The role of adjuvant radiation therapy in the treatment of colorectal cancer

The hypercatabolic response to trauma, extensive surgery and sepsis is characterized by an increased metabolic rate, severe muscle wasting and a negative nitrogen balance. This process of 'autocannibalism' may be in part a consequence of a disordered growth hormone (GH)/insulin-like growth factor (IGF) axis. In this chapter the normal physiology of the GH/IGF axis is first briefly reviewed. This is followed by a discussion of the changes that accompany fasting and catabolic illness, the effects of IGF-1 administration in health and disease and a comparison of the effects of IGF-1, GH and insulin on catabolism. Although initial investigations of IGF-1 administration in animals and human volunteers have often been encouraging, studies in catabolic patients have so far proved disappointing. Combined treatment with GH, IGF-1 (and insulin) or with IGF-1 and its major binding protein, may prove more effective, especially when used in conjunction with nutritional supplements such as glutamine.     

Adjuvant treatment of colorectal cancer

Surgical operation remains the most effective method of treatment for patients with cancer of the large bowel. However, innovative surgical techniques have not improved survival rates for colorectal cancer in 25 years. Attempts at increasing survival with chemotherapy as an adjunct to surgical procedures remain inconclusive and controversial. Many adjuvant chemotherapy trials have failed to recognize those prognostic factors-such as nodal involvement, serosal penetration, vascular or perineural invasion, and microscopic invasion at margins of resection-that characterize certain patients at high risk for recurrent cancer. Failure to include only high risk patients in adjuvant chemotherapy is, in part, responsible for the lackluster performance to date. For rectal cancer, preoperative irradiation increases the chances of cure with surgical operation by reduction of pathologic staging, but it has not increased survival in patients with persistent nodal involvement. Immunotherapy is a possibly valuable method of treatment; however, it is clinically untested. An adjuvant immunotherapy protocol for high risk patients is described.     

Surgical treatment for the recurrence of colorectal cancer

Analysis by two-dimensional gel electrophoresis of the N-laurylsarkosinate(Sarkosyl)-insoluble envelope complexes of L-[35]S-cysteine-labeled elementary bodies of Chlamydia pneumoniae strain IOL-207, Chlamydia trachomatis serovar LGV2, D, and F, and Chlamydia psittaci strain 6BC showed differences in the molecular charges of chlamydial outer membrane proteins. The apparent isoelectric point (pI) of the major outer membrane protein of C. pneumoniae strain IOL-207 was 6.4, whereas the pI of the major outer membrane protein of the C. trachomatis and C. psittaci strains differed little from one another, ranging from 5.3 to 5.5. The 60-kDa cysteine-rich protein of C. pneumoniae was the only 60-kDa chlamydial protein with a pI value (5.9) more acidic than that of the corresponding major outer membrane protein. As a general rule, the charges of both the 60-kDa and the low-molecular-mass (12-15 kDa) cysteine-rich proteins were widely variable, depending on the strain. However, in each individual strain, the variation of the charge of the 60-kDa protein had a compensatory change in the low-molecular-mass cysteine-rich protein.     

Oral fluoropyrimidines in the treatment of colorectal cancer

5-Fluorouracil (5-FU) has been the mainstay of systemic therapy for colorectal cancer since its initial development 40 years ago. Efforts to improve the therapeutic index of 5-FU have included alteration of schedule and addition of biochemical modulators. An understanding of 5-FU mechanisms of action has resulted in major therapeutic advances in the past 10 years; however, a plateau has been reached in the efficacy of 5-FU, mandating a paradigm shift for those involved in colorectal cancer drug development. One direction vigorously pursued is the development of orally administered fluoropyrimidines that maintain or improve upon the effectiveness of intravenous 5-FU. In this paper the preclinical and clinical development of oral fluoropyrimidines and their modulators is reviewed, including UFT, capecitabine, ethynyluracil and S-1.     

Comparison of 5-fluoro-2'-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancer

Despite more than 30 years of intensive studies on new drugs against advanced colorectal cancer, the fluoropyrimidines remain the drugs of choice for systemic treatment and for hepatic artery infusion (HAI). This overview describes new developments in advanced colorectal cancer chemotherapy, providing a rationale for more effective use of the fluoropyrimidines, with biochemical modulation, scheduling or by revealing biochemical mechanisms of action that correlate with antitumour activity. In human colorectal cancer cell lines and various animal tumour model systems 5-fluoro-2'-deoxyuridine (FdUrd) is more effective than 5-fluorouracil (5-FU). Comparably, FdUrd's modulation by leucovorin (LV) is more potent than 5-FU. In animal studies it is shown that intermittent high-bolus administration of FdUrd generates better antitumour activity, compared with equal toxic doses or any other schedule of 5-FU. These effects are related to prolonged-thymidylate synthase (TS) inhibition and the prevention of TS induction, rather than RNA incorporation. Preclinical studies with modulators such as N-phosphonacetyl-L-aspartate (PALA), WR-2721, mitomycin C and platinum derivatives provide a rationale for clinical use in the future. The first choice systemic chemotherapy of patients with advanced colorectal cancer remains 5-FU combined with LV. Some improvement in therapeutic efficacy has been achieved with locoregional HAI. In randomised studies HAI FdUrd improves the quality of life and survival as compared with optimal systemic therapy. Chronomodulation decreases toxicity, allowing dose intensification, while modulators such as LV or dexamethasone increase survival of patients treated with HAI FdUrd to 86% after 1 year. In conclusion, the clinical use of FdUrd has not been fully explored. Intermittent high-dose FdUrd, chronomodulation together with the use of modulators or drugs focused on prolonged TS inhibition, should be studied in large randomised studies.     

Videolaparoscopic access in the surgical treatment of colorectal cancer: critical analysis]

Clozapine was approved by the U.S. Food and Drug Administration in 1989 for treatment of severely ill schizophrenic patients. It has activity against both the positive and negative symptoms of schizophrenia, which has made it an alternative to traditional antipsychotic medications such as haloperidol. However, clozapine must be used cautiously due to its side effect profile. These side effects include agranulocytosis, seizures, and cardiorespiratory symptoms. We report the case of a patient who developed polyserositis (pericardial effusion, pleural effusion, and pericarditis) after being started on clozapine, and whose symptoms remitted upon discontinuation of clozapine. The literature is reviewed and the treatment implications are discussed.     

Chemotherapy for the treatment of patients with metastatic colorectal cancer: an overview

Approximately 50% of patients with colorectal cancer develop locally recurrent or distant metastatic disease during the course of their illness and eventually die. Since the 1950s the mainstay of treatment for patients in need of palliative therapy has been and continues to be the fluoropyrimidines. When 5-fluorouracil (5-FU) was first introduced into the clinic it was used as a single agent given by rapid intravenous injection. Results with this drug have been disappointing, with response rates consistently low, usually of brief duration, and with little or no impact on survival. During the 1970s and 1980s, multidrug regimens were evaluated with little or no improvement in outcome. More recently, our understanding of the metabolism, pharmacology, and the mechanisms of action as well as the potential mechanisms of resistance to 5-FU has led to its more rational use. This knowledge has resulted in the design of treatment programs with improved therapeutic effects by changing its route of administration, combining it with biochemical modulators and using it in conjunction with other chemotherapeutic agents. These strategies have created new optimism for improved results with less toxicity. More potent inhibitors of thymidylate synthase (TS) such as tomudex and trimetrexate have been developed and are currently being evaluated in the clinic either alone or in combination with 5-FU. Semisynthetic topoisomerase inhibitors such as irinotecan have shown encouraging results as first-line therapy, in combination with 5-FU or as salvage therapy.     

Endoscopic diagnosis and treatment of early colorectal cancer

Colorectal adenomas and early cancers are grossly classified into three groups: protruded, flush or slightly elevated (so-called flat adenomas), and depressed. Protruded lesions and flat adenomas are not invasive until they are rather large, whereas depressed lesions can invade the submucosa even when very small. It is not difficult to detect protruded and flat adenomas, but depressed carcinomas are often overlooked. Keys to the detection of depressed carcinomas are a slight color change, bleeding spots, interruptions of the capillary network pattern, slight deformation of the colonic wall, shape change of the lesion with insufflation and deflation of air, and interruption of the innominate grooves by the lesion. Spraying of indigo carmine dye helps to clarify the lesions. Pit pattern analysis with magnifying colonoscopy is useful for diagnosis of early colorectal cancer. Pit pattern analysis and histologic examination suggest that depressed carcinomas probably have arisen de novo, without going through an adenomatous step. Some adenomas appear at first to have a depression, but such cancer-mimicking adenomas with pseudodepression must be distinguished from depressed carcinomas because they are quite different in nature. Protruded and flat adenomas can usually be removed with polypectomy or hot biopsy techniques. Depressed carcinomas are treated with an endoscopic mucosal resection (EMR) technique; but when they massively invade the submucosa, surgical resection is indicated. Some neoplastic lesions, which we call laterally spreading tumors, extensively and circumferentially spread along the colonic wall, although they are short in height. They tend to have a rather benign nature despite their large size; therefore EMR or a piecemeal EMR method is indicated.     

Improving discharge: the role of the discharge co-ordinator

Discharge of patients from hospital has in the past been handled haphazardly by healthcare professionals. Co-ordination of this important part of a person's experience of hospital would have psychological and emotional benefits for patients, staff and the NHS as a whole. In this article, the author describes the role of the discharge co-ordinator in planning strategically for patient discharge. In a second article, to follow shortly, the author discusses how multidisciplinary liaison can be improved.     

Current data on the role of APC protein in the origin of colorectal cancer

The adenomatous polyposis coli (APC) gene has been found to be mutated during the development of sporadic colorectal cancers as well as in familial adenomatous polyposis (FAP). These conditions result from initially somatic and germ line mutations respectively. In both cases, the expressed protein is truncated at its carboxyterminal region. Investigations into the role of wild-type APC have led to a better understanding of the importance of mutations in the genesis and progression of adenomas. APC was shown to regulate cell growth and cell death, to bind beta-catenin, and to colocalize with microtubules. APC truncation was therefore hypothesized to alter cell multiplication and cells are no longer able to undergo apoptosis. Owing to its beta-catenin binding, APC can modify the pool of beta-catenin which is in part utilized in the assembly of adherens junctions and in nuclear signalling. Truncated APC is unable to regulate this pool thereby altering adhesion and cell signalling. Finally, APC involvement in microtubule-dependent locomotion may explain some changes in cell movement which are observed in adenomas. The establishment of murine mutants and of normal and malignant intestinal cell cultures have allowed to assess biochemical and physiological properties of APC and its putative role in the genesis of colorectal carcinogenesis. Moreover, these experimental models have suggested a variety of possible therapeutic approaches.     

Prevention of gastrointestinal cancer--the potential role of NSAIDs in colorectal cancer

Gastrointestinal cancers are among the leading sites of cancer and leading causes of cancer-related deaths. Gastrointestinal cancers are often at an advanced stage at the time of diagnosis, and are highly resistant to non-surgical therapy. Thus early diagnosis and prevention are approaches that are under active investigation. Screening and surveillance are considered secondary prevention. Primary prevention is the use of dietary or environmental modification or chemopreventive agents. This written review will emphasize the potential role of acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of gastrointestinal cancer, and specifically colorectal cancer. Cell culture and animal studies have shown that NSAIDs possess anti-proliferative and anti-neoplastic effects. Recent epidemiologic surveys also suggest that individuals who regularly take NSAIDs, particularly acetylsalicylic acid, have about a 50% decrease in colorectal cancer incidence and mortality. However, in the only interventional trial of aspirin (and beta-carotene), a retrospective analysis had inadequate statistical power to demonstrate any protective effect against colorectal cancer. About a dozen small prospective intervention studies have been done in a total of about a hundred patients with familial adenomatous polyposis to test the efficacy of NSAIDs, particularly sulindac. All human trials have shown substantial partial and some complete regression of colorectal and perhaps also duodenal adenomatous polyps. But virtually all patients had regrowth of adenomatous polyps after sulindac was stopped. In addition, sulindac and other NSAIDs result in occasional adverse events such as gastrointestinal bleeding. Thus sulindac cannot be recommended for routine use outside of a study setting. One valid current approach to the prevention of gastrointestinal cancer, and colorectal cancer in particular, is the adoption of a healthy lifestyle and appropriate screening and surveillance. Screening and surveillance guidelines have been developed by several public agencies and their recommendations should be adopted. In addition, we should adopt a healthy lifestyle and diet, which consists of low fat ( < 30% to total calories), and high fiber (> 3 daily servings of fruits/vegetables), with the avoidance of red meats ( < 3 weekly servings) and alcohol ( < 2 drinks daily), and the absolute avoidance of tobacco smoking.     

Studies on the role of specific dietary fibres in protection against colorectal cancer

Although dietary fibre is generally thought to protect against the development of colorectal cancer, some of the results of animal and epidemiological studies are equivocal. We believe that this may be because the term dietary fibre covers a range of complex materials and some may protect but others may not. Dietary fibre is mainly composed of plant cell walls which vary in composition and properties according cell type and plant species. In addition to polysaccharides, the walls of some plant cell types contain the hydrophobic polymers lignin or suberin. Two groups of mechanisms have been proposed for the way dietary fibres may protect against colorectal cancer: those in which the dietary fibre may act directly and those in which the dietary fibre may have an indirect effect as a consequence of it being degraded by colonic bacterial enzymes and the products fermented. Direct mechanisms include the adsorption of carcinogens onto undegraded dietary fibres which pass out of the intestinal tract in the faeces. we have shown that different types of plant cell walls adsorbed a range of carcinogens, including heterocyclic aromatic amines, to different extents. Cell walls that contained lignin or suberin adsorbed hydrophobic carcinogens particularly well. Furthermore, the presence of lignin, and probably suberin, in the walls makes them resistant to degradation in the colon. Wheat bran, which is a good source of dietary fibre, contains some cell types with lignified walls. We used Fischer-344 rats to test the ability of wheat bran to protect against the formation of aberrant crypts (which are considered to be precursors to colon cancer) caused by the heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Our results indicate that wheat bran protects and probably does so by a direct mechanism.     

Advanced colorectal carcinoma: redefining the role of oral ftorafur

The therapeutic performance, effect on quality of life and cost effectiveness of an orally administered medication in a home care setting were examined prospectively in a group of 61 patients presenting with advanced colorectal carcinoma. A regimen of daily ftorafur capsules (370 mg/m2) and leucovorin tablets (20 mg/m2) was offered to 35 symptomatic patients with poor performance status; the standard in-hospital i.v. protocol of 5-fluouracil and leucovorin was given to the remaining 26 patients. Follow-up and survival analysis indicated that there was no compromise in survival associated with home care and oral chemotherapy. There were statistically significant advantages in terms of reduced toxicity and improved Karnofsky performance status in this group. Home care was approximately 70% less expensive. A home treatment program based on oral ftorafur may be the most desirable option for all patients with advanced colorectal carcinoma.     

5-Fluorouracil prodrug: role of anabolic and catabolic pathway modulation in therapy of colorectal cancer

Following p.o. administration to rats bearing advanced colorectal carcinoma, Ftorafur (FT) is converted to 5-fluorouracil (FUra) by microsomal P450 in the liver. To optimize the therapeutic selectivity of the FUra generated from FT, three approaches were utilized: (a) inhibition of FUra degradation to dihydrofluorouracil by uracil as an alternative substrate for uracil reductase in the molar ratio of 4 uracil:1 FT (UFT); (b) modulation of drug inhibition of thymidylate synthase by leucovorin (LV); and (c) by increasing the level of FUra incorporation into cellular RNA by N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate transcarbomylase. The maximum tolerated dose (MTD) of FT and UFT, administered 3 times a day for 28 days, was 150 mg/kg/day and 60 mg/kg/day, respectively. The MTDs were not significantly modified by LV (150 or 600 mg/kg/day), administered by the p.o. route with the drugs, or by PALA (100 mg/kg) administered weekly by the i.v. route. The dose-limiting toxicity of FT alone and in combination with the modulators was stomatitis. The severe alopecia observed with FT alone was reduced significantly by uracil. At the MTD, the antitumor activity of UFT was superior to those of FT and FUra alone and in combination with LV and/or PALA. The 3-month sustained complete tumor regression for UFT, FT, and FUra was 38%, 0%, and 13% (for the weekly schedule), respectively. Although uracil, LV, and PALA individually increased the antitumor activity of FT at its MTD, the combination of the three modulators produced the highest therapeutic efficacy in rats bearing advanced colorectal carcinoma, in which 100% of the treated animals achieved complete and sustained tumor regression. The therapeutic efficacy observed with FT modulation could not be achieved with FUra administered by different schedules, each at its MTD alone or in combination with either LV or PALA. In brief, modulation of FT produced greater therapeutic efficacy and selectivity than FUra. Furthermore, the combined use of modulators capable of inhibiting the degradation pathway of FUra and potentiating the effects of the anabolic metabolites action appears to offer the greatest therapeutic potential.     

Treatment of colorectal cancer: hepatic metastasis

Almost one-third of patients dying from colorectal cancer have tumor limited to the liver. Systemic chemotherapy is the appropriate palliative management of patients with metastases to the liver and other sites. For many patients with isolated hepatic metastases, systemic chemotherapy is also the most appropriate treatment. However, results with systemic chemotherapy indicate that one-third or less of patients will respond to such treatments, and long-term survival is rare. In this report we provide information concerning the natural history of colorectal hepatic metastases, followed by the expected benefits with systemic chemotherapy. This information provides background for the regional therapeutic strategies of surgical resection, cryosurgery, and hepatic artery chemotherapy. We discuss the selection factors appropriate for such treatments, morbidity and mortality, and the potential long-term benefits of such approaches. The last section focuses on surgical considerations in hepatic resection and hepatic artery chemotherapy.     

The role of radiotherapy in the palliative treatment of cancer]

Radiotherapy has a well-established role in palliative care of patients with cancer. It is a local treatment of short duration, the number of fractions should be kept to a minimum without loss of efficacy. Radiotherapy can control superior vena caval obstruction, spinal cord compression, brain metastases, painful bone metastases, and tumor-related bleeding.     

Flexible sigmoidoscopy: screening for colorectal cancer

Flexible sigmoidoscopy is an important screening procedure because of its ability to detect early changes in the distal colon. The 60-cm flexible sigmoidoscope provides excellent visualization with minimal discomfort to patients. Successful sigmoidoscopy requires adequate patient preparation, proper equipment and an experienced examiner who can recognize both normal and abnormal findings. Complications arising from sigmoidoscopy are rare, but patients may experience some cramping, gas or watery stools. Screening and primary preventive measures, including regular exercise and increased dietary fiber intake, can lower the morbidity and mortality associated with colorectal cancer.