Rectal Cancer Trial Research Articles

Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time

Expression of the macrophage antigen CD163 in breast cancer cells is recently shown to be related to early distant recurrence and shortened survival. In this study, 163 patients with rectal cancer, included in the Swedish rectal cancer trial and followed up for a median of 71 months, were examined for the expression of CD163 in the primary tumors. The cancer cells expressed CD163 in the primary tumors in 23% (n = 32) of the patients. In pretreatment biopsies from 101 patients, 10 had CD163-positive cancers and these patients had earlier local recurrence (p < 0.044) and reduced survival time (p < 0.045) compared with those with CD163-negative tumors. When studying surgical specimens from 61 patients randomized to preoperative irradiation (5 x 5 Gy delivered in 1 week), it was found that 31% were CD163 positive whereas the corresponding figure was only 17% for 78 patients who were nonirradiated (p < 0.044), which tentatively may be consistent with X-rays inducing fusion. In CD163-positive tumors there was a reduced apoptotic activity as measured with the Termina deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) technique (p = 0.018). There tended also to be an increased proliferation activity measured as an expression of Ki-67 non significant (NS). It is concluded that primary rectal cancers may express CD-163, and this phenotypic macrophage trait is related to early local recurrence, shorter survival time and reduced apoptosis. Furthermore, the expression of CD163 is more common after irradiation.

Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society

BackgroundThe additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (LARC) dramatically. But a major achievement has been the development of total mesorectal excision (TME) as a surgical standard and the recognition that the surgeon is the predominant prognostic factor. The benefit of preoperative hypofractionated radiotherapy (SCRT; five fractions each of 5 Gy), initially established by the Swedish Rectal Cancer Trial, has been demonstrated in conjunction with TME by the Dutch Colorectal Cancer Group. The concept of combined neoadjuvant radiochemotherapy (conventional radiation of about 50 Gy with chemotherapy) has not been compared over surgery alone with TME. However, the German Rectal Cancer Study Group recently demonstrated that preoperative radiochemotherapy (RCT) was better than postoperative radiochemotherapy in terms of local control.Methods and designPatients with histological proven rectal cancer staged T2N+ or T3 are randomized to receive either SCRT (25 Gy in five fractions of 5 Gy) plus TME-surgery within 5 days or RCT (50.4 Gy in 28 fractions of 1.8 Gy, continuous infusion 5-fluorouracil) plus TME-surgery 4–6 weeks later. All patients receive adjuvant chemotherapy (12 weeks continuous infusional 5-FU) and are followed up for 5 years. TME-quality is independently documented by the surgeon and the pathologist. Hypothesis of the study is that RCT is superior to SCRT in terms of local recurrence after five years. Secondary endpoints are overall survival, disease-free survival, complete resection rate (R0 resection), rate of sphincter saving resection, acute and late toxicity (radiation related side effects), and quality of life (including long term bowel function).DiscussionSimilar long-term survival, local control and late morbidity have been reported for both concepts of preoperative therapy in non-comparative studies. In addition to other ongoing (and recently published) comparative trials we include a larger number of patients for adequate power, apply quality-controlled TME and try to avoid the adjuvant treatment bias by mandatory adjuvant chemotherapy in both groups. Further more, stratification of the initially planned surgical procedure and sphincter-preservation will generate valid evidence whether RCT will allow a less aggressive (sphincter saving) surgical approach.

Surrogate endpoints in neoadjuvant rectal cancer trials: Statistical evaluation using data from the FFCD 9203 trial

4086 Background: Neo-adjuvant rectal cancer trials use overall survival (OS) and local control as standard endpoints. Using earlier endpoints as primary outcomes in phase III trials requires them to be validated as surrogates for OS or local control. The aim of this study was to evaluate the statistical validity of specimen sterilization, pT and pN stages and circumferential resection margin as surrogate endpoints for OS and local recurrence free survival (LRFS). Methods: We used data from the FFCD 9203 trial (Gérard et al. J Clin Oncol 2006): preoperative radiotherapy (RT) vs preoperative chemoradiation (CT-RT) in T3–4 rectal cancers. Based on logistic regressions and Cox proportional hazards regression models we applied single-trial validation methods: Prentice criteria, proportion of treatment effect explained (PTE), relative effect, adjusted association and the proportion of variation explained (R²). OS was defined as time interval between randomization and death (all causes) and LRFS as time interval between randomization and local recurrence. Survival curves were estimated using Kaplan-Meier method and compared using Log-Rank tests. Results: Our analyses were based on the 742 eligible patients of the trial (367 patients in the RT arm and 375 in the CT-RT arm). Complete sterilization of the operative specimen was more frequent in the CT-RT arm (11.4% vs 3.6%, p<.0001) and the 5-year local recurrence rate was significantly lower (16.5% vs 8.1%, p=0.004) while the 5-year OS did not differ (67.9% vs 67.4%, p=0.69). None of the variables fulfilled the four Prentice criteria whatever final endpoint. The most surrogate variable was specimen sterilization categorized as pT0 or few residual cells (S1) vs evolutive residual cells (S0). It explained 12% of the effect of treatment on LRFS (PTE=0.119) but the lower bound of the 95% CI was under the critical limit of 0.5. After adjusting for treatment, relative risk of local recurrence (S1 vs S0) was 0.56 (95% CI [0.28–1.10], p=0.09, R²=0.05). With OS as final endpoint, PTE for sterilization was not interpretable (PTE=-249.3%). Conclusions: Our data did not allow validating relevant surrogates for long term outcomes in neo- adjuvant rectal cancer trials. To increase power, an individual meta-analysis is planned. No significant financial relationships to disclose.

The Quality Initiative in Rectal Cancer (QIRC) trial: study protocol of a cluster randomized controlled trial in surgery.

BackgroundTwo unfortunate outcomes for patients treated surgically for rectal cancer are placement of a permanent colostomy and local tumor recurrence. Total mesorectal excision is a new technique for rectal cancer surgery that can lead to improved patient outcomes. We describe a cluster randomized controlled trial that is testing if the above patient outcomes can be improved through a knowledge translation strategy called the Quality Initiative in Rectal Cancer (QIRC) strategy. The strategy is designed to optimize the use of total mesorectal excision techniques.Methods and DesignHospitals were randomized to the QIRC strategy (experimental group) versus normal practice environment (control group). Participating hospitals, and the respective surgeon group operating in them, are from Ontario, Canada and have an annual procedure volume for major rectal cancer resections of 15 or greater. Patients were eligible if they underwent major rectal surgery for a diagnosis of primary rectal cancer. The surgeon-directed QIRC interventions included a workshop, use of opinion leaders, operative demonstrations, a post-operative questionnaire, and, audit and feedback. For an operative demonstration participating surgeons invited a study team surgeon to assist them with a case of rectal cancer surgery. The intent was to demonstrate total mesorectal excision techniques. Control arm surgeons received no intervention. Sample size calculations were two-sided, considered the clustering of data at the hospital level, and were driven by requirements for the outcome local recurrence. To detect an improvement in local recurrence from 20% to 8% with confidence we required 16 hospitals and 672 patients – 8 hospitals and 336 patients in each arm. Outcomes data are collected via chart review for at least 30 months after surgery. Analyses will use an intention-to-treat principle and will consider the clustering of data. Data collection will be complete by the end of 2007.DiscussionLower rates of permanent colostomy and local tumour recurrence in the intervention arm would suggest the QIRC strategy is efficacious. The strategy may act as a template for efforts to improve surgical quality in other areas and will contribute to knowledge on influencing surgeon practice.Trial registrationCurrent Controlled Trials ISRCTN78363167

New Approaches to Assessing and Treating Early-Stage Colon and Rectal Cancers: Cooperative Group Strategies for Assessing Optimal Approaches in Early-Stage Disease

The U.S. Gastrointestinal Intergroup (GI Intergroup), including the National Cancer Institute of Canada, has created a portfolio of clinical trials for patients with stage II and III colon and rectal cancer, integrating therapeutic strategies from recent advanced disease trials. Fluoropyrimidine-based combination therapy for metastatic disease, with either irinotecan or oxaliplatin plus bevacizumab, has resulted in significant improvement in response and disease-free and overall survival. Cetuximab and irinotecan have produced intriguing response and progression-free survival data from randomized phase II trials. Although patients with stage II and III rectal cancer are uniformly included in individual clinical trials, the GI Intergroup conducts separate trials in patients with stage II and III colon cancer, with the exception of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which continues to merge both stages in their statistical designs. The U.S. chemotherapy platform for adjuvant therapy clinical trials is based on the positive adjuvant data from NSABP C-07 [FLOX with bolus 5-fluorouracil (5-FU)] and the MOSAIC trial (FOLFOX with infusional 5-FU). Three irinotecan-based adjuvant trials (one U.S. and two European) did not reach designated statistical end points. In addition, the GI Intergroup has consistently integrated molecular biological and other laboratory projects as important components of past and current trials. NSABP has recently completed accrual of patients to C-08, which is evaluating FOLFOX with or without bevacizumab in stage II/III colon cancer. E5202, the largest U.S. stage II colon cancer trial, determines patient risk by the initial evaluation of tumor 18q loss of heterozygosity and microsatellite instability status. Low-risk patients are observed, whereas high-risk patients are randomized to FOLFOX with or without bevacizumab. N0147 evaluates FOLFOX with or without cetuximab in patients with stage III disease. Two large rectal cancer trials have begun to accrue patients. NSABP R-04 compares neoadjuvant radiation with either continuous infusion 5-FU with or without oxaliplatin versus capecitabine with or without oxaliplatin. E5204 is the adjuvant comparison of FOLFOX with or without bevacizumab and is also available to NSABP R-04 patients.

Management of Early Rectal T1 and T2 Cancers

The treatment of rectal cancer has undergone a tremendous surgical evolution over the past century. Initially, in the 19th century, the only possible safe treatment was a diverting colostomy, which then evolved first to local treatment, primarily via the Lisfranc and Kraske procedures (posterior approach), and later, in the 20th century, to the abdominal-perineal resection popularized by Miles. Subsequently, anterior resection and low anterior resection gained a solid foothold as the most efficacious ways to treat most cancers of the rectum. In the past 3 decades, transanal excision has reemerged as a popular treatment option for T1 and selected T2 rectal adenocarcinomas, allowing less morbidity for early cancers. The selection criteria for this treatment have often included mobile tumor, size <4 cm, favorable histology without lymphovascular invasion, and anatomic accessibility with the ability to achieve 1-cm circumferential margins. Although the use of transanal excision for T1 rectal cancer increased from 26% to approximately 44% between 1989 and 2003, multiple recent retrospective studies have suggested that locoregional recurrence after this procedure is as high as 18% for T1 cancers and 47% for T2 cancers. Of interest, limited available prospective data reveal much better results (4-5% locoregional recurrence rate for T1 and 14-16% for T2). Much of the apparent discrepancy is due to patient selection, which is far more rigid in prospective trials. Conflicting data also exist as to how this outcome affects overall survival, although surgical salvage averages approximately 50% with close follow-up. The following topics will be discussed in this article: the surgical evolution of rectal cancer, best patient selection criteria for transanal excision versus more radical operation, utility and effect of adjuvant therapy in early-stage rectal cancer, current trends in the treatment of early-stage rectal cancer, and current early-stage rectal cancer trials.

Surgical and oncology trials for rectal cancer: Who will participate?

The assessment of patients' and clinicians' willingness to participate in clinical trials is advisable as part of a feasibility exercise prior to the commencement of randomized controlled trials (RCTs) to ensure adequate support in terms of likely accrual to achieve the required sample size in a timely fashion. Furthermore, understanding why patients are unwilling to enter RCTs is imperative before the current trend of low participation can be reversed. Patients, colorectal surgeons, and medical and radiation oncologists, were presented with 5 different, detailed treatments for locally advanced rectal cancer. They were asked whether they would be willing to enter an RCT comparing each treatment choice. Patients who would not participate were asked to indicate their reason for refusal. Patients' willingness to participate in each trial was consistently low (19% to 32%). Similar low levels of participation were indicated by each clinical subspecialty (15% to 38%). Of the scenarios, patients and clinicians were most willing to enter a trial investigating surgery plus preoperative radiotherapy. A dislike of randomization, a desire to be involved in decision-making, and quality of life considerations were the most commonly stated reasons for refusal. This study highlights the difficulties in performing RCTs in surgery and oncology. However, results suggest that improvements in communication regarding randomization and clinical trial processes and the actual, rather than perceived, side effects of treatments are strategies that may enhance patient participation.

Clarifying the TNM staging of rectal cancer in the context of modern imaging and neo‐adjuvant treatment: ‘y’‘u’ and ‘p’ need ‘mr’ and ‘ct’

Recent developments in cross-sectional imaging, particularly computerized tomography and magnetic resonance imaging have provided increasingly accurate noninvasive preoperative staging, especially for rectal cancer. Image-based TNM staging, by definition a pathological system, has entered both the literature and everyday usage with no universal agreement as to the exact terminology. Clarification of the current terminology and suggestions to reflect recent developments are outlined to facilitate multidisciplinary team decision processes and objective stratification for entry to, and monitoring of, future clinical trials in rectal cancer.

Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma

Preoperative radiotherapy (PRT) has become part of standard practice offered to improve treatment outcomes in patients with rectal cancer. To determine if PRT improves outcome for patients with localized resectable rectal cancer and how it compared with other adjuvant or neoadjuvant strategies. A computerized search was performed December 2006 on MEDLINE (from 1966 to December 2006) and the Cochrane Central Register of Controlled Trials (CENTRAL), conference proceedings, using MeSH and textwords where appropriate to identify randomized trials in PRT and rectal cancer. In addition, MetaRegister of Clinical Trials was searched for ongoing trials. Randomized trials with a PRT arm versus surgery alone, or other neoadjuvant or adjuvant (NA/A) strategies, targeted patients with localized rectal cancer planned for radical surgery were included. Trials were selected, data extracted and quality assessed by 2 authors. Quality was assessed using a 14 point checklist. Summary statistics included Hazard ratios and variances (for the outcomes: overall (OA) mortality, cause specific (CS) mortality, any recurrence and local recurrences (LR)) and Odds Ratio (OR) for other outcomes. Potential sources of heterogeneity hypothesized a priori included study quality, biological effective dose (BED), radiotherapy RT technique, and total mesorectal excision (TME) surgery. Nineteen trials compared PRT versus surgery alone. Overall (OA) mortality was marginally improved HR 0.93 [95% CI -0.87-1](absolute difference is 2% if the expected survival rate is 60%). Local recurrence (LR) was improved but the magnitude of benefit was heterogeneous across trials. Sensitivity analyses suggested greater benefits in patients treated with BED>30Gy(10) and multiple field RT techniques. There was significantly more pelvic or perineal wound infection, late rectal and sexual dysfunction. Nine trials compared PRT vs. other NA/A. Available evidence did not support an OA mortality or sphincter preserving benefit with the use of combined chemoradiotherapy (CRT) or selective postoperative RT. CRT provides incremental benefit for local control compared with PRT, which was independent of the timing of the CT. There was no significant difference in outcome for different intervals between RT and surgery (2 vs. 8 wk). Dose escalation with endocavitary boost showed significant effect on sphincter preservation. Optimal PRT improves LR, OA mortality, but no increase in sphincter sparing procedure. CRT further increases local control. If the objective is to increase the incidence of sphincter sparing surgery, endocavitary boost showed the most promise. Strategies with the potential to improve outcomes, especially OAS and sphincter sparing while reducing acute and late toxicities (rectal and sexual function) are needed to guide future strategy designs.

An individual patient data meta-analysis of adjuvant therapy with uracil–tegafur (UFT) in patients with curatively resected rectal cancer

Uracil–Tegafur (UFT), an oral fluorinated pyrimidine chemotherapeutic agent, has been used for adjuvant chemotherapy in curatively resected colorectal cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with rectal cancer. The objective of this study was to perform a reappraisal of randomised clinical trials conducted in this field. We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of UFT for curatively resected rectal cancer in terms of overall survival (OS), disease-free survival (DFS), and local relapse-free survival (LRFS). We analysed individual patient data of five adjuvant therapy randomised clinical trials for rectal cancer, which met the predetermined inclusion criteria. These five trials had a combined total of 2091 patients, UFT as adjuvant chemotherapy compared to surgery-alone, 5-year follow-up, intention-to-treat-based analytic strategy, and similar endpoints (OS and DFS). In a pooled analysis, UFT had significant advantage over surgery-alone in terms of both OS (hazard ratio, 0.82; 95% confidence interval (CI), 0.70–0.97; P=0.02) and DFS (hazard ratio, 0.73; 95%CI, 0.63–0.84; P<0.0001). This individual patient-based meta-analysis demonstrated that oral UFT significantly improves both OS and DFS in patients with curatively resected rectal cancer.

Rectal Cancer Trial Supports Preoperative Radiation

Rectal Cancer Trial Supports Preoperative Radiation

Alternative clinical end points in rectal cancer—are we getting closer?

Background: In rectal cancer a high risk of local recurrence has been reported for patients treated by surgery alone. It is also recognised that 20%–40% of rectal cancer patients continue to develop distant metastases and die, even when a very low risk of local recurrence has been achieved with the use of preoperative radiotherapy and total mesorectal excision (TME). Hence, the current design of randomised trials in rectal cancer continues to use the standard end points of local control and survival. This strategy is time-consuming. The recently published EORTC 22921 trial, which compared radiotherapy with chemoradiotherapy and tested the role of postoperative adjuvant chemotherapy, has taken 14 years from planning to results. The aim of this review was to use the evidence from both phase II and phase III trials to provide a comprehensive survey of alternative clinical trial end points in rectal cancer, where preoperative chemoradiation has now become the standard treatment. We describe their strengths and weaknesses. Some are clearly defined, easy to assess and can be obtained early, because surgical resection usually takes place within 6–8 weeks of the completion of treatment. Some pathological response end points reflect biological activity, although their effect on survival has yet to be validated in randomised controlled trials. We will propose measurement and analytical techniques for minimising bias and intra- and inter-observer variability of the non-validated end points in the hope of basing these judgements on as firm a ground as possible.Methods: A literature search identified both randomised and non-randomised trials of preoperative radiation therapy (RT) and chemoradiation therapy (CRT) in rectal cancer from 1993 to 2005. The aim was to find those studies that documented potential alternative end points.Results: Pathological parameters have been used as early end points to compare studies of preoperative radiotherapy or chemoradiation. In the light of the German CAO/ARO/AIO-94 study, which demonstrated an improved therapeutic ratio for preoperative treatment, enthusiasm for preoperative chemoradiation in the management of rectal cancer is increasing. Current evidence cannot indicate whether the degree of response to chemoradiation (e.g. complete pathological response; downsizing the primary tumour; sterilizing the regional nodes; tumour regression grades or residual cell density) or the achievement of a curative resection (CRM/R0 resection) is the best early clinical end point. Problems with these end points include lack of structured measurement and analysis techniques to control for intra- and inter-observer variation and lack of validation as surrogates for long-term clinical end points such as local control and survival. However, retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. Further end points of current clinical relevance for which adequate methodologies for assessment are lacking include sphincter sparing end points, and assessment of long-term toxicities, ano-rectal function and their specific impact on quality of life. Recommendations are made as to the most appropriate information, which should be documented in future trials.Conclusions: Pathological complete response following preoperative chemoradiation does not reliably predict late outcome. There are other events not mediated through this end point and there are also unintended effects (often an excess of non-cancer related deaths). Disease-free survival currently remains the best (because it is relatively quick) primary end point in designing randomised phase III studies of preoperative chemoradiation in rectal cancer, although it is necessary to control for postoperative adjuvant chemotherapy. However, the CRM status can substantially account for effects on disease-free and overall survival after chemoradiation, radiation or surgery alone. Hopefully, randomised controlled trials, which utilise these alternative clinical end points, will in future determine the precise percentages of the effect of different chemoradiation schedules on disease-free and overall survival.

Low Rectal Cancer: A Call for a Change of Approach in Abdominoperineal Resection

Despite the major improvements that have been made due to total mesorectal excision (TME), low rectal cancer still remains a challenge. By investigating a prospective randomized rectal cancer trial in which surgeons had undergone training in TME the factors responsible for the poor outcome were determined and a new method for assessing the quality of surgery was tested. Survival differed greatly between abdominoperineal resection (APR) and anterior resection (AR; 38.5% v 57.6%, P = .008). Low rectal carcinomas have a higher frequency of circumferential margin involvement (26.5% v 12.6%, P < .001). More positive margins were present in the patients operated with APR (30.4%) compared to AR (10.7%, P = .002). Furthermore, more perforations were present in these specimens (13.7% v 2.5%, P < .001). The plane of resection lies within the sphincteric muscle, the submucosa or lumen in more than 1/3 of the APR cases, and in the remainder lay on the sphincteric muscles. We systematically described and investigated the pathologic properties of low rectal cancer in general, and APR in particular, in a prospective randomized trial including surgeons who had been trained in TME. The poor prognosis of the patients with an APR is ascribed to the resection plane of the operation leading to a high frequency of margin involvement by tumor and perforation with this current surgical technique. The clinical results of this operation could be greatly improved by adopting different surgical techniques and possibly greater use of radiochemotherapy.

603 ORAL The swedish rectal cancer trial — long-term effects of preoperative radiotherapy

The fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody panitumumab has been shown to improve progression-free survival when administered as a monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) and is approved in this setting. Two large randomized clinical trials have investigated panitumumab in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a first-line therapy for mCRC and 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as a second-line therapy for mCRC. In these studies, the combination of panitumumab with FOLFOX or FOLFIRI resulted in improved progression-free survival compared with FOLFOX or FOLFIRI alone. Improved tumor response was also observed with the addition of panitumumab to FOLFIRI. As in monotherapy trials, the clinical benefits associated with panitumumab treatment were confined to patients with wild-type KRAS tumors, further showing the validity of KRAS mutational status as a predictive biomarker in mCRC. In addition to KRAS mutational status, a number of other potential predictive biomarkers are currently being investigated in mCRC and may eventually help identify patients who are likely to benefit from treatment with anti-EGFR monoclonal antibodies. Toxicities observed during treatment with panitumumab combined with FOLFOX or FOLFIRI were generally manageable and commonly included skin toxicities and gastrointestinal toxicities. Because it can lead to dose delays, dose reductions, and discontinuation, physicians and patients should carefully manage skin toxicity. Overall, the results of these two studies show that panitumumab improves outcomes when added to FOLFOX or FOLFIRI among patients with mCRC with wild-type KRAS.

Swedish Rectal Cancer Trial: Long Lasting Benefits From Radiotherapy on Survival and Local Recurrence Rate

To evaluate the long-term effects on survival and recurrence rates of preoperative radiotherapy in the treatment of curatively operated rectal cancer patients. Of 1,168 randomly assigned patients in the Swedish Rectal Cancer Trial between 1987 and 1990, 908 had curative surgery; 454 of these patients had surgery alone, and 454 were administered preoperative radiotherapy (25 Gy in 5 days) followed by surgery within 1 week. Follow-up was performed by matching against three Swedish nationwide registries (the Swedish Cancer Register, the Hospital Discharge Register, and the Cause of Death Register). Median follow-up time was 13 years (range, 3 to 15 years). The overall survival rate in the irradiated group was 38% v 30% in the nonirradiated group (P = .008). The cancer-specific survival rate in the irradiated group was 72% v 62% in the nonirradiated group (P = .03), and the local recurrence rate was 9% v 26% (P < .001), respectively. The reduction of local recurrence rates was observed at all tumor heights, although it was not statistically significant for tumors greater than 10 cm from the anal verge. Preoperative radiotherapy with 25 Gy in 1 week before curative surgery for rectal cancer is beneficial for overall and cancer-specific survival and local recurrence rates after long-term follow-up.

ATM expression in rectal cancers with or without preoperative radiotherapy

Patients with ATM (Ataxia-Telangiectasia mutated) mutation show increased sensitivity to radiation and have a higher risk of developing malignancies. The present study aimed to investigate whether ATM expression was related to radiotherapy, and clinicopathological and biological variables in rectal cancers. ATM expression was immunohistochemically examined in 78 rectal cancers from patients who participated in a Swedish rectal cancer trial of preoperative radiotherapy. Of 78 patients, 44 underwent surgery alone, and 34 underwent both preoperative radiotherapy and surgery. Fifty-eight cases had normal rectal mucosa adjacent to the tumour. The results showed that, compared to normal mucosa, tumours had less nuclear (p=0.03) but more cytoplasmic expression of ATM (p=0.004). In tumours, less expression of ATM, either in the nucleus (p=0.07) or in the cytoplasm (p=0.02 for staining intensity, and p=0.07 for staining percentage), tended to be correlated with male patients. Also, ATM expression was not related to radiotherapy or other clinicopathological and biological variables (p>0.05). In conclusion, the pattern of ATM expression was changed from normal mucosa to tumour. Less expression of ATM may be related to males.

Therapy for Colorectal Cancer

Recent advances in systemic therapy involve the biochemical modulation of fluorouracil. New trials combining either leucovorin or N-(phosphonoacetyl)-L-aspartate (PALA) with fluorouracil have demonstrated increased response rates. Recent trials of interferon-alpha with fluorouracil have not confirmed the high response rates reported in previous trials. Advances in regional therapy include the addition of either leucovorin or systemic therapy to fluorodeoxyuridine. Some adjuvant trials of portal vein infusion have shown increased survival, though the incidence of liver metastases was not decreased. A large adjuvant trial in rectal cancer demonstrated improved survival and decreased local recurrences when fluorouracil and methyl-CCNU were added to radiation therapy.

Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy

Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p < or = 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors.

Occurrence of Second Cancers in Patients Treated With Radiotherapy for Rectal Cancer

To analyze the occurrence of second cancers in patients with rectal cancer treated with external radiotherapy (RT) in addition to surgery. The analyses were based on the Uppsala Trial (completed in 1985), with patients randomly assigned to preoperative RT to all stages or postoperative RT for stage II and III cancers, and the Swedish Rectal Cancer Trial (completed in 1990), with patients randomly assigned to preoperative RT or surgery alone. Patients from the trials were matched against the Swedish Cancer Registry. A total of 115 (7%) of the 1,599 patients developed 122 second cancers. More patients treated with RT developed a second cancer (relative risk [RR], 1.85; 95% CI, 1.23 to 2.78). A significant increased risk for second cancers in the RT group was seen in organs within or adjacent to the irradiated volume (RR, 2.04; 95% CI, 1.10 to 3.79) but not outside the irradiated volume (RR, 1.78; 95% CI, 0.97 to 3.27). For the Swedish Rectal Cancer Trial, 20.3% of the RT patients got either a local recurrence or a second cancer, compared with 30.7% of the non-RT patients (RR, 0.55; 95% CI, 0.44 to 0.70). An increased risk of second cancers was found in patients treated with RT in addition to surgery for a rectal cancer, which was mainly explained by an increase in the risk of second cancers in organs within or adjacent to the irradiated volume. However, a favorable effect of radiation seemed to dominate, as shown by the reduced risk of the sum of local recurrences and second cancers.

Adverse Effects of Preoperative Radiation Therapy for Rectal Cancer: Long-Term Follow-Up of the Swedish Rectal Cancer Trial

To analyze the occurrence of subacute and late adverse effects in patients treated with preoperative irradiation for rectal cancer. The study population included 1,147 patients randomly assigned to preoperative radiation therapy or surgery alone in the Swedish Rectal Cancer Trial conducted 1987 through 1990. Patient data were matched against the Swedish Hospital Discharge Register to identify patients admitted to hospital after the primary treatment of the rectal cancer. Patients with known residual disease were excluded, and patients with a recurrence were censored 3 months before the date of recurrence. Relative risks (RR) with 95% CIs were calculated. Irradiated patients were at increased risk of admissions during the first 6 months from the primary treatment (RR = 1.64; 95% CI, 1.21 to 2.22); these were mainly for gastrointestinal diagnoses. Overall, the two groups showed no difference in the risk of admissions more than 6 months from the primary treatment (RR = 0.95; 95% CI, 0.80 to 1.12). Regarding specific diagnoses, however, RRs were increased for admissions later than 6 months from the primary treatment in irradiated patients for unspecified infections, bowel obstruction, abdominal pain, and nausea. Gastrointestinal disorders, resulting in hospital admissions, seem to be the most common adverse effect of short-course preoperative radiation therapy in patients with rectal cancer. Bowel obstruction was the diagnosis of potentially greatest importance, which was more frequent in irradiated than in nonirradiated patients.