Download pdf

Bowel cancer: from prevention to palliation

|
Vol 38
Issue No 1
Guest editor: Finlay Macrae

Adjuvant therapy for colorectal cancer

Authors:

Details:

Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

Abstract

Patients with resected colon cancer (stage III [T1 to T4, N1-N2] or high-risk stage II [T3 or T4, N0]) or stage II/III rectal cancers (T3 or T4, N0-2) are at significant risk of local and distant failure, with reduced survival due to microscopic residual disease. To reduce this risk, adjuvant therapy has been the standard of care for both cancer populations, as stated in the 2005 Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer developed through Cancer Council Australia’s Clinical Guidelines Network. This review provides an update to the guidelines. Patients, with resected stage III colon cancer should, where possible, be offered six months of adjuvant chemotherapy. The optimal regimen is oxaliplatin-5FU or -capecitabine, based on relevant clinical factors. For patients with resected stage II colon cancer, adjuvant 5FU-based chemotherapy should be considered for those at particularly high risk of relapse. For patients with stage II/III rectal cancer, treatment approaches include: (i) short course radiotherapy and immediate total mesorectal excision; or (ii) neoadjuvant chemoradiotherapy (with 5FU infusion or capecitabine) followed by TME. Post-operative adjuvant chemotherapy should be offered to all medically fit patients. At present, there are no markers to identify patients who may not require neoadjuvant chemoradiotherapy or who can avoid surgery.

Approximately 70-80% of newly diagnosed cases of colorectal cancer (CRC) undergo curative resection, however 40% of these develop incurable recurrent disease due to undetected micrometastases.1-2 In particular, patients with stage III (T1 to T4, N1-2) or Dukes’ C colon cancer have a five-year survival rate of between 44-88%, with a three-year disease-free survival (DFS) ranging from 45 to 52%. Those with stage II (T3 or T4, N0) or Dukes B colon cancer have a five-year survival rate of between 45–60% and three-year DFS of 64–75%.1,3 The inability to cure all such patients is a direct consequence of residual disease left behind after surgery. Over the last two decades, adjuvant chemotherapy has been offered to such high risk patients with the aim to decrease relapse and improve overall survival (OS) by attempting to eliminate this microscopic residual disease.

Patients with rectal cancer are at even greater risk of local recurrence following surgery alone, relative to the more proximal colon primaries.4 In particular, tumours that have penetrated the rectal wall (T3 or T4) and/or with nodal involvement (N1-2) are at increased risk of local or distant relapse, with recurrence rates up to 25-65%.5 A positive circumferential resection margin (CRM) (tumour 1mm of resection margin) is an important independent prognostic marker, accounting for up to 85% of local recurrences,6-7 and correlates with  lymphovascular/perineural invasion and nodal involvement.8 Hence the optimum strategy to improve the outcome of rectal cancer patients must address the problems of local and distant recurrence.9 Multimodality treatment comprising total mesorectal excision (TME), with chemotherapy and radiotherapy, has been the standard of care for locally advanced (stage II and III) rectal cancer. The current nomograms include preoperative short course RT or preoperative chemoradiotherapy (CRT), followed by TME and adjuvant chemotherapy, and in limited patients, post-operative CRT with adjuvant chemotherapy.9 These approaches have dramatically reduced local recurrence, however approximately one-third of patients will expire from their disease within five years.10

This article will review the current data and practice regarding the adjuvant treatment of both colon and rectal cancers, and will serve as an update beyond the 2005 Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer, developed through Cancer Council Australia’s Clinical Guidelines Network and approved by the National Health and Medical Research Council (NHMRC).9,11

Adjuvant therapy of resected colon cancer

Adjuvant chemotherapy is offered to high risk patients with the aim of decreasing relapse and improving OS by attempting to eliminate this microscopic residual disease. Its benefits must outweigh the risks from chemotherapy-related toxicities. For over two decades, it has been offered to patients with stage III disease as standard therapy,12 a practice reinforced by two recent meta-analyses.13-14

In the case of patients with stage II disease, the role of adjuvant therapy is controversial given the difficulty in identifying patients at the highest of risk who would benefit the most from adjuvant therapy.15 The recognised poor prognostic markers for patients with stage II disease include: (1) poorly differentiated histology;16 (2) obstruction or perforation at presentation;17 (3) lymphovascular invasion;18 (4) less than 12 lymph nodes retrieved during primary resection;17,19-21 and (5) T4 disease (with invasion into adjacent organs).16,22 The issues regarding treating patients with stage II disease will be addressed below.

Adjuvant chemotherapy for resected stage III colon cancer (T1-4, N1-2, M0)

Adjuvant chemotherapy has been the standard of care for stage III disease for the last two decades. Initial efforts concentrated on the evaluation of 5-fluorouracil (5FU)-based regimens and 5FU biomodulation, and more recently the evaluation of oral 5FU prodrugs.11 Two recent meta-analyses have shown a significant reduction in mortality by biomodulation of 5FU.13-14 Subsequent large randomised trials have demonstrated that a weekly 5FU-low dose leucovorin (LV) regimen is preferred, based upon efficacy and toxicity relative to alternative regimens, or the use of 5FU-Levamisole with six months as the optimal duration of therapy. The randomised phase III X-ACT trial has also demonstrated the equivalent efficacy, and near superiority of the oral 5FU prodrug, capecitabine, (24 weeks, 1250 mg/m2 b.i.d, days 1-14, 1 week rest) relative to six months bolus 5FU-LV as adjuvant therapy for stage III colon cancer, both in terms of survival parameters, toxicity and pharmacoeconomics.11,23-24

The advances in the treatment of metastatic disease including oral 5FU prodrugs, oxaliplatin, irinotecan and the biologicals (including epidermal growth factor receptor [EGFR] and anti-vascular endothelial growth factor [VEGF] monoclonal antibodies), have led to these agents being evaluated in patients with stage III disease. The evidence will be summarised in the sections below. It must be noted that during this time, three year DFS rate has been validated as an appropriate endpoint for adjuvant trials given its strong correlation with five-year OS,25 and recently six-year OS.26 In modern adjuvant trials, six or seven years may now be required to demonstrate OS improvements.27

Oxaliplatin and 5FU or Capecitabine

The efficacy of oxaliplatin plus 5FU in the adjuvant setting was demonstrated by two pivotal trials – the MOSAIC,28 and the more recent NSABP C07 trials.29 In the MOSAIC trial, 2246 patients who had stage II or III colon cancer were randomised to receive a combined bolus/infusional 5FU regimen (LV5FU2) alone, or with oxaliplatin (FOLFOX4), for six months. The primary end point was DFS.28 A total of 1123 patients were randomly assigned and on final analysis reported in 2009, the five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups respectively (HR =0.80; P <0.005). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 versus LV5FU2 groups, respectively (HR =0.84; P<0.05). The  corresponding six-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR =0.80; P <0.05). There was no difference in OS seen in the stage II population.30

The NSABP C07 trial, published in 2007, randomised 2492 patients with stage II and III colon cancer to either 5FU 500mg/m2, plus LV 500mg/m2 both IV weekly for six weeks during each eight-week cycle (Roswell Park regimen) for three cycles, or the same 5FU-LV regimen with oxaliplatin 85 mg/m2 IV administered on weeks one, three and five of each eight-week cycle for three cycles.29 The additional benefit provided by oxaliplatin in terms of DFS, as observed from the MOSAIC trial, was confirmed.29

A subsequent study, the NO1968 trial, compared capecitabine plus oxaliplatin (XELOX; oxaliplatin 130mg/m2 on day one plus capecitabine 1000 mg/m2 b.i.d on days one to 14, every three weeks for 24 weeks) with bolus 5FU-LV (Mayo Clinic for 24 weeks or Roswell Park for 32 weeks) in patients with stage III colon cancer.31 The three-year DFS rate was 70.9% with XELOX and 66.5% with 5FU-LV (HR =0.80, P <0.005). XELOX is thus considered an additional adjuvant treatment option for these patients.31

The efficacy of adjuvant oxaliplatin therapy has also been evaluated in the elderly. A subgroup analyses of the NO1968 trial above, demonstrated reduced risk of recurrence in all groups receiving oxaliplatin, including patients <65 years of age and those ≥65 years of age, however in the latter group the trend was not significant.31 A post-hoc analysis of the NSABP CO7 trial also demonstrated that oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; P <0.05), but no positive effect was evident in older patients.32

Irinotecan and 5FU

Despite the activity of irinotecan in the treatment of advanced CRC, randomised phase III trials in the adjuvant setting (including CALBG 89803, PETACC3 and ACCORD 2 trials) have failed to demonstrate an added benefit relative to 5FU-LV alone.33-35

Biological agents + combination adjuvant chemotherapy

In the metastatic setting, the antiangiogenic agent, bevacizumab, a monoclonal antibody to VEGF, and the EGFR monoclonal antibodies, cetuximab and panitumumab, have shown added benefit when added to conventional chemotherapy backbones, whether oxaliplatin-,36 or irinotecan-based,37 or 5FU-LV.38-39 However, recent phase III trials in the adjuvant setting have demonstrated that these biological agents provide no additional benefit and may actually be detrimental when added to a chemotherapy backbone, usually oxaliplatin-5FU. These have included the NSABP C08 and AVANT trials for bevacizumab and the NCCTG-N0147 trial for cetuximab.40-42 The mechanisms for this lack of synergy with chemotherapy and the biological agents in this setting are not clear, but may be explained by the induction of therapy resistance mechanisms by VEGF or EGFR inhibition; this has been discussed elsewhere.43

In terms of bevacizumab, two large relevant trials await reporting: the QUASAR 2 study, randomising patients to capecitabine +/- bevacizumab; and the ECOG E5202,44 discussed below. Cetuximab is being further assessed in the PETTAC-8 trial. The FoxTROT trial evaluating FOLFOX or XELOX ± panitumumab is also to be reported.45

Adjuvant therapy of patients with resected stage II colon cancer

The case for and against?

In the case of patients with stage II disease, the role of adjuvant therapy is controversial given the difficulty in identifying patients at the highest risk who would benefit the most from adjuvant therapy whilst avoiding potential toxicity in patients who would not benefit.15

The efficacy of systemic adjuvant chemotherapy for patients with stage II cancer has still not been confirmed.11 The previously reported analyses from the IMPACT-B group,46 the pooled analysis of the NSABP C01–4 trials,47 and the large phase III QUASAR trial,48 have been inconsistent. In terms of modern combination therapy, there is relevant data from the MOSAIC and the NSABP C07 trials, above, in patients with stage II disease. In terms of the MOSAIC trial, 899 patients with stage II disease were randomised,30 and with a median follow-up of 6.8 years, the five-year DFS was 79.9% versus 83.7% (HR =0.84, P>0.05) and the six-year OS 86.8% versus 86.9% (P >0.05).30 From the NSABP CO7 trial, 29% overall had resected stage II disease and the four year DFS was 81% versus 84.2% in favour of oxaliplatin-5FU.29 

A recent Cochrane analysis considered all randomised trials or meta-analyses containing data on stage II colon cancer patients undergoing adjuvant therapy versus surgery alone; overall 8642 patients were considered.49 In terms of the effect of adjuvant therapy, the pooled relative risk ratio for OS was 0.96 (95% CI 0.88-1.05), and for DFS 0.83 (95% CI 0.75-0.92). Hence the benefit was in terms of DFS only.49

Thus the overall the benefits of adjuvant systemic chemotherapy in patients with stage II patients are modest, but should be discussed in those with high risk features. The co-morbidities and likelihood of tolerating adjuvant systemic chemotherapy should be considered as well.49 

Identifying high risk stage II patients

Given the modest benefit for adjuvant therapy in such patients, there is an urgent need to better characterise high risk patients who would gain the greatest benefit. At present the identifiers of high risk relate to the tumour as well as clinical factors, as listed above, albeit inconsistently.15 Considerable effort has been directed to identify molecular prognostic and predictive factors. However, as expected, there is considerable heterogeneity in terms of the cohorts evaluated, prospective versus retrospective analyses, and analytical methodology. The markers evaluated thus far include anueploidy/tetraploidy DNA, 18q allelic loss, as well as microsatellite status (MS), p53, Kras, BRAF and thymidylate synthase.50-54 A detailed review of these molecular factors with regard to stage II disease has been published recently.55

MSI

The assessment of microsatellite instability (MSI), which serves as a marker for DNA mismatch repair (MMR) system function, has emerged as a useful tool for risk stratification of patients with stage II colon cancer. It seems clear, by retrospective studies and meta-analyses, that patients with stage II and III tumours classified as MSI–High (MSI-H) or defective MMR [dMMR]), have a better prognosis, independent of adjuvant therapy, relative to MS-Stable tumours.56-58 While the prognostic importance of MSI has been confirmed,  its importance in predicting response to adjuvant chemotherapy is unclear.51 However, it appears from two retrospective studies that patients with dMMR do not benefit from adjuvant 5FU therapy.59-60 Based on the body of current data, with the caveat that MSI status is still to be validated prospectively as a predictive biomarker, the current NCCN guidelines recommend that where adjuvant therapy is being considered in patients with stage II disease, MSI status must be assessed and those with MSI-H tumor should not be offered 5FU-based therapy.17, 44

It is unclear whether this also applies to oxaliplatin-5FU adjuvant regimens. A recent study investigated the clinical implication of MSI-H/dMMR and p53 expression in 121 patients with resected colon cancer (13 stage II and 108 stage III disease) who received post-operative FOLFOX therapy.61 The study observed that MMR status was not associated with DFS or OS, and thus adding oxaliplatin to adjuvant chemotherapy may overcome the negative impact of 5-FU on colon cancers with MSI-H/dMMR.61 There is also preclinical evidence that MSI-H/dMMR tumour cells may be equally sensitive to oxaliplatin and possibly more sensitive to irinotecan.62

18q Allelic Imbalance (18qAI)

Chromosome 18q, contains the tumor suppressor genes deleted in colon cancer and the SMAD4 gene, which are lost in the oncogenic development of CRC.63 The allelic loss of 18q is manifested as a loss of heterozygosity (LOH). The 18qLOH or 18 allelic imbalance (18qAI) have been correlated with a poorer prognosis in patients with stage II and III disease, albeit inconsistently.64-65 The recently closed ECOG E5202 study had randomised stage II patients, stratified by MSI status and 18q allele imbalance, to observation for low risk patients (MS-S or MSI-Low with retention of 18q or MSI-H) and high risk patients (MS-S/18qLOH  or MSI-L/18qLOH) to FOLFOX4 +/ bevacizumab. It was closed early following the reports that demonstrated the lack of benefit of bevacizumab in the adjuvant setting. We are still awaiting its final analysis.44 

Gene expression approaches

Quantitative gene expression assays have been evaluated to assess recurrence risk, though with less utility for the benefits from chemotherapy in patients with stage II disease. There are at present, two commercially available gene expression classifiers (Coloprint and Oncotype DX) that have been developed and subsequently validated to prognostically classify patients with early stage colon cancer at high risk of relapse, rather than to determine their predictive ability in terms of outcomes from adjuvant chemotherapy.66-67 Others have also been reported and are or are being validated.68-69

Adjuvant therapy of rectal cancer

As stated above, patients with rectal cancer are at greater risk of local recurrence following surgery alone relative to the more proximal colon primaries.4  An increased risk of local or distant relapse is observed, especially in tumours that have penetrated the rectal wall (T3 or T4) and/or with nodal involvement (N1-2).5 A positive circumferential resection margin (CRM) (tumour ?1mm of resection margin) is also an important independent prognostic marker, accounting for up to 85% of local recurrences.6-8 Hence the optimum strategy to improve the outcome of rectal cancer patients must address the problems of local and distant recurrence.9

Multimodality treatment comprising of TME, with chemotherapy and radiotherapy, have been the standard of care for locally advanced (stage II and III) rectal cancer, as discussed in the 2005 Australian guidelines.9 The current treatment nomograms will be discussed below, and include preoperative short-course radiotherapy or preoperative CRT followed by TME and adjuvant chemotherapy, and in select patients post-operative CRT with adjuvant chemotherapy.9 These approaches have dramatically reduced local recurrence, however approximately one-third of patients will still die from their disease within five years.10 Current work is also now being directed towards identifying low risk patients who may avoid pre-operative radiotherapy or even surgery.

Current treatment nomograms for rectal cancer

Short-course preoperative radiotherapy (25Gy in 5 fractions) followed by TME

The advantages for preoperative radiotherapy include possible tumour downstaging, reduction of radiation field size and hence toxicity, and increasing radiosensitivity of the well-oxygenated un-manipulated tumour bed. Three meta-analyses have confirmed that preoperative radiotherapy is associated with a reduced local recurrence rate and reduction in cancer-specific mortality relative to surgery alone,70-72 which extended to 10 years.71 Short intensive course preoperative radiotherapy appeared to be as effective as longer schedules.71 The pivotal Dutch Colorectal Cancer Group phase III trial, confirmed the benefit of preoperative radiotherapy (25Gy in five fractions) followed by TME one week later relative to TME alone in terms of local recurrence rate.73 Follow-up data at five years, reported in 2007, had demonstrated that local recurrence was 5.6% versus 10.9%, respectively (P<0.001), but there was no OS difference.74 As expected, short-course radiotherapy followed by immediate TME had not induced downstaging of the primary.75

Short-course preoperative radiotherapy (25Gy in 5 fractions) followed by TME versus TME and selective post-operative CRT

As TME reduces the risk of local recurrence, it was suggested that the role of preoperative radiotherapy needed to be reassessed. The MRC-C07 trial had compared short-course preoperative RT (25Gy/5 fractions) versus immediate surgery, with selective postoperative CRT (45Gy/25 fractions with concurrent 5FU) in patients with positive resection margins.76 Overall, 1350 patients were randomised and the primary outcome measure was local recurrence. At four years follow-up, there was a 61% reduction in the relative risk for local recurrence in patients receiving preoperative radiotherapy (HR =0.39, P<0.0001), with an absolute difference at three years of 6.2% (4.4% versus 10.6%). The relative improvement in DFS was 24% for pre-operative radiotherapy (HR 0.76, P <0.05).76

Preoperative (long-course) CRT versus short course preoperative radiotherapy

This has been directly compared in three randomised phase III trials.77-79 A Polish study randomised 316 clinical stage T3–T4 rectal cancer patients to short-course radiotherapy (25Gy/5 fractions) plus TME one week later, versus long-course CRT (50.4Gy plus bolus 5F-LV) plus surgery. The primary endpoint was sphincter preservation.78 There was no difference between the arms in terms of survival, local recurrence, late toxicity or sphincter preservation. The rates of positive CRM involvement though, were lower in the CRT arm (4% versus 13%, P<0.05).78 A smaller Lithuanian phase III trial (n =83) compared the downstaging post long-course CRT versus short-course radiotherapy. The former resulted in a significant greater tumoural downsizing and downstaging (P>0.05), but there was no difference in the R0 resection rates.77

The third study is the Australian TROG 01.04 trial that randomised 326 patients to short-course radiotherapy (5×5 Gy) versus long-course preoperative CRT (with daily bolus 5FU–LV, weeks one and five), followed by surgery and post-operative adjuvant chemotherapy.79 The primary endpoint was local recurrence, which was not statistically signficant between the arms – 7.5 % versus 4.4 %, respectively. Nevertheless, in patients with distal tumours, long-course CRT did appear to be associated with lower rates of local recurrence. There were no differences between the arms for distant recurrence, relapse-free survival, OS or late toxicity.79

Based on current evidence, pre-operative long-course CRT, where downstaging effects are more pronounced, may be preferable particularly for patients with distal or low rectal tumors or those with threatened radial margins. For patients with small, relatively proximal tumors for whom the duration of therapy is an important consideration, short-course preoperative radiotherapy appears to be appropriate.80

Preoperative CRT versus postoperative CRT

The comparision between preoperative and postoperative CRT has been addressed by two pivotal phase III trials, updated since the guidelines.9 The first is the German CAO/ARO/AIO-94 trial which randomised 800 patients with clinical stage T3/T4 or node-positive disease with OS as the primary endpoint.9,81 The initial results from 2004 were confirmed when updated in 2012.82 At a median follow-up of 134 months, OS at 10 years was approximately 60% in both arms (P>0.05), and there were no significant differences for DFS and 10-year cumulative incidence of distant metastases. However, the 10-year cumulative incidence of local relapse was 7.1% versus 10.1% in the pre and postoperative CRT arms, respectively (P<0.05).82

The NSABP R 03 trial, reported in 2009, randomised patients with T3–T4 or node-positive rectal cancers to either: (i) preoperative therapy – weekly bolus 5FU-LV for six weeks, followed by CRT (50.4Gy/28 fractions with bolus 5FU-LV). Patients then proceeded to surgery followed by 24 weeks of weekly 5FU-LV; or (ii) post-operative therapy – surgery followed by CRT (50.4Gy/28 fractions with bolus 5FU-LV) and then followed by 24 weeks of weekly 5FU-LV. The trial was closed prematurely, with only 267 of the planned 900 patients recruited.83 In the preoperative arm, sphincteric preservation occured in 48%, compared with 39% of patients in the postoperative group (P>0.05). The five year DFS for the preoperative group was signifcantly higher (65% versus 53%; P<0.05).83 Thus preoperative CRT is preferred to postoperative CRT.84

The optimal chemotherapy backbone for concurrent long course pelvic radiotherapy

5FU-based therapy: Infusion and oral 5FU prodrugs  

The use of continuous infusion 5FU over bolus 5FU has become the standard of care in the CRT treatment of rectal cancers, primarily for its low toxicity profile.85 Two randomised phase III studies have now confirmed the equivalent efficacy of capecitabine as a radiosensitizing agent in preoperative CRT. A German phase III trial randomised patients to either: (i) preoperative CRT 50.4Gy plus capecitabine (825mg/m2 b.i.d), days 1-38 and post-surgery capecitabine 1250 mg/m2/day b.i.d days one–14, q3 weeks for five additional cycles; or (ii) preoperative CRT 50.4Gy with infusional 5-FU and post-surgery four additional cycles of bolus 5FU.86 At a median follow-up of 52 months, the local recurrence rate was equal (capecitabine 6% versus 5-FU 7%, P>0.05), but with significantly fewer patients developing distant metastases in the capecitabine arm (18.8% vs 27.7%; P<0.05).87 The five-year OS rate was 75.7% for the capecitabine group and 66.6% for the 5FU group (P>0.05).86

The second, the NSABP R-04 trial, was a 2×2 factorial design randomising patients to continuous infusion 5FU during preoperative RT versus capecitabine (825mg/m2 b.i.d) on the days of radiotherapy only, and the second randomisation was with and without oxaliplatin.88 In terms of the capecitabine versus 5FU, no differences were seen with regards to pathological complete response (pCR), tumour downstaging, or sphincter-sparing surgery. Local recurrence and overall survival have yet to be reported.88 

It thus appears that capecitabine is a reasonable alternative to infusional 5FU as a radiosensitiser in pre-operative CRT, especially in those patients seeking an oral regimen or where a central venous access device is not preferred.

The utility of other chemotherapy agents and biologicals concurrent with long-course radiotherapy

With the advances in systemic therapy in advanced CRC, there has been considerable effort to increase the effectiveness of CRT in terms of pathological downstaging, and systemic control. At this stage, based on trials discussed below, there has been no change from the 5FU (infusion or oral prodrug) chemotherapy backbone for CRT.

  1. Oxaliplatin

There have been five reported phase III trials evaluating oxaliplatin with 5FU backbone versus 5FU alone as part of preoperative CRT. The STAR-01,89 NASBP-R04,88 and the PETACC-6,90 trials all demonstrated the absence of additional benefit for tumoral pathological response or downstaging, but with an increased rate of toxicity. The German CAO/ARO/AIO4-04,91 showed that patients who received oxaliplatin with 5-FU during CRT relative to 5FU alone had a pathological complete response (pCR) of 17.6% versus 13.1% (P<0.05). The Accord 12/0405-Prodige 2 trial of oxaliplatin plus capecitabine versus capecitabine during CRT, demonstrated a similar trend: 19.2% versus 13.9% (P>0.05).92 To date, no DFS or OS advantage has been demonstrated. At this stage oxaliplatin cannot be a standard of care in preoperative CRT.

  1. Monoclonal antibodies to VEGF and EGFR

Phase I and II trials of bevacizumab,93-96 and cetuximab,97-99,100 or panitumumab,101-102 have been combined with neoadjuvant CRT. The reported pathological response rates range from 0-25%, not providing a significant advantage in this regard, but associated with increased gastrointestinal toxicity and issues with wound healing.80,103-104 Thus the use of monoclonal antibodies cannot be considered as standard of care in preoperative CRT.

Current issues regarding the adjuvant therapy of rectal cancer

The role of post-operative adjuvant therapy patients undergoing neoadjuvant CRT or radiotherapy treatment

The role of post-operative adjuvant therapy in patients treated in the neoadjuvant setting is unclear. It is standard practice to offer patients adjuvant therapy to reduce distant disease failure and improve OS. The optimal regimen and whether some patients, based upon pathological response or baseline stage, can be spared treatment is unclear. The only trial to evaluate this question was the EORTC Radiotherapy Group Trial 22921, which randomised patients to preoperative radiotherapy, preoperative CRT, preoperative radiotherapy plus postoperative chemotherapy, or preoperative CRT plus postoperative chemotherapy.10 This showed no significant difference in OS or DFS between those that received post-operative chemotherapy versus those who did not (P>0.05).10 However, it must be noted that 43% of patients only completed the planned postoperative chemotherapy.105 

Several retrospective series have shown that patients post-neoadjuvant CRT who achieve a pCR may have no, or minimal benefit from adjuvant chemotherapy.106-107 A post-hoc analysis of patients who underwent neoadjuvant CRT or radiotherapy and post-operative chemotherapy from the EORTC 22921 trial above, demonstrated an improved DFS and OS in those with resected pT0-2 versus pT3-4 disease (P<0.05).108 Thus patients that have tumoural downstaging post CRT or radiotherapy do benefit from adjuvant chemotherapy,108 an observation confirmed by others.109-110 For treatment non-responders, it is not clear if additional 5FU chemotherapy or even multi-agent chemotherapy improves their poor outcomes.111 Prospective data are required.

Hence at present, adjuvant chemotherapy should be offered to all medically fit patients with locally advanced, completely resected rectal cancer post-preoperative CRT or short-course radiotherapy. However, it is not clear which patients derive the most benefit from this approach. Patients treated with pre-operative CRT should have four months of a 5FU-LV or capecitabine regimen, and those post short-course radiotherapy a six month course postoperatively. If there is nodal disease at baseline or in the resected specimen, they should be offered an oxaliplatin-5FU/capecitabine based regimen, unless contraindicated.105

Role of TME after pre-operative CRT

Overall, approximately 15-20%,89, 92, 112 of patients achieve a pCR at the time of TME post CRT, which is associated with substantially improved local control, distant control and DFS.82, 113-116 A recent meta-analysis, involving 16 studies and 3363 patients, evaluated the long-term outcomes of patients found to have a pCR post neoadjuvant CRT.113 Overall, 1263 had a pCR with a mean local recurrence rate of 0.7% (range 0-2.6%). Compared with non-responders, a pCR was associated with fewer local recurrences (OR 0.25; P<0.005), reduced distant failure (P<0.001), and a greater OS (OR 3.28, P<0.005) and DFS (OR 4.33, P<0.001) at five years.113 At present, there are no validated predictive biomarkers that identify patients most likely to undergo a pCR post-neoadjuvant therapy.117

Given these outcomes of pCR, some have advocated avoiding surgical resection totally in very select patients achieving clinical CR (cCR) post neoadjuvant CRT. However, the ability to predict cCR using clinical parameters is not robust.118-119 The evidence is based upon a number of retrospective trials or prospective series,120-126 without randomised data. A recent systematic review of 30 publications (9 series, 650 patients) evaluated a non-operative approach after CRT.127 Overall the cCR rates varied from 10.9 to 56%.127 The most recent Habr-Gama series,123 reported a loco-regional failure rate of 4.6%, with five-year OS and DFS of 96% and 72%, respectively. These variable results reflect the significant heterogeneity in study design, including aspects of baseline and post-treatment staging, the definition of cCR and the nature of follow-up. The avoidance of TME requires, at the least, long-term prospective observational and randomised studies. Validated methods are also required to distinguish residual scar from viable tumor and document residual mesorectal deposits. Current MRI,128-129 or PET,130-132 imaging data have been inconsistent in this regard. A number of European prospective trials are evaluating this question.

Novel alternative neoadjuvant approaches

These include intensifying systemic chemotherapy prior to neoadjuvant CRT or radiotherapy and surgery in an effort to reduce systemic failure, especially as 20%-40% of patients do not receive post-operative adjuvant chemotherapy.10,84 A phase II trial in high risk patients (distal lesions, threatened CRM, cT4 or cN2),133 and a prospective study,134 have evaluated an induction oxaliplatin-capecitabine combination pre-CRT. The studies have observed reduced toxicity,134 higher response rates with favourable survival parameters.133 Phase III trial data are required to validate the utility of such induction chemotherapy.

Other approaches have been to identify patients with low risk disease at baseline, can proceed with surgery alone without neoadjuvant therapy. There is retrospective evidence indicating that there is a subgroup of patients with early T3N0 disease who may not benefit from additional therapy, apart from surgery.135-136 The MERCURY study evaluated 374 patients with stage I–III rectal cancer, who underwent baseline high resolution pelvic MRI imaging.137 Overall, 33% of these patients were deemed to have good prognosis, based upon predicted clear CRM (T2-T3a/b disease), and thus underwent surgery alone. The five-year DFS for stage II–III patients in this category was 85%, with a 3% local recurrence rate.137 There is also the current US Intergroup PROSPECT phase II/III trial, evaluating the need for pre-operative radiotherapy in patients with mid to high rectal tumors who are candidates for TME with sphincter preservation. Patients are randomised to a standard arm of neoadjuvant CRT with 5FU, followed by TME and adjuvant chemotherapy. In the experimental arm, patients will receive neoadjuvant chemotherapy alone with FOLFOX, but will only receive post-operative radiation therapy if they have a <20% pathological response to chemotherapy.138

Conclusions

In conclusion, adjuvant therapy is recommended for patients with resected stage III colon cancer. Patients, based on fitness and preference, with completely resected stage III cancer, should be offered six months of adjuvant chemotherapy, which optimally should start within eight weeks of surgery. The optimal regimen is oxaliplatin in combination with 5FU-LV or capecitabine, based on relevant consideration of the therapeutic ratio, especially in regard to neurotoxicity, and perhaps age. Patients not considered suitable for oxaliplatin should be offered 5FU-LV or capecitabine.50 Current trials are now investigating the optimal length of therapy i.e. three versus six months, and the additional benefit of the EGFR monoclonal antibody panitumumab, (the FOxTROT trial).43

In terms of patients with resected stage II disease, adjuvant chemotherapy may be discussed with patients at high risk of disease relapse, based upon clinico-pathological factors discussed above and while considering the patients’ comorbidities, age and the risk of therapy-related toxicity. MSI status must be assessed for those patients being considered for adjuvant therapy. Those with a MSI-H tumor should not be offered 5FU-based therapy.17,44 The utility of oxaliplatin-based therapy in this setting is controversial, given the marginal benefit and greater risk of toxicity. Where available, commercial gene expression classifiers may also be considered to further classify patients based on risk of relapse. However, at this stage they cannot identify patients who are likely to respond to therapy.

For patients with stage II/III rectal cancer (T3 or T4 and/or with nodal involvement [N1-2]), the optimal strategy is to reduce local and distant recurrence. Current treatment approaches may include: (i) short-course radiotherapy and immediate TME (especially in proximal tumours); or (ii) long-course neoadjuvant CRT (with 5FU infusion or capecitabine) followed by TME. Post-operative adjuvant chemotherapy should be offered to medically fit patients. Postoperative CRT therapy may be preferred, for example where patients who have undergone surgery for very small or proximal T3 tumors, or tumors that are either T2/3. In these circumstances, post CRT and adjuvant chemotherapy should be considered if unexpected nodal involvement or a positive margin is identified. At present, there are no validated markers that can identify patients who may not require neoadjuvant radiotherapy, or who can be safely spared surgery post CRT or radiotherapy, though these are areas of active research. In an effort to increase pCR, the intensification of neoadjuvant chemotherapy is also being evaluated.

References

  1. Lombardi L, Gebbia V, Silvestris N, Testa A, Colucci G, Maiello E. Adjuvant therapy in colon cancer. Oncology. 2009; 77 Suppl 1: 50-6.
  2. Chou JF, Row D, Gonen M, Liu YH, Schrag D, Weiser MR. Clinical and pathologic factors that predict lymph node yield from surgical specimens in colorectal cancer: a population-based study. Cancer. 2010; 116(11): 2560-70.
  3. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004; 96(19): 1420-5.
  4. Cass AW, Million RR, Pfaff WW. Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum. Cancer. 1976; 37(6): 2861-5.
  5. Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer. 1983; 52(7): 1317-29.
  6. Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet. 1986; 2(8514): 996-9.
  7. Bokey EL, Chapuis PH, Dent OF, Newland RC, Koorey SG, Zelas PJ, et al. Factors affecting survival after excision of the rectum for cancer: a multivariate analysis. Dis Colon Rectum. 1997; 40(1): 3-10.
  8. Moriya Y, Hojo K, Sawada T, Koyama Y. Significance of lateral node dissection for advanced rectal carcinoma at or below the peritoneal reflection. Dis Colon Rectum. 1989; 32(4): 307-15.
  9. Committee. aCNCCGR. Adjuvant chemotherapy for rectal cancer Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer: National Health and Medical Research Council 2005. p. 186-93.
  10. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006; 355(11): 1114-23.
  11. Committee. ACNCCGR. Adjuvant chemotherapy for colon cancer Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer: National Health and Medical Research Council 2005. p. 172-85.
  12. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990; 264(11): 1444-50.
  13. Dube S, Heyen F, Jenicek M. Adjuvant chemotherapy in colorectal carcinoma: results of a meta-analysis. Dis Colon Rectum. 1997; 40(1): 35-41.
  14. Gray R. 5’fluorouracil (FU) and folinic acid (FA) in either the weekly ‘Roswell Park’ or the 4-weekly ‘Mayo’ regimen should be standard chemotherapy for colon cancer. Eur J Cancer. 2003; 39(14): 2110.
  15. Dotan E, Cohen SJ. Challenges in the management of stage II colon cancer. Semin Oncol. 2011; 38(4): 511-20.
  16. Gill S, Loprinzi CL, Sargent DJ, Thome SD, Alberts SR, Haller DG, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004; 22(10): 1797-806.
  17. Engstrom PF, Arnoletti JP, Benson AB, 3rd, Chen YJ, Choti MA, Cooper HS, et al. NCCN Clinical Practice Guidelines in Oncology: colon cancer. J Natl Compr Canc Netw. 2009; 7(8): 778-831.
  18. Ouchi K, Sugawara T, Ono H, Fujiya T, Kamiyama Y, Kakugawa Y, et al. Histologic features and clinical significance of venous invasion in colorectal carcinoma with hepatic metastasis. Cancer. 1996; 78(11): 2313-7.
  19. Berger AC, Sigurdson ER, LeVoyer T, Hanlon A, Mayer RJ, Macdonald JS, et al. Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol. 2005; 23(34): 8706-12.
  20. Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer. 2000; 88(7): 1739-57.
  21. Le Voyer TE, Sigurdson ER, Hanlon AL, Mayer RJ, Macdonald JS, Catalano PJ, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol. 2003; 21(15): 2912-9.
  22. Gunderson L, Jessup J, Sargent D, Greene F, Stewart A. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol. 2010; 28: 264-71.
  23. Twelves CJ. Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial: overview of efficacy, safety, and cost-effectiveness. Clin Colorectal Cancer. 2006; 6(4): 278-87.
  24. Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, et al. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012; 23(5): 1190-7.
  25. Sargent D, Shi Q, Yothers G, Van Cutsem E, Cassidy J, Saltz L, et al. Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. Eur J Cancer. 2011; 47(7): 990-6.
  26. Franko J, Shi Q, Goldman CD, Pockaj BA, Nelson GD, Goldberg RM, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol. 2012; 30(3): 263-7.
  27. de Gramont A, Hubbard J, Shi Q, O’Connell MJ, Buyse M, Benedetti J, et al. Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: simulations based on the 20,800 patient ACCENT data set. J Clin Oncol. 2010; 28(3): 460-5.
  28. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004; 350(23): 2343-51.
  29. Kuebler JP, Wieand HS, O’Connell MJ, Smith RE, Colangelo LH, Yothers G, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007; 25(16): 2198-204.
  30. Andre T, Boni C, Navarro M, Tabernero J, Hickish 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(19): 3109-16.
  31. Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011; 29(11): 1465-71.
  32. 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(28): 3768-74.
  33. 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(23): 3456-61.
  34. 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(19): 3117-25.
  35. Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009; 20(12): 1964-70.
  36. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008; 26(12): 2013-9.
  37. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26(14): 2311-9.
  38. Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009; 20(11): 1842-7.
  39. Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005; 23(16): 3697-705.
  40. Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, 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(1): 11-6.
  41. 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(13): 1383-93.
  42. de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012; 13(12): 1225-33.
  43. de Gramont A, Chibaudel B, Bachet JB, Larsen AK, Tournigand C, Louvet C, et al. From chemotherapy to targeted therapy in adjuvant treatment for stage III colon cancer. Semin Oncol. 2011; 38(4): 521-32.
  44. Van Loon K, Venook AP. Adjuvant treatment of colon cancer: what is next? Curr Opin Oncol. 2011; 23(4): 403-9.
  45. Graham JS, Cassidy J. Adjuvant therapy in colon cancer. Expert Rev Anticancer Ther. 2012; 12(1): 99-109.
  46. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol. 1999; 17(5): 1356-63.
  47. Mamounas E, Wieand S, Wolmark N, Bear HD, Atkins JN, Song K, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol. 1999; 17(5): 1349-55.
  48. Kerr DJ, Gray R, McConkey C, Barnwell J. Adjuvant chemotherapy with 5-fluorouracil, L-folinic acid and levamisole for patients with colorectal cancer: non-randomised comparison of weekly versus four-weekly schedules–less pain, same gain. QUASAR Colorectal Cancer Study Group. Ann Oncol. 2000; 11(8): 947-55.
  49. Figueredo A, Coombes ME, Mukherjee S. Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev. 2008; (3): CD005390.
  50. Jonker DJ, Spithoff K, Maroun J. Adjuvant systemic chemotherapy for Stage II and III colon cancer after complete resection: an updated practice guideline. Clin Oncol (R Coll Radiol). 2011; 23(5): 314-22.
  51. Tejpar S, De Roock W, Jonker D. KRAS Genotypes and Outcome in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer Treated With Cetuximab-Reply. JAMA. 2011; 305(6): 564-6.
  52. Donada M, Bonin S, Nardon E, De Pellegrin A, Decorti G, Stanta G. Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability. J Cancer Res Clin Oncol. 2011; 137(2): 201-10.
  53. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010; 28(3): 466-74.
  54. Farina-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ, et al. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 2010; 21(12): 2396-402.
  55. Tejpar S, Bertagnolli M, Bosman F, Lenz HJ, Garraway L, Waldman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010; 15(4): 390-404.
  56. Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000; 342(2): 69-77.
  57. Gray RG, Quirke P, Handley K, Lopatin M, Magill L, Baehner FL, 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(35): 4611-9.
  58. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005; 23(3): 609-18.
  59. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003; 349(3): 247-57.
  60. Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, 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(20): 3219-26.
  61. Kim ST, Lee J, Park SH, Park JO, Lim HY, Kang WK, et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol. 2010; 66(4): 659-67.
  62. Damia G, D’Incalci M. Genetic Instability Influences Drug Response in Cancer Cells. Curr Drug Targets. 2010.
  63. Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990; 247(4938): 49-56.
  64. Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med. 1994; 331(4): 213-21.
  65. Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001; 344(16): 1196-206.
  66. Salazar R, Roepman P, Capella G, Moreno V, Simon I, Dreezen C, et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol. 2011; 29(1): 17-24.
  67. O’Connell MJ, Lavery I, Yothers G, Paik S, Clark-Langone KM, Lopatin M, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010; 28(25): 3937-44.
  68. Van Laar RK. An online gene expression assay for determining adjuvant therapy eligibility in patients with stage 2 or 3 colon cancer. Br J Cancer. 2010; 103(12): 1852-7.
  69. Roth A, Di Narzo A, F., Tejpar S, Bosman F, Popovici V, C., Wirapati PX, T., et al. Validation of two gene-expression risk scores in a large colon cancer cohort and contribution to an improved prognostic method. J Clin Oncol. 2012 30, (suppl; abstr 3509).
  70. Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA. 2000; 284(8): 1008-15.
  71. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet. 2001; 358(9290): 1291-304.
  72. Rahbari NN, Elbers H, Askoxylakis V, Motschall E, Bork U, Buchler MW, et al. Neoadjuvant Radiotherapy for Rectal Cancer: Meta-analysis of Randomized Controlled Trials. Ann Surg Oncol. 2013.
  73. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001; 345(9): 638-46.
  74. Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 2007; 246(5): 693-701.
  75. Marijnen CA, Nagtegaal ID, Klein Kranenbarg E, Hermans J, van de Velde CJ, Leer JW, et al. No downstaging after short-term preoperative radiotherapy in rectal cancer patients. J Clin Oncol. 2001; 19(7): 1976-84.
  76. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009; 373(9666): 811-20.
  77. Latkauskas T, Pauzas H, Gineikiene I, Janciauskiene R, Juozaityte E, Saladzinskas Z, et al. Initial results of a randomized controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long-term chemoradiotherapy, both with delayed surgery. Colorectal Dis. 2012; 14(3): 294-8.
  78. 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(10): 1215-23.
  79. Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, 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(31): 3827-33.
  80. Rodel C, Hofheinz R, Liersch T. Rectal cancer: state of the art in 2012. Curr Opin Oncol. 2012; 24(4): 441-7.
  81. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004; 351(17): 1731-40.
  82. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012; 30(16): 1926-33.
  83. Roh MS, Colangelo LH, O’Connell MJ, Yothers G, Deutsch M, Allegra CJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009; 27(31): 5124-30.
  84. Khrizman P, Niland JC, ter Veer A, Milne D, Bullard Dunn K, Carson WE, 3rd, et al. Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis. J Clin Oncol. 2013; 31(1): 30-8.
  85. O’Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994; 331(8): 502-7.
  86. Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012; 13(6): 579-88.
  87. Hofheinz RW, FK. Post, S. Matzdorff, A. Laechelt, S. Hartmann, JT. Müller, L. Link, H. Moehler, MH. Kettner, E. Fritz, E. . Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Long-term results of a randomized, phase III trial. J Clin Oncol 29: 2011 (suppl; abstr 3504). 2013.
  88. Roh MY, GA. O’Connell, MJ. Beart, RW. Pitot, HC. Sheilds, AF. Allegra, CJ. Petrelli, NJ. Landry, JC. Ryan, DP. Arora, A. Evans, TL. Soori, GS. Chu, L. Landes, RV. Mohiuddin, M. Lopa, S. Wolmark, N. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R04. . Journal of Clinical Oncology. 2011; 29, Suppl 18: Abstr: 3503.
  89. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011; 29(20): 2773-80.
  90. Schmoll H-JH, K. Price, TJ. Nordlinger, B. Hofheinz, R. Daisne, J-F. Janssens, J. . Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: First results of the PETACC-6 randomized phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 3531). 2013.
  91. Rodel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012; 13(7): 679-87.
  92. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol. 2010; 28(10): 1638-44.
  93. Resch G, De Vries A, Ofner D, Eisterer W, Rabl H, Jagoditsch M, et al. Preoperative treatment with capecitabine, bevacizumab and radiotherapy for primary locally advanced rectal cancer–a two stage phase II clinical trial. Radiother Oncol. 2012; 102(1): 10-3.
  94. Gasparini G, Torino F, Ueno T, Cascinu S, Troiani T, Ballestrero A, et al. A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer. Angiogenesis. 2012; 15(1): 141-50.
  95. Crane CH, Eng C, Feig BW, Das P, Skibber JM, Chang GJ, et al. Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2010; 76(3): 824-30.
  96. Dellas K, Hohler T, Reese T, Wurschmidt F, Engel E, Rodel C, et al. Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer. Radiat Oncol. 2013; 8(1): 90.
  97. Sun PL, Li B, Ye QF. Effect of neoadjuvant cetuximab, capecitabine, and radiotherapy for locally advanced rectal cancer: results of a phase II study. Int J Colorectal Dis. 2012; 27(10): 1325-32.
  98. Weiss C, Arnold D, Dellas K, Liersch T, Hipp M, Fietkau R, et al. Preoperative radiotherapy of advanced rectal cancer with capecitabine and oxaliplatin with or without cetuximab: A pooled analysis of three prospective phase I-II trials. Int J Radiat Oncol Biol Phys. 2010; 78(2): 472-8.
  99. Rodel C, Arnold D, Hipp M, Liersch T, Dellas K, Iesalnieks I, et al. Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys. 2008; 70(4): 1081-6.
  100. Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012; 30(14): 1620-7.
  101. Helbling D, Bodoky G, Gautschi O, Sun H, Bosman F, Gloor B, et al. Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07. Ann Oncol. 2013; 24(3): 718-25.
  102. Pinto C, Di Fabio F, Maiello E, Pini S, Latiano T, Aschele C, et al. Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study). Ann Oncol. 2011; 22(11): 2424-30.
  103. Gollins S. Radiation, chemotherapy and biological therapy in the curative treatment of locally advanced rectal cancer. Colorectal Dis. 2010; 12 Suppl 2: 2-24.
  104. Aklilu M, Eng C. The current landscape of locally advanced rectal cancer. Nat Rev Clin Oncol. 2011; 8(11): 649-59.
  105. Schrag D. Evolving role of neoadjuvant therapy in rectal cancer. Curr Treat Options Oncol. 2013; 14(3): 350-64.
  106. Beets G, Neleman, PJ. et al. Evaluation of response after chemoradiation for rectal cancer as a predictive factor for the benefit of adjuvant chemotherapy: a pooled analysis of 2,724 individual patients. J Clin Oncol. 2012; 29 (suppl 4; abstr 361).
  107. Chang GE, C. et al. Exploratory analysis of adjuvant chemotherapy benefits after preoperative chemoradiotherapy and radical resection for rectal cancer. J Clin Oncol. 2012; 3556. .
  108. Collette L, Bosset JF, den Dulk M, Nguyen F, Mineur L, Maingon P, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol. 2007; 25(28): 4379-86.
  109. Janjan NA, Crane C, Feig BW, Cleary K, Dubrow R, Curley S, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol. 2001; 24(2): 107-12.
  110. Chan AK, Wong AO, Langevin J, Jenken D, Heine J, Buie D, et al. Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study. Int J Radiat Oncol Biol Phys. 2000; 48(3): 843-56.
  111. Nelson VM, Benson AB, 3rd. Pathological complete response after neoadjuvant therapy for rectal cancer and the role of adjuvant therapy. Curr Oncol Rep. 2013; 15(2): 152-61.
  112. Park IJ, You YN, Agarwal A, Skibber JM, Rodriguez-Bigas MA, Eng C, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012; 30(15): 1770-6.
  113. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012; 99(7): 918-28.
  114. Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010; 11(9): 835-44.
  115. Kim JC, Kim CW, Yoon YS, Lee HO, Park IJ. Levator-sphincter reinforcement after ultralow anterior resection in patients with low rectal cancer: the surgical method and evaluation of anorectal physiology. Surg Today. 2012; 42(6): 547-53.
  116. Agarwal A, Chang GJ, Hu CY, Taggart M, Rashid A, Park IJ, et al. Quantified pathologic response assessed as residual tumor burden is a predictor of recurrence-free survival in patients with rectal cancer who undergo resection after neoadjuvant chemoradiotherapy. Cancer. 2013.
  117. Solanki AA, Chang DT, Liauw SL. Future directions in combined modality therapy for rectal cancer: reevaluating the role of total mesorectal excision after chemoradiotherapy. Onco Targets Ther. 2013; 6: 1097-110.
  118. Glynne-Jones R, Hughes R. Critical appraisal of the ‘wait and see’ approach in rectal cancer for clinical complete responders after chemoradiation. Br J Surg. 2012; 99(7): 897-909.
  119. Curvo-Semedo L, Lambregts DM, Maas M, Thywissen T, Mehsen RT, Lammering G, et al. Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging. Radiology. 2011; 260(3): 734-43.
  120. Habr-Gama AdS, PM. Ribeiro, U. Nadalin, W. Gansl, R. Sousa, AH. et al.. . Low rectal cancer: impact of radiation and chemotherapy on surgical treatment. Dis Colon
    Rectum. 1998; 41: 1087-96.
  121. Habr-Gama A, de Souza PM, Ribeiro U, Jr., Nadalin W, Gansl R, Sousa AH, Jr., et al. Low rectal cancer: impact of radiation and chemotherapy on surgical treatment. Dis Colon Rectum. 1998; 41(9): 1087-96.
  122. Habr-Gama A. Assessment and management of the complete clinical response of rectal cancer to chemoradiotherapy. Colorectal Dis. 2006; 8 Suppl 3: 21-4.
  123. Habr-Gama A, Perez RO, Sao Juliao GP, Proscurshim I, Gama-Rodrigues J. Nonoperative approaches to rectal cancer: a critical evaluation. Semin Radiat Oncol. 2011; 21(3): 234-9.
  124. Smith JD, Ruby JA, Goodman KA, Saltz LB, Guillem JG, Weiser MR, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg. 2012; 256(6): 965-72.
  125. Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011; 29(35): 4633-40.
  126. Dalton RS, Velineni R, Osborne ME, Thomas R, Harries S, Gee AS, et al. A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management? Colorectal Dis. 2012; 14(5): 567-71.
  127. Aggarwal A, Gayadeen S, Robinson D, Hoskin PJ, Mawdsley S, Harrison M, et al. Clinical target volumes in anal cancer: calculating what dose was likely to have been delivered in the UK ACT II trial protocol. Radiother Oncol. 2012; 103(3): 341-6.
  128. Alberda WJ, Dassen HP, Dwarkasing RS, Willemssen FE, van der Pool AE, de Wilt JH, et al. Prediction of tumor stage and lymph node involvement with dynamic contrast-enhanced MRI after chemoradiotherapy for locally advanced rectal cancer. Int J Colorectal Dis. 2013; 28(4): 573-80.
  129. Cho YB, Chun HK, Kim MJ, Choi JY, Park CM, Kim BT, et al. Accuracy of MRI and 18F-FDG PET/CT for restaging after preoperative concurrent chemoradiotherapy for rectal cancer. World J Surg. 2009; 33(12): 2688-94.
  130. Kim JW, Kim HC, Park JW, Park SC, Sohn DK, Choi HS, et al. Predictive value of (18)FDG PET-CT for tumour response in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy. Int J Colorectal Dis. 2013; 28(9): 1217-24.
  131. Yeung JM, Kalff V, Hicks RJ, Drummond E, Link E, Taouk Y, et al. Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome. Dis Colon Rectum. 2011; 54(5): 518-25.
  132. Martoni AA, Di Fabio F, Pinto C, Castellucci P, Pini S, Ceccarelli C, et al. Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer. Ann Oncol. 2011; 22(3): 650-6.
  133. Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010; 11(3): 241-8.
  134. Fernandez-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol. 2010; 28(5): 859-65.
  135. Kachnic LA, Hong TS, Ryan DP. Rectal cancer at the crossroads: the dilemma of clinically staged T3, N0, M0 disease. J Clin Oncol. 2008; 26(3): 350-1.
  136. Gunderson LL, Sargent DJ, Tepper JE, Wolmark N, O’Connell MJ, Begovic M, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol. 2004; 22(10): 1785-96.
  137. Taylor FG, Quirke P, Heald RJ, Moran B, Blomqvist L, Swift I, et al. Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg. 2011; 253(4): 711-9.
  138. Alliance for Clinical Trials in Oncology.Preoperative Radiation or Selective Preoperative radiation and Evaluation before Chemotherapy and TME. NCT01515787. Accessed on Ocober 20, 2013. http://wwwcancergov/clinicaltrials/search/vie. 2013.

Bowel cancer: from prevention to palliation

|
Vol 38
Issue No 1
Guest editor: Finlay Macrae

Be the first to know when a new issue is online. Subscribe today.