Adjuvant therapy Adjuvant therapy for resected colon for resected colon

cancercancer

Dr.vahedian ardakaniDr.vahedian ardakaniMedical oncologistMedical oncologist

1390/10/11390/10/1

Adjuvant therapyAdjuvant therapy  Following potentially curative Following potentially curative

resection of colon cancer, the goal of resection of colon cancer, the goal of adjuvant chemotherapy is to adjuvant chemotherapy is to eradicate micrometastases, thereby eradicate micrometastases, thereby reducing the likelihood of disease reducing the likelihood of disease recurrence and increasing the cure recurrence and increasing the cure rate. rate.

Adjuvant therapyAdjuvant therapyThe benefits of adjuvant The benefits of adjuvant

chemotherapy have been most chemotherapy have been most clearly demonstrated in stage III clearly demonstrated in stage III (node-positive) disease (an (node-positive) disease (an approximately 30 percent reduction approximately 30 percent reduction in the risk of disease recurrence and in the risk of disease recurrence and a 22 to 32 percent reduction in a 22 to 32 percent reduction in mortality), whereas benefit is less mortality), whereas benefit is less certain for stage II disease. certain for stage II disease.

management of invasive management of invasive cancer in a polypcancer in a polyp

• Endoscopic resection alone is a Endoscopic resection alone is a reasonable approach for reasonable approach for favorable-risk early stage colon favorable-risk early stage colon cancers arising in a polyp. cancers arising in a polyp.

• Large polypoid lesions may Large polypoid lesions may require a segmental resectionrequire a segmental resection

radical resection if any of the following are radical resection if any of the following are present:present:

• Poorly differentiated histology Poorly differentiated histology • Lymphovascular invasion Lymphovascular invasion • Cancer at the resection or stalk margin Cancer at the resection or stalk margin • Invasion into the muscularis propria of the Invasion into the muscularis propria of the

bowel wall (T2 lesion) bowel wall (T2 lesion) • Invasive carcinoma arising in a sessile Invasive carcinoma arising in a sessile

(flat) polyp with unfavorable features (eg, (flat) polyp with unfavorable features (eg, lower third submucosal penetration, lower third submucosal penetration, lymphovascular invasion, poorly lymphovascular invasion, poorly differentiated) differentiated)

• Invasive carcinoma with incomplete Invasive carcinoma with incomplete polypectomypolypectomy

management of invasive cancer management of invasive cancer in a polypin a polyp

• Following a complete resection of a Following a complete resection of a stage I lesion, no further adjuvant stage I lesion, no further adjuvant therapy is required. therapy is required.

• Patients managed in this way can Patients managed in this way can expect a more than 95% 5-year expect a more than 95% 5-year survival.survival.

• The primary management of stage II and III The primary management of stage II and III colon cancer is surgical resectioncolon cancer is surgical resection

• The role of adjuvant therapy is to eradicate The role of adjuvant therapy is to eradicate that microscopic metastatic disease. Because that microscopic metastatic disease. Because current diagnostic techniques are unable to current diagnostic techniques are unable to identify those patients with or without identify those patients with or without micrometastases, patients at sufficient risk micrometastases, patients at sufficient risk of clinical recurrence are treated of clinical recurrence are treated postoperativelypostoperatively

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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,

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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 Chemotherapy was associated with improved outcome in both stage II and improved outcome in both stage II and stage III patients with MSS or MSI-L,stage III patients with MSS or MSI-L,

• . In contrast, in patients with MSI-H . In contrast, in patients with MSI-H tumors, treatment did not improve tumors, treatment did not improve survival, and in fact was associated survival, and in fact was associated with a trend toward worse outcome for with a trend toward worse outcome for both stage II and stage III cancers both stage II and stage III cancers

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Allelic Status of 18qNo. of Patients

5-Year Survival )%(P Value

No loss11269.005

Loss10950 

• 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 high-risk 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)

FOLFOX-4 (n = 1,123)

Hazard Ratio (95% Confidence Interval)

3-year disease-free survival stage III patients (60% of

total)

66%72%.76( 0.02-0.92)

3-year disease-free survival, stage II patients

(40% of total)

84%87%.82( 0.57-1.17)

Overall survivalNot availableNot available-Grade 3-4 neutropenia5%41%-

Neutropenic fever0%1%-Grade 3-4 diarrhea0%1%-Grade 3-4 vomiting7%11%-

Neuropathy, any grade0%92%-Neuropathy, grade 30%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 oxaliplatin-based regimen rather than bolus 5-FU plus leucovorin (FU/LV) or capecitabine for patients who are likely to tolerate oxaliplatin

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• For patients with a contraindication to oxaliplatin eg, preexisting neuropathy), 5-FU/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 5-FU 500 mg/m2 iv bolus 1 h after the start of leucovorinLeucovorin 500 mg/m2 iv over 2 hrsQw x 6 wks every 8 wks for 3-4 cycles

Mayo clinic regimen

• 5-FU + LV5-• FU 370-425 mg/m2/d iv bolus d1-5

Leucovorin 20-25 mg/m2/d iv bolus d1-5Q4w x 6 cycles

Capecitabine

• Capecitabine (Xeloda) 1250 mg/m2 po bid x 14 daysQ3w x 8 cycles

FOLFOX4

• Leucovorin 200 mg/m2 iv over 2 hrs before 5-FU, d1 and 2

• 5-FU 400 mg/m2 iv bolus and then 600 mg/m2 iv over 22 hrs, d 1 and d2

• Oxaliplatin (Eloxatin) 85 mg/m2 iv d1Q2w x 12 cycles

FOLFOX6

• Leucovorin 400 mg/m2 iv over 2 hrs before 5-FU d1

• 5-FU 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 5-FU d1

• 5-FU 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

• 5-FU 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 Older patients derive as much benefit from 5-FU-based adjuvant chemotherapy as do 5-FU-based adjuvant chemotherapy as do younger patients, although the incremental younger patients, although the incremental benefit from benefit from oxaliplatinoxaliplatin may be less 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 For less fit individuals with stage III disease, patients who are deemed disease, patients who are deemed less likely to tolerate less likely to tolerate oxaliplatinoxaliplatin, , those with comorbid conditions that those with comorbid conditions that are likely to limit their five-year are likely to limit their five-year survival, and those with high-risk survival, and those with high-risk stage II disease, we suggest 5-FU/LV stage II disease, we suggest 5-FU/LV or single agent or single agent capecitabinecapecitabine rather  rather than FOLFOXthan FOLFOX

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