Transcript Adjuvant therapy for resected colon cancer

Adjuvant therapy
for resected colon cancer
Dr.vahedian ardakani
Medical oncologist
1390/10/1
Adjuvant therapy
Following potentially curative resection of colon
cancer, the goal of adjuvant chemotherapy is to
eradicate micrometastases, thereby reducing the
likelihood of disease recurrence and increasing
the cure rate.
Adjuvant therapy
The benefits of adjuvant chemotherapy have been
most clearly demonstrated in stage III (nodepositive) disease (an approximately 30 percent
reduction in the risk of disease recurrence and a
22 to 32 percent reduction in mortality), whereas
benefit is less certain for stage II disease.
management of invasive cancer in a
polyp
• Endoscopic resection alone is a reasonable
approach for favorable-risk early stage
colon cancers arising in a polyp.
• Large polypoid lesions may require a
segmental resection
management of invasive cancer in a polyp
radical resection if any of the following are present:
• Poorly differentiated histology
• Lymphovascular invasion
• Cancer at the resection or stalk margin
• Invasion into the muscularis propria of the bowel
wall (T2 lesion)
• Invasive carcinoma arising in a sessile (flat) polyp
with unfavorable features (eg, lower third
submucosal penetration, lymphovascular invasion,
poorly differentiated)
• Invasive carcinoma with incomplete polypectomy
• Following a complete resection of a stage I lesion,
no further adjuvant therapy is required.
• Patients managed in this way can expect a more
than 95% 5-year survival.
• The primary management of stage II and III colon cancer
is surgical resection
• The role of adjuvant therapy is to eradicate that
microscopic metastatic disease. Because current diagnostic
techniques are unable to identify those patients with or
without micrometastases, patients at sufficient risk of
clinical recurrence are treated postoperatively
• The optimal management of stage II colon cancer patients remains
undefined. Although the role of adjuvant therapy in stage II colon
cancer patients has not been firmly established,
• Using the Surveillance, Epidemiology, and End Results (SEER)Medicare linked database, Schrag et al identified 3,151 patients aged
65 to 75 with resected stage II colon cancer and no adverse
prognostic features
• Their review identified that 27% of patients received chemotherapy
during the 3-month postoperative period. Younger age, white race,
unfavorable tumor grade, and low comorbidity were associated with a
greater likelihood of receiving treatment. The 5-year survival was
75% for untreated patients and 78% for those patients who received
therapy in this nonrandomized comparison.
• Several prognostic indicators have been identified that correlate with a higher risk
for subsequent failure in stage II patients. These include :
1. obstruction or
2. perforation of the bowel wall as well as other less-established risk
factors such as
3. elevated preoperative CEA,
4. poorly differentiated histology, or a
5. high S-phase fraction, and
6. tumors not demonstrating high levels of microsatellite instability, or
7. tumors with an 18q deletion in colorectal tumors may correlate with
a poor prognosis.
12
• The CAP consensus statement suggests that a
minimum of 12 to 15 lymph nodes should be
examined in order to determine node
negativity.
• Availability of fewer nodes should therefore be
regarded as a relative high-risk factor in terms
of prognosis and should be factored into
decisions regarding adjuvant therapy.
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• the number of lymph nodes analyzed, presence
of high-risk clinicopathologic features (fewer
than 12 nodes in the surgical specimen;
• T4 or perforated/obstructed lesion
• poorly differentiated histology (including signet
ring and mucinous);
• lymphovascular or perineural invasion),
• mismatch repair enzyme (MMR) status,
• It appears that stage II patients with one or more of these risk factors
have a poorer prognosis and a prognosis closer to patients with
stage III disease. Whether adjuvant chemotherapy can provide
similar benefits in these patients as it does in stage III patients
currently remains a matter of conjecture. In the absence of definitive
data, definitive recommendations cannot be made at this time. In
fully informed high-risk stage II patients, it is reasonable to consider
adjuvant treatment using stage III treatment regimens.
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• Patients without high-risk features who have
MSI-H/dMMR tumors have a favorable
prognosis and are not likely to benefit from
adjuvant fluoropyrimidine-based therapy.
• We suggest observation alone for most of these
patients
• Chemotherapy was associated with improved
outcome in both stage II and stage III patients
with MSS or MSI-L,
• . In contrast, in patients with MSI-H tumors,
treatment did not improve survival, and in fact
was associated with a trend toward worse
outcome for both stage II and stage III cancers
Allelic Status of 18q
No. of Patients 5-Year Survival (%)
No loss
112
69
Loss
109
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P Value
.005
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• We suggest a fluoropyrimidine-based regimen
leucovorin-modulated FU or capecitabine alone) rather
than an oxaliplatin-based regimen for most patients with
stage II disease who are average risk,
• We discuss the results of the MOSAIC trial and the
potential toxicity of oxaliplatin in patients who have highrisk stage II disease, particularly with multiple risk factors
• For patients who have deficient mismatch repair (dMMR)
tumors but other high risk features, the use of
oxaliplatin should be considered more strongly given at
the apparent lack of benefit from single agent
fluoropyrimidines.
LV5FU2 (n =
1,123)
3-year disease-free survival stage III
patients (60% of total)
3-year disease-free survival, stage II
patients (40% of total)
Overall survival
FOLFOX-4 (n =
1,123)
Hazard Ratio (95%
Confidence Interval)
66%
72%
.76 (0.02-0.92)
84%
87%
.82 (0.57-1.17)
Not available
Not available
-
Grade 3-4 neutropenia
5%
41%
-
Neutropenic fever
0%
1%
-
Grade 3-4 diarrhea
0%
1%
-
Grade 3-4 vomiting
7%
11%
-
Neuropathy, any grade
0%
92%
-
Neuropathy, grade 3
0%
12%
-
Persistent neuropathy, grade 2-3, 1
year after treatment
0%
5%
-
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• The benefits of adjuvant chemotherapy have
been most clearly demonstrated in stage III
(node-positive) disease (an approximately 30
percent reduction in the risk of disease
recurrence and a 22 to 32 percent reduction in
mortality), whereas benefit in stage II disease
remains controversial
• We recommend adjuvant systemic therapy after
resection of stage III colon cancer
• If possible, chemotherapy should be initiated
within six to eight weeks of surgery
• We recommend a six month course of an oxaliplatinbased regimen rather than bolus 5-FU plus
leucovorin( FU/LV) or capecitabine for patients
who are likely to tolerate oxaliplatin
• It is clear that in the absence of medical or psychiatric
contraindications, patients with node-positive colon cancer
should receive postoperative chemotherapy. At the very
least, a 5-FU based regimen would appear to be
appropriate, and approximately a half year of therapy would
be supported by the majority of trials.
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• this time, the data for incorporation of oxaliplatin into the
routine adjuvant treatment of colon cancer appear
compelling, and the FOLFOX schedule is now the most
widely used adjuvant therapy.
• Weekly irinotecan plus bolus 5-FU/leucovorin should not
be used in the adjuvant setting, as randomized data have
shown increased risk of early death and no long-term
benefit. The available randomized data overall do not
support the routine use of any irinotecan-based regimens in
the adjuvant setting.
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• For patients with a contraindication to
oxaliplatin eg, preexisting neuropathy), 5FU/LV is an acceptable option, although
outcomes may not be as favorable.
• An alternative is six months of oral
capecitabine
• We recommend not using bevacizumab ,
cetuximab or an irinotecan-based regimen in
the adjuvant setting.
Roswell park regimen
• -FU + LV
-5FU 500 mg/m2 iv bolus 1 h after the start of
leucovorin
Leucovorin 500 mg/m2 iv over 2 hrs
Qw x 6 wks every 8 wks for 3-4 cycles
Mayo clinic regimen
• -5FU + LV-5
• FU 370-425 mg/m2/d iv bolus d1-5
Leucovorin 20-25 mg/m2/d iv bolus d1-5
Q4w x 6 cycles
Capecitabine
• Capecitabine (Xeloda) 1250 mg/m2 po bid x 14
days
Q3w x 8 cycles
FOLFOX4
• Leucovorin 200 mg/m2 iv over 2 hrs before 5-FU, d1 and 2
• -5FU 400 mg/m2 iv bolus and then 600 mg/m2 iv over 22
hrs, d 1 and d2
• Oxaliplatin (Eloxatin) 85 mg/m2 iv d1
Q2w x 12 cycles
FOLFOX6
• Leucovorin 400 mg/m2 iv over 2 hrs before 5-FU d1
• -5FU 400 mg/m2 iv bolus d1 followed by 2400
mg/m2 iv over 46 hrs
• Oxaliplatin (Eloxatin) 100 mg/m2 in 500 ml dextrose
5% iv over 2 hours d1
• Q2w x 12 cycles
Modified FOLFOX6
• Leucovorin 400 mg/m2 iv over 2 hrs before 5FU d1
• -5FU 400 mg/m2 iv bolus d1 followed by 2400
mg/m2 iv over 46 hrs
• Oxaliplatin (Eloxatin) 85 mg/m2 iv d1
• Q2w x 12 cycles
FLOX
• -5FU 500 mg/m2 iv bolus 1 hr after start of leucovorin
qw x 6 weeks every 8 weeks for 3 cycles
• Leucovorin 500 mg/m2 iv over 2 hrs qw x 6 weeks
every 8 weeks for 3 cycles
• Oxaliplatin (Eloxatin) 85 mg/m2 iv over 2 hrs before
5-FU and Leucovorin week 1, 3, 5 of each 8-week cycle
for 3 cycles
XELOX
• Capecitabine (Xeloda) 1000 mg/m2 po bid x 14
days
• Oxaliplatin (Eloxatin) 130 mg/m2 iv over 2 hrs
d1
• Q3w x 8 cycles
Modified FOLFOX7
• Leucovorin 200 mg/m2 iv d1
• FU 2400 mg/m2 iv over 46 hrs
• Oxaliplatin (Eloxatin) 85 mg/m2 iv d1
• Q2w x 12 cycles
• Older patients derive as much benefit from 5FU-based adjuvant chemotherapy as do younger
patients, although the incremental benefit from
oxaliplatin may be less
• We routinely recommend adjuvant
chemotherapy for fit older patients with stage
III and high-risk stage II colon cancer
• If an oxaliplatin regimen is chosen, we prefer the
modified FOLFOX6 regimen in this population
• For less fit individuals with stage III disease,
patients who are deemed less likely to tolerate
oxaliplatin, those with comorbid conditions
that are likely to limit their five-year survival, and
those with high-risk stage II disease, we suggest
5-FU/LV or single agent capecitabine rather
than FOLFOX
•
Large, established hepatic metastases derive their blood supply primarily from the hepatic
artery. However, tumors less than 5 mm in diameter obtain substantial portions of their
blood supply from both the hepatic and portal circulations.
•
Delivery of chemotherapy directly into the portal vein would appear to be a reasonable
maneuver in the adjuvant treatment of colorectal cancer as the liver is the most common
extraregional site of metastases. It would appear that cancer cells enter the liver through the
portal vein along the same channels used by nutrients traveling from the gut.
•
Initial dose-finding studies demonstrated that because of the extraction, or first-pass
clearance of 5-FU by the liver, substantially higher doses of 5-FU can be safely given by
intraportal than by intravenous infusion.
•
The NSABP C-02 trial randomized 1,158 patients with Dukes A, B, or C colon cancers to
either a 7-day portal vein infusion of 5-FU (600 mg/m2/day) or to surgery alone. A modest,
albeit statistically significant, advantage in disease-free survival (74% vs. 64% at 4 years) was
demonstrated for the group receiving intraportal chemotherapy; however, no difference was
seen in the incidence of hepatic recurrences.
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•
The peritoneal cavity is drained by portal lymphatics into the portal vein. Intraperitoneal
chemotherapy therefore delivers high concentrations of drug to the portal circulation, without the
need for portal vein canalization. In addition, extremely high concentrations of chemotherapy can
be given directly onto the peritoneal surfaces, thereby increasing local cytotoxicity.
•
The high first-pass hepatic clearances of floxuridine and 5-FU make these drugs good agents for
intraperitoneal administration. Pharmacokinetic studies of intraperitoneal 5-FU and floxuridine
show that intraperitoneal administration of these agents results in intraperitoneal concentrations
200- to 400-fold higher than those achieved systemically.
•
A randomized trial of 241 stage II and III patients compared intraperitoneal plus systemic 5FU/leucovorin with systemic 5-FU/levamisole.With a 4-year median follow-up, no benefit was
seen for the stage II patients. Among the 196 eligible patients with stage III disease, however, a
43% reduction in mortality was seen.
•
This small trial is encouraging, but would require further corroboration before being accepted into
standard practice.
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• In summary, a rational postoperative surveillance program should
include :
1. CEA measurements every 3 months, and
2. a yearly CT scan of the chest, abdomen, and pelvis (for rectal
cancer) for the first 3 years.
3. Colonoscopy can be performed every 3 to 5 years following the
resection
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• At the time of CEA measurements, a
physician encounter should be scheduled
wherein a discussion of patient symptoms
and a physical examination can be
performed. If a rising serum CEA is detected
on two consecutive measurements in the
absence of imageable disease by CT scan, a
PET scan with 18-FDG can be considered.
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