Rectal cancer adjuvant chemotherapy: when is more useful?

UNLABELLED: THE AIM of the study was to evaluate time-to-progression (TTP) of rectal cancer in a group of patients receiving adjuvant chemotherapy (CHT) after combined neoadjuvant treatment. A secondary end-point was to identify the possible influence of clinical TNM (cTNM) or pathological TNM (pTNM) on TTP and overall survival (OS). PATIENTS AND METHODS: From January 2000 to December 2005, 101 consecutive rectal cancer patients who had been neoadjuvantly treated and had underne adjuvant CHT were retrospectively examined. The variables considered were age, gender and clinical and pathological effect of CHT administration. RESULTS: The mean age was 59 years (29-78 years) and the male:female ratio, 61:40. Forty-two patients had a lower (< or =5 cm from the anal verge), 54 a middle (from 6 to 10 cm) and 5 a higher (=10 cm) rectal lesion. All the patients had received the full course of neoadjuvant radiotherapy (RT) while 26.7% patients had received a reduced number of neoadjuvant CHT cycles. All the patients had undergone surgery and had received adjuvant chemotherapy which was completed in only 77.2% of the cases. Tumour down-staging and complete remissions were reported in 75.2% and 14.8% of cases, respectively. TTP and OS at 3 years were 81.2% and 91.1%, respectively. Out of locally recurrent patients, 77.8% were N+ (p=0.0026) at the pathological evaluation. CONCLUSION: In our series, neither administration of oxaliplatin-based adjuvant chemotherapy (p=0.44) nor age > or =70 years (p=0.51), clinical stage III (p=0.67), tumour down-staging (p=0.44) and achievement of pCR (p=0.66) appeared to have a significant impact on TTP; only pN+ (patients "not responders" to a neoadjuvant CHT-RT) influenced local relapse requiring more accurate postoperative treatment and confirming the literature data about the utility of adjuvant therapy in stage III disease.

Glutathione S-transferase P1 Ile105Val polymorphism is associated with haematological toxicity in elderly rectal cancer patients receiving preoperative chemoradiotherapy.

BACKGROUND: Increasing evidence suggests that common gene polymorphisms may influence the toxicity of various cytotoxic agents used in the treatment of cancer. OBJECTIVE: To evaluate the predictive value of acute toxicity of methylenetetrahydrofolate reductase 677T polymorphism, glutathione S-transferase P1 (GSTP1) substitution of isoleucine with valine at codon 105 (Ile105Val) polymorphism and the tandem repeat polymorphism in the thymidylate synthase gene promoter in elderly patients with rectal cancer receiving preoperative chemoradiotherapy (CRT). METHOD: From 1994 to 2002, 166 Caucasian patients underwent surgery following CRT for mid-low rectal cancer at a single institution, 42 (male-to-female ratio, 25 : 17) of whom were aged > or =65 years (median age 70 years, range 65-79). The pre-treatment clinical stage was tumour (T) stage 3-4 in 38 patients and node (N)-positive in 29 patients. Patients received external-beam radiotherapy with conventional fractionation and fluorouracil-based chemotherapy. Blood samples were used to extract and amplify DNA. Gene polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. Acute toxicity to preoperative therapy was reported according to the National Cancer Institute Common Toxicity Criteria, version 2. Univariate and multivariate analyses were performed using one-way analysis of variance and linear regression, respectively. RESULTS: Haematological toxicity (grade 1-2) was observed in 15 of 40 patients for whom toxicity data were available and gastrointestinal toxicity (grade 1-4) in 24 of these same 40 patients. At univariate analysis, female sex (p = 0.036) and GSTP1 Ile105Val (p = 0.0376) were associated with haematological toxicity. At multivariate analysis, GSTP1 Ile105Val polymorphism (p = 0.041) was the only factor found to be associated with haematological toxicity. Patients carrying the Val/Val genotype in the GSTP1 gene had a lower risk of haematological toxicity (odds ratio = 0.322, 95% CI 0.101, 0.957) than patients with the Ile/Ile genotype. CONCLUSION: GSTP1 Ile105Val polymorphism is a promising marker of potential haematological toxicity in elderly patients with rectal cancer receiving preoperative CRT.

Neoadjuvant chemoradiotherapy with 5-fluorouracil by bolus.

BACKGROUND: Neoadjuvant chemoradiotherapy (CT-RT) with continuous infusion (c.i.) 5-fluorouracil (5-FU) before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. Since the presence of cardiomiopathy may contraindicate c.i. of 5-FU, an alternative regimen of 5-FU CT-RT was prospectively studied in these patients. PATIENTS AND METHODS: From October 2000 to December 2006, patients with clinical stage T3 or T4, or node-positive disease were assigned according to their cardiological status to receive weekly 5-FU bolus administration during radiotherapy (RT). The preoperative treatment consisted of 5,040 cGy, delivered infractions of 180 cGy per day, five days per week, and 5-FU, given in 15 minutes at a dose of 450 mg/m2 of body surface area weekly during all radiotherapy. Surgery was performed six weeks after the completion of CT-RT. The primary endpoint was disease-free survival (DFS). RESULTS: Fifty-one patients received preoperative CH-RT. The 2-year OS rate was 92.3% and the 3-year DFS was 87.5%. The five-year cumulative incidence of local relapse was 3.9%. Grade 3 acute toxic effects occurred in 19.6% of the patients; worsening of patient's cardiopathy was never reported. CONCLUSION: Patients with cardiopathy developed similar local control and DFS, toxicity and OS with 5-FU administered weekly by bolus as those reported by literature data.

Role of neoadjuvant treatment in cT3N0M0 rectal cancer.

BACKGROUND: The aim of the study was to evaluate the pathological response (pTNM), local relapse and overall survival (OS) in clinical T3N0M0 (cT3N0M0) rectal cancer after a neoadjuvant chemoradiotherapy (CHT-RT) with 5-fluorouracil (5-FU) continuous infusion (c.i.) (+/- oxaliplatin) or bolus or capecitabine (an oral fluorpyrimidine). A secondary endpoint was to identify the local relapse rate and OS in those patients also receiving an adjuvant chemotherapy. PATIENTS AND METHODS: From January 2000 to January 2006, 48 consecutive cT3N0M0 rectal cancer cases neoadjuvantly treated were retrospectively examined. Variables considered were age, gender, modality of 5-FU administration and tumour site. RESULTS: Median age was 64 years (range, 22-84 years) and the male:female ratio was 28:20. All the patients received the full course of CHT-RT. Twenty-eight patients received c.i. 5-FU neoadjuvant chemotherapy, 17 received bolus 5-FU administration and 3 patients received capecitabine-based therapy. The mean number of chemotherapy weeks was 4.9 (range, 2-6). A total of 85.4% of patients were operated on without relevant postoperative complications but another 4 are awaiting surgery. Twenty-one patients had a lower (< or = 5 cm from the anal verge) and 27 had a middle rectal lesion (from 6 to 10 cm). In those patients with the lower site of lesion, a sphincter-saving (SS) procedure was achieved in 88.9%. Downstaging was reported in 66.7%. Ninety percent of cases are still free from progression after a median follow-up of 22.1 months; 7.5% are dead. CONCLUSION: The down-staging, the good level of SS and the disease-free survival (DFS) obtained here suggests that a neoadjuvant therapy may also be useful for stage II rectal cancer at diagnosis. The use of a postoperative chemotherapy should probably be outlined better.

Colorectal cancer screening in elderly patients: when should be more useful?

Current guidelines endorse colon cancer screening every 5-10 years in persons over 50 years of age. However, there is no consensus regarding what age is appropriate to stop screening. Prior history of neoplasia seems to be a strong risk factor for colorectal neoplasia development in elderly people and should be considered when deciding the need for continuing screening/surveillance, however, clinical judgment of comorbidities is still required to individualize screening practice. Screening colonoscopy in very elderly persons (aged 80 years), i.e. should be performed only after careful consideration of potential benefits, risks and patient preferences. The aims of this paper are to: (1) determine the best type of colorectal cancer screening (faecal occult blood testing, flexible sigmoidoscopy, double-contrast barium enema and colonoscopy) and its association with age and health status among elderly veterans and (2) describe the outcomes of colorectal cancer screening among older veterans who have widely differing life expectancies (based on age and health status).

Rectal cancer neoadjuvant treatment in elderly patients.

BACKGROUND: The aim of the study was to evaluate the differences in terms of toxicity and feasibility of neoadjuvant 5-fluorouracil (5FU) continuous infusion (c.i.) or bolus in combination with pelvic radiotherapy (RT) in locally advanced rectal cancer "fit" or "vulnerable" elderly patients. A secondary endpoint was to identify any specific comorbidity that affected either effectiveness or morbidity of treatment. PATIENTS AND METHODS: From June 2000 to June 2005, 36 patients over 70 years of age out of a total of 88 consecutive elderly cases were retrospectively examined. Variables considered were age, gender, modality of 5FU administration and comorbidities (evaluated according to Cumulative Illness Rating Scale-Geriatric, CIRS-G). RESULTS: Median age was 74 years (range, 70-82) years and the male:female ratio, 22:14. Fourteen % of the patients healthy and 25% with slight comorbidities were considered "fit" and 61% "vulnerable". All the patients received the full course of RT. The mean number of chemotherapy weeks was 5.34 (range, 2-6); "vulnerable" patients did not experience higher toxicity compared to "fit" patients (p = 0.69). Eighty-nine % of the patients were operated without relevant postoperative complications. Thirteen out of 20 "vulnerable" and 10 out of 12 "fit" patients had a pathological downstaging of disease (p = 0.24). CONCLUSION: Selected elderly "vulnerable" patients with rectal cancer can receive the same neoadjuvant 5FU-based chemoradiotherapy (either bolus or c.i.) and undergo surgery as well as "fit" elderly patients, since tolerability and response rate seem to be similar in both categories of patients.

A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation.

OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.

The role of capecitabine in the treatment of colorectal cancer in the elderly.

To overcome 5-Fluorouracil (5FU) infusion-related problems, oral 5FU precursors and inhibitors of 5FU degradation have been developed. Capecitabine is one of these new oral fluoropyrimidines. Capecitabine treatment of advanced colorectal carcinoma, when compared to 5FU, results in superior response rates (26.6% versus 17.9%, p=0.013), equivalent times to progression and survival, and improved safety, including less stomatitis and myelosuppression. The benefits are principally derived from the avoidance of hospital visits for intravenous drug administration, less expensive drug therapy for the treatment of toxic side-effects, and fewer treatment-related hospitalisations required during the course of therapy for adverse drug reactions. In this review, the use of capecitabine, alone or in association with other drugs, in neoadjuvant, adjuvant and metastatic settings, was analysed in a selected group of elderly patients (> or = 70 years old) affected by colorectal cancer.

The development of platinum compounds and their possible combination.

Cisplatin plays a central role in cancer chemotherapy in spite of its toxicity. To circumvent this toxicity and to enhance its therapeutic index a lot of preclinical and clinical studies have been conducted and several thousand analogues have been synthesized. Much more analysis remains to be done, but nowadays, the absence of any definitive, biologically interpretable molecular predictor of activity is consistent with the idea that platinum compounds have multiple intracellular targets and that cells can have multiple mechanisms of resistance. This review analyses a part of these platinum compounds analyzed to date, their mechanism of action, resistance and the future trends in this sector.