Jaime Feliu

Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study

PURPOSE To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS Fifty-one patients with advanced CRC who were >/= 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m(2) twice daily. RESULTS A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported. CONCLUSION Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.

KRAS Mutations in Primary Colorectal Cancer Tumors and Related Metastases: A Potential Role in Prediction of Lung Metastasis

Background KRAS mutations in colorectal cancer primary tumors predict resistance to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody therapy in patients with metastatic colorectal cancer, and thus represent a true indicator of EGFR pathway activation status. Methodology/Principal Findings KRAS mutations were retrospectively studied using polymerase chain reactions and subsequent sequencing of codons 12 and 13 (exon 2) in 110 patients with metastatic colorectal tumors. These studies were performed using tissue samples from both the primary tumor and their related metastases (93 liver, 84%; 17 lung, 16%). All patients received adjuvant 5-Fluorouracil-based polychemotherapy after resection of metastases. None received anti-EGFR therapy. Mutations in KRAS were observed in 37 (34%) of primary tumors and in 40 (36%) of related metastases, yielding a 94% level of concordance (kappa index 0.86). Patients with primary tumors possessing KRAS mutations had a shorter disease-free survival period after metastasis resection (12.0 vs 18.0 months; P = 0.035) than those who did not. A higher percentage of KRAS mutations was detected in primary tumors of patiens with lung metastases than in patients with liver metastases (59% vs 32%; p = 0.054). To further evaluate this finding we analyzed 120 additional patients with unresectable metastatic colorectal cancer who previously had their primary tumors evaluated for KRAS mutational status for clinical purposes. Separately, the analysis of these 120 patients showed a tendency towards a higher degree of KRAS mutations in primary tumors of patients with lung metastases, although it did not reach statistical significance. Taken together the group of 230 patients showed that KRAS was mutated significantly more often in the primary tumors of patients with lung metastases (57% vs 35%; P = 0.006). Conclusions/Significance Our results suggest a role for KRAS mutations in the propensity of primary colorectal tumors to metastasize to the lung.

Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis

Objective Hypomethylation of LINE-1 elements has emerged as a distinguishing feature in human cancers. Limited evidence indicates that some LINE-1 elements encode an additional internal antisense promoter, and increased hypomethylation of this region may lead to inadvertent activation of evolutionarily methylation-silenced downstream genes. However, the significance of this fundamental epigenetic mechanism in colorectal cancer (CRC) has not been investigated previously. Design We analysed tissue specimens from 77 CRC patients with matched sets of normal colonic mucosa, primary CRC tissues (PC), and liver metastasis tissues (LM). LINE-1 methylation levels were determined by quantitative bisulfite pyrosequencing. MET, RAB3IP and CHRM3 protein expression was determined by western blotting and IHC. MET proto-oncogene transcription and 5-hydroxymethylcytosine (5-hmc) were evaluated by quantitative real-time-PCR. Results Global LINE-1 methylation levels in LM were significantly lower compared with the matched PC (PC=66.2% vs LM=63.8%; p<0.001). More importantly, we observed that specific LINE-1 sequences residing within the intronic regions of multiple proto-oncogenes, MET (p<0.001), RAB3IP (p=0.05) and CHRM3 (p=0.01), were significantly hypomethylated in LM tissues compared with corresponding matched PC. Furthermore, reduced methylation of specific LINE-1 elements within the MET gene inversely correlated with induction of MET expression in CRC metastases (R=−0.44; p<0.0001). Finally, increased 5-hmc content was associated with LINE-1 hypomethylation. Conclusions Our results provide novel evidence that hypomethylation of specific LINE-1 elements permits inadvertent activation of methylation-silenced MET, RAB3IP and CHRM3 proto-oncogenes in CRC metastasis. Moreover, since 5-hmc content inversely correlated with LINE-1 hypomethylation in neoplastic tissues, our results provide important mechanistic insights into the fundamental processes underlying global DNA hypomethylation in human CRC.

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.

EFFICACY OF ORAL TEGAFUR MODULATION BY URACIL AND LEUCOVORIN IN ADVANCED COLORECTAL CANCER. A PHASE II STUDY

A phase II study was performed to assess the efficacy and toxicity of UFT (tegafur-uracil in the molar ratio 1:4) modulated with leucovorin (LV) in previously untreated patients with advanced colorectal carcinoma (CRC). 79 patients with measurable advanced colorectal cancer (CRC) and no prior chemotherapy were included. 75 patients were evaluable for toxicity and response. The regimen consisted of LV 500 mg/m2 administered intravenously on day 1, followed by oral UFT 390 mg/m2 on days 1-14. Patients received oral LV 15 mg every 12 h on days 2-14. Treatment was repeated every 28 days for a minimum of four courses per patient. Three hundred and ninety-eight cycles of chemotherapy were delivered (median five per patient). 7 patients (9%) had a complete response, and 22 a partial response for an overall response rate of 39%. Mild gastrointestinal toxicity was dose limiting: grade 3-4 diarrhoea appeared in 9% of patients. Other grade 3-4 toxicities were nausea/vomiting and mucositis in 4% of patients, gastric pain and leucopenia in 3%. Oral UFT modulated by oral LV is active in advanced CRC and can be administered on an outpatient basis with no significant toxicity requiring hospitalisation. Given its excellent tolerance profile and low toxicity, the regimen should be thoroughly studied and compared with 5-fluorouracil modulated by LV.

Usefulness of megestrol acetate in cancer cachexia and anorexia. A placebo-controlled study.

To assess the effect of megestrol acetate (MA) on the appetite and weight of cancer patients with nonhormone-dependent tumors, a double-blind, placebo-controlled trial was designed. One hundred fifty patients were included: 76 were given MA (240 mg/day orally) for at least 2 months, and 74 were given placebo (P). Body weight, subjective sense of appetite (SSA) evaluated by an analogic linear visual scale scored from 1 to 10, and performance status (PS) were measured before therapy and monthly thereafter. No differences in body weight before and after treatment could be found in any group. However, 32% of the patients in the MA group (95% confidence interval: 20.1–44.6%) gained 2 or more kilograms (P < 0.001). This group also showed an improvement in SSA (P < 0.01): an increase 2 points appeared in 57.5% of patients (95% confidence interval 44.6–69.4%). There was no significant difference in PS for the treatment groups before or after therapy. The percentage of reported adverse events did not differ significantly from one treatment group to the next. We conclude that therapy with MA at a dose of 240 mg/day improved SSA and was associated with moderate weight gain in patients with hormone-insensitive malignancies.

Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: beyond KRAS mutations.

The advent of the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), cetuximab and panitumumab has expanded the range of treatment options for metastatic colorectal cancer (CRC). Despite these agents have paved the way to individualized therapy, our understanding why some patients respond to treatment whereas others do not remain poor. The realization that detection of positive EGFR expression by IHC does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of benefit to anti-EGFR mAbs. Oncologists are now facing emerging issues in the treatment of metastatic CRC, including the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients, the explanation of rare cases of patients carrying KRAS-mutated tumours who have been reported to respond to cetuximab and panitumumab and the discovery of mechanisms of secondary resistance to EGFR-targeted therapy. Current data suggest that, together with KRAS mutations, the evaluation of EGFR gene copy number (GCN), BRAF, NRAS, PIK3CA mutations or loss of PTEN expression could also be useful for selecting patients with reduced chance to benefit from anti-EGFR mAbs. This review aims to provide an updated of the most recent data on predictive and prognostic biomarkers within the EGFR pathway, the challenges this emerging field presents and the future role of these molecular markers in CRC treatment.

Classification of anticancer drugs--a new system based on therapeutic targets.

The arrival of a great number of new antineoplastic agents has made it necessary to reclassify all of them. Anticancer drugs may act at different levels: cancer cells, endothelium, extracellular matrix, the immune system or host cells. The tumour cell can be targeted at the DNA, RNA or protein level. Most classical chemotherapeutic agents interact with tumour DNA, whereas monoclonal antibodies and small molecules are directed against proteins. The endothelium and extracellular matrix may be affected also by specific antibodies and small molecules.

Gemcitabine plus vinorelbine in nonsmall cell lung carcinoma patients age 70 years or older or patients who cannot receive cisplatin

Although the prevalence of nonsmall cell lung carcinoma (NSCLC) is high among elderly patients, few data are available regarding the efficacy and toxicity of chemotherapy in this group of patients. Recent reports indicate that single agent therapy with vinorelbine (VNB) or gemcitabine (GEM) may obtain a response rate of 20–30% in elderly patients, with acceptable toxicity and improvement in symptoms and quality of life. In the current study the efficacy and toxicity of the combination of GEM and VNB in elderly patients with advanced NSCLC or those with some contraindication to receiving cisplatin were assessed.

Serum albumin and other prognostic factors related to response and survival in patients with advanced non-small cell lung cancer

The standard therapy for advanced non-small cell lung cancer (NSCLC) remains to be defined. The poor results from chemotherapy have favored the search for prognostic factors that help identify patients more likely to respond. Our objective was to find factors related to response, the duration of response, and overall survival in patients with advanced NSCLC. We reviewed the clinical records of 292 patients with non-operable NSCLC, all of whom had a good performance status and had received chemotherapy. Ninety percent were male and the median age was 59 years. The therapeutic regimens included MACC (methotrexate, adriamycin, cyclophosphamide and CCNU), cisplatin + vindesine or etoposide, MIP (mitomycin, ifosfamide and cisplatin) and MVP (mitomycin, vindesine and cisplatin). In the multivariate analysis, a normal albumin level and the inclusion of cisplatin were related to the achievement of a response (40% if both favorable factors were present). No factors appeared related to the duration of response. The following factors were predictive for survival: weight loss, performance status, lymphocyte count, albumin level, number of metastases and the presence of bone metastases. We conclude that the albumin level identifies a group of patients with advanced NSCLC who are more likely to respond to cisplatin-containing chemotherapy.