1) Adjuvant therapy refers to additional treatment given after primary treatment like surgery to eradicate micrometastasis and reduce the risk of cancer recurrence. 2) For colon adenocarcinoma, common adjuvant therapy options include chemotherapy regimens like FOLFOX and CapeOX. Clinical trials have shown these regimens improve disease-free and overall survival for stage III colon cancer patients. 3) Side effects of adjuvant chemotherapy include nausea, diarrhea, fatigue and neuropathy, though most symptoms improve after treatment completion. Elderly patients may receive less intensive regimens due to higher risk of side effects.

1. ADJUVANT THERAPY FOR COLON
ADENOCARCINOMA
CU: “ O Doente com Cancro”
Professor Doutor JL Passos Coelho
24 April 2018
Helena Carolina Dias 2013231 | João Augusto Ribeiro 2013233

2. Treatment that is given in addition to the primary
treatment in order to erradicate micrometastasis
Aims to:
• Decrease the risk of disease recurrence
• Increase disease-free survival
• Increase life expectancy
ADJUVANT THERAPY FOR COLON ADENOCARCINOMA
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

3. It depends
Adjuvant therapy
ADJUVANT THERAPY FOR COLON ADENOCARCINOMA
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

4. Chemoterapy
• 5-FU
• Leucorovin
• Oxaliplatin
• Capecitabine
Radiotherapy
• T4, positive
margins or high
relapse risk
Therapies Directed
to Specific Targets
• Metastatic cancer
TREATMENT OPTIONS
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

5. Accepted approach:
6th to 8th week after surgery
 For each 4 weeks: ↓14% global
survival
 If delated > 2M, efficacy and survival
decreases dramatically
After recovery from surgery
WHEN TO START
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

6. Recommended therapies:
5-FU/Leucovorin
FOLFOX
FLOX
Capecitabine
CapeOX
CHEMOTHERAPY REGIMENS
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

7.  5-FU – inhibition of thymidilate
synthase + disruption of DNA
 Leucorovin – stabilizes TS + 5-FU
metabolite.
ADR: diarrhea, náusea/vomting, myelossupression
Mechanism of action
5-FLUOROURACIL / LEUCOVORIN
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

8. Mechanism of action of Oxaliplatin
 Adducts formation
 Arrest and Inhibition of mRNA synthesis
 Immunologic mechanisms – mediated by T-cells and
dendritic cells
 Inhibition of thymidylate synthase
 Downregulation of dihydropyrimidine dehydrogenase
ADR: peripheral neuropathy, diarrhea
FOLINIC ACID (LEUCOROVIN) + 5-FU + OXALIPLATIN
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

9. ADR: neurotoxicity, hand-foot syndrome, mucositis, thrombocytopenia
Capecitabine 5-FU
Hepatic metabolization
CAPEOX/XELOX – CAPECITABINE + OXALIPLATIN
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

10. Preferential regimen of FOLFOX in stage III
Stage II Stage III
MOSAIC TRIAL
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

11. Disease free survival for stage III Overall survival for stage III
XELOX vs FOLFOX?
No significant diferences were observed in the efficacy of FOLFOX vs.
XELOX as adjuvant treatment in high-risk stage II or III CRC patients,
but definitive conclusions cannot be drawn because of the small size.
XELOXA TRIAL
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

12. QUASAR, 2007
O’ CONNOR,
2011
 Controversial trials
 No preferential regímen in high-risk stage II
REGIMEN EVIDENCE
FOLFOX / FLOX
Category 2 ACapeOX
Capecitabine
5-FU / Leucovorin
STAGE II
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

13. Tumours from individuals should be tested for MSI in
the following situations:
o Colorectal cancer diagnosed in a patient who is <50
years of age.
o Presence of synchronous, metachronous colorectal
or other Lynch-associated tumours, regardless of
age.
o Colorectal cancer with the MSI-H histology
diagnosed in a patient who is <60 years of age.
o Colorectal cancer diagnosed in one or more first-
degree relatives with a Lynch-related tumour, with
one of the cancers being diagnosed under age 50
years.
o Colorectal cancer diagnosed in two or more first- or
second-degree relatives with Lynch-related
tumours, regardless of age.

14. MICROSATELITE INSTABILITY (MSI)
MSI sporadic CRCs are characterized by specific clinicopathological
features:
o Mainly female gender
o Older age
o Right colon location
o Mucinous differentiation
o Peritumoural lymphocytic infiltrate and Crohn-like inflammatory
reaction
o Lower stage ( more common in stage II than III)
 Better prognosis
 Present in 15% of all CRC
MSI is considered a favourable prognostic factor in early stage CRCs,
with longer disease free and overall survival.
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

15.  CT reduces the 5-year risk of cancer recurrence or death by about 30%
 CT only consensually proven beneficial for stage III
 Therapy duration – 3 or 6 months.
REGIMEN EVIDENCE
FOLFOX Category 1 A
CapeOX Category 1 A
FLOX Category 1 A
Capecitabine Category 2 A
5-FU / Leucovorin Category 2 A
STAGE III
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

16. SIDE EFFECTS
• Nausea and vomiting
• Diarrhea
• Mucositis
• Fatigue
• Alopecia
• Febrile neutropenia
• Palmar-plantar erythrodysesthesia
(hand-foot syndrome)
• Death – 0,5 to 1% of cases
Most symptoms revert after the end of
QT.
*Oxaliplatine-related neurotoxicity is more prolonged
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

17. ELDERLY PATIENTS
• Do not benefit from oxaliplatin therapy
• Higher risk due to higher prevalence of comorbilities
• Cardiac insuficiency – 5-FU and capecitabine → vasospasm
• Worse renal function – impared metabolism of capecitabine
• More vulnerable to myelosupression
1st line: 5-FU / LV >70 years
ADJUVANT
THERAPY
TREATMENT
OPTIONS
CHEMO
THERAPY TRIALS STAGE II STAGE III
SIDE
EFFECTS
ELDERLY

18. REFERENCES
• https://emedicine.medscape.com/article/277496-treatment#d11, consulted on 15/10/2017 at 15h29
• •https://www.uptodate.com/contents/adjuvant-therapy-for-resected-stage-iii-node-positive-colon-cancer (consulted on 18/10/2017 at
17h)
• •http://www.uptodate.com/contents/adjuvant-chemotherapy-for-resected-stage-ii-colon-cancer (consulted on 18/10/2017 at 19h)
• •National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology. Colon Cancer. NCCN 1.2018
• •National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology. Colon Cancer. NCCN 2.2016
• •Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal
cancer. Ann Oncol. 2016;0(July)
• •Yothers G, O’Connell MJ, Allegra CJ, et al. Oxaliplatinas as adjuvant therapy for colon cancer: updated results of NSABP C-07,
including survival and subset analysis. J Clin Oncol 2011;29:3768-3774.
• Mlecnik, Bernhard, et al. "Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than
microsatellite instability." Immunity 44.3 (2016): 698-711.
• Kannarkatt, Joseph, et al. "Adjuvant chemotherapy for stage II colon cancer: A clinical dilemma." Journal of oncology practice13.4
(2017): 233-241.
• Pectasides, Dimitrios G., et al. "Randomized phase III trial of FOLFOX versus XELOX as adjuvant chemotherapy in patients with early-

19. REFERENCES
• Rustum, YM. Biochemical rationale for the 5-fluorouracil leucovorin combination and update of clinical experience. Journal of
Chemotherapy 2003; 2 Suppl 1:5-11.
• •Alcindor, T. Oxaliplatin: a review in the era of molecularly targeted therapy. Current Oncology 2011; 18-25.
• •André, T., de Gramont A, Vernerey D, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer:
updated 10-year survival and outcomes acoording to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin
Oncol 2015;33:4176-4187.
• •Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant
therapy for stage III colon cancer. J Clin Oncol 2011;29:1465-1471.
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29(25):3381-8.
• •Gray R, Barnwell J, McConkey C, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a
randomised study. Lancet 2007;370:2020-2029.
• •O’Connor, E. Adjuvant Chemotherapy for Stage II Colon Cancer With Poor Prognostic Features. J Clin Oncol. 2011 Sep
1;29(25):3381-8.
• •Buckowitz, A; Knaebel, H. P.; Benner, A; Bläker, H; Gebert, J; Kienle, P; von Knebel Doeberitz, M; Kloor, M (2005).
"Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant