Intended for healthcare professionals

Clinical Review ABC of colorectal cancer

Treatment of advanced disease

BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7271.1278 (Published 18 November 2000) Cite this as: BMJ 2000;321:1278
  1. Annie Young,
  2. Daniel Rea

    Advanced colorectal cancer can be defined as colorectal cancer that at presentation or recurrence is either metastatic or so locally advanced that surgical resection is unlikely to be carried out with curative intent. Despite most patients undergoing potentially curative surgery and the availability of adjuvant chemotherapy, about 50% of patients presenting with colorectal adenocarcinoma die from subsequent metastatic disease. The five year survival rate for advanced colorectal cancer is lower than 5%.

    In the past few years several therapeutic advances—underpinned by multiprofessional, site specialised team working—have finally changed the view that advanced colorectal cancer is an untreatable disease. Although cytotoxic chemotherapy is not suitable for all patients, widespread use in appropriate situations can improve survival and quality of life

    Clinical presentation

    Local recurrence of a tumour is more common in rectal than colon primaries. It may be identified early in the asymptomatic phase by follow up monitoring or may present with similar symptoms to the primary lesion. Blood loss through the rectum, mucous discharge, altered bowel habit, and straining are common features of recurrent rectal cancer. Pain and urinary symptoms are features of localised pelvic recurrence. Recurrent intra-abdominal disease can present as small or large bowel obstruction, and recurrence at other sites may be indicated by focal features such as hepatic capsular pain, jaundice, dyspnoea, localised bone pain, or neurological symptoms. Systemic features of weight loss, anorexia, nausea, and asthenia are symptoms commonly associated with advanced colorectal cancer. The tumour is often palpable on rectal or abdominal examination, and malignant ascites may also be evident.

    Clinical presentation

    • About 20% of colorectal cancer cases will present with advanced disease

    • About 50% of patients treated with curative surgery will develop advanced disease

    • About 80% of relapses will occur within three years of primary surgery

    • About 50% of patients with advanced disease will present with liver metastasis

    • About 20% of patients with advanced disease have disease confined to the liver

    Which patients should be referred for palliative chemotherapy*?

    Patients in whom chemotherapy should be considered
    • Able to carry out all normal activity without restriction

    • Restricted in physically strenuous activity but able to walk about and carry out light work

    • Able to walk about and capable of all self care but unable to carry out any work; out of bed or chair for more than 50% of waking hours

    Patients unlikely to benefit from chemotherapy
    • Capable only of limited self care; confined to bed or chair for more than 50% of waking hours

    • Severely disabled; cannot carry out any self care; totally confined to bed or chair

    Referral

    Despite clear evidence of the value of chemotherapy and the apparent willingness of cancer patients to have chemotherapy, in the United Kingdom only about 25% of patients with advanced disease are referred to an oncology tertiary centre for consideration of chemotherapy. Referral patterns and treatment policies for patients with advanced colorectal cancer vary widely in the United Kingdom. Currently many regions are in the throws of reorganising their cancer services as part of the implementation of the Calman report, A Policy Framework for Commissioning Cancer Services. It is envisaged that referrals to oncologists will increase considerably owing to the publication in 1997 of guidelines for managing colorectal cancer.

    Overview of management

    The management of patients with advanced colorectal cancer involves a combination of specialist active treatment, symptom control measures, and psychosocial support. Active treatment comprises an individual plan (often combining palliative surgery), cytotoxic chemotherapy, and radiation therapy.

    Current status of chemotherapy

    • Many patients with advanced colorectal cancer die without having received chemotherapy

    • Chemotherapy improves survival by an average of about six months, compared with supportive care alone

    • Chemotherapy improves overall quality of life

    • Stabilisation of disease with chemotherapy improves both survival and disease related symptoms

    • Early chemotherapy treatment (rather than waiting until symptoms appear) prolongs survival

    The outcome measures of the impact of active treatment have traditionally been survival, response, and toxicity. Alternative end points—for example, quality of life, convenience, acceptability to patients, and patients' preferences—assume greater importance in those with advanced disease, and they should now also be incorporated into the assessment of the relative worth of treatments.

    Surgery

    Palliative surgical procedures for advanced colorectal cancer are commonly used to overcome obstructing lesions and to alleviate pelvic symptoms. The liver is the most frequent site of metastasis, and in selected patients with no extrahepatic metastases surgical resection offers the only hope of cure. Five year survival rates of 25-35% have been reported with this highly specialised procedure (Cady and Stone, 1991).

    Abdominal computed tomogram showing a hepatic metastasis (arrow) before chemotherapy (top) and 17 weeks after chemotherapy (bottom); the later image shows a substantial reduction in the bulk of the hepatic tumour

    Abdominal computed tomogram showing a hepatic metastasis (arrow) before chemotherapy (top) and 17 weeks after chemotherapy (bottom); the later image shows a substantial reduction in the bulk of the hepatic tumour

    Radiotherapy

    In advanced colon cancer, radiotherapy is rarely indicated. In locally advanced rectal disease, localised radiation may render some tumours resectable. Radiotherapy can also be effective in palliation of symptoms—it can improve pain, stop haemorrhage, and lessen straining. In the absence of distant metastases, radiation may afford long term control of the tumour. Pain from isolated bone metastases can also be alleviated with short courses of radiation.

    Conventional chemotherapy

    In patients with advanced colorectal cancer, chemotherapy is delivered with palliative rather than curative intent. For over four decades fluorouracil has been the mainstay of treatment for advanced colorectal cancer. Folinic acid is given intravenously before fluorouracil to enhance the fluorouracil's cytotoxicity. Large randomised trials of chemotherapy versus best supportive care have shown that fluorouracil based chemotherapy adds about 4-6 months to the remaining life of patients with advanced colorectal cancer. Chemotherapy delays the occurrence or progression of symptoms by about six months and improves symptoms, weight gain, and functional performance in about 40% of patients. Palliative chemotherapy in advanced colorectal cancer should not be restricted by chronological age but by fitness and activity level.

    Is failure to respond a failure of treatment?

    Less than a third of patients receive an objective tumour response—complete or partial—with fluorouracil based therapy. In a further 20-30% of patients, the disease is stabilised during chemotherapy. The patients with stable disease (“no change” category) also derive a symptomatic and survival advantage from chemotherapy.

    Definitions for assessing response and progression after chemotherapy

    Complete response—Disappearance of all known disease, determined by two observations not less than four weeks apart

    Partial response—Decrease of at least 50% of the sum of the products of the largest perpendicular diameters of all measurable lesions as determined by two observations not less than four weeks apart

    No change—Less than 50% decrease and less than 25% increase in the sum of the products of the largest perpendicular diameters of all measurable lesions; no new lesions should appear

    Progressive disease—More than 25% increase in the size of at least one lesion or appearance of a new lesion

    Which regimen?

    Current evidence supports the use of infusional fluorouracil regimens over bolus schedules in terms of both toxicity and efficacy, but infusional chemotherapy is more complex to administer, requiring permanent vascular access technology or admission to hospital. In the United Kingdom a 48 hour regimen of fluorouracil plus folinic acid repeated every 14 days is commonly used. Ideally, chemotherapy for advanced colorectal cancer should be given within the umbrella of a clinical trial to help resolve outstanding questions of optimal type, duration, and scheduling of therapy.

    Data from trials by the Nordic Gastrointestinal Tumour Therapy Group support the early use of chemotherapy, before the patient's condition deteriorates

    Tailoring treatment

    The optimum duration of chemotherapy is unknown and is currently being tested in clinical trials. The current approaches are either to treat for a fixed period (usually six months) or to treat until progression occurs. Irrespective of which of these approaches is adopted, the overriding need is to monitor rigorously the effect of treatment in terms of response, palliative benefit, and toxicity. This ensures that any toxicity or disease progression is recognised as soon as possible and that the appropriate individualised treatment or cessation of chemotherapy can be implemented without delay.

    Figure2

    Basic elements of caring for patients with advanced colorectal cancer

    Chemotherapy toxicity

    Chemotherapy for advanced colorectal cancer should be prescribed by experienced oncologists familiar with the toxicity profile of the drug regimens used. Despite concerns over toxicity, currently used infusional regimens are remarkably well tolerated. Management of toxicities in the community requires close liaison with the hospital team, and severe toxicity requires immediate admission. The most common effects of toxicity from chemotherapies for advanced colorectal cancer are diarrhoea, mucositis, asthenia, and neutropenia. Nausea, alopecia, and anorexia can also be experienced. Diarrhoea can be substantially relieved with oral antimotility drugs. Mucositis should be managed with antiseptic mouthwash and prophylactic or early treatment of oral candidiasis. Neutropenia is less common with current infusional regimens but must always be suspected in patients with fever. Prolonged treatment with fluorouracil can produce painful blistering erythema of palms and soles of the feet (palmar plantar erythrodysaesthesia), which often improves with pyridoxine.

    Patient receiving chemotherapy through central venous catheter in hospital outpatient department (top); and small, battery assisted pump, worn on the waist and used to deliver chemotherapy through a central venous catheter (bottom). Patients are free to perform many normal activities during “ambulatory” chemotherapy

    Patient receiving chemotherapy through central venous catheter in hospital outpatient department (top); and small, battery assisted pump, worn on the waist and used to deliver chemotherapy through a central venous catheter (bottom). Patients are free to perform many normal activities during “ambulatory” chemotherapy

    Cost effectiveness

    In 1995 Glimelius et al showed that the overall cost of early intervention with chemotherapy in patients with advanced colorectal cancer is similar to that of no treatment or delayed chemotherapy, indicating that chemotherapy as part of the management of the advanced disease is indeed cost effective. Inevitably, it is becoming increasingly difficult for the health service to fund modern drugs to treat advanced colorectal cancer. The NHS is struggling to fund the new chemotherapy treatments that are proved to extend life by only a few months or to improve the quality of life only.

    Current controversies in advanced colorectal cancer

    • For how long should chemotherapy be given?

    • Are new delivery routes for fluorouracil—for example, orally and by intrahepatic arterial administration—superior to conventional intravenous fluorouracil?

    • Should newer agents with similar efficacy but more convenient intravenous regimens be used in place of fluorouracil?

    • What is the optimum combination and sequence for fluorouracil based therapies and the new chemotherapy drugs?

    • Is home chemotherapy viable?

    • How are the new, more expensive drug therapies to be funded?

    Ambulatory and domiciliary chemotherapy

    The emergence of primary care health teams, together with developing technology, has allowed for more complex care to be carried out in the community or at home.

    Ambulatory infusional chemotherapy is administered via a small pump (battery assisted and disposable elastomeric infuser). The chemotherapy may be connected and disconnected at the hospital outpatient clinic by oncology nurses, or patients can be taught to do this themselves.

    A feasibility study of home chemotherapy has been undertaken in Birmingham for patients with advanced colorectal cancer. This shows that a nurse led service (backed up by oncology medical and nursing staff from both primary and secondary health care) is safe and that patients and carers find home therapy of immeasurable value. Early analysis shows that the cost of this home service is similar to and often cheaper than the current hospital based service.

    New drugs

    In recent years the availability of several new drugs has revived interest in the treatment of advanced colorectal cancer. New treatments include alternative fluoropyrimidines, new thymidylate synthase inhibitors, new modulators of fluorouracil and also mechanistically new drugs.

    New thymidylate synthase inhibitors

    Raltitrexed is a quinazoline analogue antifolate that gains entry to cells via the reduced folate carrier and is polyglutamated to a potent, long acting, specific inhibitor of thymidylate synthase. Its regimen—a short intravenous infusion every three weeks—has similar efficacy to that of fluorouracil plus folinic acid and is clearly more convenient, although potentially more toxic.

    Figure4

    Liver with over 50% hepatic replacement by metastatic colorectal cancer

    Oral fluorouracil prodrugs and modulators

    Fluoropyrimidine analogues have been developed with reliable oral bioavailability. In addition, oral inhibitors of fluorouracil catabolism can facilitate oral dosing. Preliminary data show similar effectiveness and lower toxicity compared with fluorouracil. Given the convenience and potential cost savings, oral therapy may soon find a place in routine practice.

    Irinotecan and oxaliplatin

    Irinotecan is a camptothecin analogue that acts through the inhibition of a DNA unwinding enzyme, topoisomerase I, resulting in replication arrest with breaks in single strand DNA. It is useful in advanced colorectal cancer, even after resistance to fluorouracil has developed, and is associated with a survival benefit (about three months) compared with best supportive care. This drug can be associated with severe late onset diarrhoea, which must be treated immediately. Selection of patients, therefore, plays an important part in the safe use of this agent.

    The Colorectal Forum is a worldwide educational service for healthcare professionals working with patients with colorectal cancer. Its website provides news on conferences and events, recommendations on management of advanced colorectal cancer, articles and visual images, reviews of recent publications, and the opportunity to debate controversial clinical issues. It can be accessed at http://www.colorectal-forum.org/

    Oxaliplatin is a new platinum derivative analogue that crosslinks DNA and induces apoptotic cell death. It shows synergism with fluorouracil. The dominant toxic effect is cumulative neurotoxicity.

    Fluorouracil plus either irinotecan or oxaliplatin is superior to fluorouracil alone as a first line treatment for advanced colorectal cancer, with improvement in progression-free survival and, in the case of irinotecan, overall survival. Questions about the optimum sequence and combination of these agents remain and are the subject of ongoing clinical trials.

    Intrahepatic arterial chemotherapy

    For patients with unresectable hepatic metastases, intrahepatic arterial chemotherapy should be considered. This approach greatly increases drug delivery to the liver and doubles the rate at which tumours shrink, with tolerable toxicity. Owing to the complexity of placing the delivery catheter, intrahepatic arterial chemotherapy is usually administered at specialist centres. Current trials should offer definitive proof of whether intrahepatic arterial chemotherapy offers survival benefits compared with conventional intravenous therapy.

    Further reading

    Supportive care

    All patients with advanced colorectal cancer need continual evaluation of symptoms and appropriate measures for controlling symptoms. Dietary advice and nutritional supplements can stop weight loss, and corticosteroids may be used for their anabolic effect. Psychosocial aspects of care should incorporate evaluation of and provision for the needs of both the patient and the family. Supportive care needs to be tailored to the individual's circumstances and should involve the close collaboration of locally available palliative care services (both in the community and in hospitals). The initial contact between the patient and the palliative team should ideally be made at the time of diagnosis rather than at a crisis point when urgent input from palliative care services is required.

    Footnotes

    • Daniel Rea is senior lecturer in medical oncology, Institute for Cancer Studies, University of Birmingham.

      The ABC of colorectal cancer is edited by D J Kerr, professor at the Institute for Cancer Studies, University of Birmingham; Annie Young, research fellow at the School of Health Sciences, University of Birmingham; and F D Richard Hobbs, professor in the department of primary care and general practice, University of Birmingham. The series will be published as a book by the end of 2000.