From Chemotherapy to Targeted Therapy in Adjuvant Treatment for Stage III Colon Cancer

From Chemotherapy to Targeted Therapy in Adjuvant Treatment for Stage III Colon Cancer Aimery de Gramont,a,b,c Armand de Gramont,a,c Benoist Chibaudel,a Jean-Baptiste Bachet,d Annette K. Larsen,c Christophe Tournigand,a,c Christophe Louvet,c,e and Thierry André,b,c,d for GERCOR (French Oncology Research Group) Colorectal cancer represents a major public health problem due to its frequency and mortality rate. Adjuvant chemotherapy has improved the prognosis of colon cancer. Six months of oxaliplatin and fluoropyrimidine in combination is the standard adjuvant treatment in stage III patients. Ongoing trials are evaluating the optimal duration of chemotherapy. A critical issue, which needs to be specifically addressed, is the role of adjuvant therapy in elderly patients. Preliminary results of trials evaluating targeted therapies in combination with chemotherapy have shown disappointing results. The monoclonal antibodies bevacizumab, targeting vascular endothelial growth factor (VEGF) and cetuximab, targeting epidermal growth factor receptor (EGFR)/HER1, which improved survival in patients with metastatic colorectal cancer, could even induce chemotherapy resistance in a significant number of patients in the adjuvant setting. A major challenge is emerging to understand the mechanism leading to this effect and to multi-target the tumor cell proliferation and survival network. Clarity regarding the clinical signal needed before launching a phase III study and optimized designs adapted to multiple agents are urgently needed for new trials. Semin Oncol 38:521-532 © 2011 Elsevier Inc. All rights reserved.

C

olorectal cancer is the third most common cancer in both men and women and the fourth leading cause of cancer deaths in the world.1 The lifetime risk of developing colorectal cancer in the United States is about 7%. Approximately 70% to 80% of the colorectal cancer cases are colon cancer as defined by the inclusion criteria in colon cancer adjuvant trials: presence of the inferior pole of the tumor above the peritoneal reflection that is at least 15 cm from the anal margin or by a distal end of the tumor more than 12 cm from the anal verge.2–5 aService

d’Oncologie médicale, Hôpital Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Paris, France. bInstitut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 938 Paris, France. cUniversité Pierre et Marie Curie (Paris 6), Paris, France. dHôpital La Pitié-Salpétrière, Assistance Publique des Hôpitaux de Paris, Paris, France. eDépartement d’Oncologie Médicale. Institut Mutualiste Montsouris, Paris, France. Disclosure: Honoraria and consulting fees: Sanofi-Aventis (A. de Gramont), Roche (A. de Gramont). Address correspondence to Aimery de Gramont, MD, Service d’Oncologie Médicale, Hôpital Saint-Antoine, 75012 Paris, France. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2011.05.006

Seminars in Oncology, Vol 38, No 4, August 2011, pp 521-532

Stage III colon cancers are defined as tumors that have spread to the lymph nodes without distant metastases. The exact incidence of stage III at presentation is not precisely known due to an important number of patients with unknown stage in registries. It ranges between 20% and 30% of all cases at presentation. In the Surveillance, Epidemiology, and End Results (SEER) database, among 127,927 colon cancer stage I to III patients who were diagnosed between 1996 and 2004, 24.2% were stage I, 38.7% stage II, 33.5% stage III, and 3.6% unknown.5 Stage III colon cancer is further divided into stage IIIA, IIIB, and IIIC according to the size of the tumor and the number of involved lymph nodes. Staging is the main prognostic factor for survival or relapse after surgery. The updated American Joint Committee in Cancer (AJCC) staging (7th edition) is summarized in Table 1.6 Of note, this updated staging identified a subset of stage III patients with better prognosis than some stage II patients. The 3-year disease-free survival (DFS) in stage III cancer without any postoperative chemotherapy ranges between 44% and 52%.7,8 It was shown in the early 1990s that adjuvant chemotherapy with 5-fluorouracil (5-FU) and levamisole improved DFS and overall survival (OS) in stage III colon cancer.7 A few years later, 5-FU and leucovorin (LV) replaced 5-FU and le521

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Table 1. Stage III Colon Cancer Staging

T1: The cancer has grown through the muscularis mucosa and extends into the submucosa. T2: The cancer has grown through the submucosa and extends into the muscularis propria (thick outer muscle layer). T3: The cancer has grown through the muscularis propria and into the outermost layers of the colon or rectum but not through them. It has not reached any nearby organs or tissues. T4a: The cancer has grown through the serosa (also known as the visceral peritoneum), the outermost lining of the intestines. T4b: The cancer has grown through the wall of the colon or rectum and is attached to or invades into nearby tissues or organs. N0: No cancer in nearby lymph nodes. N1a: Cancer cells are found in 1 nearby lymph node. N1b: Cancer cells are found in 2 to 3 nearby lymph nodes. N1c: Small deposits of cancer cells are found in areas of fat near lymph nodes, but not in the lymph nodes themselves. N2a: Cancer cells are found in 4 to 6 nearby lymph nodes. N2b: Cancer cells are found in 7 or more nearby lymph nodes. A satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the site-specific factor category Tumor Deposits. M0: Cancer has not spread to distant sites. Stage IIIA One of the following applies. T1–T2, N1, M0 T1, N2a, M0 Stage IIIB T3–T4a, N1, M0 T2–T3, N2a, M0 T1–T2, N2b, M0 Stage IIIC T4a, N2a, M0. T3–T4a, N2b, M0 T4b, N1–N2, M0 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com.

vamisole as the new standard adjuvant therapy; this is now challenged by oral fluoropyrimidines.8,9 The next step was achieved in 2004 by the success of the 5-FU, LV, and oxaliplatin combination.3,4 Of note, in the development of adjuvant therapy for colon cancer, 3-year DFS has been recommended by the US Food and Drug Administration (FDA) Oncology Drugs Advisory Committee (ODAC) as a new regulatory endpoint for full approval in adjuvant colon cancer based on the validation of its surrogacy for 5-year OS.10 This review is dedicated to adjuvant therapy in stage III colon cancer from the pivotal clinical trials to the ongoing trials involving targeted therapies. Biomarkers and special issues, like the results of adjuvant therapy in elderly patients or the disappointing results of targeted therapies, also will be discussed.

STANDARD ADJUVANT CHEMOTHERAPY 5-Fluorouracil The Intergroup study INT-0089 showed equivalence between the modified Roswell Park regimen (weekly high dose LV and bolus 5-FU) and the Mayo Clinic regimen (daily ⫻ 5 bolus LV and 5-FU), as well as equivalence between 6 months and 12 months of adjuvant chemotherapy.11 At the same time, Sargent and colleagues demonstrated that elderly patients could benefit from adjuvant therapy.12 Interestingly, the LV5-FU2 (fortnightly LV and 5-FU bolus plus infusion) regimen, the backbone of combination chemotherapies, also was compared to monthly high-dose LV and bolus 5-FU in a trial including stage II and III colon cancer. There was no statistical improve-

Adjuvant therapy of colon cancer

ment in DFS, but LV5-FU2 became an accepted standard due to the improved safety profile.13,14

Oral Fluoropyrimidines: Capecitabine and UFT The X-ACT trial compared intravenous (IV) bolus 5-FU/LV (Mayo Clinic regimen) with oral capecitabine for 6 months in stage III colon cancer. DFS in the capecitabine arm was at least equivalent to the control arm (hazard ratio [HR] 0.87, P ⬍.001 for noninferiority).15 UFT (oral uracil and tegafur) plus LV, initially developed and used in Japan, was compared to weekly bolus 5-FU, and the results showed similar DFS and OS.16,17

Combinations With Fluoropyrimidines Several phase III trials conducted in the late nineties in patients with metastatic colorectal cancer demonstrated that adding irinotecan or oxaliplatin to 5-FU/LV increased the response rates up to 50%, and prolonged progression-free survival (PFS) and OS.18 –20 Both drugs have been tested as adjuvant chemotherapy in combination with fluoropyrimidines.

Oxaliplatin Fluoropyrimidine and oxaliplatin combination trials led to a significant advantage in term of survival in three phase III trials.3,4,21 The MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) adjuvant chemotherapy study recruited 2,246 patients with stage II or III colon cancer.3 FOLFOX4 (FOLinic acid, 5-FU and OXaliplatin) which combines LV5-FU2 and oxaliplatin was compared to LV5-FU2 alone for 6 months. In stage III patients, adding oxaliplatin resulted in a 23% improvement of DFS (HR 0.77, P ⫽ .002). Updated results showed 5-year DFS rates of 66.4% and 58.9% for FOLFOX 4 and LV5-FU2, respectively (HR 0.78; P ⫽ .005; a difference of 7.5% favoring FOLFOX); in the stage III subgroup 6-year OS rates were 72.9% and 68.7%, respectively (HR 0.80; P ⫽ .023).3,22 Of note, in the 460 stage IIIC patients, the difference in OS was 11.8% favoring FOLFOX4 (unpublished data). Based on these results, FOLFOX4 was approved as adjuvant therapy after surgery in patients with stage III colon cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial C-07 evaluated the FLOX regimen (oxaliplatin added to weekly bolus of 5-FU/LV) in 2,492 stage II and III colon cancer patients.4 The extent of benefits afforded by oxaliplatin on 3-year DFS was equivalent to the one reported in the MOSAIC study (HR 0.80, P ⬍.004); a later follow-up indicated a persistence of this DFS advantage over the 5-FU/LV bolus regimen. Lastly, the superiority of XELOX (capecitabine and oxaliplatin) over bolus 5-FU/LV as adjuvant treatment

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Table 2. Results Achieved in the Oxaliplatin

Trials in Stage III Patients Stage III ⌬ DFS DFS HR ⌬ OS OS HR N1 DFS HR N2 DFS HR Grade 5 toxicity

MOSAIC (FOLFOX4)

C07 (FLOX)

XELOXA (XELOX)

7.5% 0.78 4.2% 0.80 0.84 0.70 0.5%

7.8% 0.80 4.2% 0.85

6.3% 0.80 3.4% 0.87 0.73 0.85 0.7%

1.2%

Abbreviations: DFS, disease-free survival; HR, hazard ratio; OS, overall survival; ⌬, difference between the oxaliplatin arm and the control arm.

for stage III colon cancer has been shown in the NO16968 trial (1,886 patients), with a 3-year DFS of 71.0% versus 67.0%, respectively (HR 0.80, P ⫽ .0045).21 Of note, the different fluoropyrimidine regimens between the two arms did not allow to attribute the benefit to oxaliplatin alone. Table 2 summarizes the main results achieved in the oxaliplatin trials in stage III patients. More toxicityrelated deaths were observed with FLOX than with FOLFOX and XELOX. Updated results are needed to confirm that the HR for survival is the same between XELOX and the other regimens. There is also another concern with the XELOX results for the stage IIIC patients, for which the results might be inferior to those observed with the other oxaliplatin-based regimens.

Irinotecan Although oxaliplatin and irinotecan can be considered equivalent in the advanced setting,23 three studies of adjuvant irinotecan added to 5-FU/LV failed to show any improvement compared to the control arms. The Cancer and Leukemia Group (CALGB) C89803 study compared the IFL regimen (irinotecan, 5-fluorouracil, leucovorin) with bolus 5-FU/LV in 1,264 patients with stage III colon cancer. Neither DFS (P ⫽ .85) nor OS (P ⫽ .74) were improved.24 The ACCORD2 and the PETACC3 (Pan European Trial in Adjuvant Colon Cancer)/V307 studies compared infusional 5-FU/LV to irinotecan plus infusional 5-FU/LV.25,26 None of these studies met the primary endpoint of superiority of the irinotecan-based chemotherapy over 5-FU alone: the ACCORD2 study showed 51% versus 60% for the 3-year DFS (HR 1.19, P ⬍.22) in 400 high-risk stage III colon cancer patients25; the PETACC3/V307 study 3-year DFS reached 63% with LV5-FU2 plus irinotecan versus 61% with LV5-FU2 alone (HR 0.90, P ⫽.106) in 2,094 pa-

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Table 3. Adjuvant Colon Cancer Pivotal Trials in Stage III Patients

Trial

n

Endpoint

Stage

INT-0035 NSABP C-04

929 2078

OS DFS, OS

INT-0089

3759

DFS

III Dukes B/C II and III

905

DFS

X-ACT

1987

DFS

Dukes B2/C III

MOSAIC NSABP C-07

2246 2407

DFS DFS

II and III II and III

CALGB 89803

1264

OS

III

PETACC-3 NO16968 NSABP C-08

3278 1886 2710

DFS DFS DFS

II and III III II and III

AVANT

3451

DFS

II and III

N0147 PETACC8

2581 2500

DFS DFS

III III

GERCOR C96

Trial Conclusions

References

5-FU/levamisole superior to observation 5 FU/LV superior to 5-FU/levamisole

7 9

Equivalency of 6- and 12-month treatment cycles and of high-dose v low-dose LV Equivalency of LV5-FU2 and monthly 5FU/LV Capecitabine equivalency with LV5-FU bolus; less toxic FOLFOX4 superior to LV5-FU2 Bolus 5-FU/LV⫹ oxaliplatin (FLOX) superior to 5-FU/LV No advantage for bolus IFL in stage III adjuvant CRC LV5-FU2 ⫹ CPT11 not superior to LV5-FU2 XELOX superior to 5-FU/LV No advantage to bevacizumab with FOLFOX No advantage to bevacizumab with FOLFOX or XELOX No advantage to cetuximab with FOLFOX Pending

11 13 15 2,22 4 24 26 21 33 38 43,44

Abbreviations: DFS, disease-free survival; OS, overall survival; 5-FU, fluorouracil; LV, leucovorin; IFL, irinotecan/fluorouracil/leucovorin; CPT11, irinotecan.

tients with stage III colon cancer.26 Thus, irinotecan should not be combined with fluoropyrimidine therapy in the adjuvant setting. Table 3 summarizes the pivotal adjuvant trials in colon cancer.

TARGETED THERAPIES IN ADJUVANT COLON CANCER THERAPY Bevacizumab Vascular endothelial growth factor (VEGF) is the main factor controlling tumor-associated angiogenesis. Bevacizumab is a humanized monoclonal antibody targeting VEGF. Adding bevacizumab to standard chemotherapy (5-FU/irinotecan, 5-FU/oxaliplatin, or 5-FU alone) improves outcomes in patients with metastatic colorectal cancer.27–30 Angiogenesis also plays an important role in early-stage colorectal cancer, which justify to test angiogenesis inhibitors in the adjuvant setting.31 In fact, adjuvant antiangiogenic treatments could suppress micrometastasis vascularization and thereby tumor growth. The NSABP C-08 and the AVANT (AVastin adjuvant) trials evaluated bevacizumab in combination with oxaliplatin-based chemotherapy in patients with stage II–III colon cancer. The NSABP C-08 trial compared, in 2,710 stage II or

III patients, the fortnightly modified FOLFOX6 regimen (LV 400 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2/46 h) for 6 months to the same regimen with bevacizumab (5 mg/kg every 2 weeks) followed by bevacizumab alone as maintenance therapy (5 mg/kg every 2 weeks) for an additional 6 months.32,33 Contrary to what was observed in advanced disease, arterial ischemia, gastrointestinal perforation, and hemorrhage events were not increased in the bevacizumab arms.32 After a short follow-up of 36 months, despite a transient DFS benefit in the first year (when bevacizumab was administered), DFS prolongation did not reach statistical significance; modified FOLFOX6 ⫹ bevacizumab and FOLFOX6 alone displayed 3-year DFS rates of 77.4% and 75.5%, respectively (HR 0.87; P ⫽ .08).33 Some preclinical models suggested that inhibition of angiogenesis could accelerate metastatic behavior.34 –36 Nonetheless, 2 years after discontinuation of treatment, no negative effect was observed in terms of recurrence, death, or second cancers in the FOLFOX6 ⫹ bevacizumab arm. The AVANT study compared FOLFOX4 (6 months) versus FOLFOX4 (6 months) with bevacizumab (12 months) versus XELOX (6 months) with bevacizumab (12 months) in 3,451 patients with stage II or III colon cancer. The primary objective of this trial was the DFS

Adjuvant therapy of colon cancer

in stage III patients only. The adverse event profile was comparable to the safety profile in metastatic disease and in the NSABP C-08 trial.37 A press released announced in September 2010 that the study did not meet its objectives and that the survival in the bevacizumab arms was inferior to the chemotherapy alone arm.38

Cetuximab Cetuximab is a chimeric human mouse monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It has been evaluated in combination with oxaliplatin- and irinotecan-based chemotherapies in advanced diseases, in which it has been shown that only tumors bearing a wild-type KRAS gene responded to cetuximab.39 In advanced disease with wild-type KRAS tumors, cetuximab plus irinotecan-based chemotherapy prolonged survival in first-line therapy,40 whereas cetuximab plus FOLFOX prolonged PFS in one trial but failed in another.41,42Two adjuvant trials tested the potential benefit of cetuximab in combination with FOLFOX in a KRAS wild-type population: NO147 and PETACC8. There was no improvement in DFS or OS with the addition of cetuximab to FOLFOX. The NO147 trial compared 12 cycles of the modified FOLFOX6 to the same regimen with cetuximab (250 mg/kg weekly after 400 mg/kg loading dose day 1) in 1,847 patients.43,44 Toxicities, especially rash (grade 3, 19% v 0%) and diarrhea (grade 3, 15% v 9%), were increased in the cetuximab arm, mainly in elderly patients. After a short follow-up of 15.9 months, the trial was closed when a preplanned analysis demonstrated no benefit for cetuximab. The 3-year DFS was even better with FOLFOX alone: 75.8% versus 72.3% for FOLFOX plus cetuximab (HR 1.2, P ⫽ .22). There was also a trend for 3-year OS inferiority: 87.8% with FOLFOX alone versus 83.9% for FOLFOX plus cetuximab (HR 1.3, P ⫽ .13). The subset of 717 patients with KRAS-mutated tumors did poorly with cetuximab. In these patients, the 3-year DFS favored FOLFOX alone with a 3-year DFS of 67.2% versus 64.2% for FOLFOX plus cetuximab (HR 1.2, P ⫽ .12) and the 3-year OS showed inferiority: 88.0% with FOLFOX alone versus 80.4% for FOLFOX plus cetuximab (HR 1.5, P ⫽ .12). Elderly patients had a poor outcome. The authors concluded that cetuximab may have a different form of activity on micrometastatic lesions compared to stage IV disease due to differences in tumor biology. This resulted in chemotherapy resistance driven by cetuximab in the KRAS-mutated tumors. The results of the PETACC8 trial, which aim to increase the DFS in the wild-type KRAS tumor patients as a primary objective, are expected in 2011.

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PROGNOSTIC FACTORS AND BIOMARKERS Unlike in stage II patients where biomarkers are urgently needed to better select the patients who need adjuvant therapy, in stage III patients with colorectal cancer, staging remains the main prognostic factor, including tumor (T) stage and the number of involved lymph nodes.6,45,46 In addition, the number of examined lymph node appears to be another strong prognostic factor.6,46,47 From the AJCC cancer staging manual, in cases of more than 15 examined lymph nodes compared to less than 10, survival benefit ranges from approximately 5% in patients with only one positive lymph node to almost 20% in patients with more than six positive lymph nodes.6 However, this difference was not observed with the FOLFOX regimen in the MOSAIC study, where survival curves are exactly the same in stage III patients with less, or at least, 12 examined lymph nodes (unpublished data).

BIOMARKERS IN PATIENTS TREATED WITH 5-FU AND IRINOTECAN Among the recent prospective translational studies, PETACC3 has shown that biomarkers were different in stage II and III diseases in patients receiving 5-FU or FOLFIRI. Pathological material was prospectively collected in 1,564 of 3,278 patients.48 The prognostic value of clinical and biological biomarkers was assessed in a multivariate analysis. In stage II tumors, poor prognostic biological biomarkers were low microsatellite instability (MSI; defective mismatch repair genes), while in stage III tumors, prognosis was impaired in presence of high p53 expression (HR 1.3, P ⫽. 015) and loss of SMAD4 (HR 1.6, P ⫽ .0002). Other data from the same translational study showed that the high MSI status is also associated with better relapse-free survival in stage III tumors (HR 0.59; 95% confidence interval [CI], 0.38 – 0.91; P ⫽ .016).47 Whereas KRAS mutation was not associated with any prognostic significance, BRAF mutation (7.9% of patients) was shown to be prognostic for death (P ⫽ .035) but not for recurrence (P ⫽ .35) in the entire population.49 Loss of heterozygosity at the 18q locus, previously described as a prognostic factor, was not confirmed in this study.50

Biomarkers in Patients Treated With 5-FU and Oxaliplatin KRAS mutation was a prognostic factor in patients receiving FOLFOX in the NO147 trial.44 In the adjuvant stage III setting, a retrospective study reported that the addition of oxaliplatin to 5-FU significantly improved the relapse-free survival in patients with deficient mismatch repair in comparison to 5-FU alone.51 However, these data have to be confirmed prospectively.

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Biomarkers in colorectal cancer and candidate biomarkers to individualize adjuvant therapy for colon cancer have been reviewed recently.52,53 In contrast to stage II patients, only a few biomarker studies have been realized in the stage III population. Among the potentially useful biomarkers, tumor-infiltrating lymphocytes and circulating tumor cells can be mentioned. The loss of the Chromobox homolog 7 (Cbx7), which may participate to the induction of the epithelial-mesenchymal transition (EMT), has been found to be a poor prognostic factor in a large series of 1,420 resected colon cancers.54 Of note, a gene signature study in stage III patients, based on a quantitative multi-gene reverse transcriptase–polymerase chain reaction (RTPCR) assay, is ongoing in patients treated in the MOSAIC and C07 trials. This new study is following the same methodology as the one used for the gene signature developed in stage II patients treated with fluoropyrimidines.55 However, validating the potential biomarkers, especially the predictive biomarkers, remains a difficult challenge56 (see also the article by Bohanes et al in this issue of Seminars in Oncology).

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This discrepancy between a permanent benefit in time to recurrence and a transient benefit in DFS and OS was mainly explained by an increase in deaths of other causes than colon cancer, especially second cancers, and by a shorter survival in the patients who relapsed. Both reflected a different management of recurrences and second cancer; fewer patients received chemotherapy and surgery of metastases in the oxaliplatin/5-FU arm compared to the 5-FU–alone arm. Whether it is due to investigators or to patients unable, or unwilling, to deal again with a demanding therapy, requires further analysis. There were also sex-related differences between the two arms of MOSAIC and, obviously, the general condition and comorbidities frequently affected the elderly population (unpublished data). Of note, in the NO147 study where all patients received oxaliplatin, the elderly population (HR 1.8; P ⫽ .07) with wild-type KRAS tumors also experienced worse survival than younger patients (HR 1.1; P ⫽ .80) when treated with cetuximab.44 Nevertheless, we believe that oxaliplatin can still be used in a well-selected population of elderly patients.

THE RECENT NEGATIVE ADJUVANT TRIALS ELDERLY PATIENTS Age is an important issue in colon cancer therapy for which the median age of the disease is over 70 years in Western countries. Life expectancy depends on sex and location. Based on United Nations data, the life expectancy in people over 70 years is approximately 10 years for males and 15 years for females.57 Adjuvant chemotherapy based on 5-FU with LV or levamisole achieved similar positive results in elderly patients, defined as patients over 70 years of age, as in younger patients in a meta-analysis of seven trials involving 3,351 patients, including 15% elderly patients.12 Combination chemotherapy with oxaliplatin achieved similar survival benefit and toxicity in young and elderly patients with metastatic colorectal cancer.58 However, a combined analysis of the two pivotal adjuvant trials evaluating oxaliplatin ⫹ 5-FU versus 5-FU failed to demonstrate a DFS and OS benefit in elderly patients despite a positive trend for time to recurrence.59 Altogether these data had a considerable impact on practice, discouraging oxaliplatin-based chemotherapy for adjuvant treatment of the elderly population. Results of the NO16968 trial comparing 5-FU/LV and XELOX appear to favor the oxaliplatin combination in the elderly population.21 However, longer follow-up and a careful analysis of data are needed to accept a difference between the oxaliplatin-based regimens.18 Reviewing the MOSAIC data, we found that the DFS and OS curves in the oxaliplatin arm were above the curves in the 5-FU alone arm until 4 years. Time to recurrence curve was clearly better in the oxaliplatin arm.60

Combinations of targeted therapy with chemotherapy have recently given a number of unexpected results that are far from being deciphered yet. Irinotecan, cetuximab, and bevacizumab are all approved and effective drugs in the treatment of metastatic colorectal cancer. However, different clinical trials had shown that these drugs are ineffective in adjuvant therapy for colorectal cancerr. In advanced disease, cetuximab restored tumor sensitivity to irinotecan in patients who had become resistant.61 Bevacizumab has been evaluated successfully in various diseases, including advanced colon cancer.27,29,30,62 Yet, cetuximab has been disregarded recently as a potential adjuvant agent and the new results of the AVANT clinical trial show that bevacizumab may compromise the chemotherapy benefit when used in an adjuvant setting.38,43,44 Deleterious results as seen in the NO147 and AVANT trials suggest that targeted agents are able to counteract the chemotherapy cytotoxic effects in the adjuvant setting. These observations raise questions. How do targeted therapies interact with chemotherapies? What may be the mechanisms by which targeted therapies induce resistance to chemotherapies in some patients? Are there common threads in resistance mechanisms that may explain, or at least hypothesize, why these drugs are ineffective in the adjuvant setting? Resistant mechanisms could be either acquired, ie, depend on the therapy, or intrinsic/inherent to the tumor itself, or even a combination of both. Table 4 summarizes some of the main potential resistance mechanisms for cetuximab, bevacizumab, and irinotecan. From their diversity, two common processes seem

Adjuvant therapy of colon cancer

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Table 4. Mechanisms of Resistance to Irinotecan, Cetuximab, and Bevacizumab

Drugs Irinotecan

Adjuvant Benefice No

Target

Potential Resistance Mechanisms

Topoisomerase I ● ● ● ●

Cetuximab

No

EGFR

Bevacizumab

No

VEGF

● ● ● ● ● ● ● ● ● ● ● ●

Uptake and metabolism alterations Multidrug resistance pathways Genetic and epigenetic alterations Protein delocalization/degradation/post-translational modifications DNA damage and replication checkpoints activation Pro-apoptotic pathways inhibition Survival pathways activation Network modularity Alternate growth and survival pathways activation Downstream pathway upregulation Receptor localization/activation/variants Hypoxia pathway activation Hypoxic selection of malignant metastatic cells Recruitment of pro-angiogenic agents Alternate angiogenesis pathways activation EMT/metastatic programs activation

Abbreviations: EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; EMT, epithelial-mesenchymal transition.

to stand out: setup of compensatory/alternate mechanisms and pro-survival pathways activation. These two processes are not exclusive of each other. Compensatory mechanisms and alternate pathway activation are the result of millions of years of evolution and adaptation. EGFR, as well as VEGF, signaling pathways are intricately connected to other signaling pathways to form a robust network. EGFR (ErbB1/HER1) is a member of the ErbB family of receptors with Her2 (ErbB2/HER2), Her3 (ErbB3/HER3), and Her4 (ErbB4/ HER4). In addition to their specific functions, ErbBs receptors share the ability to activate common pathways. Modularity will thus be one of the first mechanisms of resistance to network perturbation. Indeed, Her2 and Her3 activation have been shown to be associated with resistance to cetuximab and more generally to anti-EGFR therapies.63,64 Besides its own network, EGFR is also interlinked with other pathways such as c-MET or IGF-1R. As a consequence, activation of these pathways can compensate for EGFR inhibition by activating common downstream effectors. Following VEGF inhibition, expression of pro-angiogenic factors by the tumor or host cells, is another way to compensate the therapy-induced perturbations. Hypoxia, which is a consequence of anti-VEGF therapies, is able to trigger angiogenesis.65 Preclinical experiments have shown that adjuvant treatment with antiangiogenic agents enhances the burden of tumor metastases.66 Accordingly, angiogenic rebound or tumor growth acceleration following bevacizumab treatment interruption has been observed.66,67

An additional mechanism of indirect compensation may be the selection, under therapeutic pressure, of tumors cells susceptible to either grow in adverse environments or to resume growth at therapy cessation. Cancer stem cells, cells undergoing therapy-dependant EMT, or cells entering quiescent state are thus good candidates to initiate relapse. These observations highlight the widespread fact that therapeutics agents are, directly or indirectly, paving the way for their own resistance. The other common thread, among the different resistance mechanisms seen in Table 4, is the activation of pro-survival pathways. Basically, the tumor fate depends on the equilibrium between pro-apoptotic and pro-survival pathways. Chemotherapeutics, such as irinotecan or oxaliplatin, induce DNA damage to cycling cells that will ideally lead the tumors towards apoptosis. Unfortunately, DNA damage also induces checkpoints that will turn on pro-survival pathways to allow time for the cells to recover. As stated above, these antagonist effects are common and the cells’ fate only comes after one effect has overtaken the other. Adding targeted molecules to chemotherapy is supposed to enhance its cytotoxic effect. Nonetheless, anti-proliferative drugs such as cetuximab and bevacizumab may render the tumor cells less sensitive to chemotherapy. The early benefit observed in the NSABP C-08 trial is lost when the cells which acquired resistance or in quiescence-like state restart to grow in the absence of chemotherapy. Reducing the cycling potential of tumor cells or

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Table 5. Ongoing Phase III Trials in Adjuvant Colon Cancer Setting

Oral drugs

Stage II

Stage II–III

SACURA (Japan UFT v observation)

ACTS-CC* (Japan, UFT v S1)

Chemotherapy 3 v 6 months

Chemotherapy ⫹/⫺ panitumumab

JCOG0205* (Japan, 5-FU/LV v UFT)

IDEA (UK: SCOT, Italy: TOSCA, France: GERCOR-PRODIGE, US: CALGB/SWOG C08702)

Chemotherapy 6 v 12 months 6 v 18 months Chemotherapy ⫹/⫺ bevacizumab

Stage III

JFMC33–0502* (Japan, UFT/LV) JFMC37–0801 (Japan, capecitabine) ECOG5202 (high-risk stage II)

QUASAR2 (UK) TOSCA (Italy) FOxTROT (UK, neoadjuvant)

NOTE. Aspirin is studied in Asia. In addition to chemotherapy duration the CALGB/SWOG (Southwest Oncology Group) C08702 is evaluating celecoxib. PSK (protein-bound polysaccharide K) is evaluated in Japan.72 IDEA (International Duration Evaluation of Adjuvant Chemotherapy) colon cancer is a prospective pooled analysis of several trials. QUASAR ⫽ Quick And Simple And Reliable; TOSCA ⫽ FOLFOX4 Three versus Six months and Bevacizumab as Adjuvant Therapy for Patients With Stage II/III Colon Cancer; SCOT ⫽Short Course Oncology Therapy.

inducing pro-survival pathways may facilitate tumor resistance. In fact, DNA-PK, HIF-1␣, and ErbB-3, respectively activated by irinotecan, anti-VEGF, and anti-EGFR therapies, are, among other activated prosurvival factors, upregulating the Akt pathway.63,64,68 As the major survival axis, the Akt pathway is often upregulated in tumors, counteracting the effects of the cytotoxic therapies. One critical objective of tumor growth inhibition is to displace the equilibrium between survival and death towards pro-apoptotic mechanisms. This can be achieved by either promoting pro-apoptotic mechanisms,69 such as inducing the death cytokine TRAIL receptor pathway, or by inhibiting pro-survival pathways like the PI3K/ Akt axis. Interestingly, compensatory mechanisms and prosurvival pathways activation also exist in successful adjuvant trials such as FOLFOX4 in colorectal cancer or trastuzumab in breast cancer. Why are certain chemotherapies or targeted drug treatments successful as adjuvant therapies whereas others are not? Assessing more precisely tumors dependence on specific oncogenes as well as discovering the main resistance pathways will certainly help to avoid, in future treatment design, compensatory and alternate pathway activation and help adjuvant curative therapies. In this perspective, clinical investigations of new agents and their association with other targeted molecules or chemotherapy treatments, is essential to uncover how the molecular network truly operates in

vivo. Translational sciences will then be able to rationalize and guide best drug association to develop our capacity to fight adapting diseases.

ONGOING TRIALS AND FUTURE DIRECTIONS Several trials are ongoing, further evaluating oral drugs,70 duration of chemotherapy, and targeted therapies. These trials are summarized in Table 5. Among these trials, IDEA (International Duration Evaluation of Adjuvant Chemotherapy) is a prospective meta-analysis of individual trials looking at the duration of chemotherapy. Shorter duration might potentially reduce the costs, inconvenience, toxicity and risks of adjuvant therapy. If beneficial, a short adjuvant treatment would be interesting for future development in the elderly population.

Future Directions The relevance of adjuvant therapy in the elderly population is not questioned directly in present trials. Planned subgroup analyses should give some information but may be insufficient to conclude because specific biases have to be eliminated. Elderly patients represent an increasing part of treated colon cancer, especially in the localized setting. Dedicated trials should be designed to answer the important question of best adjuvant treatment in this population. The recent failure of promising agents evaluated in

Adjuvant therapy of colon cancer

529

Oxalipla
n benefit 80

3%

5%

10%

70

Poten
al oxalipla
n benefit Observed 5-year survival

Survival (%)

60

50

40

30

20

10

0

TNM stages Figure 1. Oxaliplatin absolute benefit in survival according to colon cancer stage (based on observed survival in the SEER database).

the advanced setting raise important questions for the future: what can we learn of the negative trials? What are the efficacy signals in earlier studies that should serve as prerequisites for proceeding to phase III? What should be the design of the future trials? We can regret that the cetuximab adjuvant trials were launched before having the results of the phase III regimen in advanced colorectal cancer therapy and the predictive role of the KRAS gene status. However, even a strong preclinical rationale, like the early need of VEGF to promote tumor growth and the knowledge derived from the successful phase III trials in the advanced setting, were not sufficient to be translated in successful adjuvant trials for bevacizumab. We have first to consider that the target is part of a network and we probably should not use a single targeted agent but a combination of targeted agents that not only inhibit the desired target but can also overcome the resistance mechanisms of the tumor cells.71 Co-development, which is not yet part of the standard development processes, raises an important regulation issue. Translational studies, evaluating therapy-dependant signals such as downstream effectors, survival and apoptotic pathways, should be integrated into the design of the new trials. Furthermore we also have to solve the ethical question raised by the negative trials that potentially increased the death rates. The

design of the new trials may incorporate an interim early analysis on a limited number of patients after a minimal follow-up, to show a positive or a negative trend on an early endpoint such as 2-year DFS (1 year might not be enough based on the NSABP C0 – 8 data).33,72

Conclusion Adjuvant chemotherapy has an important role in patients with stage III colon cancer while still debated in patients with stage II disease. Nevertheless, it is possible to identify subgroups of stage III patients to optimize the risk/benefit ratio of adjuvant therapy, especially when using oxaliplatin in combination. Figure 1 illustrates the potential benefit of oxaliplatin added to fluoropyrimidine based on the figures of relative survival in the SEER database, assuming that patients in the database only received 5-FU– based therapy and that the HR for survival with the addition of oxaliplatin was 0.8.22 The goal is not to replace decision tools, such as adjuvant on line,73 but to illustrate what can be expected with oxaliplatin-based therapy. Of note, 3% or more benefit in survival is the accepted figure to receive oxaliplatin by a majority of patients with colorectal cancer.74 Moving ahead of fluoropyrimidines and

530

oxaliplatin is a difficult challenge that can only be solved using targeted therapies in a global concept based on an increased knowledge of tumor biology, which has to be verified in trials with new designs.

REFERENCES 1. http://globocan.iarc.fr/summary_table_pop.asp?selection⫽ 219900&title⫽World&sex⫽0&type⫽0&window⫽1& sort⫽0&submit⫽%A0Execute%A0. 2. American Cancer Society. Cancer facts & figures 2009. Atlanta: American Cancer Society; 2009. Available at: www.cancer.org/downloads/STT/500809web.pdf. 3. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. The Multicenter International Study of Oxaliplatin/5- Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. N Engl J Med. 2004;350:2343–51. 4. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25:2198 –204. 5. Chou JF, Row D, Gonen M, Liu YH, Schrag D, Weiser MR. Clinical and pathologic factors that predict lymph node yield from surgical specimens in colorectal cancer: a population-based study. Cancer. 2010;116:2560 –70. 6. American Joint Committee on Cancer. AJCC cancer staging manual. 7th edition. New York: Springer; 2010. 7. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352– 8. 8. International Multicentre Pooled Analysis of Colorectal Cancer Trials (IMPACT). Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995;345:939 – 44. 9. Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol. 1999;17:3553–9. 10. Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2005;23:8664 –70. 11. Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in highrisk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005;23:8671– 8. 12. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001;345: 1091–7. 13. André T, Colin P, Louvet C, et al. A semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003;21:2896 –903.

A. de Gramont et al

14. André T, Quinaux E, Louvet C, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007;20:3732– 8. 15. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696 –704. 16. Sakamoto J, Ohashi Y, Hamada C, Buyse M, Burzykowski T, Piedbois P. Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol. 2004;22:484 –92. 17. Lembersky BC, Wieand HS, Petrelli NJ, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006;24:2059 – 64. 18. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first line treatment in advanced colorectal cancer. J Clin Oncol. 2000; 18:2938 – 47. 19. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000;343:905–14. 20. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355: 1041–7. 21. Haller DG, Cassidy J, Tabernero J, et al. Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): no impact of age on disease-free survival (DFS) [abstract 284]. 2010 Gastrointestinal Cancers Symposium. Orlando, FL; January 22–24, 2010. 22. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109 –16. 23. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229 –37. 24. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007;25:3456 – 61. 25. Ychou M, Hohenberger W, Thezenas S, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/ folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009;20:1964 –70. 26. Van Cutsem, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009;27:3117–25. 27. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for

Adjuvant therapy of colon cancer

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38. 39.

40.

41.

42.

metastatic colorectal cancer. N Engl J Med. 2004;350: 2335– 42. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in firstline metastatic colorectal cancer. Results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol. 2007;25: 1539 – 44. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9. Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989;339:58 – 61. Allegra C, Yothers G, O’Connell M, et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009;27:3385–90. Wolmark N, Yothers G, O’Connell MJ, et al. A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: results of NSABP protocol C-08 [abstract LBA-4]. J Clin Oncol. 2009;27 18s:793s. Loges S, Mazzone M, Hohensinner P, et al. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009;15:167–70. Ebos JM, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15: 232–9. Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220 –31. Hoff P, Clarke S, Cunnigham D, et al. A three-arm phase III randomized trial of FOLFOX-4 vs. FOLFOX-4 plus bevacizumab vs. XELOX plus bevacizumab in the adjuvant treatment of patients with stage III or high-risk stage II colon cancer: results of the interim safety analysis of the AVANT trial. Eur J Cancer Suppl. 2009;7:324. http://www.roche.com/investors/ir_update/inv-update2010-09-18b.html. Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374 –9. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408 –17. Bokemeyer C, Bondarenko I, Hartmann J, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2008;27:663–71. Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of ad-

531

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

vanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011, Jun 3. [Epub ahead of print]. Alberts SR, Sargent DJ, Smyrrk TC, et al. Adjuvant mFOLFOX6 with or without cetuximab in KRAS wild-type patients with resected stage III colon cancer: results from NCCTG intergroup phase III trial NO147. J Clin Oncol. 2010:28 18S:959s. Goldberg RM, Sargent DJ, Thibodeau N, et al. Adjuvant mFOLFOX6 plus or minus cetuximab in patients with KRAS mutant resected stage III colon cancer: NCCTG intergroup phase III trial NO147. J Clin Oncol. 2010:28 15S:262s. Bachet JB, Laurent-Puig P, de Gramont A, André T. Microsatellite status and adjuvant chemotherapy in patients with stage II colon cancer. Curr Colorectal Cancer Rep. In press. Johnson PM, Porter GA, Ricciardi R, Baxter NN. Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol. 2006;24:3570 –5. Berger AC, Sigurdson ER, LeVoyer T, et al. Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol. 2005;23:8706 –12. Roth AD, Tejpar S, Yan P, et al. Molecular markers in colon cancer have a stage specific prognostic value. Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60 – 00 trial. J Clin Oncol. 2009;27 15S:4002. Roth AD, Tejpar S, Delorenzi M, et al, Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60 – 00 trial. J Clin Oncol. 2010:28: 466 –74. Watanabe T, WU TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196 –206. Zaanan A, Cuilliere-Dartigues P, Guilloux A, et al. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin. Ann Oncol. 2010;21:772– 80. Gangadhar T, Schilsky R. Molecular markers to individualize adjuvant therapy for colon cancer. Nat Rev Clin Oncol. 2010;7:318 –25. Deschoolmeester V, Baay M, Specenier O, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist. 2010;15:699 –731. Pallante PL, Terracciano L, Carafa V, et al. The loss of the CBX7 gene expression represents an adverse prognostic marker for survival of colon carcinoma patients. Eur J Cancer. 2010;46:2304 –13. Kerr D, Gray R, Quirke P, et al. A quantitative multi-gene RT-PCR assay for prediction of recurrence in stage II colon cancer: selection of the genes in 4 large studies and results of the independent, prospectively-designed QUASAR validation study. J Clin Oncol. 2009;27 15S: 4000. Buyse M, Sargent DJ, Grothey A, Matheson A, de Gramont A. Biomarkers and surrogate end points: the chal-

532

57. 58.

59.

60.

61.

62.

63.

64.

A. de Gramont et al

lenge of statistical validation. Nat Rev Clin Oncol. 2010;7:309 –17. http://data.un.org/Data.aspx?d⫽GenderStat&f⫽inID% 3A36. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006; 24:4085–91. Jackson McCleary NA, Meyerhardt J, Green E, et al. Impact of older age on the efficacy of newer adjuvant therapies in ⬎12500 patients with stage II/III colon cancer: findings from the ACCENT database. J Clin Oncol. 2009;27 15S:4010. Tournigand C, André T, Bacher JB, et al. FOLFOX4 as adjuvant therapy in elderly patients with colon cancer: subgroup analysis of the MOSAIC trial. J Clin Oncol. 2010;28 15S:266s. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337– 45. de Gramont A, Van Cutsem E. Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer. Oncology. 2005;69 suppl 3:46 –56. Wheeler DL, Huang S, Kruser TJ, et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008;27:3944 –56. Jain A, Penuel E, Mink S, et al. HER kinase axis receptor dimer partner switching occurs in response to EGFR

65. 66.

67.

68.

69.

70. 71.

72.

73. 74.

tyrosine kinase inhibition despite failure to block cellular proliferation. Cancer Res. 2010;70:1989 –99. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592– 603. Loges S, Mazzone M, Hohensinner P, Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009;15:167–70. Cacheux W, Boisserie T, Staudacher L, et al. Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Ann Oncol. 2008;19:1659 – 61. Rasheed ZA, Rubin EH. Mechanisms of resistance to topoisomerase I-targeting drugs. Oncogene. 2003;22: 7296 –304. Sinicrope FA, Rego RL, Foster NR, et al. Proapoptotic Bad and Bid protein expression predict survival in stage II and III colon cancers. Clin Cancer Res. 2008;14:4128 –33. Watanabe T. Ongoing colorectal cancer adjuvant trials in Japan. Curr Colorectal Cancer Rep. 2010;6:168 –174. Amit I, Wides R, Yarden Y. Evolvable signaling networks of receptor tyrosine kinases: relevance of robustness to malignancy and to cancer therapy. Mol Syst Biol. 2007; 3:151. Sargent DJ, Patiyil S, Yothers G, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT group. J Clin Oncol. 2007;25:4569 –74. http://www.adjuvantonline.com/index.jsp. Love N, Bylynd C, Meropol NJ, et al. How well do we communicate with patients concerning adjuvant systemic therapy? A survey of 150 colorectal cancer survivors. J Clin Oncol. 2007;25 18S:168s.