The association of nutritional assessment criteria with health-related quality of life in patients with advanced colorectal carcinoma.

Health-related quality of life (QoL) is a goal in nutritional oncology but the association between nutritional status and QoL is rarely explored. The aim of the study was to investigate the association of nutritional assessment criteria with QoL in 50 patients with advanced colorectal carcinoma. A second aim was to investigate changes in body weight and QoL during a 3-month follow-up. Muscle mass, nutritional risk, malnutrition and cachexia according to three different criteria were assessed, as well as health-related QoL. At inclusion, 36 patients experienced weight loss, 10 patients sarcopenia, 25 were at nutritional risk, 16 were malnourished and 11, 14 and 31 patients had cachexia according to different criteria. All nutritional assessment criteria discriminated between groups of patients with worse or better QoL to varying degrees. Malnutrition and cachexia defined by the European Palliative Care Research Collaborative and adjusted for recent gain or stabilisation of body weight discriminated on most QoL scores. Weight loss at follow-up was associated with a decrease in several QoL scores. Recognition of weight loss as well as diagnosing malnutrition and cachexia should be the first steps in an interventional pathway to enhance nutritional status and QoL in patients with advanced colorectal carcinoma.

Introducing national guidelines on perioperative chemotherapy for gastric cancer in Norway: a retrospective audit.

BACKGROUND: In 2006, perioperative chemotherapy with epirubicin, cisplatin/oxaliplatin, and capecitabine was recommended in the National Guidelines for patients with resectable gastric cancer in Norway. We conducted a national audit related to clinical aspects, local organisation and the implementation of this multimodal treatment. PATIENTS AND METHODS: All Norwegian departments of oncology were asked to submit aggregated data on gastric cancer patients who had started perioperative chemotherapy for cure; departments of surgery were asked to report on patients undergoing resection after preoperative chemotherapy. Data were retrospectively collected. RESULTS: All 20 departments of oncology and 20 of 21 departments of surgery responded. Of 336 patients operated on for gastric cancer and reported by surgeons, 144 (43%) received preoperative chemotherapy. 169 patients were reported by departments of oncology. 152 (90%) completed the preoperative cycles; 92 (54%) started the postoperative cycles; and 68 (40%) completed all cycles. Toxicity grade >or= 3, overall and haematological, increased during postoperative compared to preoperative cycles, 50 vs. 34% (P = 0.012) and 35 vs. 20% (P = 0.012), respectively. Surgical morbidity and mortality were 26 and <2%, respectively. R0 resection was achieved in 86% of surgically treated patients. Five per cent had a complete pathological response (ypT0) and 48% were node negative (ypN0). Within the first year, the National Guidelines were implemented in 19 of 25 hospitals (76%). CONCLUSIONS: In this population-based series, the tolerability of perioperative chemotherapy reported in the MAGIC trial was reproduced. Toxicity grade >or= 3 was considerable and significantly increased related to postoperative cycles. The National Guidelines were rapidly adopted.

Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer.

BACKGROUND: The purpose of these studies was to compare efficacy and toxicity of docetaxel alone with the combination of gemcitabine and docetaxel for treatment of metastatic esophageal carcinoma. PATIENTS AND METHODS: These studies enrolled patients with histopathologically verified squamous cell carcinoma or adenocarcinoma of the esophagus or cardia. Between March 1997 and June 1999, 52 patients were enrolled in the initial Phase II study (Study 1). They were scheduled for treatment with docetaxel 100 mg/m2 every third week as a 1-h infusion. The second Phase II study between September 2000 and March 2003 included 65 patients (Study II). They were given docetaxel 30 mg/m2, administered as a 30-min i.v. infusion weekly for four times, followed by 2 weeks of rest, and gemcitabine starting with a dose of 750 mg/m2 (if well-tolerated 1,000 mg/m2) on days 1 and 15, followed by 3 weeks of rest. A new cycle began on day 36. Patients were premedicated with betamethasone 8 mg p.o. on the evening before, and 8 mg i.v. 30-60 min before the docetaxel infusion. Response was confirmed by computed tomography and assessed at 12 and 24 weeks. Toxicity was assessed according to WHO scales. RESULTS: In study I, 38 out of the 52 enrolled patients were valuable. Two patients experienced complete remission (CR) (5%), 10 patients partial remission (PR) (26%), nine patients stable disease (SD) (24%), and 17 patients showed progressive disease (PD) (45%). Toxicity mainly involved leukopenia, which in some cases required hospitalization and treatment with antibiotics. In Study II, 46 out of the 65 enrolled patients (70%) were assessable. Out of these, three patients (7%) had CR, eight patients (17%) had PR, 10 patients (22%) had SD, and 25 (54%) PD. Overall response was 24% while an additional 22% showed stable disease. Toxicity mainly consisted of leucopenia and pain. CONCLUSION: Docetaxel as a single agent is active in esophageal cancer, both in treatment naive and in previously treated patients with recurrent disease. The overall response rate was 31%, with a good-safety profile. The addition of gemcitabine is well tolerated, but adds no efficacy. Weekly administration of docetaxel may be less effective. It demonstrates moderate efficacy and the doses used provide an acceptable safety profile.

Combined chemo- and radiotherapy vs. radiotherapy alone in the treatment of primary, nonresectable adenocarcinoma of the rectum.

PURPOSE: In a randomized study in primarily inextirpable rectal cancer, conventional radiotherapy to reduce the tumor mass was compared with combined chemotherapy and radiotherapy. METHODS AND MATERIALS: The combined treatment (CRT) was given every other week, four times, during a 7-week period. The drugs used were methotrexate, 5-fluorouracil in bolus injection followed by continuous infusion and leucovorin rescue. Radiotherapy (RT) was given simultaneously with five 2-Gy fractions in 3 days to a dose of 10 Gy to a total dose in the four courses of 40 Gy. This regimen was compared with radiotherapy in 2-Gy fractions to a total dose of 46 Gy in the radiotherapy group. Surgery was performed 3-4 weeks after finished treatment. Seventy patients were included between November 1988 and August 1996; 36 patients were allocated to RT and 34 to CRT. RESULTS: Twenty-five (74%) of the patients in the CRT group underwent a locally radical resection with 20 (59%) patients without any known metastases. The corresponding figures in the RT group were 23 (64%) and 18 (50%), respectively. Among the patients who underwent any tumor resection, 5/29 (17%) in the CRT group and 12/27 (44%, p = 0.05) in the RT group have had a local recurrence. After a locally radical resection, the corresponding figures are 4% and 35% (p = 0.02), respectively. Local disease-free survival was significantly superior in the CRT group (66% at 5 years) compared with the RT group (38%, p = 0.03 log-rank test). Five-year survival was 29% (9 patients) in the CRT group and 18% (6 patients) in the RT group, a nonsignificant difference (p = 0.3). Five patients in the RT group did not complete planned treatment, mainly due to the appearance of metastatic disease. In this group toxicity was usually of Grade 0-1. In the experimental group, the toxicity usually was Grade 2 or higher, and 6 patients did not manage to fulfill the planned treatment due to toxicity. CONCLUSION: In this study, with fewer included patients than intended, resectability rates were high in both groups. The addition of chemotherapy to radiotherapy significantly improved local control rates, but no statistically significant difference was found in survival between the groups. The acute toxicity after CRT was higher than after RT alone, but manageable.

Preoperative radiotherapy in rectal carcinoma--aspects of acute adverse effects and radiation technique.

PURPOSE: To explain a possible association between treatment technique and postoperative mortality after preoperative radiotherapy of rectal carcinoma, the dose distributions were compared in model experiments. METHODS AND MATERIALS: Preoperative radiotherapy with a three-beam technique delivered in five fractions to 25 Gy (5 Gy/daily for 5 or 7 days) was given to patients with primary resectable rectal carcinoma. The adverse effects of this treatment, both acute and late, have been low. In a parallel trial using an identical fractionation schedule and total dose but with a two-beam technique, the postoperative mortality was higher. Two-, three-, and four-beam techniques were analyzed in 20 patients with computed tomography based, three-dimensional dose planning. Dose distributions and dose-volume histograms in the planning target volume (PTV) and in the organs at risk were considered. A numerical "biological" model was used to compare the techniques. RESULTS: The two-beam and the four-beam box techniques give the most homogeneous dose distributions in the PTV, although all techniques result in dose distributions that would be considered adequate, provided 16 MV or higher photon energies are used. Three- and four-beam techniques show advantages over the two-beam technique with respect to organs at risk, particularly the small bowel. With the two-beam technique and the upper beam limit at mid-L4, the volume of the bowel that receives > 95% of the prescribed dose, and hence, is included in the treated volume (TV), is more than twice as large as that with three- and four-beam techniques, and that of the total body between 1.5 and 2 times as large. The results of the analyses using the biological model indicate that the three- and four-beam techniques result in less small bowel complication rates than the two-beam technique. The integral energy to the total body is similar for all treatment modalities compared. CONCLUSIONS: The volume of bowel included in the TV, rather than the energy imparted to the body, influences postoperative mortality, and emphasizes the importance of precise radiotherapy planning to minimize normal tissue toxicity.

Acute lumbosacral plexopathy during and after preoperative radiotherapy of rectal adenocarcinoma.

The benefit of preoperative radiotherapy of adenocarcinoma of the rectum with respect to a reduced local recurrence rate and an improved survival should be weighed against adverse effects. For 14 years a three-beam, isocentric technique was employed at our hospital to deliver five fractions (5.0 or 5.1 Gy), over 5 or 7 days preoperatively, to patients with rectal cancer which was considered primarily resectable. The adverse effects of the radiotherapy were few, but acute pain and subacute neurological symptoms and signs did occur. An apparent increase in the frequency of these symptoms/signs was noted during 1993. The pain and neurological symptoms are described in case reports and the individual treatments are reviewed. The three-beam technique was analyzed in detail with individual, CT-based, three-dimensional dose-planning and dose distributions in the vicinity of the lumbar nerve plexus are presented. The major result of this analysis showed that technical errors could be excluded, that human errors were unlikely, and that the culprit probably was an unexpected sensitivity to marginal changes in the daily dose and unknown or unexpected radiosensitizing effects of concurrent diseases or medication.

Treatment of local recurrences of rectal carcinoma.

From 1978-1992, 159 patients were treated for local recurrences of rectal carcinoma. They could be subdivided into three groups according to the type of primary treatment given; 82 patients underwent primary surgery without irradiation, 37 patients had preoperative and 40 patients postoperative radiotherapy. The localizations of the recurrences and the curative and palliative potentials of surgery and radiotherapy in the treatment of local recurrences were studied. There was no difference in the localisation of the recurrences in the three groups. Median time between initial surgery and recurrence was also almost the same in the three groups and 75% of the recurrences appeared within 2 years. Twenty percent of the patients in the primary surgery alone group, compared with 49% and 38% in the preoperative and postoperative irradiation groups, respectively, had distant metastases at the time of the diagnosis of local recurrence. The predominant symptom from the local recurrence was pain and, after treatment of the recurrence, pain relief was registered in 63%. In 66%, 16% and 22%, respectively, of the patients in the three groups, the intention of the treatment was curative, with either radiotherapy alone, radiotherapy combined with surgery or surgery alone. The 5-years-survival after recurrence was 6% in the primary surgery alone group and 0% in the other 2 groups. Of the 69 patients treated with a curative intention, 32% were locally symptom-free at death or the last follow-up. Our conclusion is that a local recurrence must be avoided due to the morbidity associated with local failure and the potentially low likelihood of curative treatment of a local recurrence.

Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects.

From 1980 to 1985, 471 patients with resectable rectal and rectosigmoid cancer were randomly allocated to receive either preoperative short-term high-dose irradiation (25.5 Gy in one week) for all patients or prolonged postoperative radiotherapy (60 Gy in seven to eight weeks) only for patients with a Dukes B or C lesion. After a minimum follow-up of five years, the local recurrence rate was statistically significantly lower after preoperative than after postoperative radiotherapy (13 percent vs. 22 percent; P = 0.02). No difference in overall survival was noted (P = 0.5). To evaluate possible late side effects on the bowel, urinary bladder, or skin after surgery and additional preoperative or postoperative radiotherapy, all patients included in the randomized trial, together with 58 patients from a preceding pilot study with the same preoperative regimen, were studied in a prolonged follow-up program. The hospital files of all patients were re-examined. Of the patients who were carefully examined, 176 had a survival exceeding five years and 19 had a survival exceeding 10 years. Overall, 7 percent (33/464) either were operated upon or have had a radiologic diagnosis of small bowel obstruction: 14/255 (5 percent) after preoperative irradiation, 14/127 (11 percent) after postoperative irradiation, and 5/82 (6 percent) after surgery alone. The cumulative risk of developing a bowel obstruction was significantly increased after postoperative radiotherapy. Among the 98 patients alive after preoperative irradiation, significant morbidity from the bowel was noted in 11 patients, from the urinary bladder in two, and from the skin in six. In the postoperatively treated group of 34 patients, the bowel, urinary bladder, and skin morbidity were significant in five, two, and five patients, respectively. Corresponding morbidity in 44 nonirradiated patients was seen in five, one, and two patients, respectively. It is concluded that preoperative, short-term, high-dose radiotherapy decreases the local recurrence rate relative to postoperative radiotherapy, with no indications of increased late morbidity after a follow-up of 5 to 10 years.

Nonresectable adenocarcinoma of the rectum assessed by MR imaging before and after chemotherapy and irradiation.

Thirty-four patients with nonresectable adenocarcinoma of the rectum, defined as tumor fixation at digital examination, were examined with MR. All 34 patients had, according to MR imaging, perirectal tumor growth. In 23 (68%) of the patients, the tumor has reached an adjacent organ. Eight of these patients had disturbances of the MR characteristics in the adjacent organ which proved to be due to overgrowth, i.e., to tumor invasion into these structures. In the remaining 15 patients, without disturbed MR characteristics, 7 had tumor overgrowth at laparotomy. When there was a visible space between the tumor and adjacent organs, there was no sign of tumor overgrowth at laparotomy, except in one case. In 24 patients, examined both before and after combined irradiation and drug therapy, tumor regression was registered after treatment. MR imaging seems to be useful in the assessment of resectability and to evaluate preoperative anticancer treatment in patients with nonresectable rectal carcinoma.

Heterogeneity in antigenic expression and radiosensitivity in human colon carcinoma cell lines.

A panel of human colon carcinoma cell lines were characterized regarding both antigenic heterogeneity and variations in radiosensitivity. Monoclonal antibodies were used to study the expression of carcinoembryonic antigen (CEA), gastrointestinal cancer antigen (GICA or CA 19-9) and carcinoma-associated antigen (CA-50). Radiosensitivity was studied with the clonogenic survival technique. Three cell lines, LS 174T, HCTC, and SW 1116 stained positive for all three antigens. HT-29 was positive for CA 19-9 and CA-50 whereas Caco-2 was positive for CEA and CA 19-9. The cell lines SW 620 and LIM 1215 only stained positive for one of the antigens, CA-50 and CEA, respectively. In nearly all positive cases the stainings were very heterogeneous with mixtures of positive and negative cells. One exception was the HCTC cells which stained homogeneously for the CA 19-9 and CA-50 antigens. The neuroendocrinelike COLO 320 cells were negative in all cases. The radiosensitivity varied strongly between the cell lines with Dq-values between 0.8 and 1.9, extrapolation numbers between 2.0 and 4.7, Do-values between 1.1 and 2.8. The surviving fraction at 2 Gy varied between 0.3 and 0.7 with HCTC as the most radiosensitive and HT-29 as the most radioresistant cell line. Thus, there were differences in antigenic expression and intrinsic radiosensitivity between the cell-lines and antigenic heterogeneities within each cell line. The analyzed panel of cell lines will be valuable in studies of dose-effect relations for monoclonal antibodies labeled with toxic radionuclides simulating both antigenic heterogeneity and variations in radiosensitivity.

Preoperative irradiation with and without chemotherapy (MFL) in the treatment of primarily non-resectable adenocarcinoma of the rectum. Results from two consecutive studies.

Twenty-one consecutive patients with primarily non-resectable adenocarcinoma of the rectum were treated with preoperative split-course radiotherapy (40 Gy) and simultaneous sequential methotrexate + 5-fluorouracil + leucovorin (MFL). An initial infusion of methotrexate (250 mg/m2) was followed in the 2nd hour by 5-FU--first a bolus injection (10 mg/kg) and then continuous infusion (35 mg/kg/24 h) for 72 h. Leucovorin rescue (15 mg every 6 h) was initiated 24 h after the initial injection. Radiotherapy (10 Gy) was given with two 2.0 Gy fractions on days 1 and 2, and one fraction on day 3. The toxicity of the treatment was mostly mild to moderate. Compared with a previous consecutive series comprising 38 patients who received preoperative irradiation (greater than or equal to 40 Gy) only, with a resectability rate of 34%, the 71% resectability rate with this treatment seems to be superior.

Early outcome after emergency and elective surgery for ulcerative colitis.

The early outcome after surgical treatment of ulcerative colitis was retrospectively analyzed in 185 patients. The operation was performed on emergency indications in 25 cases, and was subacute in 53 and elective in 107. The postoperative mortality was 7% overall, 24% in the emergency group, 8% in the subacute group and 2% in the elective group. At least one early postoperative complication occurred in 71 (38%) of the 185 patients (92%, 38% and 26% in the respective groups). Infection was the predominant problem, occurring in 26% of the patients. The mortality was highest after colectomy and ileostomy, but this procedure was used in the most sick patients. Proctocolectomy was associated with the highest morbidity in all groups, whereas colectomy and ileorectal anastomosis carried no mortality and little morbidity.

Ischaemic strictures in patients treated with a low anterior resection and perioperative radiotherapy for rectal carcinoma.

In five (6 per cent) of 78 consecutive patients treated with an anterior resection for rectal carcinoma, a stenosis of the sigmoid colon just above the anastomosis was observed. Four patients had received preoperative radiotherapy over a period of 1 week to a total dose of 25.5 Gy and one patient had received postoperative radiotherapy (60 Gy) over a total of 8 weeks. The length of the stenosis varied from 4 to 120 cm. Two patients subsequently underwent reoperation with an abdominoperineal resection and three patients with a Hartmann procedure. In all patients the inferior mesenteric artery had been ligated close to the aorta. It is proposed that the stenosis may have been due to insufficient circulation in the marginal artery. This insufficiency may have been aggravated by the irradiation, as the retained part of the sigmoid colon was partly included in the irradiation target.

Homogeneous penetration but heterogeneous binding of antibodies to carcinoembryonic antigen in human colon carcinoma HT-29 spheroids.

The monoclonal antibodies 38S1, directed against the carcinoembryonic antigen (CEA), were tested for penetration and binding in human colon carcinoma HT-29 spheroids. Penetration was studied with a method which has not previously been used in immunological investigations. The method, which allows unbound substances to be visualized, is based on freeze drying, vapour fixation, dry sectioning and dry autoradiography. The antibodies penetrated easily and all parts of the HT-29 spheroids seemed to be reached within 15 min. The penetration was even faster than in control glioma U-118MG spheroids that did not express CEA. Binding of the 38S1 antibodies was demonstrated after processing with conventional histology and autoradiography. The binding in the HT-29 spheroids was, after a 1-h incubation period, extremely heterogeneous and occurred mainly in the peripheral parts. More cells were binding the antibodies after 8-h and 32-h incubations and these cells were arranged in peripheral clusters. No binding at all was seen in the CEA-negative glioma spheroids. The distribution of CEA antigens in monolayers and in frozen sections of spheroids of HT-29 cells was analysed with immunohistochemical staining using polyclonal CEA antibodies. The CEA antigens were heterogeneously distributed in both spheroids and monolayers and were as heterogenous as the binding of the monoclonal antibodies in the living spheroids. Thus, the heterogeneous binding in the living spheroids was not due to penetration barriers, but instead to the heterogeneity in the CEA antigen expression.

Expression of the carcinoma-associated antigens CA 19-9 and CA-50 in inflammatory bowel disease.

The expression of gastrointestinal cancer antigen, CA 19-9, and of carcinoma-associated antigen, CA-50, was studied in formalin-fixed and paraffin-embedded tissue from 18 patients with ulcerative colitis, 29 with Crohn's disease in the colon, four with diverticular disease, and eight with sigmoid volvulus. None of the patients with inflammatory bowel disease showed strong dysplasia or had manifest carcinoma. Both antigens were expressed frequently in patients with inflammatory bowel disease. Of the 18 patients with ulcerative colitis, 17 were positive for both CA 19-9 and CA-50, and of the 29 with Crohn's colitis, 21 were positive for CA 19-9 and 22 for CA-50. No distinct differences in antigenic expression were found between Crohn's disease and ulcerative colitis. CA-50 was expressed in normal colonic mucosa from 10 of 12 patients with sigmoid volvulus or diverticular disease, and such mucosa was positive for CA 19-9 in three of the four patients with diverticular disease and in two of the eight patients with sigmoid volvulus. It is concluded that immunodetection of CA-50 or CA 19-9 is of limited value in the differential diagnosis of inflammatory bowel disease. The usefulness of these antigens as markers for precancerous changes in inflammatory bowel disease is also doubtful, since the expression is also frequent in cases of inflammatory lesions, with no obviously increased risk of malignancy.

Visual perception of lifted weight.

The weight of a box can be seen by observing another person lifting and carrying it. Evidence is provided in two experiments, the first of which employed videotaped events with the actor and box visible only as 21 bright patches. Observers judged the weight of the box rather linearly with an average slope of .87 and with a pooled standard deviation of 3.8 kg. The second experiment compared visual and haptic perception of box weight in similar events under conditions of live action. Average slopes of 1.00 in the visual mode and 1.20 in the haptic mode were obtained with standard deviations of 3.1 kg and 2.0 kg, respectively. It is concluded that the weight of the box, as a dynamic variable of the event, is well specified in the kinematic pattern and hence in the optic array. Furthermore, the visual system is efficient in picking up such information.