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Minimally invasive surgery (MIS) is gaining popularity in rectal tumor treatment. However, contrasting data are available regarding its safety and efficacy. Our aim is to compare the open and MIS approaches for rectal cancer treatment. Two-hundred-thirty-seven patients were included: 113 open and 124 MIS rectal resections. After the propensity score matching analysis (PS), the cases were matched into 42 open and 42 MIS. Short- and long-term outcomes, and pathological findings were analyzed before and after PS. A further comparison of the same outcomes and costs was conducted between the laparoscopic and the robotic approaches. As a whole, a sphincter-preserving procedure was more frequently performed in the MIS group (110 vs 75 cases; p < 0.0001). The estimated blood loss during MIS was significantly lower than during open surgery [127 (± 92) vs 242 (± 122) mL; p < 0.0001], with clear advantages for the robotic approach over laparoscopy [113 (± 87) vs 147 (± 93) mL; p 0.01]. Complication rate was comparable between the two groups. A higher rate of CRM positivity was evidenced after open surgery (12.4% vs 1.7%; p 0.004). A higher number of lymph nodes was harvested in the MIS group [12.5 (± 6.4) vs 11 (± 5.6); p 0.04]. After PS, no difference in terms of perioperative outcomes was noted, with the only exception of a higher blood loss in the open approach [242 (± 122) vs 127 (± 92) mL; p < 0.0001]. For the matched cases, no difference in 5-year overall and disease-free survival was evidenced (p 0.50 and 0.88, respectively). Mean costs were higher for robotics as compared to laparoscopy [9812 (±1974)€ vs 9045 (± 1893)€; p 0.02]. MIS could be considered as a treatment option for rectal cancer. The PS study evidenced clear advantages in terms of estimated blood loss over the open surgery. Costs still remain the main limit for robotics.

Background and Purpose: Capecitabine-based radiochemotherapy (cbRCT) is standard for preoperative long-course radiochemotherapy of locally advanced rectal cancer. This prospective, parallel-group, randomised controlled trial investigated two intensification regimens. cT4 lesions were excluded., Primary Objective: pathological outcome (TRG 1-2) among arms., Materials and Methods: Low-located cT2N0-2M0, cT3N0-2M0 (up to 12 cm from anal verge) presentations were treated with cbRCT randomly intensified by either radiotherapy boost (Xelac arm) or multidrug concomitant chemotherapy (Xelox arm). Xelac: concomitant boost to bulky site (45 Gy/1.8 Gy/die, 5 sessions/week to the pelvis, +10 Gy at 1 Gy twice/week to the bulky) plus concurrent capecitabine (1650 mg/mq/die). Xelox: 45 Gy to the pelvis + 5.4 Gy/1.8 Gy/die, 5 sessions/week to the bulky site + concurrent capecitabine (1300 mg/mq/die) and oxaliplatin (130 mg/mq on days 1,19,38). Surgery was planned 7-9 weeks after radiochemotherapy., Results: From June 2005 to September 2013, 534 patients were analysed: 280 in Xelac, 254 in Xelox arm. Xelox arm presented higher G ≥ 3 haematologic (p = 0.01) and neurologic toxicity (p < 0.001). Overall, 98.5% patients received curative surgery. The tumour regression grade distribution did not differ between arms (p = 0.102). TRG 1+2 rate significantly differed: Xelac arm 61.7% vs. Xelox 52.3% (p = 0.039). Pathological complete response (ypT0N0) rates were 24.4 and 23.8%, respectively (p non-significant). Median follow-up:5.62 years. Five-year disease-free survival rate were 74.7% (Xelac) and 73.8% (Xelox), respectively (p = 0.444). Five-year overall survival rate were 80.4% (Xelac) and 85.5% (Xelox), respectively (p = 0.155)., Conclusion: Xelac arm significantly obtained higher TRG1-2 rates. No differences were found about clinical outcome. Because of efficacy on TRG, inferior toxicity and good compliance, Xelac schedules or similar radiotherapy dose intensification schemes could be considered as reference treatments for cT3 lesions., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: Robotic surgery has gradually gained importance in the treatment of rectal cancer. However, recent studies have not shown any advantages when compared with laparoscopy. The objective of this study is to report a single surgeon's experience in robotic rectal surgery focusing on short-term and long-term outcomes., Methods: Sixty consecutive robotic rectal resections for adenocarcinoma, over a 4-year period, were retrospectively reviewed. Patients' characteristics and perioperative outcomes were analyzed. Oncological outcomes and surgical resection quality as well as overall and disease-free survival were also assessed., Results: Thirty patients out of 60 (50%) underwent neoadjuvant therapy. Anterior rectal resection was performed in 52 cases (86.7%), and abdominoperineal resection was done in 8 cases (13.3%). Mean operative time was 283 (±68.6) minutes. The conversion rate was 5% (3 patients). Postoperative complications occurred in 10 cases (16.7%), and reoperation was required in 1 case (1.7%). Mean hospital stay was 9 days, while 30-day mortality was 1.7% (1 patients). The histopathological analysis reported a negative circumferential radial margin and distal margins in 100% of cases with a complete or near complete total mesorectal excision in 98.3% of patients. Mean follow-up was 32.8 months with a recurrence rate of 3.4% (2 patients). Overall survival and disease-free survival were 94% and 87%, respectively., Conclusions: Robotic surgery for rectal cancer proves to be safe and feasible when performed by highly skilled surgeons. It offers acceptable perioperative outcomes with a conversion rate notably lower than with the laparoscopic approach. Adequate pathological results and long-term oncological outcomes were also obtained.

Background: The McKittrick-Wheelock syndrome is a rare depletion syndrome caused by a secretory villous adenoma or a carcinoma of the rectosigmoid tract. An aggressive hydroelectrolyte rebalancing is often needed, and curative treatment is obtained only with complete removal of the lesion, by endoscopy or surgery. Low clinical suspicion often delays the diagnosis, resulting in detrimental complications., Case Presentation: We report the case of a 75-year-old woman, presenting to the emergency department with acute renal failure and electrolyte imbalance, reporting an history of recurrent episodes of dehydration and chronic diarrhea. After being admitted to the nephrology department she underwent diagnostic investigation that revealed the presence of a giant adenoma of the rectum. The patients received supportive therapy and was subsequently treated with surgery, with a favorable outcome., Conclusions: A prompt diagnosis plays an important role in the treatment of McKittrick-Wheelock syndrome. We describe a case of this condition in detail and review the related literature, underlining the typical diagnostic features and exploring the possible therapeutic options.

We investigated risk factors and prognostic implications of symptomatic anastomotic leakage after anterior resection for rectal cancer, and the influence of a diverting stoma. Our retrospective review of prospective collected data analyzed 475 patients who underwent anterior resection for rectal cancer. Uni- and multivariate analysis was made between anastomotic leakage and patient, tumor, and treatment variables, either for the overall group (n = 475) and in the midlow rectal cancer subgroup (n = 291). Overall rate of symptomatic leakage was 9 per cent (43 of 475) with no related postoperative mortality. At univariate analysis, significant factors for leak were a tumor less than 6 cm from the anal verge (13.7 vs 6.6%; P = 0.011) and intraoperative transfusions (16.9 vs 4.3%; P = 0.001). Similar results were observed in the midlow rectal cancer subgroup. At multivariate analysis, no parameter resulted in being an independent prognostic factor for risk of leakage. In patients with a leakage, a temporary enterostomy considerably reduced the need for reoperation (12.5 vs 77.8%; P < 0.0001) and the risk of a permanent stoma (18.7 vs 28.5%; P = 0.49). The incidence of anastomotic failure increases for lower tumors, whereas it is not influenced by radiotherapy. Defunctioning enterostomy does not influence the leak rate, but it mitigates clinical consequences.

Background: The aim of this study was to investigate the effect of neoadjuvant chemoradiotherapy on the lymph node yield of rectal cancer surgery., Methods: Data for patients who underwent neoadjuvant chemoradiotherapy followed by surgery for resectable rectal cancer from June 1992 to June 2009 were reviewed. The primary outcomes measured were the number of lymph nodes retrieved, their status, and patient survival., Results: In total, 345 patients underwent neoadjuvant chemoradiotherapy followed by surgery, and 95 patients had surgery alone. Neoadjuvant chemoradiotherapy decreased both the median (range) number of lymph nodes retrieved (7 (1-33) versus 12.5 (0-44) respectively; P < 0.001) and the number of positive lymph nodes (0 (0-11) versus 0 (0-16); P = 0.001). After neoadjuvant chemoradiotherapy, the number of retrieved lymph nodes was inversely correlated with tumour regression, and with the interval between treatment and surgery. The 5-year overall and disease-free survival rates were 86.5 and 79.1 per cent respectively. After neoadjuvant therapy, lymph node status was found to be an independent predictor of survival, whereas the number of retrieved lymph nodes did not represent a prognostic factor for either overall or disease-free survival., Conclusion: Low lymph node count after neoadjuvant chemoradiotherapy for rectal cancer does not signify an inadequate resection or understaging, but represents an increased sensitivity to the treatment., (© 2013 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Neoadjuvant chemoradiation (CRT), tailored mesorectal excision, and intraoperative radiotherapy (IORT) have become the leading measures for rectal cancer treatment. The objective of this study was to evaluate early and long-term results of a multimodal treatment model for rectal cancer followed by curative surgery. Prospectively collected hospital records of 338 patients surgically treated for rectal cancer between January 1998 and December 2008 were retrospectively reviewed. Patients with high rectum level cancers and those with middle and low rectum cancers with clinical stage T1 to T2 underwent surgery, whereas those with T3 to T4 and N+ disease at the middle and low rectum received neoadjuvant CRT in 96.2 per cent of cases. Short-course neoadjuvant radiotherapy was not considered for neoadjuvant treatment. Postoperative major complications and mortality rates were 12.7 and 2.3 per cent, respectively. Overall 5-year disease-specific and disease-free survival were 80 and 73.1 per cent, respectively, whereas local recurrence rate was 6.1 per cent. At multivariate analysis, nodal status and circumferential margin status were independently associated with poor survival; local recurrence rates were independently affected by nodal and marginal status and tumor stage. The extent of mesorectal excision should be tailored depending on tumor location and the use of neoadjuvant chemotherapy, combined with IORT in advanced middle and low rectal cancer, leading to remarkable tumor downstaging with excellent prognosis in responding patients.

Background: The purpose of this study is to analyze the pooled results of multimodality treatment of locally advanced rectal cancer (LARC) in four major treatment centers with particular expertise in intraoperative radiotherapy (IORT)., Patients and Methods: A total of 605 patients with LARC who underwent multimodality treatment up to 2005 were studied. The basic treatment principle was preoperative (chemo)radiotherapy, intended radical surgery, IORT and elective adjuvant chemotherapy (aCT). In uni- and multivariate analyses, risk factors for local recurrence (LR), distant metastases (DM) and overall survival (OS) were studied., Results: Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). In all, 42% of the patients received aCT, independent of tumor-node-metastasis stage or radicality of the resection. LR rate, DM rate and OS were 12.0%, 29.2% and 67.1%, respectively. Risk factors associated with LR were no downstaging, lymph node (LN) positivity, margin involvement and no postoperative chemotherapy. Male gender, preoperatively staged T4 disease, no downstaging, LN positivity and margin involvement were associated with a higher risk for DM. A risk model was created to determine a prognostic index for individual patients with LARC., Conclusions: Overall oncological results after multimodality treatment of LARC are promising. Adding aCT to the treatment can possibly improve LR rates.

Background: Pelvic recurrent rectal cancer is still a challenging clinical problem, and patients generally have a dismal prognosis and a poor quality of life. Surgical resection represents the only potentially curative treatment; neoadjuvant treatments are presently being taken into consideration to increase the resectability rate and to improve long-term survival., Methods: Among 157 patients observed with recurrent rectal cancer, a series of 58 patients who underwent surgical exploration with curative intent for isolated local recurrence at a single referral institution was retrospectively analyzed. Demographic, pathologic, and therapeutic factors were evaluated to assess long-term prognosis and local control., Results: Forty-four (75.9%) of 58 patients underwent surgical resection. The overall 5-year survival rate for patients who underwent surgical resection was 54.2%, whereas none of the unresected patients lived 5 years (P < 0.001). Patients with R0 resection showed a statistically higher 5-year overall survival and local control rate (72.4 and 70.2%, respectively) compared to R1 patients (37.5 and 31.2%, respectively). At multivariate survival analysis, feasibility of a surgical resection and radicality of excision proved to be independent positive prognostic factors. In contrast, increased presalvage carcinoembryonic antigen serum levels, back pain at diagnosis, and an increasing degree of fixation of recurrent disease to the pelvic wall at preoperative computed tomographic scan were statistically significantly linked to decreased overall survival. Preoperative chemoradiation and radicality of the surgical excision independently influenced the local control among surgically resected patients., Conclusions: Surgical resection still remains the most important therapeutic and prognostic factor for patients with locally recurrent rectal cancer. Multimodal treatments can be safely performed by an experienced team in referral tertiary centers and can result in a safer outcome, better local disease control, and even long-term survival in carefully selected patients.

Purpose: To report the final data of a Phase I and II study (1839IL/0092) on the combination of an anti-epidermal growth factor receptor drug (gefitinib), infusional 5-fluorouracil, and preoperative radiotherapy in locally advanced, resectable rectal cancer., Methods and Materials: Patients received 45 Gy in the posterior pelvis plus a boost of 5.4 Gy on the tumor and corresponding mesorectum. Infusional 5-fluorouracil (5-FU) and gefitinib (250 and 500 mg/day) were delivered during all radiotherapy course. An IORT boost of 10 Gy was allowed. The main endpoints of the study were to establish dose-limiting toxicity (DLT) and to evaluate the rate of pathologic response according to the tumor regression grade (TRG) Mandard score., Results: A total of 41 patients were enrolled. The DLT was not reached in the 6 patients enrolled in the dose-escalation part of the study. Of the 33 patients in the Phase II, TRG 1 was recorded in 10 patients (30.3%) and TRG 2 in 7 patients (21.2 %); overall 17 of 33 patients (51.5%) had a favorable endpoint. Overall, Grade 3+ toxicity was recorded in 16 patients (41%); these included Grade 3+ gastrointestinal toxicity in 8 patients (20.5%), Grade 3+ skin toxicity in 6 (15.3%), and Grade 3+ genitourinary toxicity in 4 (10.2%). A dose reduction of gefitinib was necessary in 24 patients (61.5%)., Conclusions: Gefitinib can be associated with 5-FU-based preoperative chemoradiation at the dose of 500 mg without any life-threatening toxicity and with a high pCR (30.3%). The relevant rate of Grade 3 gastrointestinal toxicity suggests that 250 mg would be more tolerable dose in a neaoadjuvant approach with radiotherapy and infusional 5-FU.

Aims and Background: To evaluate the impact of preoperative chemoradiation on sphincter preservation in patients with low-medium locally advanced resectable rectal cancer treated by four chemoradiation schedules., Materials and Methods: Between 1990 and 2002, 247 patients were treated according to four schedules of chemoradiotherapy: FUMIR (5-fluorouracil, mitomycin, external beam radiotherapy 37.8 Gy), PLAFUR (cisplatinum, 5-fluorouracil, external beam radiotherapy 50.4 Gy),TOMRT (raltitrexed, external beam radiotherapy 50.4 Gy), and TOMOXRT (raltitrexed, oxaliplatin, external beam radiotherapy 50.4 Gy). Four to five weeks after chemoradiation, patients were restaged and surgery was performed 2-3 weeks later., Results: Overall, the sphincter-saving surgery was performed in 82.5% of patients. In patients candidate to an abdominoperineal resection before chemoradiaton (distance tumor-anorectal ring, < 30 mm) a sphincter-saving surgery was possible in 58% of cases: 44% (FUMIR), 52% (PLAFUR), 63% (TOMRT), 76% (TOMOXRT) (P < 0.017). The involved surgeons kept the same surgical criteria in performing sphincter-saving surgery. After chemoradiation, patients with tumor location still between 0 and 30 mm received sphincter-saving surgery according to the protocols: 33% (FUMIR), 42% (PLAFUR), 50% (TOMRT), 64% (TOMOXRT) (P = 0.066)., Conclusions: Even though the surgeons' skill in performing sphincter-saving surgery could be improved with time, the high rate of this procedure in the latest schedules suggests an impact of the new drugs in promoting tumor downsizing and therefore sphincter-saving surgery.

Background: Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated on for rectal cancer following neoadjuvant chemoradiation., Methods: A case series of 68 patients with extraperitoneal rectal cancer treated with neoadjuvant chemoradiation and surgery (including total mesorectal excision) were investigated for presence of neoplastic MMF., Results: MMF were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of the bowel wall (P = 0.0006), Mandard's tumor regression grading (P = 0.0006), and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. One out of nine pT0 or TRG1 patients (11.1%) had distant metastases compared with 15 out of 59 pT1-4 or TRG2-5 (25.4%, P = 0.70)., Conclusions: A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induced complete regression of primary tumor (pT0-TRG1), we found that node metastases and neoplastic MMF also disappeared. These features should be confirmed to assess the impact of these microfoci in treatment decision making in rectal cancers.

Background: Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated upon for rectal cancer following neoadjuvant chemoradiation., Methods: A case series of 68 patients with extraperitoneal rectal cancer, treated with neoadjuvant chemoradiation and surgery (including total mesorectal excision), was investigated for the presence of neoplastic MMF., Results: Mesorectal microfoci were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of bowel wall (P = 0.0006), Mandard's tumor regression grading (P = 0.0006) and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. Out of 9 pT0 or TRG1 patients, 1 (11.1%) had distant metastases, compared to 15 out of 59 pT1-4 or TRG2-5 (25.4%, P = 0.70)., Conclusions: A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induces complete regression of primary tumor (pT0-TRG1), node metastases and neoplastic MMF could also disappear, as shown in our cases. These features should be confirmed because they could significantly impact the treatment decision-making of rectal cancers.

Purpose: The combination of irradiation and total mesorectal excision for rectal carcinoma has significantly lowered the incidence of local recurrence. However, a new problem is represented by the patient with locally recurrent cancer who has received previous irradiation to the pelvis. In these patients, local recurrence is very often not easily resectable and reirradiation is expected to be associated with a high risk of late toxicity. The aim of this multicenter phase II study is to evaluate the response rate, resectability rate, local control, and treatment-related toxicity of preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis., Methods and Materials: Patients with histologically proven pelvic recurrence of rectal carcinoma, with the absence of extrapelvic disease or bony involvement and previous pelvic irradiation with doses < or =55 Gy; age > or =18 years; performance status (PS) (Karnofsky) > or =60, and who gave institutional review board-approved written informed consent were treated by preoperative chemoradiation. Radiotherapy was delivered to a planning target volume (PTV2) including the gross tumor volume (GTV) plus a 4-cm margin, with a dose of 30 Gy (1.2 Gy twice daily with a minimum 6-h interval). A boost was delivered, with the same fractionation schedule, to a PTV1 including the GTV plus a 2-cm margin (10.8 Gy). During the radiation treatment, concurrent chemotherapy was delivered (5-fluorouracil, protracted intravenous infusion, 225 mg/m(2)/day, 7 days per week). Four to 6 weeks after the end of chemoradiation, patients were evaluated for tumor resectability, and, when feasible, surgical resection of recurrence was performed between 6-8 weeks from the end of chemoradiation. Adjuvant chemotherapy was prescribed to all patients, using Raltitrexed, 3 mg/square meter (sm), every 3 weeks, for a total of 5 cycles. Patients were staged using the computed tomography (CT)-based F-classification (F0: no side-wall involvement; F1, F2, F3: 1, 2, and 3-4 side-walls involved, respectively). Toxicity was evaluated on the basis of the Radiation Therapy Oncology Group (RTOG) criteria., Results: Fifty-nine patients (38 male, 21 female; median age, 62 years; range, 43-77 years) were enrolled in the study, by 12 different Italian radiotherapy departments. Previous surgery was anterior resection in 45 patients (76.3%) and abdominal-perineal resection in 14 patients (23.7%); previous radiotherapy dosage ranged between 30 and 55 Gy (median, 50.4 Gy); the median interval between prior radiation therapy to the onset of reirradiation was 27 months (range, 9-106 months); 44 patients (74.6%) had received some form of previous chemotherapy (concurrent and/or adjuvant). Fifty-one of 59 patients (86.4%) completed chemoradiation without treatment interruptions: 6 patients (10.2%) had temporary treatment interruption due to toxicity or patient compliance, and 2 patients (3.4%) had definitive treatment interruption. The incidence of Grade 3 lower gastrointestinal acute toxicity was only 5.1%. No patient developed Grade 4 acute toxicity. After chemoradiation, 5 patients (8.5%) had complete response (CR), 21 patients (35.6%) had partial response (PR), 31 patients (52.6%) had no change (NC) and 2 patients (3.4%) showed progressive disease (PD). Overall, the response rate (PR + CR) was 44.1% (95% confidence interval, 29.0-58.9%). Twenty of 24 patients (83.3%) with pelvic pain before treatment had symptomatic response. Tumor resection was performed in 30 of 59 patients (50.8%) including 2 local excisions, 4 anterior resections, 18 abdominoperineal resections, and 6 other. Surgical resection resulted as R0 and R1 in 21 patients (35.6%) and 3 patients (5.1%), respectively. The possibility of radical resection was influenced by tumor response to chemoradiation (PD/NC: 7/33; PR/CR: 14/26; p = 0.009). Thirty-three patients received adjuvant chemotherapy, which was completed in 30 (50.8%). At a median follow-up of 36 months (range, 9-69 months), 28 patients (47.5%) developed local recurrence or tumor progression in the unresected pelvic disease and 18 patients (30.5%) developed distant metastasis. Seven patients showed late toxicity, including 2 skin fibrosis, 2 impotence, 2 urinary complications requiring nephrostomy, and 1 small bowel fistula requiring surgical diversion. Overall median survival was 42 months. Five-year actuarial survival was 39.3%; 66.8% in R0 resected patients and 22.3% in patients treated without surgery or undergoing subtotal tumor removal. Local control and disease-free survival were significantly correlated with the interval between surgical treatment for primary tumor and local recurrence (p = 0.028 and p = 0.003, respectively). Radical resection significantly influenced local control, disease-free survival, and overall survival (p = 0.010, p = 0.010, and p = 0.050 respectively). The multivariate analysis confirmed the impact of surgery-relapse interval on local control (p = 0.016) and disease-free survival (p = 0.002), and confirmed the correlation between R0 surgery with local control and disease-free survival (p = 0.016)., Conclusions: Use of hyperfractionated chemoradiation was associated with a low rate of acute toxicity and an acceptable incidence of late complications. Pain control was excellent. The overall 5-year survival was 39%. Despite 87.4% of patients having F1-3 stage disease, approximately one-third (35%) achieved R0 resection, and two-thirds of patients in this cohort of patients were alive at the 5-year mark. However, further studies using innovative treatment algorithms are warranted to, hopefully, improve the local tumor response and control.

Purpose: Fecal incontinence may occur in patients who have undergone anterior resection for rectal cancer without presenting sphincter lesions. Chemoradiation may contribute to disrupting continence mechanisms. Treatment is controversial. Assessment of fecal incontinence in patients who agreed to integrate treatment for rectal cancer and treatment with sacral neuromodulation are reported., Methods: Fecal incontinence following preoperative chemoradiation and anterior resection for rectal cancer was evaluated in four patients. A good response was observed during the percutaneous sacral nerve evaluation test, and so permanent implant of sacral neuromodulation system was performed. Reevaluation was performed at least two months after implant., Results: After device implantation, the mean fecal incontinence scores decreased, and the mean number of incontinence episodes dropped from 12.0 to 2.5 per week (P < 0.05). Permanent implant resulted in a significant improvement in fecal continence in three patients, and incontinence was slightly reduced in the fourth. Manometric parameters agreed with clinical results: maximum and mean resting tone and the squeeze pressure were normal in three patients and reduced in one. In these same three patients, neorectal sensation parameters increased when the preoperative value was normal or below normal and decreased when the preoperative value was higher than normal, whereas in one patient in whom extremely low values were recorded all of the parameters decreased significantly., Conclusions: Fecal incontinence following anterior resection and neoadjuvant therapy should be carefully evaluated. If a suspected neurogenic pathogenesis is confirmed, sacral neuromodulation may be proposed. If the test results are positive, permanent implant is advisable. Failure of this approach does not exclude the use of other, more aggressive treatment.

Purpose: To evaluate the impact of preoperative chemoradiation with raltitrexed (Tomudex(1)) on tumor response, sphincter preservation, and toxicity in patients with locally advanced rectal cancer., Methods and Materials: Between 1998 and 2002, 54 consecutive patients with Stage T3 or T2N+ resectable rectal carcinoma were treated with preoperative chemoradiation, i.v. bolus of raltitrexed on Days 1, 19, and 38 and concurrent 50 Gy external beam radiotherapy. Surgery was performed 6-8 weeks after the end of chemoradiation., Results: No patients had Grade 4 acute toxicity. Grade 3 acute toxicity occurred in 16.6% of cases and was hematologic in 6 patients and GI in 2. The overall clinical response rate was 88.8%, with a complete response in 5.5%, partial response in 83.3%, and no change in 9.2%. No patient showed disease progression. All patients underwent surgery. Sphincter saving was obtained in 83.3% of patients. No perioperative mortality occurred, and the perioperative morbidity rate was 5.5%. Of 20 resected patients (37%) who were candidates for abdominoperineal resection at diagnosis (anorectal ring distance < or =30 mm), 13 (65%) underwent a sphincter-saving procedure. At pathologic examination, 13 (24%) of 54 patients had a complete pathologic response (pT0) and 10 (18.5%) had rare isolated residual cancer cells (pT, microscopic foci). Overall, 42.5% had major downstaging. The tumor regression grade (TRG), using Mandard's score system, was also applied and was TRG1 in 13 patients, TRG2 in 11, TRG3 in 20, and TRG4 in 10 patients; no patient had TRG5., Conclusion: The use of raltitrexed in a neoadjuvant chemoradiation schedule promoted high pathologic tumor downstaging and use of a sphincter-saving procedure. The low toxicity profile supports the rationale to explore raltitrexed combined with other drugs with different biologic targets.

Purpose: The survival advantage of preoperative radiotherapy in patients with rectal cancer is still a matter of debate, because its incremental benefit in the total mesorectal excision setting is unclear. This study was designed to evaluate early and long-term results of preoperative radiotherapy plus intraoperative radiotherapy in a homogeneous population of T3 middle and lower rectal cancer patients submitted to total mesorectal excision., Methods: A series of 113 patients with middle and lower T3 rectal cancer consecutively submitted to total mesorectal excision at a single surgical unit from 1991 to 1997 were divided into two groups according to type of neoadjuvant treatment: preoperative radiotherapy (38 Gy) plus intraoperative radiotherapy (10 Gy; n = 69), and no preoperative treatment (total mesorectal excision; n = 44). Standard statistical analyses were used to evaluate early (downstaging, intraoperative factors, hospital morbidity, and mortality rates) and long-term results (recurrence and survival)., Results: Overall, 68.2 percent of patients were downstaged by the preoperative regimens (T0 specimens in 3 cases). Postoperative complications were comparable in the two groups. Five-year, disease-specific survival was 81.4 and 58.1 percent in preoperative radiotherapy plus intraoperative radiotherapy group and total mesorectal excision group, respectively (P = 0.052). Corresponding figures for disease-free survival were 73.1 and 57.2 percent in the two groups, respectively (P = 0.096). The rates of local recurrence at five years were 6.6 and 23.2 percent in preoperative radiotherapy plus intraoperative radiotherapy and total mesorectal excision groups, respectively (P = 0.017)., Conclusions: Preoperative radiotherapy plus intraoperative radiotherapy associated with total mesorectal excision reduce local recurrence rate and improve survival in T3 rectal cancer compared with total mesorectal excision alone.

Purpose: Patients with unresectable, locally advanced rectal cancer are reported to have a dismal prognosis. The aim of this study was to analyze the effect of combined-modality therapy on clinical outcome., Methods: From March 1990 to December 1997, 43 patients (28 males; median age, 62 years; median follow-up, 74 months) with locally advanced (T4 and/or N3) nonmetastatic rectal cancer received external-beam radiation (23.6 plus 23.6 Gy (split course), 8 patients; 45 Gy, 35 patients) plus 5-fluorouracil (96-hour continuous infusion, Days 1-4, at 1,000 mg/m(2)/day) and mitomycin C (10 mg/m, intravenous bolus, Day 1). Concomitant chemotherapy was repeated at the beginning of the second course (split-course group) or in the last week of radiotherapy (continuous-course group). After 6 to 8 weeks, patients were evaluated for surgical resection and intraoperative radiation therapy (10 to 15 Gy). Thereafter, adjuvant chemotherapy (5-fluorouracil plus leucovorin, 6-9 courses) was prescribed., Results: During chemoradiation, 5 patients (11.6 percent) developed Grade 3 to 4 hematologic toxicity. After chemoradiation, 29 patients (67.4 percent) had an objective clinical response (complete response, 2.3 percent; partial response, 65.1 percent). Thirty-eight patients underwent radical surgery (anterior resection, 24 patients; abdominoperineal resection, 14 patients; intraoperative radiation therapy boost on the tumor bed, 19 patients), and 2 patients had partial tumor resection. No perioperative deaths occurred in the patient group. Five-year survival and local control rates were 59.9 and 69.1 percent, respectively. Distant metastasis occurred in 44.2 percent of patients. Statistically significant relationships between intraoperative radiation therapy and local control (P = 0.0104), radical surgery and survival (P = 0.0120), and adjuvant chemotherapy and disease-free survival (P = 0.0112) were observed., Conclusions: Our data suggest that combined-modality therapy was relatively well tolerated and resulted in good local control and survival. With regard to the impact of surgical resection on survival, additional studies aimed at improving the local response rate are necessary, whereas the positive impact of intraoperative radiotherapy on local control appears to justify the inclusion of this therapeutic modality in prospective multi-institutional trials.

Purpose: To evaluate the impact of tumor response; tumor and nodal downstaging; and cTNM, yTNM (clinical stage after chemoradiation, based on preoperative imaging), and pTNM classifications on long-term outcome in patients with rectal cancer treated with preoperative 5-fluorouracil (5-FU)-based concurrent chemoradiation., Methods and Materials: Between January 1990 and March 1998, 165 consecutive patients with locally advanced extraperitoneal cancer of the rectum were treated with preoperative chemoradiation. Four patients had a cT2 lesion (2.5%), 120 had a cT3 lesion (74.5%), and 41 had a cT4 lesion (23%). The nodal involvement at combined imaging was cN0 in 21%, cN1 in 41%, cN2 in 34%, and cN3 in 4%. Preoperative chemoradiation was delivered according to 1 of 3 schedules: (1) FUMIR-T3 (from 1990 to 1995) for patients with cT3N0-2 or cT2N1-2 rectal carcinoma (82 patients): 37.8 Gy (1.8 Gy/fraction) plus 5-FU, 1 g/m(2)/d on Days 1-4, continuous infusion, and mitomycin-C, 10 mg/m(2)/d on Day 1; (2) FUMIR-T4 (from 1990 to 1999) for patients with cT4N0-3 or cT3-4N3 rectal carcinoma (40 patients): 45 Gy (1.8 Gy/fraction) plus 5-FU, 1 g/m(2)/d on Days 1-4 and 29-32, continuous infusion, and mitomycin-C, 10 mg/m(2)/d on Days 1 and 29; and (3) PLAFUR-4 (from 1995 to 1998) for patients with cT3N0-2 or cT2N1-2 rectal carcinoma (42 patients): 50.4 Gy (1.8 Gy/fraction) plus 5-FU, 1 g/m(2)/d on Days 1-4 and 29-32, continuous infusion, and cisplatin, 60 mg/m(2)/d on Days 1 and 29. Four to five weeks after chemoradiation, patients were reevaluated for clinical response by imaging studies (CT scan, transrectal ultrasonography, barium enema, liver ultrasonography, chest X-rays) and restaged (yTNM). Surgery was performed 6-8 weeks after chemoradiation. Adjuvant chemotherapy (5-FU + l-folinic acid) was delivered to 26 patients in the FUMIR-T4 protocol group. Local control (LC), freedom from distant metastases (FDM), disease-free survival, and overall survival (OS) were evaluated according to the clinical response and cTNM, yTNM, and pTNM classification. The median follow-up was 67 months., Results: The 5-year survival rate was 100% for cT2, 77% for cT3, and 62% for cT4 (p = 0.0497); after chemoradiation, it ranged between 81% and 91% for pT0-pT2 and dropped to 66% for pT3 and 47% for pT4 (p = 0.014). The 5-year local control rate was, at the first staging, 84% for cT3 and 72% for cT4; after chemoradiation, the pT stage correlated significantly with LC (p = 0.0012): 100% for pT0, 83% for pT1, 88% for pT2, 79% for pT3, and 46% for pT4. N stage was statistically significant in predicting FDM and OS at any staging step. A significant impact of tumor response, tumor downstaging, and nodal downstaging on LC, FDM, disease-free survival, and OS was also recorded. If the residual tumor, before surgery, had a tumor index <30 (i.e., width less than one-quarter of rectal circumference and length in its caudocranial axis < or =30 mm), the 5-year LC, FDM, disease-free survival, and OS rates were significantly higher at both the univariate and the multivariate analyses. The surgical procedure was tailored according to tumor downstaging, and thus the choice of sphincter-preserving surgery was based on the distance between the lower pole of the tumor and the anorectal ring "after" chemoradiation. In 36 patients with the lower pole of the lesion in the range of 0-30 mm from the anorectal ring, 16 patients (44%) underwent a sphincter-saving procedure. All clinical outcomes were similar compared with 20 patients with tumor located at the same rectum level who received an abdominoperineal resection., Conclusion: After preoperative chemoradiation, clinical response and tumor/nodal pathologic downstaging showed a close correlation with improved outcomes. The better 5-year survival and local control in pT0-2 patients regardless of their initial stage seems to confirm a heterogeneity in rectal cancer patients. The responder population showed a behavior similar to rectal cancer diagnosed at Stage cT1-2 and treated with conservative surgery alone. Additional studies aimed at improving local tumor response seem justified. Trials of sphincter-saving surgery after a major response are warranted.

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.

The use of raltitrexed ('Tomudex') as concomitant chemotherapy during preoperative radiotherapy in chemonaïve patients with stage II/III rectal cancer has been examined in this study and its recommended dose in conjunction with radiotherapy investigated. Forty-five Gray (Gy) of radiotherapy (1.8 Gy daily, 5 days per week) was delivered to the posterior pelvis, followed by a 5.4 Gy boost. Single doses of raltitrexed (2.0, 2.5 and 3.0 mg/m(2)) were administered on days 1, 19 and 38. Only 1 of the 15 patients entered experienced a dose limiting toxicity (DLT) (grade 3 leucopenia) at the 3.0 mg/m(2) dose level. The overall response rate was 80% (five complete responses, seven partial responses). These preliminary data suggest that raltitrexed is a well tolerated and effective treatment when combined with preoperative radiotherapy in patients with stage II/III rectal cancer. The recommended dose of raltitrexed for future phase II studies will be 3.0 mg/m(2).

Background: Local recurrence remains one of the most complex problem in the management of rectal carcinoma. Often, surgery alone is not able to prevent local recurrence development, particularly in locally advanced cancer. A better local control is obtained using the association with radiotherapy and chemotherapy. Intraoperative Radiation Therapy (IORT) represents an innovative therapeutic modality., Patients and Methods: 141 patients, 97 with "high risk" cancer (T2N1-2 or T3N0-2) and 44 with "locally advanced" tumor (T3N3, T4N0-3 or local recurrence). 64 patients with extraperitoneal "high risk" rectal cancer have been treated with preoperative radiotherapy (38 Gy), surgical excision and IORT (10 Gy). In other 33 "high risk" cases, preoperative radio- (50.4 Gy) chemotherapy (Tomudex 2-3 mg), surgery and IORT (10 Gy) have been given. Fourty four patients with "locally advanced" rectal tumor have had external radiotherapy (48 Gy) + chemotherapy (5FU + Mitomicin C) preoperatively, surgery, IORT (10-15 Gy) and chemotherapy (5FU + Levamisolo) postoperatively., Results: Among "high risk" patients, 52-83% of cases have had a sphincter-saving surgical procedure, 5-year local control is 93%, 5-year overall survival 80%, and 5-year disease free survival 77%. In 50-60% of "high risk" tumors treated with preoperative chemo-radiotherapy the pathologic staging have found a T0-1 tumor. Among "locally advanced" primary tumors, 5-year local control is 90.9%, 5-year disease free survival 47.1%, 5-year overall survival 60.7%. Among patients treated for local recurrence, in 60% a complete tumor resection has been performed; 5-year local control is 79.5%, 5-year disease free survival 19.4%, 5-year overall survival 41.4%., Conclusions: Integrated treatment with radiotherapy, chemotherapy, surgery and IORT has allowed a good local control and seems prolong survival also.

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.

In our University, many different radiosurgical options are available to treat rectal carcinoma. Selecting the patients to submit to treatment requires accurate clinical and radiological staging. A team of radiologists, radiotherapists, surgeons, endoscopists and pathologists has been created to stage the patients and to follow the final results. The team have decided the diagnostic and therapeutic protocols. The patients with rectal cancer undergo radiotherapy after staging and are subsequently restaged. If indicated, surgery is performed and histology is compared with restaging, to assess the accuracy of the diagnostic procedures. All diagnostic and therapeutic decisions are made collectively by the team, during scheduled meetings. All data are stored in a computer program. This paper deals with the working method we used, its advantages and the outcome of the first 23 studied patients. Restaging was compared with histology: transrectal US (performed in 8 patients) showed 100% accuracy in evaluating local tumor spread (T). CT had 91% accuracy in defining T and 60% accuracy in N, with a tendency to overstaging. In 78% of patients > 50% reduction of tumor size was observed and the distance from the anal canal increased in 95.5%. This study will provide the overall accuracy of the clinico-radiologic staging, the survival rates and the indication of prognostic signs.

The EEA Stapler is widely employed in the rectal cancer surgery, particularly allowing a more frequent sphincteric preservation after low anterior resection. The authors rather employ the manual suture whenever possible and report their own experience on EEA Stapler employment in the surgical management of rectal cancer located 12 to 6 cm. from the anal verge. They emphasize this technique pointing out the necessity of further investigations which may confirm the possibility of obtaining a curative complete surgical removal as well as by abdomino-perineal resection.