Transcript BMED1300_A_Potter_Problem_1

Future Strategy for
Pancreatic Cancer Screening
presenters: Grant Stearns, Robert Joung
facilitator:
Dr. Steve Potter
The Problem
• A current screening strategy that diagnoses pancreatic
cancer at a stage that offers resectability and treatment
(pre-stage 2) is needed.
• An accurate non-invasive technique is needed to justify
more invasive techniques.
• Maintain specificity while increasing sensitivity.
AUC above 0.9 is considered highly accurate.
Analytic Methods
• Researched Current Screening Methods.
• Analyzed Current Screening Methods. (ROC Curves)
• Researched Future Strategies.
• Chose Future Strategy and Created Layout for Future
Strategy.
• Created Additive Value Model Risk Assessment Worksheet.
• Refined Future Strategy.
Future Strategy Template
[Iacobuzio-Donahue, C. A., S. Yachida, et al. 2010.]
Bob is an obese 52 year-old black
male who has had chronic
pancreatitis for less than two years
and who also has one immediate
family member that developed
pancreatic cancer.
Bob has 45 points on the Risk
Assessment.
This makes Bob a High Risk patient.
Why biomarkers?
• Many methods of testing
Reverse Phase Protein Array
(RPPA)
o Luminex Assays
o Forward phase or antibody
array
o Multiplexed Bead Assays
o
• Decreasing cost
• Mass diagnosis
• Good ROC values
[Li, C. et al. 2011] [Grote, T. et al. 2008] [http://www.oasiswebdevelopment.com/newrpci/services/multiplex.html]
[Ryozawa, S., H. Iwano, et al. 2011] [http://www.mcponline.org/content/4/4/346.full]
Biomarker Panels Comparison
Biomarker Panel 1
[Hoimes, C. et al. 2009] [Farrell, J. et al. 2009]
Biomarker Panel 2
Step 2: Selected Biomarker Panel
• Combination of 3 mRNA
biomarkers (ACVR1,
DMXL2, DPM1)
• Addition of a bacterial
biomarker (S. Mitis) to the
panel
• Differentiate between
pancreatic cancer patients
and all others
• Differentiates between
subjects with pancreatic
cancer, chronic
pancreatitis, and healthy
controls
• Sensitivity of 93% and
Specificity of 90%
• Sensitivity of 93% and a
Specificity of 85%
[Hoimes, C. et al. 2009]
Invasive Techniques Comparison
[Glasbrenner, B. 2000.] [Kitano, M. 2011.] [Grenacher, L. 2004.] [Li, K. C. 1988] [Pennant, M. 2010.]
Invasive Techniques Comparison
CT
Sensitivity: 94.76%
Specificity: 89.165%
AUC: 0.9196
EUS
Sensitivity: 80.738%
Specificity: 89.119%
AUC: 0.85
EUS - ERCP
Sensitivity: 92%
Specificity: 85%
AUC: 0.885
EUS - FNA
Sensitivity: 86.5%
Specificity: 87.5%
AUC: 0.87
MRI
Sensitivity: 89.375%
Specificity: 86.725%
AUC: 0.8805
PET
Sensitivity: 89.5%
Specificity: 91.5%
AUC: 0.905
[Glasbrenner, B. 2000.] [Kitano, M. 2011.] [Grenacher, L. 2004.] [Li, K. C. 1988] [Pennant, M. 2010.]
Selected Invasive Technique
EUS guided FNA
• Advantages
o SN of 86.5%
o SE of 87.5%
o AUC of 0.87
• Cost
o $2,440-$3,300
• Access
• Risk
[Glasbrenner,B. et al ; Kitano, M. et al.] [Ashida, R., Y. Arisaka, et al. 2011]
[Ryozawa, S., H. Iwano, et al. 2011] [ Powis,M. et al. 2000.]
Recommendations
• Incorporate the use of the AVM Risk Assessment Sheet to
determine the risk level of a patient.
• Incorporate the use of the salivary biomarker panel to
further assess the overall risk of a patient post-risk
assessment.
• Incorporate the use of EUS-FNA, after a positive biomarker
test, specifically to stage and identify the location of
pre-stage 2 pancreatic cancer.
Citations
Hassan, M. M., Bondy, M. L., Wolff, R. A., Abbruzzese, J. L., Vauthey, J.-N., Pisters, P. W., . . . Li, D. (2007). Risk factors for
pancreatic cancer: case-control study. The American Journal Of Gastroenterology, 102(12), 2696-2707.
Zavoral, M., Minarikova, P., Zavada, F., Salek, C., & Minarik, M. (2011). Molecular biology of pancreatic cancer. World Journal Of
Gastroenterology: WJG, 17(24), 2897-2908.
Institute, N. C. (2011). SEER Stat Fact Sheets: Pancreas Retrieved September 11, 2011, from
http://seer.cancer.gov/statfacts/html/pancreas.html
B. Glasbrenner, M. Schwarz, S. Pauls, G. Preclik, H. G. Beger, and G. Adler, "Prospective comparison of endoscopic ultrasound
and endoscopic retrograde cholangiopancreatography in the preoperative assessment of masses in the pancreatic head," Digestive
Surgery, vol. 17, pp. 468-474, 2000.
Kitano, M., Sakamoto, H., Komaki, T., & Kudo, M. (2011). New techniques and future perspective of EUS for the differential
diagnosis of pancreatic malignancies: contrast harmonic imaging. Digestive Endoscopy: Official Journal Of The Japan
Gastroenterological Endoscopy Society, 23 Suppl 1, 46-50. doi: 10.1111/j.1443-1661.2011.01146.x
Grenacher, L., Klauss, M., Dukic, L., Delorme, S., Knaebel, H. P., Düx, M., . . . Richter, G. M. (2004). [Diagnosis and staging of
pancreatic carcinoma: MRI versus multislice-CT -- a prospective study]. Röfo: Fortschritte Auf Dem Gebiete Der Röntgenstrahlen
Und Der Nuklearmedizin, 176(11), 1624-1633.
Li, K. C., & Poon, P. Y. (1988). Sensitivity and specificity of MRI in detecting malignant spinal cord compression and in
distinguishing malignant from benign compression fractures of vertebrae. Magnetic Resonance Imaging, 6(5), 547-556.
Pennant, M., Takwoingi, Y., Pennant, L., Davenport, C., Fry-Smith, A., Eisinga, A., . . . Hyde, C. (2010). A systematic review of
positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast
cancer recurrence. Health Technology Assessment (Winchester, England), 14(50), 1-103.
Ashida, R., Y. Arisaka, et al. (2011). "The role of linear array EUS for diagnosis of pancreatic malignancies in the current situation."
Digestive Endoscopy: Official Journal Of The Japan Gastroenterological Endoscopy Society 23 Suppl 1: 12-16.
Ryozawa, S., H. Iwano, et al. (2011). "Genetic diagnosis of pancreatic cancer using specimens obtained by EUS-FNA." Digestive
Endoscopy: Official Journal Of The Japan Gastroenterological Endoscopy Society 23 Suppl 1: 43-45. Kapke, G., & Stoddard, J. J.
(2008). Biomarkers – boon or bane for researchers? Retrieved September 14, 2011, from
http://www.covancecareers.com/biomarkers/pdf/boonorbane.pdf
Chang, M. E. P. a. K. J. (2000). Endoscopic Ultrasound in the Clinical Staging and Management of Pancreatic Cancer: Its Impact on
Cost of Treatment. CANCER CONTROL: JOURNAL OF THE MOFFITT CANCER CENTER, 7(5).
Li, C., Zolotarevsky, E., Thompson, I., Anderson, M. A., Simeone, D. M., Casper, J. M., . . . Lubman, D. M. (2011). A multiplexed
bead assay for profiling glycosylation patterns on serum protein biomarkers of pancreatic cancer. Electrophoresis, 32(15), 20282035. doi: 10.1002/elps.201000693
Grote, T., Siwak, D. R., Fritsche, H. A., Joy, C., Mills, G. B., Simeone, D., . . . Logsdon, C. D. (2008). Validation of reverse phase
protein array for practical screening of potential biomarkers in serum and plasma: accurate detection of CA19-9 levels in pancreatic
cancer. Proteomics, 8(15), 3051-3060.
Farrell, J. J., Zhang, L., Sugimoto, M., Hirayama, A., Soga, T., Zhou, H., . . . Wong, D. T. (2009). Multiple Salivary Biomarkers for
Pancreatic Cancer Detection. [Meeting Abstract]. Gastroenterology, 136(5), A147-A147.
Iacobuzio-Donahue, C. A., S. Yachida, et al. (2010). "Distant metastasis occurs late during the genetic evolution of pancreatic
cancer." Nature 467(7319): 1114-U1126.
Hoimes, C. J., Moyer, M. T., & Saif, M. W. (2009). Biomarkers for early detection and screening in pancreatic cancer. Highlights from
the 45th ASCO annual meeting. Orlando, FL, USA. May 29-June 2, 2009. JOP: Journal Of The Pancreas, 10(4), 352-356.
Fishman, K. S. V. C. E. K. Y. L. D. (2005). Use of Reverse Phase Protein Microarrays and Reference Standard Development for
Molecular Network Analysis of Metastatic Ovarian Carcinoma. Molecular and Cellular Proteomics, 346-355.
*Title slide photo credit: Adapted from Pancreatic Cancer Cell, SEM , Steve Gschmeissner /Science Photo Library
QUESTIONS
(Question) Specifics: Risk Assessment
* Family History should include pancreatic cancer as well as breast cancer and
colon cancer.
** A secondary relative is defined as a patient's aunts, uncles, and first cousins.
*** A primary relative is defined as a patient's parents, grandparents, and siblings.
**** Having an age less than 20 years puts the patient into the No Risk category,
and all other points are void.
***** A light smoker is defined as a patient who has smoked for less than 20 years.
****** A heavy smoker is defined as a patient who has smoked for more than 20
years.
[Hassan, M. M. et al. 2007] [Zavoral, M. et al. 2011],[Institute, N. C. 2011]
(Question) Risk Assessment Creation
1. Determined weighting of points with Additive Value Model.
• Rank Risk Factors1,3
• Assign point values to risk factors. Give 100 pts to Rank 1 and Rank 2 onward will decend by a value
equal to 100/ # of ranks.
• Weighting will be: ( Rank point value ) / (Sum of all points )
• Adding the weighting values should give you a value of 1.0 if done correctly.
2. The highest risk characteristic from each risk factor was assigned that risk factor's weighting multiplied by
100.
3. The lowest risk characteristic from each risk factor was assigned the value of zero. Assigning a point
value for all risk factors would make the point system less accurate and meaningful.
4. The intermediate characteristics within each risk value was assigned a point value based on NCI and
research statistics relative to the highest risk characteristic. Hypothetically, if the highest risk characteristic's
value were to be 100 points, and the statistic for that risk characteristic was 50%, then the second
characteristic whose statistical value is 25% would be assigned a value of 50 points. 2
5. The point scale was designed to set the highest possible risk at 100 points and the lowest possible risk at
0 points.
6. The Low Risk cut-off point for testing was determined to be 15 points based on the highest lowest value
that one could have with only the characteristics of gender, race, the lowest age, and one secondary relative
with a history of the relevant cancers.
7. The Low Risk/ High Risk transition point of 40 points was determined using a peer-reviewed research
article's assessments of risk levels for patients as well as an adjustment for potential under-estimation of
certain risks.
[Hassan, M. M. et al. 2007], [Zavoral, M. et al. 2011],[Institute, N. C. 2011].
(Question) How often should a patient
have a risk assessment?
First Assessment: Age 20
Future assessments should be determined by the doctor.
Guidelines:
- Re-assessment every 2 years at the least.
- If the patient has more than 10 points, there should be a reassessment at every annual checkup.
- If the patient is categorized as Low Risk and has Type-II
Diabetes or Pancreatitis, the decision of future testing should
be left to the patient's physician.
*All values based off of Risk Assessment Chart.
(Question) Stages and rates
• Less than 5% of patients survive 5 years
• In stage I, 21.5% of patients survive 5 years
• In stage II, 8.6% of patients survive 5 years
• In stages III and IV combined, 1.8% of patients survive 5 years
• In unknown stages, 4.2% of patients survive¹
• The median survival rate is between 8 and 14 months²
1National
Institute of Cancer, http://seer.cancer.gov/statfacts/html/pancreas.html
A. et Al., Induction Gemcitabine and Stereotactic Body Radiotherapy for Locally Advanced Nonmetastatic Pancreas Cancer
2Mahadevan
(Question) Stages of Pancreatic Cancer
• Stage 0: abnormal cells are found in the lining of the pancreas.
• Stage I: cancer has formed in pancreas.
-Stage Ia: The tumor is 2 cm or smaller
-Stage Ib: The tumor is larger than 2 cm
• Stage II: The cancer has spread.
-Stage IIa: The cancer had spread to nearby tissues and organs
-Stage IIb: The cancer has spread to lymph nodes
• Stage III: The cancer has spread to the major blood vessels near the
pancreas.
• Stage IV: The cancer may be of any size and may have spread to distant
organs (liver, lung and, peritoneal cavity). The cancer has metastasized.
National Institute of Cancer, http://seer.cancer.gov/statfacts/html/pancreas.html
(Question) Fine Needle Aspiration
Fine Needle Aspiration Biopsy, Fine needle Aspiration Cytology
• Cost: about $2,000 (With EUS/ Lung lesion)
• Interpretation: Dyed sample tissues or cells.
• Limit: Anesthesia might be needed. Most patients feel pain
during the procedure.
• Risk: The disease can be spread out through the needle tip.
1Everyday
Health (http://www.everydayhealth.com/pancreatic-cancer/biopsy-and-staging.aspx)
library. (http://www.alkalizeforhealth.net/Lneedlebiopsy.htm)
3W.E. Khalbuss,3rd KAMC CYTOPATHOLOGY SYMPOSIUM
(http://www.ngha.med.sa/English/MedicalCities/AlRiyadh/Centers/Lab/Symposiums/Documents/Day2/FNA7.EBUS.EUS.pdf )
2AFH
(Question) Current Technique - CT
• Cost: $900-$1800
• Invasiveness: Use of an IV for
contrast agent.
• Limitation: Cannot be used on
obese patients and not
recommended for pregnant
women.
Sensitivity: 94.76%
Specificity: 89.165%
AUC: 0.9196
Grenacher, L. et al. "[Diagnosis and staging of pancreatic carcinoma: MRI versus multislice-CT -- a prospective study]"
(Question) Current Technique - EUS
and ERCP
• cost: [EUS] $500 [ERCP] $740
• Invasiveness: Very Invasive
• Limitation:[EUS] limited diagnostic
[ERCP] Iodine allergy. Empty
stomach
• Risk: [ERCP] Complications.
Sensitivity: 92%
Specificity: 85%
AUC: 0.885
Glasbrenner,B. et al. "Prospective comparison of endoscopic ultrasound and endoscopic retrograde cholangiopancreatography in the
preoperative assessment of masses in the pancreatic head"
(Question) Current Technique - EUS
and FNA
•
•
•
•
cost: $2,440-$3,300
Invasiveness: Very Invasive
Limitation:[EUS] limited diagnoses
risk:[EUS] allergic reaction
[FNA] bruising.
Sensitivity: 86.5%
Specificity: 87.5%
AUC: 0.87
[Glasbrenner,B. et al] ; [Kitano, M. et al.]; [J Gastroenterol 2004]; [Digestive Endoscopy 201]
(Question) Current Technique - EUS
•
•
•
•
Cost: around $500
Invasiveness: Very Invasive
Limitation: Limited diagnostic
Risk: allergic reaction
Glasbrenner,B. et al "Prospective comparison of endoscopic
ultrasound and endoscopic retrograde cholangiopancreatography in
the preoperative assessment of masses in the pancreatic head"
Kitano, M. et al. "New techniques and future perspective of EUS for
the differential diagnosis of pancreatic malignancies: contrast
harmonic imaging,"
Sensitivity: 80.738%
Specificity: 89.119%
AUC: 0.85
(Question) Current Technique - MRI
•
•
•
•
Cost: $400 - $3000
Invasiveness: None Invasive
Limitation:Sensitive to motion
Risk: cannot be used if
ferromagnetic materials are in the
body. Can cause skin irritation.
Grenacher, L. et al. "[Diagnosis and staging of pancreatic carcinoma:
MRI versus multislice-CT -- a prospective study]"
Li, K. C. et al. "Sensitivity and specificity of MRI in detecting malignant
spinal cord compression and in distinguishing malignant from benign
compression fractures of vertebrae"
Sensitivity: 89.375%
Specificity: 86.725%
AUC: 0.8805
(Question) Current Technique - CT and
MRI
• Cost: [CT] $1800, [MRI] $400$3000
• Invasiveness: non invasive
• Limitation: The image might not be
accurate if certain metal is
involved in the body.
• Risk:[CT] [MRI] No metal, can
cause skin irritation
Sensitivity: 90%
Specificity: 100%
AUC: 0.95
Fusari, M. et al. "Comparison between multislice CT and MR imaging in the diagnostic evaluation of patients with pancreatic masses"
(Question) Current Technique - PET
• Cost: $3,000-6,000
• Limitation: Is not as good as
other methods at staging and
testing for resectability.
• Risk: the exposure to radiation.
Sensitivity: 89.5%
Specificity: 91.5%
AUC: 0.905
Pennant, M. et al. "A systematic review of positron emission tomography (PET) and positron emission tomography/computed
tomography (PET/CT) for the diagnosis of breast cancer recurrence"