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Chemotherapy Of GI Malignancies Flashcards

1
Q

Carcinogenesis of Colon Cancer: Pathway to Tumor Formation (1A-3A)

A
  1. Genetic mutation in adenomatous polyposis coli gene
    A. Formation of small benign polyp
  2. Activation of oncogene K-RAS
    A. Enlargement of polyp
  3. Loss of p53 gene functionality
    A. Transformation to a malignant lesion
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2
Q

Prevention of Colon Cancer (1C-3B)

A
  1. Diet and exercise
    A. High fiber, low fat diet
    B. High fruits and veggies
    C. Calcium and Vitamin D supplementation
  2. COX inhibition
    A. COX-2 expression enhanced in 90% colorectal cancers
    B. Aspirin/NSAIDs
    C. Strongly dose-dependent
  3. US Preventative Services Task Force Recommendation
    A. Initiate low-dose aspirin for primary prevention of CVD and colorectal cancer in adults 50-59
    B. Must have 10% or greater CVD risk and no bleeding risk
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3
Q

Screening for Primary Colorectal Cancer Detection (1B-2A)

A 
1. Stool-based tests
A. Fecal occult blood testing (FOBT)
a. Guiac-based, low sensitivity/specificity
b. Inexpensive, non-invasive
c. High false positive rate
B. Fecal immunochemical test (FIT)
a. Can be used in place of FOBT
b. Antibody-based to detect hemoglobin in the stool
c. More expensive
  1. Digital rectal exam (DRE)
    A. Not recommended
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4
Q

Detection of Adenomatous Polyps and Cancer (1A-D)

A 
1. Visualized exams
A. Flexible sigmoidoscopy
B. Colonoscopy
a. High sensitivity
C. Barium enema
a. Contrast study visualized entire large bowel
b. Use has declined due to use of endoscopic and CT procedures
D. CT colonography
a. May help identify metastatic disease
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5
Q

ACS Screening Recommendations (1F-2A)

A 
1. Average Risk (Age > 50)
A. FOBT or FIT annually
B. Flexible sigmoidoscopy - every 5 years
C. Colonoscopy - every 10 years
D. CT of the colon - every 5 years
E. Barium enema - every 5 years
F. Stool DNA test - every 3 years
  1. High Risk (family hx: 35-40, FAP: age 10-12, Lynch syndrome: 20-25)
    A. Colonoscopy - annually
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6
Q

Tumor Marker for Colorectal Cancer (1A-C)

A
  1. Carcinoembryonic Antigen (CEA)
    A. Marker of choice for monitoring response to treatment
    B. Not for screening
    C. Monitor if patient will require further intervention:
    a. Baseline
    b. Every 3-6 months for 2 years
    c. Every 6 months to complete 5 years total
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7
Q

Stages and 5-year Survival Rate for Colorectal Cancers (4)

A
  1. Stage I: local disease, no invasion of surrounding tissue - >90%
  2. Stage II: invasion of muscular mucosa, no extracolonic spread - 55-85%
  3. Stage III: lymph node involvement - 25-55%
  4. Stage IV: metastatic disease - <5%
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8
Q

Colorectal Cancer Stages and Goals of Therapy (4)

A
  1. Stage I: Cure - remove polyps during colonoscopy
  2. Stage II: Cure - partial colectomy to remove cancer and adjuvant chemotherapy
  3. Stage III: Cure - partial colectomy to remove cancer and tumor infiltrated lymph nodes and adjuvant chemotherapy; FOLFOX (5-FU, leucovorin, oxaliplatin) or CapeOX (capecitabine and oxaliplatin) regimens
  4. Stage IV: Palliative Care - surgical options depend on the extend and size of metastases; often used to prevent or relieve symptoms such as removing blockages in the colon; chemotherapy to control the cancer - FOLFOX, FOLFIRI (leucovorin, 5-FU, irinotecan), CapeOx
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9
Q

High-Risk Factors for Recurrence (5)

A
  1. Grade 3, 4 lesions
  2. Bowel perforation/obstruction
  3. Lymph node involvement
  4. Positive surgical margins
  5. <12 lymph nodes examined
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10
Q

Treatment Options for Colorectal Cancer (1B-3B)

A
  1. Surgery: partial colectomy
    A. Curative for localized disease (Stage I, II, and maybe III)
    B. Palliative Stage III and IV
  2. Radiotherapy
    A. Minimal role in colon cancer
    B. Rectal cancer: neoadjuvant to improve regional control and adjuvant to prevent local recurrence
    C. Palliation for pain and bleeding control in colon cancer
  3. Chemotherapy: adjuvant or primary treatment
    A. Begin 4-6 weeks after surgical resection
    B. 5-FU based regimen is standard of care
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11
Q

Chemotherapy Agents for Colorectal Cancer (6)

A
  1. 5-Fluorouracil (5-FU): leucovorin given along to enhance effectiveness
  2. Capecitabine: oral prodrug of 5-FU
  3. Oxaliplatin
  4. Irinotecan
  5. EGFR inhibitors: cetuximab, panitumumab
  6. VEGF inhibitors: bevacizuman, Ziv-afilbercept, Regorafenib (multi-kinase inhibitor)
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12
Q

5-FU and capecitabine toxicities (3)

A

Hand-foot-mouth syndrome, diarrhea, mucositis

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13
Q

Oxaliplatin toxicity (1C-3C)

A
  1. Hypersensitivity reaction: 10-25%
    A. Flushing, urticaria, fever, rash, hypotension, bronchospasm
    B. Occurs after 6-9 cycles (cumulative dose 650 mg/m2)
    C. Stop infusion, administer diphenhydramine, steroids, IVF, epinephrine, albuterol
  2. Acute neurotoxicity: 85-95%
    A. Metabolite chelates magnesium and calcium, causing hyper-excitable sodium channels
    B. Exacerbated by cold
    C. Occurs within hours to days oxaliplatin infusion
  3. Cumulative neurotoxicity: 16-21%; may be permanent
    A. Associated with doses > 580 mg/m2 or > 6 cycles
    B. Discontinuing oxaliplatin after 6 cycles reduces toxicity w/ similar OS
    C. May pre-treat with calcium and magnesium infusions
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14
Q

FOLFOX toxicity (3)

A

Neuropathy, neutropenia, thrombocytopenia

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15
Q

FOLFIRI toxicity (3)

A

Fatigue, diarrhea, neutropenia

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16
Q

Irinotecan toxicity (1A-3C)

A
  1. Active metabolite, SN-38, excreted into bile
    A. Accumulation in the intestine causes mucosal damage
  2. Acute diarrhea
    A. Via acetylcholinesterase inhibition
    B. Occurs up to 24 hours after infusion
    C. Management: atropine 0.25 mg SubQ or IV
3. Delayed diarrhea (dose-limiting)
A. Via SN-38 metabolite
B. Median onset ~5days after infusion
C. Management: IVF with electrolytes
a. Can giver loperamide 4 mg x 1, then 2 mg Q4H or after every loose stool
17
Q

EGFR Inhibitors (MOA and targeted therapy)

A

MOA: Inhibits epidermal growth factor-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells

Targeted therapy: EGFR is overexpressed in 49-82% of colorectal tumors. Routine testing for EGFR overexpression is not recommended. KRAS mutation status testing is recommended prior to therapy; KRAS mutation (+) predicts lack of response to EGFR and KRAS wild-type patients may proceed with anti-EGFR treatment. Cetuximab or panitumumab plus FOLFOX or FOLFIRI adds demonstrable benefit.

18
Q

EGFR Inhibitor toxicities (1C-3)

A
  1. Acneiform rash: associated with improved response- desquamation (95%) and acneiform eruption (15-88%, grade 3/4: 1-18%).
    A. Occurs in 75-90% of patients on anti-EGFR therapy.
    B. *Positive correlation between rash severity and overall survival/tumor response.
    C. Management:
    a. Grade 1- topical hydrocortisone and clindamycin.
    b. Grade 2- topical hydrocortisone, oral doxycycline or minocycline
    c. Grade 3 or 4- modify anti-EGFR dose + topical hydrocortisone, PO doxycycline or minocycline, PO predisone
  2. Hypomagnesemia
  3. Hypersensitivity reaction
19
Q

VEGF inhibitors (MOA and targeted therapy)

A

MOA: Binds to vascular endothelial cell growth factor (VEGF) and inhibits the ligand binding to the receptor. Inhibits angiogenesis and cell survival.

Targeted therapy:

  1. Bevacizumab: can be added to first-line 5-FU regimens for Stage IV disease; modestly improves responses in first and second-line setting
  2. Ziv-aflibercept: for combination with FOLFIRI after failing FOLFOX first line; no better than bevacizumab at increased cost
  3. Ramucirumab: for combination with FOLFIRI
20
Q

VEGF inhibitor toxicities (5)

A
  1. Hypertension
  2. Wound dehiscence
  3. Proteinurea
  4. Arterial thrombosis
  5. Hemorrhage

Must wait at least 6 weeks after last administration of anti-VEGF and any elective surgery

21
Q

BRAF mutations (1C-2C)

A
  1. KRAS wild-type tumors that do not respond to anti-EGFR therapies may involve downstream pathways
    A. 5-9% have BRAF mutations
    B. BRAF mutations are limited to KRAS wild-type tumors
    C. BRAF mutation products are constitutively active, bypassing inhibition of EGFR
  2. BRAF mutations (e.g. BRAF V600E) seem to be strong prognostic markers
    A. Confer poor response to anti-EGFR therapy
    B. NCCN recommends BRAF genotyping for stage IV disease
    C. Use as a predictive marker is unclear
22
Q

Colon Cancer: Stages I and II (Specific Treatments)

A

Potentially curable.

Stage I, non-invasive:
1. Surgery only

Stage II, invasive:
1. Surgery alone with removal of regional lymph nodes
2. Low risk- adjuvant chemotherapy considered
3. High risk- any of the following regimens for 6 months
A. Capecitabine or infusion 5-FU/leucovorin
B. FOLFOX: 5-FU/leucovorin/oxaliplatin
C. CAPOX: capecitabine/oxaliplatin
D. FLOX: bolus 5-FU/leucovorin/oxaliplatin

23
Q

Colon Cancer: Stage III (Specific Treatments)

A

Stage III, lymph node involvement:
1. Surgery with removal of at least 12 regional lymph nodes + adjuvant chemotherapy for 6 months
A. FOLFOX or CapeOx preferred
B. FLOX
C. Capecitabine, 5-FU/leucovorin for poor PS
2. Chemotherapy benefit in Stage III: 25% risk reduction of recurrence

24
Q

Rectal Cancer: Stages I, II, and III (Specific Treatments) [4]

A
  1. Potentially curable
  2. Neo-adjuvant chemotherapy improves resectability and decreases risk of local recurrence
  3. Adjuvant chemotherapy for all patients who receive neo-adjuvant chemotherapy
  4. Chemotherapy regimens are similar to colon cancer
25
Adjuvant Chemotherapy for Rectal Cancer (3)
1. Adjuvant chemotherapy with oxaliplatin is beneficial in Stage III or high risk Stage II A. FOLFOX and CapeOX are superior to 5-FU/leucovorin B. Capecitabine alone is equivalent to 5-FU/leucovorin 2. Oxaliplatin has not survival benefit in Stage II disease A. No data in patients of age > 70 years 3. The use of targeted therapy has no role in Stage I, II, or III disease
26
Colorectal Cancer: Stage IV Metastatic Disease (Specific Treatments) [1B-6]
1. Surgery still has a role A. Resection of primary tumor to relieve obstruction/bleeding B. Resection of isolated, solitary metastatic sites of lung or liver 2. Chemotherapy and radiation palliation A. 5-FU-based regimens are standard of care 3. Regimen choice is patient-specific A. More intense regimens: potentially resectable cancer, rapidly progressing, symptomatic metastases B. Less intense regimens: unresectable asymptomatic metastases, patients with comorbidities 4. Neoadjuvant chemotherapy A. For unresectable liver or lung metastases B. Goal to covert to resectable status 5. Neoadjuvant and adjuvant therapy recommended for a total perioperative treatment time of 6 months 6. Regimens should be the same preoperatively as postoperatively
27
Colorectal Cancer: Stage IV Metastatic Disease (Neoadjuvant therapy) [1C-3]
1. Advantages of neoadjuvant chemotherapy A. Control of micro-metastases B. Determination of responsiveness to chemotherapy C. Avoidance of local therapy for those with disease progression 2. Disadvantages A. Potentially missing the window of opportunity for resection B. Risk of steatohepatitis or sinusoidal liver injury 3. Neoadjuvant period should be limited to 2-3 months to avoid hepatotoxicity
28
Colorectal Cancer: Stage IV Metastatic Disease (Recommended chemotherapy regimens) [1E-4]
``` 1. Recommended regimens: A. FOLFOX B. FOLFIRI C. CapeOX D. Capecitabine or infusional 5-FU/leucovorin E. FOLFOXIRI ``` 2. Can add targeted therapies 3. Often adjusted for toxicities 4. No preference of one over the other is made
29
Tumor Sidedness (1B-4)
1. Side of primary tumor plays a predictive role: A. Non-random distribution of molecular subtypes across the colon B. Investigations are ongoing 2. Right-sided primary tumor site: A. KRAS wild-type tumors had longer OS (overall survival) for anti-VEGF treatment than with anti-EGFR 3. Left-sided primary tumor site: A. KRAS wild-type tumor had longer OS for anti-EGFR than with anti-VEGF 4. NCCN guidelines: only patients with left-sided primary tumors should be offered cetuximab or panitumumab during first-line treatment
30
Colorectal Cancer: Relapsed Stage IV (Targeted Therapy) [1-4]
1. Regorafenib: multi-kinase inhibitor, including BRAF 2. Improved overall survival to 6.4 months vs. 5 months 3. Dose modification required in 76% of patients A. Grade 3/4 ADRs: fatigue, diarrhea, HTN, rash, HAND-FOOT-MOUTH REACTION B. BLACK BOX WARNING- hepatotoxicity 4. For patients previously treated with chemotherapy (i.e. second-line)
31
Beneficial use of adjuvant 5-FU-based chemotherapy
Beneficial in non-metastatic stage III or high risk stage II patients

Gastrointestinal (7 decks)

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