Alicia Lozano

Cetuximab May Inhibit Tumor Growth and Angiogenesis Induced by Ionizing Radiation: A Preclinical Rationale for Maintenance Treatment After Radiotherapy

BACKGROUND The benefits of radiotherapy and cetuximab have encouraged evaluation of cetuximab after radiotherapy. The aims of this study were to preclinically evaluate the efficacy of cetuximab maintenance after radiotherapy and eventually determine its mechanisms of action. METHODS The A431 human carcinoma cell line was treated in culture with fractionated radiotherapy and cetuximab. The surviving cells were injected s.c. into nude mice to mimic microscopic residual disease. The animals were randomized to receive either cetuximab or saline solution. Tumor growth, cell proliferation (Ki-67), microvessel density (MVD), epidermal growth factor receptor (EGFR) and transforming growth factor (TGF-α) mRNA transcription, and vascular endothelial growth factor (VEGF) secretion were measured. RESULTS Tumors from irradiated cells had a faster growth rate, higher Ki-67 index, and greater angiogenesis than tumors from untreated cells. This aggressive phenotype was associated with in vitro radiation-induced extracellular signal-related kinase (ERK)-1/2 and Akt activation, greater EGFR and TGF-α transcription, and augmented VEGF secretion, all of which were inhibited by cetuximab. In cetuximab-treated mice with tumors arising from irradiated cells, time to volume was longer by a factor of 3.52, whereas the Ki-67 index and MVD were 1.57 and 1.49 times lower, respectively, a larger enhancement than seen in tumors from untreated cells. These findings suggest that cells surviving radiation may express factors that promote cell survival and induce an aggressive phenotype that may potentially be blocked by cetuximab maintenance therapy. CONCLUSIONS These results support the clinical evaluation of adjuvant therapy with cetuximab after radiotherapy in EGFR-dependent carcinomas.

A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck

PURPOSE Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN. METHODS AND MATERIALS A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m(2) day 1; cisplatin, 75 mg/m(2) day 1; 5-fluorouracil [5-FU], 750 mg/m(2) day 1-5) and cetuximab, 250 mg/m(2) weekly (loading dose of 400 mg/m(2)). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF. RESULTS Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%). CONCLUSIONS C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.

Management of Cutaneous Toxicity and Radiation Dermatitis in Patients with Squamous Cancer of the Head and Neck Undergoing Concurrent Treatment with Cetuximab and Radiotherapy

Skin toxicity is the most common adverse event associated with the use of EGFR inhibitors. Radiation dermatitis occurs to some degree in most of the patients who receive radiotherapy, either alone or in combination with EGFR inhibitors. The effects of both toxicities might be additive because the irradiated skin zone in squamous cell cancer of the head and neck (SCCHN) patients is the same area in which the EGFR inhibitor-related acne-like rash is more common. This article summarizes the principal issues discussed during a symposium that took place in Madrid in January 2009, in which the management of cutaneous toxicity and radiation dermatitis in patients with SCCHN was reviewed. Selection of the most appropriate control measures was discussed in an interactive debate with the audience using five case reports. It was concluded that early establishment of adequate preventive measures and proper management of both the EGFR inhibitor-related, acne-like rash and radiation dermatitis in SCCHN patients undergoing concomitant treatment will prevent treatment interruption, potentially allowing better locoregional control of the disease.

Nutritional changes in patients with locally advanced head and neck cancer during treatment

OBJECTIVE The purpose of the study is to evaluate changes in body composition and nutritional status that occur throughout the oncological treatment in head and neck cancer patients. METHODS A prospective cohort observational study in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) that underwent treatment with induction chemotherapy (iCT) followed by chemoradiotherapy or bioradiotherapy were invited to participate. All patients had dietetic counseling from the diagnosis and a close monitoring throughout the treatment implementing nutritional support as needed. RESULTS From June 2011 until October 2012, 20 patients were included. Nutritional and anthropometric parameters were collected at diagnosis, post iCT, after radiotherapy, 1 and 3months post radiotherapy. According to Patient Generated Subjective Global Assessment, 30% of patients were malnourished at diagnosis. After iCT there was an increase in weight, body mass index (BMI) and fat free mass (FFM) with almost complete improvement in dysphagia and odynophagia. Nevertheless a significant nutritional deterioration (p=0.0022) occurred at the end of radiotherapy with 95% of patients becoming severe or moderate malnourished. Nutritional parameters such as weight, BMI and hand grip strength also decrease significantly during treatment. CONCLUSIONS Despite an intensive nutritional support from the diagnosis throughout the oncological treatment in advanced HNSCC cancer patients, nutritional status deteriorates during radiotherapy. Our findings suggest that iCT may help improve nutritional status by ameliorating the symptoms that limit the oral intake. This improvement in the nutritional status could contribute to minimize further deterioration. Further investigations are needed involving novel approaches to avoid nutritional deterioration.

Influence of Treatment Received in Long-Surviving Patients of Head-and-Neck Cancer

e17010 Background: Modification of radiotherapy (RT) schedules or the addition of CT/biologics in patients (pts) with locally advanced head-and-neck carcinomas (LAHNC) have resulted in improving su...

Hyperfractionated Radiotherapy: Improvement of Survival in Locally Advanced Nasopharyngeal Carcinoma

Objectives Standard treatment with concomitant chemotherapy (CT) and radiotherapy (RT) for nasopharyngeal cancer has shown rates of locoregional control of 80% and has improved the rate of 5-year survival to 67% to 84%. Hyperfractionated radiotherapy (HFRT) may increase locoregional control of tumors of the head and neck, but the addition of concomitant CT involves an unacceptable level of toxicity. Adding induction CT may control distant metastasis. Here we compare the results of our protocol with induction CT followed by HFRT alone with the results obtained with concomitant treatments. Methods Between October 1994 and May 2002, 46 patients with nasopharyngeal carcinoma were treated with HFRT. The patients with N+ or T4 lesions also received cisplatin-based induction CT (55%). Results The patients received a mean of 3 CT cycles (range, 2 to 5). At 5 years, the rate of progression-free survival was 66% (range, 51.3% to 82.1%), and the global survival rate was 75.7% (range, 61.9% to 89.5%). Conclusions The use of HFRT in association with induction CT in patients with the greatest risk of metastasis may be as effective as concomitant CT-RT for treatment of nasopharyngeal cancer. Efforts should now concentrate on minimizing the acute and chronic toxicities.