Acta Oncologica, 2015; 54: 1–4
EDITORIAL
Twenty-five years with adjuvant chemotherapy for colon cancer – a continuous evolving concept
OLAV DAHL1 & FRANK PFEFFER2
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1Section
of Oncology, Institute of Clinical Science, MOF, University of Bergen and Department of Oncology, Haukeland University Hospital, Haukeland, Norway and 2Section of Gastric Surgery, Institute of Clinical Medicine, University of Bergen and Department of Surgery, Haukeland University Hospital, Haukeland, Norway
In the early 1970s all colorectal cancer patients with metastases received intravenous 5-fluorouracil (5FU) chemotherapy which often continued despite tumor progression. Some patients also received chemotherapy after radical resection as it was thought that the treatment at least could slow down the progress of the cancer. This practice was terminated at our hospital in 1976, supported by the paper of Moertel who questioned the role of 5FU, stating that it was a nontreatment and also emphasized its side effects [1]. Despite his skepticism, Moertel continued his search for combinations which could influence the course of colorectal cancers. In 1989 and 1990, two seminal papers reported that 5FU combined with the antihelmintic drug levamisol for one year improved disease-free survival (DFS) and cancer-specific survival (CSS) [2,3]. After the National Institute of Health Consensus Statement, this regimen rapidly was accepted in USA and most countries worldwide [4]. However, in the Scandinavian countries the new treatment was met with initial skepticism by the surgeons who had learned that 5FU had limited success in colorectal cancer. To introduce the treatment, separate studies were therefore launched in Sweden, Norway and Denmark, mostly using the original Moertel regimen [5,6]. Later 5FU combined with calciumfolinate (leukovorin) (FLv) replaced the Moertel regimen as this could be administered for six months instead of one year with similar efficacy [7]. Based on these studies and a convincing number of other confirmatory studies, adjuvant treatment was then accepted as standard therapy for colon cancer in all Nordic countries as in other countries.
In the current issue of Acta Oncologica, Böckelman et al. present an updated review on the prognosis for colon cancer stage II and III [8]. The review is one in a series of papers from an Acta Oncologica initiative to promote young scientists in the Nordic countries, ‘young scientist’s workshop’ held during the Acta Oncologica 50 year celebration in 2013 [9,10]. During the workshop, groups of young scientist started working with systematic reviews in challenging, edge cutting and clinically relevant topics. Another review from the workshop, dealing with the predictive role of mutations in signaling pathways downstream of EGFR to EGFR inhibition in metastatic colorectal cancer was recently published [11]. From totally 2600 published papers they report on 15 559 colon cancer patients with stage II and 18 425 patients with stage III, of which 84% were treated between 2000 and 2008. This is important information reflecting the current status of treatment of colon cancer, in contrast to a continuous improvement in treatment of rectal cancer including more extensive surgery termed total mesorectal excision, staging with MRI, multidisciplinary team and use of preoperative radiochemotherapy [12–14]. Recently a similar focus on careful systematic surgery for colon cancer with central lymph node dissection (D3 resection) and total mesocolic excision has been accepted and is introduced in clinical practice [15–18]. Colon cancer surgery is becoming more limited to gastrointestinal surgeons specially trained in colorectal surgery [19]. Also the pathology assessment of the operation specimens has improved [20,21]. While diagnosis of one or two lymph node metastases was considered suffi-
Correspondence: O. Dahl, University of Bergen, Section of Oncology, Institute of Medicine, Haukeland University Hospital, Bergen 5021, Norway. E-mail: [email protected] (Received 14 August 2014 ; accepted 21 August 2014 ) ISSN 0284-186X print/ISSN 1651-226X online © 2015 Informa Healthcare DOI: 10.3109/0284186X.2014.958533
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2
O. Dahl & F. Pfeffer
cient for diagnosis of stage III, currently at least 12 lymph node should be assessed, and the prognosis in stage II is even better if more than 20 lymph nodes are examined [22–24]. Not only assessment of total number lymph nodes, but also the lymph node ratio has emerged as a prognostic factor in stage III [21,25,26]. The more thorough assessment of the whole operation specimen may also contribute to a better staging, diagnosis of extralymphaticmesocolic tumor deposits that might lead to stage migration over time [18,27] and higher rate of mesocolic plane surgery [28]. By better diagnostic procedures and postoperative care, more advanced cases are offered radical surgery today, even in higher age groups. Böckelman et al. classified the quality of the publications and could show better outcome in the studies with best reporting quality, indicating different quality levels of colon cancer treatment in clinical practice. Based on the updated review by Böckelman et al. the current status is that colon cancer patients with resected lymph node metastases should continue to receive adjuvant chemotherapy. A small weakness in the work is that only 312 patients with stage III in the reported studies did not receive adjuvant chemotherapy, but it is reassuring that 97% of the published patients received the treatment which is currently recommended in guidelines [29,30]. However, the review did not show an overall DFS benefit of adjuvant chemotherapy for colon cancer stage II. A significant role for prognostic factors were documented when stage I–III and stage II–III were jointly analyzed, but we must acknowledge that we still have no simple way of identifying of the 2–5% of all patients in stage II who actually survive due to adjuvant chemotherapy. A clear role for some clinical factors has been documented [31]. Other studies have shown that at least proximal colon cancer stage II with documented mismatch repair deficiency have only half the chance of recurrence and seems not to benefit from 5FU [32–34]. Böckelman et al. confirmed the prognostic value of pT stage, emergency surgery, number of lymph nodes, differentiation, neural invasion, mismatch repair deficiency and preoperative CEA level, raising the question whether all parameters should be part of routine diagnostics in these patients. We and others try to find predictive factors to identify those patients who actually benefit from adjuvant chemotherapy, but until now no predictive molecular marker is yet in routine use for adjuvant chemotherapy in colon cancer stage III [35–39]. Böckelman et al. classified the regimens as surgery with and without adjuvant chemotherapy without differentiation between the actually given regimens. Several different regimens are used, but basically a fluoropyrimidine (5FU intravenously or
capecitabine orally) alone or combined with oxaliplatin is the standard therapy for colon cancer stage III [40,41]. It is noteworthy that oxaliplatin still has not unequivocally shown a survival benefit for colon cancer stage II patients [40,42,43] and for elderly patients above 70 years [43,44]. Thus these patients can be saved for the side effects associated with oxaliplatin. It is also a puzzle that irinotecan [45–47] and targeted antibodies cetuximab [48,49] or bevacizumab [50,51] which are active drugs in a metastatic setting, did not improve adjuvant therapy above fluoropyrimidines alone in an adjuvant setting. Timing after surgery and dosing are also factors which may influence the efficacy of the regimens [52,53]. Thus the review accompanying this editorial documents that the benefit of adjuvant chemotherapy is at least as effective in patients treated today as the initial studies showed. One should still strive for reliable predictive markers also in stage III patients, as at yet half of the patients are cured by surgery alone and hence does not need adjuvant chemotherapy which is associated with toxicity, while 30–35% of the patients will develop recurrences and need more effective chemotherapy despite adjuvant chemotherapy. Future trends With preoperative CT imaging it is now possible to identify tumors with more than 5 mm extramural tumor growth, large lymph node metastases and T4 tumors, thus identifying patients which currently are offered postoperative adjuvant chemotherapy [54,55]. The preliminary results from the British Foxtrot study indicate that three preoperative chemotherapy courses with a modified de Gramont regimen (OxMdG) followed by nine additional courses seems feasible and effective [56]. In a similar protocol, where 22 Spanish patients with locally advanced colon cancer received four courses of CapeOx before surgery and four courses postoperatively, the authors report tumor downstaging and even three cases with complete tumor regression at surgery [57,58]. Inspired by the Foxtrot study, Professor Anders Jacobsen in Veijle, Denmark has performed a phase II study giving three courses of oral capecitabine with oxaliplatin (Xelox) preoperatively. He currently leads a Nordic phase III study on his preliminary experience with this regimen (ClinicalTrials.gov). In order to improve the outcome of colon cancer treatment all patients should be discussed at multidisciplinary team meetings. If radical surgery is intended, complete mesocolic excision with central vascular ligation should be performed. Postoperative risk stratification should routinely include the above-mentioned prognostic parameters and adjuvant therapy in stage II patients should be considered individually.
Adjuvant chemotherapy for colon cancer Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Acta Oncol Downloaded from informahealthcare.com by Nyu Medical Center on 05/21/15 For personal use only.
References [1] Moertel CG. Clinical management of advanced gastrointestinal cancer. Cancer 1975;36:675–82. [2] Laurie JA, Moertel CG, Fleming TR, Wieand HS, Leigh JE, Rubin J, et al. Surgical adjuvant therapy of large-bowel carcinoma: An evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 1989;7:1447–56. [3] Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352–8. [4] Conference, National Institutes of Health. Adjuvant therapy for colon and rectal cancer. JAMA 1990;264:1444–50. [5] Dahl O, Fluge O, Carlsen E, Wiig JN, Myrvold HE, Vonen B, et al. Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group. Acta Oncol 2009;48:368–76. [6] Glimelius B, Dahl O, Cedermark B, Jakobsen A, Bentzen SM, Starkhammar H, et al. Adjuvant chemotherapy in colorectal cancer: A joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Acta Oncol 2005;44:904–12. [7] Ragnhammar P, Hafström LO, Nygren P, Glimelius B. A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol 2001;40:282–308. [8] Böckelman C, Engelmann BE, Kaprio T, Hansen TF, Glimelius B. Risk of recurrence in patients with colon cancer stage II and III: A systematic review and meta-analysis of recent literature. Acta Oncol 2015;54:5–16. [9] Glimelius B. 50 years with Acta Oncologica. Acta Oncol 2013;52:1–2. [10] Glimelius B, Johansen C, Muren LP, Nilbert M. Acta Oncologica and a new generation of scientists in oncology. Acta Oncol 2014;53:849–51. [11] Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncol 2014;53:852–64. [12] MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993;341:457–60. [13] Wibe A, Carlsen E, Dahl O, Tveit KM, Wedon-Fekjaer H, Hestvik UE, et al. Nationwide quality assurance of rectal cancer treatment. Colorectal Dis 2006;8:224–9. [14] Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedermark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Stockholm Colorectal Cancer Study Group, Basingstoke Bowel Cancer Research Project. Lancet 2000;356:93–6. [15] Hohenberger P, Du W, Post S. Extended resections for colorectal cancer – indications for supraradical lymphadenectomy. Colorectal Dis 2011;13(Suppl 7):74–7. [16] Sondenaa K, Quirke P, Hohenberger P, Sugihara K, Kobayashi H, Kessler H, et al. The rationale behind complete mesocolic excision (CME) and a central vascular ligation for colon cancer in open and laparoscopic surgery: Proceedings of a consensus conference. Int J Colorectal Dis 2014;29:419–28.
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[17] West NP, Kobayashi H, Takahashi K, Perrakis A, Weber K, Hohenberger W, et al. Understanding optimal colonic cancer surgery: Comparison of Japanese D3 resection and European complete mesocolic excision with central vascular ligation. J Clin Oncol 2012;30:1763–9. [18] Munkedal DLE, West NP, Iversen LH, Hagemann-Madsen R, Quirke P, Laurberg S. Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens. Eur J Surg Oncol 2014;40:1494–501. [19] Jullumstro E, Wibe A, Lydersen S, Edna TH. Colon cancer incidence, presentation, treatment and outcomes over 25 years. Colorectal Dis 2011;13:512–8. [20] Nagtegaal ID, West NP, van Krieken JH, Quirke P. Pathology is a necessary and informative tool in oncology clinical trials. J Pathol 2014;232:185–9. [21] Jestin P, Påhlman L, Glimelius B, Gunnarson U. Cancer staging and survival in colon cancer is dependent on the quality of the pathologists’ specimen examination. Eur J Cancer 2005;41:2071–8. [22] Iachetta F, ReggianiBonetti L, Marcheselli L, Di Gregorio C, Crilli C, Messinese S, et al. Lymph node evaluation in stage IIA colorectal cancer and its impact on patient prognosis: A population-based study. Acta Oncol 2013; 52:1682–90. [23] Nedrebø BS, Søreide K, Nesbakken A, Eriksen MT, Søreide JA, Kørner H; Norwegian Colorectal Cancer Group. Risk factors associated with poor lymph node harvest after colon cancer surgery in a national cohort. Colorectal Dis 2013;15:e301–8. [24] Soreide K, Nedrebø BS, Søreide JA, Sleva A, Kørner H. Lymph node harvest in colon cancer: Influence of microsatellite instability and proximal tumor location. World J Surg 2009;33:2695–703. [25] Huh JW, Kim YJ, Kim HR. Ratio of metastatic to resected lymph nodes as a prognostic factor in node-positive colorectal cancer. Ann Surg Oncol 2010;17:2640–6. [26] Stanisavljevic L, Søndenaa K, Storli KE, Leh S, Nesvik I, Gudlaugsson E, et al. The total number of lymph nodes in resected colon cancer specimens is affected by several factors but the lymph node ratio is independent of these. APMIS 2014;122:490–8. [27] Shi Q, Andre T, Grothey A, Yothers G, Hamilton SR, Bot BM, et al. Comparison of outcomes after fluorouracilbased adjuvant therapy for stages II and III colon cancer between 1978 to 1995 and 1996 to 2007: Evidence of stage migration from the ACCENT database. J Clin Oncol 2013;31:3656–63. [28] West NP, Sutton KM, Ingeholm P, Hagemann-Madsen R, Hohenberger W, Quirke P. Improving the quality of colon cancer surgery through a surgical education program. Dis Colon Rect 2010;53:1594–603. [29] van Gils CW, Koopman M, Mol L, Redekop WK, Ulyl-de Groot CA, Punt CJ. Adjuvant chemotherapy in stage III colon cancer: Guideline implementation, patterns of use and outcomes in daily practice in The Netherlands. Acta Oncol 2012;51:57–64. [30] van den Broek CB, Bastiaannet E, Dekker JW, Portielje JE, de Craen AJ, Elferink MA, et al. Time trends in chemotherapy (administration and costs) and relative survival in stage III colon cancer patients – a large population-based study from 1990 to 2008. Acta Oncol 2013;52:941–9. [31] Lin HH, Chang YY, Lin JK, Jiang JK, Lin CC, Lan YT, et al. The role of adjuvant chemotherapy in stage II colorectal cancer patients. Int J Colorectal Dis 2014;29:1237–43. [32] Berg M, Guriby M, Nordgård O, Nedrebø BS, Ahlquist TC, Smaaland R, et al. Influence of microsatellite instability,
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Acta Oncol Downloaded from informahealthcare.com by Nyu Medical Center on 05/21/15 For personal use only.
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O. Dahl & F. Pfeffer KRAS and BRAF mutations on lymph node harvest in stage I–III colon cancers. Mol Med 2013; (in press). Bertagnolli MM, Redston M, Compton CC, Niedzwiecki D, Mayer RJ, Goldberg RM, et al. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: Prospective evaluation of biomarkers for stages II and III colon cancer – a study of CALGB 9581 and 89803. J Clin Oncol 2011;29:3153–62. Merok MA, Ahlquist T, Røyrvik EC, Tufteland KF, Hektoen M, Sjo OH, et al. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: Results from a large, consecutive Norwegian series. Ann Oncol 2013;24:1274–82. Fluge O, Gravdal K, Carlsen E, Vonen B, Kjellevoll K, Refsum S, et al. Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br J Cancer 2009;101:1282–9. Myklebust MP, Li Z, Tran TH, Rui H, Knudsen ES, Elsaleh H, et al. Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer. Br J Cancer 2012;107:1684–91. Johnston PG. Identification of clinically relevant molecular subtypes in colorectal cancer: The dawning of a new era. Oncologist 2014;19:568–73. Sadanandam A, Wang X, de Sousa e Melo F, Gray JW, Vermeulen L, Hanahan D, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 2013;19:619–25. Sveen A, Nesbakken A, Ågesen TH, Guren MG, Tveit KM, Skotheim RI, et al. Anticipating the clinical use of prognostic gene expression-based tests for colon cancer stage II and III: Is Godot finally arriving? Clin Cancer Res 2013;19:6669–77. Andre T, Boni C, Navarro M, Tabernero J, Hikish T, Topham C, 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. Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 2011;29:3768–74. Church DN, Midgley R, Kerr D. Stage II colon cancer. Chin Clin Oncol 2013;2:16. Tournigand C, Andre T, Bonnetain F, Chibaudel B, Liedo G, Hickish T, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: Subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol 2012;30:3353–60. McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gramont A, Van Cutsem 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;31:2600–6. Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, 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.
[46] Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, 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. [47] Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, et al. A phase III randomised trial of LV5FU2 ⫹ irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol 2009;20:674–80. [48] Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): An open-label, randomised phase 3 trial. Lancet Oncol 2014;15:862–73. [49] Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: A randomized trial. JAMA 2012;307:1383–93. [50] Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Petrelli NJ, Lopa SH, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: Results of NSABP protocol C-08. J Clin Oncol 2011;29:11–6. [51] de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, et al. Bevacizumab plus oxaliplatinbased chemotherapy as adjuvant treatment for colon cancer (AVANT): A phase 3 randomised controlled trial. Lancet Oncol 2012;13:1225–33. [52] Andre T, Iveson T, Labianca R, Meyerhardt JA, Souglakos I, Yoshino T, et al. The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) collaboration: Prospective combined analysis of phase III Trials investigating duration of adjuvant therapy with the FOLFOX (FOLFOX4 or Modified FOLFOX6) or XELOX (3 versus 6 months) regimen for patients with stage III colon cancer: Trial design and current status. Curr Colorectal Cancer Rep 2013;9:261–9. [53] Berglund A, Cedermark B, Glimelius B. Is it deleterious to delay the start of adjuvant chemotherapy in colon cancer stage III? Ann Oncol 2008;19:400–2. [54] Dighe S, Swift I, Magill L, Handley K, Gray R, Quirke P, et al. Accuracy of radiological staging in identifying highrisk colon cancer patients suitable for neoadjuvant chemotherapy: A multicentre experience. Colorectal Dis 2011; 14:438–44. [55] Norgaard A, Dam C, Jakobsen A, Pløen J, Lindebjerg J, Rafaelsen SR. Selection of colon cancer patients for neoadjuvant chemotherapy by preoperative CT scan. Scand J Gastroenterol 2014;49:202–8. [56] Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial. Lancet Oncol 2012;13:1152–60. [57] Arredondo J, Gonzalez I, Baixauli J, Martinez P, Roderiguez J, Pastor C, et al. Tumor response assessment in locally advanced colon cancer after neoadjuvant chemotherapy. J Gastrointest Oncol 2014;5:104–11. [58] Arredondo J, Pastor C, Baixauli J, Rodriguez J, Gonzalez I, Vigil C, et al. Preliminary outcome of a treatment strategy based on perioperative chemotherapy and surgery in patients with locally advanced colon cancer. Colorectal Dis 2013;15:552–7.
EDITORIAL
Twenty-five years with adjuvant chemotherapy for colon cancer – a continuous evolving concept
OLAV DAHL1 & FRANK PFEFFER2
Acta Oncol Downloaded from informahealthcare.com by Nyu Medical Center on 05/21/15 For personal use only.
1Section
of Oncology, Institute of Clinical Science, MOF, University of Bergen and Department of Oncology, Haukeland University Hospital, Haukeland, Norway and 2Section of Gastric Surgery, Institute of Clinical Medicine, University of Bergen and Department of Surgery, Haukeland University Hospital, Haukeland, Norway
In the early 1970s all colorectal cancer patients with metastases received intravenous 5-fluorouracil (5FU) chemotherapy which often continued despite tumor progression. Some patients also received chemotherapy after radical resection as it was thought that the treatment at least could slow down the progress of the cancer. This practice was terminated at our hospital in 1976, supported by the paper of Moertel who questioned the role of 5FU, stating that it was a nontreatment and also emphasized its side effects [1]. Despite his skepticism, Moertel continued his search for combinations which could influence the course of colorectal cancers. In 1989 and 1990, two seminal papers reported that 5FU combined with the antihelmintic drug levamisol for one year improved disease-free survival (DFS) and cancer-specific survival (CSS) [2,3]. After the National Institute of Health Consensus Statement, this regimen rapidly was accepted in USA and most countries worldwide [4]. However, in the Scandinavian countries the new treatment was met with initial skepticism by the surgeons who had learned that 5FU had limited success in colorectal cancer. To introduce the treatment, separate studies were therefore launched in Sweden, Norway and Denmark, mostly using the original Moertel regimen [5,6]. Later 5FU combined with calciumfolinate (leukovorin) (FLv) replaced the Moertel regimen as this could be administered for six months instead of one year with similar efficacy [7]. Based on these studies and a convincing number of other confirmatory studies, adjuvant treatment was then accepted as standard therapy for colon cancer in all Nordic countries as in other countries.
In the current issue of Acta Oncologica, Böckelman et al. present an updated review on the prognosis for colon cancer stage II and III [8]. The review is one in a series of papers from an Acta Oncologica initiative to promote young scientists in the Nordic countries, ‘young scientist’s workshop’ held during the Acta Oncologica 50 year celebration in 2013 [9,10]. During the workshop, groups of young scientist started working with systematic reviews in challenging, edge cutting and clinically relevant topics. Another review from the workshop, dealing with the predictive role of mutations in signaling pathways downstream of EGFR to EGFR inhibition in metastatic colorectal cancer was recently published [11]. From totally 2600 published papers they report on 15 559 colon cancer patients with stage II and 18 425 patients with stage III, of which 84% were treated between 2000 and 2008. This is important information reflecting the current status of treatment of colon cancer, in contrast to a continuous improvement in treatment of rectal cancer including more extensive surgery termed total mesorectal excision, staging with MRI, multidisciplinary team and use of preoperative radiochemotherapy [12–14]. Recently a similar focus on careful systematic surgery for colon cancer with central lymph node dissection (D3 resection) and total mesocolic excision has been accepted and is introduced in clinical practice [15–18]. Colon cancer surgery is becoming more limited to gastrointestinal surgeons specially trained in colorectal surgery [19]. Also the pathology assessment of the operation specimens has improved [20,21]. While diagnosis of one or two lymph node metastases was considered suffi-
Correspondence: O. Dahl, University of Bergen, Section of Oncology, Institute of Medicine, Haukeland University Hospital, Bergen 5021, Norway. E-mail: [email protected] (Received 14 August 2014 ; accepted 21 August 2014 ) ISSN 0284-186X print/ISSN 1651-226X online © 2015 Informa Healthcare DOI: 10.3109/0284186X.2014.958533
Acta Oncol Downloaded from informahealthcare.com by Nyu Medical Center on 05/21/15 For personal use only.
2
O. Dahl & F. Pfeffer
cient for diagnosis of stage III, currently at least 12 lymph node should be assessed, and the prognosis in stage II is even better if more than 20 lymph nodes are examined [22–24]. Not only assessment of total number lymph nodes, but also the lymph node ratio has emerged as a prognostic factor in stage III [21,25,26]. The more thorough assessment of the whole operation specimen may also contribute to a better staging, diagnosis of extralymphaticmesocolic tumor deposits that might lead to stage migration over time [18,27] and higher rate of mesocolic plane surgery [28]. By better diagnostic procedures and postoperative care, more advanced cases are offered radical surgery today, even in higher age groups. Böckelman et al. classified the quality of the publications and could show better outcome in the studies with best reporting quality, indicating different quality levels of colon cancer treatment in clinical practice. Based on the updated review by Böckelman et al. the current status is that colon cancer patients with resected lymph node metastases should continue to receive adjuvant chemotherapy. A small weakness in the work is that only 312 patients with stage III in the reported studies did not receive adjuvant chemotherapy, but it is reassuring that 97% of the published patients received the treatment which is currently recommended in guidelines [29,30]. However, the review did not show an overall DFS benefit of adjuvant chemotherapy for colon cancer stage II. A significant role for prognostic factors were documented when stage I–III and stage II–III were jointly analyzed, but we must acknowledge that we still have no simple way of identifying of the 2–5% of all patients in stage II who actually survive due to adjuvant chemotherapy. A clear role for some clinical factors has been documented [31]. Other studies have shown that at least proximal colon cancer stage II with documented mismatch repair deficiency have only half the chance of recurrence and seems not to benefit from 5FU [32–34]. Böckelman et al. confirmed the prognostic value of pT stage, emergency surgery, number of lymph nodes, differentiation, neural invasion, mismatch repair deficiency and preoperative CEA level, raising the question whether all parameters should be part of routine diagnostics in these patients. We and others try to find predictive factors to identify those patients who actually benefit from adjuvant chemotherapy, but until now no predictive molecular marker is yet in routine use for adjuvant chemotherapy in colon cancer stage III [35–39]. Böckelman et al. classified the regimens as surgery with and without adjuvant chemotherapy without differentiation between the actually given regimens. Several different regimens are used, but basically a fluoropyrimidine (5FU intravenously or
capecitabine orally) alone or combined with oxaliplatin is the standard therapy for colon cancer stage III [40,41]. It is noteworthy that oxaliplatin still has not unequivocally shown a survival benefit for colon cancer stage II patients [40,42,43] and for elderly patients above 70 years [43,44]. Thus these patients can be saved for the side effects associated with oxaliplatin. It is also a puzzle that irinotecan [45–47] and targeted antibodies cetuximab [48,49] or bevacizumab [50,51] which are active drugs in a metastatic setting, did not improve adjuvant therapy above fluoropyrimidines alone in an adjuvant setting. Timing after surgery and dosing are also factors which may influence the efficacy of the regimens [52,53]. Thus the review accompanying this editorial documents that the benefit of adjuvant chemotherapy is at least as effective in patients treated today as the initial studies showed. One should still strive for reliable predictive markers also in stage III patients, as at yet half of the patients are cured by surgery alone and hence does not need adjuvant chemotherapy which is associated with toxicity, while 30–35% of the patients will develop recurrences and need more effective chemotherapy despite adjuvant chemotherapy. Future trends With preoperative CT imaging it is now possible to identify tumors with more than 5 mm extramural tumor growth, large lymph node metastases and T4 tumors, thus identifying patients which currently are offered postoperative adjuvant chemotherapy [54,55]. The preliminary results from the British Foxtrot study indicate that three preoperative chemotherapy courses with a modified de Gramont regimen (OxMdG) followed by nine additional courses seems feasible and effective [56]. In a similar protocol, where 22 Spanish patients with locally advanced colon cancer received four courses of CapeOx before surgery and four courses postoperatively, the authors report tumor downstaging and even three cases with complete tumor regression at surgery [57,58]. Inspired by the Foxtrot study, Professor Anders Jacobsen in Veijle, Denmark has performed a phase II study giving three courses of oral capecitabine with oxaliplatin (Xelox) preoperatively. He currently leads a Nordic phase III study on his preliminary experience with this regimen (ClinicalTrials.gov). In order to improve the outcome of colon cancer treatment all patients should be discussed at multidisciplinary team meetings. If radical surgery is intended, complete mesocolic excision with central vascular ligation should be performed. Postoperative risk stratification should routinely include the above-mentioned prognostic parameters and adjuvant therapy in stage II patients should be considered individually.
Adjuvant chemotherapy for colon cancer Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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