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mutated gene had a median PFS of 5.5 months in the cetuximab armbest supportive care (BSC) in patients with refractory mCRC (20).30 - newsletter fall 2008This analysis was conducted to determine whether the effect ofpanitumumab monotherapy on PFS differed between patients withtumours having a mutant KRAS and those with tumours having awild-type KRAS. When panitumumab was compared to BSC alone, acompared with 8.6 months in the chemotherapy-only arm (P = .02),showing that the addition of cetuximab to FOLFOX had a detrimentaleffect on outcomes in patients who had tumours with KRAS mutationscompared with those who had received FOLFOX alone (34).statistically significant improvement in PFS was observed in patientswhose tumours harboured wild-type KRAS; median PFS was 12.3weeks for panitumumab and 7.3 weeks for BSC (P < .0001). Incontrast, panitumumab treatment conferred no additional benefitcompared with BSC alone (median PFS = 7.4 vs 7.3 weeks) inpatients carrying the mutant KRAS gene (Table 1) (20). Consistentwith these findings, the response rate to panitumumab was 17% inthe wild-type KRAS group, while no patients in the KRAS mutationgroup responded to therapy.The EVEREST trial evaluated the benefit of cetuximab in combinationwith irinotecan after the failure of irinotecan-based treatment. In thisstudy, the PFS estimate in patients with a mutant KRAS was 83 dayscompared to 173 days for patients with the nonmutated KRAS (37).Taken together, these trials provide compelling evidence of thepredictive nature of KRAS in EGFR-targeted therapy. The KRASmutation is a biomarker for nonresponse to panitumumab andto cetuximab, both as monotherapy and in combination withTable 1: Randomised Trials of Anti-EGFR Agents Based on Mutationalchemotherapy. It should be noted that a similar correlation withStatusKRAS mutant status has also been observed in patients treated withsmall-molecule TKIs in non–small cell lung cancer (38-40), as well asMedian PFS (HR) pancreatic cancer (41).Patients, Mutant Wild-typeStudy Treatment No. KRAS KRASImplications for Nursing PracticeIt is imperative that oncology nurses understand the clinicalAmado BSC vs 427 7.3 vs 7.3 vs relevance of these data to treatment decisions for patients with CRC.panitumumab 7.4 wk 12.3 wk Like human epidermal growth factor receptor 2 (HER2) status for(third-line) (HR = 0.99) (HR = 0.45;breast cancer, KRAS status is the first indicator allowing personalisedP < .0001)treatment of CRC. KRAS testing is likely to become a criticalVan Cutsem FOLFIRI vs 540 8.1 vs 8.7 vs(CRYSTAL) FOLFIRI + 7.6 mo 9.9 mocomponent in patient selection for anti-EGFR therapy.All patients being considered for panitumumab or cetuximabtherapy, as well as all patients with newly diagnosed advancedcetuximab(first-line)(HR = 1.07;P = .75)(HR = 0.68;P = .017)Bokemeyer FOLFOX vs 233 8.6 vs 7.2 vs CRC, should have their tumour biopsies tested for EGFR mutation(OPUS) FOLFOX + 5.5 mo 7.7 mo status. Tumour samples should therefore be obtained at the timecetuximab (HR = 1.83; (HR = 0.57; of surgery, regardless of whether the surgery is for diagnostic or(first-line) P = .02) P = .02) therapeutic purposes. Available data indicate that both the primaryTejpar Irinotecan + 148 83 d 173 d and metastatic colorectal tumours exhibit the same KRAS mutation(EVEREST) cetuximabstatus because the mutation of the KRAS gene occurs early in the(irinotecanrefractorypatients may present at the clinic with metastatic disease that wasdevelopment of the disease (42). This is important because manypatients)diagnosed following surgical resection of their primary site or mayBSC, best supportive care; FOLFIRI, irinotecan, 5-fluorouracil,leucovorin ; FOLFOX, 5-fluorouracil, leucovorin, oxaliplatin.; HR,hazard ratio.only have testing results available from the metastatic site. Oncologynurses may play a key role in ensuring that testing for the KRASmutation is requested at the time of surgery and completed prior tothe initiation of treatment.The same result has been found with cetuximab and is the basisfor the recent recommendation by the EMEA to restrict the use ofcetuximab to patients with EGFR-expressing, KRAS wild-type mCRC.The most recent data on this subject come from the retrospectiveanalyses of 3 randomised trials of cetuximab in combination withchemotherapy, the CRYSTAL trial (33), the OPUS trial (34), and theEVEREST trial (37) (see Table 1).Nurses may also play a key role in educating patients about theclinical relevance of the mutant KRAS. It is extremely importantto convey to patients who have a KRAS mutation that currentchemotherapy regimens remain active and effective against theirdisease. The use of the KRAS mutation as a marker for nonresponseallows clinicians to avoid treatment delays with other potentiallyeffective regimens. In addition, clinicians now have a tool to avoidIn the randomised phase 3 CRYSTAL trial, the addition of cetuximabto folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) in the overallunselected patient population resulted in a small PFS benefit forprescribing costly therapies with known toxicities to those patientswho may derive little or no benefit; and as a result, both the patientand the healthcare system benefit.cetuximab(8.9 vs 8.0 months, P = .0479) (17). As shown in Table1, patients with wild-type KRAS had a median PFS of 9.9 monthswhen treated with chemotherapy plus cetuximab compared with 8.7months when treated with chemotherapy alone (P = .017). Patientswith the mutated gene had a median PFS of 7.6 months in thecetuximab arm compared with 8.1 months in the chemotherapy-onlyarm (P = .75) (33).ConclusionAs new agents are being introduced into clinical practice, moreoptions are available to oncology healthcare professionals and to thepatients they treat. Targeted therapies, and in particular EGFR-directedtherapies, are a key component of treatment for patients with CRC,and the optimal use of these agents is essential. As we enter theera of personalised medicine, the discovery that the mutation in theSimilar results were observed in the OPUS trial, which evaluatedthe benefit of adding cetuximab to folinic acid, 5-fluorouracil, andKRAS gene is a biomarker for nonresponse to the anti-EGFR agentspanitumumab and cetuximab promises to be practice-changing.oxaliplatin (FOLFOX) chemotherapy (see Table 1). In this retrospectiveanalysis, patients with wild-type KRAS had median PFS of 7.7 monthswhen treated with chemotherapy plus cetuximab compared with7.2 months when treated with chemotherapy alone (P = .02), thusconfirming the benefit of cetuximab in this population. Patients with theAcknowledgementsThe author thanks Mary Jensen Camp, Pharm D, BCOP, and SupriyaSrinivasan, PhD, for writing and editorial support. Amgen (Europe)GmbH sponsored an external agency for writing support.
References1. Field K, Lipton L: Metastatic colorectal cancer–past, progress andfuture, World J Gastroenterol 13:3806-3815, 2007.2. Gerber DE: Targeted therapies: a new generation of cancertreatments, Am Fam Physician 77:311-319, 2008.3. Saltz LB et al: Phase II trial of cetuximab in patients with refractorycolorectal cancer that expresses the epidermal growth factorreceptor, J Clin Oncol 22:1201-1208, 2004.4. Biomarkers Definitions Working Group: Biomarkers and surrogateendpoints: preferred definitions and conceptual framework, ClinPharmacol Ther 69:89-95, 2001.5. Bos J: ras Oncogenes in human cancer: a review, Cancer Res49:4682-4689, 1989.6. Boguski MS, McCormick F: Proteins regulating ras and its relatives,Nature 366:643-654, 1993.7. Salomon DS et al: Epidermal growth factor-related peptides andtheir receptors in human malignancies, Crit Rev Oncol Hematol19:183-232, 1995.8. Johnston JB et al: Targeting the EGFR pathway for cancer therapy,Curr Med Chem 13: 3483-3492, 2006.9. Spano JP et al: Impact of EGFR expression on colorectal cancerpatient prognosis and survival, Ann Oncol 16:102-108, 2005.10. Galizia G et al: Prognostic significance of epidermal growth factorreceptor expression in colon cancer patients undergoing curativesurgery, Ann Surg Oncol 13:823-835, 2006.11. Press O et al: Gender-related survival differences associated withEGFR polymorphisms in metastatic colon cancer, Cancer Res68:3037-3042, 2008.12. Roche-Lima CM et al: EGFR targeting of solid tumors, CancerControl 14:295-304, 2007.13. Cunningham D et al: Cetuximab monotherapy and cetuximab plusirinotecan in irinotecan refractory metastatic colorectal cancer, NEngl J Med 351: 337-345, 2004.14. Jonker DJ, et al: Cetuximab for the treatment of colorectal cancer,N Engl J Med 357: 2040-2048, 2007.15. Van Cutsem E et al: Open-label phase III trial of panitumumab plusbest supportive care compared with best supportive care alonein patients with chemotherapy-refractory metastatic colorectalcancer, J Clin Oncol 25:1658-1664, 2007.16. Bokemeyer C et al: Cetuximab plus 5-FU/FA/oxaliplatin(FOLFOX-4) versus FOLFOX-4 in the first-line treatment ofmetastatic colorectal cancer: a large-scale phase II study (OPUS),Eur J Cancer 5(suppl 4):236, 2007. Abstract O3004.17. Van Cutsem E et al: Randomized phase III study of irinotecan and5-FU/FA with or without cetuximab in the first-line treatment ofpatients with metastatic colorectal cancer (mCRC): The CRYSTALtrial, J Clin Oncol 25(18S):164S, 2007. Abstract 4000.18. Hecht JR et al: Interim results from PACCE: irinotecan/bevacizumab +/– panitumumab as first-line treatmentfor metastatic colorectal cancer, http://asco.org, ASCOGastrointestinal Cancers Symposium 2008. Abstract 279.19. Siena S et al: Phase III study (PRIME/20050203) of panitumumabwith FOLFOX compared with FOLFOX alone in patients withpreviously untreated metastatic colorectal cancer: pooled safetydata, J Clin Oncol 26(15S):186s, 2008. Abstract 4034.20. Amado R et al: Wild-type KRAS is required for panitumumabefficacy in patients with metastatic colorectal cancer, J Clin Oncol26:1626-1634, 2008.21. Chung KY et al: Cetuximab shows activity in colorectal cancerpatients with tumors that do not express the epidermal growthfactor receptor by immunohistochemistry, J Clin Oncol 23:1803-1810, 2005.22. Lenz HJ et al: Multicenter phase II and translational study ofcetuximab in metastatic colorectal carcinoma refractory toirinotecan, oxaliplatin, and fluoropyrimidines, J Clin Oncol 24:4914-4921, 2006.23. Hecht J et al: Panitumumab (pmab) efficacy in patients (pts) withmetastatic colorectal cancer (mCRC) with low or undetectablelevels of epidermal growth factor receptor (EGFr): final efficacy andKRAS analyses, http://asco.org, ASCO Gastrointestinal CancersSymposium 2008. Abstract 343.24. Frattini M et al: PTEN loss of expression predicts cetuximabefficacy in metastatic colorectal cancer patients, Br J Cancer97:1139-1145, 2007.25. Cappuzzo F et al: EGFR FISH assay predicts for response tocetuximab in chemotherapy refractory colorectal cancer patients,Ann Oncol 19:717-723, 2007.26. Gravalos C et al: Analysis of potential predictive factors of clinicalbenefit in patients (pts) with metastatic colorectal cancer (mCRC)treated with single-agent cetuximab as first-line treatment, J ClinOncol 25(18S):193S, 2007. Abstract 4120.27. Khambata-Ford S et al: Expression of epiregulin and amphiregulinand K-ras mutation status predict disease control in metastaticcolorectal cancer patients treated with cetuximab, J Clin Oncol25:3230-3237, 2007.28. Lemmens L: How to deal with toxicity of targeted therapies: EGFRinhibitors.EONS Newsletter. Spring 2008:12-15, 2008.29. Agero AL et al: Dermatologic side effects associated with theepidermal growth factor receptor inhibitors, J Am Acad Dermatol55:657-670, 2006.30. Saltz LB: Biomarkers in colorectal cancer: added value or justadded expense?, Expert Rev Mol Diagn 8:231-233, 2008.31. De Roock W et al: KRAS wild-type state predicts survival and isassociated to early radiological response in metastatic colorectalcancer treated with cetuximab, Ann Oncol 19:508-15, 2008.32. Benvenuti S et al: Oncogenic activation of the RAS/RAF signalingpathway impairs the response of metastatic colorectal cancers toanti-epidermal growth factor receptor antibody therapies, CancerRes 67:2643-2648, 2007.33. Van Cutsem E et al: KRAS status and efficacy in the first-linetreatment of patients with metastatic colorectal cancer treatedwith FOLFIRI with or without cetuximab: the CRYSTAL experience, JClin Oncol 26(15S):5s, 2008. Abstract 2.34. Bokemeyer C et al: KRAS status and efficacy in the first-linetreatment of patients with metastatic colorectal cancer treatedwith FOLFIRI with or without cetuximab: the OPUS experience, JClin Oncol 26(15S):178s, 2008. Abstract 4000.35. Andreyev HJ et al: Kirsten ras mutations in patients with colorectalcancer: the multicenter “RASCAL” study, J Natl Cancer Inst 90:675-684, 1998.36. Andreyev HJ et al: Kirsten ras mutations in patients with colorectalcancer: the “RASCAL II” study, Br J Cancer 85:692-696, 2001.37. Tejpar S et al: Relationship of efficacy with KRAS status (wild typeversus mutant) in patients with irinotecan-refractory metastaticcolorectal cancer (mCRC), treated with irinotecan (q2w) andescalating doses of cetuximab (q1w): The EVEREST experience(preliminary data), J Clin Oncol 26(15S):178S, 2008. Abstract4001.38. Pao W et al: KRAS mutations and primary resistance of lungadenocarcinomas to gefitinib or erlotinib, PLoS Medicine 2:e17,2005.39. Tsao M, et al: An analysis of the prognostic and predictiveimportance of K-ras mutation status in the National CancerInstitute of Canada Clinical Trials Group BR.21 study of erlotinibversus placebo in the treatment of non-small cell lung cancer, J ClinOncol 24(18S):365s, 2006. Abstract 7005.40. Massarelli E, et al: KRAS mutation is an important predictor ofresistance to therapy with epidermal growth factor receptortyrosine kinase inhibitors in non-small-cell lung cancer, Clin CancerRes 13:2890-2896, 2007.41. Moore MJ et al: The relationship of K-ras mutations and EGFRgene copy number to outcome in patients treated with erlotinib onNational Cancer Institute of Canada Clinical Trials Group trial studyPA.3, J Clin Oncol 25(18S):202s, 2007. Abstract 4521.42. Loupakis F et al: Evaluation of PTEN expression in colorectal cancermetastases and in primary tumors as predictors of activity ofcetuximab plus irinotecan treatment, J Clin Oncol 26 (15S):178s,2008. Abstract 4003.newsletter fall 2008 -31
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