Adjuvant Treatment Of Rectal Cancer Research Articles

The complementary role of lymphovascular invasion and perineural invasion in the TNM staging process of rectal cancer.

The aim of this study is to clarify the association between lymphovascular invasion (LVI) and/or perineural invasion (PNI) and the clinical characteristics and prognostic importance of rectal cancer, to provide a basis for early adjuvant treatment of rectal cancer. We retrospectively analyzed patients diagnosed with rectal cancer. This study involved rectal cancer tissue samples were obtained by surgical methods. Data on histological form, tumor classification, tumor size, gross growth pattern, blood and lymphatic vessel invasion, and PNI of the slice by HE staining were obtained from pathological examination. Immunohistochemical analysis of tissue samples was performed to determine p53 and EGFR expressions. There were 330 rectal cancer patients included in the study. LVI and/or PNI can be used as a high-risk factor for the prognosis of rectal cancer, predict prognostic survival, and guide adjuvant therapy. The detection rates of LVI and PNI were 32.1% and 16.1%. Differentiation grade, Union for International Cancer Control staging, tumor-lymph node-metastasis staging are significantly related to LVI or PNI. Multivariate logistic regression analysis shows that poor differentiation and N ≥ 1 can be used as independent risk factors and predictive factors for LVI. At the same time, poor differentiation and T > 3 is an independent risk factor for PNI. Only poor differentiation is the risk factor for poor prognosis in Cox risk regression analysis. In addition, the simultaneous occurrence of LVI and PNI is an independent prognostic factor.

Intraoperative radiotherapy as an immediate adjuvant treatment of rectal cancer due to limited access to external-beam radiotherapy

BackgroundNeoadjuvant external-beam radiotherapy (EBRT) with concomitant chemotherapy is the current standard-of-care for locally-advanced rectal cancer. Intraoperative radiotherapy (IORT) is to date only recommended for pelvic recurrences or incompletely resectable tumors. We here report on patients with stage II/III rectal cancer that were treated with IORT in a regional Russian university center due to limited access to EBRT.MethodsWe retrospectively analyzed data from patients that were diagnosed with locally-advanced rectal cancer and underwent surgery from December 2012 to October 2016 at a regional oncological center in Russia (Krasnodar). During this period, access to EBRT was limited due to a temporary lack of a sufficient number of EBRT facilities. Patients unable to travel to a distant radiotherapy site received IORT alone, those that could travel received neoadjuvant external beam (chemo-) radiotherapy. Factors of interest were tumor stage, tumor differentiation, resection status, surgery type and neoadjuvant or adjuvant chemotherapy. We assessed local progression-free survival (L-PFS), PFS and overall survival (OS).ResultsA total of 172 patients were included in this analysis. Of those, 92 (53.5%) were treated with IORT alone (median dose: 15 Gy [8.4–17 Gy]) and 80 (46.5%) received both neoadjuvant EBRT (median dose: 50.4 Gy [40–50.4 Gy]) and IORT (median dose: 15 Gy [15–17 Gy]). The median age was 65 years [33–82]. The median follow-up was 23 months [0–63 months]. The incidence of toxicity was low in both groups with an overall complication rate of 5.4%. Local PFS at 4 years was comparable with 59.4% in the IORT group and 65.4% in the IORT/EBRT group (p = 0.70). Similarly, there was no difference in OS or PFS (p = 0.66, p = 0.51, respectively).ConclusionsIORT is a valuable option for patients with locally-advanced rectal cancer in the absence of access to EBRT.

Intensity modulated radiotherapy delivers competitive local control rate with limited acute toxicity in the adjuvant treatment of rectal cancer.

Intensity-modulated radiotherapy (IMRT) has yet to show its capability in the adjuvant treatment of locally advanced rectal cancer. The purpose of this study is to evaluate the clinical efficacy and safety profile of IMRT in the adjuvant treatment of rectal cancer. Consecutive patients with resected locally advanced rectal cancer who had IMRT as part of adjuvant treatment between 2008 and 2014 were identified. The medical records and dosimetric parameters of 72 patients were retrospectively examined. The median follow-up time was 4.36 years (range 0.16-8.49 years). Overall survival rate and disease-free survival rate at 3 year was 79% (95% CI: 66.4-7.3%) and 70% (95% CI: 56.6-79.6%), respectively. Local control rate was 95%. The median bowel bag V45 was 282 ml (249-458 ml) and bone marrow V40 was 29%. Most acute toxicities were self-limited. Concurrent use of chemotherapy was associated with greater odds of ≥Grade 2 acute neutropenia (OR 25.44, P = 0.022). Integration of IMRT in the adjuvant treatment of rectal cancer is promising with competitive local control rate. Acute toxicities are mostly self-limited.

Update on advances and controversy in rectal cancer treatment.

Changes in the multidisciplinary treatment of rectal cancer have been recently proposed. We performed a comprehensive review of the current data on neoadjuvant and adjuvant treatment of rectal cancer, focussing on chemoradiotherapy treatment and timing of surgery. Six components were proposed as the framework for the treatment of rectal cancer: neoadjuvant therapy and changing patterns in patient selection, long- or short-course radiotherapy, adverse effects of radiotherapy, timing of surgery, non-operative management of rectal cancer and postoperative adjuvant therapy. Lack of a consistent difference in terms of local recurrence has been observed between short-course radiotherapy and long-course chemoradiotherapy. Indications for preoperative radiotherapy have been reconsidered in the last years. An interval of 10-11 weeks seemed to be the optimal timing, with no impact on patient safety. Since assessment criteria of clinical complete response are not well defined, and the basis for non-operative management of rectal cancer is still not clear, further investigations are required. There is controversy about standard treatments for patients with locally advanced rectal cancer that are being analyzed by ongoing studies. Tailored treatments could avoid over-treatment for a large number of patients without any impairment of the oncologic results.

Adjuvant treatment for rectal cancer: Short-course radiation vs. long-course chemoradiation

Adjuvant preoperative therapy for rectal cancer is delivered by two fractionation schedules: short-course radiation and long-course chemoradiation. Patients selected for treatment with short-course radiation included those with cT1–3 disease, whereas those selected for chemoradiation include cT3 and/or N+ disease. Therefore, retrospective comparisons were not possible. There are two randomized trials that have included patients with cT3 and/or N+ disease as well delivered sequential or postoperative chemotherapy thereby allowing a more relevant comparison with chemoradiation. New trials of short-course radiation have included patients with stages cT3 and/or N+ as well delivered sequential or chemotherapy.

Abstract 1145: CXCR4-CXCL12-CXCR7 axis predicts prognosis in locally advanced-Chemo Radiotherapy (CRT) treated rectal cancer patients.

Abstract With optimized local treatment and the shift from a postoperative to a preoperative treatment approach, distant metastases have become the predominant mode of failure in locally advanced rectal cancer (LARC). Therefore, the intensification of chemotherapy appears today as an essential approach to improve distant control and survival in LARC. However, extensive evidence have indicated that the LARC presents a considerable heterogeneity in terms of prognostic and response to preoperative treatment. Thus a critical issue is the selection of patients for postoperative chemotherapy strongly favoring a risk-adapted strategy rather than “one size fits all” approach. The chemokine receptor CXCR4 is expressed in colorectal cancer (CRC) and correlates with reduced survival and disease-free interval. A novel receptor for CXCL12, CXCR7, was recently identified. Despite the signal transduction of CXCR7 is not defined it certainly regulates the activity of CXCR4. The aim of the present study is to evaluate the possible prognostic role of CXCR4-CXCL12-CXCR7 axis in LARC patients subjected to CRT neoadjuvant treatment and total mesorectal excision. Sixty-eight LARC patients treated with different scheme of CRT and with persistence of pathological tumor were evaluated for the expression of CXCR4, CXCR7, CXCL12 through immunohistochemistry. CXCR4 and CXCR7 were rated as negative (0-50%) CXCL12 was rated as low (50%). At a median follow up of 65 months, high CXCR4 expression (>50%) impacted significantly on 5- years-relapse free survival (RFS) and -cancer specific survival (CSS); high CXCR4 patients had a 5-year RFS of 51,5% versus 93,7% negative-low CXCR4 (HR 0.10; 95% CI, 0.07-0.44) (p = 0.0003), patients with high CXCR4 had a 5-year CSS of 69% versus the 100% of negative-low CXCR4 (HR 0.00; 95% CI, 0.03-0.43) (p = 0.001). The expression of CXCR7 and CXCL12 alone did not correlate with survival; concomitant expression of CXCR4/CXCR7 or CXCR4/CXCL12 improved the prediction of survival. High CXCR4 expression/ neg-low CXCR7 (< 50%) impacted on 5 years- RFS (p = 0.0001) as well as CSS (p = 0.0278); high CXCR4 expression plus neg-low CXCL12 (<50%) affected 5 years-RFS (p = 0.0166) and CSS (p = 0.0145). Interestingly evaluating CXCR4 categories (negative/low and high) versus the lymph nodal status (negative and positive) significantly improved the predictive power of CXCR4 and N status. High CXCR4 expression plus N+ identified patients with a worse 5 years RFS (p= 0.0001). The valuation of the CXCR4-CXCL12-CXCR7 axis is a valuable prognostic tool in rectal cancer patients treated with CRT neoadjuvant. Moreover CXCR4 inhibitors might be considered in the adjuvant treatment of rectal cancer. Citation Format: Crescenzo D'Alterio, Antonio Avallone, Paolo Delrio, Fabiana Tatangelo, Biagio Pecori, Elena Di Gennaro, Rosario Vincenzo Iaffaioli, Paolo Muto, Gerardo Botti, Stefania Scala. CXCR4-CXCL12-CXCR7 axis predicts prognosis in locally advanced-Chemo Radiotherapy (CRT) treated rectal cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1145. doi:10.1158/1538-7445.AM2013-1145

5-Flourouracil–Induced Encephalopathy in Parkinson’s disease

A 59 year-old male with Parkinson’s disease developed encephalopathy during adjuvant treatment of rectal cancer. Acute neurotoxicity related to high dose 5-Flourouracil infusion is well described, but encephalopathy with low dose bolus 5-Flourouracil is rare. The advanced Parkinson’s disease patients may be more prone to hyperammonemia associated encephalopathy caused by 5-Flourouracil . The prompt recognition of the symptoms is key to diagnosis and treatment.

Cancer du rectum et chimiothérapie adjuvante : quelles conclusions ?

Adenocarcinoma of the rectum represents about a third of cases of colorectal cancer, with an annual incidence of 12,000 cases in France. On the contrary of colon cancer, the benefice of adjuvant chemotherapy in rectal cancer has not been definitively proved, more because this question was assessed in few recent studies than because negative results. Preoperative radiochemotherapy is now the reference treatment for mid and lower rectal cancers, and allow to increase the local control without improvement of progression free survival and overall survival. The data of the “historical studies” of adjuvant treatment in rectal cancer published before 1990, of the meta-analysis of adjuvant trials in rectal cancer and of the QUASAR study suggest that adjuvant chemotherapy with fluoropyrimidines (intravenous or oral), in absence of pre-operative treatment, decrease the risk of metastatic relapse after curative surgery for a rectal cancer of stage II or III. This benefice seems similar to the one observed in colon cancer. In the EORTC radiotherapy group trial 22921, an adjuvant chemotherapy with 5-fluorouracil and low dose of leucovorin was not associated with a significantly improvement of overall survival but, despite the fact that only 42.9% of patients received all planed cycles, the progression free survival was increased (not significantly) in groups receiving adjuvant chemotherapy. The French recommendations are to discuss the indication of adjuvant chemotherapy by fluoropyrimidines in cases of stage III rectal cancer on histopathologic reports and no chemotherapy in case of stade II. Despite the fact that none study have assessed a combination of fluoropyrimidines and oxaliplatin in adjuvant setting in rectal cancer, like in colon cancer, the Folfox4, modified Folfox6 or Xelox regimens are valid options in stage III (experts opinion). In cases of pathologic complete remission or in absence of involved nodes, the benefice of adjuvant chemotherapy is not assessed. In all cases, the decision of adjuvant chemotherapy has to be taken during a multidisciplinary meeting. The interest of a combination of fluoropyrimidine and oxaliplatin is assessed in currently adjuvant trials (PETTAC-6 and CAO/ARO/AIO-04), and future trials will assess the interest of neoadjuvant chemotherapy.

Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to develop a cutoff-dose normal tissue complication probability (NTCP) model. There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.

Safety analysis of the French Intergroup R98 trial comparing 5FU-leucovorin alone or with irinotecan in resected stages II-III rectal cancers

4088 Background: Irinotecan combined with 5FU/LV improves the outcome of patients (pts) with advanced colorectal cancer. R98 trial tests the hypothesis that this combination is superior to 5FU/LV alone to prevent recurrence or death in resected stages II-III rectal cancers. Methods: Between 03/1999 and 12/2005, 357 pts were postoperatively randomized to 5FU/LV (control arm) or 5FU/LV + irinotecan. Primary endpoint was DFS. The control arm consisted of either a Mayo-Clinic regimen (A: LV 20 mg/m², 5FU 425 mg/m² bolus days 1–5, repeated at d29, d57, d92, d127 and d162) or a LV5FU2 regimen (A’: LV 200 mg/m² over 2-hour, 5FU 400 mg/m² bolus and 600 mg/m² 22-hour infusion, d1–2, Q2W for 12 cycles), depending on centre choice. Experimental arm (B) consisted of LV5FU2 + irinotecan 180 mg/m² d1 of every cycle. Results: We present here the final safety analysis based on 341 evaluable pts. 172 pts were treated in the control arm (A, 56 pts or A’,116 pts), and 169 pts in the experimental arm (B). Pretreatment characteristics were well balanced between the groups; median age 62 years, stage II in 32% of pts. 68% of pts received preoperative RT, and 80% had sphincter conservation. 95% arm A and A’, and 72% arm B pts received more than 75% of planned chemotherapy dose. No toxic death was reported. G3–4 toxicity per pt was as follows for arms A, A’, and B: neutropenia 36%, 6%, 33%; diarrhea 9%, 9%, 13%; nausea-vomiting 2%, 1%, 7%; mucositis: 5%, 0%, 1%; infection: 7%, 2%, 1%; any toxicity (except alopecia): 50%, 20%, 47%; other G3–4 toxicities <5%. G3- 4 neutropenia and vomiting were significantly higher in the experimental arm than in the control arm (33% vs 16%; P<0.0001 and 5% vs 0%; p=0.002, respectively). RT was not associated with a statistically significant increase risk of diarrhea. Conclusions: The addition of irinotecan to a LV5FU2 regimen led to a decrease of dose intensity, and to an increase of neutropenia and of vomiting in the adjuvant treatment of rectal cancer. The safety profile of 5FU/LV + irinotecan remained however acceptable compared to 5FU/LV alone. First efficacy analysis is expected at the end of 2008. Study supported by Pfizer, France Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Roche Baxter, Merck, Pfizer, sanofi-aventis Pfizer, sanofi-aventis

Residual Treatment Disparities After Oncology Referral for Rectal Cancer

Black patients with rectal cancer are considerably less likely than white patients to receive adjuvant therapy. We examined the hypothesis that the lower treatment rate for blacks is due to underreferral to medical and radiation oncologists. We used 1992-1999 Surveillance, Epidemiology, and End Results-Medicare data to identify elderly (> or = 66 years of age) patients who had been hospitalized for resection of stage II or III rectal cancer (n = 2716). We used chi(2) tests to examine associations between race and 1) consultation with an oncologist and 2) receipt of adjuvant therapy. We then used logistic regression to analyze the influence of sociodemographic and clinical characteristics (age at diagnosis, sex, marital status, median income and education in area of residence, comorbidity, and cancer stage) on black-white differences in the receipt of adjuvant therapy. All statistical tests were two-sided. There was no statistically significant difference between the 134 black patients and the 2582 white patients in the frequency of consultation with a medical oncologist (73.1% for blacks vs 74.9% for whites, difference = 1.8%, 95% confidence interval [CI] = > 5.9% to 9.5%, P = .64) or radiation oncologist (56.7% vs 64.8%, difference = 8.1%, 95% CI = > 0.5% to 16.7%, P = .06), but blacks were less likely than whites to consult with both a medical oncologist and a radiation oncologist (49.2% vs 58.8%, difference = 9.6%, 95% CI = 0.9% to 18.2%, P = .03). Among patients who saw an oncologist, black patients were less likely than white patients to receive chemotherapy (54.1% vs 70.2%, difference = 16.1%, 95% CI = 6.0% to 26.2%, P = .006), radiation therapy (73.7% vs 83.4%, difference = 9.7%, 95% CI = 0.4% to 19.8%, P = .06), or both (60.6% vs 76.9%, difference = 16.3%, 95% CI = 4.3% to 28.3%, P = .008). Patient and provider characteristics had minimal influence on the racial disparity in the use of adjuvant therapy. Racial differences in oncologist consultation rates do not explain disparities in the use of adjuvant treatment for rectal cancer. A better understanding of patient preferences, patient-provider interactions, and potential influences on provider decision making is necessary to develop strategies to increase the use of adjuvant treatment for rectal cancer among black patients.

Consumer impact of an interactive decision aid for rectal cancer patients offered adjuvant therapy

There is increasing interest in the use of decision aids (DAs) to facilitate patient involvement in clinical decisions. This study explored the views of patients with colorectal cancer and participants in a community bowel screening service regarding an interactive DA concerning adjuvant treatment for rectal cancer, and the impact of the aid on knowledge, anxiety, attitudes and preferences for treatment options. Fourteen patients with colorectal cancer participated in four focus groups. Eighty-nine participants in a community bowel screening service completed a questionnaire before and 1 week after viewing the DA. Thirty were randomly selected to participate in a telephone interview to obtain qualitative feedback about the DA. Focus group participants reported using information to evaluate their doctor's care and expertise, or to prepare themselves for future symptoms and side-effects. Most supported the use of a DA and preferred pie charts to convey risk information. Within the community sample, anxiety remained stable and knowledge increased after exposure to the DA. Almost all participants found the DA useful and easy to understand, and felt it would make the process of decision making easier. A DA regarding adjuvant therapy for rectal cancer appears to be valued and to produce positive outcomes. A randomized controlled trial of this intervention is now required.

Hand-Foot Syndrome Variant in a Dihydropyrimidine Dehydrogenase–Deficient Patient Treated with Capecitabine

We present a case with dihydropyrimidine dehydrogenase (DPD) deficiency that manifested a variant of hand-foot syndrome (HFS). A 52-year-old man received capecitabine for adjuvant treatment of rectal cancer. On the ninth day of the first cycle, he presented to the clinic with a rash on the dorsum of both hands accompanied by symptoms of pain, erythema, swelling, and desquamation consistent with grade 3 HFS. The palms of his hands and soles of his feet were only tender with no apparent rash or discoloration. Dihydropyrimidine dehydrogenase activity was evaluated by radio assay using peripheral blood mononuclear cells. Dihydropyrimidine dehydrogenase activity was below normal: 0.12 nmol/minute/mg protein. Capecitabine was not resumed, and the rash resolved in 3 weeks with the use of pyridoxine and Udderly Smooth balm. Interestingly, HFS is rarely seen with 5-fluorouracil regimens containing selective DPD-inhibitors. This patient with DPD deficiency manifested a variant of HFS. The pharmacologic basis for the development of HFS in DPD-deficient patients warrants further investigation. Dihydropyrimidine dehydrogenase deficiency, if undiagnosed, can lead to death. In addition to severe to life-threatening toxicities akin to 5-fluorouracil, capecitabine can lead to unusual variants of common toxicities, including HFS, in DPD-deficient patients.

Postoperative Adjuvant Irradiation With or Without Chemotherapy for Rectal Carcinoma.

p atients with rectal carcinoma who are candidates for adjuvant treatment, in spite of complete surgical resection with negative margins, are those with a moderate to high risk of local or systemic failure or decreased survival when treated with surgery alone. The high-risk factors include primary tumor extension beyond the rectal wall, involved nodes, or both (Dukes' stage B or C; Astler-Coller B2, Cl, or C2; modified Astler-Coller B2.3, C1.3; TNM T3-4 NO, Tis-4 N1-3). The ideal adjuvant treatment for resectable highrisk rectal cancer would preferably decrease both local and systemic failures, increase both disease-free and overall survival, and accomplish such with acceptable tolerance. At the 1990 National Institutes of Health (NIH) Consensus Conference on Adjuvant Therapy of Large Bowel Cancer, 1 the efficacy of adjuvant treatment for rectal cancer was evaluated by outcomes of three scientific endpoints: (1) incidence of pelvic (local) recurrence, (2) disease-free survival (time to relapse), and (3) overall survival. Inclusion of local recurrence as a separate endpoint is based on the significant morbidity of pelvic recurrence 2 and the difficulty in achieving subsequent salvage for cure. Standard treatment of pelvic recurrence results in short-term palliation (usually 6 to 12 months) and infrequent cure. 3 Although distant metastases result in less patient months of morbidity than local recurrence in high-risk patients treated with surgery alone, 2 subsequent cure can be achieved only when solitary or adjacent metastases can be resected. Reduction in the incidence of distant metastases with effective systemic adjuvants would be a justifiable separate endpoint in future trials.

The Role of Radiation Therapy and 5-Fluorouracil in Colon and Rectal Cancer.

Since the original report improved survival of patients with locally unresectable gastric cancer treated with irradiation and 5-fluorouacil (5-FU) in 1968, there has been extensive investigation of this treatment combination in a variety of gastrointestinal tumors, including colon and rectal cancer. There are now extensive data supporting the use of 5-FU-based chemotherapy with irradiation in the adjuvant treatment of rectal cancer and increasing experience defining its role in negotiant therapy. The value of adjuvant 5-FU-based chemotherapy and irradiation in colonies cancer is controversial, but there may be subsets of patients who benefit from this treatment. Ongoing studies in rectal and colon cancer are evaluating the role of irradiation with various modes of 5-FU adminstration (bolus v short or continuous infusion) as well as its modulation with other agents.

Adjuvant Therapy in Rectal Cancer: What is the Truth?

It’s just like deja vu. Japanese surgeons have often been dismissive of the value of adjuvant treatment for gastric cancer reported from Europe and America (1,2) because of differences in the degree of lymph node dissection between Japan and Europe/America (3). In contrast, Japanese surgeons may be surprised and delighted at the results of the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC) of postoperative adjuvant chemotherapy for rectal cancer published in this issue of the JJCO (4), the results of which have not been so exciting for European and American oncologists. Such differences have resulted from attitudes towards the basic surgical procedures and the strategy of postoperative adjuvant treatment for rectal cancer. In Europe and America, adjuvant therapy for rectal cancer has included radiotherapy as a standard. In Japan, postoperative chemotherapy has been the primary treatment mainly because of excellent outcomes of surgery including autonomic nerve-preserving D3 dissection (lateral lymphadenectomy). The latest National Comprehensive Cancer Network (NCCN) guidelines prescribe preoperative concomitant radiotherapy and chemotherapy (FU – LV or Capecitabine) and postoperative chemotherapy (FU – LV or FOLFOX or Capecitabine) or, when preoperative chemoradiotherapy was not given, postoperative concomitant radiotherapy and chemotherapy (FU – LV or FOLFOX or Capecitabine) (5). The use of chemotherapy has been based on the evidence of postoperative adjuvant chemotherapy in colon cancer, not rectal cancer. As for radiotherapy, local recurrence was reduced but the survival rate not increased in most reports. In the USA, postoperative radiotherapy following surgery for rectal cancer has been used from the beginning for local control. A randomized controlled trial of MOF therapy and postoperative adjuvant radiotherapy using surgery alone as the control arm has been performed (NSABP R-01 study). The 5 year disease-free survival (DFS) and overall survival (OS) rates were significantly higher in the MOF therapy group. Local control was significantly better in the postoperative adjuvant radiotherapy group, but DFS and OS were not (6). Although these findings did not clarify the significance of postoperative adjuvant radiotherapy, the 1990 NCI Consensus Development Conference defined chemotherapy + postoperative adjuvant radiotherapy as a standard postoperative adjuvant therapy for stage II and III rectal cancer (7). The subsequent NSABP R-02 study concluded that postoperative adjuvant radiotherapy did not improve the prognosis of rectal cancer. This study used the MOF therapy group, which was effective compared with the surgery alone group in the NSABP R-01 study, as the control. It investigated MOF versus MOF + postoperative adjuvant radiotherapy, MOF versus 5-FU/LV, and 5-FU/LV versus 5-FU/LV + postoperative adjuvant radiotherapy. No significant differences were noted in DFS or OS between the groups treated with adjuvant chemotherapy alone and chemotherapy + adjuvant radiotherapy after surgery. Disease free survival was significantly higher in the 5-FU/LV group when compared with MOF, but there was no difference in OS (8). These findings had a great impact on postoperative adjuvant radiotherapy, and the American Society of Clinical Oncology (ASCO) initiated discussion on the role of postoperative adjuvant radiotherapy. A subsequent meta-analysis performed by the Colorectal Cancer Collaboration Group confirmed that postoperative adjuvant radiotherapy significantly reduced local recurrence, but showed no significant difference in OS (9). Since it was clarified that postoperative adjuvant radiotherapy did not improve the prognosis of rectal cancer, the emphasis turned to the role of preoperative adjuvant radiotherapy. Various trials on the role of preperative adjuvant radiotherapy for rectal cancer have been reported, but a final conclusion is not yet reached. Two recent meta-analyses have shown that preoperative adjuvant radiotherapy reduces local recurrence rates by almost 50% and overall mortality by 2–10% (9, 10). Preoperative radiotherapy with higher biologically effective doses (of at least 30 Gy) have shown a larger reduction than either preoperative radiotherapy with lower doses or postoperative radiotherapy. However, the trials included in these meta-analyses all started before the broad introduction of total mesorectal excision (TME) surgery. The only randomized trial of TME with or without preoperative radiotherapy was that conducted by the Dutch Colorectal Cancer Group. After 2 years follow-up the estimated local recurrence rates were 2.4% with preoperative radiotherapy and 8.2% without preoperative radiotherapy. This relative reduction of local control For reprints and all correspondence: Hiroya Takiuchi, Internal Medicine II, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan. E-mail: in2028@poh.osaka-med.ac.jp

The argument for pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer

Although not universally accepted, chemoradiation is considered a standard adjuvant treatment for patients with resected pancreatic cancer. Theoretical advantages of reduced toxicity and increased efficacy with the use of pre-operative chemoradiation compared to post-operative adjuvant chemoradiation have recently been validated with the publication of a phase III trial in the adjuvant treatment of rectal cancer. Additional advantages of pre-operative chemoradiation that apply specifically to pancreatic cancer include increased access to therapy in patients treated before surgery, addressing the systemic disease recurrence risk without delay, and optimal patient selection for pancreaticoduodenectomy through exclusion of patients with rapidly progressive metastatic disease. Critical components of a pre-operative treatment strategy for pancreatic cancer include adherence to a strict definition of resectability, accurate radiographic staging capable of identifying patients with potentially resectable disease, and a safe and efficient means of obtaining a tissue diagnosis and relieving biliary obstruction. Herein, we discuss the rationale for the use of pre-operative chemoradiation in pancreatic cancer, the results of treatment, and future strategies to address the pattern of disease recurrence.

Late small bowel toxicity after adjuvant treatment for rectal cancer

For locally advanced rectal cancer surgery as sole treatment results in poor local control and survival. After adjuvant radiotherapy for locally advanced rectal cancer, small bowel toxicity has been the most frequent and serious side effect. The gain in survival and local control was accompanied by severe late chronic toxicity reducing the benefit of adjuvant treatment. Clinical factors, pathology and treatment of late small bowel toxicity after adjuvant radiotherapy for locally advanced rectal cancer will be discussed. This review will focus on different surgical and radiotherapeutic means reducing the risk of late small bowel damage.

PREOPERATIVE CHEMOTHERAPY AND RADIOTHERAPY FOR LOCALLY ADVANCED RECTAL CANCER

The adjuvant treatment of rectal cancer is a rapidly evolving field. The standard approach is a combination of chemotherapy and radiotherapy, with the optimal treatment combination and sequencing yet to be determined. Here, we report our early experience of preoperative chemotherapy and radiotherapy (CRT) in locally advanced rectal cancer at Radiation Oncology Victoria to determine its efficacy and the rate of sphincter preservation. Sixty-nine patients (46 men and 23 women) with locally advanced rectal cancer (T3-4 or N1) were treated with preoperative CRT followed by surgical resection of disease. Chemotherapy consisted of either bolus or continuous venous infusion of 5-fluorouracil (5-FU). Radiotherapy to a dose of 45 Gy was delivered to the pelvis followed by a boost of 5.4-14.4 Gy in the majority of patients. Surgical resection was carried out 4-8 weeks following completion of preoperative CRT. Univariate and multivariate analyses were performed to examine variables that may influence local recurrence and overall survival rates. All patients underwent a complete macroscopic resection, including the three patients that had unrecognized distant metastases discovered at the time of operation. Only two patients had microscopic residual disease. Sphincter preservation was achieved in 16 of 25 patients who were thought to require an abdominoperineal resection. Tumour and/or nodal downstaging were achieved in 47 patients (68%), with a pathological complete response in 12 (17%). At a median follow up of 29 months post-surgery, five patients (7.2%) have developed a local recurrence. Overall 21 patients (30%) have progressed and 12 (18%) have died. Treatment-related toxicity was acceptable and there was no treatment-related mortality. There was no significant relationship found between the pathological response to treatment and any clinical endpoint. Our results confirm the high response rates and acceptable toxicity of preoperative treatment. Further studies are required to better define the impact of preoperative chemotherapy and radiotherapy on long-term outcomes.

Radiation induces different changes in expression profiles of normal rectal tissue compared with rectal carcinoma

Radiotherapy is a very effective adjuvant treatment for rectal cancer with little side effects. Its killing effect on tumor cells seems to be more profound than the effect on normal tissue. The molecular events caused by irradiation are mainly analyzed in in vitro and animal models; investigations on human material are rare. In the current study, we analyzed the effects of irradiation on gene expression in normal and tumor tissue of rectal cancer patients. Normal and carcinoma tissue of patients from a randomized clinical trial of the benefits of preoperative radiotherapy were analyzed using the Affymetrix Human Cancer Gene Chip. Preoperative radiotherapy was given within 5 days prior to surgery. Results for normal tissue and tumor were compared to investigate the radiation-related differences between normal and tumor cells. We clustered the differentially expressed genes based on their functional annotation. Results were compared with immunohistochemical and literature data. The majority of the investigated cancer-related genes remained unchanged by irradiation (92% in tumor tissue and 93% in normal tissue). The differentially expressed genes varied between tumor and normal tissue except for maspin and IL-8. Both in tumor and normal tissue, differentially expressed genes were present related to cell signaling and cycle control, apoptosis and cell survival and tissue response and repair. However, the spectrum of affected genes was totally different. Pre-existing differences in gene expression between normal tissue and tumor tissue might explain the differences in their responses to radiation. This change in response may explain the clinical beneficial effect of radiotherapy on tumor cells (low local recurrence rate) and the less severe effects on normal tissue (minor side effects).