Bevacizumab in association with de Gramont 5‐fluorouracil/folinic acid in patients with oxaliplatin‐, irinotecan‐, and cetuximab‐refractory colorectal cancer

BACKGROUND:

The aim of the current study was the investigation of the value of bevacizumab + 5‐fluorouracil(5–FU)/folinic acid in patients with advanced colorectal cancers who have exhausted standard chemotherapy options.

METHODS:

The authors included 48 heavily pretreated patients (colon:rectum, 33:15; men:women, 23:25; median age, 63 years; range, 27‐79 years) whose disease had progressed during or within an oxaliplatin‐based first‐line chemotherapy, an irinotecan‐based second‐line regimen, and a third‐line treatment with cetuximab plus weekly irinotecan. Bevacizumab was given at a dose of 5 mg/kg. 5‐FU/folinic acid was administered according to the de Gramont schedule.

RESULTS:

The response rate was 6.25%, and 30.4% of patients demonstrated stable disease as the best response. The median time to disease progression was 3.5 months (95% confidence interval [95% CI], 2.3‐6.9 months), and the median survival time was 7.7 months (95% CI, 3.9‐11.9 months). The most common grade 3 to 4 side toxicities (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) were: diarrhea (20.8%), fatigue (14.5%), and stomatitis (12.5%). Grade 3 to 4 hemorrhage occurred in 8 patients (16.6%), including 4 cases of bleeding in the gastrointestinal tract. Other relatively common adverse events such as hypertension, thrombosis, and bowel perforation were reported in 50%, 18.7%, and 4.16%, of patients respectively.

CONCLUSIONS:

The data from the current study suggest a modest but significant clinical benefit of bevacizumab + de Gramont schedule in heavily pretreated colorectal cancer patients. Cancer 2009. © 2009 American Cancer Society.     

KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

Background:

KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC.

Methods:

We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients.

Results:

Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P=0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P=0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P=0.047) and worse PFS (HR: 0.45, P=0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients.

Conclusion:

Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.     

Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study

Background

The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients.

Methods

Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50?mg/m² as a 30-min infusion on day 1, leucovorin 200?mg/m² in a 2-h infusion, and 5-FU 2,800?mg/m² in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75?mg/m², every 3?weeks).

Results

Thirty-four patients were enrolled, with an average age of 64?years (range 34–69). The main cumulative grade 3–4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9–54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6?months, respectively.

Conclusions

For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.     

Early and late outcome after surgery for colorectal cancer: elective versus emergency surgery

AIMS AND BACKGROUND: Emergency surgery for colorectal cancer is associated with a higher postoperative morbidity and mortality rate and a poor long-term outcome compared with elective surgery. The aim of the present study was to compare early and late outcome after elective and emergency surgery for malignant colorectal cancer, looking for the principal determinants of a worse outcome after emergency colorectal surgery. METHODS: A retrospective study of 236 patients presenting with colorectal cancer over an 8-year period was undertaken. Of these, 118 presented as emergencies, whereas 118 patients, well matched for age, sex, site of tumor and TNM admitted as elective, were included in the study. Data reviewed included postoperative mortality and morbidity and long-term outcome. RESULTS: The 30-day operative mortality rate was significantly higher in the emergency group than in the electively treated group (11.9% versus 3.4%, P < 0.01). The higher mortality rate was observed in the perforation group. The 30-day operative morbidity was higher in the emergency group (27.1% versus 12.7%, P < 0.05). Anastomotic failure was a serious complication: following primary resection, we observed 4 non-fatal (5.4%) and two fatal (2.7%) anastomotic leaks after 74 primary anastomoses. Among emergency-treated patients, the procedures characterized by the highest percentage of postoperative complications were three-stage resections (63.6%). The 5-year survival rate was greater after elective surgery (59% versus 39%). CONCLUSIONS: The early and long-term outcome following emergency colorectal surgery was significantly lower than that after elective surgery. Although medical complications in patients with end-stage cancer played an important role, surgical failures still had an important impact on outcome.     

Immunomodulating role of bisphosphonates on human gamma delta T cells: an intriguing and promising aspect of their antitumour activity

Vgamma9Vdelta2 T cells have the ability to produce inflammatory cytokines involved in protective immunity against intracellular pathogens and tumours and to display strong cytolytic as well as bactericidal activities. This suggests a direct involvement of Vgamma9Vdelta2 T lymphocytes in immune control of cancer and infections. These observations have recently aided development of novel immunotherapeutic approaches aimed at Vgamma9Vdelta2 T cell activation. Nitrogen-containing bisphosphonates (N-BPs) play a crucial role in Vgamma9Vdelta2 T lymphocyte activation and in the acquisition of effector functions. The preliminary results of these innovative strategies are encouraging. Moreover, compelling evidence in the literature supports the hypothesis that the antitumour effect of bisphosphonates is exerted through direct as well as indirect mechanisms. An additional and not yet well explored mechanism by which N-BPs may display antineoplastic effect is related to their immunomodulatory properties. It is fascinating that N-BPs influence the immune system in various but interrelated ways, being able to enhance the innate and to promote the adaptive immune responses. For all these reasons, Vgamma9Vdelta2 T lymphocytes represent a particularly interesting target for immunotherapeutic protocols based on N-BP administration. All these unexpected effects of N-BPs on the immune system have opened new and intriguing possibilities of therapeutic use for these drugs.     

Role of carbon monoxide in electrically induced non-adrenergic, non-cholinergic relaxations in the guinea-pig isolated whole trachea

BACKGROUND AND PURPOSE: Nitric oxide (NO) and vasoactive intestinal peptide (VIP) are considered transmitters of non-adrenergic, non-cholinergic (NANC) relaxations in guinea-pig trachea, whereas the role of carbon monoxide (CO) is unknown. This study was designed to assess the participation of CO, and to investigate the localization of haem oxygenase-2 (HO-2), the CO-producing enzyme, in tracheal neurons. EXPERIMENTAL APPROACH: NANC responses to electrical field stimulation (EFS) at 3 and 10 Hz were evaluated in epithelium-free whole tracheal segments as intraluminal pressure changes. Drugs used were: L-nitroarginine methyl ester (L-NAME, 100 microM) to inhibit NO synthase (NOS), alpha-chymotrypsin (2 U ml(-1)) to inactivate VIP, zinc protoporphyrin-IX (ZnPP-IX, 10 microM) to inhibit HO-2, and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), a soluble guanylyl cyclase inhibitor. For immunohistochemistry, tissues were exposed to antibodies to PGP 9.5, a general neuronal marker, HO-2 and NOS, and processed with an indirect immunofluorescence method.Key results:alpha-Chymotrypsin did not affect NANC relaxations. ODQ inhibited NANC responses by about 60%, a value similar to that obtained by combining L-NAME and ZnPP-IX. The combination of ODQ, L-NAME and ZnPP-IX reduced the responses by 90%. Subpopulations of HO-2 positive neurons containing NOS were detected in tracheal sections. CONCLUSIONS AND IMPLICATIONS: In the guinea-pig trachea, NANC inhibitory responses at 3 and 10 Hz use NO and CO as main transmitters. Their participation is revealed following inhibition of NOS, HO-2 and soluble guanylyl cyclase. The involvement of CO as a relaxing transmitter paves the way for novel therapeutic approaches in the treatment of airway obstruction.     

Outcome prediction and risk assessment by quantitative pyrosequencing methylation analysis of the SFN gene in advanced stage,high‐risk,neuroblastic tumor patients

The aim of our study was to identify threshold levels of DNA methylation predictive of the outcome to better define the risk group of stage 4 neuroblastic tumor patients. Quantitative pyrosequencing analysis was applied to a training set of 50 stage 4, high risk patients and to a validation cohort of 72 consecutive patients. Stage 4 patients at lower risk and ganglioneuroma patients were included as control groups. Predictive thresholds of methylation were identified by ROC curve analysis. The prognostic end points of the study were the overall and progression‐free survival at 60 months. Data were analyzed with the Cox proportional hazard model. In a multivariate model the methylation threshold identified for the SFN gene (14.3.3σ) distinguished the patients presenting favorable outcome from those with progressing disease, independently from all known predictors (Training set: Overall Survival HR 8.53, p = 0.001; Validation set: HR 4.07, p = 0.008). The level of methylation in the tumors of high‐risk patients surviving more than 60 months was comparable to that of tumors derived from lower risk patients and to that of benign ganglioneuroma. Methylation above the threshold level was associated with reduced SFN expression in comparison with samples below the threshold. Quantitative methylation is a promising tool to predict survival in neuroblastic tumor patients. Our results lead to the hypothesis that a subset of patients considered at high risk—but displaying low levels of methylation—could be assigned at a lower risk group.