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How do we best deploy novel agents for T cell lymphoma – what have we learned from key clinical trials ? : Should they be employed upfront?
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How do we best deploy novel agents for T cell lymphoma – what have we learned from key clinical trials ? : Should they be employed upfront?
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This slide deck is made available for patients/caregivers. It is not a substitute for seeking medical help. Please check original sources listed in the deck and consult your physician for the latest information and advice.
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Learning objectives:
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1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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Oncology 101 2013
1. The following material is intended for MSKCC internal medicine housestaff teaching
purposes only. The slides were updated for the LibGuide in 2012-2013.
3. Overall U.S. Cancer Stats
The U.S. population:
SEER database (Surveillance, Epidemiology and End
Results):
National Cancer Institute database tabulating cancer
incidence and mortality figures from 17 sites around the
country
4. Overall U.S. Cancer Stats
Based on SEER database (Surveillance,
Epidemiology and End Results)
How many NEW cancer cases in the U.S. expected
for 2010?
*not including CIS except bladder and basal cell and squamous cell skin cancers
1.6 million American Cancer Society, Cancer Facts and Figures, 2012
How many cancer deaths in the U.S. expected for
2010?
577,190 (about 1,500/day; 1 in 4 deaths) American Cancer Society,
Cancer Facts and Figures, 2012
5. Who is at “risk”?
Everyone
Most significant risk factor: AGE
78% all cancers > 55 years
Lifetime risk
Men: ~ 1 in 2 (45% risk)
Women: ~ 1 in 3 (37% risk)
Relative Risk (RR)
lung CA in male smokers – RR is 23
Breast CA in women w 1st degree relative – RR is 2
What is the Cost?
NIH estimates: Total $ 263.8 billion in 2010
6. Cancer Epidemiology
Name the four most common cancers in the
overall U.S. population
1. PROSTATE
2. BREAST
3. LUNG
4. COLON
Name the four leading cancers with the
highest mortality in the overall U.S. population
1. LUNG
2. COLON
3. BREAST
4. PANCREAS
11. Cancer Death Rates by
Race/Ethnicity (2003-2008)
American Cancer Society, Cancer Facts & Figures 2012
12. Cancer Deaths Avoided in Men
and Women from 1991-2008
American Cancer Society, Cancer Facts & Figures 2012
13. Global Cancer Stats
Source: Globocan 2008, IARC
7.6 million deaths in 2008
What Types of Cancer Cause the Greatest
Number of Deaths Worldwide?
1. Lung cancer: 1.4 million deaths
2. Gastric cancer: 740,000 deaths
3. Liver cancer: 700,000 deaths
4. Colorectal cancer: 610,000 deaths
5. Breast cancer: 460,000 deaths
16. What makes a tumor
malignant?
Hanahan & Weinberg. Cell, Vol. 100, 57–70, January 7, 2000
Multiple cumulative mutational events are required for
the progression from normal to malignant phenotype.
At each successive step, mutated cells gain a growth
advantage.
19. Definitions
Oncogene: a gene which, upon being
activated through gain-of-function
mutation or over-expression, promotes
replication or tissue invasion
Growth factors
Transcription factors
Receptor tyrosine kinases
Proteins involved in cell cycle
20. Definitions
Tumor Suppressor
Gene:
a gene which, upon being
inactivated through loss-
of-function mutation or
under-expression, leads to
cell growth
Proteins which restrict cell
growth
Proteins which promote
apoptosis
21. Genetic mutations and
chromosomal abnormalities
Point mutations
Insertions / deletions
Microsatellite instability
Epigenetic changes (e.g. methylation)
Telomere lengthening
Loss of DNA repair genes accelerate the
above changes
22. Tumor Classifications
Essentially, any cell type in the body can
become cancerous.
Depending on lineage, a malignant cell
will have certain morphology, staining
characteristics on
immunohistochemistry, and will be
classified accordingly.
26. Getting a biopsy sample
Types
FNA
Often insufficient;
○ No tissue architecture
○ Limited sample size
Core biopsy
Incisional/Excisional biopsy
Choose your site wisely
Sampling the lymph node or presumed metastatic site can
give both diagnosis and staging information at the same
time
Safety, accessibility are always key concerns
27. How we analyze the biopsy
Tissue level:
architecture; invasion
Cellular level:
histology / morphology
Immunohistochemistry
○ Expression of
proteins, receptors,
etc.
surface (CD) markers
(flow cytometry)
Chromosomal level:
Karyotyping
Translocations (FISH)
Genetic level:
PCR
28. Karyotyping
Performed during metaphase, when chromosomes are easily
seen
Used often in lymphomas and leukemias
www.pathology.washington.edu
31. Flow Cytometry
How Flow Cytometry Works
Lymphomas are
classified by cell
differentiation
markers (CD)
○ CD 2, 3, 4, 7, 8:
T-Cells
○ CD 19/20: B-cells
○ CD 34: Stem
Cells
32. Polymerase Chain Reaction
(PCR)
Analyze for specific mutations
May have prognostic implications
○ AML: FLT3, NMP1
May identify therapeutic targets
○ NSCLC: EGFR
33. Microarray
Used for Oncotype Dx
Level of fluorescence denotes level of
expression compared to control sample http://www.eye-research.org
Adapted from Universitäts-Augenklinik Mainz, Experimentelle Ophthalmologie, Leitung: PD Dr. Dr. F. Grus
35. Concepts in Staging: Solid
tumors
Solid tumors primarily use a TNM system
T = Tumor size and invasion into nearby structures
N = Lymph node involvement
M = Presence of metastasis
There are variations on this system
Some use tumor markers (serum markers) as part of
staging
○ Testicular cancer
○ Melanoma
36. Concepts in Staging
cT1N2M0
pT1N2M0
yT1N0M0
c: stage given by clinical
examination of a patient.
p: stage given by pathologic
examination of a surgical
specimen.
y: stage assessed after
neoadjuvant therapy.
37. Prognosticating Cancers
Staging (T,N,M)
Prognostic Tools
IPI for diffuse large B-cell lymphoma
Adjuvant! Online for breast cancer
Performance Status
39. Prognostic or Predictive
Prognostic Biomarkers:
Predictive Biomarkers:
Stratifies patients based on risk of an outcome
(recurrence, overall survival) independent of
treatment
• e.g. abnormal LDH in lymphoma
Stratifies patients based on response to specific
treatment regimen
• e.g. Hormone receptor profiling in Breast Cancer
40. Ann Arbor Staging System for
Hodgkin's Disease and Non-
Hodgkin's Lymphoma
Stage I Stage II Stage III Stage IV
• A: Absences of symptoms
• B: B symptoms
• E: Extranodal extension
Adapted from Skarin. Dana-Farber Cancer
Institute Atlas of Diagnostic Oncology. 1991;
with permission.
41. IPI and DLBCL
Sehn L H et al. Blood 2007;109:1857-1861
For diffuse large B cell lymphoma treated
with CHOP:
0, 1 factor = low risk: 35% of cases; 5-
year survival, 73%
2 factors = low-intermediate risk: 27% of cases; 5-
year survival, 51%
3 factors = high-intermediate risk: 22% of cases; 5-
year survival, 43%
4, 5 factors = high risk: 16% of cases; 5-
year survival, 26%
For diffuse large B cell lymphoma treated
with R-CHOP:
0 factor = very good: 10% of cases; 5-
year survival, 94%
1, 2 factors = good: 45% of cases; 5-
year survival, 79%
3, 4, 5 factors = poor: 45% of cases; 5-
year survival, 55%
•Age >60
•Elevated LDH
•ECOG ≥2
•Ann Arbor stage III
or IV
• >1 site of
extranodal
involvement
43. Types of Treatment
Surgery
e.g. Lumpectomy
Radiation (brachytherapy vs. XRT)
Chemotherapy
Adriamycin, Cytoxan, Taxol
Molecularly Targeted Therapies
Trastuzumab (herceptin)
Hormonal Therapy
Immunologic Therapy
Interferon, ipilimumab
Local Therapy
Systemic Therapy
44. Adjuvant vs. Neoadjuvant
Adjuvant Therapy:
Additional cancer treatment given after the
primary treatment to lower the risk that the
cancer will come back.
○ Goal is often to treat micrometastatic disease
for curative intent
Neoadjuvant therapy:
Treatment given as a first step to shrink a
tumor before the main treatment, which is
usually surgery, is given.
45. Salvage and Palliative Therapy
Salvage:
Treatment that is given after the cancer has
not responded to other treatments.
Palliative:
Treatment given to relieve the symptoms
and reduce the suffering caused by cancer
and other life-threatening diseases.
52. RECIST- Response Evaluation
Criteria in Solid Tumors
Complete Response (CR)
No radiographic and no pathologic evidence of disease
Partial Response (PR)
30% decrease in sums of longest diameters of lesions
(unidimensional)
Progression of Disease (POD)
20% increase in sum of diameters of target lesions and an
absolute increase of at least 5 mm.
○ Note: the appearance of one or more new lesions is also
considered progression
Stable Disease (SD)
any tumor shrinkage or growth that does NOT meet above criteria
Note: Hematologic Malignancies have own scales
53. Understanding Clinical
Research: Survival Outcomes
Progression-free survival (PFS): length of
time during and after treatment in which a
patient with cancer does not get worse
Disease-free survival (DFS): length of time
during and after treatment in which a
patient survives without evidence of
disease
Overall survival (OS)
54. Dr. Bosl’s Four Principles of
Oncology
1. It’s not cancer until proven to be cancer.
2. It’s curable until proven otherwise.
3. It’s treatable until proven otherwise.
4. Even if the cancer isn’t treatable, the patient
is always treatable.
Editor's Notes
There is no national cancer registry, so incidence is from NCI’s SEER database which tabulates cancer incidence and death figures from 17 sites (26% population) and from population data from U.S. Census Bureau
There is no national cancer registry, so incidence is from NCI’s SEER database which tabulates cancer incidence and death figures from 17 sites (26% population) and from population data from U.S. Census Bureau
Lifetime risk: prob that a person will develop or die from cancerRelative risk: compares risk of cancer with exposure/trait to risk of cancer without characteristic
Lung ProstateBreastColonLung ColonBreastPancreas
-This chart is for ages 40 years and older-Overall, cancer incidence has been declining by 2% each year since 1992-2nd leading cause of death behind heart disease, but in patients over 85 years old – number 1 cause of death is CANCER-in those younger than 40 – leukemia is #1 cause of cancer death.
-This chart is for ages 40 years and older-Note that the overall incidence is highest in lung/bronchus, accounting for 29% (15% in men and 14% in women) but specifically for men it is prostate and women breast.-Overall, cancer incidence has been declining by 2% each year since 1992-2nd leading cause of death behind heart disease, but in patients over 85 years old – number 1 cause of death is CANCER-in those younger than 40 – leukemia is #1 cause of cancer death.
-This chart is for ages 40 years and older-Note that the overall incidence is highest in lung/bronchus, accounting for 29% (15% in men and 14% in women) but specifically for men it is prostate and women breast.-Overall, cancer incidence has been declining by 2% each year since 1992-2nd leading cause of death behind heart disease, but in patients over 85 years old – number 1 cause of death is CANCER-in those younger than 40 – leukemia is #1 cause of cancer death.
Incidence for all sites is highest in africanamerican males
In 2002,11 million new cancer cases and 7 million cancer deaths world widenow up to 12 million-45% in asia, 26% europe, 14.5% NA, 7% central/south ameria, 6% africa, 1% australia/New Zealand-Lung cancer is most common cancer in world, breast is second -Cancer death in the world: 1)lung, 2)stomach, 3)liver, 4)colon 5)breast
Neoplasia: abnormal proliferation of cells This may be benign, pre-malignant or malignant.Hyperplasia: excessive rate of cell division, but normal architecture & functionMetaplasia: replacement of one differentiated cell type by anotherDysplasia: loss of normal cell maturation, structure & functionAnaplasia: de-differentiation
You need only ONE copy of a mutated oncogene for the phenotype
Microsatellite instability = long stretches of short nucleotide repeats. They are prone to errors in replications, and may result in frame shifts or changes in promotor regions
Red = upregulationGreen = downregulationBlack = constituent expression