Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer.

BACKGROUND: The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC). METHODS: Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses. RESULTS: Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis. CONCLUSION: Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²7Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²7Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²7Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²7Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

Radiation modifiers: treatment overview and future investigations.

Many radiosensitizers are in current clinical use. In addition, a myriad of potential new targeted therapies, which may also interact with radiation, are in clinical development. The clinical utility of new targeted therapies, in combination with existing radiation sensitizers (chemotherapies) requires further evaluation, as does the understanding of their acute and late radiation effects. Free radical scavengers appear to show promise as radioprotectors, but data for mucoprotection are less convincing.

P53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma.

PURPOSE: We recently presented evidence for tumor site and gender-specificity in the survival benefit from adjuvant chemotherapy in Stage III colorectal cancer (CRC). In the current study, we examined whether p53 alteration or the microsatellite instability (MSI) phenotype provide additional predictive information in CRC patients. EXPERIMENTAL DESIGN: A retrospective series of 891 Stage III CRC patients with negative surgical margins was investigated. Thirty percent (270 of 891) received postoperative adjuvant chemotherapy with curative intent and comprising of 5-fluorouracil/levamisole. Adjuvant treatment and nontreatment patient groups were well matched for tumor site, grade, p53 alterations, and MSI. Surgical tumor specimens were investigated for p53 overexpression using immunohistochemistry and for p53 mutation and MSI using single-strand conformation polymorphism analysis. The predictive value of these markers was evaluated by comparing the survival of adjuvant-treated and nonadjuvant treated patients. RESULTS: A strong inverse correlation was observed between p53 alteration and MSI (P < 0.0001). In univariate analysis, the factors of sex, site, p53 alteration, and MSI were each strong predictors of a survival benefit from chemotherapy. Multivariate analysis revealed that chemotherapy provided maximal survival benefit for female patients (P = 0.005) and for patients whose tumors contained normal p53 (P = 0.041). Males whose tumors contained a p53 alteration and were negative for MSI appeared not to benefit from chemotherapy. CONCLUSIONS: Our findings suggest that p53 alteration and MSI could be clinically useful molecular predictive markers for the identification of CRC patients who might benefit from 5-fluorouracil-based chemotherapy.

TP53 gene mutation status in pretreatment biopsies of oesophageal adenocarcinoma has no prognostic value.

Identification of markers which help to predict response to treatment and overall survival at the time of diagnosis would assist in the management of patients with oesophageal adenocarcinoma. In the present study we investigated the prognostic significance of mutations to the TP53 tumour suppressor gene in a large, consecutive series of oesophageal adenocarcinomas. The incidence of TP53 mutation determined by molecular analysis of endoscopic biopsy specimens was 36% (49/135). No statistically significant difference was observed in patient survival according to the TP53 status of the tumour biopsy. The median survival time for patients with mutation was 12 +/- 1 months compared with 14 +/- 2 months for patients with TP53. These results demonstrate that mutation of the TP53 gene is not a useful predictive marker for patient survival in oesophageal adenocarcinoma.

Prognostic significance of TP53 gene mutation in 995 cases of colorectal carcinoma. Influence of tumour site, stage, adjuvant chemotherapy and type of mutation.

Previous studies on the prognostic significance of TP53 gene alterations in colorectal cancer (CRC) have led to conflicting results. The present study investigated the prognostic significance of TP53 gene mutation in a very large series of 995 Dukes' B and C CRC patients, the majority of whom did not receive chemotherapy. Mutations were found in 385 (39%) cases and were not associated with tumour stage, histological grade, patient age or sex. Significantly more mutations were found in tumours from the left-sided colon compared with those from the right side (43% versus 34%, P=0.006). TP53 gene mutation had no prognostic value in the overall series or in different site or stage subgroups. None of the different types of TP53 gene mutation showed prognostic value. A trend for association with worse survival was observed in the patient subgroup that received adjuvant chemotherapy (Hazard Ratio (HR) 1.4, 95% confidence interval (CI) 0.89-2.21, P=0.15). These results indicate that mutation of the TP53 gene is not a useful prognostic marker for CRC patients who do not receive adjuvant chemotherapy. Further study is required to determine whether different types of TP53 mutation might be of value in predicting the response of CRC patients to chemotherapy.

Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients.

PURPOSE: Radiation therapy is an important treatment modality for oncology patients. DNA sequence variants have so far been identified in only a few genes in radiosensitive cancer patients. Patients known to be clinically radiosensitive were tested for mutation of a gene involved in DNA double-strand break repair and sister chromatid cohesion--hHR21. METHODS AND MATERIALS: Clinically radiation-sensitive patients were accrued to the study after giving informed consent. Blood samples were obtained and lymphoblastoid cell lines established. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the hHR21 gene, and the DNA product was sequenced to identify any genetic abnormalities. Northern blot analysis, cell survival, and growth assays were performed on control cells and cells with hHR21 variants, and a restriction digest assay was developed to screen for carriers of a detected gene variant. RESULTS: The DNA sequence of the hHR21 gene was determined in 19 radiation-sensitive cancer patients. In 6 of the 19 patients, a thymidine (T) to cytosine (C) transition was detected at position 1440 of the hHR21 open reading frame (T1440C). This variant did not alter the amino acid sequence and was likely to be a polymorphism. One patient with a particularly severe radiation reaction had a second sequence variant immediately adjacent to the first. This was a guanine (G) to adenine (A) transition (G1441A), resulting in a change of the amino acid sequence (glycine --> arginine) in a portion of the protein conserved in evolution. This suggests that this DNA alteration may be biologically significant. Restriction digest with the HpaII enzyme confirmed the presence of both sequence variants on the same allele. CONCLUSIONS: We describe the first two DNA sequence variants ever found in the hHR21 gene, in patients with clinical radiation hypersensitivity. Although no direct evidence for the involvement of hHR21 alterations in the radiosensitivity of the cancer patients examined has been demonstrated, the possibility exists that homozygous mutations or other mutations of this gene could contribute to radiosensitivity. A simple test is described that could be applied to screening for these variants in relevant populations.

Can p53 alterations be used to predict tumour response to pre-operative chemo-radiotherapy in locally advanced rectal cancer?

PURPOSE: To examine whether p53 tumour suppressor gene alterations can be used to predict tumour response to pre-operative chemo-radiation in locally advanced rectal cancer in terms of reduction in tumour size and local failure. METHODS: p53 alterations were studied in pre-treatment biopsy specimens of rectal carcinomas from 48 patients by immunohistochemistry (IHC) and polymerase chain reaction/single strand conformation polymorphism (PCR-SSCP) gene mutation analysis. Pre-operative pelvic radiotherapy was delivered with four fields, 45 Gy to the ICRU point in 25 fractions over 5 weeks. A radio-sensitising dose of 5-fluorouracil (500 mg/m(2)) was delivered concurrently for 6 days of the 5-week schedule (days 1, 2, 3 and days 22, 23 and 24). Total meso-rectal excision was planned 4 to 6 weeks from completion of pre-operative treatment. Response to therapy was assessed by macroscopic measurement of the surgical specimen by a pathologist who was unaware of the pre-treatment tumour size or of the p53 status. RESULTS: IHC evidence of p53 protein accumulation was found in 40% of tumours, p53 gene mutation in 35% and p53 alteration (either or both changes) in 46%. The average reduction in tumour size was 53% in the group with 'wild-type' p53 (IHC-/SSCP-) and 63% in the group with altered p53 (either IHC+ or SSCP+; P=0.18). No significant differences in tumour size reduction or local failure were observed in the groups with p53 overexpression or p53 mutation compared with normal. CONCLUSIONS: p53 alteration detected by IHC or SSCP analysis is not a clinically useful predictor of local response to pre-operative adjuvant therapy in advanced rectal carcinoma.

P53 alterations have no prognostic or predictive significance in Dukes' C rectal carcinomas.

We investigated the prognostic significance of p53 alterations in a consecutive series of 122 Dukes' C rectal carcinomas with a median patient follow-up period of 56 months. One third of patients were treated with post-operative adjuvant chemotherapy. Overexpression of p53 protein was observed in 42% (50/118) of cases using immunohistochemical analysis and mutation of the p53 gene in 38% (47/122) using single strand conformation polymorphism technique. Neither p53 overexpression nor mutation were associated with significantly worse patient survival in the overall group or in the subgroup of 35 patients who received standard post-operative chemotherapy with 5-fluorouracil and levamisole. Our results do not support the use of p53 alteration as a clinically useful prognostic marker for the overall survival of rectal cancer patients or for predicting their response to chemotherapy.

Routine analysis of p53 mutation in clinical breast tumor specimens using fluorescence-based polymerase chain reaction and single strand conformation polymorphism.

Improved prognostic and predictive markers in breast cancer management would help considerably in therapeutic decision making, particularly in patients with early-stage breast cancer. Tumor factors currently used for prognostication and management decisions are tumor size, histologic type and grade, axillary lymph node status, and estrogen receptor content. The discovery of various somatic genetic alterations in breast cancer has raised the possibility that these may provide additional and independent prognostic and predictive information. Alterations of the p53 tumor suppressor gene in particular have received the most attention as potential prognostic and predictive factors. In multivariate analysis, p53 gene mutation is consistently associated with a two- to threefold increased risk of relapse and death from breast cancer. One of the major reasons preventing the introduction of p53 mutation as a routine marker to assist in therapeutic decision making is the lack of a simple, reproducible, and inexpensive assay. In the present study the authors optimized a polymerase chain reaction-based mutation screening method, fluorescence-single strand conformation polymorphism (F-SSCP), that allows p53 status to be assessed accurately and reproducibly in routinely handled, formalin-fixed and paraffin-embedded tumor specimens. The frequency of p53 mutation observed using F-SSCP in a consecutive series of invasive ductal breast carcinomas was 17% (28/164). The authors propose that the prognostic and predictive values of p53 mutation in breast cancer should be further evaluated in prospective, randomized studies using this standardized technique.

Microsatellite instability is a predictive marker for survival benefit from adjuvant chemotherapy in a population-based series of stage III colorectal carcinoma.

Tumors with the microsatellite instability (MSI) phenotype appear to comprise a biologically and clinically distinct group of colorectal carcinomas (CRC). MSI+ has been associated with favorable prognosis; however, it is not clear whether this is because MSI+ tumors are inherently less aggressive or because they are more sensitive to chemotherapy. We investigated the prognostic and predictive significance of this molecular alteration along with its association with nodal burden in a large, population-based cohort of stage III CRC patients. Eight hundred seventy-six stage III CRC patients with long median follow-up (76 months) were included in the study. MSI status was determined by screening for deletions in the BAT-26 mononucleotide repeat. Systemic adjuvant fluoropyrimidine-based chemotherapy was delivered to 266 patients (30%). MSI+ was more common in tumors from female patients and tumors that originated in the proximal colon. It was predictive of excellent survival benefit from chemotherapy but was not associated with better prognosis for patients who did not receive treatment. Lower nodal burden was a prognostic factor for improved survival. MSI+ was associated with lower nodal burden in the overall group (P = 0.02, chi 2 test) but not for patients who received chemotherapy. In stage III CRC, MSI+ was not prognostic in nonadjuvant-treated patients, suggesting that the biological behavior of MSI+ tumors in the absence of chemotherapy is the same as MSI- tumors. Tumors with the MSI+ phenotype appear to be more sensitive to chemotherapy, as observed by improved survival for patients receiving this treatment. MSI along with other molecular markers could be used in the future for a more refined selection of CRC patients to receive fluoropyrimidine-based chemotherapy.

Differences in toxicity across gender in patients treated with chemoradiation for rectal cancer.

The primary objective was to prospectively investigate the efficacy and toxicity of bolus 5-fluorouracil (5-FU) chemotherapy compared with the infusional 5-FU in combination with preoperative radiation in patients with locally advanced rectal cancer. Furthermore, in light of previous reports, toxicity profiles between men and women were also compared. Eighty-four consecutive patients with rectal adenocarcinoma were prospectively treated. There were no differences in tumour response, local recurrence or survival between bolus versus infusional groups or gender groups. In locally advanced rectal cancer, preoperative infusional chemotherapy combined with radiation was found to be less toxic than bolus chemotherapy and radiotherapy. Both regimens produced more toxic effects in women compared with men.

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

Small cell carcinoma of the vagina.

A case of localized small cell neuroendocrine carcinoma of the vagina is reported. The patient was treated with concurrent chemoradiation with significant toxicity but obtained a complete response. Thirteen months after therapy the patient developed distant metastasis and died shortly thereafter. Review of the literature found that patients treated with local therapy alone had a shorter survival and died of systemic disease. As with small cell neuroendocrine carcinomas arising from other sites, systemic relapse remains an important issue that warrants combination therapies, although in pelvic sites this may be associated with an increase in side-effects.

A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil.

High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the enhancer region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes' C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30-1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52-0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy.

Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer.

Ki-ras mutations are associated with an increased risk of relapse and death in colorectal cancer (CRC) patients, with some mutations being more aggressive than others. The present study examined the predictive value of different Ki-ras mutation types in a retrospective series of 430 Dukes' C stage CRC patients, of whom 208 (48%) had received adjuvant chemotherapy with 5-fluorouracil/levamisole or 5-fluorouracil/leucovorin. A total of 140 mutations were detected, the majority (58%, 81/140) being glycine to aspartate mutations in codons 12 and 13. Glycine to valine mutations in codon 12 (14%, 20/140) and other less frequent, non-specified mutation types (28%, 39/140) accounted for the remaining mutations. Kaplan-Meier survival analysis revealed that both Ki-ras wild-type and mutant patient groups derived significant survival benefit from chemotherapy. However, when patients were stratified according to the type of mutation, those with non-aspartate mutations appeared to gain more benefit from this treatment than those with aspartate mutations. Multivariate analysis that included other possible predictive factors in Dukes' C CRC (tumour site, patient sex, TP53 mutation) demonstrated that non-aspartate mutations in particular were associated with a significant survival benefit from chemotherapy (HR=0.11, 95% CI: 0.04-0.30, p<0.001). These results suggest that the type of Ki-ras mutation could be a clinically useful molecular marker for the identification of CRC subgroups that are likely to benefit from 5-fluorouracil-based adjuvant chemotherapy.

Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Adjuvant chemotherapy can improve 5-year survival in Dukes' C colorectal carcinoma. Improved selection of patients who will respond to adjuvant treatments is required. We investigated whether site of tumour origin, sex, and presence of microsatellite instability (MSI) phenotype were associated with a survival benefit from adjuvant chemotherapy. METHODS: We analysed data for 656 consecutive patients with Dukes' C colorectal carcinoma, with median follow-up of 54 months (range 7-104) and mean age 66.7 years (SD 12.9). We screened tumour samples by PCR for deletions in the BAT-26 mononucleotide repeat to establish MSI status. Details of chemotherapy and survival were obtained by review of hospital and health-department records. Adjuvant chemotherapy (fluorouracil and levamisole) was given with curative intent to 272 (42%) patients. FINDINGS: Striking survival benefits were seen for patients who had right-sided tumours and who received adjuvant chemotherapy compared with those who did not (48 vs 27% alive at end of study [95% CI 0.25-0.56], p<0.0001), for women (53 vs 33% [0.25-0.56], p<0.0001), and for patients with MSI tumours (90 vs 35% [0.01-0.53], p=0.0007). MSI-positive tumours were slightly more frequent in women than in men (10 vs 7%). Right-sided tumours were more frequently MSI positive than left-sided tumours (20 vs 1%). Men with right-sided tumours benefited from chemotherapy (37 vs 12% [0.24-0.69], p=0.0007) but men with left-sided tumours did not. INTERPRETATION: The survival benefits seen in patients treated with adjuvant chemotherapy suggest that data from previous trials of adjuvant chemotherapy should be reassessed and the predictive value of MSI status confirmed. Validation of our results will allow better selection of patients for chemotherapy.

p53 gene mutation, microsatellite instability and adjuvant chemotherapy: impact on survival of 388 patients with Dukes' C colon carcinoma.

Two common genetic alterations in colon carcinoma, p53 mutation and microsatellite instability (MSI), were investigated to determine their prognostic importance for cancer-specific survival and response to adjuvant chemotherapy in patients with Dukes' C colon cancer. The p53 tumour suppressor gene encodes for a nuclear phosphoprotein involved in cellular response to DNA damage, while MSI is a characteristic feature of tumours with defective DNA mismatch repair. The cellular response mechanisms to DNA-damaging agents in tumours with mutant p53 or MSI may as a consequence differ, and this might translate into different outcomes following adjuvant chemotherapy. A consecutive series of 388 Dukes' C colon carcinomas with 5-year median follow-up was analysed for p53 mutation and for MSI (in proximal/transverse carcinomas only) using polymerase chain reaction single-strand conformation polymorphism. The incidence of p53 mutation was 28% in all carcinomas while that of MSI in proximal/transverse carcinomas was 19%. One hundred and thirty-three patients (34%) received adjuvant chemotherapy (5-fluorouracil/levamisole) with curative intent. The presence of p53 mutation did not predict for survival in either the treated or untreated groups. The presence of MSI in the proximal/transverse colon carcinoma group was associated with significantly better 5-year survival: 58 versus 32% (p = 0.015, log rank test). This was largely due to better survival observed in the MSI subgroup that received adjuvant chemotherapy (p = 0.017, log rank test). Further work in prospective, randomised clinical trials investigating the effects of adjuvant therapy should consider incorporating MSI status in order to determine whether this is an independent predictive factor for survival and/or response to adjuvant chemotherapy.

Pre-operative chemoradiotherapy in locally advanced rectal cancer.

BACKGROUND: The aim of the present study was to investigate the effectiveness and toxicity of pre-operative chemoradiation in locally advanced rectal cancer (T3-T4). METHODS: Forty-seven patients were assessed (38 T3 and nine T4 tumours). Pre-operative pelvic radiotherapy was delivered in four fields, 45 Gy in 25 fractions over 5 weeks. Bolus 5-fluorouracil (5-FU) was delivered 500 mg/m2 on days 1, 2, 3 and days 22, 23, 24. Total mesorectal excision of the rectal tumour either by anterior or abdomino-perineal resection was planned at 4-6 weeks from completion of pre-operative treatment. Response to therapy was assessed by fresh macroscopic measurement of the surgical specimen. RESULTS: All patients undergoing chemoradiation completed therapy as planned, with no treatment-related interruptions. The regimen had a low acute toxicity profile with an estimated 50% or greater response in 38 out of 47 patients (four patients had complete responses). Forty-three (97%) of 44 patients who underwent surgery were operable. Patients who were operated on between 4 and 7 weeks had a statistically better response then those who were operated on after 7 weeks (P = 0.013; Fisher's exact test). Eight of 10 patients who were considered to be inoperable prior to the treatment underwent total mesorectal excision with negative radial margins. Anastomotic leakage occurred in four patients (9%); one required surgical intervention. Wound infection occurred in three patients (6%); one patient required re-exploration for haemorrhage. Delayed complications occurred in three patients (6%); one requiring surgery for a stomal stricture. After a median follow-up of 20 months, two patients (4%) had developed local recurrence. CONCLUSION: The pre-operative chemoradiation regimen employed had a low acute toxicity profile and all patients completed therapy. The majority of patients considered inoperable prior to receiving this treatment underwent successful excision. Appropriately fractionated pre-operative chemoradiotherapy is a reasonable option in this disease and deserves further evaluation.