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Colorectal Cancer Therapy

Adjuvant therapy - ABC of Colorectal Cancer

Rachel S J Midgley

Despite substantial improvements in surgical technique and postoperative care, colorectal cancer continues to kill 95 000 people in Europe alone each year.

Of the annual 150 000 newly diagnosed cases, about 80% have no macroscopic evidence of residual tumour after resection. More than half of patients, however, develop recurrence and die of their disease. This is a result of occult viable tumour cells that have metastasised before surgery and which are undetectable by current radiological techniques (the limit of detection of standard computed tomography is about 1 [cm.sup.3], equivalent to [10.sup.9] cells).

Adjuvant treatment (chemotherapy and radiotherapy) has developed as an auxiliary weapon to surgery and is aimed at eradicating these micrometastatic cancer cells before they become established and refractory to intervention. As the presence of the primary tumour can exert an inhibitory influence on micrometastases, theoretically the removal of the tumour might stimulate growth of any residual cells, increasing the proliferating fraction and rendering them more susceptible to the cytotoxic effects of the widely used cytotoxic agent, fluorouracil.

It is reasonable to predict therefore that the earlier chemotherapy is started after surgery, the greater the potential benefit, although this has not yet been formally addressed in adjuvant trials. Implicit in this belief is a necessity for a multidisciplinary effort between surgeon, oncologist, and the community care team to provide seamless, streamlined cancer care for the individual patient.

Pharmacology of fluorouracil

Fluorouracil has remained the cornerstone chemotherapy for colorectal cancer for over 40 years. It is a prodrug that is converted intracellularly to various metabolites that bind to the enzyme thymidylate synthase, inhibiting synthesis of thymidine, DNA, and RNA. Increasing understanding of the molecular pharmacology of fluorouracil has led to the development of strategies to increase its efficacy.

The first strategy to be tested was coadministration with the immunostimulatory, antihelminthic drug levamisole, but despite promising early results, recent trials have not convincingly shown significant improvements in outcome compared with fluorouracil alone. In addition, no persuasive mechanism for the assumed synergism between fluorouracil and levamisole has been found.

In contrast, addition of folinic acid increases and prolongs the inhibition of the target enzyme (thymidylate synthase) and seems to confer improved clinical outcome compared with fluorouracil alone in advanced disease and when used in adjuvant therapy.

The side effects of chemotherapy based on fluorouracil vary according to the regimen (most commonly given as bolus intravenously daily for 5 days every 4 weeks or bolus weekly). They include nausea, vomiting, an increased susceptibility to infection, oral mucositis, diarrhoea, desquamation of the palms and soles, and, rarely, cardiac and neurological toxic effects.

Established benefits of fluorouracil based adjuvant chemotherapy

Early adjuvant trials were retrospective and underpowered and failed to show any therapeutic benefit with respect to recurrence rate or survival. In 1990, however, the results of the intergroup trial were published. In this study 318 patients with stage B colorectal malignancy were randomised for surgical treatment alone or surgery followed by fluorouracil plus levamisole. In addition, 929 patients with stage C malignancy received surgery alone, surgery plus levamisole, or surgery plus fluorouracil and levamisole. For these patients there was a 33% reduction in the odds of death and a 41% decrease in recurrence among those treated with fluorouracil plus levamisole compared with surgery alone or surgery plus levamisole.

In contrast with levamisole, combining folinic acid with fluorouracil is pharmacologically rational, and documented benefit in advanced disease led to the logical extension of this combination into adjuvant therapy. Three large randomised adjuvant phase III trials produced confirmatory evidence of improved, disease-free survival at three years and improved overall survival in patients treated with fluorouracil plus folinic acid, with a 25-30% decrease in the odds of dying from colon cancer (or an absolute improvement in survival of 5-6% compared with controls).

Recently a meta-analysis of updated individual data from all unconfounded randomised studies of adjuvant chemotherapy (including the above three trials) has been undertaken (Colorectal Cancer Collaborative Group, unpublished). Overall, there was a 6-7% absolute improvement in survival with chemotherapy compared with surgery alone (SD 2.3, P = 0.01). The analysis advised that on current evidence the combination of fluorouracil plus folinic acid should be accepted as "standard" adjuvant chemotherapy for patients with Dukes's type C colon cancer.

Controversies in adjuvant therapy

Despite convincing evidence that adjuvant chemotherapy improves disease-free survival and overall survival in Dukes's type C colon cancer (an estimated six deaths prevented for 100 patients treated), several controversies surrounding the application of this form of treatment still exist.

Length of treatment and optimal dose of fluorouracil plus folinic acid

Lengthy adjuvant treatment has adverse effects on patients' quality of life as well as financial implications. A recent North American study, however, has shown that six months' treatment is as effective as 12 months'.

Determining the optimal dose is important: high dose folinic acid is 10 times as expensive as low dose. This issue has been addressed in the "certain" arm of the United Kingdom Co-ordinating Committee on Cancer Research's QUASAR ("quick and simple and reliable") trial (patients with Dukes's type C colon cancer). The trial uses the principle of randomising according to certain or uncertain indication: if, for a particular subgroup of patients the worth in receiving some form of adjuvant chemotherapy is definitely established from published randomised controlled trials (for example, patients with Dukes's type C colon cancer) then these patients are randomised to the certain indication arm (with a choice of different drugs and regimens); if, however, no definitive evidence exists of worth in a particular subgroup (for example, in patients with Dukes's type B colon cancer or with rectal cancer) then the patients are randomised into the uncertain indication arm (chemotherapy v no chemotherapy). The results from QUASAR's certain arm show that neither high dose folinic acid nor levamisole contribute to improved survival.

Role of adjuvant chemotherapy in lower risk groups

Inadequate data exist on the effect of chemotherapy in stage B colon cancer. The proportional reduction in annual risk is probably similar for stage B and stage C patients. If the proportional reductions in mortality are similar, the absolute benefits in terms of five year survival would be somewhat smaller for stage B patients than for stage C patients because of lower risk of recurrence (perhaps two to three lives saved per 100 patients treated).

Patients with stage B cancers who have prognostic indicators that suggest a high risk of recurrence (for example, perforation, vascular invasion, poor differentiation) might benefit proportionately more than patients with stage B cancer without high risk indicators and these variables might define a subgroup of patients who might merit adjuvant chemotherapy. Little evidence exists, however, on the prognostic predictability of these various features.

Use of adjuvant therapy in rectal cancer

Insufficient evidence exists to support the routine use of systemic chemotherapy in either Dukes's type B or type C rectal cancer. Anatomical constraints make the rectum less accessible to the surgeon, so it is much more difficult to achieve wide excision of the tumour, and about 50% of recurrences are in the pelvis itself rather than at distant sites. This means that locally directed radiotherapy is a useful adjuvant weapon, and this has been assessed for rectal cancer both before and after surgery.

In the largest trial of preoperative radiotherapy (the Swedish rectal cancer trial), radiotherapy produced a 61% decrease in local recurrence and an improvement in overall survival (58% v 48%) compared with surgery alone. Radiotherapy after surgery seems to be less effective, even at higher doses, possibly because of rapid repopulation of tumour cells after surgery or relative hypoxia around the healing wound.

Only one trial, the Uppsala trial in Sweden, has directly compared radiotherapy before and after surgery. Despite a higher dose after surgery, a significant reduction occurred in local recurrence rates among patients treated before surgery (12% v 21%, P [is less than] 0.02).

Animal studies have suggested that fluorouracil may prime the tumour cells and increase the cytotoxic effect of subsequent radiotherapy. Some clinical data support the role of chemoradiotherapy combinations in rectal cancer, but further clinical evidence of benefit needs to be provided before this treatment could be considered for routine use. The uncertain arm of the QUASAR trial will help to resolve this issue.

Role of portal venous infusional therapy

Fluorouracil is an S phase specific drug, and yet its active metabolites have a half life of about 10 minutes, which limits its target, when given as a bolus, to the small fraction of cells in the S phase at the time of administration. Infusional therapy can therefore affect a greater proportion of cells. In addition, the most common site for micrometastases after resection of a colorectal tumour is the liver. In contrast with macroscopically identifiable metastases of advanced disease, which derive their blood supply from the hepatic artery, these micrometastases are thought to be supplied by the portal vein. Therefore delivering chemotherapy via the portal vein should provide high concentrations of the drug at the most vulnerable site and lead to substantial first pass metabolism, which should attenuate any systemic toxicity. The established regimen for portal fluorouracil in adjuvant therapy is a course of 5-7 days starting immediately after surgery. A meta-analysis of 10 randomised trials showed a 4.7% improvement in absolute survival with portal venous infusion therapy compared with surgery alone; however, the confidence intervals were wide and the statistical benefit is not robust. Indeed the AXIS trial, the largest single trial of portal venous infusion to date, randomising 4000 patients after surgery either to the infusion therapy or to observation alone at five years, suggests no significant differences in overall survival.

Future role of adjuvant therapy

The use of adjuvant therapy in colorectal cancer over the past 40 years has centred on fluorouracil, alone and in combination, and on the fine tuning of regimen and route of administration. Current trials are considering new drugs (eg irinotecan and oxaliplatin) and their sequencing, as well as innovative techniques, such as immunotherapy and gene therapy. These techniques will be considered in detail later in the series. Gene therapy and immunotherapy are likely to function optimally, however, when cellular load is low, blood supply is good, and small clusters of cells are surrounded by effectors of the immune system; these therapies may therefore be most suitable as adjuvant therapy rather than for use in advanced disease.

All cytotoxic agents are rigorously tested and applied in advanced disease before being used in adjuvant therapy. New agents that are now entering adjuvant trials will be fully described in the next article in this series.

[ILLUSTRATIONS OMITTED]

Results of three international randomised controlled trials of adjuvant chemotherapy (fluorouracil plus folinic acid v control) for patients with colon cancer. Values are percentage survival and P values

                                   Disease-free   Overall
Trial                                survival     survival

Overview of French, Italian, and     71 v 62      83 v 78
Canadian trials (n = 1493)(*)      (< 0.0001)      (0.03)

Intergroup study                     74 v 58      74 v 63
(n = 309)([dagger])                  (0.004)       (0.02)

NSABP C-03 trial                     73 v 64      84 v 77
(n = 1080)([double dagger])          (0.0004)      (0.003)

NSABP C-03 = national surgical adjuvant breast and bowel project--colon (protocol No 3).

(*) Fluorouracil plus high dose folinic acid v observation alone, 3 year follow up.

([dagger]) Fluorouracil plus low dose folinic acid v observation alone, 5 year follow up.

([double dagger]) Fluorouracil plus high dose folinic acid v methylCCNU, oncovin, or fluorouracil.

Benefits of adjuvant therapy

Site and stage         Chemotherapy           Radiotherapy

Dukes's type C colon   Worth established;     No benefit
cancer                 fluorouracil plus
                       folinic acid optimal
                       to date; six lives
                       per 100 treated
                       saved; new drugs
                       entering trial

Dukes's type B colon   Worth not              No benefit
cancer                 established;
                       particular subgroups
                       of patients may
                       benefit (on basis of
                       histological and
                       other prognostic
                       factors)

Dukes's type B or C    Worth not              Worth established;
rectal cancer          established            preoperative may be
                                              superior to
                                              postoperative in
                                              terms of both
                                              efficacy and
                                              reducing toxicity

Controversies still surrounding adjuvant therapy

* For how long should adjuvant therapy be continued, and what is the optimal dose of fluorouracil plus folinic acid?

* What is the role of adjuvant chemotherapy in lower risk groups?

* Is adjuvant therapy useful in rectal cancer?

* What is the role of new agents (eg irinotecan and oxaliplatin)?

Adjuvant--helpful, assisting, auxiliary (from Latin ad to, and juvare to help)

The uncertain arm of the QUASAR trial is aiming to establish whether chemotherapy is justified in Dukes's type B colon cancer and to define which factors might help to predict chemotherapeutic benefit

The United Kingdom Co-ordinating Committee on Cancer Research's AXIS study, in which 4000 patients have been randomised to portal vein infusion versus surgery alone, will contribute substantially to the debate on this type of therapy