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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.)

Objective: To correlate imaging parameters from baseline MRI diffusion-weighted imaging (DWI) and fludeoxyglucose (FDG) positron emission tomography (PET)-CT with synchronous and metachronous metastases in mucinous carcinoma (MC) and non-mucinous carcinoma (NMC) rectal cancer., Methods: 111 patients with extraperitoneal locally advanced rectal cancer, who underwent pelvic MRI, DWI and FDG PET-CT, were stratified into MC (n = 23) and NMC (n = 88). We correlated adverse morphologic features on MRI [mT4, mesorectal fascia involvement, extramural venous invasion (mEMVI), mN2] and quantitative imaging parameters [minimum apparent diffusion coefficient (ADC min ), maximum standardized uptake value, total lesion glycolysis, metabolic tumour volume, T 2 weighted and DWI tumour volumes] with the presence of metastatic disease. All patients underwent pre-operative chemoradiation therapy (CRT); 100/111 patients underwent surgery after CRT and were classified as pathological complete response (PCR) and no PCR [tumour regression grade (TRG)1 vs TRG2-5] and as ypN0 and ypN1-2. Median follow-up time was 48 months. Metastases were confirmed on FDG PET-CT and contrast-enhanced multidetector CT., Results: The percentage of mucin measured by MRI correlates with that quantified by histology. On multivariate analysis, the synchronous metastases were correlated with mEMVI [odds ratio (OR) = 21.48, p < 0.01] and low ADC min (OR = 0.04, p = 0.038) in NMC. The difference of metachronous recurrence between the MC group (10-90% mucin) and NMC group was significant (p < 0.01) (OR = 21.67, 95% confidence interval 3.8-120.5). Metachronous metastases were correlated with ypN2 (OR = 8.24, p = 0.01) in MC and in NMC. In NMC, mEMVI correlated with no PCR (p = 0.018) and ypN2 (p < 0.01)., Conclusion: mEMVI could identify patients with NMC, who are at high risk of synchronous metastases. The MC group is at a high risk of developing metachronous metastases. Advances in knowledge: Patients at high risk of metastases are more likely to benefit from more aggressive neoadjuvant therapy.

Purpose: To evaluate whether metabolic changes in the primary tumour during and after preoperative radiochemotherapy (RCT) can predict the histopathological response in patients with locally advanced rectal cancer as well as disease-free survival (DFS) and overall survival (OS)., Methods: Consecutive patients with cT2-4 N0-2 rectal adenocarcinoma were included. (18)F-FDG PET/CT was performed at baseline, at the end of the second week of RCT (early PET/CT) and before surgery (late PET/CT). The PET/CT results were compared with histopathological data (ypT0 N0 vs. ypT1-4 N0-2 as well as TRG1 vs.TRG2-5) and survival., Results: The study included 126 patients. Among 124 patients in whom TNM classification was available, 28 (22.6 %) were ypT0 N0, and among all 126 patients, 31 (24.6 %) were TRG1. The areas under the curve of the early response index (RI) for identifying non-complete pathological response (non-cPR) were 0.74 (95 % CI 0.61 - 0.87) for ypT1-4 N0-2 patients and 0.75 (95 % CI 0.62 - 0.88) for TRG2-5 patients. The optimal cut-off for differentiating patients with non-cPR and cPR was found to be a reduction of 61.2 % (83.1 % sensitivity and 65 % specificity in ypT1-4 N0-2 patients; 85.4 % sensitivity and 65.2 % specificity in TRG2-5 patients). The optimal cut-off for late RI could not be found. The qualitative analysis of images obtained after RCT demonstrated 81.5 % sensitivity and 61.3 % specificity in predicting TRG2-5. After a median follow-up of 68 months, the low number of patients with local/distant recurrence or who had died did not allow the value of PET/CT for predicting DFS and OS to be calculated., Conclusion: The early assessment of response to RCT by (18)F-FDG PET/CT can predict non-cPR allowing practical modification of preoperative treatment. Conversely, late RI is not sufficiently accurate for guiding the decision as to whether local excision or even observation is appropriate in an individual patient. Qualitative analysis of late PET/CT images is also not sensitive enough alone to rule out the presence of residual disease.

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.)

Background: Transanal endoscopic microsurgery (TEM) after radiochemotherapy (RCT) has been reported in selected cases of locally advanced rectal cancer as an alternative to traditional radical resection with total mesorectal excision with a curative intent or as diagnostic tool to confirm a pathological complete response of the primary tumor. No study has evaluated functional outcome after TEM in preoperatively irradiated patients., Methods: This study was designed to evaluate short-term morbidity (according to Clavien's classifications) and establish (by a questionnaire) continence and evacuative function after RCT and TEM, at 1 year from surgery, analyzing the impact of RCT on postoperative outcomes. Patients with locally advanced rectal cancer treated by RCT and TEM (group 1) or with early T1 or adenomas treated only by TEM (group 2) entered this cohort comparative study., Results: Twenty-two patients entered the study as group 1 and 25 as group 2. No postoperative mortality occurred. The morbidity rate was 36.4 % in group 1 vs. 16 % in group 2 (p = 0.114). The rate of suture dehiscence was 22.7 % in group 1 vs. 4 % in group 2 (p = 0.068). No grade III complications, reoperation, or hospital readmission within 30 days was recorded in either group. One year after surgery, continence and evacuative scores in group 1 were 1.05 ± 1.25 and 24.72 ± 2.79, respectively, which were similar to group 2 (p = 0.081 and 0.288, respectively)., Conclusions: TEM after RCT in selected rectal cancer patients has an acceptable morbidity and functional results at 1 year from surgery. Preoperative irradiation could increase postoperative short-term morbidity, but it does not seem to influence evacuative or sphincter function after 1 year from surgery.

Purpose: To prospectively monitor the response in patients with locally advanced nonmucinous rectal cancer after chemoradiotherapy (CRT) using diffusion-weighted magnetic resonance imaging. The histopathologic finding was the reference standard., Methods and Materials: The institutional review board approved the present study. A total of 62 patients (43 men and 19 women; mean age, 64 years; range, 28-83) provided informed consent. T(2)- and diffusion-weighted magnetic resonance imaging scans (b value, 0 and 1,000 mm(2)/s) were acquired before, during (mean 12 days), and 6-8 weeks after CRT. We compared the median apparent diffusion coefficients (ADCs) between responders and nonresponders and examined the associations with the Mandard tumor regression grade (TRG). The postoperative nodal status (ypN) was evaluated. The Mann-Whitney/Wilcoxon two-sample test was used to evaluate the relationships among the pretherapy ADCs, extramural vascular invasion, early percentage of increases in ADCs, and preoperative ADCs., Results: Low pretreatment ADCs (<1.0 × 10(-3)mm(2)/s) were correlated with TRG 4 scores (p = .0011) and associated to extramural vascular invasion with ypN+ (85.7% positive predictive value for ypN+). During treatment, the mean percentage of increase in tumor ADC was significantly greater in the responders than in the nonresponders (p < .0001) and a >23% ADC increase had a 96.3% negative predictive value for TRG 4. In 9 of 16 complete responders, CRT-related tumor downsizing prevented ADC evaluations. The preoperative ADCs were significantly different (p = .0012) between the patients with and without downstaging (preoperative ADC ≥1.4 × 10(-3)mm(2)/s showed a positive and negative predictive value of 78.9% and 61.8%, respectively, for response assessment). The TRG 1 and TRG 2-4 groups were not significantly different., Conclusion: Diffusion-weighted magnetic resonance imaging seems to be a promising tool for monitoring the response to CRT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In recent years, preoperative therapy has become standard procedure for locally advanced rectal cancer. Tumor shrinkage due to preoperative chemotherapy-radiation therapy (CRT) is now a reality, and pathologically complete responses are not uncommon. Some researchers are now addressing organ preservation, thus increasing the demand for both functional and morphologic radiologic evaluation of response to CRT to distinguish responding from nonresponding tumors. On magnetic resonance (MR) images, post-CRT tumor morphologic features and volume changes have a high positive predictive value but a low negative predictive value for assessing response. Preliminary results indicate that diffusion-weighted MR imaging, especially at high b values, would be effective for prediction of treatment outcome and for early detection of tumor response. Some authors have reported that the use of apparent diffusion coefficient values in combination with other MR imaging criteria significantly improves discrimination between malignant and benign lymph nodes. Sequential determination of fluorodeoxyglucose uptake at positron emission tomography/computed tomography has proved useful in differentiating responding from nonresponding tumors during and at the end of CRT. However, radionuclide techniques have limitations, such as low spatial resolution and high cost. Large studies will be needed to verify the most effective morphologic and functional imaging modalities for post-CRT restaging of rectal cancer. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.303095085/-/DC1.

Background: Our objective was evaluate the outcome of primary clinical T4M0 extraperitoneal rectal cancer treated by neoadjuvant radiochemotherapy. Prognosis of clinical T4 rectal cancer is poor. Preoperative chemoradiation therapy may be beneficial. The results obtained are unclear due to lack of objective and strictly applied staging methods., Methods: Patients with primary, clinical, T4MO, extraperitoneal rectal cancer, defined by transrectal ultrasonography, computed tomography or magnetic resonance imaging, were considered. Intraoperative radiotherapy and adjuvant chemotherapy were employed in some patients after curative resection (R0). Variables influencing the possibility to perform an R0 resection and a sphincter-saving procedure were investigated as predictors of outcome., Results: 100 patients were included. R0 resection was performed in 78 patients. R0 resection rate was greater in females (93% vs 67%) and in responders to neoadjuvant chemoradiation (94% vs 60%). The ability to perform a sphincter-saving procedure was 57%, greater in middle rectal location (85% vs 51%) and in responders to the chemoradiation (70% vs 47%). Median follow-up was 31 months (range, 4-136). Local recurrences were found in 7 patients (10%). Five-year local control in R0 patients was 90% and better in the IORT group (100%). Distant relapse occurred in 24 patients (30%). Five-year overall survival was 59%, and was better after an R0 versus an R1 or R2 resection (68% vs 22%). Overall and disease free survival in R0 patients improved after overall downstaging. Adjuvant chemotherapy given in addition to the neoadjuvant therapy did not appear to offer benefit in improving survival., Conclusion: A multimodal approach enabled us to obtain a 5-year overall survival of about 60%. IORT increased local control. The role of adjuvant chemotherapy needs to be further investigated.

Purpose: To prospectively differentiate, at magnetic resonance (MR) imaging, patients with locally advanced nonmucinous rectal cancer who will respond to long-course chemotherapy and radiation therapy (CRT) from those who will not respond, with histopathologic results as the reference standard., Materials and Methods: Institutional review board approval for this study was obtained, and all patients provided written informed consent. High-spatial-resolution T2-weighted MR images were acquired before and 6-8 weeks after CRT in 53 patients (33 men, 20 women; mean age, 63 years; age range, 42-79 years). Patients were categorized as responders to CRT (patients with T3 cancer that converted to T2 or a lower stage, patients with T4 cancer that converted to T3 or a lower stage) or as nonresponders (patients with stable or progressive disease). At the posttreatment MR imaging examination, a decrease in signal intensity was considered to represent a morphologic response with fibrosis. Before CRT and surgery, tumor volume was calculated at MR imaging by multiplying cross-sectional area by section thickness. Tumor length was measured at MR imaging and in the histopathologic specimen. Nodal downstaging was evaluated. The relationship between pathologic response, morphologic MR imaging response, and percentage volume reduction was evaluated with the Mann-Whitney-Wilcoxon two-sample test., Results: Morphologic response assessment with MR imaging achieved a positive predictive value (PPV) of 84.2% (32 of 38) and a negative predictive value (NPV) of 66.7% (10 of 15). Volume reduction extent (> or = 70%) was significantly different between patients in whom disease was downstaged and those in whom it was not downstaged (P = .000005) and showed additional diagnostic value, with an overall accuracy of 86.8% (46 of 53). Presurgical MR imaging and histopathologic tumor length did not show a significant difference. MR imaging accuracy for lymph node (N) stage was 86.8% (46 of 53) on the basis of morphologic criteria., Conclusion: After CRT, morphologic and volumetric evaluation at MR imaging had a high PPV and a low NPV for response assessment. The detection of small clusters of residual tumor cells within fibrosis remains a problem., Supplemental Material: http://radiology.rsnajnls.org/cgi/content/full/250/3/730/DC1., (RSNA, 2009)

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.

Correlation between pathological response of primary tumour and mesorectal lymph node involvement was prospectively evaluated to assess the role of local excision (LE) in rectal cancer after complete response to neoadjuvant treatment. A series of 272 consecutive rectal cancer, submitted to neoadjuvant radiochemotherapy (RCT) and surgery with total mesorectal excision (TME) were analysed. Tumour downstaging (pT) and tumour regression grade (TRG) together with sex, age, location of the tumour, pre-treatment clinical stage, type of chemoradiation and operation performed entered in an univariate and multivariate analysis. Pathological complete response on primary tumour was found in 56 patients (20.6%). Lymph node metastases were found in 72 patients (26.5%). The rate of positive nodes was 1.8% for pT0 and TRG1 cases, respectively, to go up to 6.3% for pT1 and 24.1% for TRG 2 cases, respectively. At the univariate analysis, factors with a statistically significant correlation with the risk of lymph node metastasis were: clinical pre-treatment N stage (p<0.05), pT stage (p<0.001) and TRG (p<0.001). At the multivariate analysis, the best predictors of pathologic lymph node involvement were pT stage (p=0.0013 ) and TRG (p=0.0011). Because LE is an adequate technique to assess the tumour pathological response and nodal involvement in pT0 or TRG1 cases seems extremely infrequent, radical resection is probably not justified after pathological complete response. Prospective randomized trials are necessary to establish if, in these cases, LE can guarantee the same oncologic results offered by the currently adopted protocols of RCT followed by radical resections.

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: To evaluate the impact on T downstaging of the vasculature supplying blood flow to rectal cancer evaluated by color Doppler ultrasound., Methods and Materials: Color Doppler images were graded in 29 T3-staged rectal carcinoma patients sonographically just before chemoradiation. Any arterial vessels detected in rectal masses were assigned one of two grades: vascularity was considered as grade 1 for vessels feeding the periphery and as grade 2 for vessels coursing in all rectal masses within its peripheral and central portions. The pulsatility indices (PI = peak systolic velocity - end-diastolic velocity/time-averaged maximum velocity) were calculated in the central and peripheral portions., Results: The pathologic observations showed a change in stage in 15 of the 23 patients graded 2, positive predictive value 65.2% (p = 0.047), and in one of the six rectal cancers graded 1 (negative predictive value, 83.3%). The minimal peripheral PI values in rectal cancer graded 2 were higher in nonresponding (2.2 +/- 1.3) than in responding lesions (1.6 +/- 0.7) p = 0.01., Conclusion: Vascularity graded 2 associated with low peripheral PI values are indicators of therapy outcome. Vascularity graded 1 and high peripheral PI values in graded 2 have negative predictive value.

Purpose: To examine the relationship between tumor regression grade (TRG) and outcomes in patients with rectal cancer treated with preoperative therapy., Methods and Materials: Specimens from 144 patients with cT3,4 rectal cancer who had received preoperative radiation +/- chemotherapy and had a minimum follow-up of 3 years were retrospectively reviewed. TRG, which involves examining the residual neoplastic cells and scoring the degree of both cytological changes, including nuclear pyknosis or necrosis and/or eosinophilia, as well as stromal changes, including fibrosis (either dense or edematous) with or without inflammatory infiltrate and giant-cell granulomatosis around ghost cells and keratin, was quantified in five grades according to the Mandard score (Cancer 1994;73:2680-2686). The greater the response, the lower the TRG score. The median follow-up was 72 months (range, 40-143 months)., Results: Of the 144 patients, 19% were TRG1, 12% were TRG2, 21% were TRG3, 46% were TRG4, and 1% were TRG5. To simplify the analysis, TRG was combined into two groups: TRG1-2 and TRG3-5. By univariate analysis, none of the pretreatment factors examined, including age, circumference, length, distance from the anorectal ring, pretreatment T and N stage, and INDpre (defined as the pretreatment reference index size based on digital rectal examination), had an impact on 5-year outcomes, including local control, metastases-free survival, disease-free survival, and overall survival. Postoperative parameters, including pathologic T stage (pT), pathologic N stage (pN), and TRG, did significantly influence 5-year outcomes. These included local failure: pT0-2: 5% vs. pT3-4: 19%, p = 0.007; pN0: 7% vs. pN1-3: 26%, p = 0.002; TRG1-2: 2% vs. TRG3-5: 17%, p = 0.013; metastasis-free survival: pT0-2: 86% vs. pT3-4: 62%, p = 0.005; pN-: 86% vs. pN*: 42%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 66%, p = 0.004; disease-free survival: pT0-2: 83% vs. pT3-4: 54%, p = 0.001; pN0: 80% vs. pN1-3: 39%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 58%, p < 0.001; and overall survival: pT0-2: 85% vs. pT3-4: 65%, p = 0.007; pN0: 86% vs. pN1-3: 45%, p < 0.001; TRG1-2: 89% vs. TRG3-5: 68%, p = 0.004. By multivariate analysis combining all pre- and posttreatment parameters, only pN (p < 0.001) and TRG (p = 0.005) significantly predicted disease-free survival. Furthermore, TRG predicted the incidence of pathologic nodal involvement (p < 0.0001)., Conclusions: By univariate analysis, TRG is a predictor for local failure, metastases-free survival, and overall survival. By multivariate analysis, it predicts improved disease-free survival. Given the ability of TRG to predict those patients with N* disease, it may be helpful, in combination with other clinicopathologic factors, in selecting patients for a more conservative procedure, such as local excision rather than radical surgery, after preoperative therapy.

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.

Purpose: To assess the local control and survival of local excision and postoperative radiation in patients with early stage rectal cancer., Methods and Materials: From 1980 to 1992, 21 patients with clinical stage T1-2NxM0 adenocarcinoma of the middle and lower rectum were treated with transanal excision and postoperative external beam radiotherapy (44.6 Gy). The pathologic T stages were: 9 T1 (43%) and 12 T2 (57%). One patient had unassessable resection margins. The median follow-up was 54 months (range: 18-128 months)., Results: The actuarial local recurrence-free survival at 5 years was 85.2%, and the overall survival at 5 years was 80.6%. One patient developed a local recurrence and distant metastases at 22 months, and two patients had local recurrence at 11 and 15 months, respectively; both had abdomino-perineal resection (APR) and one remained free of disease 16 months after APR. The incidence of Grade 3 diarrhea was 5%. Sphincter function was good to excellent in the 18 patients with local control. No patients developed clinical evidence of pelvic lymph node recurrence., Conclusion: These results are similar to other published series and suggest that this approach is feasible in selected patients with T1-2NxM0 rectal cancer and results in good long-term control of the disease.

Aim of this phase I-II study was to evaluate the efficacy of preoperative concomitant radiochemotherapy in resectable high risk (TNM stage: II and III) rectal tumors, 64 patients entered the study: 37 had low rectal cancer, 27 mid-rectal cancer. 50 patients were clinically staged as stage III (Dukes C) and 14 as stage II (Dukes B). Treatment protocol included bolus mitomycin C at the dose of 10 mg/m2 on day 1 and 5FU continuous infusion at the daily dose of 1000 mg/m2 on day 1, 2, 3, 4. Concomitant external radiotherapy up to a dose of 3780 cGy was delivered at the daily dose of 180 cGy. Surgery was performed 4 to 5 weeks after radiation therapy (RT). Before surgery all patients were clinically restaged to evaluate the response to concomitant radiochemotherapy. Treatment compliance was 97%. Toxicity was 27% prevalently shown as bone marrow depletion and radiodermatitis. In 37 patients (61%) there was 50% reduction (partial response) of neoplastic volume. In 5 patients (8%) no neoplastic cells were evidenced in the surgical specimen on histology (complete response). The distance between the lower margin of the tumor and the internal anal orifice increased in 72% of cases. Postoperative morbidity was 28%. The incidence of anastomotic dehiscences was 8.7% over 46 anterior resections. Postoperative mortality was nil. Definitive staging evidenced 24 patients (39%) stage I or with no evidence of tumor. The incidence of local recurrence was 5% and that of distant metastasis 8%.

Over a 4-year period 35 patients with mid- (15 patients) and low (20 patients) rectal cancer clinically staged as T2 N1-2, T3 N0-2 underwent a protocol of combined surgery and radiotherapy. The protocol included: preoperative external beam radiotherapy (38 Gy, ICRU50); surgical resection; IORT on tumor bed (10 Gy). Toxicity of preoperative treatment was mild with a single case (2.9%) of grade 3 gastrointestinal toxicity. 18 patients underwent anterior resection and 17 abdominoperineal resection. Perioperative mortality and morbidity were 0% and 17.1% respectively. At a mean follow-up of 25 months all patients were alive. The single anastomotic recurrence observed was rescued with abdominoperineal resection.

The pathologist's role in the diagnosis and therapy of rectal cancer is reviewed. Basically, it concerns the diagnosis established at biopsy, the staging and the definition of prognostic factors. The biopsy-proven diagnosis confirms the clinical or radiologic diagnosis of malignancy while the histological type and grading is also assessed. The latter includes three levels and is based on the tubular clumping of neoplastic cells. The most commonly used staging systems: Dukes' classification, TNM, and Jass' system are presented. The staging aspects which impact on prognosis are stressed. Particular attention is paid to the specific problems of preoperative radiochemotherapy which frequently affects the initial grading and staging. Finally, the role the pathologist plays in the definition of histopathologic prognostic factors complementary to the conventional morphological study, is underlined.

Purpose: The aim of this study was to examine the effectiveness of a combination of preoperative radiotherapy and chemotherapy for operable locally advanced rectal cancer (Stages II and III)., Methods: Chemotherapy and radiotherapy are started jointly on day one of the therapy. 5-Fluorouracil is given in a dosage of 1000 mg/m2/day as a continuous 24-hour infusion for 4 days. Mitomycin C is given as a bolus intravenous at a dosage of 10 mg/m2 the first day. The radiation therapy is given to a total dosage of 37.8 Gy. Surgery is generally performed four to five weeks following completion of the radiation therapy. From March 1990 to April 1993, 34 patients with histologically documented adenocarcinoma of the rectum have been treated. Twenty-one lesions were located in the lower third of the rectum. Twenty-nine neoplasms were judged by initial clinical staging as Stage III., Results: Patients compliance to the treatment have been 97 percent. Toxicity of treatment has been low (15 percent). Tumor sizes decreased 50 percent or more in about 80 percent of patients. Distance of the tumor from the anal canal increased in all but seven cases. Twenty-two anterior resections have been performed. The morbidity rate has been 24 percent. No postoperative mortality has been reported. Histologic examination of surgical specimens after integrated treatment showed in 10 cases a tumor confined to the rectal wall (T2), in 3 patients only a residual tumor limited to submucosa (T1), and in 5 (15 percent) patients no evidence of neoplastic cells (T0)., Conclusions: We conclude that preoperative radiochemotherapy was generally well tolerated; in all cases we had a reduction of tumor sizes, surgery presented no technical difficulties, and there was the effect of stage reduction.

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.

31 colonic polyps in 21 patients between 2 and 30 years of age removed by endoscopy were studied. The site, size, cytohistological characteristic and tissue CEA content of these polyps were evaluated. 58% of the polyps were located in the rectum and sigmoid, the remaining 42% were in the descending colon. At histological examination 13 polyps proved to be neoplastic, 3 of which had severe dysplasia. In 3 cases of juvenile hyperplastic hamartomatous polyps and in 5 cases of inflammatory polyps the tissue C.E.A. was low; in 13 neoplastic polyps it was in direct correlation with the degree of dysplasia. Moreover in 10 patients with neoplastic polyps, 5 presented further adenomas at follow-up, and in 3 of them the C.E.A. tissue content of the first polyps obtained was medium to high. The occurrence in young patients of polyps of the colon with C.E.A. content medium to high must be followed by endoscopic examination at close intervals.