[Compliance of oral UFT plus leucovorin adjuvant chemotherapy in patients who underwent curative resection for colorectal cancer].

NSABP C-06 study showed that an oralUFT /Leucovorin(LV)regimen proved to be equivalent to an infusional 5-fluorouracil/LV regimen in an adjuvant setting for colorectalcancer. Thus, the oralregimen has been approved as the treatment of choice in Japan, but compliance of the regimen for Japanese patients has scarcely been reported. We assessed the compliance of oralUFT /LV adjuvant chemotherapy(5 cycles, 25weeks)in 99 consecutive colorectal cancer patients undergoing curative resection. Eighty-two percent(81 of 99)received all scheduled doses of UFT plus LV for five cycles. The mean relative dose intensity was 0. 87. Mean treatment courses given were 4. 5. The treatment was discontinued because of toxicity in 18 of the 99 patients. Nine of 18 received UFT only after the toxicities resolved. The remaining nine patients had no chemotherapy. The toxicity was generally mild. Six patients each had grade 3 diarrhea or anorexia, despite inclusion of overlapping cases. Fifteen of the 99 patients(15%)developed grade 3 toxicities. These results suggest that the compliance of oral UFT/LV treatment was equivalent to that of oral UFT adjuvant treatment for various cancers(80-90%).

Health-related quality of life in patients with advanced colorectal cancer: results from a phase II study of S-1 combined with irinotecan (CPT-11).

BACKGROUND: We carried out this study to examine the health-related quality of life (HRQOL) of patients with advanced colorectal cancer treated with the oral fluoropyrimidine S-1 plus irinotecan (CPT-11). METHODS: HRQOL was assessed at baseline (pretreatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires. The HRQOL data for 12 preselected scales and 21 courses of treatment were then analyzed longitudinally. RESULTS: Thirty-seven patients completed the baseline and post-treatment HRQOL assessments. Statistically significant differences between the baseline and post-treatment HRQOL scores were observed for the global QOL, social function, and pain scales (all QLQ-C30), as well as the body image, future perspective, gastrointestinal tract symptoms, weight loss, and chemotherapy side effects scales (all QLQ-CR38); favorable post-treatment results were observed for all the scales except for body image and chemotherapy side effects, for which post-treatment deteriorations were observed. The changes in body image, future perspective, weight loss, and chemotherapy side effects were each greater than ten points and seemed clinically significant. CONCLUSION: Combined treatment with S-1 plus CPT-11 resulted in an acceptable deterioration in HRQOL functioning and symptoms, compared with baseline levels.

Health-related quality of life of colorectal cancer patients receiving oral UFT plus leucovorin compared with those with surgery alone.

BACKGROUND: Adjuvant chemotherapy of oral uracil/ftorafur (UFT) plus leucovorin (LV) has been accepted as the standard of care in the treatment of patients with stage II and III carcinoma of the colon. The objective of the study was to compare HRQOL reported by patients receiving oral UFT plus LV (UFT/LV group) versus no adjuvant treatment (control group) following surgery for colorectal cancer. METHODS: Ninety nine patients in the UFT/LV group and 83 in the control group participated. HRQOL was assessed with the European Organization for Research and Treatment of Cancer QLQ-C30 and HRQOL data measured longitudinally following surgery were compared between the groups. RESULTS: Eighty-eight percent (87 of 99) received all scheduled doses of UFT plus LV during the first three cycles, and 82 percent (81 of 99) did so for five cycles. The most common type of toxicity in the UFT/LV group was fatigue, which was generally mild. Six patients each had grade 3 diarrhea or anorexia. There were significant differences in the scores for role function, and specific limitations such as fatigue, nausea, and vomiting, dyspnoea, appetite loss, and financial difficulties, which deteriorated in the UFT/LV group. CONCLUSIONS: HRQOL in colorectal cancer patients with adjuvant chemotherapy with oral UFT plus LV deteriorated during this phase of treatment compared with those with surgery alone, despite the biased stage of tumor between the groups. Symptom management and social support would improve HRQOL in such a group of patients.

Health-related quality of life in patients with colorectal cancer who receive oral uracil and tegafur plus leucovorin.

OBJECTIVE: Adjuvant chemotherapy with oral uracil/tegafur plus leucovorin has been acknowledged to be a standard treatment for Stage II or III cancer of the colon. The objective of the study was to examine the health-related quality of life during treatment in patients with colorectal cancer who receive oral uracil/tegafur plus leucovorin. METHODS: Health-related quality of life was assessed at baseline (pre-treatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaires. Health-related quality of life data for five courses of treatment were then analyzed longitudinally. RESULTS: Ninety-four patients completed the baseline and post-treatment health-related quality of life assessments. The post-treatment assessments changed significantly from the baseline values and favored post-treatment for all the scales except cognitive function, dyspnea, insomnia, constipation and diarrhea. Role function and social function changed by 10 or more points considered clinically significant. Most of the scales in patients with Grade 0-1 toxicities were better than those with Grade 2-3 toxicities, but Grade 2-3 toxicities were not associated with post-treatment deteriorations in health-related quality of life. The development of Grade 3 toxicities negatively affected on the four scales at the next assessment, compared with Grade 1-2 toxicities. CONCLUSIONS: Overall health-related quality of life did not deteriorate during adjuvant chemotherapy with oral uracil/tegafur plus leucovorin in patients with colorectal cancer, despite the effect from surgical damage, whereas the development of Grade 3 toxicities negatively affected on short-term health-related quality of life. Further comparative studies are needed.

Prospective randomized trial for determination of optimum size of side limb in low anterior resection with side-to-end anastomosis for rectal carcinoma.

PURPOSE: Functional outcome after low anterior resection with side-to-end anastomosis is comparable with that after a colonic J-pouch construction. The optimum size of the side limb has yet to be determined. This prospective randomized trial compared a 3-cm (short) and 6-cm (long) side limb. METHODS: Forty-four patients with a mid or low rectal cancer undergoing low anterior resection were randomly assigned to each group. Physiologic and clinical assessments were performed preoperatively and at 3, 6, and 12 months after ileostomy closure. Defecography was performed at six months after ileostomy closure. RESULTS: Twenty patients in each group completed the study. Among them, one patient with a short limb and two others with a long limb developed leakage. Sphincter function and reservoir function were similar between the groups. Bowel function or incontinence scoring was similar between the groups. The incidence of incomplete evacuation assessed by defecography in the long limb group was significantly greater than in the short limb group (13/20 long and 5/20 short, P = 0.025). One patient in the long limb group experienced fecal impaction. CONCLUSION: The study showed similar clinical results in patients with either a short limb or a long limb but seemed to be underpowered. A long limb may be associated with fecal impaction in patients undergoing low anterior resection with side-to-end anastomosis.

Effect of mosapride on recovery of intestinal motility after hand-assisted laparoscopic colectomy for carcinoma.

PURPOSE: Mosapride citrate (mosapride) is a serotonin 5-hydroxytryptamine 4 receptor agonist known to promote gastric emptying and large-intestine motility. We assessed the effect of mosapride on postoperative ileus following colon surgery. METHODS: Forty patients with colon cancer undergoing hand-assisted laparoscopic colectomy were randomly assigned to a mosapride group or a control group. The mosapride group received 15 mg of mosapride by mouth with 50 ml of water three times a day, starting on postoperative day 1. The control group received 50 ml of water on the same schedule. Patients were allowed to resume oral feeding on the evening of postoperative day 2. Postoperative time to first bowel movement was evaluated by one investigator blinded to treatment. Postoperative gastric emptying was evaluated with the [(13)C]-acetate breath test at 24 and 48 hours after the operation. RESULTS: Postoperative time to first bowel movement was significantly shorter in the mosapride group than in the control group (48.5 vs. 69.3 hours, P = 0.0149). The time to maximal gastric emptying rate as determined by the breath test was significantly shorter in the mosapride group than in the control group at the 48-hour time point (27.9 vs. 35.3 minutes, P = 0.0294). Postoperative hospital stay was shorter in patients receiving mosapride than in controls (6.7 vs. 8.4 days, P = 0.0398). No adverse effects were observed with mosapride. CONCLUSIONS: Gastric emptying was improved by mosapride. The results suggested that the period of postoperative ileus following hand-assisted laparoscopic colectomy can be shortened by treatment with mosapride.

Quality of life after low anterior resection and temporary loop ileostomy.

PURPOSE: Low anterior resection has become the operation of choice for mid rectal or low rectal cancer. A defunctioning stoma is routinely created at some centers to decrease the risk of leakage requiring surgical intervention. This study was designed to evaluate the quality of life in patients undergoing low anterior resection with a temporary ileostomy. METHODS: A prospective longitudinal study was conducted in 22 patients with rectal cancer who underwent low anterior resection with a loop ileostomy. Quality of life was assessed by using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires. Twenty-five patients who underwent high anterior resection for rectosigmoid cancer were studied concurrently to evaluate the impact of major colorectal resection without a stoma. RESULTS: Patients' scores on the quality of life questionnaires generally improved after high anterior resection; however, for patients who underwent low anterior resection, the scores for physical and role functioning before ileostomy closure were worse than the preoperative values. The scores on the quality of life questionnaires generally improved after ileostomy closure. Ileostomy closure required a short hospital stay and was rarely associated with complications. CONCLUSION: Patients who underwent low anterior resection with ileostomy had significant reductions in physical and role functioning, which apparently improved after ileostomy closure. Similar declines in these quality of life variables were not found in patients who underwent high anterior resection. A temporary ileostomy should be created in selected patients with the highest risk of anastomotic leakage. Increased resources for not only surgical care but also for stoma therapy are necessary for patients who undergo low anterior resection with a temporary ileostomy.

Prospective analysis of quality of life in the first year after colorectal cancer surgery.

Little is known of how the quality of life (QOL) of patients with colorectal cancer changes with time following an operation, and whether or not there are predictors of QOL after one year in this population. The European Organization for Research and Treatment of Cancer QLQ-C30 QOL questionnaire was administered to patients before their operation for colorectal cancer, and monthly following the operation for up to one year. Multivariate regression analysis was performed to examine the predictors of QOL one year after the operation. One hundred patients with a mean age of 64 years participated. The scores of five QOL dimensions (physical function, role function, fatigue, pain, and dyspnoea) dropped significantly below the preoperative values at one month following the operation. The scores returned to the preoperative values within three months following the operation. The scores of seven QOL dimensions (global QOL, emotional function, social function, insomnia, appetite loss, diarrhea, and financial difficulties) had improved within three months after the operation. Other scores, including cognitive function, nausea and vomiting, and constipation remained unchanged. Stepwise regression analyses showed that preoperative performance status predicted various QOL scales one year following the operation. The overall QOL of colorectal cancer patients became stabilized about three months after the operation.

[Combination chemotherapy with S-1 plus CPT-11 for patients with advanced or recurrent colorectal cancer].

Various kinds of combination chemotherapies with 5-FU as a base agent have been performed for patients with advanced or recurrent colorectal cancer. S-1 was a newly developed 5-FU derivative and was orally administered. One of the combination therapies with S-1 plus irinotecan (CPT-11) has also been expected to have a better therapeutic value. Recently this combination therapy has been undertaken by our department, and its clinical use and toxicities are described in this article.

Gastric and intestinal phenotypic cell marker expressions in gastric differentiated-type carcinomas: association with E-cadherin expression and chromosomal changes.

Gastric and intestinal phenotypic cell markers are widely expressed in gastric carcinomas, irrespective of their histological type. In the present study, the relations between the phenotypic marker expression of the tumour, histological findings, expression of cell adhesion molecules, and the chromosomal changes in gastric differentiated-type carcinomas were examined. The phenotypic marker expression of the tumour was determined by the combination of the expression of the human gastric mucin (HGM), MUC6, MUC2 and CD10, and was evaluated in comparison with the expression of cell adhesion molecules, such as E-cadherin and beta-catenin, and chromosomal changes by comparative genomic hybridization (CGH) in 34 gastric differentiated-type carcinomas. Tumours were classified into the gastric- (G-), gastric and intestinal mixed- (GI-), intestinal- (I-), or unclassified- (UC-) phenotype according to the immunopositivity of staining for HGM, MUC6, MUC2, and CD10. G-phenotype tumours were significantly associated with a higher incidence of differentiated-type tumours mixed with undifferentiated-type component, compared with GI- and I-phenotype tumours (88.9 vs 33.3%, P=0.0498 and 88.9 vs 42.9%, P=0.0397; respectively). HGM-positive tumours were significantly associated with a higher incidence of tumours with abnormal expression of E-cadherin, compared with HGM-negative tumours (66.7 vs 21.1%, P=0.0135). GI-phenotype tumours were significantly associated with a higher incidence of tumours with abnormal expression of E-cadherin, compared with I-phenotype tumours (77.8 vs 21.4%, P=0.0131). HGM-negative tumours were significantly associated with higher frequencies of the gains of 19q13.2 and 19q13.3, compared with HGM-positive tumours (57.9 vs 20.0%, P=0.0382 and 63.2 vs 13.3%, P=0.0051; respectively). MUC6-positive tumours were significantly associated with higher frequencies of the gains of 20q13.2, compared with MUC6-negative tumours (71.4 vs 30.0%, P=0.0349). MUC2-positive tumours were significantly associated with the gain of 19p13.3, compared with MUC2-negative tumours (41.2 vs 5.9%, P=0.0391). I-phenotype tumours were significantly associated with higher frequencies of gains of 5p15.2 and 13q33-34, compared with G-phenotype tumours (66.7 vs 0%, P=0.0481, each) and also associated with higher frequencies of gain of 7p21, compared with GI-phenotype tumours (66.7 vs 0%, P=0.0481). Our present results show that gastric differentiated-type carcinomas have different characteristics according to the phenotypic marker expression of the tumour in terms of histological findings, E-cadherin expression and pattern of chromosomal changes.

[A case report of poorly-differentiated adenocarcinoma in sigmoid colon cancer with liver and pulmonary metastasis responding to TS-1 and CPT-11].

A 66-year-old woman (156 cm, 58 kg) underwent sigmoid colectomy for cancer. She was found to have simultaneous liver and peritoneal metastases at operation, which had not been detected with CT examination before operation. After operation, CT showed multiple liver metastasis and a high level of CEA and CA19-9 . Pathological findings were type 3, 30 x 20 mm, poorly-differentiated adenocarcinoma, se, ly 2, v 2, n 2 (+), ow (-), aw(-), H 3, P 0 (stage IV). Treatment of the patient consisted of daily oral administration of 80 mg TS-1 for 21 days and 60 mg CPT-11 on 1 day and 15 day as one course. After 2 courses, tumor sizes of liver metastases and the level of tumor markers became reduced. The current case suggested that the administration of TS-1 and CPT-11 may have a potent therapeutic efficacy in advanced colorectal cancer.

Anxiety, depression and quality of life in colorectal cancer patients.

BACKGROUND: Few studies have examined psychological distress and its relationship with quality of life (QL) dimensions in colorectal cancer patients. METHODS: One hundred and twenty-eight outpatients were given psychological tests for anxiety and depression (Hospital Anxiety and Depression Scale; HADS) and QL The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) on the same occasion. The association between the patients' emotional function (EF) scoring on EORTC QLQ-C30 and their HADS scores was analyzed by multiple linear regression. RESULTS: Statistically significant negative relationships were found between EF and HADS-A (anxiety), HADS-D (depression), and HADS-T (total score), respectively, with the highest correlation coefficient being for HADS-A. However, HADS-D was significantly more highly correlated than HADS-A to other QL dimensions, and depression was more highly correlated than anxiety with reduced QL. CONCLUSION: The EF dimension of the EORTC QLQ-C30 predominantly assesses anxiety. Depression has a stronger impact on the global QL of patients than anxiety; therefore, the use of an additional instrument is recommended for the assessment of depression in outpatients with colorectal cancer.

Development of hepatocellular carcinoma following treatment with 6-mercaptopurine for ulcerative colitis: investigation of chromosomal aberration by comparative genomic hybridization.

In a 64-year-old man who had been treated with prednisolone (PSL) and 6-mercaptopurine (6MP) for a long period, for ulcerative colitis (UC), hepatocellular carcinoma (HCC) was detected incidentally. The UC was in remission with these medications. After he had been taking these medications for about 8 years, HCC was detected by computed tomography (CT), done for the evaluation of an other disease. Blood chemistry examination results were normal, except that the protein induced by vitamin K antagonist (PIVKA)-II level was 7940 AU/ml. We performed resection of liver segment V. With comparative genomic hybridization, chromosomal aberrations were recognized; these were gains of 1q, 3ptel-21, 8p12, and 22q11.23-22q13.1. Generally, HCC is associated with hepatitis virus infection in most cases, but in this patient, the HCC was not related to hepatitis C virus (HCV) or HBV. It is presumed that this case was related to the immunosuppressive therapy for UC and was associated with the gains of 1q, 3p, and 8p.

Analysis by comparative genomic hybridization of gastric cancer with peritoneal dissemination and/or positive peritoneal cytology.

Peritoneal metastasis is an important prognostic factor in cases of gastric cancer. Although studies on comparative genomic hybridization (CGH) in gastric cancer have been reported, there are few reports on the peritoneal metastasis (P) and peritoneal cytology (CY) factors in this cancer. In this study, we analyzed the chromosomal changes in the primary tumor with a combination of laser microdissection analysis and CGH in an attempt to detect the unknown abnormal chromosomal regions. We analyzed 34 primary tumors, including 13 primary tumors with peritoneal metastasis (P1) and/or positive peritoneal cytology (CY1) using a combination of laser microdissection and CGH. The minimal overlapping regions in gains were assigned to 5p14 (46.2%), 7q21.3 (61.5%), 7q31 (46.2%), 7q36 (46.2%), 8q23 (53.8%), 15q26 (46.2%), 20q12 (61.5%), 20q13.1 (53.8%), and 20q13.2 (53.8%) in primary tumors with P1 and/or CY1. The minimal regions of losses that occurred most frequently were 4q34-q35 (23.1%) and 22q11.2 (23.1%). There were significant differences in the minimal regions of 5p14 (P=0.033), 7q21.3 (P < 0.0001), 7q31 (P=0.013), 7q36 (P=0.033), and 22q11.2 (P=0.048) between primary tumors with and without P1 and/or CY1. In this study, gain/amplification of 5p14, 7q21.3, 7q31, and 7q36, and loss of 22q11.2 were significant in gastric cancer cases with peritoneal dissemination and/or positive peritoneal cytology.

Fractional genomic alteration detected by array-based comparative genomic hybridization independently predicts survival after hepatic resection for metastatic colorectal cancer.

PURPOSE: Although liver resection is the primary curative therapy for patients with colorectal hepatic metastases, most patients have a recurrence. Identification of molecular markers that predict patients at highest risk for recurrence may help to target further therapy. EXPERIMENTAL DESIGN: Array-based comparative genomic hybridization was used to investigate the association of DNA copy number alterations with outcome in patients with colorectal liver metastasis resected with curative intent. DNA from 50 liver metastases was labeled and hybridized onto an array consisting of 2,463 bacterial artificial chromosome clones covering the entire genome. The total fraction of genome altered (FGA) in the metastases and the patient's clinical risk score (CRS) were calculated to identify independent prognostic factors for survival. RESULTS: An average of 30 +/- 14% of the genome was altered in the liver metastases (14% gained and 16% lost). As expected, a lower CRS was an independent predictor of overall survival (P = 0.03). In addition, a high FGA also was an independent predictor of survival (P = 0.01). The median survival time in patients with a low CRS (score 0-2) and a high (> or =20%) FGA was 38 months compared with 18 months in patients with a low CRS and a low FGA. Supervised analyses, using Prediction Analysis of Microarrays and Significance Analysis of Microarrays, identified a set of clones, predominantly located on chromosomes 7 and 20, which best predicted survival. CONCLUSIONS: Both FGA and CRS are independent predictors of survival in patients with resected hepatic colorectal cancer metastases. The greater the FGA, the more likely the patient is to survive.

Array-based comparative genomic hybridization from formalin-fixed, paraffin-embedded breast tumors.

Identification of prognostic and predictive genomic markers requires long-term clinical follow-up of patients. Extraction of high-quality DNA from archived formalin-fixed, paraffin-embedded material is essential for such studies. Of particular importance is a robust reproducible method of whole genome amplification for small tissue samples. This is especially true for high-resolution analytical approaches because different genomic regions and sequences may amplify differentially. We have tested a number of protocols for DNA amplification for array-based comparative genomic hybridization (CGH), in which relative copy number of the entire genome is measured at 1 to 2 mb resolution. Both random-primed amplification and degenerate oligonucleotide-primed amplification approaches were tested using varying amounts of fresh and paraffin-extracted normal and breast tumor input DNAs. We found that random-primed amplification was clearly superior to degenerate oligonucleotide-primed amplification for array-based CGH. The best quality and reproducibility strongly depended on accurate determination of the amount of input DNA using a quantitative polymerase chain reaction-based method. Reproducible and high-quality results were attained using 50 ng of input DNA, and some samples yielded quality results with as little as 5 ng input DNA. We conclude that random-primed amplification of DNA isolated from paraffin sections is a robust and reproducible approach for array-based CGH analysis of archival tumor samples.

High-resolution analysis of DNA copy number alterations in colorectal cancer by array-based comparative genomic hybridization.

Array-based comparative genomic hybridization (CGH) allows for the simultaneous examination of thousands of genomic loci at 1-2 Mb resolution. Copy number alterations detected by array-based CGH can aid in the identification and localization of cancer causing genes. Here we report the results of array-based CGH in a set of 125 primary colorectal tumors hybridized onto an array consisting of 2463 bacterial artificial chromosome clones. On average, 17.3% of the entire genome was altered in our samples (8.5 +/- 6.7% gained and 8.8 +/- 7.3% lost). Losses involving 8p, 17p, 18p or 18q occurred in 37, 46, 49 and 60% of cases, respectively. Gains involving 8q or 20q were observed 42 and 65% of the time, respectively. A transition from loss to gain occurred on chromosome 8 between 41 and 48 Mb, with 25% of cases demonstrating a gain of 8p11 (45-53 Mb). Chromosome 8 also contained four distinct loci demonstrating high-level amplifications, centering at 44.9, 60, 92.7 and 144.7 Mb. On 20q multiple high-level amplifications were observed, centering at 32.3, 37.8, 45.4, 54.7, 59.4 and 65 Mb. Few differences in DNA copy number alterations were associated with tumor stage, location, age and sex of the patient. Microsatellite stable and unstable (MSI-H) tumors differed significantly with respect to the frequency of alterations (20 versus 5%, respectively, P < 0.01). Interestingly, MSI-H tumors were also observed to have DNA copy number alterations, most commonly involving 8q. This high-resolution analysis of DNA copy number alterations in colorectal cancer by array-based CGH allowed for the identification of many small, previously uncharacterized, genomic regions, such as on chromosomes 8 and 20. Array-based CGH was also able to identify DNA copy number changes in MSI-H tumors.