1. To Treat or Not to Treat Stage II Colon Cancer = Yes (sometimes)
Al B. Benson III, MD, FACP
Professor of Medicine
Associate Director for Clinical Investigations
Robert H. Lurie Comprehensive Cancer Center
of Northwestern University
Summit Markers talk Gen sess
Metastatic Colorectal Cancer: Scope of the Problem and Unmet Needs

2. Disclosures
Research = Genentech, Amgen, Astellas, Gilead, Bayer, Novartis
Consultant = Sanofi, Bayer, Genentech, Lilly/ImClone, Bristol-Myers Squibb
Genomic Health (Uncompensated)

6. The Stage II Colon Cancer Controversies/Dilemmas
Imperfect risk factors/assessments are not linked to treatment efficiency
Growing list of risk factors and tools to define risk
Overall good prognosis but subsets clearly recur

7. The Stage II Colon Cancer Controversies/Dilemmas
Proof of principle: chemotherapy reduces risk but for whom?
Choice extrapolated from Stage III benefits – is this correct?
Role of oxaliplatin: Stage T4, MSI-H

8. The Stage II Colon Cancer Controversies/Dilemmas
Complicated discussion with patients
Patient perceptions of risk (and MD’s)
Cannot predict absolute risk for individual
Cannot link risk and treatment benefit
Cannot define which factors are most important

9. AJCC v7
Stage II
Stage III
Gunderson et al, JCO 2009

10. QUASAR: 5FU/LV Chemotherapy Benefit in the 1,436 Evaluable Stage II Colon Cancer Patients
RFI (recurrence-free interval)
DFS (disease-free survival)
OS (Overall Survival)
Key points:
For the evaluable 1,436 stage II colon cancer patients in the validation study, the impact of 5FU/LV chemotherapy for all three clinical endpoints was generally consistent with the results observed for stage II patients in the overall QUASAR study. The benefit of chemotherapy in this study, as reported previously, was small.
Details:
Impact of adjuvant 5FU/LV chemotherapy in 1,436 stage II colon cancer patients. Kaplan-Meier analyses for surgery alone vs surgery+5FU/LV patients in the present study, according to RFI (recurrence-free interval), DFS (disease-free survival), and OS (overall survival). RFI was primary clinical endpoint for the study while DFS and OS were secondary clinical endpoints.
Kerr et al., ASCO 2009, #4000
Stage II Colon Cancer:  Who to Treat, Who Not to Treat with Adjuvant Therapy

11. Kaplan-Meier estimates of disease-free survival (A) by treatment arm and (B) by treatment arm and by stage (intent-to-treat population).
Kaplan-Meier estimates of disease-free survival (A) by treatment arm and (B) by treatment arm and by stage (intent-to-treat population). FL, fluorouracil and leucovorin.
André T et al. JCO 2009;27:
©2009 by American Society of Clinical Oncology

12. Kaplan-Meier estimates of overall survival (A) by treatment arm and (B) by treatment arm and by stage (intent-to-treat population).
Kaplan-Meier estimates of overall survival (A) by treatment arm and (B) by treatment arm and by stage (intent-to-treat population). FL, fluorouracil and leucovorin.
André T et al. JCO 2009;27:
©2009 by American Society of Clinical Oncology

13. Rates of (A) disease-free, (B) relapse-free, (C) overall, and (D) post–disease-free survival in patients with high-risk stage II colon cancer treated with leucovorin and fluorouracil with oxaliplatin (FOLFOX4) or without (FL).
Rates of (A) disease-free, (B) relapse-free, (C) overall, and (D) post–disease-free survival in patients with high-risk stage II colon cancer treated with leucovorin and fluorouracil with oxaliplatin (FOLFOX4) or without (FL). DFS, disease-free survival; HR, hazard ratio.
Tournigand C et al. JCO 2012;30:
©2012 by American Society of Clinical Oncology

14. Oxaliplatin trials with censoring analyses of different time points.
Oxaliplatin trials with censoring analyses of different time points. (A) Disease-free survival; (B) overall survival; (C) time to recurrence.
McCleary N J et al. JCO 2013;31:
©2013 by American Society of Clinical Oncology

15. Recurrence Risk & Treatment Benefit Markers Currently Used for Stage II Colon Cancer
Bowel obstruction or perforation
T-Stage
# of nodes assessed
Tumor grade
Lymphatic/vascular invasion
Margin status
Treatment Benefit
None
How are stage II colon cancer patients being assessed for their recurrence risk today?
There are a limited set of clinical and pathologic markers that are in current practice and recommended by guidelines: obstruction or perforation, T stage, the number of nodes examined, tumor grade, lymphatic vascular invasion, and margin status.
Conspicuously, on the right-hand side, with respect to markers that predict treatment benefit, there are none.
According to the current guidelines, it’s quite striking that unlike in breast cancer where we’ve had decades of use of molecular markers (e.g. ER, PR, HER2) to guide treatment decisions, there are no molecular markers that are established for stage II colon cancer. There are no markers in stage II colon cancer that identify patients specifically with very high or very low proportional risk reduction with chemotherapy. These are limitations to the system that we have today.
* NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009
ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004.
Stage II Colon Cancer:  Who to Treat, Who Not to Treat with Adjuvant Therapy 15

16. Numeracy calculator www.adjuvantonline.com:
· three choices for lymph nodes (none, 1–4, 5+ lymph nodes),
· three choices for tumor stage (T1/T2, T3, T4),
· two choices for grade (low, high),
· four choices for age (49 years or younger, 50–59, 60–69, 70 or older).
Adjuvant! tool three additional options:
gender (male, female), comorbidity (perfect health, minor problems, average for age, or major problems), and the number of examined lymph nodes (0, 1–3, 4–10, >10).

17. Overall survival by stage group (Kaplan-Meier).
Overall survival by stage group (Kaplan-Meier). Cox regression–based test for equality of survival curves confirms significant differences between stage groups (likelihood-ratio χ2 = ; P < .001).
O'Connor E S et al. JCO 2011;29:
©2011 by American Society of Clinical Oncology

18. Average Distance Between Clusters Average Distance Between Clusters
Similar Coexpression of 48 Recurrence Risk Genes Stage II vs Stage III Colon Cancer
UMPS
MYBL2
CSEL1
CMYC
NME1
HNRPD
SKP2
RRM1
MCM2
RRM2
KI_67
CDC20
P16_INK4
P14ARF
KLK6
GRB10
TGFBI
LAMC2
P21
CDC42BPA
HSPA1A
S100A4
OPN__OSTEOPONTIN
PAI1
GADD45B
EGR1
STMY3
DLC1
IGFBP3
SFRP4
PDGFC
IGFBP7
CALD1
TIMP3
TGFB3
SFRP2
INHBA
FAP
CTHRC1
LOXL2
SPARC
COL1A1
BGN
TIMP2
ANTXR1
ITGB1
AKT3
AKAP12
Average Distance Between Clusters
0.0
0.2
0.4
0.6
0.8
1.0
1.2
HNRPD
UMPS
NME1
MYBL2
CSEL1
CMYC
SKP2
RRM1
MCM2
RRM2
KI_67
CDC20
P16_INK4
P14ARF
GRB10
HSPA1A
STMY3
LAMC2
S100A4
KLK6
TGFBI
P21
CDC42BPA
OPN__OSTEOPONTIN
PAI1
GADD45B
EGR1
IGFBP3
IGFBP7
TIMP3
LOXL2
SFRP4
PDGFC
TGFB3
SFRP2
INHBA
CTHRC1
FAP
SPARC
COL1A1
BGN
TIMP2
ANTXR1
ITGB1
DLC1
CALD1
AKT3
AKAP12
Average Distance Between Clusters
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Stage II
Stage III
Stromal Genes
Cell CycleGenes
Stage II Colon Cancer:  Who to Treat, Who Not to Treat with Adjuvant Therapy

19. Calculated from Tumor Gene Expression
QUASAR RESULTS: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery
Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711)
RECURRENCE SCORE
Calculated from Tumor Gene Expression
Group Risk (by Kaplan-Meier)
12%
18%
22%
STROMAL
FAP
INHBA
BGN
CELL CYCLE
Ki-67
c-MYC
MYBL2
GADD45B
REFERENCE
ATP5E
GPX1
PGK1
UBB
VDAC2
p=0.004
Stage II Colon Cancer:  Who to Treat, Who Not to Treat with Adjuvant Therapy

20. QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer
Multivariate Analysis
Stage II Colon Cancer:  Who to Treat, Who Not to Treat with Adjuvant Therapy

21. QUASAR Results: Recurrence Risk in Pre-specified Recurrence Risk Groups
Range of RS
Proportion of patients
Low
<30
43.7%
Intermediate
30-40
30.7%
High
≥41
25.6%
Key points:
The validation study protocol specified secondary analyses to characterize risk resolution across the range of Recurrence Score. These secondary analyses are presented on this slide.
Protocol-specified cutpoints at 30 and 41 were used to separate the population into 3 groups of patients of sufficient size to enable statistical analyses (table at top left indicates the proportion of patients in each of the low, intermediate, and high recurrence risk groups). These cutpoints were NOT intended to be clinically actionable, particularly as thresholds of risk and benefit will likely be dependent on the specific characteristics (age, comorbidities, patient preference) of the individual colon cancer patient.
At right, Kaplan-Meier analysis of the 3 groups defined by the pre-specified cutpoints demonstrates a separation of 3 year recurrence risk between the groups, with average risk in the low risk group of 12% and average risk in the high risk group of 22%.
At bottom left, protocol-specified comparison of the high vs low recurrence risk groups in a Cox model shows significant HR 1.47 (with p<0.05)
Details:
The pre-specified recurrence risk groups were defined in the protocol to enable statistical analysis of different regions of the Recurrence Score risk profile. The cutpoints of 30 and 41 were selected from the Development study data to capture statistically meaningfully sized proportions of patients in 3 recurrence risk groups. These cutpoints were NOT intended a priori to indicate clinically actionable patient populations (i.e. low risk indicating one treatment path while high risk indicating another).
Three recurrence risk groups were chosen instead of two because, as with every laboratory measurement, Recurrence Score will have a standard deviation, and with only two groups, patients with Recurrence Scores very near a cutpoint could be assigned to one group or the other simply due to normal variation in laboratory measurement.
It is important to note that the clinical utility of the assay resides in the continuous Recurrence Score, which provides individualized recurrence risk information over a range from 9-11% at the low end to 25-27% at the high end. Our discussions with oncologists would suggest that thresholds for clinical actionability (i.e. the decision to recommend treatment or not) will depend on the individual patient’s clinical situation.
Comparison of High vs. Low Recurrence Risk Groups using Cox Model: HR = 1.47 (p=0.046)
n=711
Kerr et al., ASCO 2009, #4000
Stage II Colon Cancer:  Who to Treat, Who Not to Treat with Adjuvant Therapy

22. Relationship between the continuous Recurrence Score (RS) and 5-year recurrence risk by stage and treatment in National Surgical Adjuvant Breast and Bowel Project C-07.
Relationship between the continuous Recurrence Score (RS) and 5-year recurrence risk by stage and treatment in National Surgical Adjuvant Breast and Bowel Project C-07. Thick lines represent fluorouracil (FU) –treated patients, thin lines represent FU + oxaliplatin–treated patients. Blue, gold, and gray colors represent stage II, IIIA/B, and IIIC, respectively. A rug plot depicting the distribution of RS is included at the bottom of the figure, and an estimated normal distribution of scores is provided below. The proportional hazards assumption held (P = .20 for the test of nonzero slope of Schoenfeld residuals v time). The relationship between continuous RS and the log hazard of recurrence was linear (P = .84 for the test of nonlinearity).
©2013 by American Society of Clinical Oncology
Yothers G et al. JCO 2013;31:

23. Recurrence-free interval for (A) all patients and (B) stage II, (C) stage IIIA/B, and (D) stage IIIC patients by Recurrence Score (RS) groups and treatment in National Surgical Adjuvant Breast and Bowel Project C-07.
Recurrence-free interval for (A) all patients and (B) stage II, (C) stage IIIA/B, and (D) stage IIIC patients by Recurrence Score (RS) groups and treatment in National Surgical Adjuvant Breast and Bowel Project C-07. Thick lines represent fluorouracil (FU) –treated patients, and thin lines represent FU + oxaliplatin (FU + Ox) –treated patients. Gray, gold, and blue colors represent low, intermediate (int), and high RS groups, respectively. Across all patients (A), FU-treated patients in the high RS group had higher risk of recurrence compared with patients treated with FU + Ox (log-rank P = .016), whereas patients in the low RS group had similar recurrence risks (log-rank P = .98). Numbers of deaths without recurrence were 20, 30, and 12 in stage II, IIIA/B, and IIIC, respectively.
Yothers G et al. JCO 2013;31:
©2013 by American Society of Clinical Oncology

24. Overall Survival by Treatment, Stage II dMMR patients
P-value = for treatment
by MMR status interaction
With overall survival, in stage II patients with dMMR tumors, there was a statistically significant decreased OS in patients who were treated, compared to control, with a p-value of 0.03 and a hazard ratio of 3.1.
In addition there is a significant treatment by dMMR status interaction, indicating that the impact of treatment differed for patients with dMMR versus pMMR patients, with a p-value of
5 yr OS
Untreated %
Treated %
HR: 3.15 ( )
p=0.03
Stage II Colon Cancer:  Who to Treat, Who Not to Treat with Adjuvant Therapy

25. Kaplan–Meier estimates of disease-free survival (DFS) in the groups of patients given 5-fluorouracil and leucovorin (FL) or FOLFOX according to tumour p53 expression and microsatellite instability (MSI) phenotype.
Kaplan–Meier estimates of disease-free survival (DFS) in the groups of patients given 5-fluorouracil and leucovorin (FL) or FOLFOX according to tumour p53 expression and microsatellite instability (MSI) phenotype. Univariate analyses of uncensored DFS were carried out according to the method of Kaplan and Meier. For statistical analyses, the follow-up data were not censored, but only the first 8 years are shown, as there were no events later on. The percentages of patients who had not recurred at 36 months are indicated on the curves. The hazard ratios and 95% confidence intervals for recurrence were compared using a two-sided log-rank test.
Zaanan A et al. Ann Oncol 2009;21:
© The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please

26. REMARK diagram of mutation profiling of NSABP trials C-07 and C-08.
Gavin P G et al. Clin Cancer Res 2012;18:
©2012 by American Association for Cancer Research

27. Overlap of mutations in the BRAF, KRAS, NRAS, and PIK3CA are shown.
Overlap of mutations in the BRAF, KRAS, NRAS, and PIK3CA are shown. Each circle is drawn roughly to scale with the total number of cases for that specific mutation indicated as n. The size of the overlap between mutations is approximated with the specific numbers indicating the number of cases within the designated overlap. The total number of cases includes only cases for which data were available for all of the mutations.
Gavin P G et al. Clin Cancer Res 2012;18:
©2012 by American Association for Cancer Research

28. Kaplan–Meier plots of BRAF and MMR status cases.
Kaplan–Meier plots of BRAF and MMR status cases. A, Kaplan–Meier plot of SAR of patients who have had a recurrence. Thin line, BRAF-wt; thick line, BRAF-mutant. B, OS of patients segregated by MMR and BRAF status. Thin solid line, MMR-proficient (p) BRAF-wt; thick solid line, MMR-proficient BRAF-mutant; thin dashed line, MMR-deficient (d) BRAF-wt; thick dashed line, MMR-deficient BRAF-mutant.
Gavin P G et al. Clin Cancer Res 2012;18:
©2012 by American Association for Cancer Research

29. Kaplan–Meier survival plots for colorectal cancer according to combined MSI/BRAF subgroup.
Kaplan–Meier survival plots for colorectal cancer according to combined MSI/BRAF subgroup. A) Colorectal cancer–specific survival. B) Overall survival. Multi-group log-rank P values demonstrate statistically significant deviation of any one of the survival curves from the null hypothesis. MSI = microsatellite instability; MSS = microsatellite stable.
Lochhead P et al. JNCI J Natl Cancer Inst 2013;105:
© The Author Published by Oxford University Press. All rights reserved. For Permissions, please

30. The phosphatidylinositol 3-kinase (PI3K) signaling pathway and its potential interaction with the influence of aspirin on colorectal cancer (CRC) and the tumor microenvironment.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway and its potential interaction with the influence of aspirin on colorectal cancer (CRC) and the tumor microenvironment. Arrows represent activation, whereas bars reflect inhibition. Activated PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), leading to activation of the AKT and 3′-phosphoinositide-dependent kinase-1 (PDK1) kinases, which in turn phosphorylate several downstream effector pathways, thereby regulating a range of cellular processes, including cancer-cell proliferation, survival, motility, and metabolism. The tumor suppressor phosphatase and tensin homolog (PTEN) antagonizes PI3K activity by dephosphorylating PIP3. The mechanisms by which aspirin influences CRC cell growth and progression are poorly understood. Beyond a potential direct inhibitory effect of aspirin on CRC cells, aspirin may indirectly inhibit CRC progression through influences on the tumor microenvironment, including immune and inflammatory cells, platelets, and several other cell types. Note that the sizes and shapes of various cells and cellular compartments in this illustration do not reflect actual sizes and shapes. FOX, forkhead box; GF, growth factor; GSK, glycogen synthase kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; RTK, receptor tyrosine kinase.
Fuchs C S , and Ogino S JCO 2013;31:
©2013 by American Society of Clinical Oncology

31. Mortality among Patients with Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA Mutation Status.
Figure 1 Mortality among Patients with Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA Mutation Status. Panels A and B show colorectal cancer–specific mortality among patients with mutant-PIK3CA tumors and those with wild-type PIK3CA tumors, respectively, and Panels C and D show overall mortality in the respective subgroups of patients.
Liao X et al. N Engl J Med 2012;367:

32. Biomarkers Indicating Aspirin Efficiency
COX - 2 over expressing tumors
PIK3CA - mutant tumors
BRAF - wild type tumors
Nurses’ Health and Health Professional follow-up study
From Tougeron et. al. Clin Cancer Res 2013

33. Colorectal Cancer: Diet and Lifestyle Impact on Cancer Patients
Many studies on diet / lifestyle and risk of DEVELOPING colorectal cancer
Few studies show whether these factors affect patients with colorectal cancer
Disease recurrence
Survival
Tolerance to chemotherapy

34. Forest plots of hazard ratios (black divided by white) for death (overall survival [OS]), recurrence or death (recurrence-free survival [RFS]), and recurrence (recurrence-free interval [RFI]).
Forest plots of hazard ratios (black divided by white) for death (overall survival [OS]), recurrence or death (recurrence-free survival [RFS]), and recurrence (recurrence-free interval [RFI]). The vertical lines indicate a hazard ratio of 1.0 (no difference between black and white race), values less than 1.0 favor black patients, and values greater than 1.0 favor white patients. Solid rectangles represent the hazard ratio of each single randomized controlled trial; the area of each rectangle is proportional to the inverse of the variance of the estimate. The horizontal line represents the 95% confidence interval and arrowheads indicate that the confidence interval extends beyond the scale of the plot. The solid diamonds represent the overall estimated hazard ratio based on multivariable Cox models of overall survival, recurrence-free survival, and recurrence-free interval controlling for sex, stage, age, and treatment, either not controlling for study (pooled) or stratifying by study (stratified); the diamond’s width represents the 95% confidence interval of the hazard ratio. A) OS. B) RFS. C) RFI. CALGB = Cancer And Leukemia Group B; CI = confidence interval; INT = Intergroup; NCCTG = North Central Cancer Treatment Group; NSABP = National Surgical Adjuvant Breast and Bowel Project.
Yothers G et al. JNCI J Natl Cancer Inst 2011;103:
© The Author Published by Oxford University Press.

35. Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy
Kaplan‐Meier plots illustrate the association of body mass index category with the time‐ to‐ recurrence and overall survival for (A,C) men and (B,D) women with resected, stage II and III colon cancer who participated in adjuvant chemotherapy trials.
© This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party.
Cancer Volume 119, Issue 8, pages , 10 JAN 2013 DOI: /cncr

36. CALGB 89803: DFS By Dietary Pattern4
1.2 2
2.2
3.9
Western diet
P, trend < 0.001
3.5 3
2.5 2
Hazard Ratio for Cancer Recurrence or Death
1.5
1.3 1
1.1
0.7 1
Prudent diet
0.5 1 2 3 4 5
Quintiles of Dietary Pattern
Meyerhardt, J. et al. JAMA (7):

37. Plasma Vitamin D and Survival in Colorectal Cancer Patients: NHS/HPFS (N = 304)1 1
0.9
0.89
0.83
0.8
P, trend = 0.01
0.7
0.6
Hazard Ratio for Death
0.5
0.49
0.4
( )
0.3
People with highest
level of vitamin D have 50% improvement
in outcome
0.2
0.1
<22.8
>33.1
Quintiles of plasma Vitamin D ng/mL
Ng et al J Clin Oncol Jun 20;26(18):

38. Clinical potential of prognostic gene expression–based tests for colon cancer stage II and III. According to standard protocols, adjuvant treatment of patients with colon cancer stage II and III is decided by assessment of risk of relapse after surgical res...
Clinical potential of prognostic gene expression–based tests for colon cancer stage II and III. According to standard protocols, adjuvant treatment of patients with colon cancer stage II and III is decided by assessment of risk of relapse after surgical resection. For patients with stage II (left), this currently relies on clinicopathological high-risk parameters (listed in the Introduction), and MSI status is also recommended for consideration. Several gene expression–based tests have shown great potential for improvement of risk assessment for patients with stage II (blue). Colon cancer stage III presents with lymph node metastases (right) and these patients are routinely offered adjuvant treatment. However, elderly and frail patients are less commonly treated with chemotherapy. For patients older than 75 years, clinical guidelines are less clear, and improved prognostic assessment could aid in the decision to treat. This patient group has received less focus, and no prognostic gene expression–based tests have been thoroughly validated for elderly patients alone. However, ColoGuidePro has been shown to have potential from analyses of a small patient series. For patients with stage III in general, prognostic potential has been shown also for ColoPrint.
Sveen A et al. Clin Cancer Res 2013;19:
©2013 by American Association for Cancer Research

39. MSS or MSI-L with retention of 18q alleles
E5202 Trial Schema
Arm A:
mFOLFOX6
q2w × 12
High-Risk Patients
MSS/18q LOH or
MSI-L/18q LOH
are
RANDOMIZED
Arm B:
mFOLFOX6 +
bevacizumab*
q2w × 12
Stratify:
Disease stage
(IIA or IIB)
Microsatellite stability
(stable vs MSI)
18q LOH
Low-Risk Patients
MSS or MSI-L with retention of 18q alleles
MSI-H
Arm C:
Observation only
MSI-L = low-level microsatellite instability
MSI-H = high-level microsatellite instability
*Bevacizumab continued for an additional 6 months
Biomarker-Driven Design: Complexities Using A Colon Cancer Model

40. Stage II CRC Treatment Summary:
Discuss risks with patients including potential link between risk and lifestyle factors and race
MSI testing for Stage II patients
Acknowledge risk is not associated with treatment efficiency (T3 MSS)

41. Stage II CRC Treatment Summary:
5FU/capecitabine remains an appropriate consideration
(T3 MSS, elderly)
Discuss lifestyle changes = diet, exercise
MSI-H T3 – no treatment
Oxaliplatin + 5FU/capecitabine (T4b MSI-H and high risk, MSS BRAF mutated)
Role of ASA for patients with mutated – PIK3CA evolving

43. Observed Survival Rates for 28,491 Cases with Adenocarcinoma of the Colon
Reproduced with permission from Springer.
Edge SB, et al (eds.) AJCC Cancer Staging Manual and Handbook,
7th edition. New York, NY: Springer; 2009.

44. Recurrence-free interval by stage and treatment in National Surgical Adjuvant Breast and Bowel Project C-07.
Recurrence-free interval by stage and treatment in National Surgical Adjuvant Breast and Bowel Project C-07. Thick lines represent fluorouracil (FU) –treated patients, and thin lines represent FU + oxaliplatin (FU + Ox) –treated patients. Blue and gold colors represent stage II and III, respectively.
Yothers G et al. JCO 2013;31:
©2013 by American Society of Clinical Oncology

45. Rates of (A) disease-free, (B) relapse-free, (C) overall, and (D) post–disease-free survival in patients older than 70 years treated with leucovorin and fluorouracil with oxaliplatin (FOLFOX4) or without (FL).
Rates of (A) disease-free, (B) relapse-free, (C) overall, and (D) post–disease-free survival in patients older than 70 years treated with leucovorin and fluorouracil with oxaliplatin (FOLFOX4) or without (FL).
Tournigand C et al. JCO 2012;30:
©2012 by American Society of Clinical Oncology

46. K-M plot of recurrence-free survival in C-07 according to treatment and MMR status.
Gavin P G et al. Clin Cancer Res 2013;19:1301
©2013 by American Association for Cancer Research

47. The effect of bevacizumab (Bev) treatment on overall survival by mismatch repair (MMR) status for colon cancer: NSABP C-08.
The effect of bevacizumab (Bev) treatment on overall survival by mismatch repair (MMR) status for colon cancer: NSABP C-08. A) MMR deficient. B) MMR proficient. In each panel, the survival estimates are derived by the Kaplan–Meier method, and the hazard ratio (HR), confidence intervals (CIs), and P value come from a Cox regression model containing only an indicator variable for treatment. The MMR–treatment interaction test (P = 0.04) is from a Cox regression model including indicator variables for MMR, bevacizumab treatment, and the interaction term. All statistical tests were two-sided. mFF6 = modified FOLFOX6.
Pogue-Geile K et al. JNCI J Natl Cancer Inst 2013;105:
© The Author Published by Oxford University Press. All rights reserved. For Permissions, please