PubMed Health. A service of the National Library of Medicine, National Institutes of Health.

National Collaborating Centre for Cancer (UK). Colorectal Cancer: The Diagnosis and Management of Colorectal Cancer. Cardiff: National Collaborating Centre for Cancer (UK); 2011 Nov. (NICE Clinical Guidelines, No. 131.)

3Management of local disease

The objectives of this chapter were to determine:

  • the effectiveness of short course preoperative radiotherapy or chemoradiotherapy in patients with operable rectal cancer
  • whether preoperative chemotherapy followed by surgery was more effective than immediate surgery in patients presenting with non-metastatic locally advanced colon cancer
  • whether preoperative radiotherapy, preoperative chemotherapy or preoperative chemoradiotherapy was more effective than immediate surgery in patients presenting with locally advanced rectal cancer
  • whether all patients presenting with obstruction as a first symptom of colorectal cancer should have a CT scan to confirm diagnosis and provide evidence of metastases and to identify the indications for stenting these patients and the optimal timing for stenting to occur
  • whether the use of prognostic factors can determine the most effective curative treatment in patients who have undergone local excision (with/without neoadjuvant treatment for low rectal tumours) and been diagnosed with stage I colorectal cancer (including/or polyp cancer)
  • the effectiveness of adjuvant chemotherapy following surgery in patients with clinical or pathological stage II and III rectal cancer
  • the effectiveness of adjuvant chemotherapy after surgery on patients with high risk stage II colon cancer.

3.1. Preoperative management of the patient’s primary tumour

3.1.1. Patients whose primary rectal tumour appears resectable at presentation

The National Bowel Cancer Audit Programme (NBOCAP, 2005)8 report recognised that the positive circumferential resection margin rates for anterior resection by total mesorectal excision (TME) and abdomino-perineal resection (APR) were 6.5% and 15.6%, respectively (assuming all missing values were negative). The inference from these results is that many patients with rectal cancer are understaged prior to surgery and/or the chosen treatment strategy was either inappropriate or suboptimal.

The effectiveness of any form of preoperative therapy is dependent on the subsequent quality of surgery. TME is the accepted standard resection for most rectal cancers. Low rectal tumours may require an APR. The value of neoadjuvant therapy for low rectal tumours is debatable at present and requires further evaluation.

The gains in local control from preoperative radiotherapy are well established but they need to be balanced against the significant late effects in terms of sexual, urinary and bowel dysfunction and the potential risk of second malignancies. Although preoperative chemoradiotherapy and short-course preoperative radiotherapy (SCPRT) are widely used to reduce the risks of local recurrence over surgery alone, and have similar biological equivalent radiation dose, there is uncertainty over which schedule to use in which particular clinical setting. SCPRT is a brief (typically 5 days) treatment with high dose per fraction radiotherapy. Short term side effects are minimal though there is some risk from long-term morbidity. Chemoradiotherapy involves a protracted (minimum of 5 weeks) course of radiotherapy with concomitant chemotherapy. Short term side effects are more marked and although long-term effects do occur there are less published data to establish their extent.

Since this topic only addressed preoperative and not postoperative therapy, the results of the large MRC CR07/NCIC-CTG C016 trial of preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer were not considered in the evidence review.

The findings of the initial pelvic imaging are key determinants of the rationale and type of preoperative radiotherapy or chemoradiotherapy administered. This is particularly important for low rectal cancers where T-staging may not be clear even with high-quality imaging. These details inform both the type of surgery and the type of preoperative strategy.

For the purposes of this guideline we have defined three different risk groups of patients with rectal cancer, according to the risk of local recurrence. These groups are defined in Table 3.1.

Table 3.1. Risk of local recurrence for rectal tumours as predicted by MRI.

Table 3.1

Risk of local recurrence for rectal tumours as predicted by MRI.

Clinical question: For patients with operable rectal cancer, what is the effectiveness of short course preoperative radiotherapy or chemoradiotherapy?

Clinical evidence

Short-course preoperative radiotherapy versus surgery alone

The evidence for this comparison comprised a systematic review (Wong et al., 2007) and data from long term follow-up of two randomised trials (Peeters et al., 2007; Birgisson et al., 2005). In addition there was a systematic review (Birgisson et al., 2007) which addressed the late adverse effects of preoperative (and postoperative) radiotherapy in patients treated for rectal cancer. The evidence was considered to be moderate to high quality on GRADE assessment (Table 3.2).

Table 3.2. GRADE profile: For patients with operable rectal cancer is short-course preoperative radiotherapy more effective than surgery.

Table 3.2

GRADE profile: For patients with operable rectal cancer is short-course preoperative radiotherapy more effective than surgery.

Wong et al. (2007) calculated a pooled hazards ratio for overall survival from fourteen studies of HR: 0.93 [95%CI: 0.87–1.0] (p=0.04) in favour of short-course preoperative radiotherapy versus surgery only, but this could not be replicated using individual patient data. Long term data from the Dutch TME trial also found no significant difference in the rate of overall survival between patients who had short course preoperative radiotherapy compared with those patients who had surgery only (64.2% versus 63.5%) (Peeters et al., 2007).

Pooled data for disease-specific survival indicated an advantage of short-course preoperative radiotherapy in improving disease-free survival (HR: 0.87 [95%CI: 0.78–0.98] (p=0.02)) but there was high heterogeneity between studies so the results may not be reliable. The data for local recurrence were highly heterogeneous and were not appropriate for pooling. However, good data showed an overall reduction in the rate of second malignancies in favour of short course preoperative radiotherapy (HR: 0.89 [95%CI: 0.82–0.97] (p<0.001)). The most common side effect of short-course preoperative radiotherapy was diarrhoea. Patients in the surgery only group experienced less post-surgical toxicity.

Peeters et al. (2007) analysed long term data from the Dutch TME trial and found no significant difference in the rate of overall survival between patients who had short-course preoperative radiotherapy compared with those patients who had surgery only (64.2% versus 63.5%). They also found no significant difference in 5-year cancer-specific survival in irradiated versus non-irradiated patients (75.4% versus 72.4%). However, there was a 49% reduction in local disease recurrence (p<0.001) for irradiated patients but no significant difference in the rate of distant recurrence after 5 years of follow-up.

Quality of life comparisons showed a non-significant trend towards worse outcomes in irradiated patients. There was more scarring of the anal sphincters in this group (33%) when compared with the non-irradiated group (13%) and most also suffered some degree of incontinence. The maximum resting and squeezing pressures were significantly lower in the irradiated group (Wong et al., 2007). Birgisson et al. (2005) observed an increased risk of infections among irradiated patients during the first 6 months after treatment (RR: 7.67 (95%CI: 1.76–33.39)) and similarly in gastrointestinal diagnoses (RR: 2.57 [95%CI: 1.55–4.26]). There was an increase in the risk of non-specific infections (n=10; RR: 8.06 [95%CI: 1.02–63.69]) in the irradiated group although the risk of cardiac arrhythmia was reduced (RR: 0.57 [95%CI: 0.36–0.91]). In relation to gastrointestinal diagnoses, increased relative risks were observed in irradiated patients for bowel obstruction, nausea and non-specific abdominal pain whereas the risk for inguinal hernia was lower.

Stephens et al. (2010) conducted a quality of life study within a randomised controlled trial that had compared short-course preoperative radiotherapy then surgery with surgery and postoperative chemotherapy (if tumour was within 1mm of resection margin). Study participants completed two questionnaires (MOS SF-36 and QLQ-CR38) at baseline (n=1,208), every 3 months for the first year and every 6 months to 3 years (n=563 at 2 years). The main, irreversible treatment effect that reduced quality of life was sexual dysfunction (p<0.001 for men, regardless of group, between baseline and 3 months) caused primarily by surgery but exacerbated by radiotherapy (p<0.001 at 6 months between groups). There were insufficient responses from females to measure this outcome. Bowel function in patients without a stoma (or in those who had a stoma reversal) was not significantly different between treatment arms. However, sub group analysis suggested that patients in the short-course preoperative radiotherapy then surgery group may have experienced an increase in the ‘unintentional release of stools’ even at 2 years post-treatment (p=0.007). Generally, there were no significant differences in treatment groups in overall general health or quality of life. Although the quality of the trial from which these data were derived may have been good, the lack of sensitivity of quality of life instruments in the questionnaires applied may have rendered them less sensitive to detecting differences in outcomes.

Preoperative chemoradiotherapy versus short course preoperative radiotherapy

The evidence for this comparison comprised four papers (Pietrzak et al., 2007, Bujko et al., 2004, Bujko et al., 2005 and Bujko et al., 2006) reporting different outcomes from the same trial comparing conventionally fractionated preoperative chemoradiotherapy with short course preoperative radiotherapy. The evidence was considered to be high quality on GRADE assessment (Table 3.3).

Table 3.3. GRADE profile: For patients with operable rectal cancer is preoperative chemoradiotherapy more effective than short course preoperative radiotherapy.

Table 3.3

GRADE profile: For patients with operable rectal cancer is preoperative chemoradiotherapy more effective than short course preoperative radiotherapy.

Bujko et al. (2006) reported no significant difference in the rate of 4 year survival (HR: 1.01 [95%CI: 0.69–1.48]) or 4 year disease free survival (HR: 0.96 [95%CI: 0.69–1.35]) between patients having received preoperative chemoradiotherapy compared with short course preoperative radiotherapy. There was also no significant difference in the 4 year incidence of local recurrence (HR: 0.65 [95%CI: 0.32–1.28]), the crude incidence of distant metastases, late toxicity (RR: 1.05 [95%CI: 0.72–1.53]) or late severe toxicity (RR: 1.43 [95%CI: 0.67–3.07]). Bujko et al. (2004) found no significant difference in the rate of sphincter preservation between patients having had short-course preoperative radiotherapy and those having had preoperative chemoradiotherapy (61% versus 58%). Bujko et al. (2006) found no significant difference in the rate of postoperative complications or severe complications, including death, between comparators but, unfortunately, as this was not the primary outcome of the trial, the study was underpowered to have detected a difference between the interventions had one existed.

Pietrzak et al., 2007 specifically addressed quality of life and observed no significant difference in the mean scores for the global health/quality of life status (p=0.22) or for anorectal and sexual function in patients having had preoperative chemoradiotherapy or short-course preoperative radiotherapy. Approximately two thirds of patients complained of faecal and gas incontinence, urgency and inability to differentiate between stool and gas. Approximately two-thirds of respondents stated that the disturbances in anorectal function had a negative impact on their quality of life, with approximately 20% stating the impact was considerable. Anorectal function was estimated as being ‘good’ or ‘very good’ by 41% of patients in the short-course preoperative radiotherapy group and by 37% of patients in the preoperative chemoradiotherapy group (p=0.52). Two percent (n=2) of patients scored anorectal function as being ‘unacceptable’ and regretted that a stoma had not been performed. There was no significant difference between the two groups in relation to the impact on sexual function (p=0.56 for males; p=0.1 for females).

Recommendations

Linking evidence to recommendations

The GDG considered the outcomes of local control and both short and long term toxicity to be the most important as these are clearly defined outcomes and have the highest impact on patients’ quality of life. The GDG agreed that the potential development of a second malignancy was important but there were insufficient data to inform the recommendations.

The overall quality of the evidence was moderate to high, as assessed by GRADE. The evidence looked at historical use of radiotherapy, surgery and imaging.

The GDG were aware that pelvic radiotherapy is associated with significant long-term morbidity and the likelihood of morbidity is independent of a patient’s risk of local recurrence. However the potential benefits of radiotherapy do depend on a patient’s risk of local recurrence and therefore the clinical benefits and harms need to be considered for each of the three risk groups in making recommendations.

The GDG noted that for patients at low-risk for local recurrence, the incidence of long term morbidity from radiotherapy outweighs the potential benefit. Therefore they decided not to recommend radiotherapy for this group of patients.

For those patients at moderate-risk for local recurrence, the GDG concluded from the evidence that both types of radiotherapy treatment offer equivalent benefit in reduction in local recurrence and similar risks of morbidity. The GDG noted that whilst SCPRT was less expensive and more convenient for patients, there will be individuals whose tumour characteristics on MRI (for example cT3d in a narrow male pelvis, concern about extent of lymph node involvement) raise concern that the tumour may be borderline between moderate and high risk of local recurrence. The opinion of the GDG based on clinical experience was that these patients would be better treated by chemoradiotherapy followed by delayed surgery. Therefore they agreed it was inappropriate to only recommend SCPRT for this group of patients. The GDG also acknowledged that there may be patients in the moderate risk group who may choose, following discussion of risks, not to have preoperative treatment but proceed directly to surgery. They therefore recommended that both treatment options be considered.

For patients at high-risk for local recurrence, the GDG noted that there were no direct data on the effectiveness of SCPRT. They were also aware that the reduction in the risk of a positive margin would be facilitated by tumour shrinkage during an appropriate interval before surgery. Since there was evidence for the effectiveness of chemoradiotherapy in this setting, and a lack of evidence for the use of SCPRT, the GDG decided to recommend the use of chemoradiotherapy.

The size of the population of patients eligible for preoperative interventions for rectal cancer is small compared with other topics in the guideline and hence this topic was considered a lower priority for economic modelling.

3.1.2. Patients whose primary colon or rectal tumour appears unresectable or borderline resectable at presentation

In contrast to rectal cancer, colon cancer occurs at several different sites along the remainder of the large bowel with variation in the anatomy affected. However, for most of these sites, the main risk is peritoneal involvement which when it occurs is usually widespread. Any strategy to reduce the risk of recurrence needs to have a systemic approach. However it is not known whether preoperative chemotherapy is able to reduce the risk of this type of recurrence.

Preoperative chemoradiotherapy is given to patients with locally advanced rectal cancer, with the intention of reducing tumour size to facilitate potentially curative surgery. There is concern that for a small proportion of patients their tumour may progress while on such therapy, thereby losing the window of opportunity for surgical resection. There is also concern that preoperative chemoradiotherapy is being used for the treatment of very low rectal tumours to facilitate sphincter saving surgery.

Clinical question: For patients presenting with a) non metastatic locally advanced colon cancer is preoperative chemotherapy followed by surgery more effective than immediate surgery and for patients presenting with b) locally advanced rectal cancer is preoperative radiotherapy, preoperative chemotherapy or preoperative chemoradiotherapy more effective than immediate surgery?

Clinical evidence

There was no evidence with which to address the issue of preoperative chemotherapy versus surgery alone in patients with locally advanced colon cancer. There was a large volume of evidence of a variety of quality with which to address the issue of preoperative treatment in patients with locally advanced rectal cancer (radiotherapy, chemoradiotherapy or chemotherapy) versus immediate surgery, though the volume and quality of evidence was dependent on the particular comparison under investigation (Tables 3.4 – 3.6).

In relation to preoperative chemoradiotherapy versus preoperative radiotherapy alone, a Cochrane review (Ceelen et al., 2009) was available along with a number of randomised trials. In relation to preoperative chemoradiotherapy versus surgery alone there were a number of case series studies available. One Cochrane review (Wong et al., 2007) was available to provide evidence for preoperative radiotherapy versus surgery alone.

There was no evidence available to address the issue of preoperative chemotherapy versus surgery alone in patients with locally advanced rectal cancer. Nor were there any studies comparing preoperative chemotherapy with preoperative radiotherapy for patients with locally advanced rectal cancer.

Preoperative chemotherapy versus surgery alone in patients with non-metastatic locally advanced colon cancer

There was no evidence with which to determine the benefits, if any, of preoperative chemotherapy versus surgery alone in patients with locally advanced colon cancer.

Preoperative chemoradiotherapy versus preoperative radiotherapy alone in patients with locally advanced rectal cancer

(see Table 3.4)

Table 3.4. GRADE profile: For patients presenting with locally advanced rectal cancer is preoperative chemoradiotherapy more effective than preoperative radiotherapy alone.

Table 3.4

GRADE profile: For patients presenting with locally advanced rectal cancer is preoperative chemoradiotherapy more effective than preoperative radiotherapy alone.

No significant difference was observed between the treatment groups in terms of overall survival (pooled odds ratio, 1.00; [95% CI: 0.74–1.36]). A significant difference in the rates of local recurrence at 5 years was observed for patients in the radiotherapy group compared to patients in the chemoradiotherapy group OR 0.53 ([95% CI: 0.39–0.72], p<0.001). From Broendengen et al. (2008), a significant difference in cancer specific survival in favour of the chemoradiotherapy group; OR 2.15 ([95% CI: 1.2–3.84], p=0.01). Using data from 2 studies, Ceelen et al., 2009 reported no significant difference in 5-year disease-free survival between the radiotherapy and chemoradiotherapy groups OR 1.11 ([95% CI: 0.92–1.34], p=0.27).

Pooled analysis showed a significant difference in pathologic complete response in favour of chemoradiotherapy: OR 3.46 ([95% CI: 2.46–4.86], p<0.00001). Pooled analysis showed significantly higher rates of grade III/IV toxicity in the chemoradiotherapy group; OR 4.51 ([95% CI: 2.15–9.49], p<0.005) although there was significant heterogeneity on pooling (I2=77%).

Preoperative chemoradiotherapy versus immediate surgery in patients with locally advanced rectal cancer

(see Table 3.5)

Table 3.5. GRADE profile: For patients presenting with locally advanced rectal cancer is preoperative chemoradiotherapy more effective than immediate surgery.

Table 3.5

GRADE profile: For patients presenting with locally advanced rectal cancer is preoperative chemoradiotherapy more effective than immediate surgery.

There was little evidence available and all evidence was drawn from a small number of case series studies, both prospective and retrospective. Numbers included in the studies were small for the most part and reporting of aims and outcomes was not clear or detailed in many cases. The evidence for this section should be interpreted and used with caution. No significant difference in either overall survival (p=0.09) or relapse free survival (p=0.1) between patients experiencing major complications and those with no major complications was observed. No numbers were given for the groups, therefore overall survival for the whole population cannot be calculated (Chessin et al., 2005).

From a second case series study (Coco et al., 2006), the actuarial overall survival at 5 years was 75.5%, at 7 years was 67.8% and at 10 years was 60.4%; actuarial cancer-related survival at 5 years was 77.9%, at 7 years was 70% and at 10 years was 65.8%. Mermershtain et al. (2005) reported a 5-year overall survival of 70% and 8-year overall survival of 58% in a retrospective case series of 30 people. One retrospective case series (Twu et al., 2009) compared patients that responded to chemoradiotherapy with patients that did not respond and found no significant difference between the two groups in relation to overall survival, though a significant difference in local recurrence rate was observed in favour of the patients responding to chemoradiotherapy (p=0.002).

Chessin et al. (2005) did not report a significant difference in relapse free survival between patients experiencing major postoperative complications and patients not experiencing major postoperative complications.

In a retrospective case series of 43 patients (Twu et al., 2009), disease free survival was higher in the group of patients responding to chemoradiotherapy compared with those patients not responding to chemoradiotherapy (p=0.06).

In a retrospective review (Klos et al., 2010) patients (n=390) treated for rectal cancer presenting with T3 or T4 disease and/or involved lymph nodes received neoadjuvant chemoradiotherapy (5′-FU) before total mesorectal excision (TME) whereas patients with T1 and T2 disease and no suspicion of involved nodes received TME directly. The time to death, local or distant recurrence was not significantly different between groups but the prognosis was more unfavourable for those patients who had positive nodes regardless of group (Klos et al., 2010).

Preoperative radiotherapy versus surgery alone in patients with locally advanced rectal cancer

(see Table 3.6)

Table 3.6. GRADE profile: For patients presenting with locally advanced rectal cancer is preoperative radiotherapy more effective than surgery alone.

Table 3.6

GRADE profile: For patients presenting with locally advanced rectal cancer is preoperative radiotherapy more effective than surgery alone.

Wong et al. (2007) reported a pooled hazards ratio (from 14 studies) for overall mortality of 0.93 [95% CI:0.87–1- in favour of preoperative radiotherapy. The magnitude of survival benefit was modest at 2% survival improvement at 5 years and 2% improvement at 8 years. Subgroup analysis suggested that non TME studies, higher biological effective dose and treatment fields focused to the posterior pelvis showed significant benefit.

Recurrence rates ranged from 11% to 54%. All but one study included in the Cochrane review (Wong et al., 2007) reported a benefit in favour of preoperative radiotherapy though again significant heterogeneity was observed between studies (p<0.05). The pooled hazards ratio was 0.71 [95% CI: 0.64–0.78].

From 15 studies, Wong et al. (2007) reported a pooled risk ratio (RR) for curative resectability of 1.02 [95% CI: 1–1.05] in favour of preoperative treatment (homogeneity Χ2=14.94; p=0.38; I2=6%). The data for overall resectability could not be pooled due to heterogeneity (Homogeneity Χ2=39.59; p=0.00004; I2=72%).

The proportion of patients experiencing no toxicities ranged from 20% to 84% with the most common reported side effect being diarrhoea (20%) (Wong et al., 2007).

The proportion of patients with no toxicities postoperatively favoured the surgery alone group; from 6 studies the risk ratio was 0.88 [95% CI: 0.82–0.94] (Wong et al., 2007).

Stephens et al. (2010) conducted a quality of life study within a randomised controlled trial that had compared short-course preoperative radiotherapy then surgery with surgery and post-operative chemotherapy (if tumour was within 1mm of resection margin). Study participants completed two questionnaires (MOS SF-36 and QLQ-CR38) at baseline (n=1,208), every 3 months for the first year and every 6 months to 3 years (n=563 at 2 years). The main, irreversible treatment effect that reduced QoL was sexual dysfunction (p<0.001 for men, regardless of group, between baseline and 3 months) caused primarily by surgery but exacerbated by radiotherapy (p<0.001 at 6 months between groups). Bowel function in those patients without a stoma (or in those who had a stoma reversal) was not significantly different between treatment arms. However, sub group analysis suggested that patients in the short-course preoperative radiotherapy then surgery group may have experienced an increase in the ‘unintentional release of stools’ even at 2 years post-treatment (p=0.007). Generally, there were no significant differences in treatment groups in overall general health or QoL.

Chemoradiotherapy with capecitabine

9 phase II trials with a total of 470 patients, all with similar inclusion/exclusion criteria, were available to address this section (Elwanis et al., 2009; DeBruin et al., 2008; De Paoli et al., 2006; Desai et al., 2007; Kim et al., 2005; Koeberle et al., 2008, Machiels et al., 2005; Rodel et al., 2003; Velenik et al., 2006).

From 8 studies grade III/IV toxicity was reported in 13.2% (62/470) of patients (range 1–43%) (Elwanis et al., 2009; DeBruin et al., 2008; Desai et al., 2007; Kim et al., 2005; Koeberle et al., 2008; Machiels et al., 2005; Rodel et al., 2003; Velenik et al., 2006). One study (De Paoli et al., 2006) reported no grade III/IV toxicity. The most commonly reported toxicity was diarrhoea; other reported toxicities included anaemia, radiation dermatitis and leucocytopenia.

Sphincter preservation rate was reported in 4 studies and ranged from 36% to 74%, though in the study reporting 74% it is unclear whether this is the rate of sphincter sparing surgery or the success rate of sphincter sparing surgery (Elwanis et al., 2009; Kim et al., 2005; Rodel et al., 2003; Velenik et al., 2006).

Recommendations

Linking evidence to recommendations

The GDG considered local recurrence and toxicity to be important outcomes due to the long term impact on patient wellbeing. There is evidence that small improvements in local control are gained at the expense of significant late morbidity. The gains in local control from radiotherapy are proportional to the risk of local recurrence and should be balanced against the significant late effects in terms of sexual, urinary and bowel dysfunction. The GDG therefore agreed it was important for these issues to be discussed with the patient prior to treatment.

There was no evidence that chemoradiotherapy facilitates an increased opportunity for sphincter sparing surgery, therefore the GDG agreed to recommend that preoperative chemoradiotherapy was not given for this intention.

Data on preoperative chemotherapy alone in patients with either colon cancer or rectal cancer were not robust and the GDG did not feel able to make a recommendation regarding the value of preoperative chemotherapy alone separate from preoperative chemotherapy concurrent with radiotherapy. However, in view of the high risk of metastatic disease in patients with locally advanced colon and rectal cancer, the GDG recommended that research should be undertaken to address this problem for both colon and rectal cancer in the preoperative setting.

This clinical question was considered a low priority for economic analysis because it focused on identifying evidence that specifically addressed the issue of sequencing/combinations of treatment modalities. Identification of treatment combinations or specific regimens were not planned. It was anticipated that the evidence base may be clinically heterogeneous. This would limit the appropriateness of combining or comparing data across studies using quantitative methods and therefore impact on the feasibility of undertaking de novo economic modelling that would help inform this topic in a comprehensive and meaningful manner.

Research recommendations

3.2. Colonic stents in acute large bowel obstruction

In the absence of population screening, up to 30% of colorectal cancer cases initially present in the emergency setting. Emergency surgery performed for obstructing lesions is associated with a high morbidity and cited peri-operative mortalities ranging from 10–20%, compared with rates less than 5% in cases of elective surgery. In addition, emergency surgery results in a high rate of stoma formation, high utilisation of intensive care and prolonged hospital stays.

The introduction of self-expanding metal stents (SEMS) has provided the opportunity for endoscopic decompression of these patients in an attempt to reduce the risks of surgery. Following decompression there is an opportunity to correct electrolyte imbalance, evaluate the extent of disease, determine the presence of synchronous lesions and evaluate comorbidities, thus enabling the planning of the most appropriate elective surgery. The placement of SEMS, however, is not without adverse effects including colonic perforation, stent migration, malposition or if the procedure is unsuccessful a delay in emergency surgery. The incidence of stent-related complications significantly increases the longer the stent remains in situ.

It has been suggested that the success rate for stent insertion is lower for tumours proximal to the sigmoid colon, but with the advent of newer devices, able to pass through the endoscopic therapy channel, the success of stent placement in the right colon is likely to increase. The potential hazards of SEMS placement in this context, however, must be balanced against the lower surgical mortality in cases of emergency surgery for right-sided colonic obstruction, when compared with left-sided lesions.

There are currently ongoing trials evaluating the efficacy of SEMS placement as a bridge to surgery, which in turn will assess long term oncological outcome.

Clinical question: For patients presenting with acute large bowel obstruction as a first presentation of colorectal cancer, what are the indications for stenting as a bridge to elective surgery? a) Should all patients presenting with obstruction as a symptom of colorectal cancer have a CT scan to confirm diagnosis and provide evidence of metastases? b) What are the indications for stenting patients and the optimal timing for stenting to occur?

Clinical evidence

There is very little evidence of any type with which to address this topic. There are no directly applicable studies and so in assessing the body of evidence, consideration was given to the possibility that relevant evidence may not be directly available and so studies which compared stenting as a bridge to surgery, stenting for palliative purposes or immediate emergency surgery were also reviewed to check whether these studies contained information relevant to the topic. Despite this consideration, very little evidence of relevance was found from these studies and what was available was of very poor quality.

In relation to the use of CT for the diagnosis of colorectal cancer in the emergency setting, 2 studies (Beattie et al., 2007; Maras-Simunic et al., 2009) comprised the body of evidence. Beattie et al. (2007) reported a sensitivity, specificity, positive predictive value and negative predictive value of 91% for the use of CT in the diagnosis of large bowel obstruction. The positive likelihood ratio was 10.1 and the negative likelihood ratio was 0.10. There were 4 reported CT errors for the presence of mechanical obstruction, 2 false positive and 2 false negative.

Maras-Simunic et al. (2009) reported that the use of multi-detector CT colonography correctly identified all obstructions resulting from colorectal cancer (41/47). Multi-detector CT colonography gave 1 false positive result in a population of 44 patients with obstruction. Overall multi-detector CT colonography correctly established diagnosis in 97.9% of patients and located all obstructive cancers correctly (46/47).

The evidence body for the indications and timing for stenting consisted of one pooled analysis of case series studies (Sebastian et al., 2004) and 2 case series (Song et al., 2007; Repici et al., 2008).

Technical Failure

From one pooled analysis with a total of 1,198 patients (Sebastian et al., 2004) there was a 5.8% failure rate on attempted placement of rectosigmoid stents, 14.5% failure rate for descending colon placement and 15.38% failure rate for more proximal colon stent placement.

Clinical Failure

Pooled analysis (Sebastian et al., 2004) showed that clinical success was achieved in 88.56% (1,061/1,198) of patients with 52 failures in the left colon and 4/5 patients with stent placement in the right colon not achieving clinical success. Causes of clinical failure included malposition, migration, proximal obstruction, stool impaction, perforation and persistent obstructive symptoms.

Perforation

From one pooled analysis (Sebastian et al., 2004) there were 45 perforations related to stent placement (3.76%) with all but one occurring at the rectosigmoid junction. Predilation was significantly associated with perforation and thought to be responsible in 16 instances. 64.4% (29/45) required emergency surgical intervention while 10 patients were treated with intravenous antibiotics and one patient had a new stent placed.

Migration

Migration occurred in 11.81% (n=132) of cases of successfully inserted stents; occurring within a week in 7.25% (n=81) patients and more than a week after insertion in the remaining 41 patients (Sebastian et al., 2004). Stents inserted as a palliative measure migrated more often (116/791) than those inserted as a bridge to surgery (16/407) (p=0.01).

Mortality

The cumulative mortality rate was 0.58% (n=7 deaths), three of which had documented colonic perforations. Six of the deaths occurred in patients stented for palliative purposes (Sebastian et al., 2004).

Bridging to Surgery

The rate of successful bridging to surgery was 100% [95% CI: 85–100%]. Median time from SEMS placement to surgery was 5 days [95% CI: 5.4–5.6 days]. In all patients, stents were removed en bloc with the tumour without any surgical complications. 2 patients experienced postoperative complication; 1 pulmonary embolism and 1 wound infection (Repici et al., 2008).

On update searches, a further two studies were found to be relevant to the current topic (Iverson et al., 2011; Vemulapalli et al., 2010).

Comparing SEMS insertion with emergency surgery, no difference in technical success of relieving colonic obstruction was observed between the two modalities (94% versus 100%, p=0.07). Patients in the SEMS group had a significantly shorter median hospital stay (2 days, range 1–24 days) compared with patients in the surgery group (8 days, range 2–43 days) (p<0.001). Patients with SEMS had significantly fewer acute complications compared with the surgery group (8% versus 30%, p=0.03) (Vemulapalli et al., 2010).

Hospital mortality for the SEMS group was 0% versus 8.5% in patients that underwent surgical decompression (p=0.04). The number of patients with SEMS who presented with late complications (22%) was higher than in the surgery group (9%) though this difference was not statistically significant (p=0.06). Overall survival did not differ significantly between the groups; median survival time in the SEMS group was 24 weeks (range: 2–196) compared with 23 weeks (range: 1–124) in the surgery group (p=0.76) (Vemulapalli et al., 2010).

From Iverson et al. (2011) SEMS insertion was successful in all 34 patients for a technical success rate of 100%. 31/34 attempted SEMS insertions were performed or supervised by a colorectal surgeon. Four patients had events which classified the procedure as a clinical failure resulting in a clinical success rate of 88%. Clinical failure occurred equally in patients with tumours located in the transverse colon or splenic flexure (1/11) and descending/sigmoid colon (3/23). Overall perforation rate was 12% (4/34) and was comparable for tumours located in the transverse colon or splenic flexure (1/11) and descending/sigmoid colon (3/23).

Median follow-up was 33.7 months independent of oncological outcome and timing of surgery; 2 year survival for the 34 patients with potentially curable disease was 85% (68–94%) and 3 year survival was 74% (53–86%). Median survival was 4.5 years (range 3.1 to 6.0 years). Curative outcome was achieved in 88% of patients (30/34); 2 and 3 year survival rates after surgery with curative outcome were 90% (range 72–97%) and 77% (range 54–89%).

Recommendations

  • If considering the use of a colonic stent in patients presenting with acute large bowel obstruction offer CT of the chest, abdomen and pelvis to confirm the diagnosis of mechanical obstruction, and to determine whether the patient has metastatic disease or colonic perforation.
  • Do not use contrast enema studies as the only imaging modality, in patients presenting with acute large bowel obstruction.
  • A consultant colorectal surgeon should consider inserting a colonic stent in patients presenting with acute large bowel obstruction. They should do this together with an endoscopist or a radiologist (or both) who is experienced in using colonic stents.
  • Resuscitate patients with acute large bowel obstruction, then consider placing a self-expanding metallic stent to initially manage a left-sided complete or near-complete colonic obstruction.
  • Do not place self-expanding metallic stents:
    • in low rectal lesions or
    • to relieve right-sided colonic obstruction or
    • if there is clinical or radiological evidence of colonic perforation or peritonitis.
  • Do not dilate the tumour before inserting the self-expanding metallic stent.
  • Only a healthcare professional experienced in placing colonic stents who has access to fluoroscopic equipment and trained support staff should insert colonic stents.
  • If a self-expanding metallic is suitable, attempt insertion urgently and no longer than 24 hours after patients present with colonic obstruction.

Linking evidence to recommendations

The GDG noted that there were no studies which were directly applicable to this topic and so consideration was given to studies which compared stenting as a bridge to surgery, stenting for palliative purposes or immediate emergency surgery. Despite the paucity of evidence, the GDG agreed that recommendations on stenting were required because of the high mortality associated with emergency surgery.

The GDG placed a high value on the outcomes of sensitivity and specificity of CT scanning in the emergency presentation of large bowel obstruction. The GDG noted that a CT scan is the most sensitive way of confirming that the obstruction is due to colonic tumour, identifying colonic perforation and imaging the extent of disease that may impact on future management. They therefore decided to recommend its use.

The GDG agreed that contrast enema studies, used on their own, do not demonstrate the longitudinal and radial extent of the tumour, are less sensitive than CT for identifying bowel perforation and give no information on metastatic status. The GDG therefore decided to recommend that they are not used in isolation but may be used to facilitate stent placement.

The GDG recognised the significant mortality/morbidity associated with operating on patients in the emergency setting. Relieving large bowel obstruction by stenting could allow patient stabilisation leading to planned elective surgery by the appropriate surgeon. Such a treatment strategy could also reduce the incidence of stomas. The GDG were interested whether stenting affected quality of subsequent surgery but no evidence was found.

The GDG believed that the decision to stent should involve a consultant colorectal surgeon in consultation with an endoscopist/radiologist experienced in the management of these cases since this decision must balance the risks between stent insertion and emergency surgery.

The GDG concluded that SEMS were most effective in left-sided complete colonic obstruction because they have a lower complication rate and higher success rate. The GDG agreed that SEMS were not appropriate in patients with low rectal lesions (because of intractable symptoms of tenesmus) or right-sided colonic obstructions (because of high complication rates, low success rate and more complicated stent insertion). Lastly, the GDG decided that SEMS are contraindicated where there is evidence of perforation or peritonitis because these patients need immediate surgery.

The GDG concluded that tumours should not be pre-dilated prior to SEMS insertion because of the high risk of tumour perforation. While there is no evidence with which to recommend a maximum delay between diagnosis of large bowel obstruction and SEMS insertion, the GDG believe strongly that delaying more than 24 hours is potentially harmful to the patient (for example increased risk of perforation and metabolic deterioration).

This topic was considered a low priority for economic analysis because high quality data on the many possible downstream outcomes of a CT scan in this setting and patient population were unlikely to be available. In addition, the second part of the topic focuses on the clinical indications and timing of stenting. Since this did not involve a comparison of costs and consequences, it did not lend itself to economic modelling.

3.3. Stage I colorectal cancer

Stage I colorectal cancer encompasses tumours which have extended either into the submucosa (T1) or into, but not beyond, the muscularis propria (T2) and in which there is no evidence of spread into the lymph nodes (N0). In patients found to have stage I colorectal cancer a five year cancer specific survival of >95% can be expected following segmental resection with clear surgical margins (where there is removal of a segment of large bowel including its associated mesentery) and in these cases, surgery is essentially a curative procedure. Stage I colorectal cancer may be identified following histopathological assessment of an endoscopically resected polyp (malignant polyp), usually unsuspected at the time of polypectomy. Alternatively, and less commonly, it may be suspected in a polypoid lesion (usually laterally spreading) that appears amenable to local resection. In these cases, specialised techniques such as endoscopic submucosal dissection (ESD) or transanal endoscopic micro surgery (TEMS) may be used to perform complete ‘en bloc’ resection of the lesion, particularly if it is situated in the left colon or rectum.

Following the introduction of the NHS bowel cancer screening programme in England and Wales, malignant colonic polyps are being detected with increasing frequency. Almost all locally removed malignant polyps are stage I cancers and would therefore be expected to have a very good prognosis. Endoscopic resection of malignant polyps may be sufficient as the only management but there is a risk of local recurrence or metastatic spread, particularly to local lymph nodes, since the mesentery, which contains the local lymph nodes, is not resected. It is uncertain, therefore, whether the same prognostic outcome can be expected as that seen in stage I tumours following segmental resection. These risks may be reduced by subsequent surgery, but the associated potential complications such as bleeding, infection or peri-operative death, and the effects on quality of life, need to be balanced against the potential benefits.

A number of retrospective studies have attempted to identify risk factors associated with recurrent malignancy in local resections, although none of these data have proven conclusive. The completeness of the endoscopic excision appears to be the most reliable predictor of tumour recurrence and, although publications vary, it can be assumed that a distance of less than 1mm from the tumour to the margin of excision is associated with a high risk of cancer recurrence. Studies have tried to refine further the prognostic features in polyp cancers that have clear margins and are thus deemed to have been completely excised. The risk of recurrence appears to correlate with degree of local advancement. Thus, in the Haggitt classification (applicable only to polyp cancers with long stalks), it is only the most advanced lesions, where there is extension of the tumour beyond the polyp stalk, (Haggitt level 4), which is suggested to be associated with a poor outcome. The Kikuchi classification (for sessile polyps) suggests that lesions extending into the lower third of the submucosa are of the highest risk (Kikuchi level SM 3). The Ueno classification suggests that the tumour volume is directly correlated with risk of recurrence. These systems are, however, not easy to apply due to the nature of the polypectomy specimens, making assessment and subsequent decision-making problematic. Furthermore, the depth of invasion, or proximity of the tumour to the resection margin, may not be possible to assess when the lesion has been resected piecemeal and thus these lesion are best regarded as high risk. Other factors that have been suggested to predict poor outcome include tumour differentiation, (with poorly differentiated tumours conferring the highest risk), the presence of venous or lymphatic invasion and tumour budding. Uncertainty exists about the benefit to patient outcome of using these prognostic factors to guide subsequent management.

Clinical question: For patients who have undergone local excision and diagnosed stage I colorectal cancer, including/or polyp cancer and with/without neoadjuvant treatment for low rectal tumours, can the use of prognostic factors determine the most effective curative treatment?

Clinical evidence

The purpose of this topic was to try to identify which treatment was the next best treatment for patients that had undergone local excision of stage I colorectal cancer (including polyps) and subsequently found to have unfavourable prognostic features. If possible, the topic aimed to identify whether treatment efficacy was impacted by specific prognostic features.

There was no evidence with which to answer this question as much of the literature concentrated on identifying the unfavourable prognostic features rather than focusing on the long term outcomes related to such features or which type of treatment is best for patients with specific unfavourable characteristics.

A small number of studies examining the outcomes of further treatment in patients with poor prognostic features following local excision were identified. These were however, non-comparative, case series of a poor quality and did not provide any insight to the best treatment option for patients.

Recommendations

9

Improving outcomes in colorectal cancer (2004). NICE cancer service guidance CSGCC. Available from www​.nice.org.uk/CSGCC

Linking evidence to recommendations

The GDG acknowledged that there was no evidence that specifically addressed this question. As a consequence of the impact of the NHS bowel cancer screening programme, there has been a significant increase in the number of patients with stage I cancers being detected. Furthermore the GDG is aware of wide variation in practice and patient experiences. Therefore the GDG considered it to be extremely important for this question to be addressed.

The GDG strongly believed that when patients had an involved resection margin (incompletely excised cancer) then further treatment was important. However, given the lack of evidence, the GDG did not feel able to make specific recommendations for the type of treatment that should be given.

The GDG also agreed that it was important for all patients with locally excised, pathological stage I cancer to be discussed at the appropriate MDT, where specialist pathological expertise is available, in order to determine future management. The GDG also agreed that it was important that full discussion of the risks and benefits of all treatment options should take place with the patient.

The GDG acknowledged that patients whose rectal cancer has been downstaged to stage I by prior treatment, are a specific group in whom treatment may/may not have altered the biology of the tumour and the information provided by the prognostic factors may not be relevant.

Research recommendation

  • An observational study should be conducted, incorporating standardised assessment of pathological prognostic factors, to assess the value of the proposed prognostic factors in guiding optimal management in patients with locally excised, pathological stage I cancer. Outcomes of interest are disease-free survival, overall survival, local and regional control, toxicity, cost-effectiveness and quality of life.

3.4. Laparoscopic surgery

The recommendations in this section are from ‘Laparoscopic surgery for colorectal cancer, NICE technology appraisal guidance 105 (NICE 2006).

Recommendations

  • Laparoscopic (including laparoscopically assisted) resection is recommended as an alternative to open resection for individuals with colorectal cancer in whom both laparoscopic and open surgery are considered suitable.
  • Laparoscopic colorectal surgery should be performed only by surgeons who have completed appropriate training in the technique and who perform this procedure often enough to maintain competence. The exact criteria to be used should be determined by the relevant national professional bodies. Cancer networks and constituent trusts should ensure that any local laparoscopic colorectal surgical practice meets these criteria as part of their clinical governance arrangements.
  • The decision about which of the procedures (open or laparoscopic) is undertaken should be made after informed discussion between the patient and the surgeon. In particular, they should consider:
    • the suitability of the lesion for laparoscopic resection
    • the risks and benefits of the two procedures
    • the experience of the surgeon in both procedures.

Linking evidence to recommendations

These recommendations are from ‘Laparoscopic surgery for colorectal cancer’, NICE technology appraisal guidance 105 (NICE 2006). They were formulated by the technology appraisal and not by the guideline developers. They have been incorporated into this guideline in line with NICE procedures for developing clinical guidelines, and the evidence to support these recommendations can be found at www.nice.org.uk/TA105.

3.5. Adjuvant chemotherapy in rectal cancer

Colonic and rectal tumours occur anatomically in continuity, and have similar histopathological features. They might therefore be expected to respond similarly to chemotherapy.

Although it is established that patients with stage III (and possibly high-risk stage II) colon cancer will benefit from adjuvant chemotherapy, uncertainty remains around the benefits of such chemotherapy for patients with stage II and III rectal cancer.

Clinical question: In patients with clinical or pathological stage II and III rectal cancer what is the effectiveness of adjuvant chemotherapy following surgery?

Clinical evidence

There was a moderate volume of evidence with which to address this topic consisting primarily of randomised trials and pooled analysis of trials (QUASAR Collaborative Group, 2007; Bosset et al., 2006; Cionini et al., 2001; Fisher et al., 1988; Akasu et al., 2006; Sakamoto et al., 2004; Sakamoto et al., 1999; Glimelius et al., 2005).

There was one systematic review (Germond et al., 1998) which was conducted as part of a Canadian guideline programme, available for this topic, though the results from this review should be considered to be indirect as not all studies included in the analysis were directly relevant to the current topic. For this reason, the relevant studies were extracted and appraised individually and where possible included in a pooled analysis. A Cochrane review protocol (Kirkeby et al., 2002), and a second trial protocol (Glynne-Jones et al., 2007) which although do not add to the body of evidence, would suggest that there is a need to address the issue of adjuvant chemotherapy specifically in patients with rectal cancer.

The evidence included in the review was directly applicable to the topic in terms of the comparisons in each study and the population of interest, however the treatments evaluated in some of the older trials are not currently clinically relevant. Although there were a number of studies investigating adjuvant chemotherapy in colorectal cancer patients, the topic relates specifically to rectal cancer patients and therefore if the results for rectal cancer patients alone were not presented, these studies were excluded from the review.

One systematic review identified three randomised trials comparing adjuvant chemotherapy to surgery alone reporting an odds ratio (OR) of 0.64 [95% CI: 0.48–0.85] in favour of adjuvant chemotherapy, representing an absolute increase in 5-year survival of 9% (Germond et al., 1998). An update of the systematic review (1998–2001) identified 4 meta-analysis and 3 randomised trials however no further updates were done on the meta-analysis. Despite evaluating the effect of adjuvant chemotherapy, no recommendations were made in the guideline relating to the use of adjuvant chemotherapy in patients with resected rectal cancer.

A total of three trials provided data which allowed a pooled analysis to be conducted for overall survival and disease/recurrence free survival (Bosset et al, 2006; Fisher et al., 1988 and QUASAR Collaborative Group, 2007). The quality of the studies included in the pooled analysis was considered to be moderate according to GRADE assessment (Table 3.7) with the only area of concern relating to the reporting of factors such as concealment and bias in the individual studies.

Table 3.7. GRADE profile: In patients with clinical or pathological stage II and III rectal cancer, what is the effectiveness of adjuvant chemotherapy following surgery.

Table 3.7

GRADE profile: In patients with clinical or pathological stage II and III rectal cancer, what is the effectiveness of adjuvant chemotherapy following surgery.

Pooled analysis of trial data gave a hazards ratio (HR) of 0.8 [95% CI: 0.69–0.92] for overall survival in favour of adjuvant chemotherapy although none of the individual trials showed a statistically significant benefit of adjuvant chemotherapy. Using the 5-year overall survival for the control arm (63.2%) from Bosset et al. (2006), this translates to an absolute reduction in the risk of death within 5 years of 4.3% [95% CI: 2.4–9.7%] for patients receiving adjuvant chemotherapy. The number needed to treat was 23 [95% CI: 10.3–42] to prevent one additional death within 5 years.

For disease/recurrence free survival, pooled analysis resulted in a hazards ratio (HR) of 0.77 [95% CI: 0.68–0.88] which translates into an absolute reduction in risk of recurrence within 5 years of 8.4% [95% CI: 4.2–12%]; using the reported 5-year disease free survival of 52.2% for the control arm of Bosset et al. (2006) and the pooled analysis hazard ratio. The number needed to treat was 12 [95% CI: 9–24] to prevent one additional recurrence within 5 years.

One trial reported quality of life as a study outcome, though this was reported for the whole population (colon and rectal); quality of life measurements directly related to expected toxicity (for example diarrhoea, nausea, vomiting, mouth pain, fatigue, appetite loss and social functioning) were worse in the chemotherapy group than in the observation group (p<0.01) though only during the course of chemotherapy treatment.

Recommendations

  • Assess pathological staging after surgery before deciding whether to offer adjuvant chemotherapy.
  • Consider adjuvant chemotherapy for patients with high-risk stage II and all stage III rectal cancer to reduce the risk of systemic recurrence.

Linking evidence to recommendations

The GDG were aware that preoperative treatment is widely used in current practice and may affect post-operative pathological staging. However, the evidence did not include studies where patients had received preoperative chemoradiotherapy and therefore the role of clinical staging in the decision around adjuvant chemotherapy is not known. The GDG decided that post-operative pathological staging took precedence over preoperative clinical staging when considering the benefit of adjuvant treatment.

The GDG placed a high value on the outcomes of survival, local recurrence, metastatic disease, complication rates and quality of life. They noted that there were limitations to the evidence. Few studies had examined 5FU alone as adjuvant treatment outside the combination with radiotherapy, and there were no completed studies that had been specifically designed to look at the effectiveness of oxaliplatin containing regimens in patients with rectal cancer. Recent randomised studies designed to evaluate the benefit of adjuvant chemotherapy, where preoperative chemoradiotherapy had been delivered, failed to recruit. The published randomised studies were underpowered; the compliance to postoperative treatment was poor; the clinical staging was variable, making classification of rectal cancer difficult; the treatments given were poorly documented; and quality of life was either doctor reported or not reported at all.

The GDG were aware of the established benefits of adjuvant chemotherapy in colon cancer. The GDG also noted that the evidence showed a survival benefit from post-operative adjuvant chemotherapy for patients with involved lymph nodes on surgical histopathology who had not received preoperative treatment. They were also aware that there were additional considerations regarding toxicity for patients who have had short course preoperative radiotherapy or chemoradiotherapy.

The GDG agreed that the gains in local control and survival from adjuvant chemotherapy were proportional to the risk of local and distant recurrence and balanced against the temporary deterioration in quality of life resulting from acute side-effects of chemotherapy, and the small risk of dying (as a result of toxicity from chemotherapy).

The GDG therefore recommended adjuvant chemotherapy should be offered to patients who had received either surgery with no preoperative treatment or short course preoperative radiotherapy followed by immediate surgery. For patients who had received preoperative chemoradiotherapy, the GDG were unable to make a recommendation.

The GDG noted that the evidence for the effectiveness of adjuvant chemotherapy in patients with rectal cancer only related to 5FU-based chemotherapy. Because of the lack of data from completed phase III trials, the GDG was unable to recommend which specific combination chemotherapy regimen should be used (oxaliplatin or irinotecan).

This clinical question was considered a medium priority for economic analysis because the estimated impact in terms of the size of the target patient population and the level of uncertainty and controversy regarding current practice were considered to be lower than for other questions.

Research recommendations

3.6. Adjuvant chemotherapy for high-risk stage II colon cancer

A benefit from adjuvant chemotherapy in colorectal cancer was first demonstrated in 1990 in patients with stage III disease. The benefit for stage III patients has been confirmed and treatment schedules refined in the intervening years.

Some of these studies of stage III disease included a proportion of patients with stage II disease. As the risk of recurrence is less with stage II disease the absolute benefit of adjuvant chemotherapy will be less than for stage III disease (assuming the relative risk reduction is the same for adjuvant chemotherapy in both stage II and stage III disease).

It is recognised that overall patients with stage II disease have a better prognosis than those with stage III disease, but that outcomes for patients within stage II vary and that there is a spectrum of risk for recurrence.

There are several pathological features which have been shown to be associated with poor prognosis in stage II disease such as extramural vascular invasion, pT4 disease (serosal breach or perforation), poorly differentiated tumours, obstructed tumours, perineural invasion and low lymph node recovery from the resection specimen. These features have been used to identify “high-risk” patients and have become, de-facto, criteria for adjuvant chemotherapy in stage II disease but their value to predict for treatment outcome has not been established.

Other tumour features, such as microsatellite instability may have both prognostic and predictive characteristics, but their exact role in the selection for adjuvant chemotherapy in patients with colon cancer is not clear.

Clinical question: In patients with high-risk stage II colon cancer what is the effectiveness of adjuvant chemotherapy after surgery?

Clinical evidence

There was very little evidence with which to address this topic and what was available consisted primarily of poor quality, indirect evidence. There were three pooled analyses (non-systematic pooling of specific trial data) which provided some indirect evidence (Erlichman et al., 1999; Labianca et al., 1995; Mamounas et al., 1999), a single randomised trial (O’Connell et al., 1997) and two case-series studies (one prospective and one retrospective) which added limited, poor quality and indirect evidence (Lin et al., 2009; Yoshimatsu et al., 2006). All of the available evidence was considered to be low to moderate quality for all outcomes on GRADE assessment (Table 3.8), primarily due to the indirect nature of the evidence and the small number of patients in each of the relevant studies.

Table 3.8. GRADE profile: In patients with high-risk stage II colon cancer what is the effectiveness of adjuvant chemotherapy after surgery?

Table 3.8

GRADE profile: In patients with high-risk stage II colon cancer what is the effectiveness of adjuvant chemotherapy after surgery?

The lack of evidence available to address this question may partly be a result of the fact that there is no standard definition for ‘high-risk’ patients thus making it difficult to identify these patients. There is however a list of prognostic factors which are used to identify potentially high-risk patients including extramural vascular invasion, grade 3/poor differentiation, T4 stage/perforation, peri-neural invasion, obstructive tumours, mucinous tumours, micro-satellite instability and tumour budding. The available evidence does not specifically address high-risk patients, rather in most cases the studies present some data which is possibly relevant to high-risk patients as a secondary analysis to the main purpose of the study.

From one prospective study (Lin et al., 2009), there was no significant difference in survival for stage II patients receiving adjuvant chemotherapy compared with patients that did not receive adjuvant chemotherapy. However in the subgroup of patients with high-risk factors, there was a significant 3-year disease free survival benefit (96.4% versus 84.7%, p=0.045) and 5-year overall survival benefit (100% versus 86.4%, p=0.015) in favour of adjuvant chemotherapy.

Considering patients with tumour exposed at the serosa or invasion of other organ as high-risk and patients with tumour invasion under the serosa as low risk, one retrospective case series observed that for patients in the high-risk group there was a significant difference in 5-year survival for patients receiving adjuvant chemotherapy (75.8%) and patients not receiving chemotherapy (44%) (p=0.0008) (Yoshimatsu et al., 2006).

The American Society for Clinical Oncology (ASCO) recommended that the optimal approach is to encourage patients with high-risk stage II disease to participate in randomised trials as there is no direct evidence that adjuvant chemotherapy confers a survival benefit in high-risk patients (Benson et al., 2004).

The toxic effects of chemotherapy were gastrointestinal and consisted primarily of nausea, stomatitis and diarrhoea (Erlichman et al., 1999; Labianca et al., 1995; O’Connell et al., 1997). There were no treatment related deaths in any of the included studies and most of the symptoms of toxicity were manageable.

Recommendations

  • Consider adjuvant chemotherapy after surgery for patients with high-risk stage II colon cancer. Fully discuss the risks and benefits with the patient.

Linking evidence to recommendations

The GDG considered overall survival was the most important outcome, as this was the primary endpoint of adjuvant studies comparing treatment to no treatment.

The overall quality of the evidence was poor. No prospective randomised studies have been performed comparing adjuvant chemotherapy to no treatment in patients deemed to have high-risk stage II colon cancer.

Despite the poor evidence, the GDG believed it was likely that patients with high-risk stage II colon cancer would benefit from chemotherapy.

The GDG was concerned that a large number of patients with (all) stage II colon cancer would need to be treated with adjuvant chemotherapy to confer a survival benefit for the few patients with high-risk stage II disease. Adjuvant chemotherapy carries significant toxicities and a small mortality rate, so a large number of patients would be treated without benefit and be exposed to potential harms, with significant costs to the health service. Therefore the GDG recommended that adjuvant chemotherapy should be considered for patients with high-risk stage II colon cancer, but only after full discussion of the risks and benefits with the patient.

The GDG considered making a research recommendation in this area but concluded that it would not be practical to conduct a randomised study as it would not be possible to recruit the large number of patients needed to show a statistically significant benefit.

3.7. Adjuvant chemotherapy for stage III colon cancer

The recommendations in this section are from ‘Capecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes’ C) colon cancer’, NICE technology appraisal guidance 100 (NICE 2006).

Recommendations

  • The following are recommended as options for the adjuvant treatment of patients with stage III (Dukes’ C) colon cancer following surgery for the condition:
  • The choice of adjuvant treatment should be made jointly by the individual and the clinicians responsible for treatment. The decision should be made after an informed discussion between the clinicians and the patient; this discussion should take into account contraindications and the side-effect profile of the agent(s) and the method of administration as well as the clinical condition and preferences of the individual.
10

Since TA100 was published, the licence for capecitabine has been extended to include combination therapy

Linking evidence to recommendations

These recommendations are from ‘Capecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes’ C) colon cancer’, NICE technology appraisal guidance 100 (NICE 2006). They were formulated by the technology appraisal and not by the guideline developers. They have been incorporated into this guideline in line with NICE procedures for developing clinical guidelines, and the evidence to support these recommendations can be found at www.nice.org.uk/TA100.

References

  • Akasu T, Moriya Y, Ohashi Y, Yoshida S. Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicentre randomised controlled trial. Japanese Journal of Clinical Oncology. 2006;36(4):237–244. [PubMed: 16675478]
  • Beattie G, Peters R, Guy S, Mendelson R. Computed tomography in the assessment of suspected large bowel obstruction. Anz Journal of Surgery. 2007;77:160–165. [PubMed: 17305992]
  • Benson AB, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG. American Society of Clinical Oncology Recommendations on adjuvant chemotherapy for stage II colon cancer (review) Journal of Clinical Oncology. 2004;22(16):3408–3419. [PubMed: 15199089]
  • Birgisson H, Pahlman L, Gunnersson U, Limelius B. Late adverse effects of radiation therapy for rectal cancer – a systematic overview. Acta Oncologica. 2007;46:504–516. [PubMed: 17497318]
  • Birgisson H, Pahlman L, Gunnarsson U, Glimelius B. Swedish Rectal Cancer Trial Group. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. Journal of Clinical Oncology. 2005;23(34):8697–8705. [PubMed: 16314629]
  • Bosset JF, Collette L, Calais G, Mineur L, Maingon Chemotherapy with preoperative radiotherapy in rectal cancer. New England Journal of Medicine. 2006;355(11):1114–1123. [PubMed: 16971718]
  • Boulis-Wassif S, Gerard A, Loygue J, Camelot D, Buyse M, Duez N. Final results of a randomised trial on the treatment of rectal cancer with preoperative radiotherapy alone or in combination with 5-fluorouracil, followed by radical surgery. Cancer. 1984;53:1811–1818. [PubMed: 6423263]
  • Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Pahlman L, Wiig JN, Bystrom P, Bujko K, Glimelius B. Randomised phase II study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. Journal of Clinical Oncology. 2008;26(22):3687–3694. [PubMed: 18669453]
  • Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomised trial comparing preoperative short course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. British Journal of Surgery. 2006;93:1215–1223. [PubMed: 16983741]
  • Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomised trial comparing preoperative short-course radiotherapy vs. preoperative conventionally fractionated chemoradiation for rectal cancer. European Journal of Cancer Suppl. 2005;3(2):169.
  • Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Pudelko M, Kryj M, Oledzki J, Szmeja J, Sluszniak J, Serkies K, Kladny J, Pamucka M, Kkolowicz Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiotherapy and oncology: Journal of the European Society for Therapeutic Radiology and Oncology. 2004;72:15–24. [PubMed: 15236870]
  • Ceelen W, Fierens K, Van NY, Pattyn P. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: a systematic review and meta-analysis. International Journal of Cancer. 2009;124(12):2966–2972. [PubMed: 19253365]
  • Chessin D, Enker W, Cohen A, Paty P, Weiser M, Saltz L, Minsky B, Wong WD, Guillem JG. Complications after preoperative combined modality therapy and radical resection of locally advanced rectal cancer: a 14 year experience from a specialty service. Journal of the American College of Surgeons. 2005;200(6):876–882. [PubMed: 15922198]
  • Cionini L, et al. Randomised study of postoperative chemotherapy after preoperative chemoradiation in locally advanced rectal cancer. preliminary results. European Journal of Cancer. 2001;37(S6):S300.
  • Coco C, Valentini V, Manno A, Mattana C, Verbo A, Cellini N, Gambacorta M, Covino M, Mantini G, Micciche F, Pedretti G, Petito L, Rizzo G, Cosimelli M, Impiombato F, Picciocchi A. Long-term results after neoadjuvant radiochemotherapy for locally advanced resectable extraperitoneal rectal cancer. Diseases of the Colon and Rectum. 2006;49(3):311–318. [PubMed: 16456636]
  • De Bruin AFJ, Nuyttens JJ, Ferenschild FTJ, Planting AST, Verhoef C, de Wilt JHW. Preoperative chemoradiation with capecitabine in locally advanced rectal cancer Netherlands. Journal of Medicine. 2008;66(2):71–76. [PubMed: 18292610]
  • De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, Del Prete S, Pasetto L, Santantonio M, Sarti E, Mantello G, Innocente R, Frusctaci S, Corvo R, Rosso R. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Annals of Oncology. 2006;17(2):246–251. [PubMed: 16282246]
  • Desai SP, El-Rayes BF, Ben-Josef E, Greenson JK, Knol JA, Huang EH, Griffith KA, Philip PA, McGinn CJ, Zalupski MM. A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer. American Journal of Clinical Oncology. 2007;30(4):340–345. [PubMed: 17762432]
  • Des Guetz G, Schischmanoff O, Nicola P, Perret GY, Morere JF, Uzzan B. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. European Journal of Cancer. 2009;45(10):1890–1896. [PubMed: 19427194]
  • Elwanis MA, Maximous DW, Elsayed MI, Mikhail NNH. Surgical treatment for locally advanced lower third rectal cancer after neoadjuvant chemoradiation with capecitabine; prospective phase II trial. World Journal of Surgical Oncology. 2009;7:52. [PMC free article: PMC2699338] [PubMed: 19508705]
  • Erlichman C. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. Journal of Clinical Oncology. 1999;17(5):1356–1363. [PubMed: 10334519]
  • Fiorica F, Cartei F, Licata A, Enea M, Ursino S, Colosimo C, Cammà C. Can chemotherapy concomitantly delivered with radiotherapy improve survival of patients with resectable rectal cancer? A meta-analysis of literature data. Cancer Treatment Reviews. 2010;36(7):539–549. [PubMed: 20334979]
  • Fisher B, Wolmark N, Rockette H, Redmond C. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. Journal of the National Cancer Institute. 1988;80(1):21–29. [PubMed: 3276900]
  • Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–T4 rectal cancers: results of FFCD 9203. Journal of Clinical Oncology. 2006;24:4620–4625. [PubMed: 17008704]
  • Germond C, Figueredo A, Taylor BM, Micucci S, Zwaal C.GI Cancer Disease Site Group. Postoperative adjuvant radiotherapy and/or chemotherapy for resected stage II or III rectal cancer. Practice Guideline report #2–3. Cancer Care Ontario Practice Guideline Initiative. 1998.
  • Glimelius B, Dahl O, Cedermark B, Jakobsen A. Adjuvant Chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Acta Oncologica. 2005;44(8):904–912. [PubMed: 16332600]
  • Glynne-Jones R, Meadows H, Wood W. Chemotherapy or no chemotherapy in clear margins after neoadjuvant chemoradiation in locally advanced rectal cancer: CHRONICLE. A randomised phase III trial of control vs. capecitabine plus oxaliplatin. Clinical Oncology. 2007;19(5):327–329. [PubMed: 17434299]
  • Iverson L, Kratmann M, Boje M, Laurberg S. Self-expanding metallic stents as bridge to surgery in obstructing colorectal cancer. British Journal of Surgery. 2011;98:275–281. [PubMed: 21082710]
  • Kim JC, Kim TW, Kim JH, Yu CS, Kim HC, Chang HM, Ryu MH, Park JH, Ahn SD, Lee S, Shin SS, Kim JS, Choi EK. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Journal of Radiation Oncology, Biology, Physics. 2005;63(2):346–353. [PubMed: 15913913]
  • Kirkeby LT, et al. Postoperative adjuvant chemotherapy for radically operated Dukes C rectal cancer (protocol) Cochrane Database of Systematic Reviews. 2002;4:4.
  • Klos CL, Shellito PC, Rattner DW, Hodin RA, Cusack JC, Bordeianou L, Sylla P, Hong TS, Blaszkowsky L, Ryan DP, Lauwers GY, Chang Y, Berger DL. The effect of neoadjuvant chemoradiation therapy on the prognostic value of lymph nodes after rectal cancer surgery. American Journal of Surgery. 2010;200(4):440–445. [PubMed: 20887837]
  • Koeberle D, Burkhard R, von Moos R, Winterhalder R, Hess V, Heitzmann F, Ruhstaller T, Terraciano L, Neuweiler J, Bieri G, Rust C, Toepfer M. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advance rectal cancer. British Journal of Cancer. 2008;98(7):1204–1209. [PMC free article: PMC2359632] [PubMed: 18349837]
  • Labianca R. Efficacy of adjuvant fluorouracil and Folinic acid in colon cancer. Lancet. 1995;345(8955):939–944. [PubMed: 7715291]
  • Lin CC, Lin JK, Chang SC, Wang HS, Yang SH, Jiang JK, Chen WS, Lin TC. Is adjuvant chemotherapy beneficial to high risk stage II colon cancer? Analysis at a single institute. International Journal of Colorectal Disease. 2009;24(6):665–676. [PubMed: 19238405]
  • Machiels JP, Duck L, Honhon B, Coster B, Coche JC, Scalliet P, Humblet Y, Aydin S, Kerger J, Remouchamps V, Canon JL, van Maele P, Gilbeau L, Laurent S, Kirkove C, Octave-Prignot M, Baurain JF, Kartheuser A, Sempoux C. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study. Annals of Oncology. 2005;16(12):1898–1905. [PubMed: 16219623]
  • Mamounas E, Wieand S, Wolmark N, Bear HD, Atkins JN, Song K, Jones J, Rockette H. 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) Journal of Clinical Oncology. 1999;17(5):1349–1355. [PubMed: 10334518]
  • Maras-Simunic M, Druzijanic N, Simunic M, Roglic J, Tomic S, Perko Z. Use of modified multidetector CT colonography for the evaluation of acute and subacute colon obstruction caused by colorectal cancer: a feasibility study. Diseases of the Colon and Rectum. 2009;52(3):489–495. [PubMed: 19333051]
  • Mermershtain W, Gluzman A, Gusakova I, Walfish S, Cohen Y, Ariad S. Preoperative radio-chemotherapy treatment in locally advanced rectal carcinoma. Results of 8 year follow-up. Onkologie. 2005;28(5):267–269. [PubMed: 15867483]
  • O’Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low dose leucovorin given for 6 Months as postoperative adjuvant therapy for colon cancer. Journal of Clinical Oncology. 1997;15(1):246–250. [PubMed: 8996149]
  • Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer JW, van de Velde CJ. Dutch Colorectal Cancer Group. 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. Annals of Surgery. 2007;246(5):693–701. [PubMed: 17968156]
  • Pietrzak L, Pietrzak L, Bujko K, Nowacki MP, Kepka L, Oledzki J, Rutkowski A, Szmeja J, Kladny J, Dymecki D, Wieczorek A, Pawlak M, Lesniak T, Kowalska T, Richter P. Polish Colorectal Study Group. Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: report of a randomised trial. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology. 2007;84(3):217–225. [PubMed: 17692977]
  • Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370(9604):2020–2029. [PubMed: 18083404]
  • Repici A, DeCaro G, Luigiano C, Fabbri C, Pagano N, Preatoni P, Danese S, Fucci L, Consolo P, Malesci A, D’Imperio N, Cennamo V. Wallfles colonic stent placement for the management of malignant colorectal obstruction: a prospective study at two centres. Gastrointestinal Endoscopy. 2008;67(1):77–84. [PubMed: 18155427]
  • Rodel C, Grabenbauer G, Papadopoulos T, Hohenberger W, Schmoll HJ, Sauer R. Phase I/II trial of capecitabine, oxaliplatin and radiation for rectal cancer. Journal of Clinical Oncology. 2003;21(16):3098–3104. [PubMed: 12915600]
  • Sakamoto J, Ohasi Y, Hamada C, Buyse M. Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5 year results from three randomised trials. Journal of Clinical Oncology. 2004;22(3):484–492. [PubMed: 14752071]
  • Sakamoto J. Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patient data meta-analysis of randomised trials. Japanese Journal of Clinical Oncology. 1999;2(29):78–86. [PubMed: 10089948]
  • Sebastian S, Johnstone S, Geoghegan T, Torreggiani W, Buckley M. Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectal obstruction. American Journal of Gastroenterology. 2004;99(10):2051–2057. [PubMed: 15447772]
  • Song HY, Kim JH, Shin JH, Kim HC, Yu CS, Kim JC, Kang SG, Yoon CJ, Lee JY, Koo JH, Lee KH, Kim JK, Kim DH, Shin TB, Jung GS, Han YM. A dual design expandable colorectal stent for malignant colorectal obstruction: results of a multi-centre study. Endoscopy. 2007;39(5):448–454. [PubMed: 17516352]
  • Stephens RJ, Thompson LC, Quirke P, Steele R, Grieve R, Couture J, Griffiths GO, Sebag-Montefiore D. Impact of short-course preoperative radiotherapy for rectal cancer on patients’ quality of life: data from the Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 randomized clinical trial. Journal of Clinical Oncology. 2010;28(27):4233–4239. [PubMed: 20585099]
  • Twu CM, Wang HM, Chen JB, Chao TH, Mar HF. Neoadjuvant concurrent chemoradiotherapy in treating locally advance rectal cancer. Journal of the Chinese Medical Association. 2009;72(4):179–182. [PubMed: 19372072]
  • Velenik V, Anderluh F, Oblak I, Strojan P, Zakotnik B. Capecitabine as a radio-sensitising agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial. Croatian Medical Journal. 2006;47(5):693–700. [PMC free article: PMC2080466] [PubMed: 17042060]
  • Vemulapalli R, Lara L, Sreenarasimhaiah J, Harford WV, Siddiqui AA. A comparison of palliative stenting or emergent surgery for obstructing incurable colon cancer. Digestive Diseases and Sciences. 2010;55(6):1732–1737. [PubMed: 19693667]
  • Wong RK, Tandan V, De SS, Figueredo A. Preoperative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database of Systematic Reviews. 2007;(2):CD002102. [PubMed: 17443515]
  • Yoshimatsu K, Umehara A, Ishibashi K, Yokomizo H, Yoshida K, Fujimoto T, Watanabe K, Ogawa K. Indication and efficacy of adjuvant chemotherapy with oral fluorouropyrimidines for Dukes B colorectal cancer. Anticancer Research. 2006;26(4B):3089–3094. [PubMed: 16886639]
Copyright © 2011, National Collaborating Centre for Cancer.
Cover of Colorectal Cancer
Colorectal Cancer: The Diagnosis and Management of Colorectal Cancer.
NICE Clinical Guidelines, No. 131.
National Collaborating Centre for Cancer (UK).

NICE (National Institute for Health and Care Excellence)

PubMed Health Blog...

read all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...