Phase II trial of induction irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for unresectable, locally advanced gastric and oesophageal-gastric junction adenocarcinoma.

PURPOSE: The prognosis of patients with unresectable M0 gastric cancer remains very poor. We performed a phase II trial to explore the efficacy and toxicity of induction irinotecan-cisplatin (IC) followed by concurrent irinotecan-cisplatin and radiotherapy (IC/RT) in this setting. METHODS AND MATERIALS: Patients with unresectable M0 gastric (GC) or oesophageal-gastric junction (EGJC) adenocarcinomas were treated with two courses of IC (irinotecan, 65 mg/m(2); cisplatin, 30 mg/m(2) on days 1 and 8 every 21 days) followed by IC/RT (daily radiotherapy-45 Gy-with concurrent IC: irinotecan, 65 mg/m(2), and cisplatin, 30 mg/m(2), on days 1, 8, 15, and 22). Resectability was reassessed after this treatment, and surgical resection was performed if feasible. The primary endpoint was the R0 resection rate after induction treatment. RESULTS: Seventeen patients were included in the study (EGJC: 6; GC: 11). An R0 resection was achieved in only 5 patients (29%), and according to the design of the trial (Simon's optimal two-stage) accrual of patients was terminated after the first stage. No patient died during IC, whereas 3 patients (24%) died during IC/RT and one of 5 resected patients (20%) died during the first 30 days after resection. The median survival was 10.5 months, and the actuarial 2-year survival rate was 27%. CONCLUSIONS: Induction IC followed by IC/RT showed poor efficacy and significant toxicity in patients with unresectable GC/EGJC.

Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial.

Expression of EGF receptor (EGFR) is frequently elevated in squamous cell carcinoma of the head and neck (SCCHN). Cetuximab is an anti-EGFR monoclonal antibody that has been shown to improve overall survival in patients with locally advanced SCCHN when combined with radiotherapy. Data from Phase II trials suggest an interesting activity of cetuximab in patients with recurrent or metastatic SCCHN who are refractory to cisplatin. The Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) Phase III trial compared platin-5-fluorouracil alone versus combined with cetuximab as first-line treatment in recurrent or metastatic SCCHN. In the cetuximab arm of this study, a significant improvement in the overall survival (the main objective), progression-free survival and response rate were observed. The quality of life analyses (QLQ-C30 and QLQ-H&N35) showed no significant differences in most of the studied scores between the two treatment arms. Nevertheless, patients in the cetuximab arm displayed significant improvements in pain, swallowing problems and scores for speech and social eating problems. The results of the EXTREME study (and other studies evaluating cetuximab for the treatment of SCCHN) suggest a lack of a predictive value for the expression of EGFR (determined by immunohistochemistry) by the tumor and other biomarkers need to be investigated. The role of other targeted drugs and of possible combinations of these new drugs with cetuximab should be investigated in properly designed preclinical studies and clinical trials.

Cetuximab, its clinical use and future perspectives.

Increase in the expression of epidermal growth factor receptors (EGFRs) has been observed in many tumours. EGFR overexpression usually correlates with a more advanced stage of the disease, a poorer prognosis and a worse chemotherapy response. For all the aforementioned reasons, EGFR inhibition can be considered an attractive approach in cancer treatment. One strategy has been extracellular domain receptor inhibition, using monoclonal antibodies. In this review, we summarize the current status as well as what is likely to be the future use of monoclonal antibodies directed against EGFR. We have focussed on cetuximab being the most developed one. It has been mainly studied in colorectal cancer, and the major portion of this review will focus on all the research that has been carried out on this tumour. Clinical development of cetuximab is also important in head and neck cancer and in lung cancer. Interesting studies have been carried out in pancreatic, gastric, oesophageal and ovarian tumours, as well as in malignant gliomas.

A Phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer.

PURPOSE: The aim of this study was to evaluate the efficacy and tolerance of preoperative chemoradiotherapy (CRT) with irinotecan (CPT-11) and 5-fluorouracil (5-FU) in patients with resectable rectal cancer. METHODS AND MATERIALS: Patients with resectable T3-T4 rectal cancer and Eastern Cooperative Oncology Group performance status <2 were included. CPT-11 (50 mg/m(2) weekly) and 5-FU (225 mg/m(2)/day continuous infusion, 5 days/week) were concurrently administered with radiation therapy (RT) (45 Gy, 1.8 Gy/day, 5 days/week), during 5 weeks. RESULTS: A total of 74 patients were enrolled: mean age, 59 years (20-74 years; SD, 11.7). Planned treatment was delivered to most patients (median relative dose intensity for both drugs was 100%). Grade 3/4 lymphocytopenia occurred in 35 patients (47%), neutropenia in 5 (7%), and anemia in 2 (3%). Main Grade 3 nonhematologic toxicities were diarrhea (14%), asthenia (9%), rectal mucositis (8%), and abdominal pain (8%). Of the 73 resected specimens, 13.7% (95% confidence interval [CI], 6.8-23.7) had a pathologic complete response and 49.3% (95% CI, 37.4-61.3) were downstaged. Additionally, 66.7% (95% CI, 51.1-80.0) of patients with ultrasound staged N1/N2 disease had no pathologic evidence of nodal involvement after CRT. CONCLUSIONS: This preoperative CRT schedule has been shown to be effective and feasible in a large population of patients with resectable rectal cancer.