Colon cancer part 2

1.  Standard adjuvant chemotherapy regimens include:
Fluoropyrimidine :
 Fluorouracil (5-FU) [with leucovorin],
 Or Capecitabine)
 as a single agent and in combination with Oxaliplatin
 A total 6-month of adjunctive therapy
(12 cycles) is the
current standard of care
after surgery
1

2. 1. Flurouracil (5-FU)
 Most active and most widely used.
 5-FU + XRT  increase risk of hematologic toxicity, diarrhea
(GI toxicity)
 MOA: inhibit thymidylate synthase (S-phase)
 Some regimens with 5-FU administer the drug for 10-30
minute bolus infusion, but others specify a much longer
continuous infusion, spanning several days (dose intensity)
 5-FU has a very short t1/2 (S-phase), infusing the drug for a
prolonged period results in greater formation of the active
metabolite and, theoretically, greater antitumor effect.
2

3.  Leucovorin enhance 5-FU
cytotoxicity
 This occur by increase
binding affinity of 5-FU
metabloire
(fluorodeoxyuridine
monophosphate
(FdUMP)) to TS enzyme
 resulting in
pronounced and
prolonged inhibition of
DNA synthesis increase
cytotoxic effect).
3

4.  Bolus administration of 5-FU is associated with more
severe neutropenia/mucositis.
 Continuous infusion administration is associated with more
stomatitis, severe hand-foot syndrome (HFS)
 HFS: painful swelling & erythroedema of soles feet /palms
hand
 Photosensitivity, hyperpigmentation (vein), nail banding may
occur.
4

5.  Severe stomatitis is uncommon, but can be significantly
reduced with the use of oral cryotherapy
a. Chew & hold ice chips in the mouth during period between 5
min prior to & 30 min. following bolus injection (local
vasoconstriction; temporarily reduces blood flow to oral
mucosa, reducing drug exposure to oral mucosa).
b. Mild mucositis managed with supportive care
c. Strategies to prevent stomatitis
5

6. 2. Capecitabine
 Oral pro-drug of 5-FU
 Convenient administration & is as effective as (IV) bolus 5-
FU modulated with leucovorin
 Enzyme involved in the final conversion of capecitabine to 5-
FU is expressed more in cancerous cells compared with
healthy cells, further biomodulation of capecitabine to
enhance activity with leucovorin is not required.
 Capecitabine usually given for 14 days (1,250 mg/m2 PO
twice daily on days 1 through 14)
 Each cycle lasts 14 days and is repeated every 21 days
 Has a similar toxicity profile to continuous infusion 5-FU
(neutropenia, stomatitis).
 Associated with a greater incidence & severity of HFS and
diarrhea compared with continuous infusions.
6

7.  Approved as a single agent in the adjuvant setting
(non-inferior) to bolus 5-FU and leucovorin in patients with
stage III colon CA)
 Recommended (as single agent) when patients are considered
unable to tolerate combination therapy.
 Approved for metastatic phase when fluoropyrimidine alone is
desired.
 Can combine with
Oxaliplatin but not Irinotecan.
(no survival benefit,
higher rate of N,V,D)
 Drug interaction
(Warfarin)
7

8. 3. Oxaliplatin
 Newest member of Platinum therapy
 Guidelines recommend oxaliplatin-containing regimens as the
preferred treatment for patients with stage III colon cancer who can
tolerate combination therapy.
 Addition of oxaliplatin resulted in a 20% risk reduction in disease
recurrence & increased 5-year DFS (73% vs. 67%) as compared
with 5-FU plus leucovorin alone.
 Oxaliplatin is not effective as a single agent in colorectal CA, only
used in combination regimens.
 Common S.E :
 GI toxicity (N,V,D)  supportive care
 Myelosupression (neutropenia)
 Peripheral neuropathy (associated with both acute and persistent
(chronic) neuropathies (paresthesias/dysesthesias /hypoesthesia and in
some instances muscle spasms).
8

9. 9

10. 1. Acute neuropathies:
 1-2 days of dosing, resolve within 2 weeks.
 Usually peripherally.
 May occur in jaw & tongue:
 Phenomenon that is distressing for patients is an involuntary
laryngo-pharyngeal dysesthesia that can create the sensation
of an inability to swallow or S.O.B.
 Rare (1-2%)
 Exacerbate/participate/trigger by exposure to cold temp./cold
objects. (Cold induced)
 Generally occur within minutes of receiving the infusion and
can persist up to 7 days.
 Instruction for the patient.
10

11. 2. Delayed/persistent neuropathies:
 May also occur and is potentially irreversible.
 Cumulative, dose-dependent effect (780-850 mg/m2)/ or 8-10
cycles.
 Develops in the distal extremities and slowly progresses.
 Functional impairment/interfere with daily activities (15%)
 Persistent sensation of numbness, tingling, or burning in the
extremities.
 This type of neuropathy usually
resolve with dose reduction/
cessation of oxaliplatin.
 Anticonvulsant/ antidepressant agents.
 STOP/GO strategy (stage IV)
11

12. 3. Hypersensitivity reactions (usually during the infusion,
delayed reactions are possible):
 Range from mild itching, flushing, to anaphylaxis.
 Premedication :
with antihistamines /corticosteroids
(e.g., diphenhydramine 50mg IV or orally with or without
hydrocortisone 50 mg 15 minutes before oxaliplatin IV) in
addition to prolonging the infusion of oxaliplatin.
4. Myelosuppression
(neutropenia & thrombocytopenia)
4. GI toxicity (N,V,D)
5. Neurotoxicity
12
are dose-limiting
toxicities associated with
its use.

13.  Fluorouracil-Based Regimens
 Fluorouracil 600 mg/m2 IV day 1
 Leucovorin 500 mg/m2 IV day 1 over 2 hours
 Repeat weekly for 6 of 8 weeks
 Leucovorin administration prior to 5-FU is the most
effective approach to enable intracellular-reduced folates
to accumulate prior to 5-FU administration.
 Leucovorin administered over 2hrs before 5-FU
13

14.  FOLFOX4
 Oxaliplatin 85 mg/m2 IV day
1
 Leucovorin 200mg/m2/Day
IV over 2 hrs days 1 & 2
 5-FU 400 mg/m2 /day IV
bolus, after leucovorin, then
600 mg/m2 /day CIV over 22
hours days 1 & 2
 Repeat every 14 days, 12
cycles (6-month)
 S.E: Sensory neuropathy,
neutropenia.
 FOLFOX6
 Oxaliplatin 100 mg/m2 IV day 1
 Leucovorin 400 mg/m2 IV on
day 1
 5-FU 400 mg/m2 IV bolus, after
leucovorin on day 1, then 1200
mg/m2/day × 2 days CIV (total
2,400 mg/m2 over 46–48 hours)
 Repeat every 14 days 12 cycles
(6-month)
 Easier administration as
compared to FOLFOX4
14

15. 15
400
400

16.  CapOx
 Oxaliplatin 130
mg/m2 IV day 1
 Capecitabine 850–1000
mg/m2 twice daily
orally for 14 days
 Each cycle lasts 14 days,
repeated every 21 days
 Capecitabine
 Capecitabine 1,250
mg/m2 PO twice daily on
days 1 through 14
 Each cycle lasts 14 days and
is repeated every 21 days
16

17.  For rectal CA:
 Stage I : Surgery
 Stage II, III : Chemo-radiation:
 Neoadjunctive : XRT + ( IV 5-FU or Capacitabine or bolus
5-FU/LV)
 This should be followed by adjunctive chemotherapy after
surgery to total 6-month (pre + post)
 Adding Oxaliplation , MoAb not recommended
 5-FU 225-300 mg/m2 IVCI Monday –Friday throughout
radiation
OR
 Capecitabine 825 mg/m2 PO BID Monday –Friday
throughout radiation
17

18.  Stage IV rectal CA :
 If there’s a chance that all of the cancer can be removed (only
a few tumors in the liver/lungs), common treatment options
include:
I. Chemoradiation therapy, followed by surgery to remove the
rectal lesion and distant tumors. This might be followed by
chemotherapy. (chemo-XRT  surgery chemo.)
II. Surgery , followed by chemo (radiation in some cases)
III. Chemo, followed by surgery, usually followed by
chemoradiation. (chemo.  surgery chemo-XRT)
 If surgery not needed, the cancer will likely be treated with
chemo (as colon CA) and/or targeted therapy drugs.
18

19.  Metastasis colorectal CA (Stage IV)
 Up to 25% of patients will present with hepatic metastases at
time of diagnosis
 60% of patients with colorectal CA will develop hepatic
metastases sometime during the disease
 Treatment include:
 Single agent therapy (5-FU, Irinotecan, Capecitabine)
(Irinotican: proven benefit in the metastatic setting.)
 Combination chemotherapy
 MoAB (bevasizumab).
 Biologic agents added to the foregoing regimens. (Improve
response rates & survival when combined with
chemotherapy)
 Surgery typically not option in extensive metastasis.
19

20.  Most patients with a good performance status will receive
Oxaliplatin plus 5-FU/leucovorin.
 Single-agent capecitabine may be the preferred option for
patients with preexisting neuropathies (diabetic patients) or
patients wishing not to receive IV chemotherapy for any other
reason.
 In metastasis colorectal CA response to capecitabine was
superior to 5-FU/leucovorin (26% vs. 17%).
 5-FU/leucovorin has limited use at this time but it is option
for Pts. who cannot receive Oxaliplatin and are unable to
tolerate or take oral capecitabine.
(Eg, patients who develop severe HFS may tolerate bolus 5-
FU/leucovorin because this toxicity is minimal with this
administration method.
20

21.  Irinotican:
 Can cause neutropenia , diarrhea, abdominal cramping and
severe.
 Diarrhea is the most S.E/reason for
dose reduction/discontinuation.
 The early-onset and late-onset diarrhea
mediated by different mechanisms
 Early-onset diarrhea (within 24hours (2-6hr) after treatment)
(cholinergic mediated)
 Patients often report other cholinergic symptoms, such as
rhinitis, increased salivation, miosis, lacrimation,
diaphoresis, flushing, and abdominal cramping
 Managed with atropine IV or SC 0.25 to 1 mg.
21

22.  Late-onset diarrhea (most common)
 (>24 hours (1-12 d) after treatment)
 leading to dehydration & electrolyte imbalances.
 Patients should promptly receive loperamide 4 mg with
the first episode of diarrhea & repeat doses of 2 mg
every 2 hours until 12 hours have passed without a
bowel movement
 May last 3-5 days
22

23.  Bevacizumab
 MoAB inhibits vascular endothelial growth factor
(VEGF)
 S.E: Bleeding, HTN, proteinuria, wound healing
complication, thrombosis, GI perforation.
 If patients receive Bevacizumab, surgery shouldn't occur
within 6 weeks of the last dose of therapy, & it should
not be restarted until 6 to 8 weeks after surgery.
23

24.  Stage IV incurable, treatment goals:
 Control CA growth
 Reduced patient symptoms
 Improve QoL & extend survival
 Multiple treatment regimen are effective in metastatic
disease.
 Most 1st line chemotherapy regimen used 5-FU/LV.
 Capacitine can substitute 5-FU/LV
 Irinotican or Oxaliplatin added to 5-FU (improve response
rate, survival , PFS).
 If Pt. not appropriate for intensive chemotherapy (5-FU/LV +
oxaliplatin or Irinotecan +biologic agent), then 5-FU (or
capicitabine) mono-therapy or combined with MoAB are
appropriate.
24

25.  Chemotherapeutic Regimens for Metastatic Colorectal
Cancer:
1. Oxaliplatin-Containing Regimens
 FOLFOX plus bevacizumab:
(Bevacizumab 5 mg/kg IV day 1 before FOLFOX Repeat
cycle every 2 weeks)
2. Irinotecan-Containing Regimens
 FOLFIRI
 FOLFIRI + bevacizumab
 FOLFOXIRI
3. Fluoropyrimidine Regimens
25

26.  FOLFIRI
 Irinotecan 180 mg/m2 IV
day 1 for 90 min
 Leucovorin 400
mg/m2 IV day 1
 5-FU 400 mg/m2 IV
bolus, after leucovorin
on day 1, then 1200
mg/m2/day × 2 days CIV
(total 2,400 mg/m2 over
46–48 hours)
 Repeat cycle every 14
days
 S.E: Diarrhea, mucositis,
neutropenia
 FOLFIRI
plus bevacizumab
 Bevacizumab 5 mg/kg IV
(30 minutes) day prior to
FOLFIRI
 Repeat cycle every 2
weeks
 S.E: HTN, thrombosis,
proteinuria
from bevacizumab added
to toxicities of FOLFIRI
26

27. 27

28.  FOLFOXIRI
 Irinotecan 165 mg/m2 IV day 1 prior to oxaliplatin
 Oxaliplatin 85 mg/m2 IV prior to leucovorin day 1
 Leucovorin 400 mg/m2 IV day 1 prior to fluorouracil
 Fluorouracil 1600 mg/m2/day × 2 days CIV (total 3,200
mg/m2 over 48 hours)
 Repeat cycle every 2 weeks
 S.E: Neutropenia, diarrhea, stomatitis, peripheral
neurotoxicity, thrombocytopenia
 Pre-medications: Ondansetron (Zofran) 16 mg IV 30 minutes prior to
chemo, Dexamethasone 20 mg IV 30 minutes prior to chemo,
Atropine sulfate 0.4 mg IVP prior to Irinotecan.
 Filgrastim (Neupogen) 5 mcg/kg/day given subcutaneously day 2 or
3 post chemo
28

29. 29

30. 30

31.  Epidermal growth factor receptor- inhibitors (EGFR
inhibitors) should be considered only in patients that have
tumors with wild-type KRAS gene. (unmuted)
 BRAF gene status should be considered with pt. with wild-
type KRAS mutation. (muted BRAF: no benefit of EGFR-I)
 EGFR inhibitors may also be used in combination with
first-line chemotherapy.
 Eg: Cetuximab, Panitumumab.
 Panitumumab, maybe used alone for refractory metastasis
disease. Not approved for used in chemo. Combination.
 Results with cetuximab in the 1st-line metastatic setting
combined with FOLFIRI suggest that the combination
improves response rates and PFS to either chemotherapy
regimen without adding substantial toxicity
31

32.  Recurrence:
 Occur within the first 2 to 3 years after completion of
adjuvant therapy.
 Physical examination, & CEA level performed every 3 - 6
months for the first 2 years, then semiannually thereafter.
 CT scan to chest, abdomen, and pelvis performed at least
annually for 3 years.
 Another colonoscopy should be performed within a year
of surgical resection or 1 year from original colonoscopy,
and then repeated again in 3 years
 Resume screening for colorectal cancer every 5 years
32

33. THANKS
33