Transcript file (Colorectal Cancer Case

Colorectal Cancer
Hannah Allegretto
University of Pittsburgh
School of Pharmacy
Pharm D. Candidate 2013
Epidemiology
• Lifetime risk: 1/20
• Slightly lower in women than in men
• 3rd leading cause of cancer-related deaths in the US
• Responsible for over 51,500 deaths in 2012
• Median age of diagnosis: 45 years old
• Survival dependent on extent of disease at diagnosis
• 5 year survival:
• 90% for localized
• 66% of regional
• 9% for distant
Risk Factors
• Genetic predisposition
• Hereditary nonpolyposis colon cancer (HNPCC) – “Lynch
Syndrome”
• Familial adenomatosis polyposis (FAP)
• Lifetime risk ~100% without intervention
• Inflammatory Bowel Disease
• Polyps
• Diet
• Red and processed meat consumption
• Smoking
• Alcohol consumption
• Obesity
• Diabetes
Prevention Strategies
• Diet
•
•
•
•
High fiber, low fat
Decrease consumption of red and processed meat
Increase fruit and vegetable consumption
Increase milk and calcium consumption
• Abstain from smoking
• Limit alcohol consumption
• Physically active lifestyle
• NSAID use
Signs and Symptoms
• Change in bowel habits
• Rectal bleeding/bloody stools
• Abdominal discomfort
• Persistent cramps, gas, or pain
• Weakness and fatigue
• Unexplained weight loss
Screening Recommendations
Average Risk Screening
• Beginning at age 50, both men and women at average risk should
use one of the following tests:
•
•
•
•
•
Flexible sigmoidoscopy every 5 years
Colonoscopy every 10 years (preferred)
Double-contrast barium enema every 5 years
CT colonography every 5 years
Digital Rectal Exam (DRE)
• Family History
• Screening at 35-40 years old
• HNPCC
• Screening at age 30
• FAP
• Screening at age 10-12
Staging
Stage
Description
0
No growth beyond the inner layer of colon or rectum
I
Cancer has grown through muscularis into the
submucosa or into the propria
II
Growth through wall of colon/rectum but not into
other tissues or organs
III
Lymph node involvement
IV
Metastatic disease
TNM Staging
T = primary tumor
Tx
No description of tumor’s extent
possible
Tis
Earliest stage (in situ). Mucosal
involvement only
T1
Extending into the submucosa
T2
Cancer extends into thick outer muscle
layer
T3
Cancer extends into outermost layers of
colon/rectum but not through them
T4a
Cancer has grown through the
outermost lining of intestines
T4b
Cancer has grown through wall of
colon/rectum and is attached to or
invades nearby tissues or organs
TNM Staging
N = Regional Lymph Nodes
NX
Regional lymph nodes cannot be
assessed
N0
No regional lymph node metastasis
N1a
Metastasis in one regional lymph node
N1b
Metastasis in 2-3 regional lymph nodes
N2a
Metastasis in 4-6 regional lymph nodes
N2b
Metastasis in 7+ lymph nodes
TNM Staging
M = distant metastasis
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1a
Distant metastasis to 1 site
M1b
Distant metastasis to more than one
site
Treatment Options
• Surgery – curative intent for stage I and II
• Local Excision
• Resection
• Anastomosis
• Colostomy
• Radiation
• External vs internal
• Pharmacological Therapy
• Chemotherapy
• Monoclonal antibodies
Treatment by Stage
• Stage 0 and I
• Local excision (stage 0)
• Resection and anastomosis
• Stage II and III
• Resection and anastomosis followed by chemotherapy
• Chemotherapy (often clinical trials) – Controversial in Stage II
• Stage IV and Recurrent
•
•
•
•
Resection and anastomosis
Surgery to remove metastasis
Radiation or chemotherapy (palliative)
Monoclonal antibodies
Pharmaceutical Options
• FOLFOX
• FOLFIRI
• CapeOX
• 5-FU and leucovorin, with or without bevacizumab
• Capecitabine, with or without bevacizumab
• FOLFOXIRI
• Irinotecan, with or without cetuximab
• Cetuximab alone
• Panitumumab alone
FOLFOX
• FOLFOX 4 and modified FOLFOX 6 most widely
used
• Combination of 5-FU, leucovorin, and oxaliplatin
• Repeated every 14 days for approximately 12 cycles
FOLFOX 4 vs 6
FOLFOX 4
FOLFOX 6
Leucovorin
200mg/m2/day given as 2
hour infusion day on day 1
400mg/m2/day given
as 2 hour infusion on
day 1
5-Fluorouracil
Bolus: 400mg/m2 and a 22
hour continuous infusion
of 600mg/m2 repeated for
2 consecutive days
Bolus: 400mg/m2 and
a 22 hour continuous
infusion of
1200mg/m2 repeated
for 2 consecutive days
Oxaliplatin
85mg/m2/day on day 1
85mg/m2/day on day
1
5-Fluorouracil
• Mechanism of Action:
• Inhibits thymidylate synthase (TS), which converts uracil to
thymidine
• Combination with leucovorin enhances toxicity of 5-FU
• Toxicities:
•
•
•
•
•
Myelosuppression
Diarrhea
Photosensitivity
Mucositis
Hand-Foot Syndrome
Leucovorin
• Enhances the effects of 5-FU by stabilizing the binding
to thymidylate synthase (TS)
• TS important for DNA repair and replication
• Advanced colorectal cancer meta-analysis project
showed that 5-FU with leucovorin generated
statistically significant response rates when compared
to 5-FU monotherapy (23% vs 11%)
• Adverse reactions:
• D/N/V
• Fatigue
Oxaliplatin
• Mechanism of Action:
• Forms cross-linking-adducts, thus blocking DNA replication
and transcription
• Combination with leucovorin + 5-FU significantly
improves response rates
• Approved for both second-line and first-line treatment of
colorectal cancer
• Adverse effects:
•
•
•
•
Sensitivity to cold
Numbness/tingling in hands and feet
Myelosuppression
Nausea/vomiting
FOLFIRI
• Leucovorin + Irinotecan + 5-FU repeated every 14
days
Agent
Dose
Leucovorin
200mg/m2 IV on day 1
5-FU
400mg/m2 IV push on day 1,
followed by 2400mg/m2 CI
over 46 hours
180mg/m2 IV on day 1
Irinotecan
Irinotecan
• Mechanism of Action:
• Inhibits topoisomerase I impedes DNA uncoiling leading to
double stranded DNA breaks
• Adverse Reactions:
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•
•
•
•
Alopecia
Diarrhea – both early and late onset
Loss of appetite
Myelosuppression (neutropenia)
Nausea/vomiting
Other Agents
• Capecitabine
• MOA: pro-drug of 5-FU, inhibits DNA synthesis and
slows growth of tumor tissue
• Dose: Initial 2500mg/m2/day in two divided doses
• 2 weeks on, 1 week off cycle
• Oral administration
• Adverse effects:
•
•
•
•
Hand-foot syndrome
Mucositis
Myelosuppression
Skin discoloration/nail changes
Monoclonal Antibodies
• Bevacizumab
• Mechanism of action:
• Monoclonal antibody against vascular endothelial growth
factor (VEGF)
• VEGF most potent proangiogenic factor
• Indicated for use in 1st or 2nd line therapy in
combination with 5-FU therapy for metastatic
colorectal cancer
• Dosing: 5mg/kg IV q 14 days
Monoclonal Antibodies
• Epidermal Growth Factor Receptor (EGFR)
• Binding of a monoclonal antibody to extracellular
domain of EGFR
• Inhibits cell growth
• Induces apoptosis
• Decreases production of growth factors
• Anti-EGFR Agents:
• Cetuximab
• Panitumumab
Cetuximab
• Indicated for metastatic colorectal cancer (k-ras mutation negative)
EGFR expressing, as monotherapy for pts failing
irinotecan/oxaliplatin, or in combination with FOLFIRI
• Dosage:
• 400mg/m2 IV loading dose of 120 minutes followed by 250mg/m2
IV over 60 minutes.
• Complete dose 1 hour before starting chemotherapy regimen
• Requires premedication with diphenhydramine 50mg IV 30 to 60
minutes before dose
• Adverse reactions:
• Skin reactions
• Acne-like rash
• Cracking on fingers and toes
• Allergic Reaction
• Diarrhea
• Malaise
Panitumumab
• Indicated for EGFR-expressing metastatic colorectal
cancer in patients progressing on or following 5-FU,
oxaliplatin, and irinotecan-containing regimens
• Dosing:
• 6mg/kg IV over 1 hour every 14 days
• Adverse Reactions:
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•
•
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Acne-form rash
Decreased magnesium
Diarrhea
Malaise
The case
• RB is a 56yo male referred to Chartwell Pharmacy to
receive 5-FU therapy
• PMH:
• Colorectal cancer
• Underwent resection and anastomosis
• GERD
• Family History: noncontributatory
• Allergies: Penicillin, aspirin
• Immunization History Unknown
• Current Medications:
• Omeprazole 20mg PO 30 minutes before breakfast
The Case
• Measurements:
• Height: 71.5in
• Weight: 78.2kg
• BMI: 23.7
• Vitals:
• BP: 138/86
HR: 82
RR: 16
• Patient reported pain scale: 0/10
• RB’s risk factors:
• Previous smoker
• Previous alcohol abuser
The Case
• Plan:
• Colorectal Cancer Management
• Initiate FOLFOX6 q14 days x 12 cycles
• Oxaliplatin: 168mg IV over 2 hours on day 1
• Leucovorin: 792mg IV over 2 hours on day 1
• 5-FU: 792mg IV bolus day 1 followed by 4752mg IV continuous
infusion over 46 hours
• Pain Management:
• Currently, no pain. Reassess at each subsequent visit.
• If moderate pain develops, initiate hydrocodone/acetaminophen
5mg/325mg PO every 4 to 6 hours as needed.
The Case
• Chemotherapy-induced Nausea/Vomiting
• FOLFOX6 = level 4 emetogenicity
• Acute nausea/vomiting prevention
• Dexamethasone 20mg IV over 20 minutes day 1
• Delayed nausea/vomiting treatment
• Prochlorperazine 10mg PO q4h PRN
• GERD Management
• Continue omeprazole 20mg PO 30 minutes before breakfast
• Unknown Immunization Status
• Give Fluzone 0.5mL IM yearly
• Discuss with PCP status of required immunizations
References
Boyle P, Leon ME. Epidemiology of colorectal cancer. British Medical Bulletin.
2002;64:1-25.
Cunningham D, Atkin W, Lenz HJ et al. Colorectal cancer. Lancet. 2010; 375:1030-47.
National Cancer Institute. Colon Cancer Treatment. Treatment Options for Colon
Cancer. http://www.cancer.gov/cancertopics/pdq/treatment/colon/Patient/page5
(accessed 2012 Nov 29).
Mayo Clinic. Colon Cancer. Symptoms. http://www.mayoclinic.com/health/coloncancer/DS00035/DSECTION=symptoms (accessed 2012 Nov 30).
American Cancer Society. Colorectal Cancer. Treatment by stage of colon cancer.
http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectalcancer-treating-by-stage-colon (accessed 2012 Nov 30).
Jeon HJ, Woo JH, Lee HY et al. Adjuvant chemotherapy using the FOLFOX regimen
in colon cancer. J Korean Soc Coloproctol. 2011;27: 140-6.
References
Longley DB, Harkin DP Johnston PG. 5-fluorouracil: mechanisms of action and clinical
strategies. Nat Rev Cancer. 2003;3: 330-38.
Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus
leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated
metastatic colorectal cancer. J Clin Oncol. 2004;22:23-30.
Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as
adjuvant treatment for colon cancer. N Engl J Med. 2004; 350:2343-51.
Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and
leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350: 2335-42.
Saltz LB, Meropol NJ, Loehrer PJ et al. Phase II trial of cetuximab in patients with refractory
colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004; 22:120108.
Douillard JY, Siena S, Cassidy J et al. Randomized, phase III trial of panitumumab with
infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as firstline treatment in patients with previously untreated metastatic colorectal cancer: the PRIME
study. J Clin Oncol. 2010; 28:4697-705.