Management of hemorrhoidal disease: new generation of oral and topical treatments.

Hemorrhoidal disease is a widespread proctologic clinical entity. Even if surgical excision is an effective treatment, it only represents the standard procedure for patients with high-grade hemorrhoids. Considering that most cases are grade I or II hemorrhoids, oral or topical therapies are widely used despite, currently, there are no satisfactory options for these kinds of treatments. The pathology involves the degeneration of the supporting tissue of the anal cushions, causing venous dilation, blood stagnation, formation of edematous venous plexus covered by mucosa and inflammation. An effective treatment must, therefore, be multi-targeted and capable of acting on all the pathological mechanisms simultaneously. During the 8th National Congress of the Italian Association of Colorectal Surgery (SICCR), some clinical evidence of hemorrhoidal disease has been discussed along with new opportunities in oral and topical treatment options. Among these, the effectiveness and the safety of two innovative products, a sublingual nanoemulsion and a liquid bandage, has been reported.

Evaluation and management of hemorrhoids: Italian society of colorectal surgery (SICCR) consensus statement.

Hemorrhoids are one of the most common medical and surgical diseases and the main reason for a visit to a coloproctologist. This consensus statement was drawn up by the Italian society of colorectal surgery in order to provide practice parameters for an accurate assessment of the disease and consequent appropriate treatment. The authors made a careful search in the main databases (MEDLINE, PubMed, Embase and Cochrane), and all results were classified on the basis of the grade of recommendation (A-C) of the American College of Chest Physicians.

Long-term results following sacral nerve stimulation for chronic constipation.

AIM: The long-term outcome of sacral nerve stimulation (SNS) for chronic functional constipation was assessed. METHOD: Patients who received a definitive SNS implant for chronic functional constipation only (according to the Rome III criteria) and were followed up for at least 3 years were included in this study. Slow transit constipation (STC) was distinguished from obstructed defaecation (OD) and mixed/undetermined constipation (MU). Constipation features, Cleveland Clinic Constipation score (CCCS) and SF-36 questionnaire data were collected; physiological tests were performed. RESULTS: Forty-two out of 61 patients suitable for SNS received a definitive implant (14 for STC, 15 for OD, 13 for MU). Following SNS device implantation (mean follow-up 51 ± 15 months), the baseline CCCS (17 ± 6) dropped to 9 ± 6 (P < 0.001) and 47% of patients had an improvement in the CCCS of more than 50%. Such improvement was more significant in patients with OD. Anal pressures did not change, while threshold and urgency rectal sensation significantly decreased, in particular in patients with OD. All aspects of patients' health status (SF-36) improved significantly following SNS; this was more marked in patients with OD. CONCLUSION: Data from this study suggest that the clinical efficacy of SNS can be prolonged in constipated patients, but in both the preliminary diagnostic assessment and pathophysiological interpretation every effort should be made to select patients for SNS. Although SNS showed efficacy in a low percentage of patients with STC, patients with OD were more responsive.

Sacral neuromodulation for bowel dysfunction: a consensus statement from the Italian group.

BACKGROUND: Representatives from the Italian centers experienced in sacral neuromodulation (SNM) for the treatment of bowel dysfunction met in order to define the current clinical practice in Italy and to produce a consensus statement regarding indications for this therapy and patient management. METHODS: Fifty Italian colonproctologists were asked to complete a questionnaire concerning their clinical practice in SNM (290 questions, grouped within 4 broad areas). Physicians expressed their opinion by completing the questionnaire, assigning to each statement their level of agreement according to the 5-point Likert scale; the data were analyzed by attributing to each expert's answers a weight proportional to the degree of experience. During a meeting held 2 months later, the critical aspects of the therapy were re-examined and discussions held with the goal of reaching an agreement on controversial topics. The available literature was reviewed. RESULTS: Patient selection criteria, etiology, diagnostic investigations, test procedures and implantation, follow-up and evaluation of results have been reviewed. The aim was to achieve an algorithm for patient management, showing the place of SNM in the treatment of bowel dysfunction. The approach in case of treatment failure was also discussed. CONCLUSIONS: Analysis of the data collected reveals substantial consensus at the national level concerning all the main points with regard to the therapy. The recommendations expressed in this article can be considered as national guidelines and taken into account by the principal international implantation centers.

Effects of a new mixture of essential amino acids (Aminotrofic(®)) in malnourished haemodialysis patients.

The aim of this study was to verify the clinical efficacy of a diet associated with already commercially available oral amino acid functional cluster (AFC) compared to the administration of a diet associated with a nitrogen protein-based supplement (casein) in antagonizing malnutrition in patients with Chronic renal failure (CRF) undergoing haemodialysis. The secondary aim was to assess the changes in protein levels during the acute phase such as the expression of inflammatory cytokines. Twenty patients in haemodialysis aged between 18 and 85 of both genders (13 m, 7f) were recruited, randomized and divided into two groups and treated for 4 months respectively with: (1) oral AFC supplement (*)8 g/die: group A, and (2) oral supplementation of a protein nitrogenous mixture compared to AFC with a casein protein source) of 6.6 g: group P. During the initial assessment and thereafter on a monthly basis all patients underwent the following: Dietary recall 24 h; Anthropometric: Weight, height, BMI, expected dry weight, actual weight; Biochemical: Albumin, transferrin, Na, K, Cl, Ca, P, Mg, long-interval creatinine (Aminotrofic(®): Errekappa Euroterapici, Milano) pre-albumin, α1 acid glycoprotein, C reactive protein (CRP), protein nitrogen appearance (PNA); Instrumental: Handgrip strength evaluation, Calorimetry by means of Armband, Bio-impedance analysis (BIA), Spitzer Index (quality of life), Subjective Global Assessment Generated by the patient (PG SGA). Considering the nutritional parameters, no significant differences concerning dry weight emerged between the beginning (T0) and the end (T4) (weight A to T0: kg 64.41 ± 6.34; weight A to T4: kg 64.51 ± 7.05: P = NS; weight P to T0: kg 60.17 ± 11.94; weight P to T4: kg 59.86 ± 11.43: P = NS); biochemical parameters, significant differences were observed only for two parameters: pre-albumin (Pre-albumin A to T0 30.12 ± 7.23; Pre-albumin A to T4: 28.91 ± 5.8; Pre-albumin P to T0 22.51 ± 6.04; Pre-albumin P to T4: 26.10 ± 9.82), and Transferrin (Transferrin A to T0 171.77 ± 28.87 mg/dL, Transferrin A to T4: 181.44 ± 38.83 mg/dL: P < 0.005; Transferrin P to T0 160.29 ± 27.46 mg/dL, Transferrin P to T4: 146.57 ± 24.96 mg/dL: P < 0.005), but not in other parameters. From a nutritional perspective, after 4 months of treatment an increase in protein synthesis was noted in group A compared to group P which was proved by the significant increase of transferrin. This pilot study suggests the AFC oral supplementation may represent a valid alternative to intradialytic parenteral treatment and may also allow for an improvement in blood chemical values and nutritional status.

Sacral nerve stimulation in faecal incontinence associated with an anal sphincter lesion: a systematic review.

AIM: The long-term results of sphincteroplasty for faecal incontinence due to an anal sphincter lesion have been disappointing. Initially sacral nerve stimulation was used only in faecal incontinence of neurogenic origin but subsequently the indications have been extended to other conditions. The aim of this review was to evaluate sacral nerve stimulation for incontinence in the presence of a sphincter defect. METHOD: The MEDLINE, Embase and Cochrane Library databases for the period between 1995 and 2011 were searched for studies in English, with no limitations concerning the study size or the length of follow-up. The major endpoints were clinical efficacy, changes in anorectal manometry and quality of life. RESULTS: Ten reports (119 patients) satisfied the inclusion criteria. The quality of the studies was low (nine were retrospective, one was prospective). All reported a lesion of the external anal and/or internal anal sphincter on endoanal ultrasound. A definitive implant was performed on 106 (89%) of the 119 patients who underwent a peripheral nerve evaluation test. The weighted average number of incontinent episodes per week decreased from 12.1 to 2.3, the weighted average Cleveland Clinic Score decreased from 16.5 to 3.8, and the ability to defer defaecation, when evaluated, increased significantly. The features at anorectal manometry did not change. The quality of life improved significantly in almost all studies. CONCLUSION: Sacral nerve stimulation could be a therapeutic option for faecal incontinence in patients with an anal sphincter lesion. However, the quality of the published studies is low. A randomized clinical trial comparing sacral nerve stimulation with other classical surgical procedures at long-term follow-up, although beset with difficulties, should be conducted.

Novel bulking agent for faecal incontinence.

BACKGROUND: Various injectable bulking agents have been used for the treatment of faecal incontinence (FI). However, encouraging early results are not maintained over time. This study aimed to assess short- and medium-term results of a new bulking agent for the treatment of FI. METHODS: The Gatekeeper(™) prosthesis comprises a thin solid polyacrylonitrile cylinder that becomes thicker, shorter and softer within 24 h after implantation. Fourteen patients with FI underwent treatment with Gatekeeper(™) under local anaesthesia. Four prostheses were implanted in the intersphincteric space in each patient, under endoanal ultrasound guidance. Number of episodes of major FI, Cleveland Clinic FI score (CCFIS), Vaizey score, anorectal manometry, endoanal ultrasonography (EUS), health status and quality of life (Short Form 36 and Faecal Incontinence Quality of Life questionnaires) were assessed before and after treatment. RESULTS: Mean(s.d.) follow-up was 33·5(12·4) months. There were no complications. There was a significant decrease in major FI episodes from 7·1(7·4) per week at baseline to 1·4(4·0), 1·0(3·2) and 0·4(0·6) per week respectively at 1-month, 3-month and last follow-up (P = 0·002). CCFIS improved significantly from 12·7(3·3) to 4·1(3·0), 3·9(2·6) and 5·1(3·0) respectively (P < 0·001), and Vaizey score from 15·4(3·3) to 7·1(3·9), 4·7(3·0) and 6·9(5·0) respectively (P = 0·010). Soiling and ability to postpone defaecation improved significantly, and patients reported significant improvement in health status and quality of life. At follow-up, manometric parameters had not changed and EUS did not demonstrate any prosthesis dislocation. CONCLUSION: The Gatekeeper(™) anal implant seemed safe, reliable and effective. Initial clinical improvement was maintained over time, and follow-up data were encouraging.

Sacral neuromodulation for the treatment of fecal incontinence: analysis of cost-effectiveness.

PURPOSE: The cost-effectiveness and budget impact of introducing sacral nerve modulation (SNM) as a treatment for fecal incontinence in Italy were evaluated in a simulation model. METHODS: A decision-analysis model with a Markov submodel was used to represent clinical pathways for treatment of patients with fecal incontinence in a scenario with SNM and a scenario without SNM. Data were obtained from published studies and from an expert panel. Evaluation of resource consumption was conducted from the perspective of the Italian National Health Service, and costs were retrieved from the Italian NHS procedures reimbursement list. The time horizon was 5 years, and a 3% discount rate was applied to costs and outcomes. Effectiveness was measured in symptom-free years and in quality-adjusted life-years (QALYs). Fecal incontinence prevalence data and SNM usage forecasts were used to estimate budget impact over the next 5 years. RESULTS: The incremental cost-effectiveness ratio for introducing SNM was €28,285 per QALY gained for patients with a structurally deficient anal sphincter and €38,662 per QALY gained for patients with intact anal sphincters. If a threshold of €40,000 per QALY gained is set as the level that a decision-maker would regard as cost-effective, the probability that the introduction of SNM will be cost-effective would be 99% for patients with a structurally deficient sphincter and 53% for patients with an intact sphincter. Budget impact analysis showed that introducing SNM would have an estimated budget impact of 0.56% over 5 years on the budget allocated for fecal incontinence treatment. CONCLUSION: Our data show SNM to be an efficient investment with an acceptable incremental cost-effectiveness ratio and a limited impact on the total allocated budget for fecal incontinence.

Sacral neuromodulation in the treatment of defecation disorders.

A large number of patients present with fecal incontinence due to idiopathic pelvic neuropathy or lesions of pelvic nerves, iatrogenic or secondary to other pelvic diseases or dysfunctions, involving sacral nerves. On the other hand, in many patients, constipation could be related to a peripheral neuropathy impairing normal defecation. Sacral neuromodulation (SNM) has been demonstrated as an effective approach in neuropathic defecation disorders. Its application is usually safe and easy, with a limited rate of complications or adverse events. The surgical procedure is made under local anesthesia. SNM effectiveness can be reliably tested during a short term period (up to 30 days) before the decision for a permanent implant. Results in most series show significant clinical improvement, with reduction in the number of incontinence episodes, decrease of incontinence score and improvement in patients' quality of life. A few reports suggest a potential and interesting application of SNM in constipation. Findings from anorectal manometry and other physiology examinations are not conclusive in order to define SNM mechanisms of actions and suggest that a multifactorial effect "modulates" the deficient neuromuscular system causing the defecation disorders.

Mesorectal microfoci adversely affect the prognosis of patients with rectal cancer.

PURPOSE: Mesorectal involvement is a common feature in rectal tumors. Neoplastic foci can be identified at pathologic examination of the mesorectum, but their incidence and prognostic significance remain to be defined. METHODS: A series of 77 patients with extraperitoneal rectal cancer, resected with total mesorectal excision, entered the study. After fixation, the excised specimens were submitted to serial transverse sections and staining. Direct tumor infiltration, lymph node involvement, and neoplastic microfoci in the mesorectum were investigated. Patients with mesorectal foci were compared with those without deposits with regard to clinical and pathologic parameters; different patterns of foci (endovasal, endolymphatic, perineural, isolated) were also considered. Univariate and multivariate analyses were used to evaluate the impact on survival rate. RESULTS: Neoplastic mesorectal involvement was found in 64 patients (83.1 percent). Direct tumor infiltration was detected in 66.2 percent, node involvement in 28.6 percent, microscopic foci in 44.2 percent of cases (endovasal in 11.7 percent, endolymphatic in 15.7 percent, perineural in 26 percent, isolated in 14.3 percent). In 7 cases (10.9 percent) microfoci alone (without any kind of other mesorectal involvement) were detected. Deposits were found in 18.8 percent of TNM Stage I tumors, in 46.9 percent of Stage II and in 59.3 percent of Stage III cancers. Similar incidence was found in patients treated with integrated therapies and surgery alone (43.3 vs. 44.7 percent, P = not significant). Poorer median (44.5 vs. 57 months, P = 0.04) five-year overall survival rate (43.4 vs. 63.3 percent, P = 0.016) and disease-free survival rate (43.3 vs. 57.7 percent, P = 0.048) were observed in patients with microscopic foci compared with those without deposits. Tumor configuration was found to be a independent prognostic factor for both overall and disease-free survival rates; furthermore, endolymphatic, perineural, and isolated foci significantly affected overall survival rate, while TNM staging affected disease-free survival rate. CONCLUSIONS: The incidence of neoplastic foci in the mesorectum is high, even in early staged tumors and despite aggressive preoperative treatment. They seem to affect prognosis. Such features should, therefore, be considered when local excision of the tumor is planned. Presence of mesorectal foci should modify conventional staging of the rectal tumor.

Buttock placement of the implantable pulse generator: a new implantation technique for sacral neuromodulation--a multicenter study.

OBJECTIVE: In the standard operation procedure for sacral neuromodulation, the implantable pulse generator (IPG) is implanted in a subcutaneous pocket at the lower part of the anterior abdominal wall. This procedure requires a long operation time and three incisions. With the IPG in the abdominal wall, some patients complain of displacement or pain at the IPG site postoperatively. By modifying the technique of placement of the IPG, these disadvantages are overcome. METHODS: Between August 1999 and July 2000, 39 patients underwent a buttock implant of the IPG. In 2 of these patients the position of the IPG was changed from abdominal region to the buttock. During follow-up, complications concerning the operation and location of the IPG were compared to the published literature. RESULTS: Operation time is reduced in all patients by approximately 1 h. No repositioning of the patient is required during surgery. Only a short subcutaneous tunnel is required to connect the lead to the IPG. Pain at the level of the IPG was noted in 10% of the patients, which needed no further treatment. No infections were seen and the IPG did not displace postoperatively. CONCLUSION: Buttock placement of the IPG in sacral nerve stimulation leads to shorter operation time; only two incisions are needed instead of three and a shorter subcutaneous tunnel is needed. Using this technique there are less complications and a lower re-operation rate.

Short-term sacral nerve stimulation for functional anorectal and urinary disturbances: results in 40 patients: evaluation of a new option for anorectal functional disorders.

PURPOSE: There are several options in the treatment of fecal incontinence; it is often difficult to choose the most appropriate, adequate treatment. The consolidated experience gained in the urologic field suggests that sacral nerve stimulation may be a further option in the choice of treatment. The aim of our study was to evaluate the preliminary results of the peripheral nerve evaluation test obtained in a multicenter collaborative study on patients with defecatory and urinary disturbances. METHODS: Forty patients (9 males; mean age, 50.2; range, 26-79 years) underwent the peripheral nerve evaluation test, 28 (70 percent) for fecal incontinence and 12 (30 percent) for chronic constipation. Fourteen (35 percent) patients also had urinary incontinence; six had urge incontinence, two had stress incontinence, and six had retention incontinence. Associated diseases were scleroderma (2 patients), spinal injuries (4 patients), and syringomyelia (1 patient). All the patients underwent preliminary investigations with anorectal manometry, pudendal nerve terminal motor latency testing, anal ultrasound, defecography, and if required, urodynamic tests. The electrode for sacral nerve stimulation was positioned percutaneously under local anesthesia in the S2 (4), S3 (34), or S4 (1) foramen unilaterally (1 patient not accounted for because of no response to acute test), based on the best motor and subjective responses of paresthesia of the pelvic floor. Stimulation parameters were average amplitude, 2.8 (range, 1-6) V and average frequency, 15 to 25 Hz. RESULTS: The mean duration of the tests was 9.9 (range, 7-30) days; tests lasting fewer than seven days were not evaluated. There were four early displacements of the electrode. In 22 of the 25 evaluable patients with fecal incontinence, there was an improvement of symptoms (88 percent), and 11 (44 percent) were completely continent to liquid or solid stools, whereas in 7 symptoms were unchanged. Mean number of episodes of liquid or solid stool incontinence per week was 8.1 (range, 4-18) in the prestimulation period and 1.7 (range, 0-12) during the peripheral nerve evaluation test. (P = 0.001; Wilcoxon's signed-rank test). The most important manometric findings were: increase of maximum rest pressure (39.4 +/- 7.3 vs. 54.3 +/- 8.5 mmHg; P = 0.014, Wilcoxon's test) and maximum squeeze pressure (84.7 +/- 8.8 vs. 99.5 +/- 1.1 mmHg; P = 0.047), reduction of initial threshold (63.6 +/- 5.2 vs. 42.4 +/- 4.7 ml; P = 0.041) and urge sensation (123.8 +/- 0.6 vs. 78.3 +/- 8.9 ml; P = 0.05). An improvement was also found in patients with constipation, with reduction in difficulty emptying the rectum, with prestimulation at 7 (range, 2-21) episodes per week and end of peripheral nerve evaluation test at 2.1 (range, 0-6) episodes per week, P < 0.01) and in the number of unsuccessful visits to the toilet, which dropped from 29.2 (7-24) to 6.7 (0-28) per week (P = 0.01). The most important manometric findings in constipated patients were an increase in amplitude of maximum squeeze pressure during sacral nerve stimulation (prestimulation, 63 +/- 0 mm Hg; end of peripheral nerve evaluation test, 78 +/- 1 mm Hg; P = 0.009) and a reduction in rectal volume for urge threshold (prestimulation, 189 +/- 52 ml; end of peripheral nerve evaluation test, 139 +/- 45 ml; P = 0.004). CONCLUSIONS: In functional bowel disorders short-term sacral nerve stimulation seems to be a useful diagnostic tool to assess patients for a minor invasive therapy alternative to conventional surgical procedure.

Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.

BACKGROUND: Rectal carcinoma patients with local recurrence are reported to have a dismal prognosis. The purpose of this study was to evaluate the effect of combined modality therapy on clinical outcome and to determine the prognostic impact of a "presurgical" staging system. METHODS: Between September 1989 and June 1997, 47 patients (with a median follow-up of 80 months) with locally recurrent, nonmetastatic rectal carcinoma were classified according to the extent of pelvic sidewall involvement as determined by pretreatment computed tomography (CT) scan. They received preoperative external beam radiation (45-47 grays [Gy] in 34 patients; 23.4 Gy in 13 preirradiated patients) plus concomitant 5-fluorouracil (1000 mg/m(2)/day as a 96-hour continuous infusion on Days 1-4 + 29-32) and mitomycin C (10 mg/m(2) as a bolus intravenously on Day 1 + 29). After 4-6 weeks, the patients were evaluated for surgical resection and intraoperative radiation therapy (IORT) procedure (10-15 Gy) or, in unresectable patients, a boost dose was planned by chemoradiation (23.4 Gy) or brachytherapy. Thereafter, adjuvant chemotherapy (5-fluorouracil and leucovorin for a total of six to nine courses) was prescribed. RESULTS: During chemoradiation, 2 patients (4.3%) developed Radiation Therapy Oncology Group Grade 3-4 acute toxicity. Twenty-five patients (53. 2%) had an objective response after chemoradiation. Twenty-one patients (45%) underwent radical surgical resection. The overall 5-year survival and local control rates were 22% and 32%, respectively. The classification system significantly predicted survival (P = 0.008). Radically resected patients had better local control and survival (P < 0.0001); in patients treated with IORT, the 5-year local control and survival rates were 79% and 41%, respectively. CONCLUSIONS: The data from the current study suggest that combined modality therapy was well tolerated and improved resectability, local control, and survival. The classification system appears to be a reliable tool with which to predict clinical outcome in patients with locally recurrent rectal carcinoma.

Structured versus long-chain triglycerides: a safety, tolerance, and efficacy randomized study in colorectal surgical patients.

BACKGROUND: After trauma or surgery, researchers have suggested that medium-chain triglycerides have metabolic advantages, although they are toxic in large doses. To try to reduce this potential toxicity, structured lipids, which provide a higher oxidation rate, faster clearance from blood, improved nitrogen balance, and less accumulation in the reticuloendothelial system, could be used. Therefore, we evaluated, through a blind randomized study, the safety, tolerance, and efficacy of structured triglycerides, compared with long-chain triglycerides (LCT), in patients undergoing colorectal surgery. METHODS: Nineteen patients were randomized to receive long-chain or structured triglycerides as a lipid source. They received the same amount of calories (27.2/kg/d), glucose (4 g/kg/d), protein (0.2 g/kg/d), and lipids (11.2 kcal/kg/d). Patients were evaluated during and after the treatment for clinical and laboratory variables, daily and cumulative nitrogen balance, urinary excretion of 3-methyl-histidine, and urinary 3-methylhistidine/creatinine ratio. RESULTS: No adverse effect that required the interruption of the treatment was observed. Triglyceride levels and clinical and laboratory variables were similar in the two groups. A predominantly positive nitrogen balance was observed from day 2 until day 5 in the LCT group and from day 1 until day 4 in the structured triglycerides group. The cumulative nitrogen balance (in grams) for days 1 to 3 was 9.7+/-5.2 in the experimental group and 4.4+/-11.8 in the control group (p = .2). For days 1 to 5 it was 10.7+/-10.5 and 6.5+/-17.9 (p = .05), respectively. The excretion of 3-methylhistidine was higher in the control group but decreased in the following days and was similar to the experimental group on day 5. CONCLUSIONS: This study represents the first report in which structured triglycerides are administered in postoperative patients to evaluate safety, tolerance, and efficacy. It suggests that Fe73403 is safe, well tolerated, and efficacious in terms of nitrogen balance when compared with LCT emulsion.

Intraoperative radiation therapy in integrated treatment of rectal cancers. Results of phase II study.

PURPOSE: Risk of local recurrence of rectal cancer remains high despite extensive therapeutic strategies, many of which have been tried to achieve better local control (i.e., external beam radiation therapy (EBRT)). Recently, intraoperative radiation therapy (IORT) has been introduced in clinical protocols to boost the areas at risk of local recurrence. METHODS: Between April 1990 and December 1995, 44 patients with "high risk" (T3,N0-2 primary tumors) extraperitoneal rectal tumors and 24 patients with "locally advanced" (2 T3,N3 and 11 T4,N0-3 primary tumors; 11 local recurrences) tumors entered a protocol that included preoperative EBRT (38 Gy), surgery plus IORT (10 Gy) in the high-risk group, and preoperative EBRT (45-48 Gy) and concomitant computerized tomography (5-fluorouracil plus mitomycin C), surgery plus IORT (10-15 Gy), and postoperative adjuvant computerized tomography (5-fluorouracil plus folinic acid) in the locally advanced group. RESULTS: In the high-risk group, acute Grade 3 (Radiation Therapy Oncology Group scale) skin toxicity, attributable to preoperative treatment, involved one patient (2.2 percent); among locally advanced cases, Grade 3 hematologic toxicity was observed in one patient (4.1 percent). Treatment was discontinued in no patients. On average, IORT prolonged surgery by 48 minutes. There was no mortality. Four anastomotic leakages, one pelvic infection, and five wound infections were observed. No chronic IORT-related toxicity occurred. After mean follow-up periods of 28.3 and 25.9 months, 41 and 15 patients in the high-risk and locally advanced groups, respectively, are alive and disease-free. In one high-risk patient, an anastomotic recurrence occurred. In four patients with locally advanced tumors (1 T4 primary, 3 local recurrences) an unresectable tumor relapse developed locally. Distant metastases occurred in two high-risk patients and in eight patients with a locally advanced tumor. Three-year actuarial survival was 100 percent in both high-risk and locally advanced primary tumors and 68.2 percent in local recurrences. CONCLUSIONS: Results of this study suggest that multimodal treatment (including IORT) in rectal cancer is safe, has no significant increase of mortality and morbidity, and also shows a trend for local improvement. A longer term follow-up and larger numbers of patients could demonstrate the therapeutic efficacy of IORT in rectal cancer.

Preoperative concomitant radiochemotherapy and IORT in locally advanced rectal cancer.

34 patients with locally advanced (T4) or recurrent rectal cancer have been treated with: 1. external beam radiotherapy (45-48 Gy) + 5FU(1000 mg/m2/daily iv continuous infusion day 1-4) + MMC (10 mg/m2/daily iv, day 1); 2. surgical resection (if feasible) + IORT (10-15 Gy); 3. adjuvant chemotherapy (5FU+leucovorin, 6-8 cycles). Grade 3 acute hematological toxicity was observed in 1 case only. 23 of 34 patients underwent radical surgery. Perioperative mortality and morbidity was 0% and 17% respectively. In the 23 operated patients with a mean follow-up of 18.6 months there were 2 local recurrences, 5 blood metastases, (1 death of disease). 16 patients were shown to be NED (3-36 months).

5-Fluorouracil (FU) with folinic acid (FA) and mitomycin C (MMC) in the adjuvant treatment of colorectal carcinoma. Part I. Evaluation of toxicity.

Ninety-six patients with colorectal cancer (stage B2-C) were randomized to the control arm or to receive adjuvant chemotherapy with folinic acid, FU and MMC. Ninety-three patients are evaluable. The median follow up is 12 months. The average time between surgery and the start of therapy is 28 days. Toxicity is evaluable in 36 of 41 treated patients. Four patients (10%) failed to complete the projected treatment due to toxicity. Toxicity observed in 208 courses of therapy was mostly gastrointestinal and hematological. No cases of treatment related death or cancer-associated hemolytic uremic syndrome (C-HUS) were reported. The average relative dose intensity (rDI) of the projected treatment was 82.6%. Our study is ongoing and further patients are required to achieve statistically significant results.