Kolorektale Karzinome – personalisierte, stadienadaptierte Tumortherapie

Zusammenfassung

Das kolorektale Karzinom (KRK) ist die zweithäufigste krebsbedingte Todesursache in Deutschland. Fast jeder zweite Patient stirbt an der Erkrankung. Beim Rektumkarzinom soll durch eine multimodale Therapie eine komplette Resektion des Tumors, eine sphinktererhaltende Operation und eine Reduktion von Lokalrezidiven und Fernmetastasen erreicht werden. In den UICC-Stadien II/III erfolgt eine neoadjuvante Radio- oder Radiochemotherapie, nach der Operation mittels totaler mesorektaler Exzision (TME) eine adjuvante Chemotherapie. Die medikamentöse Therapie des kolorektalen Karzinoms wurde durch neue Chemotherapeutika und biologische Substanzen im letzten Jahrzehnt entscheidend verbessert. Zielgerichtete Substanzen führten zu einer Verlängerung des Überlebens bei guter Lebensqualität. Die Mutationsanalyse des k-ras-Onkogens, des ersten prädiktiven molekularen Markers, führte zur Personalisierung der Therapie des KRK. Diese Übersicht stellt den aktuellen Stand der personalisierten und stadienadaptierten Therapie des metastasierten Kolon- und Rektumkarzinoms (KRK) dar.

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer death in the western world. Every second patient dies of the disease. The introduction of new and effective chemotherapeutic substances and biologics during the past decade has significantly improved the systemic treatment of patients with CRC. In stage III colon cancer combination chemotherapy with oxaliplatin is the standard of care. Primary resection of metastases or resection after combination therapy and downsizing of lesions offers a chance for cure for some patients. In the treatment of rectal carcinoma, multimodality and neoadjuvant treatment concepts have replaced adjuvant chemoradio-therapy for locally advanced rectal cancer. In the palliative setting intensive combination treatment is indicated in colorectal cancer if tumor related symptoms or a rapid progress of the disease occur. The aim of palliative therapy is the prolongation of survival and the improvement of quality of life. The introduction of the mutational status of the KRAS oncogene as the first predictive marker into clinical care is an important step towards the personalization of treatment in CRC.

Schlüsselwörter

kolorektales Karzinom - personalisierte Tumortherapie - zielgerichtete Substanzen - adjuvante Therapie - Palliativtherapie

Keywords

colorectal cancer - personalized therapy - biologicals - adjuvant treatment - palliative treatment

• Literatur

• 1 Adams RA, Meade AM et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer. Lancet Oncol 2011; 12: 642-653
• 2 Allegra CJ, Yothers G, O'Connell MJ 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: 3385-3390
• 3 Allegra CJ, Yothers G et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon. J Clin Oncol 2011; 29: 11-16
• 4 Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 1626-1634
• 5 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: 3109-3116
• 6 Bennouna J, Sastre J, Arnold D et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147). Lancet Oncol 2013; 14: 29-37
• 7 Benson AB, Schrag D, Somerfield MR et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004; 22: 3408-3419
• 8 Biagi JJ, Raphael MJ, Mackillop WJ et al. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer. JAMA 2011; 305: 2335-2342
• 9 Bokemeyer C, Bondarenko I, Makhson A et al. Fluorouracil, leucovorin and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27: 663-671
• 10 Bokemeyer C, Van Cutsem E, Rougier P et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012; 48: 1466-1475
• 11 Chibaudel B, Maindrault-Goebel F, Lledo G et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 2009; 27: 5727-5733
• 12 Chibaudel B, Tournigand C, André T et al. Therapeutic strategy in unresectable metastatic colorectal cancer. Ther Adv Med Oncol 2012; 4: 75-89
• 13 Douillard J, Siena S, Cassidy J et al. Randomized phase III trial of pantinumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME trial. J Clin Oncol 2010; 28: 4697-4705
• 14 Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first line treatment for metastatic colorectal cancer. Lancet 2000; 355: 1041-1047
• 15 Folprecht G, Gruenberger T, Bechstein BO et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab. Lancet Oncol 2010; 11: 38-47
• 16 Green BL, Marshall HC et al. Long-term follow-up of the Medical Research Council CLASICC trial of conventional versus laparoscopically assisted resection in colorectal cancer. Br J Surg 2013; 100: 75-82
• 17 Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT). Lancet 2013; 381: 303-312
• 18 Gunderson LL, Jessup JM, Sargent DJ et al. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol 2010; 28: 264-271
• 19 Haller DG, Tabernero J et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011; 29: 1465-1471
• 20 Heald B, Husband EM, Ryall RD. The mesorectum in rectal cancer surgery – the clue to pelvic recurrence?. Br J Surg 1982; 69: 613-16
• 21 Kabbinavar FF, Hambleton J, Mass RD et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005; 23: 3706-3712
• 22 Kerr D, Gray R, Quirke P et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 2011; 29: 4611-4619
• 23 Maak M, Simon I, Nitsche U et al. Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer (CC) patients. Ann Surg 2013; 1053-1058
• 24 Masi G et al. A randomized phase III study evaluating the continuation of bevacizumab (BV) beyond progression in metastatic colorectal cancer (mCRC) patients (pts) who received BV as part of first-line treatment: results of the BEBYP trial by the Gruppo Oncologico Nord Ovest (GONO). ESMO 2012; abstr. LBA 17
• 25 Masi G, Allegrini G, Cupini S et al. First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI). Ann Oncol 2004; 12: 1766-1772
• 26 McCleary NJ, Meyerhardt J, Green E et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: Findings from the ACCENT Database. J Clin Oncol 2013; Jun 3 [Epub ahead of print]
• 27 Niedzwiecki D, Bertagnolli MM, Warren RS et al. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation. J Clin Oncol 2011; 29: 3146-3152
• 28 Nordlinger B, Sorbye H, Glimelius B et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983). Lancet 2008; 371: 1007-1016
• 29 Piessevaux H, Buyse M, De Roock W et al. Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial). Ann Oncol 2009; 20: 1375-1382
• 30 Porschen R, Arkenau HT, Kubicka S et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 2007; 25: 4217-4223
• 31 QUASAR Collaborative Group. Gray R et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer. Lancet 2007; 370: 2020-2029
• 32 Reinacher-Schick AC, Bechstein WO. Kolorektale Leberfiliae. Neoadjuvante Chemotherapie aus internistischer und chirurgischer Sicht. Internist 2007; 48: 51-58
• 33 Robert Koch-Institut. Krebs in Deutschland 2008. http://www.rki.de (letzter Zugriff 24.6.2013)
• 34 Rödel C, Liersch T, Becker H et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer. Lancet Oncol 2012; 13: 679-687
• 35 Rosenberg R, Maak M, Schuster T et al. Does a rectal cancer of the upper third behave more like a colon or a rectal cancer?. Dis Colon Rectum 2010; 53: 761-770
• 36 Saltz LB, Clarke S, Diaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer. J Clin Oncol 2008; 26: 2013-2019
• 37 Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905-914
• 38 Sargent DJ, Marsoni S, Monges G et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28: 3219-3226
• 39 Schmiegel W, Reinacher-Schick A, Arnold D et al. Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer. Ann Oncol 2013; 24: 1580-1587
• 40 Schmiegel W, Pox C (Steuerungsgruppe für Planung und Durchführung über DGVS). Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): S3-Leitlinie Kolorektales Karzinom, Langversion 1.0, AWMF Registrierungsnummer: 021-007OL (letzter Zugriff 11.07.2013)
• 41 Schmoll HJ, Van Cutsem E, Stein A et al. ESMO consensus guidelines for management of patients with colon and rectal cancer. Ann Oncol 2012; 23: 2479-2516
• 42 Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer. J Clin Oncol 2004; 22: 229-237
• 43 Tournigand C, André T, Bonnetain F et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer. J Clin Oncol 2012; 30: 3353-3360
• 44 Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol 2006; 24: 394-400
• 45 Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352: 2696-2704
• 46 Van Cutsem E, Köhne CH, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360: 1408-1417
• 47 Van Cutsem E, 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: 3117-3125
• 48 Van Cutsem E, Peeters M et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25: 1658-1664
• 49 Van Cutsem E, Tabernero J, Lakomy R et al. 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 Oncol 2012; 30: 1658-1664
• 50 Wittekind C, Meyer HJ. UICC: TNM Klassifikation maligner Tumoren. . 7. Aufl. Weinheim: Wiley VCH; 2010
• 51 Schmoll H, Haustermans K et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer. J Clin Oncol 2007; 25 suppl; abstr 3531
• 52 Primrose J, Falk S et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer. J Clin Oncol 2013; 31 suppl; abstr 3504
• 53 Oliner KS, Douillard JY et al. Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). J Clin Oncol 2013; 31 suppl; abstr 3511