Adjuvant chemotherapy of colorectal cancer

Rationale

Nearly half the patients undergoing apparently curative resection of bowel cancer are destined to relapse and eventually die with either locally recurrent or distant metastatic disease. This is due to the presence of residual micro-metastases invisible at the time of surgery. The aim of adjuvant chemotherapy is to eradicate these micro-metastases and thereby prevent future relapse.

Current available chemotherapy does not completely eradicate bulky, advanced metastatic bowel cancer. It does however eradicate micro-metastases in a proportion of patients. In view of the high incidence of colorectal cancer, even a small percentage benefit with adjuvant chemotherapy may have a significant impact in terms of prevention of death and morbidity.

Indications

Adjuvant chemotherapy is an exercise in risk reduction. Questions to be considered after a potentially curative operation:

♦ What is the probability of micro-metastases?

♦ Will adjuvant therapy prevent/delay relapse?

♦ What are the side-effects?

♦ Multidisciplinary team is essential.

The risk that the patient has micro-metastases is estimated, after surgery, by examining the pathological features of the primary cancer; best-established is the histological stage (Dukes' or Astler—Coller). Dukes' A cancers, ie those which have not breached the muscle layers of the bowel wall, carry only a 10% chance of relapse, and adjuvant therapy is not considered worthwhile. Dukes' C cancers, which have spread to the nearby lymph nodes, carry a much higher risk (around 50%). There is good evidence that this risk is reduced by adjuvant chemotherapy, which is now offered routinely in most centres unless there is a strong contraindication.

Dukes' B cancers, which have breached the muscle layers but not spread to lymph nodes, carry an intermediate risk of around 30%. The evidence for adjuvant chemotherapy is less clear-cut in these patients, and other factors including other pathological features, the patient's age, fitness, and attitudes come into the equation. Further trials to assess benefits in these groups are under way.

Molecular markers in the primary tumour may potentially predict invasiveness or determine sensitivity to chemotherapy; sensitive PCR-based tests are being developed to detect micro-metastases in blood, bone marrow, or other tissues.

Rectal cancer, which accounts for nearly 40% of bowel cancers, presents some special considerations. A relative lack of a barrier to lateral spread and increased technical difficulty of surgery in the pelvis combine to make local recurrence a particular problem. Radiotherapy, targeted to the pelvis either before or after surgery, reduces local recurrence rates. Adjuvant therapy for rectal cancer may therefore include both radiotherapy and chemotherapy aimed, respectively, at local and systemic micro-metastases. The evidence for the contribution of chemotherapy in these combined programmes is less clear than for chemotherapy alone in colon cancer.

Treatment

The current 'international standard' adjuvant chemotherapy regimen for colon carcinoma is 5-fluorouracil (5FU) given in combination with folinic acid, by bolus intravenous injection. Two commonly used schedules involve treatment for five consecutive days, repeated every four weeks, or treatment on one day each week, in both cases continued for six months. 5FU interferes with nucleotide synthesis, and hence the synthesis of DNA in dividing cells. It also has effects on RNA. The addition of folinic acid enhances the DNA-directed effects of 5FU and prolongs its duration of action.

5FU given by these standard schedules appear to reduce the relative risk of death by around a quarter. For a patient with Dukes' C colon cancer the absolute gain may be more than 10%, but for a patient with an earlier-stage cancer, who is already at low risk following surgery, the absolute gain from adjuvant therapy may be much smaller.

5FU is also a radiosensitiser. For patients with rectal cancer, pre- or postoperative pelvic radiotherapy is sometimes given concurrently with chemotherapy to harness this effect. This may be followed by a more prolonged course of standard adjuvant chemotherapy aimed at distant micrometastases.

Side-effects

Both the wanted and the unwanted effects of 5FU are critically dependent upon the dose and schedules used, and vary considerably from patient to patient. The side-effect profile should, for most patients, be quite easily tolerable and consistent with continuing normal activity, including work. Treatment is feasible even in the elderly.

Side-effects:

Hair loss and vomiting

♦ Oral mucositis

Rare side-effects of 5FU include:

♦ Red, painful palms and soles

♦ Photosensitivity of face

♦ Irritation to eyes and nose

♦ Myleosuppression

♦ Cardiotoxicity (angina, infarction, or arrhythmias)

♦ Cerebellar syndrome (ataxia, slurred speech, and nystagmus) Some patients may also experience unwanted psychological or social effects of adjuvant chemotherapy:

♦ Prolongation of the 'patient' status

♦ Feelings of anxiety or depression

♦ Loss of earnings

♦ Strains on family relationships

Newer treatments

It is known from research in patients with advanced colorectal cancer that there are more effective methods of giving 5FU, involving higher doses delivered by continuous or intermittent intravenous infusions. Ongoing randomized trials are evaluating whether these are worthwhile as adjuvant therapy.

5FU itself is not reliably absorbed if given by mouth, but a number of new oral preparations involving pro-drugs of 5FU and/or inhibitors of 5FU catabolism are being evaluated. Other research approaches involve regional delivery of 5FU to the tissues most at risk of containing micro-metastases, via the peritoneal cavity or the hepatic portal vein.

New cytotoxic agents are continually under investigation, the most promising of which are:

♦ Irinotecan (a drug which works by interfering with the nuclear enzyme topoisomerase-I)

♦ Oxaliplatin (which forms covalently bonded adducts with DNA)

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment