Emerging Treatments in Recurrent and Metastatic Colorectal Cancer

Metastatic colorectal cancer (mCRC) is a prevalent disease for which many new therapies have been developed over the past decade. Currently, standard of care chemotherapeutic regimens for mCRC include doublet cytotoxic chemotherapy with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab with or without chemotherapy, and single-agent cytotoxic chemotherapy or targeted therapy for patients intolerant of combination regimens. Recent studies have investigated the efficacy of triplet cytotoxic chemotherapeutic regimens, bevacizumab in combination with chemotherapy beyond first-line therapy disease progression, dual anti-VEGF and anti-EGFR antibody therapy, and the more novel agents ziv-aflibercept and regorafenib for treatment of mCRC. Furthermore, molecular profiling of CRC has identified several genetic alterations for which targeted therapies are currently being developed. Optimal drug combinations and treatment sequences have yet to be defined, but an expanding armamentarium of therapies with which to treat CRC offers a promising future.

Abstract

Metastatic colorectal cancer (mCRC) is a prevalent disease for which many new therapies have been developed over the past decade. Currently, standard of care chemotherapeutic regimens for mCRC include doublet cytotoxic chemotherapy with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab with or without chemotherapy, and single-agent cytotoxic chemotherapy or targeted therapy for patients intolerant of combination regimens. Recent studies have investigated the efficacy of triplet cytotoxic chemotherapeutic regimens, bevacizumab in combination with chemotherapy beyond first-line therapy disease progression, dual anti-VEGF and anti-EGFR antibody therapy, and the more novel agents ziv-aflibercept and regorafenib for treatment of mCRC. Furthermore, molecular profiling of CRC has identified several genetic alterations for which targeted therapies are currently being developed. Optimal drug combinations and treatment sequences have yet to be defined, but an expanding armamentarium of therapies with which to treat CRC offers a promising future.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

This activity is accredited for 1.25 contact hours. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

NCCN designates this continuing education activity for 1.25 contact hour(s) (0.125 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-13-115-H01-P.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/30361; and 4) view/print certificate.

Release date: October 4, 2013; Expiration date: August 31, 2014

Supported by education grants from Bayer HealthCare Pharmaceuticals Inc.; Genentech, USA; Lilly USA, LLC.; and sanofiaventis U.S. and Regeneron Pharmaceuticals.

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Differentiate the various treatment options for mCRC
  • Appraise the recent clinical trial results of anti-EGFR and anti-VEGF therapies for determining optimal drug combinations and treatment sequences for mCRC
  • Describe the 2 proven examples of genetic alterations leading to personalized therapy for patients with mCRC

Colorectal cancer (CRC) is both the third most prevalent and third most fatal tumor type in the United States, with an estimated 143,460 new cases and 51,690 deaths in 2012 alone.1 Although surgical resection with or without adjuvant chemotherapy can be a curative strategy for localized disease, a substantial number of patients with CRC will experience disease recurrence. Furthermore, a significant proportion of patients with newly diagnosed CRC have advanced disease. As a result, effective therapies for metastatic CRC (mCRC), whether recurrent or newly diagnosed, are greatly needed. Several new drugs have recently been approved for the treatment of CRC or are currently under development for this indication, and novel combinations of available drugs are also under investigation. This article reviews current standard therapies, novel drugs, emerging new therapeutic strategies, and unanswered questions regarding the treatment of mCRC.

Current Standards of Care in mCRC

For many years, fluoropyrimidines in combination with leucovorin were the sole efficacious agents for the treatment of mCRC.2,3 With the advent of oxaliplatin4 and irinotecan,5,6 however, treatment of mCRC with various combinations of these agents in addition to fluoropyrimidines led to significant improvement in overall survival. In general, doublet cytotoxic chemotherapy regimens have been effective and tolerable as palliative therapy for mCRC, and many standard options exist, including FOLFOX (5-FU, leucovorin, oxaliplatin), FOLFIRI (5-FU, leucovorin, irinotecan), XELOX (capecitabine, oxaliplatin), and others.7-9 For patients unable to tolerate doublet chemotherapy, infusional 5-FU and leucovorin or oral capecitabine, or single-agent irinotecan are still reasonable treatment options.6,9-11 In addition, first-line capecitabine plus bevacizumab was recently shown to improve both progression-free survival and response rate compared with capecitabine alone in elderly patients with mCRC in the open-label phase III AVEX trial.12 Targeted therapies against vascular endothelial growth factor (VEGF), such as bevacizumab and zivaflibercept (Tables 1 and 2); epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab (Tables 2 and 3); or multiple tyrosine kinases, such as regorafenib,13,14 have also improved the efficacy of mCRC treatment in selected patients, both in combination with cytotoxic chemotherapy and as single agents in some cases. In addition to systemic chemotherapy, surgical resection of limited metastatic disease can play an important, and sometimes curative, role in the treatment of select patients with mCRC.15,16 Despite the efficacy of these agents and techniques, optimal drug combinations and treatment sequences remain unclear, and this is currently an intense area of research in mCRC.

Triplet Cytotoxic Chemotherapy Regimens

In addition to standard doublet cytotoxic chemotherapy regimens, regimens containing all 3 active cytotoxic chemotherapeutic agents in the first-line setting have also been explored in the hope of significantly increasing response rates and overall survival for patients with mCRC. An Italian phase III trial randomized 244 patients with mCRC to either FOLFOXIRI (irinotecan, 165 mg/m2 day 1; oxaliplatin, 85 mg/m2 day 1; leucovorin, 200 mg/m2 day 1; and 5-FU, 3200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks) or the Douillard FOLFIRI regimen (irinotecan, 180 mg/m2 day 1; leucovorin, 200 mg/m2 days 1 and 2; and 5-FU, 400 mg/m2 bolus then 600 mg/m2 over 22 hours days 1 and 2, every 2 weeks) for 6 months as induction chemotherapy in the first-line metastatic setting.17,18 With a primary end point of response rate (RR), the FOLFOXIRI group was significantly superior to FOLFIRI (66% vs 41%; P=.0002). With a median follow-up of 60.6 months, patients in the FOLFOXIRI arm had statistically significant improvements in median progression-free survival (9.8 vs 6.8 months; hazard ratio [HR], 0.59; 95% CI, 0.45-0.76; P<.001) and median overall survival (23.4 vs 16.7 months; HR, 0.74; 95% CI, 0.56-0.96; P=.026). This survival advantage was partly from the patients who were able to undergo metastasectomy, because the survival benefit of FOLFOXIRI was no longer statistically significant compared with FOLFIRI when postmetastasectomy patients were excluded from the analysis. The 5-year survival rate of patients receiving FOLFOXIRI treatment was improved compared with those who received FOLFIRI, with a 7% absolute survival benefit over this period (15% vs 8%).

Table 1

Phase III Trials of Anti-VEGF Therapies in Metastatic Colorectal Cancer

Table 1

A similarly sized phase III study of first-line FOLFOXIRI (irinotecan, 150 mg/m2 day 1; oxaliplatin, 65 mg/m2 day 2; leucovorin, 200 mg/m2 days 2 and 3; and 5-FU, 400 mg/m2 intravenous bolus and 600 mg/m2 as a 22-hour continuous infusion on days 2 and 3) versus FOLFIRI (irinotecan, 180 mg/m2 day 1; leucovorin, 200 mg/m2 days 2 and 3; and 5-FU, 400 mg/m2 intravenous bolus and 600 mg/m2 as a 22-hour continuous infusion on days 2 and 3) every 2 weeks was also completed.19 In contrast to the Italian study, however, no overall survival advantage was seen for the FOLFOXIRI cohort (median overall survival, 19.5 and 21.5 months for FOLFIRI and FOLFOXIRI, respectively; P=.337), although this group did have statistically significant higher rates of toxicity. Lower cytotoxic chemotherapy doses and possible selection bias leading to superior median overall survival in this trial have been cited as possible reasons for this intertrial discordance.

Table 2

Phase III Trials of Anti-VEGF and Anti-EGFR Therapies in Metastatic Colorectal Cancer

Table 2

Before triplet cytotoxic chemotherapy regimens such as FOLFOXIRI can be considered standard of care in the first-line mCRC setting, however, their survival advantage and tolerable toxicity profile must be confirmed in larger, multinational studies. In the meantime, given the improved response rates and complete metastasectomy rates with FOLFOXIRI versus FOLFIRI, a possible role for this regimen is in patients with initially unresectable disease who might become surgical candidates with a robust response to chemotherapy, as suggested by Masi et al.20 Other active questions under investigation include the safety and efficacy of adding either anti-EGFR or anti-VEGF therapies to triplet cytotoxic regimens; preliminary results of these trials appear promising.21-24

Bevacizumab Beyond Progression

Prior studies have investigated whether bevacizumab, the monoclonal antibody targeting VEGF-A, affords a survival advantage when combined with cytotoxic chemotherapy either in the first- or second-line treatment of CRC.25,26 Until recently, however, whether the addition of bevacizumab to chemotherapy improved survival if started in the first-line setting and continued with chemotherapy beyond initial disease progression was unclear. In addition to registry-based retrospective analyses that attempted to answer this question, a European phase III trial prospectively randomized 820 patients to continuing bevacizumab or not with second-line chemotherapy after disease progression while on first-line bevacizumab-containing chemotherapy (“bevacizumab beyond progression”).27 Median overall survival for the bevacizumab plus chemotherapy group was significantly prolonged compared with the chemotherapy alone group (11.2 vs 9.8 months; P=.0062), as was progression-free survival (5.7 vs 4.1 months; P<.0001). Achievement of confirmed disease response was not statistically different between the groups, and no statistically significant increase was seen in bevacizumab-related adverse events.

Table 3

Phase III Trials of Anti-EGFR Therapies in Metastatic Colorectal Cancer

Table 3

Despite this small overall survival benefit for patients with mCRC receiving bevacizumab, significant risks are associated with the therapy, including arterial thromboembolic events, hemorrhage, and bowel perforation, and the cost for this therapy remains high. Whether particular subgroups of patients would benefit more from the addition of bevacizumab to chemotherapy is currently unclear, because validated predictive markers of response to bevacizumab have not yet been developed. In the United States, however, bevacizumab in combination with chemotherapy remains a standard of care for patients with mCRC who have no contraindication to this therapy.

VEGF and/or EGFR Antibody Therapy

Given the survival advantage conferred when targeting either VEGF or the EGFR in mCRC, the combination of these therapies was hypothesized to be additive to or synergistic with chemotherapy. The phase II BOND2 trial randomized 83 bevacizumab- and cetuximab-naïve patients with chemorefractory mCRC to cetuximab and bevacizumab with or without irinotecan.28 Time to progression (TTP), RR, and overall survival were all improved for the cetuximab/bevacizumab/irinotecan (CBI) arm compared with the cetuximab/bevacizumab (CB) arm, and toxicity profiles were similar. However, 2 subsequent larger phase III trials that combined chemotherapy with bevacizumab and either cetuximab or panitumumab in the first-line setting failed to demonstrate a similar survival advantage with the 3-pronged therapeutic approach.29,30 Patients in the PACCE trial were randomized to chemotherapy and bevacizumab with or without panitumumab, 6 mg/kd every 2 weeks. After early discontinuation of the trial because of futility, both median progression-free survival (10.0 vs 11.4 months; HR, 1.27; 95% CI, 1.06-1.52) and median overall survival (19.4 vs 24.5 months; HR, 1.43; 95% CI, 1.11-1.83) were found to be worse in the panitumumab-containing arm of the oxaliplatin-receiving patient cohort, even in patients with KRAS wild-type tumors. Toxicities were also much more significant in the panitumumab-containing arm. In CAIRO2, patients with mCRC were randomized to capecitabine, oxaliplatin, and bevacizumab with or without weekly cetuximab. Similar to the PACCE trial, median progression-free survival in the cetuximab-containing arm of CAIRO2 was only 9.4 months, in contrast to a median progression-free survival of 10.7 months in the non-cetuximab-containing arm (P=.01).30 Patients in the cetuximab-containing arm also had a worse quality of life in this trial because of increased toxicities associated with therapy. Based on these results, chemotherapy combined with anti-VEGF and anti-EGFR therapy is not recommended in the first-line setting, although whether this combination is also detrimental in later lines of therapy is unclear and is an ongoing area of research.

Furthermore, investigation is ongoing with regard to superiority of either anti-EGFR or anti-VEGF therapy in combination with FOLFIRI chemotherapy in the first-line setting, with results from the AIO KRK-0306 (FIRE-3) study recently reported.31 In this trial, although the primary end point of overall response rate was comparable between arms in the intent-to-treat analysis, superior overall survival was seen in patients with KRAS wild-type tumors receiving cetuximab plus FOLFIRI compared with those receiving bevacizumab plus FOLFIRI (28.8 vs 25.0 months; HR, 0.77; P=.0164; 95% CI, 0.620-0.953). From these trials and others, it is clear that the optimal sequences and/or combinations of biologics with or without chemotherapy have yet to be determined in mCRC.

Ziv-Aflibercept

In 2012, the anti-VEGF and anti-placental growth factor (anti-PlGF) agent ziv-aflibercept was approved by the FDA in combination with FOLFIRI for the treatment of patients with mCRC who had previously received an oxaliplatin-containing chemotherapeutic regimen. Ziv-aflibercept, a functional decoy VEGF receptor with a propensity to bind VEGF-A, VEGF-B, PlGF-1, and PlGF-2, was shown to improve progression-free and overall survivals in combination with FOLFIRI in the prospective, randomized, placebo-controlled phase III VELOUR trial.32 Patients in this study received FOLFIRI plus either ziv-aflibercept, 4 mg/kg intravenously, or placebo every 2 weeks until unacceptable toxicity or disease progression. Efficacy analysis of the 1226 randomized patients showed a small overall survival advantage for the ziv-aflibercept group compared with the placebo group (median overall survival, 13.50 vs 12.06 months; P=.0032) and improved progression-free survival (median progression-free survival, 6.90 vs 4.67 months; P<.001). Response rates of 19.8% and 11.1%, respectively, were seen (P<.001), with 30.4% of the patients overall having received prior bevacizumab. Grade 3 and 4 adverse events, both those associated with antiangiogenic agents and those typically associated with FOLFIRI, were seen more frequently in the ziv-aflibercept arm (83.5% vs 62.5%). Interestingly, efficacy of ziv-aflibercept was maintained even in prespecified subgroup analysis of patients having previously received bevacizumab. It is currently unclear, however, how significant a role ziv-aflibercept will play in the mCRC treatment landscape given its cost and the availability of other antiangiogenic agents, as well as negative studies of ziv-aflibercept both as a single agent and in preliminary studies in combination with oxaliplatin-containing regimens in the first-line setting.33,34 Importantly, studies are ongoing to define predictive biomarkers for response to ziv-aflibercept.

Regorafenib

Regorafenib, a multikinase inhibitor, was approved by the FDA in 2012 for the treatment of patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy, and with an anti-EGFR therapy, if KRAS wild-type. Regorafenib is an oral inhibitor of such tyrosine kinases as VEGFR1, VEGFR2, VEGFR3 and TIE2, among others. A preplanned interim analysis of the placebo-controlled phase III CORRECT study demonstrated an overall survival advantage for the regorafenib arm over placebo (6.4 vs 5.0 months; one-sided P=.0052), and progression-free survival advantage (1.9 vs 1.7 months; one-sided P<.000001).13 Notably, grade 3 or 4 treatment-related adverse events occurred in 54% of patients in the regorafenib arm compared with 14% of patients in the placebo arm; these regorafenib-related adverse events included hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Like ziv-aflibercept, predictive biomarkers have not yet been defined for regorafenib. However, unlike ziv-aflibercept or bevacizumab, regorafenib monotherapy seems to play a role in the treatment of refractory mCRC distinct from other therapies, provided the patients for whom it is prescribed have an adequate performance status.

Genomics-Driven Therapy of mCRC

Advances in the field of genomics, as recently exemplified by The Cancer Genome Atlas Network and others, have led to an increasing understanding of the genetic alterations underlying particular tumors such as CRC.35 Knowledge of these genetic alterations has led to initial efforts in CRC to personalize therapy for patients according to the biology of their tumors. Two proven examples of this approach are the selective treatment of KRAS wild-type tumors with anti-EGFR therapies, such as cetuximab or panitumumab,36-38 and the decision to forego adjuvant fluoropyrimidine monotherapy for patients with stage II CRC whose tumors have features of microsatellite instability.39-41

As more genetic alterations in CRC are discovered, however, efforts both to determine appropriate subgroups of patients for known therapies and to develop and test novel targeted agents for these tumors have escalated. For example, the PICCOLO study showed improved progression-free survival and response rate, although not overall survival, for patients with all-wild-type (KRAS codons 12, 13, 61, 146; BRAF codon 600; NRAS codons 12, 13, 61; PIK3CA codons 542, 545, 546 [exon 9] and 1047 [exon 20]) CRC treated with irinotecan and panitumumab compared with those treated with irinotecan alone.42 However, in patients with any of these mutations, panitumumab had no effect on progression-free survival or response rate, and an adverse effect on overall survival. These data emphasize the need for more comprehensive CRC genotyping and studies of tumor mutational effects on treatment efficacy.

In terms of developing novel therapies against these tumor subtypes, treatment of BRAF-mutated CRC with BRAF inhibitor monotherapy has not been as effective as was hoped,43 for example, partly because of upregulation of compensatory pathways.44,45 However, efforts are underway to develop rationally designed combinations of targeted therapies (eg, BRAF/MEK inhibition46 and others) for increased efficacy against these tumors. In addition, a recent observation that the regular use of aspirin correlates with improved survival among patients with PIK3CA-mutated CRC compared with PIK3CA wild-type CRC47 confirms the need for improved mechanistic understanding of tumor response to agents, both novel and approved. As underlying mechanisms of these novel drugs are elucidated, CRC clinical trials will need to become increasingly biomarker- and genomics-driven, as exemplified by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial in lung cancer48 and the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis (I-SPY 1) trial in breast cancer.49

Conclusions

The treatment landscape of mCRC has changed considerably over the past decade with the development of efficacious new agents and novel strategies with which to administer them. Many unanswered questions remain, however, including the best combinations and sequences in which to use these therapies. Interestingly, unlike in other tumor types, such as melanoma, immunotherapies do not seem to be effective in CRC, and investigational targets in CRC have primarily focused on signal transduction pathways. In this realm, better prognostic and predictive biomarkers are greatly needed. As the biologic underpinnings of these tumors are increasingly discovered and understood, molecular profiling and the selection of therapies according to an individual’s specific tumor biology will become more important. Understanding the genetic heterogeneity of tumors, optimizing treatment tolerability for patients, maximizing cost-effectiveness of these agents, and developing strategies to overcome both intrinsic and acquired resistance to these therapies will dominate the efforts to improve patient quality of life and survival in this disease.

Dr. Ciombor has disclosed that she has served on an advisory board for Bayer AG and is supported by NIH K12 CA9060625. Dr. Bekaii-Saab has disclosed that he has served as a consultant for Bristol-Myers Squibb Company; Bayer AG; Amgen Inc.; Genentech, Inc.; Regeneron Pharmaceuticals, Inc.; and sanofi-aventis U.S. LLC, and has received research grant funding from Pfizer Inc.; Oncolytics Biotech Inc.; and the National Cancer Institute.
EDITORKerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer NetworkMs. Green has disclosed that she has no relevant financial relationships.
CE AUTHORSDeborah J. Moonan, RN, BSN, Manager, CE Supporter OutreachMs. Moonan has disclosed the following relationship with commercial interests: AstraZeneca: Stockholder/Former Employee.Nicole B. Harrold, BS, Manager, Continuing Education and GrantsMs. Harrold has disclosed that she has no relevant financial relationships.Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information OperationsMs. Gregory has disclosed that she has no relevant financial relationships.

References

  • 1.

    SiegelRNaishadhamDJemalA. Cancer statistics, 2012. CA Cancer J Clin2012;62:1029.

  • 2.

    ThirionPMichielsSPignonJP. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol2004;22:37663775.

    • Search Google Scholar
    • Export Citation
  • 3.

    BuyseMThirionPCarlsonRW. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet2000;356:373378.

    • Search Google Scholar
    • Export Citation
  • 4.

    deBraudFMunzoneENoleF. Synergistic activity of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer with progressive disease while on or after 5-fluorouracil. Am J Clin Oncol1998;21:279283.

    • Search Google Scholar
    • Export Citation
  • 5.

    RougierPVan CutsemEBajettaE. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet1998;352:14071412.

    • Search Google Scholar
    • Export Citation
  • 6.

    CunninghamDPyrhonenSJamesRD. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet1998;352:14131418.

    • Search Google Scholar
    • Export Citation
  • 7.

    CassidyJClarkeSDiaz-RubioE. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol2008;26:20062012.

    • Search Google Scholar
    • Export Citation
  • 8.

    CheesemanSLJoelSPChesterJD. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer2002;87:393399.

    • Search Google Scholar
    • Export Citation
  • 9.

    AndreTLouvetCMaindrault-GoebelF. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer1999;35:13431347.

    • Search Google Scholar
    • Export Citation
  • 10.

    Van CutsemETwelvesCCassidyJ. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol2001;19:40974106.

    • Search Google Scholar
    • Export Citation
  • 11.

    FuchsCSMooreMRHarkerG. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol2003;21:807814.

    • Search Google Scholar
    • Export Citation
  • 12.

    CunninghamDLangILorussoV. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): results of a randomized international phase III trial (AVEX) [abstract]. J Clin Oncol2012;30(Suppl 34):Abstract 337.

    • Search Google Scholar
    • Export Citation
  • 13.

    GrotheyAVan CutsemESobreroA. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet2013;381:303312.

    • Search Google Scholar
    • Export Citation
  • 14.

    SchultheisBFolprechtGKuhlmannJ. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol2013;24:15601567.

    • Search Google Scholar
    • Export Citation
  • 15.

    AbdallaEKVautheyJNEllisLM. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg2004;239:818825.

    • Search Google Scholar
    • Export Citation
  • 16.

    CharnsangavejCClaryBFongY. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol2006;13:12611268.

    • Search Google Scholar
    • Export Citation
  • 17.

    MasiGVasileELoupakisF. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst2011;103:2130.

    • Search Google Scholar
    • Export Citation
  • 18.

    FalconeARicciSBrunettiI. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol2007;25:16701676.

    • Search Google Scholar
    • Export Citation
  • 19.

    SouglakosJAndroulakisNSyrigosK. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer2006;94:798805.

    • Search Google Scholar
    • Export Citation
  • 20.

    MasiGLoupakisFPollinaL. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg2009;249:420425.

    • Search Google Scholar
    • Export Citation
  • 21.

    LoupakisFCremoliniCMasiG. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer: results of the phase III randomized TRIBE trial [abstract]. J Clin Oncol2012;30(Suppl 34):Abstract 336.

    • Search Google Scholar
    • Export Citation
  • 22.

    SteinAAtanackovicDHildebrandtB. FOLFOXIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer: preliminary safety results from the OPAL study [abstract]. J Clin Oncol2012;30(Suppl 34):Abstract 515.

    • Search Google Scholar
    • Export Citation
  • 23.

    SaridakiZAndroulakisNVardakisN. A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Br J Cancer2012;107:19321937.

    • Search Google Scholar
    • Export Citation
  • 24.

    FalconeACremoliniCMasiG. FOLFOXIRI/bevacizumab versus FOLFIRI/bevacizumab as first-line treatment in unresectable metastatic colorectal cancer patients: results of the phase III TRIBE trial by GONO group [abstract]. J Clin Oncol2013;31(Suppl):Abstract 3505.

    • Search Google Scholar
    • Export Citation
  • 25.

    MacedoLTda Costa LimaABSasseAD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer2012;12:89.

    • Search Google Scholar
    • Export Citation
  • 26.

    GiantonioBJCatalanoPJMeropolNJ. 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 Oncol2007;25:15391544.

    • Search Google Scholar
    • Export Citation
  • 27.

    BennounaJSastreJArnoldD. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol2013;14:2937.

    • Search Google Scholar
    • Export Citation
  • 28.

    SaltzLBLenzHJKindlerHL. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol2007;25:45574561.

    • Search Google Scholar
    • Export Citation
  • 29.

    HechtJRMitchellEChidiacT. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol2009;27:672680.

    • Search Google Scholar
    • Export Citation
  • 30.

    TolJKoopmanMCatsA. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med2009;360:563572.

  • 31.

    HeinemannVvon WeikersthalLFDeckerT. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3) [abstract]. J Clin Oncol2013;31(Suppl):Abstract LBA3506.

    • Search Google Scholar
    • Export Citation
  • 32.

    Van CutsemETaberneroJLakomyR. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol2012;30:34993506.

    • Search Google Scholar
    • Export Citation
  • 33.

    TangPACohenSJKollmannsbergerC. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res2012;18:60236031.

    • Search Google Scholar
    • Export Citation
  • 34.

    PericayCSaundersMThomasA. Phase 2 randomized, noncomparative open-label study of aflibercept and modified FOLFOX6 in the first line treatment of metastatic colorectal cancer (AFFIRM) [abstract]. Ann Oncol2012;23(Suppl 4):iv518. Abstract O-0024.

    • Search Google Scholar
    • Export Citation
  • 35.

    Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature2012;487:330337.

  • 36.

    KarapetisCSKhambata-FordSJonkerDJ. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med2008;359:17571765.

    • Search Google Scholar
    • Export Citation
  • 37.

    LievreABachetJBBoigeV. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol2008;26:374379.

    • Search Google Scholar
    • Export Citation
  • 38.

    AmadoRGWolfMPeetersM. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol2008;26:16261634.

    • Search Google Scholar
    • Export Citation
  • 39.

    RibicCMSargentDJMooreMJ. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med2003;349:247257.

    • Search Google Scholar
    • Export Citation
  • 40.

    PopatSHubnerRHoulstonRS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol2005;23:609618.

    • Search Google Scholar
    • Export Citation
  • 41.

    SargentDJMarsoniSMongesG. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol2010;28:32193226.

    • Search Google Scholar
    • Export Citation
  • 42.

    SeymourMTBrownSRMiddletonG. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol2013;14:749759.

    • Search Google Scholar
    • Export Citation
  • 43.

    KopetzSDesaiJChanE. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors [abstract]. J Clin Oncol2010;28(15 Suppl):Abstract 3534.

    • Search Google Scholar
    • Export Citation
  • 44.

    CorcoranRBEbiHTurkeAB. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov2012;2:227235.

    • Search Google Scholar
    • Export Citation
  • 45.

    PrahalladASunCHuangS. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature2012;483:100103.

    • Search Google Scholar
    • Export Citation
  • 46.

    CorcoranRBFalchookGSInfanteJR. Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer [abstract]. J Clin Oncol2013;31(Suppl):Abstract 3507.

    • Search Google Scholar
    • Export Citation
  • 47.

    LiaoXLochheadPNishiharaR. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med2012;367:15961606.

  • 48.

    KimESHerbstRSWistubaII. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov2011;1:4453.

  • 49.

    EssermanLJBerryDADeMicheleA. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657. J Clin Oncol2012;30:32423249.

    • Search Google Scholar
    • Export Citation
  • 50.

    HurwitzHFehrenbacherLNovotnyW. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med2004;350:23352342.

    • Search Google Scholar
    • Export Citation
  • 51.

    SaltzLBClarkeSDiaz-RubioE. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol2008;26:20132019.

    • Search Google Scholar
    • Export Citation
  • 52.

    StathopoulosGPBatziouCTrafalisD. Chemotherapy with or without bevacizumab in advanced colorectal cancer: a phase III trial [abstract]. Presented at the 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Abstract 606P.

    • Search Google Scholar
    • Export Citation
  • 53.

    MasiGLoupakisFSalvatoreL. A randomized phase III study evaluating the continuation of bevacizumab beyond progression in metastatic colorectal cancer patients who received bevacizumab as part of first-line treatment: results of the BEBYP trial by the Gruppo Oncologico Nord Ovest (GONO) [abstract]. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA17.

    • Search Google Scholar
    • Export Citation
  • 54.

    Van CutsemEKohneCHHitreE. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med2009;360:14081417.

    • Search Google Scholar
    • Export Citation
  • 55.

    Van CutsemEKohneCHLangI. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol2011;29:20112019.

    • Search Google Scholar
    • Export Citation
  • 56.

    TveitKMGurenTGlimeliusB. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol2012;30:17551762.

    • Search Google Scholar
    • Export Citation
  • 57.

    MaughanTSAdamsRASmithCG. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet2011;377:21032114.

    • Search Google Scholar
    • Export Citation
  • 58.

    DouillardJYSienaSCassidyJ. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol2010;28:46974705.

    • Search Google Scholar
    • Export Citation
  • 59.

    PeetersMPriceTJCervantesA. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol2010;28:47064713.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Tanios Bekaii-Saab, MD, Division of Medical Oncology, Section of Gastrointestinal Oncology, The Ohio State University Comprehensive Cancer Center, A454 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. E-mail: Tanios.Bekaii-Saab@osumc.edu
  • 1.

    SiegelRNaishadhamDJemalA. Cancer statistics, 2012. CA Cancer J Clin2012;62:1029.

  • 2.

    ThirionPMichielsSPignonJP. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol2004;22:37663775.

    • Search Google Scholar
    • Export Citation
  • 3.

    BuyseMThirionPCarlsonRW. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet2000;356:373378.

    • Search Google Scholar
    • Export Citation
  • 4.

    deBraudFMunzoneENoleF. Synergistic activity of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer with progressive disease while on or after 5-fluorouracil. Am J Clin Oncol1998;21:279283.

    • Search Google Scholar
    • Export Citation
  • 5.

    RougierPVan CutsemEBajettaE. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet1998;352:14071412.

    • Search Google Scholar
    • Export Citation
  • 6.

    CunninghamDPyrhonenSJamesRD. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet1998;352:14131418.

    • Search Google Scholar
    • Export Citation
  • 7.

    CassidyJClarkeSDiaz-RubioE. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol2008;26:20062012.

    • Search Google Scholar
    • Export Citation
  • 8.

    CheesemanSLJoelSPChesterJD. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer2002;87:393399.

    • Search Google Scholar
    • Export Citation
  • 9.

    AndreTLouvetCMaindrault-GoebelF. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer1999;35:13431347.

    • Search Google Scholar
    • Export Citation
  • 10.

    Van CutsemETwelvesCCassidyJ. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol2001;19:40974106.

    • Search Google Scholar
    • Export Citation
  • 11.

    FuchsCSMooreMRHarkerG. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol2003;21:807814.

    • Search Google Scholar
    • Export Citation
  • 12.

    CunninghamDLangILorussoV. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): results of a randomized international phase III trial (AVEX) [abstract]. J Clin Oncol2012;30(Suppl 34):Abstract 337.

    • Search Google Scholar
    • Export Citation
  • 13.

    GrotheyAVan CutsemESobreroA. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet2013;381:303312.

    • Search Google Scholar
    • Export Citation
  • 14.

    SchultheisBFolprechtGKuhlmannJ. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol2013;24:15601567.

    • Search Google Scholar
    • Export Citation
  • 15.

    AbdallaEKVautheyJNEllisLM. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg2004;239:818825.

    • Search Google Scholar
    • Export Citation
  • 16.

    CharnsangavejCClaryBFongY. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol2006;13:12611268.

    • Search Google Scholar
    • Export Citation
  • 17.

    MasiGVasileELoupakisF. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst2011;103:2130.

    • Search Google Scholar
    • Export Citation
  • 18.

    FalconeARicciSBrunettiI. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol2007;25:16701676.

    • Search Google Scholar
    • Export Citation
  • 19.

    SouglakosJAndroulakisNSyrigosK. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer2006;94:798805.

    • Search Google Scholar
    • Export Citation
  • 20.

    MasiGLoupakisFPollinaL. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg2009;249:420425.

    • Search Google Scholar
    • Export Citation
  • 21.

    LoupakisFCremoliniCMasiG. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer: results of the phase III randomized TRIBE trial [abstract]. J Clin Oncol2012;30(Suppl 34):Abstract 336.

    • Search Google Scholar
    • Export Citation
  • 22.

    SteinAAtanackovicDHildebrandtB. FOLFOXIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer: preliminary safety results from the OPAL study [abstract]. J Clin Oncol2012;30(Suppl 34):Abstract 515.

    • Search Google Scholar
    • Export Citation
  • 23.

    SaridakiZAndroulakisNVardakisN. A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Br J Cancer2012;107:19321937.

    • Search Google Scholar
    • Export Citation
  • 24.

    FalconeACremoliniCMasiG. FOLFOXIRI/bevacizumab versus FOLFIRI/bevacizumab as first-line treatment in unresectable metastatic colorectal cancer patients: results of the phase III TRIBE trial by GONO group [abstract]. J Clin Oncol2013;31(Suppl):Abstract 3505.

    • Search Google Scholar
    • Export Citation
  • 25.

    MacedoLTda Costa LimaABSasseAD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer2012;12:89.

    • Search Google Scholar
    • Export Citation
  • 26.

    GiantonioBJCatalanoPJMeropolNJ. 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 Oncol2007;25:15391544.

    • Search Google Scholar
    • Export Citation
  • 27.

    BennounaJSastreJArnoldD. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol2013;14:2937.

    • Search Google Scholar
    • Export Citation
  • 28.

    SaltzLBLenzHJKindlerHL. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol2007;25:45574561.

    • Search Google Scholar
    • Export Citation
  • 29.

    HechtJRMitchellEChidiacT. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol2009;27:672680.

    • Search Google Scholar
    • Export Citation
  • 30.

    TolJKoopmanMCatsA. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med2009;360:563572.

  • 31.

    HeinemannVvon WeikersthalLFDeckerT. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3) [abstract]. J Clin Oncol2013;31(Suppl):Abstract LBA3506.

    • Search Google Scholar
    • Export Citation
  • 32.

    Van CutsemETaberneroJLakomyR. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol2012;30:34993506.

    • Search Google Scholar
    • Export Citation
  • 33.

    TangPACohenSJKollmannsbergerC. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res2012;18:60236031.

    • Search Google Scholar
    • Export Citation
  • 34.

    PericayCSaundersMThomasA. Phase 2 randomized, noncomparative open-label study of aflibercept and modified FOLFOX6 in the first line treatment of metastatic colorectal cancer (AFFIRM) [abstract]. Ann Oncol2012;23(Suppl 4):iv518. Abstract O-0024.

    • Search Google Scholar
    • Export Citation
  • 35.

    Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature2012;487:330337.

  • 36.

    KarapetisCSKhambata-FordSJonkerDJ. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med2008;359:17571765.

    • Search Google Scholar
    • Export Citation
  • 37.

    LievreABachetJBBoigeV. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol2008;26:374379.

    • Search Google Scholar
    • Export Citation
  • 38.

    AmadoRGWolfMPeetersM. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol2008;26:16261634.

    • Search Google Scholar
    • Export Citation
  • 39.

    RibicCMSargentDJMooreMJ. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med2003;349:247257.

    • Search Google Scholar
    • Export Citation
  • 40.

    PopatSHubnerRHoulstonRS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol2005;23:609618.

    • Search Google Scholar
    • Export Citation
  • 41.

    SargentDJMarsoniSMongesG. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol2010;28:32193226.

    • Search Google Scholar
    • Export Citation
  • 42.

    SeymourMTBrownSRMiddletonG. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol2013;14:749759.

    • Search Google Scholar
    • Export Citation
  • 43.

    KopetzSDesaiJChanE. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors [abstract]. J Clin Oncol2010;28(15 Suppl):Abstract 3534.

    • Search Google Scholar
    • Export Citation
  • 44.

    CorcoranRBEbiHTurkeAB. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov2012;2:227235.

    • Search Google Scholar
    • Export Citation
  • 45.

    PrahalladASunCHuangS. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature2012;483:100103.

    • Search Google Scholar
    • Export Citation
  • 46.

    CorcoranRBFalchookGSInfanteJR. Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer [abstract]. J Clin Oncol2013;31(Suppl):Abstract 3507.

    • Search Google Scholar
    • Export Citation
  • 47.

    LiaoXLochheadPNishiharaR. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med2012;367:15961606.

  • 48.

    KimESHerbstRSWistubaII. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov2011;1:4453.

  • 49.

    EssermanLJBerryDADeMicheleA. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657. J Clin Oncol2012;30:32423249.

    • Search Google Scholar
    • Export Citation
  • 50.

    HurwitzHFehrenbacherLNovotnyW. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med2004;350:23352342.

    • Search Google Scholar
    • Export Citation
  • 51.

    SaltzLBClarkeSDiaz-RubioE. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol2008;26:20132019.

    • Search Google Scholar
    • Export Citation
  • 52.

    StathopoulosGPBatziouCTrafalisD. Chemotherapy with or without bevacizumab in advanced colorectal cancer: a phase III trial [abstract]. Presented at the 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Abstract 606P.

    • Search Google Scholar
    • Export Citation
  • 53.

    MasiGLoupakisFSalvatoreL. A randomized phase III study evaluating the continuation of bevacizumab beyond progression in metastatic colorectal cancer patients who received bevacizumab as part of first-line treatment: results of the BEBYP trial by the Gruppo Oncologico Nord Ovest (GONO) [abstract]. Presented at the 37th European Society for Medical Oncology (ESMO) Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA17.

    • Search Google Scholar
    • Export Citation
  • 54.

    Van CutsemEKohneCHHitreE. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med2009;360:14081417.

    • Search Google Scholar
    • Export Citation
  • 55.

    Van CutsemEKohneCHLangI. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol2011;29:20112019.

    • Search Google Scholar
    • Export Citation
  • 56.

    TveitKMGurenTGlimeliusB. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol2012;30:17551762.

    • Search Google Scholar
    • Export Citation
  • 57.

    MaughanTSAdamsRASmithCG. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet2011;377:21032114.

    • Search Google Scholar
    • Export Citation
  • 58.

    DouillardJYSienaSCassidyJ. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol2010;28:46974705.

    • Search Google Scholar
    • Export Citation
  • 59.

    PeetersMPriceTJCervantesA. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol2010;28:47064713.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 39 34 3
PDF Downloads 3 3 1
EPUB Downloads 0 0 0