Chemotherapy and radiotherapy are important therapeutic modalities in colorectal cancer. This section is subdivided into adjuvant chemotherapy, adjuvant radiotherapy, chemotherapy for metastatic disease and radiotherapy for locally advanced disease.

Chemotherapy and radiotherapy should be prescribed, dispensed, administered and supervised in a safe and effective manner in accordance with the Joint Collegiate Council for Oncology guidelines159 and Scottish Executive advice.160

Both radiotherapy and chemotherapy can improve survival rates after potentially curative surgery, and chemotherapy prolongs overall survival in cohorts of patients with advanced disease. However, neither radiotherapy nor chemotherapy can guarantee cure, it is not possible to identify which individuals will benefit personally and there is a “cost” in terms of disruption of lifestyle and treatment related toxicity.

It is essential that the pros and cons of intervention be discussed carefully with the patient so that each individual can make an informed choice that is consistent with their wishes and personal circumstances.

9.1 Adjuvant chemotherapy

There is evidence showing absolute survival benefit (of 4%-13% at five years) from adjuvant chemotherapy for patients with Dukes’ C colon cancer.^{161, 162, 163} Somewhat weaker evidence suggests that there is also survival benefit from adjuvant chemotherapy for rectal cancer.¹⁶⁴ It is, however, difficult to distinguish the benefits of radiotherapy from those of chemotherapy in patients with rectal cancer. Evidence level 1++,1+

Patients with Dukes’ C tumours of the colon or rectum should be considered for adjuvant chemotherapy.

Chemotherapy may not be appropriate for all patients due to comorbidity or personal preference. The proportion of older (>70 years) patients entered into trials of adjuvant therapy is small, and not representative of the population suffering from colorectal cancer in Scotland (see Table 3).

Table 3: Comparison of age distribution of patients randomised into the QUASAR study¹⁶⁵ with the population data for people suffering from colorectal cancer in Scotland (ISD data).¹⁶⁶

In older patients or in patients with significant coexisting illness (eg cardiovascular problems) the risks of toxicity may increase and decisions about adjuvant chemotherapy should be based on careful discussion between the patient and oncologist.

The evidence for patients with Dukes’ B tumours shows no overall benefit from adjuvant chemotherapy. ^{163, 167} Evidence level 1+

Patients with Dukes’ B tumours of the colon or rectum should not be treated routinely with adjuvant chemotherapy.

9.1.1 PORTAL VEIN INFUSION AND INTRAPERITONEAL ADJUVANT CHEMOTHERAPY

There is conflicting evidence on the survival benefit from portal venous infusion of fluorouracil (5-FU). Some studies suggest a modest effect with a 4.7% absolute increase in five year survival (Number Needed to Treat, NNT=20).^{168, 169, 170} Preliminary results of the AXIS trial indicate no difference in absolute survival rate.¹⁷¹ Further data are required to clarify this question. Greater benefits can be achieved with systemic administration of chemotherapy. Evidence level 1++,1+

Portal vein chemotherapy should not be used as the sole regimen in postoperative adjuvant treatment.

There is a single RCT which suggests a benefit from combining intra-peritoneal fluorouracil and folinic acid (FUFA) with systemic chemotherapy in colorectal cancer but the control arm comprised a different systemic regimen (fluorouracil/levamisole) and this trial therefore does not demonstrate a clear advantage for intraperitoneal therapy.¹⁷² Evidence level 1+

9.1.2 ADJUVANT IMMUNOTHERAPY

Evidence on the use of monoclonal antibody 17 1A is conflicting: one RCT¹⁷³ showed improved survival in Dukes’ C cancer of the colon compared to no treatment, but a second, reported in abstract only, showed no benefit from adding 17 1A to FUFA chemotherapy.¹⁷⁴ Evidence level 1+

Two randomised trials have failed to show benefit from adding interferon alfa to conventional chemotherapy.^{175, 176} There is also evidence that adding levamisole to FUFA provides no additional benefit.¹⁷⁷ Evidence level 1++

Adjuvant immunotherapy with the monoclonal antibody 17 1A should not be used except in a randomised controlled trial.

The addition of levamisole or interferon alfa to FUFA chemotherapy as adjuvant treatment is ineffective in colorectal cancer and should not be considered.

Active specific immunotherapy (ASI) has been evaluated in a single randomised trial, but this was of insufficient quality to allow a conclusion to be drawn and further studies with this mode of treatment are needed.¹⁷⁸ Evidence level 1-

9.1.3 WHAT IS THE MOST EFFECTIVE CHEMOTHERAPY REGIMEN FOR ADJUVANT TREATMENT OF COLORECTAL CANCER?

FUFA given by intravenous injection for five days every four weeks for six cycles is the regimen for which the most evidence is available and it is clearly effective in prolonging survival in patients with Dukes’ C tumours.^{161, 162} One study has shown no benefit from higher (175 mg) as opposed to lower (25 mg) doses of L-folinic acid.¹⁷⁹ Low dose FUFA has not been shown to be superior to 12 months of fluorouracil in combination with levamisole, but levamisole is not licensed in Scotland. Evidence level 1+

The recommended adjuvant regimen in patients with Dukes’ C tumours is bolus fluorouracil and low-dose folinic acid (FUFA), administered over five days every four weeks. The duration of treatment should be six months.

In a retrospective analysis of data from the QUASAR (QUick And Simple And Reliable) trial, it has been shown that weekly bolus FUFA is as active and less toxic than five day, four weekly FUFA, but the level of evidence supporting its use, is lower than that for the four weekly schedule.¹⁸⁰ Evidence level 2++

The schedule of FUFA given once weekly for 30 weeks used in the QUASAR (QUick And Simple And Reliable) trial may be an acceptable option for certain patients.

Preliminary results from the SAFFA study show that, compared to six months of bolus FUFA, three months of protracted venous infusion (PVI) flourouracil is superior, in terms of disease-free survival, but there was no difference in survival between the two arms of this study.¹⁸¹ Quality of life whilst on treatment is better with PVI flourouracil and there are fewer life-threatening adverse effects.

Randomised trials of adjuvant treatment using other regimens, such as de Gramont FUFA, capecitabine and tegafur/uracil (UFT) were identified. De Gramont FUFA and capecitabine have been shown to be more effective and less toxic, than bolus FUFA in patients with advanced disease.^{182, 202} Increased response rates have been reported in patients with metastatic disease when combination chemotherapy is administered (see section 9.3.3). Data from RCTs in the adjuvant setting, including these regimens, will be available in the near future.

9.2 Adjuvant radiotherapy

Local failure may be distressing for patients and is both difficult and expensive to treat effectively. Improving local control, even if without improvement in survival, is a worthwhile therapeutic goal. There is no easy or obvious explanation for the fact that improvement in local control apparently fails to translate into improved survival.

There is unequivocal evidence from 27 randomised trials and two meta-analyses that adjuvant radiotherapy improves local control in patients undergoing potentially curative resections for rectal cancer.^{183, 184} The pooled estimate for the absolute reduction in risk of loss of local control favouring radiotherapy and surgery, as opposed to surgery alone, is 9% (NNT=11). Evidence level 1++,1+

The evidence for increased survival is less convincing. Meta-analyses show no overall benefit. Only one trial, the Swedish Rectal Trial, showed convincing benefit with survival as an endpoint: an absolute risk reduction in survival of 10% in favour of preoperative radiotherapy (NNT=10).¹⁸⁵ Follow up of the long term survivors from the Swedish Rectal Trial shows that bowel function is significantly worse in irradiated patients; the survival benefits are at the cost of increased late toxicity.¹⁸⁶ See Box 1 for a discussion of the difficulties involved in generalising from research evidence. Evidence level 1+

There is strong evidence of an increase in non-cancer deaths during the first year after treatment in patients irradiated preoperatively¹⁸⁷ which may, in part, offset any potential survival benefit of improved local control. Further evidence indicates that this excess mortality is related to radiotherapy technique, in particular outmoded regimens which treated large volumes with parallel opposed fields.^{188, 189} Trials using three or four field plans to more conservative volumes fail to show any increase in non-cancer deaths.¹⁹⁰ Evidence level 1++,1+

Preoperative radiotherapy, planned with three or four fields, should be considered in patients with operable rectal cancer.

Where there is doubt about the value of preoperative radiotherapy, patients should be considered for inclusion into a randomised trial (eg CR07).

9.2.1 PREOPERATIVE VERSUS POSTOPERATIVE TREATMENT

Only one randomised trial has directly compared preoperative radiotherapy with postoperative radiotherapy.¹⁹¹ The dose of postoperative radiotherapy used in this study was relatively high, 60 to 64 Gy in 2 Gy fractions, split course. The results favour preoperative radiotherapy with a significant excess of late morbidity in long term survivors who had been irradiated postoperatively. The absolute rate difference was 21% (Number Needed to Harm, NNH=5). However, this study has a high risk of bias with wide confidence intervals and cannot support a recommendation. Evidence level 1-

Indirect evidence from systematic reviews also suggests that radiotherapy may be more effective if given preoperatively.¹⁹² When trials of preoperative radiotherapy are compared with trials of postoperative radiotherapy, the magnitude of benefit, in terms of local control, is similar. The preoperative trials used lower doses of radiotherapy, <40 Gy at 2 Gy equivalent fractions based on a/b=10 Gy, whereas the postoperative trials used doses ³40 Gy. Similar effects on tumours were produced using lower biological doses with preoperative, as opposed to postoperative, treatment. Evidence level 1+

Postoperative radiotherapy should be considered in patients with rectal cancer who did not receive preoperative radiotherapy and who are at high risk of local recurrence (see section 8).

When postoperative radiotherapy is indicated, a schedule of 45Gy in 25 fractions over five weeks is recommended. Patients should not be treated with parallel opposed fields; a planned technique with three or four fields should be used.

9.2.2 CHEMOTHERAPY SYNCHRONOUS WITH RADIOTHERAPY

There are no results from studies comparing short course (five fractions) radiotherapy with and without chemotherapy. The following discussion applies to long course (>20 fractions) radiotherapy.

Only three trials have randomised patients with rectal cancer to radiotherapy as opposed to chemotherapy synchronous with radiotherapy (CRT). All were of low quality and reporting is incomplete. The more useful evidence comes from several prospective cohort studies.^{193, 194} The addition of chemotherapy to radiotherapy improves complete response rate and the resectability rate in more advanced tumours. The design of the studies does not allow an assessment of survival. The regimens using intermittently infused FUFA (Bosset) or continuous flourouracil (Lokich) have been widely and safely used. Evidence level 2+,4

Chemotherapy should be given synchronously with the radiotherapy using one of the following three regimens: intermittently infused FUFA (Bosset); continuous flourouracil (Lokich) or bolus FUFA.

9.3 Chemotherapy for metastatic disease

There is evidence from two systematic reviews that chemotherapy for metastatic colorectal cancer can improve survival, and should be considered in all cases.^{199, 200} This form of therapy is given with palliative intent, and a major aim should be to alleviate symptoms or delay their onset. Evidence level 1++

All patients with metastatic colorectal cancer should be considered for chemotherapy.

Some patients experience the toxicity of treatment without benefit and patients should be informed of the potential benefits and morbidity of treatment and fully involved in decision-making. Ideally, a consultant oncologist should carry out the assessment of a patient and discuss management with them in a socially supportive environment and offer the opportunity for relatives or friends and a clinical nurse specialist to be present. Patients should receive written as well as verbal information about treatment and should be informed about other sources of information such as other health care professionals, Cancer BACUP (www.cancerbacup.org.uk) and other internet sites. Patients often require time to discuss issues with others and a second appointment may be required before patients decide between treatment options.

The benefits and morbidity of chemotherapy should be discussed with a consultant oncologist in the presence of relatives/friends if the patient chooses. Access to a clinical nurse specialist should be offered to the patient. Patients should also receive written information.

9.3.1 DEFERRED VS IMMEDIATE CHEMOTHERAPY IN ASYMPTOMATIC PATIENTS

Two systematic reviews demonstrate that chemotherapy prolongs survival, but insufficient, high quality data are available relating to the timing of chemotherapy.^{199, 200} There are no useful data on quality of life or relief of symptoms. The patients included in the 13 randomised trials attempting to address this question are unrepresentative. In the Cochrane overview only 16/858 (<2%) of the patients for whom individual patient data were available were over 75 years old. Scottish Cancer Registry data show that 57% of patients with colorectal cancer are over 70 years old, 24% are over 80 years.

There remains no clear indication for immediate, as opposed to deferred, chemotherapy in asymptomatic patients with metastatic colorectal cancer. The advantages and disadvantages of immediate treatment should be carefully discussed with each patient and, if an appropriate randomised trial is available, entry into the trial should be considered.

9.3.2 FIRST LINE CHEMOTHERAPY REGIMEN

The regimen of bolus FUFA (Mayo) has been compared with other regimens in several randomised controlled trials and protracted infusions of fluorouracil was compared with bolus fluorouracil alone.^{182, 201, 202, 203} Tegafur/uracil (UFT) in combination with folinic acid has also been compared with one Mayo regimen and has shown similar efficacy and reduced toxicity (published in abstract only).^{204, 205} Bolus fluorouracil regimens have been shown in a meta-analysis to be inferior to fluorouracil infusion regimens in terms of response rate.²⁰⁶ The Mayo regimen itself is the least effective and the most toxic of the regimens that have been widely tested in randomised trials. The de Gramont regimen (intermittently infused FUFA), the Lokich regimen (continuously infused fluorouracil), and oral capecitabine are more effective than regimens using bolus 5-FU in terms of response rate, and are also less toxic.^{182, 207, 208} Evidence level 1++

Other orally administered agents are undergoing clinical trials and the results of these studies are likely to influence future recommendations.

Raltitrexed is as effective as the Mayo FUFA regimen, but evidence concerning its toxicity is conflicting.^{209, 210, 211} A randomised adjuvant trial of raltitrexed compared to fluorouracil and folinic acid (PETACC-1) was stopped prematurely when drug-related deaths in the raltitrexed arm were double those of the control arm and a greater proportion of patients failed to complete the intended treatment.²¹² Some of these problems may be related to the effects of impaired renal function upon toxicity associated with raltitrexed.²¹³ Evidence level 1++,3,4

In patients with metastatic disease, raltitrexed was also associated with an increased incidence of treatment related deaths (6%) when compared to the de Gramont and Lokich regimens, although overall survival was similar in each of the three groups. Nevertheless, ralixitred may be useful in the management of patients with severe coronary artery disease as it does not, in contrast to the other regimens, induce coronary vasospasm.²¹⁴ Evidence level 1++,3,4

The results of the MRC CR06 trial show that, in a randomised comparison of raltitrexed, the de Gramont (intermittently infused FUFA) regimen, and the Lokich (continuously infused fluorouracil) regimen, the regimens were of similar effectiveness in terms of survival and response rates.²¹⁵ Raltitrexed was more toxic than the other regimens and the quality of life of patients treated with raltitrexed was inferior to that of patients treated with the other two regimens. Evidence level 1+

Bolus 5-FU regimens are not recommended as routine first line chemotherapy for advanced disease.

Outside a clinical trial, the choice of an appropriate regimen includes continuous infusional flourouracil (Lokich), FUFA infusion (de Gramont) or capecitabine.

Raltitrexed is not recommended as a first line therapy but may be considered as an alternative in those patients intolerant of 5-FU regimens or in whom 5-FU is contraindicated due to cardiotoxicity.*

* Although as efficacious as alternative regimens, raltitrexed is associated with significantly greater toxicity and its benefit to patients who are intolerant to 5FU or with coronary heart disease should be carefully weighted against the potential harms. This recommendation differs from the HTBS comment ²¹⁶ on the NICE appraisal (March 2002) which recommends that the use of raltitrexed is restricted to clinical studies.

Each of these regimens is very different in terms of administration, scheduling, hospital admission and potential toxicity, and the choice of treatment will be influenced by a number of factors. The most important factors are patient preference and availability of expertise.

9.3.3 COMBINATION CHEMOTHERAPY

Evidence from two randomised trials shows that adding irinotecan to FUFA increases the response rate and also produces a modest improvement in survival.^{217, 218} Two randomised trials comparing FUFA alone with FUFA plus oxaliplatin fail to show survival benefit but there is improvement in response rate.^{219, 220} Interpretation of survival data from these studies is confused by crossover issues: patients failing FUFA were able to crossover to the combination regimen. There is good evidence to support initial combination chemotherapy for patients with metastatic colorectal cancer, but any benefit from the use of these regimens has to be set against the increase in toxicity when compared with FUFA alone. Evidence level 1+

In a randomised study assessing the value of adding mitomycin to protracted infusion flourouracil, it was shown that the response rate increased and time to progression was prolonged but there was no difference in overall survival and haematological toxicity was increased by the addition of mitomycin.²²¹ Evidence level 1++

Until the balance between benefits and harms can be better defined, there is no justification for the routine use of combination therapy as first line treatment for all patients with metastatic colorectal cancer, but the decision should be made on an individual basis.

Evidence from a large cohort study of combination chemotherapy with oxaliplatin and fluorouracil and folinic acid on the treatment of liver metastases showed that chemotherapy allowed surgical resection in 13.5% of patients treated and subsequent survival was similar to a comparable series of operable patients treated by surgical resection. This evidence supports the use of neoadjuvant chemotherapy to allow surgical resection of liver metastases.²²² Evidence level 2+

Initial combination chemotherapy, including oxaliplatin, should be considered in patients fit for hepatic resection but who have inoperable hepatic metastases that might become resectable on treatment.

The optimal route and schedule of administration of palliative chemotherapy remains uncertain and all patients should be considered for entry into prospective randomised clinical trials.

9.3.4 HEPATIC ARTERY INFUSION (HAI) FOR LIVER METASTASES.

Two meta-analyses^{223, 224} and two randomised trials^{225, 226} have found that response rates are higher with HAI but improvements in survival are meagre. Any advantages achieved through the use of hepatic artery infusion are offset by the technical difficulties associated with the technique. Evidence level 1++,1+

HAI use should be confined to specialist centres or clinical trials.

9.3.5 SECOND LINE CHEMOTHERAPY

Two randomised trials show that patients who have failed to respond to, or who have progressed after treatment with 5FU/FA may respond to treatment with irinotecan.^{227, 228} These responses may translate into improved survival although the benefits are modest - an increase of 10 weeks in median survival - and by 24 months the survival curves converge again. Evidence level 1+

Carefully selected patients with good performance status, normal liver function tests and no evidence of gastrointestinal obstruction with metastatic colorectal cancer,who have progressive disease despite treatment with 5FU/FA, should be considered for second line treatment with irinotecan.

9.3.6 THERAPIES BASED ON MANIPULATION OF THE IMMUNE SYSTEM

Two randomised trials show no benefit from adding interferon alfa to conventional chemotherapy.^{175, 176} A further trial, using the anti-idiotypic monoclonal antibody 105 AD7 showed no benefit in survival in comparison with placebo.²²⁹ Evidence level 1+

Immune modulation should not be used routinely in the management of advanced colorectal cancer.

9.3.7 CHRONOMODULATED THERAPY

Chronomodulation is a method of delivering chemotherapy in which programmable pumps are used to vary the rate of drug delivery over a 24 hour period. The hypothesis is that scheduling therapy in this way will improve selective toxicity by exploiting differences in circadian rhythms between tumours and normal tissues. Only one randomised trial has addressed directly the issue of benefit from chronomodulated therapy in patients with colorectal cancer.²³⁰ The study utilised a non-standard control arm which was relatively toxic resulting in no convincing evidence that chronomodulated chemotherapy offers any significant survival advantage over conventionally scheduled treatment for patients with metastatic colorectal cancer.

9.4 Radiotherapy for advanced disease

The potential roles for radiotherapy in advanced rectal cancer are:

• to improve the operability of unresectable disease;
• in the curative treatment of inoperable disease;
• in the palliative management of symptoms in patients with persistent or locally recurrent disease.

9.4.1 IMPROVING THE OPERABILITY OF UNRESECTABLE DISEASE

Evidence indicates that adding synchronous chemotherapy to local radiotherapy increases the response rate of rectal cancer.^{231, 232, 233} Regimens using intermittently infused 5FU/FA²³⁴ or continuous 5FU^{235, 236} have been widely and safely used. Evidence level 1+,2+

Radiotherapy to convert inoperable rectal cancer into operable disease should be combined with chemotherapy. Suitable regimens include intermittent infusional 5FU/FA (Bosset), continuously infused 5FU (Lokich) or bolus 5FU/FA.

9.4.2 CURATIVE TREATMENT OF TOTALLY INOPERABLE DISEASE

If surgery is not feasible, either because of the local extent of disease or owing to the patient’s general medical condition, then the use of higher doses of radiotherapy, in conjunction with chemotherapy, should be considered. In these circumstances, the chances of cure are slender and disruption and toxicity from treatment are certain. It is essential that the harms as well as the potential benefits from an aggressive approach should be carefully discussed with the patient. Ultimately, the decision whether or not to opt for radical therapy should rest with the patient.

The presence of hepatic metastases is not in itself a contraindication to the radical treatment of the primary tumour. If the local tumour has been controlled then resection or in situ ablation of the liver metastases should be considered.

For patients with totally inoperable rectal cancer, and who are fit for an aggressive approach to treatment, chemo-radiotherapy should be offered as for potentially resectable disease.

9.4.3 PALLIATION OF LOCAL SYMPTOMS

There is no high quality evidence on the effectiveness of radiotherapy in relieving symptoms caused by residual or recurrent rectal cancer. Evidence suggests that 44 Gy in 12 fractions over 10 to 12 weeks may be effective and will produce minimal toxicity, either acute or late.²³⁷ A regimen of 30 Gy in 10 to 15 fractions is widely used, but there is no good evidence to support this practice. Evidence level 3

The choice of regimen will depend upon a number of factors including the patient’s preference and general condition; the distance from the treating centre and the nature and severity of symptoms.

Palliative radiotherapy should be considered for patients who have distressing pelvic symptoms from rectal cancer.