Simposio de coloproctología, 26.05.2018. Hotel Intercontinental Medellín.

1. Quimioterapia Neoadyuvante y Adyuvante de Cáncer de
Colon: Ensayos Clínicos y Posibles Indicaciones
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
Medellín, 26.05.2018

2. Conflicts of interest for this lecture
Mauricio Lema
None for this lecture.

3. @onconerd

4. Non-metastatic Colon Cancer
1. Neoadjuvant therapy
5. Adjutant chemotherapy in the Elderly
4. Adjuvant chemotherapy and MSI
3. Adjuvant chemotherapy in stage II
2. Adjuvant chemotherapy in stage III

5. Neoadjuvant chemotherapy

6. Accuracy of radiological staging in identifying high-risk colon cancer patients
suitable for neoadjuvant chemotherapy: a multicentre experience.
Dighe S, Colorectal Dis, 2012
Radiologic Prognostic criteria
Good prognosis tumours: including, T1/T2
Intermediate prognosis: T3 < 5 mm tumour invasion beyond the muscularis propria (MP)
Poor prognosis tumours: including T3 with tumour extension ≥ 5 mm beyond the MP or T4.
Variable Sensitivity Specificity
Poor prognosis (71%) 87% 49%
Tumor infiltration beyond the MP (T3/T4 vs T1/T2) 95% 50%
Conclusion
CT scanning identified high-risk (T3/4) colon cancers with minimal overstaging of T1/T2
tumours, thus establishing the feasibility of radiologically guided neoadjuvant chemotherapy.

7. Outcomes of preoperative chemoradiotherapy followed by surgery in patients
with unresectable locally advanced sigmoid colon cancer.
Qui B, Chin J Cancer, 2016
The primary
objective of this
prospective study
was to assess the
R0 resection rate
Locally-advanced colon cancer with:
(1) curative resection was deemed
impossible because preoperative
imaging examinations showed that the
tumor extensively involved adjacent
organs/structures, such as the bladder,
ureter, or great vessels, thus
compromising a clean radial margin;
and/or (2) curative resection was
deemed impossible after exploratory
laparotomy
Neo-adjuvant
Radiotherapy +
Capecitabine
Adjuvant
chemotherapy
n=21

8. Outcomes of preoperative chemoradiotherapy followed by surgery in patients with
unresectable locally advanced sigmoid colon cancer.
Qui B, Chin J Cancer, 2016

9. Outcomes of preoperative chemoradiotherapy followed by surgery in patients with
unresectable locally advanced sigmoid colon cancer.
Qui B, Chin J Cancer, 2016

10. Neoadjuvant chemotherapy in locally advanced colon cancer.
A phase II trial.
Jakobsen A, Acta Onco, 2015
Surgery
Resectable colon cancer.
Non-metastatic locally-advanced
colon cancer defined as: CT scan
showing a T3 tumor with ETI > 5
mm or a T4 tumor, no metastases
on chest and abdominal CT,
PS ≤ 2
XELOX x3
(+/- Panitumumab)
Adjuvant
Chemotherapy x
5 (without
Panitumumab)
in high-risk
stage II and
stage III
n=77
The primary endpoint was the fraction of patients not fulfilling the criteria for
adjuvant chemotherapy (converted patients).
Secondary endpoints were recurrence rate, disease-free survival (DFS), and toxicity

11. Neoadjuvant chemotherapy in locally advanced colon cancer.
A phase II trial.
Jakobsen A, Acta Onco, 2015
Surgery
Resectable colon cancer:
Non-metastatic locally-advanced
colon cancer defined as: CT scan
showing a T3 tumor with ETI > 5
mm or a T4 tumor, no metastases
on chest and abdominal CT,
PS ≤ 2
XELOX x3
(+/- Panitumumab)
Adjuvant
Chemotherapy x
5 (without
Panitumumab)
in high-risk
stage II and
stage III
n=77
There is no major difference, but less than half of the wild-type
patients (42%) were converted to a low-risk status compared to 51%
in the chemotherapy only group for a total conversion rate of 48%.

12. Neoadjuvant chemotherapy in locally advanced colon cancer.
A phase II trial.
Jakobsen A, Acta Onco, 2015

13. Feasibility of preoperative chemotherapy for locally advanced, operable colon
cancer: the pilot phase of a randomised controlled trial.
FOxTROT Collaborative Group, Lancet Oncol, 2012
Locally advanced (T4 or T3 with
extramural depth ≥5 mm)
adenocarcinoma of the colon, with
staging determined preoperatively by
either spiral or multidetector CT and for
whom a 24-week course of oxaliplatin
and fluoropyrimidine-based adjuvant
chemotherapy would be judged
appropriate
FOLFOX x6w
FOLFOX x6w
Panitumumab
Surgery
Surgery
FOLFOX x18w
FOLFOX x18w
FOLFOX x24w
FOLFOX x24w
Panitumumab x6 weeks
R
Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of
preoperative therapy, and accuracy of radiological staging.

14. Feasibility of preoperative chemotherapy for locally advanced, operable colon
cancer: the pilot phase of a randomised controlled trial.
FOxTROT Collaborative Group, Lancet Oncol, 2012

15. Feasibility of preoperative chemotherapy for locally advanced, operable colon
cancer: the pilot phase of a randomised controlled trial.
Variable Post-Op Chemo Pre-Op Chemo p
T3 or more at resection 50/51 (98%) 90/99 (91%) 0.1
Downstaging 0.04
CR 2/99
Apical node involvement 10/50 (20%) 1/98 (1%) 0.001
R1 10/50 (20%) 4/99 (4%) 0.002
Tumor regression 1/46 (2%) 29/94 (31%) 0.0001
Preoperative chemotherapy for radiologically staged, locally advanced
operable primary colon cancer is feasible with acceptable toxicity and
perioperative morbidity.
FOxTROT Collaborative Group, Lancet Oncol, 2012

16. Adjuvant chemotherapy in stage
III

17. FU/Lev superior a la
cirugía
FU/LV superior a
cirugía
Timeline – Terapia adyuvante en cáncer de colon
Fluoropirimidinas & Oxaliplatino
1990 1994 1998 2006
FU/LV > FU/Lev
6 m = 12 m
Levamizol futil
HD LV = LD LV
C/mes = C/semana
De Gramont menos tóxico
que Mayo
Capecitabina…
Capecitabina menos
tóxico que FU/LV
FOLFOX > FU/LV

18. MOSAIC: Adjuvant FOLFOX4 in Stage II-III Colon
Cancer: Study Schema
FOLFOX4
Leucovorin 200 mg/m2 IV
5-fluorouracil 400 mg/m2 bolus
5-fluorouracil 800 mg/m2 IV
Oxaliplatin 85 mg/m2 IV
(n = 1123)
LV5FU2
Leucovorin 200 mg/m2 IV
5-fluorouracil 400 mg/m2 bolus
5-fluorouracil 800 mg/m2 IV
(n = 1123)
Patients with previously
untreated, completely
resected stage II-III
colon cancer
(N = 2246)
André T, NEJM, 2004

19. MOSAIC: Adjuvant FOLFOX4 in Stage II-III Colon
Cancer: DFS
André T, NEJM, 2004
DFS

20. MOSAIC: Adjuvant FOLFOX4 in Stage II-III Colon
Cancer: DFS – Stage II and III
André T, NEJM, 2004

21. MOSAIC: Adjuvant FOLFOX4 in Stage II-III Colon
Cancer: 6-yr OS
de Gramont A, et al. ASCO 2007. Abstract 4007.

22. MOSAIC: Adjuvant FOLFOX4 in Stage II-III Colon
Cancer: Study Schema
André T, NEJM, 2004

23. Adjuvant FOLFOX4 in Stage II-III Colon Cancer: Final MOSAIC
Trial Results
• Final 5-yr DFS demonstrated advantage for FOLFOX4 over LV5FU2
(73.3% vs 67.4%; P = .003)
• Stage III: FOLFOX 4 vs LV5FU2 (66.4% vs 58.9%; P = .005)
• Stage II: no statistically significant DFS difference
• Final OS at 6 yrs of follow-up consistent with earlier results
de Gramont A, et al. ASCO 2007. Abstract 4007.
OS, % LV5FU2 (n =
1123)
FOLFOX4 (n =
1123)
HR (95% CI) P Value
Overall population 76.0 78.6 0.85 (0.72-1.01) .057
▪ Stage II 86.8 86.9 1.00 (0.71-1.42) .996
▪ Stage III 68.6 73.0 0.80 (0.66-0.98) .029

24. Adjuvant FOLFOX4 in Stage II-III Colon Cancer:
Final MOSAIC Trial Results
• Rate of peripheral sensory neuropathy decreased over time
• At 4 yrs
• Grade 1: 12.0%
• Grade 2: 2.8%
• Grade 3: 0.7%
• Neutropenia ≥ grade 3 in 41.0% of patients receiving FOLFOX4 vs 4.7%
of patients receiving LV5FU2
• Febrile neutropenia in 1.8% of patients receiving FOLFOX4
de Gramont A, et al. ASCO 2007. Abstract 4007.

25. XELOXA: Capecitabine Plus Oxaliplatin Compared With
Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer:
Final Results of the NO16968 Randomized Controlled Phase III Trial.:
Study Schema
XELOX regimen consisted of a 2-hour
intravenous infusion of oxaliplatin 130
mg/m2 on day 1 and outpatient oral
capecitabine 1,000 mg/m2 twice daily on
days 1 to 14 of a 3-week cycle for a total
of eight cycles
FU/FA regimens from the Mayo Clinic of
24 weeks, six cycles and from Roswell
Park of 32 weeks
Age 18 years or older,
Stage III colon carcinoma
(T1 to T4, N1 to N2, M0)
Surgery with curative intent within
8 weeks
(1,886)
Schmoll, HJ, JCO, 2015
Primary Endpoint: DFS

26. XELOXA: Capecitabine Plus Oxaliplatin Compared With
Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer:
Final Results of the NO16968 Randomized Controlled Phase III Trial.:
Study Schema
Schmoll, HJ, JCO, 2015

27. XELOXA: Capecitabine Plus Oxaliplatin Compared With
Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer:
Final Results of the NO16968 Randomized Controlled Phase III Trial.:
Study Schema
Schmoll, HJ, JCO, 2015

28. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer (IDEA)
Grothey A, NEJM, 2018
…6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in
patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a
shorter duration of therapy could spare toxic effects…
A prospective, preplanned, pooled analysis of six
randomized, phase 3 trials that were conducted
concurrently to evaluate the noninferiority of
adjuvant therapy with either FOLFOX (fluorouracil,
leucovorin, and oxaliplatin) or CAPOX
(capecitabine and oxaliplatin) administered for 3
months, as compared with 6 months
The primary end point was the rate of disease-free
survival at 3 years.
Noninferiority of 3 months versus 6 months of
therapy could be claimed if the upper limit of the
two-sided 95% confidence interval of the hazard
ratio did not exceed 1.12.
Trials: CALGB/ SWOG 80702, IDEA France, SCOT,
ACHIEVE, TOSCA, and HORG

29. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer (IDEA)
Grothey A, NEJM, 2018
Significant Peripheral Neuropathy
%

30. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer (IDEA)
Hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P =
0.11 for noninferiority of 3-month therapy; P = 0.045 for
superiority of 6-month therapy.
3-yr DFS: 74.6% (3 Months) vs 75.5% (6 Months)
Grothey A, NEJM, 2018
n=12,834 patients

31. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer (IDEA)
Grothey A, NEJM, 2018
Disease-free Survival at 3 Yr, According t Subgroup
5,071
patients
7.471
patients
T1/T2/T3 N1
Exploratory analysis
Non-inferiority (mathematically) satisfied

32. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer (IDEA)
Grothey A, NEJM, 2018
Disease-free Survival at 3 Yr, According t Subgroup
5,256 patients
T4 and/or N2
7,763 patients
Exploratory analysis
Non-inferiority (mathematically) not satisfied

33. Stage III Colon
Cancer
T1-3 N1
(Low-Risk)
XELOX x3 Mo
(preferred)
T4 or N1
(High-Risk)
FOLFOX x 6 Mo
(preferred)
Schilsky, NEJM, 2018 (Editorial)

34. Adjuvant chemotherapy in stage
II

35. MOSAIC: Adjuvant FOLFOX4 in Stage II-III Colon
Cancer: DFS – High-Risk stage II
André T, NEJM, 2004

36. Adjuvant therapy for completely resected stage II colon cancer.
Figueredo A, Cochrane Database Syst Rev, 2008
OS RR: 0.96
(95% confidence interval 0.88, 1.05).
DFS RR: 0.83
(95% confidence interval 0.75, 0.92).
It seems reasonable to discuss the benefits of
adjuvant systemic chemotherapy with those stage II
patients who have high risk features, including
obstruction, perforation, inadequate lymph node
sampling or T4 disease.

38. FU chemotherapy and MSI-H
Ribic CM., Sargent DJ., Moore MJ. et al. Tumor Microsatellite-Instability Status as a
Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer N
Engl J Med 2003 349: 247-257
No adjuvant chemotherapy

39. FU chemotherapy and MSI-H
Ribic CM., Sargent DJ., Moore MJ. et al. Tumor Microsatellite-Instability Status as a
Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer N
Engl J Med 2003 349: 247-257
Adjuvant chemotherapy

40. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of
recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin
(FU/LV) and FU/LV plus oxaliplatin.
Yothers G, JCO, 2013
An independent,
prospectively designed
clinical validation study of
Recurrence Score, with
prespecified end points and
analysis plan, in archival
specimens from patients with
stage II and III colon cancer
randomly assigned to
fluorouracil (FU) or FU plus
oxaliplatin in NSABP-C07.

41. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of
recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin
(FU/LV) and FU/LV plus oxaliplatin.
Yothers G, JCO, 2013

42. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of
recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin
(FU/LV) and FU/LV plus oxaliplatin.
Relative benefit of
oxaliplatin was similar
across the range of
Recurrence Score
(interaction P = .48
Yothers G, JCO, 2013

43. Prospective multicenter study of the impact of oncotype DX colon cancer assay results
on treatment recommendations in stage II colon cancer patients.
Srivastava G, Oncologist, 2014
This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding
adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients.
Stage IIA (pT3 N0 M0)
Physician’s prior
recommendation
OncoTypeDx colon (in MMR-P)
Physician’s actual
recommendation
Variable Results (confidence interval)
Change in treatment recommendation 63/141 – 45% (0.36-0.53)
Treatment intensity decrease 47/141 – 33%
Treatment intensity increase 16/141 – 11%
Chemo recommended prior to test 73/141 – 52%
Chemo recommended post test 42/141 – 30%
Treatment intensity associated with high RS p= 0.011

44. Stage II Colon
Cancer
Clinical Low Risk High Risk
XELOX x 3 Mo
(preferred)
Schilsky, NEJM, 2018 (Editorial)
IDEA, NEJM, 2018
(ie, T4, obstruction,
perforation, less than 12
nodes)
Observe
+
OncoType Dx
Observe or
FUFA x6 Mo
MSI-H
-

45. Adjuvant chemotherapy in stage
II

46. A pooled analysis of adjuvant
chemotherapy for resected
colon cancer in elderly
patients
Sargent D, NEJM, 2001

47. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients
Sargent D, NEJM, 2001
Death from any cause Recurrence

48. Impact of Age on the Efficacy of Newer Adjuvant Therapies in Patients With Stage
II/III Colon Cancer: Findings From the ACCENT Database
McCleary NJ, JCO, 2013
11,953 patients age < 70 and 2,575 age ≥ 70 years from seven adjuvant therapy trials comparing IV FU with oral
fluoropyrimidines (capecitabine, uracil, or tegafur) or combinations of fluoropyrimidines with oxaliplatin or irinotecan in
stage II/III colon cancer. End points were disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR).
DFS
OS
Patients age ≥ 70 years seemed to experience reduced benefit from adding oxaliplatin to fluoropyrimidines in the
adjuvant setting, although statistically, there was not a significant effect modification by age, whereas oral
fluoropyrimidines retained their efficacy.
IV FU betterExp better IV FU betterExp better

49. Adjuvant chemotherapy
indicated
Elderly (> 70 yr) with
resected stage II or III colon
cancer
Consider FUFA

50. Conclusions
• Neoadjuvant chemotherapy in non-metastatic colon cancer is not a standard of care.
• 6-Mo adjuvant Oxaliplatin + FU/Capecitabine should be administered to stage III colon
cancer
• 3 Mo adjuvant Oxaliplatin + FU/Capecitabine causes less neuropathy than 6 Mo
• 3-Mo adjuvant XELOX may be offered to lower-risk stage III patients
• Adjuvant chemotherapy may not be as effective in stage II colon cancer
• MSI, clinical and genomic expression profiles may aid in the selection of stage II
patients likely to benefit from adjuvant chemotherapy
• Elderly patients should not be denied adjuvant chemotherapy
• Oxaliplatin-based chemotherapy may be less effective in the elderly.

51. @onconerd