progress cytotoxic therapyfor gastrointestinal carcinoma · contrast with the great majority...

Gut, 1976, 17, 313-322

Progress reportCytotoxic therapy for gastrointestinalcarcinomaThe purpose of this review is to outline what has been achieved in the drugtreatment of alimentary carcinoma in recent years. It is suggested that theresults demonstrate the increasing value of cytotoxic therapy in these diseasesand indicate ways in which the development of such treatment may proceed.Cytotoxic drugs have been used alone and in combination with either surgeryor radiotherapy in the management of gastrointestinal carcinoma.

Cytotoxic drugs alone

At present the use of cytotoxic therapy is almost invariably restricted to theadvanced stages of the disease when surgery and radiotherapy have no moreto offer. Carcinomas of the gut are relatively slow growing tumours withdoubling times of about three months'. In advanced disease the proportionof dividing cancer cells (the growth fraction) declines and avascular andnecrotic areas of tumour appear, harbouring viable cancer cells in the resting(Go) phase of the cell cycle2. Cytotoxic drugs damage only dividing cells andare carried to those cells by the blood stream. So the diminished growthfraction and increasing avascularity in the late stages of solid tumour growthserve to inhibit cytotoxic action. Giving the drugs so late in the course of thedisease is to give them at the least opportune time and the earlier cytotoxictherapy is started the greater the chance of success3. This is true of all solidtumours but patients with gut cancer are at an additional disadvantage in thatthey are the group least likely to tolerate the gastrointestinal side effects sooften associated with cytotoxic therapy.

This is especially true of squamous cell carcinoma of the oesophaguswhere the advanced stage of disease at presentation and the general debility ofthe patient by the time drug treatment is considered have meant that chemo-therapy has been little used in this condition. As a result, it has the reputationof being one of the most cytotoxic-resistant of all cancers3. There have beenhopes that this situation might be changed by bleomycin. This antimitoticantibiotic was originally developed in Japan4 and was subsequently found tobe selectively concentrated in squamous cells and therefore of particular valuein squamous cell carcinoma5. A number of series have reported promisingresults with this drug in oesophageal cancer with response rates as high as60 %6,7 and in 1973 a review of the world experience with bleomycin found anoverall response rate of 33 % in 42 patients8. None of these papers, however,gives full clinical details. Encouraged by these apparent successes, a subse-quent prospective study failed to show any subjective or objective improve-ment in 14 patients with squamous cell carcinoma of the oesophagus treatedwith Bleomycin and concluded that the drug was of no value, when usedalone, in this disease9. Although its value as a single agent is therefore indoubt, one promising feature of bleomycin is that it is not myelotoxic, in

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contrast with the great majority of anticancer drugs, and may therefore be auseful agent in combination chemotherapy.

For many years the chemotherapy of gastrointestinal adenocarcinoma hasbeen dominated by a single drug-the antimetabolite 5-fluorouracil. To tryand exploit this agent to the full, a variety of dosage regimes and techniquesof administration have been employed and in the past there has been con-siderable controversy over their relative merits.

Initially, an intravenous loading dose of 15 mg/kg daily for three to fivedays followed by once or twice weekly maintenance therapy was recom-mended10"11. Subsequent studies showed that a single weekly intravenousinjection, with no loading dose, gave comparable results with less toxicityl2"13.It was then suggested that prolonged intravenous infusion of the drug over 60or 120 hours was superior to rapid intravenous injection. In some centres thisidea still prevails14, although prospective studies have in the past clearlyshown the superiority of rapid intravenous injection15.For patients with hepatic metastases arterial infusion of 5-fluorouracil into

the hepatic artery or aorta was a popular method of treatment in America inthe 1960s. A number of workers reported favourable results using this tech-nique with response rates up to 60 %16-19. A review of this technique hasconsidered, however, that the discomfort to the patient, the morbidity andmortality associated with the procedure, and its expense could not be justifiedby the results obtained20. Indeed, there has never been any convincingevidence that the results were better than those achieved with intravenous5-fluorouracil2l.A variation of this technique was reported in 1970 when promising results

were obtained by combining infusion of 5-fluorouracil into the portal veinwith hepatic artery ligation22. A recent study has reiterated the value ofcombining hepatic artery ligation and cytotoxics, though in this case the5-fluorouracil was given intravenously23. There has, however, been noprospective study to confirm that hepatic artery ligation improves the resultsof 5-fluorouracil therapy.The latest fashion in 5-fluorouracil therapy was initiated in 1971 when a

report suggested the value of oral administration24. A clinical trial at thattime also showed an increased response rate when the drug was given bymouth25.

Subsequent pharmacological studies have shown that the uptake of5-fluorouracil from the gut is highly unreliable26 and a recent prospectivetrial has shown that, although it may be possible to obtain similar remissionrates with oral therapy, the duration of these remissions is significantly shorterthan those seen as a result of intravenous administration27.No method of 5-fluorouracil administration has been proven to be superior

to once weekly intravenous therapy. If the treatment of gastrointestinaladenocarcinoma is to progress, it must be by the use of new drugs or drugcombinations and not by further exploitation of single agent therapy with5-fluorouracil28. The results of 5-fluorouracil therapy are summarized inTable 1.Another drug of value in advanced gut cancer is mitomycin-C. This anti-

mitotic antibiotic was developed in Japan and is still associated, in manypeople's minds, with unacceptable toxicity. This is largely due to the initialstudies on the drug in America which suggested that the response rate wasonly marginally greater than the mortality from treatment29. Subsequent review

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of these results, however, revealed that the dose used in these studies had beengreatly in excess of that recommended by the Japanese30. Once a suitable doseregime was established, mitomycin proved to be a useful drug31. Results ofMitomycin therapy are summarized in Table 2.A recent development in cancer chemotherapy has been the isolation of the

nitrosoureas. These drugs are still under investigation and are not generallyavailable in Britain. Initial reports from America on their use as single agentsin gastrointestinal cancer have been encouraging and these results are sum-

marized in Table 3.Two other cytotoxic drugs have caused considerable interest in recent

years. The first of these is streptozotocin which was initially shown to have adiabetogenic action due to the disruption of beta cells in the islets of Langer-hans32. In 1968 it was successfully used in the treatment of a malignant islet-cell tumour33 and subsequent reports have established its value in thiscondition3436 and also indicated its value in malignant carcinoid tumour34.It was hoped that it might prove of value in adenocarcinoma of the pancreasbut apart from one marginally favourable report37 there has been no evidenceof this.The second agent is doxorubicin. This new drug has been of great value in

adenocarcinoma of the breast and soft tissue sarcoma and is probably themost effective single agent in these conditions38. The results of its use in gutcancer have therefore been awaited with great interest but, unfortunately,have proved relatively unimpressive39. The results are summarized in Table 4

Site Patients (no.) Response (%) Reference

Stomach 448 23 Comis and Carter (1974)72Pancreas 212 28 Carter and Comis (1975)73Large bowel 2107 21 Carter and Friedman (1974)'4

Table 1 Results of 5-fluorouracil therapy in gastrointestinal adenocarcinoma

Site Patients (no.) Response (2%) Reference

Stomach 211 30 Comis and Carter (1974)72Pancreas 44 27 Carter and Comis (1975)7"Large bowel 218 16 Carter and Friedman (1974)7'

Table 2 Results ofmitomycin-C therapy in gastrointestinal adenocarcinoma

Site Drug Patients (no.) Response (%) Reference

Stomach BCNU 33 18 Comis and Carter (1974)72Methyl-CCNU 27 11 Moertel (1975)28

Pancreas BCNU 18 0 Moertel (1975)28Large bowel BCNU 64 12-5 Carter and Friedman (1974)7"

Methyl-CCNU 40 17-5 Moertel (1975)28

Table 3 Results of nitrosourea therapy in gastrointestinal adenocarcinoma

Site Patients (no.) Response (%) Reference

Stomach 8 50Pancreas 3 0 }Frytak (1975)39Large bowel 57 7

Table 4 Results of Doxorubicin in gastrointestinal adenocarcinoma

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and it was concluded that, if nothing else, the drug might prove of value incombination therapy in gastric cancer.Many of the advances in cancer chemotherapy in recent years have been as

a result of the use of intermittent combination drug treatment. While thistechnique has led to dramatic improvements in some diseases, evidence forits value in gastrointestinal cancer has accumulated more slowly. A number ofregimes have been reported as being of value and these are summarized inTable 5.

It is important that these results are seen as a starting point and not a

conclusion. Pessimism over the value ofchemotherapy and the relative successand simplicity of single agent therapy with 5-fluorouracil have tended toinhibit the trial of new agents or combinations of drugs as they have becomeavailable. Indeed, in a recent review of the data available to the NationalCancer Institute, it was found that in carcinoma of the oesophagus only oneof the 30 common cytotoxic drugs had been adequately assessed and incarcinoma of the pancreas only three agents had been studied. The situationwas little better in gastric cancer where only eight drugs had been evaluated40.There is still a great deal to be learnt about cytotoxic therapy for gastro-intestinal cancer.

Chemotherapy and radiotherapy

With the possible exception of oesophageal cancer, the primary treatmentfor gastrointestinal carcinoma is surgery wherever possible and radiotherapyhas been reserved for inoperable, residual, or recurrent growth.Dysphagia is the most distressing symptom for patients with carcinoma of

the oesophagus and this may be exacerbated in the early stages of radiationtreatment as a result of the inflammatory reaction associated with radio-therapy. It has been reported that the injection ofmethotrexate or 5-fluoroura-cil before starting radiotherapy reduces the likelihood of this complication41.The principal interest in combining cytotoxic and radiation therapy, however,has been in their simultaneous use in the hope that the drugs would act as

radiosensitisers making radiation more effective in these relatively radio-resistant cancers.Bleomycin has been shown to potentiate radiation in squamous cell

carcinoma in animals42 and there have been a number of reports suggesting

Site Response (Y%) Reference

Stomach1 5FU + BCNU* 41 Kovachetal(1974)7"2 5FU + mitomycin +

cytosine arabinoside 55 Ota et al (1972)76Pancreas

1 5FU + BCNU* 33 Kovachetal(1974)72 5FU + BCNU 75 Lokich and Skarin (1972)"

Large bowel1 5FU + methyl-CCNU +

vincristine* 43 Moertel etal (l975)"72 5FU + vincristine +BCNU + imidazole carboxamide 43 Falkson etal (1974)7'

3 5FU + vincristine +cyclophosphamide + methotrexate 66 Priestman and Hanham (1972);

Priestman (1973)80.81

Table 5 Drug combinations of value in gastrointestinal adenocarcinoma

*Prospective studies in which combination therapy was superior to single agent therapy with 5FU.

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Cytotoxic therapy for gastrointestinial carcinoma

the possible value of combined radiotherapy and Bleomycin in the treatmentof oesophageal cancer43,44. The clinical details available are too few and thenumbers reported too small to form an opinion on the value of such therapyat present.More information is available with 5-fluorouracil and radiotherapy in

adenocarcinoma. A synergistic effect with radiation and 5-fluorouracil wasnoted in 195845 and its action as a radiosensitiser was subsequently con-firmed45. After promising results from random series47,48, a prospective trialof radiation versus radiation + 5-fluorouracil (given on the first three days oftreatment only) in patients with inoperable adenocarcinoma was reported49.These impressive results are summarized in Table 6. The figures for gastricand pancreatic carcinoma were at once supported by results from SouthAfrica50 and the rectal series has been substantiated by another recent paper51.Despite these results, the use of combined radiotherapy and chemotherapyhas not been extensively pursued and is another area for further investigation.

Chemotherapy and surgery

The use of cytotoxic treatment in addition to surgery, with the object of tryingto prevent recurrent or metastatic cancer, has been termed adjuvant chemo-therapy. The concept is not new and its application has had a great impact onthe survival figures in a number of childhood cancers52 and recent results havesuggested its value in carcinoma of the breast53.Adjuvant chemotherapy has been used in gut cancer, thiotepa54,55

mitomycin-C56, and 5-fluorouracil57 have been used in stomach cancer, andnitrogen mustard58 and 5-fluorouracil (given intravenously59 and intra-luminally60) have been employed in carcinoma of the bowel. The results ofthese studies have been generally disappointing with, at best, only minimalevidence of improved survival.

These studies may, however, have been based on a false premise. For inthese series, cytotoxic therapy was given only at operation or during theimmediate postoperative period. The aim of treatment was to destroy cancercells released into the circulation at operation, which, it was presumed, mightform future metastases. Attitudes to the circulating cancer cell have changedin recent years and it is now felt that its importance in the formation ofmetastases has been overstated61 and there is good evidence that in rectalcarcinoma this is the case62.

In recent years, therefore, the emphasis in adjuvant therapy has changedfrom an attempt to destroy the circulating cancer cell to efforts to eradicateminute foci of residual disease or clinically undetectable micrometastases. Inslow growing tumours such as the gastrointestinal adenocarcinomas suchtreatment must be prolonged for periods of up to two years if it is to succeed.

Site Mean survival time in months

Placebo + XRT SFU + XRT

Stomach 5 8 12-8Pancreas 6-6 10 4Large bowel 16-5 22-6

Table 6 Results of radiotherapy and 5-fluorouracil in advanced gastrointestinal carcinoma(Moertel, 1969)

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Studies have recently been reported employing long-term adjuvant chemo-therapy with cyclophosphamide in stomach cancer63 and 5-fluorouracil incolorectal carcinoma64 65. Unfortunately, the results have again beenequivocal with no definite evidence of improved survival.

These studies have employed only single agent therapy and it is reasonableto suggest that the full potential of adjuvant cytotoxic therapy will not havebeen explored until a trial using intermittent combination therapy is under-taken. It is important, however, that great caution be used in the selection ofpatients for such treatment. In advanced disease all patients will ultimatelydie from their cancer but in early disease a number of patients will survivewhether or not cytotoxic therapy is given. The long-term side effects of anti-cancer drugs are still relatively unknown. The fact that a number of patientsreceiving adjuvant therapy would already have been cured by their primarysurgery, but will still be exposed to the immediate side-effects of cytotoxicagents and survive to experience any long-term complications of treatment,means that such adjuvant therapy should only be given to groups of patientswhere there is known to be a high risk of recurrence or metastases. Probably,the condition most suited to such a trial is rectal carcinoma where previousclinicopathological studies have allowed the definition of such an at riskgroup (those patients with Dukes stage B or C disease or those who havetumour in the lower two-thirds of the rectum)66'67.

Chemotherapy and immunostimulation

The importance of the immune system in cancer therapy is only just beingexplored but there have been results (using Corynebacterium parvum) indi-cating that non-specific immunostimulation may enhance the results ofcytotoxic therapy in advanced cancer68. More recently, it has been shown thatCorynebacteriumparvum used alone may induce remission in advanced cancerincluding carcinoma of the gastrointestinal tract69. The possibility of futurecombined chemotherapy and immunostimulation is a further avenue for thedevelopment of cytotoxic therapy.

Conclusions

It is easy to be pessimistic about the results of cytotoxic therapy in gastro-intestinal carcinoma. All too often this pessimism is based on personalexperience comprising the treatment of a handful of near terminal patientswith single agent 5-fluorouracil therapy. The object of this review is to showthat there have been modest successes in this field in recent years and thatthese achievements justify the further exploration of the use of cytotoxictherapy in gastrointestinal carcinoma. Ways in which this exploration couldproceed may be summarized as follows:

1 Controlled trials to evaluate new drugs, and more particularly drugcombinations, in these carcinomas in order to establish optimum treatmentschedules.

2 Further study ofthe combination ofradiation and cytotoxics in inoperabledisease.

3 Controlled trials to assess the value of non-specific immunostimulationas an adjuvant to cytotoxic therapy.

4 Consideration of the use of combination schedules of proven value in

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Cytotoxic therapy for gastrointestinal carcinoma 319

advanced disease being employed as adjuvant therapy after primary surgeryin those patients considered to be 'at risk' of developing local recurrence ormetastases.Some work on these various aspects is already in progress but, before

embarking on any new studies with cytotoxic drugs, it is important to bear inmind certain factors if this work is to contribute to the understanding ofcytotoxic therapy in gut cancer as well as benefiting individual patients.The search for the optimum drug regime should proceed in logical stages

by a series of prospective clinical trials initially testing single agents to findthose which are of most value in a given condition and subsequently by trialsof different combinations and different dose schedules of those drugs. Such aprocess is time consuming and tedious but is the only way to extract themaximum benefit from the drugs available.The criteria for assessing the response to treatment should be standardized.

In solid tumour chemotherapy the criteria of response to treatment varyconsiderably and, as a result, some series appear to have vastly better resultsthan others using similar regimes70. To try and standardize criteria of responsein given diseases is an important and difficult task. A start has been made inbreast cancer by the recent suggestions put forward by the British BreastGroup7l. In gut cancer, the problem is complicated by the frequent lack ofclinically measurable disease and it would seem that the most importantcriteria in assessing response in this region is to compare survival times insimilar groups of patients on different treatments. After all, prolonged survivalis the ultimate objective of treatment and therefore the best measure of itssuccess.

T. J. PRIESTMANUniversity Hospital of Wales

Cardiff

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