.
• Caregivers should wear disposable gloves when touching the medicine. Throw the gloves in the trash
afterward.
• If you are pregnant or trying to get pregnant, do not handle chemotherapy or biotherapy.
• Do not crush, break or open any pills or capsules unless your doctor tells you to.
• If a child or pet accidentally swallows the medicine, call Poison Control immediately at 800‐222‐1222.
Handling Waste
Understanding drug‐to‐drug interactions
Integration of Early Palliative Care Into Routine Lung Cancer Care
• ASCO has issued a provisional clinical opinion recommending that patients with metastatic NSCLC be offered concurrent palliative care and standard oncologic care at initial diagnosis1
• Studies have documented that palliative care is often not included in lung cancer care until very late in the disease
• Growing body of evidence suggests that patients with lung cancer
experience longer survival and improved quality of life with early integration of palliative care
• Palliative care can address physical symptoms common in lung cancer (eg, pain, fatigue, dyspnea, cough, etc)
• Patients with lung cancer are often faced with psychosocial concerns (eg, anxiety, depression, uncertainty) → can benefit from comprehensive assessment and support
1. Smith TJ et al. J Clin Oncol. 2012 Feb 6 [Epub ahead of print].
Summary
•
Histology influences treatment selection; therefore, NSCLC NOS should be avoided whenever possible •
Molecular tumor assessment is now part of standard of care: All patients with non‐squamous subtypes of NSCLC should undergo mutation testing
•
Interdisciplinary collaboration and building of strong relationships among different experts (medical oncologist, nurse, cytologist/pathologist/
molecular specialist, interventional radiologist, pulmonologist, surgeon) is increasingly important •
Greater emphasis must be placed on patient‐centered care; patient education essential so that patients can participate in shared decision‐making
•
Treatment selection throughout the disease course must be individualized and be based on collaborative decision‐making considering all the relevant disease‐
and patient‐related factors and patient preference
Culkin - Alphabet of NSCLC
Future
• Re‐biopsy? What to look for in molecular testing?
• Development of acquired‐resistance drugs
• Treatments
Overcoming EGFR Resistance: Candidate Agents/Combinations Under Investigation
Single Agents
Combinations
Neratinib (HKI-272)
Everolimus + erlotinib
XL647
Cetuximab + erlotinib
Afatinib (BIBW 2992)
Dasatinib + erlotinib
Dasatinib
Cetuximab + afatinib
AUY922 + erlotinib
ARQ 197 + erlotinib
47
DeBoer - Advances in Treatment of Prostate Cancer
Advances in the Treatment of
Prostate Cancer
Colleen A. De Boer, MSN, ANP-BC
Tisch Cancer Institute,
Mount Sinai Medical Center
Disclosures
• Has no relationships to disclose
Cancer Incidence Rates Among Men,
US, 1975-2005
Rate Per 100,000
250
Prostate
200
150
Lung & bronchus
100
Colon and rectum
50
Urinary bladder
Non-Hodgkin lymphoma
Melanoma of the skin
0
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
2005
*Age-adjusted to the 2000 US standard population and adjusted for delays in reporting.
Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database:
SEER Incidence Delay-adjusted Rates, 9 Registries, 1975-2005, National Cancer Institute, 2008.
49
Cancer Death Rates Among Men,
US,1930-2005
100
Rate Per 100,000
Lung & bronchus
80
60
Stomach
Prostate
40
Colon & rectum
20
Pancreas
2005
2000
1995
1990
1985
1980
1975
1970
1965
1960
Liver
1955
1950
1940
1935
1930
0
1945
Leukemia
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.
U.S. Cancer Statistics:
Prostate Cancer
• Leading cause of cancer in men (192,280
cases, 25%)
• Second leading cause of cancer death in
men, after lung (27,360 deaths, 9%)
• Cancer-specific survival estimates
– 5 years 100%
– 10 years 93%
– 15 years 77%
American Cancer Society 2009
Known Risk Factors
• Age
– Strong association with aging
• Race/Geographic Origin
– Increased risk in African Americans
• Family History/Genetics
– New intriguing genetic links (8q24)
• Diet
DeBoer - Advances in Treatment of Prostate Cancer
Family History And Risk Of
Prostate Cancer
# of Affected FirstDegree Relatives
1
Odds Ratio (95% CI)
2
4.9 (2.0-12.3)
3
10.9 (2.7-43.1)
2.2 (1.4-3.5)
Dietary Factors
•
•
•
•
•
•
Fat
Soy Protein
Lycopene
Vitamin E
Selenium
Vitamin D/Calcium
Trends in Overweight* Prevalence (%), Adults 18 and Older,
US, 1992-2007
1992
1995
1998
Less than 50%
2007
50 to 55%
More than 55%
State did not participate in survey
*Body mass index of 25.0 kg/m2or greater. Source: Behavioral Risk Factor Surveillance System, CD-ROM (1984-1995,
1998) and Public Use Data Tape (2004-2007), National Center for Chronic Disease Prevention and Health Promotion,
Centers for Disease Control and Prevention, 1997, 2000, 2005, 2007, 2008.
51
Vitamin E/Selenium
• Two large randomized trials evaluated
chemoprevention
– Lung cancer: vitamin E
– Skin cancer: selenium
• Secondary endpoint of prostate cancer
– Vitamin E decreased risk by 32%
– Selenium decreased risk by 60%
Chemoprevention:
The SELECT Trial
• Selenium and Vitamin E Cancer
Prevention Trial (2001-2004)
• 35,533 men
• 2 x 2 factorial design
– Vitamin E (400 IU/d) vs placebo
– Selenium (200 ug/d) vs placebo
• Endpoint: prostate cancer incidence
SELECT: No Difference in
Prostate Cancer Rates
Lippman, S. M. et al. JAMA 2009;301:39-51.
DeBoer - Advances in Treatment of Prostate Cancer
Conclusions
• After median follow up 5.4 yrs, no
difference in prostate cancer incidence
with selenium or vitamin E
• No differences in lung, colorectal or other
cancers
• Do genetic differences in antioxidant
metabolizing enzymes determine benefit
vs risk from antioxidants?
Prostate Cancer Prevention
Trial (PCPT)
• 18,882 men aged > 55 years with normal
DRE and PSA < 3 ng/ml
• Randomized to finasteride 5 mg/day vs
placebo
• Patients followed and biopsied if PSA>4
or abnormal DRE
• All patients had end-of-study biopsy at 7
yrs
Thompson NEJM 2003
Finasteride Reduces Risk Of
Prostate Cancer By 25%
53
Greater Risk Of High Grade
Cancers With Finasteride
• Gleason 7-10 cancers
– 270 (37%) of finasteride group
– 237 (22%) of placebo group
• High-grade cancers increase risk of death
from prostate cancer BUT…
• Decreased prostate volume and selective
inhibition of low-grade cancers increased
detection of high grade cancers
Lucia JNCI 2007
Tuesday, June 17, 2008
New Take on a Prostate Drug, and a New Debate
Chemoprevention Conclusions
• Finasteride reduces prostate cancer risk
– Reduces anxiety, diagnosis, treatment
• Prior concerns in PCPT about increased
risk of high-grade cancer may be artifact
of cancer detection
• No role for selenium or vitamin E based
on SELECT trial
DeBoer - Advances in Treatment of Prostate Cancer
Screening
• DRE
• Prostate-specific antigen (PSA)
Clear Impact Of Screening
•
•
•
•
Diagnosis made 5-6 years earlier
Average age at diagnosis has fallen
Fewer advanced cases at diagnosis
Proportion of “good risk” patients at
diagnosis has increased
• Mortality rates have decreased in US
– With the randomized data, what
contribution has screening had?
European Randomized Screening
for Prostate Cancer (ERSPC)
• In order to prevent a single prostate
cancer death over 10 yrs:
– You need to screen 1410 men
– Of those, you need to treat 48 patients who
are diagnosed with prostate cancer
• Is this worth the morbidity and cost?
55
Conclusions of Randomized
Screening Studies
•
•
•
•
•
2 large randomized trials
Relatively short follow up
Significant contamination in control arm
Modest survival benefit to screening
Need to consider patient age, relative
risks and benefits of screening
• Consider active surveillance more often
once diagnosis is made
Screening Recommendations:
ACS, AUA
• DRE and PSA in men > 50 years old
• High risk men (AA and +FH)
– > 40-45 years old
• Frequency? Annually
• End screening? <10 year life expectancy
– Very difficult for patients to accept
– Recent USPHS Task Force recommended no
screening
False Positive PSA
• Benign Prostatic Hyperplasia (BPH)
• Prostatitis
DeBoer - Advances in Treatment of Prostate Cancer
Markers To Improve Accuracy
•
•
•
•
Age-Specific PSA
PSA Density
% Free PSA
PSA Doubling Time (Velocity)
Lower % Free PSA Suggests
Higher Likelihood Of Cancer
• For PSA 4-10 ng/ml
– Free PSA > 25% means less than 10%
chance of cancer
– Free PSA <10% means over 50% chance of
cancer
• 25% free PSA cutoff detects 95% of
cancers and avoids 25% of unnecessary
biopsies
PSA Rise > 2 ng/ml/yr Predicts
Higher Risk Of Cancer Death
D’Amico NEJM 2004
57
Summary
• PSA and DRE are standard screening
tools, though randomized data are
lacking for definite evidence of benefit
• PSA screening results in earlier diagnosis
• Tools such as % free PSA and PSA
velocity can improve accuracy of
diagnosing cancer
• However, there may be no true “PSA
cutoff” separating cancer from no cancer
Diagnosis Suspected
• Abnormal PSA
• Abnormal DRE
• Cancer detected on TURP (rare)
Diagnosis
• Biopsy
– TRUS guidance
– 6-18 cores by spring-loaded biopsy gun
• Pathology
– Gleason score assigned based on
differentiation from 2 (well) to 10 (poorly)
DeBoer - Advances in Treatment of Prostate Cancer
Treatment Options
• Watchful waiting
• Radical prostatectomy
– Open vs laparoscopic vs robotic
– Retropubic vs perineal
• External beam radiotherapy
– 3D conformal
– IMRT
• Seed implants (brachytherapy)
• Cryosurgery
• Androgen deprivation therapy (ADT)
Watchful Waiting
•
•
•
•
•
•
767 patients in Connecticut
Mean age: 68 years
Mean f/u: 15.4 years
Diagnosis: TURP (60%), needle bx (26%)
Stage: 21% had no bone scan
Death certificates, path reviewed
Albertson JAMA 2005
Prostate Cancer-Specific Death
Rates At 20 Years
Gleason Score
Mortality Rate (95% CI)
Per 1000 person-yrs
2-4
6 (2-11)
5
12 (6-19)
6
30 (23-37)
7
65 (49-83)
8-10
121 (90-156)
59
Randomized Study: Surgery
Versus Watchful Waiting
•
•
•
•
•
•
695 Scandinavian men, 1989-1999
Median f/u 8.2 years
Mean age: 64.7 years
Mean PSA: 12.8 ng/ml
Stage T1b (12%), T1c (11%), T2 (76%)
Gleason: 2-6 (61%), 7 (23%), 8-10 (5%)
Bill-Axelson NEJM 2005
Conclusions
• Radical local treatment in a non-screened
population with localized cancer leads to
improved OS, PFS, decreased distant
metastases and local progression
• The absolute benefit is small, requiring
17 RPs for 1 life saved (in 8 yrs)
• Benefit most significant in men < 65 yrs
old
Treatment for Localized
Prostate Cancer: Conclusions
• Reasonable to consider surgery, radiation
or seed implants in younger, healthier
men
• Reasonable to consider watchful waiting
in older men with low grade disease and
decreased life expectancy
• Options depend on risk group
DeBoer - Advances in Treatment of Prostate Cancer
Failure Of Local Therapy
• Most men treated for localized prostate
cancer are cured
• As many as a third recur, usually
manifested initially as a rising PSA alone
• Little is known about optimal
management of rising PSA patients
Natural History Of Rising PSA
• 304 men relapsed after surgery
• No hormones until (+) bone scan
• Time to PSA rise, Gleason, PSADT were
predictors of survival
RP
8 yrs
First Rise
in PSA
5 yrs
Bone scan
(+)
Death
Pound JAMA 1999
Hormonal Therapy
• Mandatory with metastatic disease
• Often used early in the setting of a rising
PSA alone (benefit?)
• Rapid PSA doubling time indicates
population at high risk of death from
prostate cancer
• Average response 1-2 years for metastatic
disease
61
Clinical States of Prostate Cancer
Clinically
localized
“Rising PSA”
state
Non-metastatic,
hormonesensitive
Non-metastatic
CRPC
Metastatic,
hormone-sensitive
Metastatic
CRPC
Death from prostate cancer
Death from other causes
10-15 years +
Adapted from George D. ASCO Prostate 2007.
Conclusions: Chemotherapy
For Metastatic CRPC
• 20% decreased mortality from
prostate cancer (~2-3 months)
• Improved PFS, PSA and pain
responses
• Current efforts to build on this
regimen: novel targeted drugs,
angiogenesis inhibitors
How Do We Incorporate The Many New Treatments for CRPC?
DeBoer - Advances in Treatment of Prostate Cancer
The Standard of Care
Disease State
Continuous
ADT
Intermittent
ADT
Metastatic
Yes
No*
Non-Metastatic,
Rising PSA
Yes
Yes
*But consider it for patients with poor QOL on ADT!
PRESENTED BY: William Oh, M.D.
Secondary Hormonal Therapies for
CRPC
Recent Trials in CRPC: OS
Therapy
Disease state
Comparator
Hazard
Ratio
P value
Sipuleucel-T
Chemo-näive
Placebo
0.775
0.032
Docetaxel
Chemo-näive
Mitoxantrone
0.76
0.009
Cabazitaxel
Post-Docetaxel
Mitoxantrone
0.70
<0.0001
Abiraterone acetate
Post-Docetaxel
Placebo
0.646
<0.0001
63
Immunotherapy
• Sipuleucel-T FDA approved April 2010
– mCRPC
– Asymptomatic or minimally symptomatic
– Generally for pre-chemotherapy pts
Sipuleucel-T
n=338
Adverse Event
Placebo
n=168
All %
Gr 3-5 %
All %
Chills
54.1
1.2
12.5
Gr 3-5 %
0
Fatigue
39.1
1.2
38.1
1.8
Back Pain
34.3
3.6
36.3
4.8
Fever
29.3
0.3
13.7
1.8
Nausea
28.1
0.6
20.8
0
Arthralgia
20.7
2.1
23.8
3
Headache
16
0.3
4.8
0
Myalgia
9.8
0.6
4.8
0
Influenza Like Illness
9.8
0
3.6
0
Hypertension
7.4
0.6
3.0
0
Kantoff et al. N ENGL J MED. 2010; 363;5:411-422
Pituitary
ACTH
Adrenal Cortex
Cholesterol
Cholesterol Side Chain
Ketoconazole
Cleavage
Pregnenolone
Progesterone
DOC
3-BHSD-I
21-hydroxylase
Corticosterone
11β-hydroxylase
Ketoconazole
18OHCorticosterone
18-hydroxylase
Mineralocorticoids
17α-hydroxylase
Abiraterone
17OH-pregnenolone
Aldosterone
18-oxidase
17OH-progesterone
11-DOC
Cortisol
Glucocorticoids
3-BHSD-I
Peripheral Tissues
C17-20 lyase
Abiraterone
DHEA
Androstenedione
Testosterone
DHT
3-BHSD-I
Androgens
Courtesy of J.A. Garcia, MD, FACP, Cleveland Clinic
17-keto-reductase
5α-reductase
DeBoer - Advances in Treatment of Prostate Cancer
Abiraterone Acetate (Zytiga ®)
• mCRPC pts that have failed docetaxel based
chemotherapy (approved April 2011)
• reduces in testosterone by inhibiting CYP17
• 4.6 month overall survival benefit
• 1000mg once daily
-250mg tablets
-Take one hr prior to or two hours after eating
• Prednisone
-5 mg BID or 10mg daily—MD discretion
Abiraterone Toxicity Profile
N=791
% Grade 3 / 4
Fatigue
8%
Arthralgias
8%
Muscle Weakness
4%
Nausea/Vomiting/Diarrhea 2 %/ 2 %/1 %
Fluid Retention / Peripheral Edema 2%
Dehydration
2%
Anorexia
2%
Hypertension
1%
Headache
1%
Abiraterone Acetate PI. Los Angeles, CA: Cougar Biotechnology, Inc.; [September] 2010
Abiraterone in the Prechemo Space
• The obvious location for a second-line
hormone agent is pre-chemo
• Was the study prematurely unblinded?
– I don’t believe so—strong trend towards OS
benefit, clear clinical benefit in delaying
progression
– Final planned analysis of OS may have been
compromised
• Multiple signals of efficacy
• No new safety concerns
65
Enzalutamide (MDV3100)
•
•
•
T
Approved August 2012
for patients with
metastatic CRPC
previously treated with
docetaxel
Oral agent designed to
target AR signaling,
impacting multiple steps
in AR signaling pathway.
No demonstrated
agonist effects in preclinical models.
T
Inhibits Binding of Androgens to AR
Enzalutamide
AR
Cell cytoplasm
Inhibits Nuclear Translocation of AR
Cell nucleus
AR
Inhibits Association
Of AR with DNA
Tran et al. Science 2009;324:787–90.
Charles Sawyers & Michael Jung
Enzalutamide had a high PSA Response
Rate
>50% confirmed PSA fall:
Enza 54% ; Placebo 2% (p<0.0001)
>90% confirmed PSA fall:
Enza 25%; Placebo 1% (p<0.0001)
Placebo
Enzalutamide
All the secondary endpoint measures favored the treatment arm
Enzalutamide AE
● Most frequently reported in clinical trials (>10%)
Enzalutamide
Toxicities (%)
Placebo
Toxicities (%)
Grade
1-4
Grade
3-4
Grade
1-4
Grade
3-4
Asthenia/fatigue
50.6
9.0
44.4
9.3
Back pain
26.4
5.3
24.3
4.0
Diarrhea
21.8
1.1
17.5
0.3
Arthralgia
20.5
2.5
17.3
1.8
Hot flush
20.3
0
10.3
0
Peripheral edema
15.4
1.0
13.3
0.8
Musculoskeletal pain
15.0
1.3
11.5
0.3
Headache
12.1
0.9
5.5
0
Upper respiratory tract infection
10.9
0
6.5
0.3
Xtandi enzalutamide prescribing information 2012.
DeBoer - Advances in Treatment of Prostate Cancer
Adverse Events of Special Interest
All Grades
Grade ≥ 3 Events
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
Fatigue
33.6%
29.1%
6.3%
7.3%
Cardiac Disorders
6.1%
7.5%
0.9%
2.0%
Myocardial
Infarction
0.3%
0.5%
0.3%
0.5%
LFT Abnormalities*
1.0%
1.5%
0.4%
0.8%
Seizure
0.6%
0.0%
0.6%
0.0%
*Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal,
transaminases increased, and blood bilirubin increased.
Enzalutamide Management
Seizures
● In clinical trial, seizures occurred from 31 to 603 days after initiation
● Should not be used in patients with a history of seizure, underlying brain injury with loss of
consciousness, transient ischemic attack within the past 12 months, cerebral vascular
accident, brain metastases, brain arteriovenous malformation or the use of concomitant
medications that may lower the seizure threshold as these patients were excluded from
trial
● Patients advised to avoid activity where sudden loss of consciousness could cause
serious harm to themselves or other
● Discontinue therapy if experiencing seizure
– In clinical trial, all seizures resolved with discontinuation of therapy
Dose modification in case of intolerablie side effects
● If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing
for one week or until symptoms
● improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if
warranted.
Use with concomitant strong CYP2C8 inhibitors
● Concomitant use of strong CYP2C8 inhibitors should be avoided if possible.
● If patients must be co-administered a strong CYP2C8 inhibitor, reduce the dose to 80 mg
once daily and return to the original dose once the strong CYP2C8 inhibitor is discontinued
Xtandi enzalutamide prescribing information 2012.
Targeting Androgen Signaling in
CRPC
• Enzalutamide targets androgen signaling and
is associated with a startling survival benefit,
even after progression on chemotherapy
• Toxicity is remarkably mild
– Seizures are uncommon but need to manage
• Should this be moved earlier?
–
–
–
–
Prechemo (AFFIRM)
Rising PSA
New metastatic
Adjuvant
67
The Curies: Discovery of Radium
The Curies informed the l'Académie des Sciences, on December 26, 1898,
that they had come upon an additional very active substance that
behaved chemically almost like pure barium. They suggested the name of
radium for the new element.
1903 was a very good year,
Madame Curie presented
her doctoral thesis and shared
the Nobel Prize with her
husband (and Henri Becquerel)
Bottom Line:
Radium223
Short Range but Deadly
Radium
2-10 cell diameter range of
alpha-particle
Radium-223
Highly localised cell killing with minimal damage to surrounding
hematopoetic tissue
Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007
Recent Trials in CRPC: OS
Therapy
Disease state
Comparator
Hazard
Ratio
P value
Sipuleucel-T
Chemo-näive
Placebo
0.775
0.032
Docetaxel
Chemo-näive
Mitoxantrone
0.76
0.009
Cabazitaxel
Post-Docetaxel
Mitoxantrone
0.70
<0.0001
Abiraterone acetate
Post-Docetaxel
Placebo
0.646
<0.0001
Pre-Docetaxel
Placebo
0.75
0.0097*
Enzalutamide
(MDV3100)
Post-Docetaxel
Placebo
0.631
<0.001
Alpharadin
(Radium-223)
Post-Docetaxel
Placebo
0.70
0.002
DeBoer - Advances in Treatment of Prostate Cancer
Treatment Landscape
Standard Androgen Deprivation Therapy
Surgery /
Radiation
Denosumab, Zoledronic Acid
Alpharadin
MDV-3100
Abiraterone
Androgen
Deprivation
Chemotherapy
Death
Local
Therapy
Therapies After
LHRH Agonists
and Antiandrogens
Postchemotherapy
Sipuleucel-T
Docetaxel
Cabazitaxel
Where Will We Be in 5 Years?
• More agents, but will they be “me too” drugs?
• Increased understanding of the biology of
CRPC
• Earlier use of therapies
– Adjuvant, neoadjuvant, rising PSA, non-mets
CRPC
• More molecular diagnostics and
personalization of prostate cancer subtypes
– CTCs, tumor signatures, etc
The Influence of Cost
• Health care reform may shift use of therapies
– Will there be rationing of care?
• Oral vs IV therapies
– Copayments, reimbursements, drug costs
• Stricter definitions of patient benefit, eligibility
for specific therapies
• Measurements of quality of care may change
69
Skripnik - Update in Treatment of Melanoma
Updates & Nursing
Implications in the Treatment
of Melanoma
Anna Skripnik, RN
Dermatology Service
Memorial Sloan Kettering Cancer Center
Functions of the Melanocytes
• Embryogenesis:
Pigment producing
cells are derived from
the Neural crest
• Differentiation:
Dermis, epidermis &
hair follicles, uvea,
meninges
• Influences skin and
hair color
Lin, J.Y. & Fisher, D.E. Nature, 2007
Integumentary system
www.nordiqc.org, 2009
http://www.lab.anhb.uwa.edu
71
UVA/UVB and their effects
• Penetration
• Nanometers
• Long term effects
• Short term effects
Melanocyte malignancy
Causes of malignant
melanocytes
• Ultraviolet radiation
(UVA 320-400nm, UVB
290- 320nm): DNA
damage
• Cumulative lifetime sunexposure
• Familial history (gene
susceptibility)
• Immunosuppression
• Ionizing Radiation
Clinical Presentations
•
•
•
•
•
Webmd.com
Asymmetry
Border (irregular)
Color (uneven)
Diameter
Evolution
Skripnik - Update in Treatment of Melanoma
Types of Melanoma
1)Superficial spreading
2) Lentigo Maligna
3) Nodular melanoma
4) Acral lentiginous melanoma
Yalesurgery.org
Staging
Diagnosis
• Breslow depth
(thickness)
• Mitotic index
• Ulceration
• Margin involvement
• Lymphocytic infiltrate
• Tumor
• Node
• Metastasis
• Sentinel node
involvement
Melanoma staging
AJCC Cancer Staging Manual. 7th ed. 2010
73
Melanoma evolution:
Total body assessments
• Melanoma surveillance
• Total body photography
Skincancerclinic.md
Nsc.gov.sg
Statistics
• Men and women dx in
2012: approx. 76,250
• 9,180 deaths
• Incidence: 21.0 per
100,000 men and
women per year
• 2.7 per 100,000 men
and women per year
• Median age at
diagnosis: 61
National Cancer Institute,
SEER Stat Fact sheet,
Melanoma 2012
Skripnik - Update in Treatment of Melanoma
Treatments: Dependent on stage of
disease
• Primary cutaneous melanoma: Excision (0.5cm-2cm
(with or without SLNB)
• Regional lymph node metastasis: SLNB, adjuvant
interferon, interferon alpha-2b, Bacille CalmetteGuerin (BCG) vaccine, radiation therapy
• Distant metastatic disease:
– Chemotherapy : Dacarbazine, CisPlatinum,Temozolomide
– Radiation therapy
– Experimental therapies (eg, biochemotherapy)
Vemurafenib (PLX4032)
• Indication: unresectable and/or metastatic
melanoma with BRAFV600E mutation.
• Dosage and administration: 240mg
tablets x4; 480mg BID
Caution: renal or hepatic impairment
• Mechanism of action: BRAF inhibitor
(including V600E)
75
Pet scan 2 weeks s/p Vemurafenib
Adverse Events
:Phase III Study
ne336
Vemurafenib
n=336
Adverse Event
All %
Gr 3
Gr4
Photosensitivity Reaction
33
3
-
Alopecia
45
<1
-
Rash
37
8
-
Fever
29.3
0.3
-
Nausea
35
2
-
Arthralgia
53
3
-
Headache
23
<1
0.6
Myalgia
9.8
Influenza Like Illness
9.8
0
Hypertension
7.4
0.6
Vemurafinib : Nursing
considerations
• Sun protection
• Medication compliance
• Detailed health history (obtain full list of
medications)
• Management of common side effects
• Allergic reactions
Skripnik - Update in Treatment of Melanoma
Ipilimumab
• Indication: Monoclonal antibody, approved
for unresectable and/or metastatic
melanoma
• Dosage and administration: 3mg/kg IV
q3weeks
• Mechanism of action: Binds to targeted Tcell antibody (CTLA-4), blocking interaction
btw CD80/86
Mechanism
77
Ipilimumab: Side effects
Ipilimumab: Nursing considerations
• Reviewing s/s of adverse effects (and
management of)
• Patient education (including family):
effects of medication on immune system,
disease process
• Support
Long term monitoring
• Survival correlates to extensiveness of
disease
• Early detection
• Self-body exams
• Total body photography
Skripnik - Update in Treatment of Melanoma
Patient Education
• Importance of application of sunscreens, sun
protective clothing and lifestyle modifications.
• Remember, individuals can still get burned in
snowy and cloudy conditions!
• Target prevention and increase awareness
Importance of sun protection
Working together towards
prevention
79
O'Dea - Therapeutic Options in MM
Therapeutic Options in
Multiple Myeloma
Denise O’Dea, ANP-BC, OCN
NYU Langone Medical Center
NYU Cancer Institute
Disclosure
• Speaker Bureau: Amgen, Celgene Corporation
Objectives
• Discuss overview of multiple myeloma.
• Review history of multiple myeloma
therapies.
• Discuss current approved novel agents
for multiple myeloma.
• Review side effects of current treatment.
• Discuss emerging therapies.
81
Multiple Myeloma
• Cancer of plasma cells
• B-cell malignancy
• Normal plasma cells transform into
malignant myeloma cells and
produce large quantities of an
abnormal immunoglobulin called
monoclonal (M) protein.
• lncreased immunoglobulins
• IgG, IgA
• Light chains (Kappa or
Lambda)
• Uncommonly IgD, IgE
• Bence Jones Proteins
.
Normal vs Abnormal
Plasma Cells
Normal
Abnormal
Stem Stem
Cell
cell cell
Stem Cell
cell
Stem
Genetic
GENETIC
GENETIC
DAMAGE
Damage
DAMAGE
T-Lymphocyte
T
lymphocyte
BB-Lymphocyte
lymphocyte
Damaged
Damaged
B lymphocyte B-Lymphocyte
B
lymphocyte
B-Lymphocyte
B lymphocyte
B lymphocyte
Antigens
Antigens
Activated
T cell
Activated
T-Cell
Plasma
Plasmacell
cell
Antigens
Antigens
Antigens
Plasma cell Malignant
Malignant
Plasma
plasma cell cell
Plasmacell
cell
Malignantplasma
plasma
cell
(Myeloma
Cell)
(myeloma
(myeloma
cell) cell)
Antibodies
Antibodies
Antibodies
Antibodies
Adapted from Multiple Myeloma Research Foundation. 2007. www.multiplemyeloma.org.
Epidemiology
• Second most common hematologic cancer
• Estimated:
– 21,700 new cases will be diagnosed in US in 2012
– 10,710 deaths are expected to occur in US in 2012
– 100,000 patients in US living with myeloma
• Median age at diagnosis: 69 years
• Slightly more common in men than women
• Two fold higher incidence in African Americans
than Caucasians
American Cancer Society http://www.cancer.org/Cancer/MultipleMyeloma/DetailedGuide/multiple-myeloma-key-statistics
SEER Stat Fact Sheets: Myeloma. http://seer.cancer.gov/statfacts/html/mulmy.html Accessed October 9, 2012.
CA: A Cancer Journal for Clinicians Volume 62, Issue 1, pages 10–29, January/February 2012
O'Dea - Therapeutic Options in MM
Risk Factors
•
•
•
•
Age
Gender
Race
Familial Inheritance
• Obesity
• Environmental Exposures to Toxins
– Ionizing radiation
– Chemicals
Presenting Features of MM
• Calcium elevated
• Renal impairment
• Anemia
• Bone pain
• Constitutional symptoms: weakness, fatigue, and
weight loss
• Infection
• Hyperviscosity (IgA)
• Neurologic dysfunction
– Spinal cord or nerve root compression
• ~33% of patient diagnosed asymptomatic
Plasma Cell Dyscrasia
MGUS
SMM
Multiple Myeloma
Plasma Cell Clone
1 x 109
1 x 1010-11
1 x 1012
M spike
<3 g/dl
>3 g/dl
>3 g/dl
BM Plasma Cells
Clonal
and <10%
or >10%
>10%
Symptoms*
None
None
Symptomatic
BJP
<1 g/day
<1 g/day
>1 g/day
Anemia
No
No
Yes
Bone Lesion
No
No
Yes
Renal Failure
No
No
Yes
Related Organ and Tissue Impairment:
CRAB: HyperCalcemia, Renal impairment, Anemia, Bone lesion
Hyperviscosity, Amyloidosis, Recurrent bacterial infections
IMWG Br J Haematol. 2203; 121:749
83
Risk Factors for MM Outcome
Low to intermediate risk
High risk
• Expected OS >7-8 years
• t(11;14)
• Hyperdiploidy
• Low β2M (<3.5 mg/L)
• Expected OS 3-4 years
• t(4;14); t(14;20) or t(14;16)
by FISH
• Deletion (17p) by FISH
• Deletion (13q) by cytogenetics
• Hypodiploidy
• High b2M (≥5.5 mg/L)
• 1p amplification
• 1q deletion
Clinical challenges
•Renal failure
•Age ≥70 years
•Increasing number of prior
therapies
•Extramedullary MM
•Advanced bone disease
Chng. Clin Lymphoma Myeloma. 2005;6:200; Stewart. J Clin Oncol. 2005;23:6339;
Barlogie. Blood. 2004;103:20; Richardson. Blood. 2005;106:2977.
Brief Myeloma History
• Skeletal evidence of myeloma obtained from
Egyptian mummies
• First case described in 1844
– 39-year-old Sarah Newbury
– Spontaneous fractures of her femurs and right
humerus
• 1845: Dr Henry Bence Jones detected heat properties
of urinary light chains
• 1929: bone marrow aspiration
• 1937: serum protein electrophoresis
• No treatment until 1960s: Alkeran and prednisone
Durie. International Myeloma Foundation. 2007. www.myeloma.org.
Hussein. Cleve Clin J Med. 1994;61(4):285.
Jones. Phil Trans R Soc Lond. 1848;138:55-62.
Multiple Myeloma Treatment:
Timeline
• Bisphosphonates
• HDT with
autologous stem
cell support
• VAD
• Allogeneic
transplant
•Melphalan +
prednisone
New
combinations
•High- dose
Dexamethason
e
•Cyclophosphamide
Ongoing
clinical Trials :
New agents
In pipeline
• Lenalidomide
• Pegylated doxorubicin
• Anti-angiogenesis agents
• Bortezomib
• Thalidomide
• “Mini allogeneic”
transplant
•Sub Q Velcade
•Carfilzomib
•Oral
melphalan
1962
1964
1969
HDT = high dose therapy
1984
1986
1996
1999
2000 2001+ 2012
2012+
O'Dea - Therapeutic Options in MM
DurieDurie-Salmon Staging System
for Multiple Myeloma
Myeloma cell mass
(×1012 cells/m2)
Stage
Criteria
I
All of the following:
Hemoglobin >10 g/dL
Serum calcium level ≤12 mg/dL (normal)
Normal bone or solitary plasmacytoma on
x-ray
Low M component production rate:
IgG <5 g/dL
IgA <3 g/dL
Bence Jones protein <4 g/24 hr
II
Not fitting stage I or III
0.6 to 1.2 (intermediate)
III
One or more of the following:
Hemoglobin <8.5 g/dL
Serum calcium level >12 mg/dL
Multiple lytic bone lesions on x-ray
High M-component production rate:
IgG >7 g/dL
IgA >5 g/dL
Bence Jones protein >12 g/24 hr
>1.2 (high)
<0.6 (low)
Subclassification Criteria
A Normal renal function (serum creatinine level <2.0 mg/dL)
B Abnormal renal function (serum creatinine level ≥2.0 mg/dL)
14
Durie, et al. Cancer. 1975.
International Staging System
Has prognostic value, but does not indicate tumor burden
Stage I
Stage II
Stage III
β2M
<3.5 mg/L
≥5.5 mg/L
Serum
Albumin
≥3.5 g/dL
Neither stage I nor
stage III
(β2M <3.5 and
albumin <3.5, or
β2M 3.5-5.5)
Median
Survival
62 mo
44 mo
Not specified
29 mo
β2M= β2-microglobulin
Greipp. J Clin Oncol. 2005;23:3412.
Agents Approved for MM
Drug
Dexamethasone
Melphalan
Pegylated liposomal
doxorubicin
Prednisone
Trade Name
Indication
Decadron
Palliative management of leukemias and
lymphomas
Alkeran
Palliative treatment of MM
Doxil
In combination with bortezomib in patients who have
not previously received bortezomib and have received at
least 1 prior therapy.
Deltasone
Palliative management of leukemias and lymphomas in
adults
85
Agents Approved for MM
Trade Name
Indication
Bortezomib
Drug
Velcade
Patients with MM
Lenalidomide
Revlimid
In combination with dexamethasone for the
treatment of MM in patients who have received at
least 1 prior therapy
Thalidomide
Thalomid
In combination with dexamethasone for the treatment of
patients with newly diagnosed MM
Carfilzomib
Kyprolis
Indicated for the treatment of patients with multiple
myeloma who have received at least 2 prior therapies
including bortezomib and an immunomodulatory.
Current Treatment Guidelines:
NCCN Guidelines V.1.2013
Initial Therapy for Transplant Eligible Patients
•VD Bortezomib Dexamethasone
•VCD Bortezomib Cyclophosphamide Dexamethasone
•VDD Bortezomib Doxorubicin Dexamethasone
•VRD Bortezomib Lenalidomide Dexamethasone
•VTD Bortezomib Thalidomide Dexamethasone
•RD Lenalidomide Dexamethasone
Initial Therapy for Transplant ineligible
Maintenance Therapies
•VD Bortezomib Dexamethasone
•RD Lenalidomide Dexamethasone
•MPV Melphalan Prednisone Bortezomib
•MPR Melphalan Prednisone Lenalidomide
•MPT Melphalan Prednisone Thalidomide
•Bortezomib
•Lenalidomide
•Thalidomide
Current Treatment Guidelines:
NCCN Guidelines V.1.2013
Salvage Therapies
•Repeat primary induction therapy if relapse >6months
•Bendamustine
•Bortezomib
•Bortezomib Dexamethasone
•Bortezomib Lenalidomide Dexamethasone
•Bortezomib Liposomal doxorubicin
•Bortezomib Thalidomide Dexamethasone
•Bortezomib Cyclophosphamide Dexamethasone
•Carfilzomib
•Cyclophosphamide Lenalidomide Dexamethasone
•Dexamethasone Thalidomide Cisplatin Doxorubicin Cyclophosphamide (DCEP)
•Dexamethasone Thalidomide Cisplatin Doxorubicin Cyclophosphamide
Etoposide (DT-PACE) +/- Bortezomib (VTD-PACE)
•High Dose cyclophosphamide
•Lenalidomide Dexamethasone
•Thalidomide Dexamethasone
O'Dea - Therapeutic Options in MM
Novel Therapies Target MM Cells and
Bone Marrow Microenvironment
• Interaction with the microenvironment is crucial for MM proliferation and survival
• Drugs that disrupt signaling between MM cells and bone marrow stromal cells
may be effective in treating MM
Lenalidomide
• Typical dosing
– Lenalidomide 25 mg orally on days 1-21 of a 28-day cycle
• Excreted substantially through kidneys
– Carefully consider use in renal impairment
– Dose reduction based on CrCl may be necessary
• Adverse events
– Myelosuppression
– DVT
– Rash
– May cause birth defects
Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2009
Lenalidomide Side Effects
Toxicity
Intervention
Asthenia
(fatigue, malaise, weakness)
• Counsel patient
• Avoid concurrent meds causing asthenia
Hyperglycemia
(with dexamethasone)
• Monitor blood sugar
• Counsel patient regarding diet
Thromboembolic complications
(DVT/PE)
• Anticoagulation recommended
• Monitor coagulation assays
Myelosuppression
(neutropenia and
thrombocytopenia)
• Interrupt therapy if platelets fall to
< 30,000/mcL or ANC falls to < 1,000/mcL
• Resume therapy at lower or same dose on first recovery
• Drop dose by 5 mg on subsequent recoveries
Gastrointestinal (constipation)
•Bowel regimen (call office if no BM in 3 days)
•Increase fluid and fiber intake
Incidences of toxicities are from 2 clinical trials of multiple myeloma patients (N = 346) with lenalidomide +
dexamethasone.
Miceli et al. Clin J Oncol Nurs. 2008:12(3 suppl):13-20; Revlimid® [package insert]. Celgene; 2006.
87
Bortezomib
•Typical dosing
• Bortezomib 1.3 mg/m2 as a 3- to 5-second bolus IV injection on days
1, 4, 8, and 11 of a 21-day cycle; 8-cycle dosing
• Can be given subcutaneously.
•Also dosed Days 1, 4, 11, 18 (usually in combination with lenalidomide
21day cycle)
•Adverse events
• Peripheral neuropathy
• Neutropenia
• Thrombocytopenia
• Anemia
• Asthenia
• Fatigue
Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2006
Bortezomib Dosing Guidelines
as Single Agent
• Dose twice weekly for 2 weeks on a 21-day cycle
– Standard 8-cycle induction schedule with an option of 3 cycles
of weekly maintenance therapy
– At least a 72-hour rest period is required between doses (allows
for restoration of proteasome function toward baseline)
• Refer to dose modification guidelines as necessary
Velcade® [package insert]. Millennium Pharmaceuticals, Inc; 2008.
Bortezomib Side Effects
Toxicity
Incidence:
Single agent vs (VMP)
Peripheral
neuropathy
Overall: 37%
Grade ≥ 3: 11%
(47%)
(13%)
• Patient education/early detection
• Baseline assessment and monitor at each visit
• Dose adjustment
• Symptom control with pharmacologic interventions
Hypotension
Overall: 12%
Grade ≥ 3: 3%
(12%)
(2%)
• Counsel patient
• Avoid concurrent meds causing hypotension
Asthenia
(fatigue, malaise,
weakness)
Overall: 62%
Grade ≥ 3: 16%
(21%)
(6%)
• Counsel patient (rest, nutrition, hydration, exercise)
• Avoid concurrent meds causing asthenia
Myelosuppression
Thrombocytopenia:
Overall: 38%
Grade ≥ 3: 32%
Neutropenia:
Overall: 18%
Grade ≥ 3: 14%
(52%)
(37%)
• Cyclical with lowest levels on Day 11 of cycle
• Consistent pattern that is not cumulative
• Hold if platelets < 25,000/µL and reintroduce at
a 25% lower dose with recovery
Diarrhea
Overall: 53%
Grade ≥ 3: 8%
Intervention
(49%)
(40%)
(46%)
(7%)
•Bulk forming laxatives such as Metamucil®, loperamide
•with caution
•Adequate fluid intake
Single-agent incidences of toxicities are based on an integrated analyses of relapsed multiple myeloma studies (N = 1008) while VMP incidences are
based on the VISTA study. Colson et al. Cancer Nurs. 2008;31:239-249; Velcade® [package insert]. Millennium Pharmaceuticals, Inc; 2008.
O'Dea - Therapeutic Options in MM
Subcutaneous Bortezomib
A Phase 3 Prospective, Randomized, International
Study (MMY-3021) Comparing Subcutaneous and
Intravenous Administration of Bortezomib in Patients
with Relapsed Multiple Myeloma
Philippe Moreau,1 Halyna Pylypenko,2 Sebastian Grosicki,3
Evgeniy Karamanesht,4 Xavier Leleu,5 Maria Grishunina,6
Grigoriy Rekhtman,7 Zvenyslava Masliak,8 Tadeusz Robak,9
Anna Shubina,10 Jean-Paul Fermand,11 Martin Kropff,12 James Cavet,13 DixieLee Esseltine,14 Huaibao Feng,15 Donna Skee,15
Helgi van de Velde,16 William Deraedt,16 Jean-Luc Harousseau17
1University Hospital, Nantes, France; 2Cherkassy Regional Oncology Dispensary, Cherkassy, Ukraine; 3Oddzial Hematologiczny
ZSM, Chorzow, Poland; 4Kiev BMT Center, Kiev, Ukraine; 5Hopital Huriez, CHRU, Lille, France; 6Nizhniy Novgorod Region Clinical
Hospital, Nizhniy Novgorod, Russia; 7Khmelnitskiy Regional Hospital, Khmelnitskiy, Ukraine;
8SI Institute of Blood Pathology and Transfusion Medicine UAMS, Lviv, Ukraine; 9Medical University of Lodz, Lodz, Poland; 10S.P.
Botkin Moscow City Clinical Hospital, Moscow, Russia; 11Hopital Saint-Louis, Paris, France; 12University of Münster, Münster,
Germany; 13The Christie NHS Foundation Trust, Manchester, UK; 14Millennium Pharmaceuticals Inc., Cambridge, MA, USA;
15Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA; 16Johnson & Johnson Pharmaceutical Research
& Development, Beerse, Belgium; 17Centre René Gauducheau, Nantes/St Herblain, France
Subcutaneous Bortezomib
Conclusions
• The efficacy of bortezomib was similar by SC and
IV administration in patients with relapsed MM
– IV and SC administration also resulted in similar PK (systemic
exposure) and PD (proteasome inhibition) profiles
• SC administration of bortezomib appeared to have
an improved safety profile compared with IV
administration
– With SC administration there were significantly fewer
all-grade, grade ≥2, and grade ≥3 PN events compared with IV
administration
• SC administration had acceptable local tolerability
SC Injection Site Rotation
Within the same cycle
8
1
7
2
R
•Injections at the same site
should be avoided.
L
6
3
5
4
•Alternate between
• right and left abdomen
• upper and lower quadrant
• right and left thigh
• proximal and distal sites
89
Pegylated Liposomal
Doxorubicin
• Typical Dosing
• PLD: 30 mg/m2 1-hr IV infusion on day 4 following
bortezomib;
21-day cycle, up to 8 cycles
• Adverse Events
• Neutropenia
• Alopecia
• Cardiac toxicity
• HFS (Hand Foot Syndrome)
Doxil [package insert]. Raritan, NJ: Ortho Biotech Products, L.P.; 2008
Carfilzomib
Typical dosing
• Administer intravenously over 2 to 10 minutes, on two
consecutive days each week for three weeks (Days 1, 2, 8, 9, 15,
and 16), followed by a 12-day rest period (Days 17 to 28).
• Recommended Cycle 1 dose is 20 mg/m2/day and if tolerated
increase Cycle 2 dose and subsequent cycles doses to 27
mg/m2/day.
• Hydrate patients prior to and following administration.
• Pre-medicate with dexamethasone prior to all Cycle 1 doses,
during the first cycle of dose escalation, and if infusion reaction
symptoms develop or reappear.
Kyprolis [Package Insert] . South San Francisco, CA. Onyx Pharmaceuticals, Inc 2012.
Carfilzomib
Adverse events
•
•
•
Hematologic
Cardiac-CHF, pulmonary edema, ejection fraction decrease
Pulmonary-hypertension
•
•
•
•
Tumor Lysis Syndrome
Renal
Hepatic
Peripheral Neuropathy
Kyprolis [Package Insert] . South San Francisco, CA. Onyx Pharmaceuticals, Inc 2012.
O'Dea - Therapeutic Options in MM
Carfilzomib Side Effects
Toxicity
Incidence
Intervention
Hematologic
Thrombocytopenia
36%
10% Grade 4
Hold treatment until recovery of counts.
•Dose reduce PRN.
Cardiac-CHF,
pulmonary edema,
ejection fraction
decrease
7%
•Baseline ECHO.
•Dose reduce.
•Patient Education.
Pulmonary
Complications
Dyspnea 35%
•Hold dose until symptoms resolve.
•Dose reduce if necessary.
Tumor Lysis Syndrome
<1%
Monitor electrolytes.
•Hydrate PRN.
Peripheral Neuropathy
14%
• Patient education/early detection
• Baseline assessment and monitor at each visit
• Dose adjustment
• Symptom control with pharmacologic interventions
Renal
Increase Creatinine
24%
Renal Failure 9%
•Dose adjustment.
•Hydration PRN.
Kyprolis [Package Insert] . South San Francisco, CA. Onyx Pharmaceuticals, Inc 2012
Pipeline Potentials
Pomalidomide (IMiD)
Immunotherapy (i.e. MAGE vaccines)
MLN9708 Proteasome Inhibitor (oral)
Elotuzumab (Humanized Monoclonal Antibody)
And Many More……..
http://clinicaltrials.gov Accessed August 20, 2012
Nursing Considerations
• Understanding Multiple Myeloma
• Understanding Clinical Trials
• Patient Education:
• Managing side effects
• Instruction regarding oral medication management
• Emotional support
• Multidisciplinary approach to patient care
91
Jurcic - Evolving Strategies for CML
Evolving Strategies for Chronic
Myelogenous Leukemia
Joseph G. Jurcic, MD
Attending Physician, Leukemia Service
Memorial Sloan-Kettering Cancer Center
Disclosures & Off-label Uses
• Has nothing to disclose
• Will be discussing investigational
agents for treatment-resistant CML
Chronic Myeloid Leukemia
• Myeloproliferative disorder of
hematopoietic stem cells
• 15% of adult leukemia
• Median age at diagnosis, 67 years
• Associated with radiation exposure
93
The Philadelphia Chromosome: t(9;22)
9
9q+
22
Ph (or 22q-)
bcr
bcr-abl
abl
Fusion Protein
with Tyrosine
Kinase Activity
Clinical Presentation of CML
Symptoms
• Fatigue
• Abdominal fullness
• Fever, chills, sweats, weight loss
Physical Findings
• Hepatosplenomegaly
• Ecchymoses
Common Laboratory Findings
• Increased mature and immature myeloid
cells
• Basophilia
• Anemia
• Thrombocytosis
CML: Peripheral Blood Smear
Jurcic - Evolving Strategies for CML
Clinical Course: Phases of CML
Advanced Phases
Chronic
Phase
Accelerated
Phase
Median 4-6
years
Blast Crisis
Variable duration
Median survival
3-6 months
Laboratory Findings by Phase
Parameter
WBC count
Chronic
Accelerated
Phase
Phase
−
≥ 20 x 109/L
Blast
Crisis
−
1-15%
≥ 15%
Basophils
↑
≥ 20%
−
Platelets
↑ or normal
↑ or ↓
↓
↑
↑
↑
Ph+
± Clonal
evolution
± Clonal
evolution
Blasts
Bone marrow
cellularity
Cytogenetics
≥ 30%
Methods for Detection of Philadelphia
Chromosome: Karyotyping
1
6
2
7
3
8
13
14
19
20
4
9
15
21
5
10
16
22
11
17
x
12
18
Y
95
Methods for Detection of
Philadelphia Chromosome: FISH
Interphase
Metaphase
Methods for Detecting Philadelphia
Chromosome: PCR
Chromosome 22
Chromosome 9
cbcr
1
2-11
2-11
2-11
Exons
Introns
CML Breakpoints
ALL Breakpoints
CML Survival
c-abl
p210 Bcr-Abl
p190 Bcr-Abl
Jurcic - Evolving Strategies for CML
Prognostic Scoring Systems
Sokal
Hasford
Age
0.116 × (age − 43.4)
0.666 when age ≥ 50 years
Spleen (cm)
0.0345 × (spleen − 7.51)
0.042 × spleen
Platelet (× 109/l)
0.188 ×[(platelet/700)2 − 0.563]
1.0956 when ≥ 1500 × 109/l
Myeloblasts (%)
0.0887 × (blasts − 2.10)
0.0584 × blasts
Eosinophils (%)
−
0.0413 × eosinophils
Basophils (%)
−
0.20399 when basophils ≥ 3%
Relative risk
Exponential of total
Total × 1000
Sokal JE et al. Blood 1984; 63: 789-799.
Hasford J et al. JNTL Cancer Inst 1998; 90: 850-858.
Treatment of CML
• Hydroxyurea
• Allogeneic HCT
• Interferon-α
• Imatinib
• Second generation TKIs
• Novel agents
Response Criteria in CML
Complete Hematologic Response
• WBC < 10 x 109/L
• Platelets < 450 x 109/L
• No immature cells
• Normal physical exam
Cytogenetic Response
• Complete (CCyR): No Ph+ cells
• Partial: 1-34% Ph+ cells
• Major (MCyR): 0-34% Ph+ cells
• Minor: 35-90% Ph+ cells
Molecular Response
•Complete: BCR-ABL mRNA undetectable by RT-PCR
•Major (MMR): ≥ 3-log reduction in International Scale (≤
0.1%)
97
Response to Therapy in Relation to
Level of BCR-ABL Transcripts
1011
100
Complete Hematologic Response
10
1010
1
Complete Cytogenetic Response
109
0.1
108
0.01
Major Molecular Response
107
0.001
106
0.0001
BCR-ABL Ratio
(according to the International Scale
Diagnosis, Pretreatment,
or Hematologic Relapse
1012
Undetectable Transcript
Complete Molecular Response
Baccarani M et al. Blood 2006; 108:1809-1820.
Cytogenetic Response and Survival
Major response
1.0
0.9
Proportion Surviving
0.8
0.7
P < .001
0.6
0.5
Minor or no response
0.4
0.3
0.2
0.1
0.0
0.0
12
24
36
Months After Treatment
48
60
Guilhot F et al. N Engl J Med 1997; 337:223-229.
Allogeneic HCT in CML
International Bone Marrow Transplant
Registry: 1990–1995
HLA-identical siblings
MUDs
Probability (%) of
Leukaemia-Free Survival
100
80
Chronic Phase (N=1756)
60
Chronic Phase (MUD) (N=391)
40
Accelerated Phase (N=262)
20
Blast Phase (N=72)
P = .0001
0
1
2
3
Years From BMT
4
5
Jurcic - Evolving Strategies for CML
Interferon-α
• Interferon-α has multiple biologic effects:
− Inhibition of proliferation
− Regulation of cytokine expression
− Modulation of immune system
• Higher doses correlate with better response
and greater toxicity
• Cytogenetic response may take 12−18 mos.
• MCyR seen in 6−38% of patients
Mechanism of Action for Imatinib
Imatinib
Goldman JM, Melo JV. N Engl J Med 2001;344:1084-1086.
Study Design for Phase III Trial
Imatinib
S
R
If:
• Progression
• Intolerance of treatment
• Failure to achieve MCR
at 24 months
Crossover
IFN-α + ara-C
S = screening
R = randomization
Progression:
• Death
• Accelerated phase or blast crisis
• Loss of MCyR or CHR
• Increasing WBC count
99
Imatinib vs. IFN + Ara-C
IRIS Study: 18-Month Summary
O’Brien SG et al. NEJM 2003;348:994-1004.
Time to Major Cytogenetic Response
Imatinib vs. Interferon + Ara-C
100
90
80
% responding
70
Estimated rate at 12 months
Imatinib:
84% (p < 0.001)
IFN + ara-C:
30%
60
50
40
30
20
Imatinib
10
IFN+Ara-C
0
0
3
6
9
12
15
18
21
Months since randomization
Annual Event Rates: Imatinib Arm
8
7.5
Event
Loss of CHR
Loss of MCyR
AP/BC
Death during treatment
AP/BC
7
6
4.8
5
4
3.3
2.8
3
2
1.8
1.5
1.7
0
1.4
0.9
1
1
2
3
0.8
4
0.5
5
0.3
0
6
1.3
0
7
0.4
8
Year
•
•
•
Overall survival 86%; event-free survival 81%; CCyR rate 82%
8% progressed to AP/BC; only 3% of those with CCyR
MMR rates and depth of molecular responses increased over time
Deininger et al. ASH 2009. Abs # 1126
Jurcic - Evolving Strategies for CML
Managing Myelosuppression:
Chronic Phase
ANC <1000/mm3 or
PLTs <50,000/mm3
Withhold imatinib and allow recovery to
ANC >1500/mm3 and PLTs >100,000/mm3
Normal Recovery
(2-4 weeks)
Slow Recovery
(>4 weeks)
Resume imatinib at 400mg
Resume imatinib at 300mg
Escalate imatinib to 400mg,
as long as recovery continues
ANC = absolute neutrophil count; PLTs = platelets.
Deininger MWN et al. JCO 2003:1637-1647.
Management of Non-Hematological
Side Effects
Liver function tests
• Interrupt treatment for grade 3/4
• Resume at reduced dose when LFTs
normalize
• Escalate after 6–12 wks as tolerated
• Avoid acetaminophen
Skin rash
• Generally mild
• Treat with antihistamines, topical
steroids
• Systemic steroids for severe rash
GI upset, nausea, vomiting, diarrhea
• Take dose with a meal and water
• Take at least 2 hours before bedtime
• Use anti-emetics for severe nausea
Edema/fluid retention
• Mild (generally periorbital):
̶ Limit salt intake
̶ Use diuretics and topical steroids
• Severe (pulmonary edema, effusions):
̶ Diuretics
̶ Dose reduction/interruption
Muscle cramps/bone pain/arthralgias
• Ca2+ supplements
• Non-steroidal anti-inflammatory drugs
(NSAIDs)
Deininger MWN et al. JCO 2003:1637-1647.
Monitoring on TKI Therapy
Marrow Cytogenetics
BCR-ABL PCR
Diagnosis
Baseline
Baseline
Treatment
response
6 & 12 mos., 18
months if no CCyR at
12 mos.
Every 3 mos.
CCyR
If clinically indicated
Every 3 mos. × 3
yrs, then every 3-6
mos.
↑ing BCR-ABL ABL kinase mutation
transcripts
analysis if no MMR
Repeat in 1-3 mos.
if MMR
Hughes T et al. Blood 2006; 108:28-37.
101
Second Generation TKIs for CML
Dasatinib1
Nilotinib2
• ABL/SCR kinase inhibitor
• Binds active and inactive
conformations of ABL
• Inhibits all ABL mutations
except T315I
• Toxicities:
–
–
–
–
–
• Competitively inhibits ATPbinding site of BCR-ABL
• Higher binding affinity and
selectivity than imatinib
• Inhibits all ABL mutations
except T315I
• Toxicities:
Myelosuppression (55%)
Pleural effusions (18%)
Edema (19%)
Diarrhea (23%)
LFT abnormalities (8%)
–
–
–
–
–
• Response:
• CHR, 92%
• CCyR, 35%
Myelosuppression (25%)
Rash (22%)
N/V (13%)
LFT abnormalities (6%)
QT prolongation & sudden
death (<0.5%)
• Response:
• CHR, 92%
• CCyR, 35%
1Talpaz
M et al. NEJM 2006; 354:2531-2541.
2Kantarjian H et al. NEJM 2006; 354:2542-2551.
When to Consider a 2nd Generation TKI
Optimal
Suboptimal
Failure
3 months
CHR and minor
CyR (Ph+ ≤ 65%)
No CyR (Ph+ >
95%)
Less than CHR
6 months
At least PCyR
(Ph+ ≤ 35%)
Less than PCyR
(Ph+ > 35%)
No CyR (Ph+ >
95%)
12 months
CCyR
PCyR (Ph+ 1–
35%)
Less than PCyR
(Ph+ > 35%)
18 months
MMR
Less than MMR
Less than CCyR
At any time
Stable or
improving MMR
Loss of MMR;
mutations
Loss of CHR, loss
of CCyR,
mutations
CHR, complete hematologic response; CCyR, complete cytogenetic response;
PCyR, partial cytogenetic response; MMR, major molecular response.
Baccarani M et al. JCO 2009; 27:6041-6051.
Relative Sensitivity of Mutations
IC50 (GI50) in Ba/F3 Cells
WT
L248V
G250E
Q252H
Y253F
E255K
E255V
D276G
E279K
V299L
T315I
F317L
M351T
F359V
L384M
H396P
H396R
G398R
F486S
IM
527
1866
3613
733.6
1888
3174
8953
1147
1872
813.7
9221
1370
926.6
1509
674.4
1280
2058
185.4
4267
DA
1.83
9.36
8.14
5.59
2.89
10.26
6.3
2.63
3
15.83
137.3
8.16
1.61
2.73
4.04
1.95
2.98
1.27
5.56
Nil
17.69
49.48
80.67
46.75
57.16
118.4
182.3
35.32
36.25
23.74
697.1
39.19
7.804
91.29
41.18
42.65
54.83
8.743
32.79
BO
41.61
147.4
179.2
33.67
40
394
230.1
25
39.7
1086
1890
100.7
29.09
38.59
19.54
18.07
33.65
48.13
96.13
IC50 (GI50) Fold Increase (WT = 1)
WT
L248V
G250E
Q252H
Y253F
E255K
E255V
D276G
E279K
V299L
T315I
F317L
M351T
F359V
L384M
H396P
H396R
G398R
F486S
IM
1
3.54
6.86
1.39
3.58
6.02
16.99
2.18
3.55
1.54
17.50
2.60
1.76
2.86
1.28
2.43
3.91
0.35
8.10
DA
1
5.11
4.45
3.05
1.58
5.61
3.44
1.44
1.64
8.65
75.03
4.46
0.88
1.49
2.21
1.07
1.63
0.69
3.04
Nil
1
2.80
4.56
2.64
3.23
6.69
10.31
2.00
2.05
1.34
39.41
2.22
0.44
5.16
2.33
2.41
3.10
0.49
1.85
BO
1
3.54
4.31
0.81
0.96
9.47
5.53
0.60
0.95
26.10
45.42
2.42
0.70
0.93
0.47
0.43
0.81
1.16
2.31
IM = imatinib
DA = dasatinib
Nil = nilotinib
BO = bosutinib
Sensitive
Mod. resistant
Resistant
Highly resistant
<2
2.01–4
4.01–10
> 10
Radaelli S et al. J Clin Oncol. 2009;27(3):469-471.
Laneuville P et al. Blood 2009;114(22):211. Abs # 510.
Jurcic - Evolving Strategies for CML
Study Design and Endpoints
R
A
N
D
O
M
I
Z
E
D
*
• N = 846
• 217 centers
• 35 countries
*Stratification
by Sokal risk
score
Nilotinib 300 mg BID (n=282)
Nilotinib 400 mg BID (n=281)
Imatinib 400 mg QD (n=283)
Follow-up 5 years
Endpoints
Description
Primary
MMR at 12 mos.
Secondary
CCyR at 12 mos.
Other
Time to and duration of MMR & CCyR, EFS, PFS,
time to AP/BC and OS
Saglio G et al. NEJM 2010; 362:2251- 2259.
CCyR Rates by 12 Months and Overall
P < .001
P < .0001
P = .017
% CCyR
P < .001
n = 282 n = 281
n = 283
n = 282
n = 281 n = 283
Larson RA et al. ASCO 2010; Abstract 6501.
MMR Rates Over Time (ITT)
p<0.0001
p<0.0001
n = 282
n = 281
n = 283
n = 178
n = 175
n = 172
n = 47
n = 48
n = 48
Larson RA et al. ASCO 2010; Abstract 6501.
103
Progression to AP/BC
on Study Treatment
20
Number of Patients
P = .006
P = .003
15
12
4.2%
10
5
0
2
1
0.7%
0.4%
Median follow-up 18.5 months
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
Larson RA et al. ASCO 2010; Abstract 6501.
Dasatinib vs. Imatinib: 18-Month Data
P = .0366
P = .0002
Kantarjian H et al. NEJM 2010; 362:2260-2270.
Shah N et al. Blood 2010; 116: Abstract 206.
Bosutinib for Imatinib-Resistant or
Intolerant CP-CML
• Dual inhibitor of SRC and ABL
• Minimal inhibition of c-KIT and PDGFR
• Total sample size: 288 patients with CP-CML
− Imatinib-resistant, n=200
− Imatinib-intolerant, n=88
• Median follow-up duration: 24.2 months
• Endpoints
− Primary: MCyR rate at 24 weeks
− Secondary: Response rate, duration of response,
PFS, OS, safety
Cortes JE et al. Blood 2011; 118:4567-4576.
Jurcic - Evolving Strategies for CML
Bosutinib: Phase II Results
Bosutinib 500 mg/daily
(N=288)
Parameter
24-week MCyR (1o endpoint)
31%
CHR
86%
MCyR
53%
12.3 weeks
Median time to MCyR
CCyR
41%
MMR (for patients in CCyR, n=78)
64%
CMR (for patients in CCyR, n=78)
53%
2-yr PFS
79%
2-yr OS
92%
Cortes JE et al. Blood 2011; 118:4567-4576.
Bosutinib after Imatinib and 2nd
Generation TKI Failure
% Responding
(n=118)
CHR
73
MCyR
32
CCyR
24
2-year PFS
73
2-year OS
83
Khoury HJ et al. Blood 2012;119:3403-3412.
Phase I Trial of Ponatinib
• Pan-BCR-ABL inhibitor, active against native
enzyme and all resistant mutants, including T315I
• Dose cohorts: 2–60 mg orally once daily
− Intra-patient dose escalation permitted
• Total sample size: 81 patients
− CP-CML, n=43; AP-CML, n=9; BP-CML, n=8; Ph+ ALL,
n=5; AML, n=12; Other, n=4
• Recommended phase II dose: 45 mg daily
− DLT’s: rash, pancreatitis
• CCyR seen in 75% of patients with T315I
Cortes J et al. ESH-iCMLf International Conference, Estoril, Portuga, September, 2011.
105
PACE: Phase II Study of Ponatinib
Results for CP-CML
Cortes JE et al. JCO (ASCO Meeting Proc) 2012; 30:6503.
Omacetaxine for CP-CML
with T315I
Response
No. of Patients (%)
(N=62)
CHR
48 (77)
MCyR
14 (23)
CCyR
10 (16)
Cortes JE et al. Blood 2012; 120:2573-2580.
Discontinuation of TKI’s:
The STIM Trial
• 100 patients in CMR for ≥ 2
years stopped imatinib
100
90
• 61% relapsed
80
70
• Factors predicting relapse:
− Higher Sokal score
− Imatinib therapy for < 50 mos.
− Female
60
50
40
30
20
• All patients responded to
retreatment with imatinib
10
0
• Similar results seen after
stopping dasatinib or nilotinib
0
3
6
9
12
15 18
21 24
27
Months since discontinuation of imatinib
Mahon F-X et al. Lancet Oncol 2010; 11:1029-1035.
Rea D et al. Blood (ASH Abstracts) 2011; 118:604.
Jurcic - Evolving Strategies for CML
Curing CML
• More effective agents
− Higher CMR rates
− Deeper remissions
• Eradication of LSC
− Hedgehog inhibition
− JAK/STAT inhibition
− Immunotherapeutic approaches
• Vaccines
• Anti-CTLA4 and PD-1 mAbs
Conclusions
• TKI’s have become of the standard-of-care.
• Initial therapy with imatinib, nilotinib, or dasatinib
produces durable remissions in most patients.
• Nilotinib and dasatinib can produce responses in
imatinib-intolerant and resistant patients.
• Bosutinib is approved for patients resistant to
imatinib and a 2nd generation TKI.
• New agents are under investigation for multi-TKIresistant patients, including those with T315I.
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New Horizons in Oncology: How Biology Will Change the
Course of Treatment and Survivorship
Robert J. Arceci, M.D., Ph.D.
King Fahd Professor of Pediatric Oncology
Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate
Program
Kimmel Comprehensive Cancer Center at Johns Hopkins
Current Report Card
The initiation and expansion of the “war on cancer” in the US began in the early 1970s
with an infusion of government support that was essential to fuel the development of
clinical cooperative groups, drug screening programs, specialty training, and
comprehensive cancer centers with a focus on research, clinical trials and prevention.
Efforts in other developed countries also contributed significantly to these developments.
On the success side of this ledger is the commonly referred to achievement of pediatric
oncology in increasing the overall cure rate of children with cancer to approximately 80%
with decreases in mortality of about 2% per year over the past three decades. Significant
gains have also been achieved for adults with specific subtypes of cancer. Work in
pediatric cancers has been able to place first claims on the biological underpinnings of
cancer with the development of the “two hit” hypothesis as well as the identification of
the retinoblastoma gene, Rb, as the first tumor suppressor gene. Such discoveries have
had a broad impact on clinical and laboratory investigators in both pediatric and medical
oncology.
A far greater percentage of children compared to adults are enrolled on experimental
clinical trials. Pediatric oncology care is nearly always multidisciplinary in its planning
and execution, thus increasing the critically important integration and timing of surgical,
radiotherapy and chemotherapy aspects of care. In addition, pediatric oncology has been
a pioneer in developing rigorous, preemptive supportive care to reduce morbidity and
mortality. There has also been an enormous amount of effective creativity in optimally
using old drugs in new ways, because very few new drugs have been developed with
specific indications first in pediatric cancers. In this regard, the use of established drugs
along with the standardized approaches to care have made the cost associated with curing
children with cancer quite a bargain, especially when considered in terms of cost per life
years saved. Furthermore, as a result of these successes and children surviving their
original cancers, pediatric oncology has been instrumental in identifying adverse late
effects and survivorship issues. On the other side of this coin is the pioneering work that
has been done in terms of palliative care and psychosocial support for patients with
cancer and their families.
There are also areas in which our report card may claim less success. We still have not
determined in detail the cause and sequence of molecular events leading to or
characterizing childhood cancers, including interactions with environmental and host risk
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factors. We have been slow in definitively testing novel approaches to care and
incorporating them into standard therapy regimens leading to the reduction of
conventional chemotherapy and radiation exposures. While some exceptions certainly
exist, such as in Hodgkin lymphoma, risk stratified care in leukemia and central nervous
system tumors, there are major areas in which much more progress is needed.
In developed countries, cancer remains the major cause of disease related death in
children and second only to accidents as an overall cause of death. Thus, a significant
percentage of children are still not cured of their cancer, and in those who are cured, there
are considerable short and long term adverse sequelae to face. The cure rate has also
shown signs of decreasing. There has furthermore been the identification of underserved
groups, such as adolescents in all settings as well as children of all ages in developing
countries. The success of some of the “twinning programs” has been laudatory but
represents just a beginning. We have not been able to affect comprehensive health care
coverage for patients with cancer or the survivors of their cancers. We have done little in
the way of prevention, which may tie into the issue of improving our understanding of the
causes of childhood cancer.
Thus, we have had excellent grades in several specific areas but average to failing grades
in other areas. To successfully finish the goal of eradicating the burden of cancer for
patients of all ages, we need to look to the future with a renewed cooperative and
expanded resolve.
How to finish the job
The first principles for achieving the eradication of the burden of cancer include
believing that it can be done, freeing ourselves from reliance on non-paradigm shifting
concepts and working globally with all stakeholders.
A critical challenge in pediatric and medical oncology is how to identify and cure
children with very high-risk cancers. Giving first priority to this challenge is not meant to
undermine the need for efforts to develop less toxic therapies for all patients. However,
patients with high-risk cancers have a poor outcome regardless of the therapeutic
approaches used. Thus, there must be an increasing emphasis on improving our
understanding of the biology of these disorders, including their mechanisms of resistance
as well as the critical survival pathways upon which they depend. Technological
approaches to generate detailed and comprehensive molecular changes that define
physiological behavior of the bulk as well as the tumor-initiating stem cells in such
cancers are essential. Such technologies are nearly all currently available; although more
robust bioinformatic approaches are being developed integrate such complex datasets into
predictive models of cell behavior and response to therapies. This type of biology does
not come cheaply. A comprehensive, integrated and adequately supported approach is
needed.
There also needs to be bold, paradigm-shifting approaches to the translation of new
knowledge into clinical trials for patients with high risk cancers. This point leads to
another significant challenge for the future, i.e., how to perform informative clinical trials
in distinct groups of patients with tumors with extensive heterogeneity. Advances in
molecular and genetic medicine have revealed that the genetic makeup of patients from
different racial backgrounds, of different gender, of different ages and of varied
socioeconomic circumstances can have profound effects on outcomes. The differences in
some instances are due to variations in the absorption and metabolism of drugs. The
problems of obesity and malnutrition and their impact on cancer etiology and outcomes
need to also be carefully studied.
An important consequence of such detailed delineation of different types of cancer and of
patients is the recognition of the extraordinary heterogeneity that exists. One logical
conclusion to be made from such information is that future clinical trials could have
cohorts with an N of 1. Obviously, this would undermine the ability to perform
informative clinical trials for determining efficacy of a new treatment. Alternative
approaches will therefore need to be carefully considered. Certainly, one aspect of a
solution will be the increasing dependence on international trials balanced by the
identification and targeting of critical genetic or molecular pathways that are shared by
groups of patients.
There are, of course, many regulatory handcuffs that currently slow down and prevent the
development, performance and reporting of clinical trials. These regulatory impediments
are local, regional, national and international. They involve exchanging tissue specimens
and data as well as the cost of clinical care and trial participation, differences in informed
consent as well as data collection and reporting standards.
An alternative approach that could also aid in drug testing is development of more
predictive preclinical models. This point brings up an enormous challenge in developing
more effective therapies. Randomized clinical trials in pediatric oncology have shown
that, over the past several decades, investigators have not been able to consistently
predict whether a new therapy will result in an improved outcome. For instance, over the
past 40 years, the introduction of new therapies has resulted in improvements (often with
increased toxicity), in about 50% of randomized trials. While this inability to predict
outcome in such trials leads to ethical equipoise, and thus, an acceptable and comfortable
paradigm for clinical investigators, a less optimistic view might be that we are quite poor
in predicting which new therapies will work.
More representative and predictive animal models should be generated with a rigorous
characterization of various human cancers as well as the acknowledgement that
genetically homogenous host animals and tumors resulting from introduced alterations in
one or two molecular pathways are unlikely to be optimal approaches. However, it is
presently unclear how to build models with underlying genetic and epigenetic
heterogeneity and instability, two fundamentally important characteristics of human
cancers.
In this regard, one might consider the utility of xenograft models.
Unfortunately, they also have significant limitations in their ability to maintain
representative genotypes, gene expression patterns and phenotypes. How we utilize the
tools of molecular medicine to improve our understanding of cancer and the patients who
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develop it will greatly impact on whether we turn this opportunity into a success leading
to improved patient outcomes. To this end, one should be able to envision the eventual
development of computer models that encompass all the host and tumor critical
characteristics such that the most effective therapy can be initiated and the response
predicted from a rapid in silico modeling program.
The issue of the quality of survivorship for many children and adolescents with cancer is
also a critical challenge. The results from a recent study of over 10,000 childhood cancer
survivors demonstrated a significantly increased risk of having chronic health care
problems as well as shortened lifespans compared to their siblings. The suggestion has
been made that the problems of the past have not been subsequently repeated and that
future generations of survivors will enjoy improved health, psychosocial and societal
opportunities. There is, of course, no guarantee that this will be the case. The 1980s and
1990s have often been characterized as the decades of dose intensification, suggesting
that there may still be significant adverse long-term sequelae awaiting this group of
survivors. In either case, there remains a growing need to understand the genetic
predisposing factors leading to increased responsiveness to chemotherapy as well as short
and long-term toxicities. Understanding genetic, predisposing factors leading to
increased responsiveness to chemotherapy as well as short and long-term toxicities will
be essential to developing effective, alternative strategies.
The best way to prevent adverse long-term sequelae from cancer and/or its treatment is to
prevent the development of cancer. While prevention efforts have become increasingly
important in a wide variety of cancers in adults, such as those of the colon, lung and
breast, the concept of prevention for pediatric cancers has been usually viewed
unenthusiastically or as, at best, unrealistic. However, success with vaccination programs
such as those against papilloma virus and its link to cervical cancer or hepatitis B and
liver cancers should provide renewed hope for such approaches.
While these biological and clinical challenges are immense, they unfortunately do not
compare in magnitude with the challenge of eradicating health care disparities and access
to care for all and all patients with cancer and other catastrophic diseases. This is an
issue for local, state, national, and global action. The means to provide such care is
within the reach of our civilization and should be an issue around which people from all
backgrounds can work together to implement solutions.
Some Parting Shots
Addressing challenges as immense as these will take comparable levels of imagination,
focus and support. Resources currently allotted for the purpose remain insufficient.
Inadequate funding of science and health care short changes current and future
generations, while being a particularly poor business strategy. There should be a “global
comprehensive cancer center” that integrates some of the scientific and clinical solutions
discussed above. There seems to be no real advantage for having unnecessary regulations
that differ among institutions, regions and countries when the goals are identical. There
are times when I wonder whether the system we have was the brainchild of the galactic
beaurocrats, the Vogons, from Douglas Adams’s Hitchhikers’s Guide to the Galaxy, who
would rather develop and discuss rules and regulations rather than real solutions. But
alas, we are those Vogons, i.e., we and the people in our institutions as well as those who
represent us in government. There should be a global cry of dissatisfaction with such a
status quo that in turn is translated into an action plan at all levels of engagement.
As part of such a “global comprehensive cancer center” one could build on some of the
successes of international trials and expand the utility of internet posting of protocols that
are straightforward, including consents, data collection and reporting. All of this can be
done electronically through internet computer or cell phone technology from nearly
anywhere. Similarly, reminders of data to be collected, etc., could be linked through
internet and cell phone technologies. Systems exist to assure the integrity and
confidentiality of data. There seems to be little reason why a child’s privacy and wellbeing should be handled differently in the US compared to other countries.
The expansion of the “twinning programs” approach is likely to continue to make a
positive impact for children with cancer in developing countries. Standard approaches to
diagnosis, clinical trials and reporting of data and outcomes as noted above would also
benefit such programs by minimizing the need to reinvent such programmatic parts with
each initiative. Such programs can also help to establish and provide standards of
culturally sensitive treatment, survivorship and palliative care.
Advocacy efforts need to be broadened to take on more global goals and organization.
Such efforts should also possibly linked to the care of children with other serious diseases
not only cancer. While support would ideally be channeled locally, there is also an
opportunity for some of the wealthier countries and organizations helping to support less
wealthy programs as is already being pioneered by several groups.
The integration of currently available and developing technologies with organizations
changes and renewed resources should provide both more effective and less toxic
curative therapies to be tested and then incorporated into standards of care. The
beneficiaries of these efforts will be patients with cancer and their families in developed
and in developing countries.
Mark Twain stated that “Twenty years from now you will be more disappointed by the
things that you didn’t do than by the ones you did do.” We should not look with regret
and disappointment for the things we didn’t do, but instead, be galvanized and unified by
what can be accomplished.
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