E. Casado

XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer.

The purpose of this phase II trial was to determine the efficacy and safety of the XELOX (capecitabine/oxaliplatin) regimen as first-line therapy in the elderly patients with metastatic colorectal cancer (MCRC). A total of 50 patients with MCRC aged ⩾70 years received oxaliplatin 130 mg m−2 on day 1 followed by oral capecitabine 1000 mg m−2 twice daily on days 1–14 every 3 weeks. Patients with creatinine clearance 30–50 ml min−1 received a reduced dose of capecitabine (750 mg m−2 twice daily). By intent-to-treat analysis, the overall response rate was 36% (95% CI, 28–49%), with three (6%) complete and 15 (30%) partial responses. In total, 18 patients (36%) had stable disease and 14 (28%) progressed. The median times to disease progression and overall survival were 5.8 months (95% CI, 3.9–7.8 months) and 13.2 months (95% CI, 7.6–16.9 months), respectively. Capecitabine was well tolerated: grade 3/4 adverse events were observed in 14 (28%) patients: 11 (22%) diarrhoea, eight (16%) asthenia, seven (14%) nausea/vomiting, three (6%) neutropenia, three (6%) thrombocytopenia, and two (4%) hand–foot syndrome. There was one treatment-related death from diarrhoea and sepsis. In conclusion, XELOX is well tolerated in elderly patients, with respectable efficacy and a meaningful clinical benefit response. Given its ease of administration compared with combinations of oxaliplatin with 5-FU/LV, it represents a good therapeutic option in the elderly.

Immunohistochemical analysis of tumour regression grade for rectal cancer after neoadjuvant chemoradiotherapy

Aim  Tumour regression grade (TRG) as defined by Rödel et al. has been used as an independent prognostic factor for rectal carcinoma after preoperative treatment by chemoradiotherapy (CRT). Determination of TRG 2 and 3, semiquantitatively defined as more or less than 50% tumour regression, respectively, does not appear to correlate with prognosis. The purpose of this study was to find an immunohistochemical pattern to permit improved stratification of intermediate responders defined by disease free (DFS) and overall survival (OS).

New insights in β-tubulin sequence analysis in non-small cell lung cancer

Scarce data are available regarding the molecular mechanisms implicated in paclitaxel resistance. There is controversial data about β-tubulin mutations role in paclitaxel resistance. We have conducted this trial to address the influence of β-tubulin mutations in paclitaxel resistance in advanced non-small cell lung cancer (NSCLC). A group of 15 patients were biopsied and diagnosed of stages IIIB and IV NSCLC. Tumor specimens were used for DNA isolation and exon 4 of HM40 β-tubulin isotype was amplified and automatically sequenced, using both intronic and exonic primers. Next, the chemotherapy schedule consisted of weekly paclitaxel (100 or 150 mg/m2×6) followed 2 weeks later by cisplatin 100 mg/m2 on day 1, gemcitabine 1000 mg/m2 on days 1 and 14, and vinorelbine 25 mg/m2 on days 1 and 14, every 28 days. Using exonic primers, gene sequence alterations were found in 13/15 (87%) patients, including transitions (codons 180 and 182) and one silent transversion (codon 195). Also, three transversions (codons 231, 234, and 235) were found in all patients and controls. All alterations disappeared when sequenced with intronic primers. Our results suggest that point mutations demonstrated with exonic primers but not with intronic ones are probably due to β-tubulin pseudogenes present in advanced NSCLC specimens. Even so, when these β-tubulin pseudogenes are found there is a clear relation with clinical response. Although these changes could be relevant in paclitaxel resistance, this observation must be proven in future clinical trials to resolve “the tubulin dilemma”.

Phase II study of neoadjuvant treatment of rectal cancer with oxaliplatin, raltitrexed and radiotherapy

3746 Background and objective: Preoperative chemoradiation can improve the outcome of surgery in rectal cancer. The aim of this phase II study was to evaluate the efficacy and toxicity of a preoperative radiochemotherapy combination including oxaliplatin, raltitrexed and radiotherapy in locoregionally advanced rectal cancer. METHODS Between January 2002 and July 2003, 43 consecutive patients (22 women, 21 men; median age 61 years, range 34-74) with stage II and III rectal adenocarcinomas have been enrolled. All patients underwent endorectal ultrasonography (uT2N1= 2, uT3N0= 14, uT3N1= 23, uT4N0= 1, uT4N1= 3), and CT scan for staging purposes. Radiotherapy was delivered with a three-field technique to a dose of 50Gy over 5 weeks with a concomitant boost approach. Chemotherapy was initiated concurrently with RT and consisted of three courses of raltitrexed 3 mg/m2 followed by oxaliplatin 130 mg/m2 every 21 days. Surgery was planned six to eight weeks after RT. Three additional cycles of chemotherapy were given after surgery. RESULTS 33 patients can be evaluated for response and 43 for toxicity. 25 patients were downstaged (76%), there were 6 pathological complete responses (18%) and sphincter sparing surgery was accomplished in 22 patients (67%). Grade 3 diarrea developed in two patients, and grade 4 in one patient (7%). Grade 3 neutropenia was observed in three patients (7%), including one febrile neutropenia. Other adverse events were mild, including grade 2 hepatotoxicity (transaminases) in 5 patients (11%). CONCLUSION The regimen is feasible, has a low toxicity profile and can be administered in a three weeks basis. This treatment achieves significant tumor downstaging with a remarkable rate of conservative surgeries and complete pathological responses. No significant financial relationships to disclose.

A inmunohistochemical expression profile as prognostic factor in locally advanced gastric cancer relapse

9697 Background: Surgical resection of gastric adenocarcinoma is curative in less than 40% of patients, so local regional or distance recurrence occurs in 40–60% of cases. New prognostic and predictive factors are needed to define the best candidates to receive adjuvant treatment. Methods: Expression of Bcl-2,p53,Cox-2,HER-2,Epo-R,β-catenin and E-cadherin proteins were evaluated by immunohistochemistry on 45 selected parafin-embedded gastrectomy specimens of gastric adenocarcinomas using an indirect inmunoperoxidase technique. All patients had received adjuvant treatment according to McDonald’s protocol(NEJM,2001;345:725). Inmunohistochemical staining for these proteins was correlated with clinico-pathological features: stage, histological subtype, differentiation, macroscopic appearance and recurrence. Results: Correlation with clinico-pathological features:p53 overexpression was higher in III-IVA vs IB-II (81%vs53%,p<0.049).In the intestinal type vs diffuse type we found p53 (91%vs51%,p<0.002) and Cox-2...

Dynamic evaluation of tumoral transcriptome for a blind study of mechanisms of chemoradiotherapy resistance in rectal cancer patients

3604 Background: Distant metastases are the major obstacule for cure of locally advanced rectal cancer. The mechanisms of chemoradiation resistance (CR) are elusive since efforts to elucidate them have been hypothesis-orientated. Unravelling them will provide the opportunity to overcome treatment failure. In this context, dynamic high throughput gene profiling, comparing tumour samples before and after CR offers great promise. To this end serial analysis of gene expression (SAGE) is a truely blind and powerful tool, as it evaluates precisely the whole transcriptome, and can be performed from very small samples (microSAGE), a key hurdle in the colorectal cancer setting. Methods: A cohort of 52 patients with advanced adenocarcinoma of the rectum had been preoperatively treated with neoadjuvant oxaliplatin-raltitrexed and radiotherapy. With a medium follow up of 30 months, we selected the four most paradigmatic patients showing clear progression during CR, and four showing complete pathological responses. 12...