Consensus statement : the 16 th Annual Western Canadian Gastrointestinal Cancer Consensus Conference ; Saskatoon , Saskatchewan ; September 5 – 6 , 2014

24/18_suppl/3509; cited February 15, 2015] 15. Lenz H, Niedzwiecki D, Innocenti F, et al. calgb/swog 80405: phase iii trial of irinotecan/5-fu/leucovorin (folfiri) or oxaliplatin/5-fu/leucovorin (mfolfox6) with bevacizumab (bv) or cetuximab (cet) for patients (pts) with expanded ras analyses untreated metastatic adenocarcinoma of the colon or rectum (mcrc) [abstract 501O]. Presented at the 2014 Annual Meeting of the European Society for Medical Oncology; Madrid, Spain; September 26–30, 2014. [Available online at: https://www.webges.com/cslide/library/esmo/browse/ itinerary/478/2014-09-29#9faw03oW; cited February 28, 2015] 16. Stintzing S, Modest D, von Weikersthal LF, et al. Independent radiological evaluation of objective response rate, early tumor shrinkage, and depth of response in fire-3 (aio krk-0306) in the final RAS evaluable population [abstract LBA11]. Ann Oncol 2014;25:1–41. 17. Salerno G, Sinnatamby C, Branagan G, Daniels IR, Heald RJ, Moran BJ. Defining the rectum: surgically, radiologically and anatomically. Colorectal Dis 2006;8(suppl 3):5–9. 18. Schoellhammer HF, Gregorian AC, Sarkisyan GG, Petrie BA. How important is rigid proctosigmoidoscopy in localizing rectal cancer? Am J Surg 2008;196:904–8. 19. Bartram C, Brown G. Endorectal ultrasound and magnetic resonance imaging in rectal cancer staging. Gastroenterol Clin North Am 2002;31:827–39. 20. Brown G, Richards CJ, Newcombe RG, et al. Rectal carcinoma: thin-section mr imaging for staging in 28 patients. Radiology 1999;211:215–22. 21. mercury Study Group. Extramural depth of tumor invasion at thin-section mr in patients with rectal cancer: results of the mercury study. Radiology 2007;243:132–9. 22. Al-Sukhni E, Milot L, Fruitman M, et al. Diagnostic accuracy of mri for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol 2012;19:2212–23. 23. Wang C, Zhou Z, Wang Z, et al. Patterns of neoplastic foci and lymph node micrometastasis within the mesorectum. Langenbecks Arch Surg 2005;390:311–18. 24. Winter L, Bruhn H, Langrehr J, Neuhaus P, Felix R, Hänninen LE. Magnetic resonance imaging in suspected rectal cancer: determining tumor localization, stage, and sphincter-saving resectability at 3-Tesla-sustained high resolution. Acta Radiol 2007;48:379–87. 25. nih consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444–50. 26. Adam IJ, Mohamdee MO, Martin IG, et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994;344:707–11. 27. Hall NR, Finan PJ, al-Jaberi T, et al. Circumferential margin involvement after mesorectal excision of rectal cancer with curative intent. Predictor of survival but not local recurrence? Dis Colon Rectum 1998;41:979–83. 28. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. on behalf of the Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638–46. 29. Sebag–Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (mrc CR07 and ncic-ctg C016): a multicentre, randomized trial. Lancet 2009;373:811–20. 30. Sauer R, Becker H, Hohenberger W, et al. on behalf of the German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–40. 31. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: nsabp R-03. J Clin Oncol 2009;27:5124–30. 32. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of ffcd 9203. J Clin Oncol 2006;24:4620–5. 33. Bosset JF, Collette L, Calais G, et al. on behalf of the eortc Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23. [Erratum in: N Engl J Med 2007;357:728] 34. Birgisson H, Påhlman L, Gunnarsson U, Glimelius B on behalf of the Swedish Rectal Cancer Trial Group. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 2005;23:8697–705. 35. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results—eortc 22921. J Clin Oncol 2005;23:5620–7. 36. Bujko K, Nowacki MP, Nasierowska–Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215–23. 37. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012;30:3827–33.

evidence is evolving.The decision should be made after discussion with the patient, with consideration given to quality of life and patient preference.
Expanded RAS (KRAS and NRAS) testing provides optimal patient selection and should be considered the standard of care for egfri treatment.

Summary of Evidence:
Infusional folfiri (fluorouracilleucovorin-irinotecan) and folfox (fluorouracilleucovorin-oxaliplatin) have been demonstrated to be equal in efficacy for treatment-naïve patients with stage iv crc.However, the optimal first-line monoclonal antibody-bevacizumab (an inhibitor of vascular endothelial growth factor A) or an egfri such as cetuximab or panitumumab-remains unclear.The efficacy of the egfri alone or in combination with cytotoxic agents has been reported in both chemotherapy-refractory and untreated advanced crc [1][2][3][4][5] .Unlike bevacizumab, cetuximab and panitumumab are both active as single agents in chemorefractory advanced crc.However, the activity of the egfris is confined to RAS wild-type tumours; patients harboring KRAS mutations in codon 12 or 13 at exon 2 do not benefit from egfris whether given alone or in combination with chemotherapy [6][7][8] .A mutation in the KRAS gene is found in 30%-40% of crcs.In a randomized trial, 1198 chemotherapy-naïve patients were randomized to folfiri with or without cetuximab.Compared with folfiri alone, combination treatment in patients with a KRAS wild-type tumour was associated with a significantly better median overall survival (mos): 23.5 months versus 20 months 5 .Likewise, in patients with a KRAS wild-type tumour and chemorefractory disease who were treated with cetuximab, the mos was 9.5 months compared with 4.8 months with best supportive care 3 .Recent data have demonstrated that 15%-25% patients carry mutations in KRAS exons 3 (codon 61) and 4 (codons 117 and 146) and in NRAS exons 2, 3, and 4, and do not respond to egfris 9-11 .For instance, a reanalysis of the addition of panitumumab to folfox in the prime study in the KRAS, NRAS, and BRAF wild-type subgroup noted statistically significant improvements in progressionfree survival (pfs) and os in the panitumumab arm 9 .Furthermore, patients with a mutated RAS tumour experienced shorter pfs and os when treated with combination therapy.
At least three trials have compared first-line egfri or bevacizumab in combination with chemotherapy [12][13][14] .The largest, the phase iii Cancer and Leukemia Group B (calgb)/swog 80405 trial, compared first-line therapy with bevacizumab or cetuximab in combination with folfox or folfiri for patients with KRAS wild-type (codons 12 and 13) stage iv crc 14 .Overall, 73.4% of patients in the trial received folfox as the chemotherapy backbone.The preliminary results were presented at the 2014 American Society of Clinical Oncology annual meeting.Patients treated with bevacizumab experienced a mos of 29 months, compared with 29.9 months for those receiving cetuximab [hazard ratio (hr): 0.925; p = 0.34].Median pfs was 10.8 months with bevacizumab and 10.4 months with cetuximab (hr: 1.04; p = 0.55).Approximately 10% of the patients underwent curative surgery.The toxicity profiles were as expected for these agents, with the incidences of grades 3 and 4 rash (7% vs. 0%) and diarrhea (11% vs. 8%) being increased in the cetuximab arm, and the incidences of grades 3 and 4 hypertension (1% vs. 7%) and gastrointestinal events (0.5% vs. 2%) being increased in the bevacizumab arm.Updated patient-reported survey data about dermatology-specific quality of life confirmed that skin rash was a significant concern for patients (p < 0.0001); however, the same concern was not reflected in the data from the European Organisation for Research and Treatment of Cancer (eortc) global quality of life survey (p = 0.0546).When comparing efficacy in the two chemotherapy groups, the results were the same, suggesting that the chemotherapy backbone did not affect the overall results.The preliminary result for the expanded wild-type RAS population was presented at the 2014 European Society for Medical Oncology annual meeting.In that population, the mos improved to beyond 30 months.Although neither cetuximab nor bevacizumab, both in combination with chemotherapy, was noted to be associated with a significant difference in mos (32 months vs. 31.2months) or pfs, the expanded RAS population in the cetuximab arm experienced a higher response rate (68.6% vs. 53.6%,p < 0.01) 15 .
The smaller phase iii fire-3 trial compared folfiri plus either cetuximab or bevacizumab in patients with KRAS wild-type stage iv crc 13 .Although no significant differences between bevacizumab and cetuximab were noted with respect to response rate and pfs, a 3.7-month os advantage was seen with cetuximab.That os advantage was not seen until about 1 year after completion of the study therapy.In a preliminary report of a subsequent analysis of the fire-3 trial, patients with expanded wild-type RAS status experienced an even more pronounced survival benefit with cetuximab than with bevacizumab (mos: 33.1 months vs. 25.9 months; hr: 0.70; p = 0.01), but no difference in pfs (median: 10.5 months vs. 10.4 months).The investigators recently presented an independent radiology review at the 2014 European Society for Medical Oncology annual meeting 16 .Based on that review, folfiri plus cetuximab was associated with a significantly higher overall response rate, a greater rate of early tumour shrinkage, and an increased depth of response than was folfiri plus bevacizumab.In the RAS wild-type population, the overall response rate was 72% in the cetuximab arm and 56.1% in the bevacizumab arm ( p = 0.003).The foregoing response-related outcomes might in part explain the significant os advantage observed with the use of folfiri plus cetuximab in the expanded RAS wildtype study population.
Lastly, in a phase ii study (peak), 285 patients with previously untreated metastatic RAS wild-type crc were randomly assigned to folfox plus either panitumumab or bevacizumab 12 .Progression-free survival was similar in both arms, but the mos was significantly better with panitumumab (34 months vs. 24 months; hr: 0.62).When the analysis was expanded to all patients with RAS wild-type tumours, panitumumab was associated with a significant improvement in pfs.The difference in mos, although clinically meaningful, was not statistically significant (41 months vs. 29 months).
Current evidence highlights the efficacy of two treatment options for patients with stage iv crc.Chemotherapy plus bevacizumab or plus cetuximab are two potential first-line options in all patients with RAS wild-type advanced crc.In settings in which tumour shrinkage is a relevant therapeutic goal, egfri in combination with chemotherapy might be the preferable first-line option.Future information about treatment characteristics (duration, secondline treatments, and so on), depth of response, and early tumour shrinkage from the largest first-line trial (calgb/swog 80405) could potentially influence selection of the initial therapeutic approach.Recent updates on patient outcomes in relation to expanded RAS testing strongly support all-RAS testing in making better selections of patients for egfri.

Question 2
What is the best way to define the rectum and to determine the location of a rectal tumour in clinical practice?
Recommendations: A multimodality assessment incorporating both endoscopic and radiographic findings is recommended if there is any question about the location of the tumour in the rectum compared with the sigmoid colon.
Standardized preoperative magnetic resonance imaging (mri) in combination with clinical and endoscopic examination by a surgeon who treats rectal cancer is recommended to determine the location of a rectal cancer for staging and treatment purposes.
Standardized synoptic reporting of the findings from mri is recommended.The report should assist a treatment decision by describing tumour location, depth, lymph node status, extramural vascular invasion, and distance of tumour or lymph nodes to the mesorectal fascia ("circumferential resection margin").

Summary of Evidence:
The rectum extends from the anorectal junction to the sigmoid colon; it measures 12-15 cm in length.Most studies have arbitrarily defined three parts of the rectum: the low rectum (up to 5 cm from the anal verge), the mid-rectum (5 cm to <10 cm), and the upper rectum (10-15 cm) 17 .Tumours with distal extension to 15 cm or less from the anal margin (as measured by rigid sigmoidoscopy) are classified as rectal; more proximal tumours are classified as colonic cancer 17,18 .
The decision between upfront surgery and neoadjuvant treatment is based largely on preoperative locoregional staging.Magnetic resonance imaging and endorectal ultrasonography are both options for that purpose.On balance, the more recent literature favours the use of mri for staging, and currently, phased-array pelvic mri is recommended for the preoperative assessment of tumour location (rectal versus sigmoid, lower versus upper rectum), depth (T1 or 2 vs. T3 or T4), lymph node status (abnormal Current OnCOlOgy-VOlume 22, number 2, April 2015 Copyright © 2015 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).nodes in the mesorectum or pelvic side wall), extramural vascular invasion, and distance of tumour or lymph nodes to the mesorectal fascia (circumferential resection margin status).However, endorectal ultrasonography might provide an advantage in differentiating the depth of invasion in early tumours (T1 vs. T2) 19 .
In prospective comparative studies using histopathology, staging by mri correlated strongly with depth of tumour invasion (82%) and extramural depth of invasion (95%) 20,21 .Lymph nodes with a short axis greater than 5 mm in size or with a spiculated and indistinct border or a mottled heterogeneous appearance are considered clinically positive.However, not all positive lymph nodes meet those criteria.A recent meta-analysis involving 1249 patients from 23 studies showed a pooled sensitivity of 77% and specificity of 71% for mri assessment of nodal involvement 22 .The low sensitivity with the use of size criteria can be explained only by the fact that, in rectal cancer, small lymph nodes still have a high prevalence of malignancy, 9% in 1-mm to 2-mm nodes, and 17% in 2-mm to 5-mm nodes respectively 23 .However, with improvements in mri techniques, staging accuracy for lymph nodes has increased to 91%, a high sensitivity of 89% 24 .In using mri, the point of peritoneal reflection can clearly be seen and is of variable height.Typically, tumours at or below the peritoneal reflexion are, by definition, rectal tumours.Magnetic resonance imaging is also used to measure the distance of a tumour from the mesorectal fascia or the circumferential radial margin (crm).Involvement of the crm is defined as a tumour within 1 mm of the mesorectal fascia.The mercury Study Group prospective trial showed 92% specificity for the preoperative mri predictions of a clear crm with surgery 21 .Overall, pelvic mri is a robust tool (high accuracy and reproducibility) for preoperative staging and assessment of crm involvement.

Question 3
What are the current indications for radiotherapy (rt) in early-stage rectal cancer?
If downstaging is required, chemoradiation (crt) therapy is the preferred option.
Chemoradiation therapy is recommended after upfront resection for patients with T3 or T4 tumours, a positive circumferential margin, or lymph node involvement.
Low-risk stage 2 rectal cancers such as T3 lesions with a wide crm as defined by high-resolution mri should be discussed at a multidisciplinary team meeting for optimal management.

Summary of Evidence:
Prognosis in rectal cancer is largely determined by TNM staging.Adjuvant f luorouracil-based crt has been associated with 10%-12% reductions in the rate of local failure and 10%-15% improvements in survival 25 .The status of the crm is an important prognostic factor for survival and local recurrence 26,27 .With the introduction of total mesorectal excision (tme), local recurrence rates have dropped to 10%-15% with surgery alone.However, the Dutch tme study showed a local control benefit for adding preoperative rt to tme surgery 28 .That result was subsequently confirmed by the U.K. Medical Research Council 07 trial, which found that, even in the setting of a high-quality tme, rt appears to improve local control rates 29 .The German Rectal Study Group compared preoperative crt with postoperative crt in patients with clinically T3/4 or node-positive rectal cancer.At a median follow-up of 46 months, the pelvic relapse rate was 6% in the preoperative crt group and 13% in the postoperative crt group 30 .The U.S. National Surgical Adjuvant Breast and Bowel Project R-03 trial (which closed prematurely) demonstrated better disease-free survival (dfs) with preoperative crt 31 .The German trial established preoperative rt as a standard treatment option for T3/4 or node-positive rectal cancer.The eortc 22921 and French phase iii Fédération Francophone de Cancérologie Digestive 9203 trials demonstrated the benefit of combining fluorouracilbased chemotherapy with preoperative rt by improving rates of pathologic complete response and local control with acceptable toxicity 32,33 .At least three phase iii trials (the Swedish Rectal Cancer trial, the Dutch tme study, and the Medical Research Council trial) evaluated short-course preoperative rt and demonstrated improved local control with short-course preoperative rt followed by surgery compared with surgery alone 28,29,34 .Several randomized trials and a meta-analysis have evaluated the role of concurrent crt with conventional-fractionation rt.Using a 2×2 factorial design, eortc 22921 compared preoperative crt with rt alone with or without adjuvant chemotherapy.A high rate of pathologic complete response and better local control with crt was revealed 35 .Two other trials, the Polish trial and the Trans-Tasman Radiation Oncology Group trial compared short-course rt (5×5-Gy fractions) with conventional-fractionation crt 36,37 .No significant differences were noted with respect to the rates of local relapse, dfs, and os.Nevertheless, a metaanalysis of six randomized trials favoured crt 38 .The addition of concurrent chemotherapy to neoadjuvant rt was associated with better local control [odds ratio for local recurrence: 0.56; 95% confidence interval (ci): 0.42 to 0.75].However, a higher rate of adverse effects was reported with crt (odds ratio: 3.96; 95% ci: 3.03 to 5.17).
The utility of preoperative high-resolution mri for selecting patients with T3 disease for preoperative Current OnCOlOgy-VOlume 22, number 2, April 2015 Copyright © 2015 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).therapy based on the depth of extramural tumour invasion was reported in an analysis from the prospective mercury trial 39 .The local recurrence rate for patients predicted to have a good-prognosis tumour on mri was 3%.Likewise, pooled data from 2551 patients enrolled in three North American rectal trials revealed that patients staged pT3N0 had a 6%-8% risk of local recurrence and might not derive benefit from adjuvant radiation 40 .Hence, in selected patients with T3N0 upper rectal cancer with clear resection margins and favourable prognostic features after upfront alone can be considered.Low-risk stage 2 rectal cancer such as T3 with a wide crm as defined by high-resolution mri should be discussed at a multidisciplinary team meeting for optimal management.

Question 4
What is the preferred adjuvant treatment in rectal cancer after neoadjuvant crt?

Recommendations:
The decision about adjuvant treatment is guided largely by evidence extrapolated from the colon cancer literature and is based on preoperative staging.
For patients who received chemotherapy as part of long-course preoperative chemoradiotherapy, fluoropyrimidine-based chemotherapy with or without oxaliplatin total 4 months is recommended.

Summary Evidence:
The use of adjuvant treatments in patients with rectal cancer after preoperative rt or crt and tme is based largely on extrapolation from data for colon cancer and postoperative adjuvant therapy before the era of neoadjuvant therapy.The results of a Cochrane meta-analysis support the use of fluorouracil-based postoperative adjuvant chemotherapy for patients with rectal cancer.Twenty-one eligible randomized controlled trials involving 9785 patients with rectal cancer were identified.The results showed a 25% relative reduction in the risk of disease recurrence (hr: 0.75; ci: 0.68 to 0.83) and a 17% reduction in the risk of death (hr: 0.83; ci: 0.76 to 0.91) among patients treated with adjuvant chemotherapy 41 .However, preoperative crt was administered to all patients in only one of the included trials.Currently, evidence about the benefit of adjuvant chemotherapy in patients treated with preoperative therapy and tme is limited 42 .
At least four randomized trials have evaluated the benefit of adjuvant chemotherapy in rectal cancer patients after neoadjuvant rt or crt therapy [43][44][45][46] .Although eortc failed to demonstrate a benefit for adjuvant chemotherapy, their trial suffered from substantial drop-out and dose reductions in the chemotherapy arm.Hence, the trial cannot be interpreted as definite evidence of a lack of benefit for adjuvant chemotherapy in rectal cancer 43 .An Italian trial conducted between 1993 and 2003 did not report a survival benefit for adjuvant fluorouracil compared with observation alone in patients with clinical T3/4 rectal cancer 44 .The U.K. chronicle and Dutch proctor/script trials also evaluated the benefit of adjuvant chemotherapy after neoadjuvant therapy in stage ii and iii rectal cancer.Although no differences in dfs or os were seen between the adjuvant chemotherapy and observation groups in either study, both trials were closed prematurely because of poor patient accrual 45,46 .Despite negative results, the available data are insufficient to conclude that postoperative chemotherapy in this setting offers no benefit.Guidelines from the U.S. National Comprehensive Cancer Network and the European Society for Medical Oncology support adjuvant chemotherapy in rectal cancer 47,48 .
The optimal adjuvant chemotherapy in rectal cancer is not known.The benefit of adjuvant oxaliplatin-based chemotherapy has been demonstrated in node-positive colon cancer 49,50 .Three prospective trials evaluated oxaliplatin-based regimens after neoadjuvant therapy in rectal cancer, two of which favoured adding oxaliplatin to fluorouracil-based adjuvant chemotherapy [51][52][53] .In the German trial, patients with cT3/4 or cN+ rectal cancer were randomized to preoperative crt with or without oxaliplatin, followed by tme and 4 cycles of bolus fluorouracil or 8 cycles of adjuvant folfox.The 3-year dfs was 71.2% in the fluorouracil group and 75.9% in the folfox group ( p = 0.03) 51 .A South Korean randomized phase ii trial compared adjuvant folfox with fluorouracil-leucovorin in rectal cancer patients whose postoperative stage was ii or iii after preoperative crt 52 .At a median follow-up of 38.2 months, the 3-year dfs was 71.6% in the folfox arm and 62.9% in the fluorouracil arm (hr: 0.657; p = 0.047).The petaac-8 trial evaluated the benefit of adjuvant capecitabine-oxaliplatin (capox) compared with capecitabine alone and reported no difference in 3-year dfs between the two arms (75% vs. 74%, p = 0.78) 53 .However, adjuvant therapy was not received by 38% of patients in the capox arm and 23% of patients in the capecitabine arm.Furthermore, only 53% of patients in the capox arm and 68% of patients in the capecitabine arm received all intended adjuvant chemotherapy cycles.
Taking all the evidence together, fluoropyrimidine-based chemotherapy with or without oxaliplatin for a total of 4 months is recommended in patients who received chemotherapy as part of long-course preoperative crt.

Question 5
What is the best sequence of treatments in patients with resectable primary rectal cancers and synchronous resectable or borderline resectable liver metastases?

Recommendations:
The best sequence of systemic and local therapies, including the sequencing of surgery, is not well defined in patients with resectable primary rectal cancers and synchronous resectable or borderline resectable liver metastases.
For borderline resectable liver disease, upfront systemic therapy is a preferred option.
After discussion in a multidisciplinary team meeting, treatment should be individualized based on the extent of primary and liver disease, patient characteristics, and local expertise.

Summary of Evidence:
The optimal sequence of systemic and therapy in patients with resectable or borderline resectable stage iv rectal cancer remains unknown.Data about optimal treatment approaches in these patients is very limited.Curative treatment usually entails a multimodality approach, with surgical resection of the primary tumour and metastatic disease, and incorporation of systemic therapy with or without rt.Most primary tumours in patients with stage iv rectal cancer represent T3/4 disease with regional lymph node involvement, which necessitates the use of rt.Furthermore, the need for surgical treatment at two different sites makes overall patient management complex, particularly with respect sequencing surgery with chemotherapy and rt.Additionally, a two-stage approach to hepatic resection might be needed in the presence of multiple bilobar metastases.Several strategies have been developed to combine the various treatment modalities.Initial treatment options for rectal cancer with synchronous resectable liver metastases include preoperative combination chemotherapy with or without a biologic agent, preoperative crt therapy, or even an upfront surgical approach.
Reports in the literature describe three approaches with respect to the appropriate timing of surgical resection of primary and metastatic tumours: • Classical approach, whereby the primary is resected first, and liver metastases are resected in a second operation • Simultaneous approach, in which both resections are performed in the same procedure 54 • Liver-first approach, in which the resection of liver metastases precedes resection of the primary tumour 55,56 ; however, such a strategy can be applied only to primary tumours without symptoms that render the surgical management of the rectal site urgent (for example, obstruction and perforation) A systematic review evaluating clinical studies compared the timing and sequence of surgical interventions in patients with synchronous liver metastases 57 .Despite the relatively large number of published studies on surgical management of synchronous liver metastases, no randomized controlled trials have been reported; all published studies are observational, usually retrospective, and often noncomparative.The review suggested that none of the three surgical strategies (primary first, liver first, or simultaneous) is inferior to the others.Another review 58 suggested that a liver-first approach is safe and feasible in selected patients with crc and synchronous liver metastases.Based on local expertise, combined and staged surgeries of the primary and metastatic disease are both appropriate options.
Chemotherapy can be used before liver resection as neoadjuvant treatment between the two procedures and after the crc resection.Systemic chemotherapy can be sequenced with crt either before or after local treatment for the primary tumour.Radiation therapy should be incorporated for T3/4 or N+ rectal cancer.A phase ii study evaluated preoperative short-course pelvic rt (5×5 Gy) followed by capox in combination with bevacizumab before radical surgical treatment in patients with potentially resectable stage iv rectal cancer 59 .Radical surgical treatment was possible in 36 of 50 patients (72%).The 2-year rates of recurrence and os were 64% and 80% respectively.This treatment scheme yielded a pathologic complete response of the primary tumour in 26% of patients and a pathologic near-complete response in 16% of patients.
For patients with resectable metastatic disease, oxaliplatin-based systemic therapy is the preferable option 60 .Few studies have assessed outcomes in patients with rectal cancer treated with neoadjuvant chemotherapy alone.A small retrospective study evaluated outcomes in patients with colon and rectal cancers who received preoperative folfox alone, either because of metastatic disease or contraindications to, or refusal of, rt.Of the 20 patients who received folfox or folfox plus bevacizumab without rt, 7 (35%) achieved a complete pathologic response.Of the 6 patients with rectal cancer who were treated with preoperative folfox, 2 achieved a complete pathologic response, and an additional 3 experienced a 90% positive treatment effect 61 .In the setting of potentially operable liver metastases, a preliminary report of the epoc trial (folfox with or without cetuximab for 12 weeks before and 12 weeks after surgery) showed that the addition of cetuximab was associated with a significantly worse pfs (14.8 months vs. 24.2months) and should be avoided 62 .

Question 6
What is the role of liver-directed therapy in patients with stage iv crc with unresectable liver-only disease?

Recommendations:
The role of liver-directed therapy in patients with stage iv crc with unresectable liveronly disease is currently not well defined.
Such therapy can be considered in selected patients after discussion in a multidisciplinary team meeting.

Current OnCOlOgy-VOlume 22, number 2, April 2015
Copyright © 2015 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

Summary of Evidence:
Liver metastases develop in approximately 40% of patients with crc 63 .In patients with liver metastases and limited extrahepatic disease, local control of the liver disease can result in better overall survival 64 .Several liver-directed therapies have been developed to improve disease control.Radiofrequency ablation has been used in liver-limited metastatic disease as an adjunct to surgery or single treatment for a lesion smaller than 3 cm.For smaller lesions, local recurrence rates with radiofrequency ablation are comparable to those with resection of the liver metastases 65 .Imageguided transarterial chemoembolization (tace) is the procedure most commonly performed for liver tumours.It is also used as salvage therapy for patients with liver metastases from neuroendocrine tumours and chemorefractory crc.Other treatments such as transarterial chemotherapy infusion, transarterial embolotherapy, and radioembolization with 90 Y are less commonly used 63 .More recently, a new method called deb-tace has been introduced, in which polymer-based microparticles [drug-eluting (debs)] replace lipiodol.Compared conventional tace, deb-tace enhances drug delivery to the tumour and significantly reduces systemic drug exposure.
Limited data suggest that hepatic arterial embolization and tace can achieve disease stabilization in 40%-60% of treated patients, but the survival benefit relative to systemic chemotherapy alone is uncertain.Several studies suggest that conventional tace is associated with improved survival in patients with chemorefractory crc with liver metastases 66,67 ; however, most studies lack a control group.Phase ii/iii trials using deb-tace have reported response rates of approximately 70%, with pfs durations of 7-8 months and a mos of 22-25 months [68][69][70] .Nonetheless, larger randomized trials are needed to confirm those results before it can be concluded that hepatic artery chemoembolization provides outcomes superior to those with standard intravenous systemic chemotherapy.

ACKNOWLEDGMENTS
The Western Canadian Gastrointestinal Cancer Consensus Conference Organizing Committee thanks all meeting participants who contributed to the development of this consensus statement.In addition, the Committee thanks the meeting sponsors, and Maureen Melnyk and Pascale Daigneault of Buksa Strategic Conference Services for support in organizing the meeting.

CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on disclosing conflicts of interest, and we declare the following interests: SA has received speaker fees and fees as an advisory board member for Roche and Amgen; SB has received honoraria from Roche and Amgen; SG has received honoraria from Amgen and Bristol-Myers Squibb; HK has received research funding and honoraria from Roche, Sanofi, and Amgen; HL has received fees as an advisory board member for Roche, Amgen, Bayer, and Sirtex, and his institution receives funding from Roche, Bayer, and Lilly for a trial in which he is co-investigator; and KM has received personal fees and nonfinancial support from Novartis Canada and Lilly Canada outside the submitted work.The remaining authors have no conflicts of interest to disclose.