Tom Boterberg

Postoperative intensity-modulated radiotherapy in sinonasal carcinoma - Clinical results in 39 patients

Carcinoma of the paranasal sinuses is rare. Standard therapeutic modalities consist of surgery and radiotherapy (RT). Because of the often advanced stage and the vicinity of optic structures, RT‐induced ocular toxicity is a feared side effect of conventional RT. Intensity‐modulated radiotherapy (IMRT) is a relatively new technique, which is implemented with the hypothesis that, compared with conventional RT, it would result in a lower rate of ocular toxicity for an equal local control (LC).

Whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT): First clinical experience

PURPOSE Whole abdominopelvic radiation therapy (WAPRT) is a treatment option in the palliation of patients with relapsed ovarian cancer. With conventional techniques, kidneys and liver are the dose- and homogeneity-limiting organs. We developed a planning strategy for intensity-modulated arc therapy (IMAT) and report on the treatment plans of the first 5 treated patients. METHODS AND MATERIALS Five consecutive patients with histologically proven relapsed ovarian cancer were sent to our department for WAPRT. The target volumes and organs at risk (OAR) were delineated on 0.5-cm-thick CT slices. The clinical target volume (CTV) was defined as the total peritoneal cavity. CTV and kidneys were expanded with 0.5 cm. In a preset range of 8 degrees interspaced gantry angles, machine states were generated with an anatomy-based segmentation tool. Machine states of the same class were stratified in arcs. The optimization of IMAT was done in several steps, using a biophysical objective function. These steps included weight optimization of machine states, leaf position optimization adapted to meet the maximal leaf speed constraint, and planner-interactive optimization of the start and stop angles. The final control points (machine states plus associated cumulative monitor unit counts) were calculated using a collapsed cone convolution/superposition algorithm. For comparison, two conventional plans (CONV) were made, one with two fields (CONV2), and one with four fields (CONV4). In these CONV plans, dose to the kidneys was limited by cerrobend blocks. The IMAT and the CONV plans were normalized to a median dose of 33 Gy to the planning target volume (PTV). Monomer/polymer gel dosimetry was used to assess the dosimetric accuracy of the IMAT planning and delivery method. RESULTS The median volume of the PTV was 8306 cc. The mean treatment delivery time over 4 patients was 13.8 min. A mean of 444 monitor units was needed for a fraction dose of 150 cGy. The fraction of the PTV volume receiving more than 90% of the prescribed dose (V(90)) was 9% higher for the IMAT plan than for the CONV4 plan (89.9% vs. 82.5%). Outside a build-up region of 0.8 cm and 1 cm away from both kidneys, the inhomogeneity in the PTV was 15.1% for the IMAT plans and 24.9% for the CONV4 plans (for CONV2 plans, this was 34.9%). The median dose to the kidneys in the IMAT plans was lower for all patients. The 95th percentile dose for the kidneys was significantly higher for the IMAT plans than for the CONV4 and CONV2 plans (28.2 Gy vs. 22.2 Gy and 22.6 Gy for left kidney, respectively). No relevant differences were found for liver. The gel-measured dose was within clinical planning constraints. CONCLUSION IMAT was shown to be deliverable in an acceptable time slot and to produce dose distributions that are more homogeneous than those obtained with a CONV plan, with at least equal sparing of the OARs.

Maximum tolerated dose in a phase I trial on adaptive dose painting by numbers for head and neck cancer

PURPOSE To determine the maximum tolerated dose (MTD) in a phase I trial on adaptive dose-painting-by-numbers (DPBN) for non-metastatic head and neck cancer. MATERIALS AND METHODS Adaptive intensity-modulated radiotherapy was based on voxel intensity of pre-treatment and per-treatment [(18)F]fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) scans. Dose was escalated to a median total dose of 80.9 Gy in the high-dose clinical target volume (dose level I) and 85.9 Gy in the gross tumor volume (dose level II). The MTD would be reached, if ≥ 33% of patients developed any grade ≥ 4 toxicity (DLT) up to 3 months follow-up. RESULTS Between February 2007 and August 2009, seven patients at dose level I and 14 at dose level II were treated. All patients completed treatment without interruption. At a median follow-up for surviving patients of 38 (dose level I) and 22 months (dose level II) there was no grade ≥ 4 toxicity during treatment and follow-up but six cases of mucosal ulcers at latency of 4-10 months, of which five (36%) were observed at dose level II. Mucosal ulcers healed spontaneously in four patients. CONCLUSIONS Considering late mucosal ulcers as DLT, the MTD of a median dose of 80.9 Gy has been reached in our trial.

Intensity-Modulated Radiotherapy for Sinonasal Tumors: Ghent University Hospital Update

PURPOSE To report the long-term outcome of intensity-modulated radiotherapy (IMRT) for sinonasal tumors. METHODS AND MATERIALS Between July 1998 and November 2006, 84 patients with sinonasal tumors were treated with IMRT to a median dose of 70 Gy in 35 fractions. Of the 84 patients, 73 had a primary tumor and 11 had local recurrence. The tumor histologic type was adenocarcinoma in 54, squamous cell carcinoma in 17, esthesioneuroblastoma in 9, and adenoid cystic carcinoma in 4. The tumors were located in the ethmoid sinus in 47, maxillary sinus in 19, nasal cavity in 16, and multiple sites in 2. Postoperative IMRT was performed in 75 patients and 9 patients received primary IMRT. RESULTS The median follow-up of living patients was 40 months (range, 8-106). The 5-year local control, overall survival, disease-specific survival, disease-free survival, and freedom from distant metastasis rate was 70.7%, 58.5%, 67%, 59.3%, and 82.2%, respectively. No difference was found in local control and survival between patients with primary or recurrent tumors. On multivariate analysis, invasion of the cribriform plate was significantly associated with lower local control (p = 0.0001) and overall survival (p = 0.0001). Local and distant recurrence was detected in 19 and 10 patients, respectively. Radiation-induced blindness was not observed. One patient developed Grade 3 radiation-induced retinopathy and neovascular glaucoma. Nonocular late radiation-induced toxicity comprised complete lacrimal duct stenosis in 1 patient and brain necrosis in 3 patients. Osteoradionecrosis of the maxilla and brain necrosis were detected in 1 of the 5 reirradiated patients. CONCLUSION IMRT for sinonasal tumors provides low rates of radiation-induced toxicity without blindness with high local control and survival. IMRT could be considered as the treatment of choice.

Acute Normal Tissue Reactions in Head-and-Neck Cancer Patients Treated With IMRT: Influence of Dose and Association With Genetic Polymorphisms in DNA DSB Repair Genes

PURPOSE To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy. MATERIALS AND METHODS The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volume histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays. RESULTS The mean dose (D(mean)) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%. CONCLUSIONS The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D(mean) to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity.

Role of the IGF-I receptor in the regulation of cell-cell adhesion: Implications in cancer development and progression

The insulin‐like growth factor‐I receptor (IGF‐IR) is a ubiquitous multifunctional tyrosine kinase that has an important role in normal cell growth and development. However, abnormal stimulation of IGF‐IR signaling has been implicated in the development of different types of tumors. The strong antiapoptotic activity of IGF‐IR has been recognized as critical in IGF‐I‐dependent tumorigenesis, however, the impact of other IGF‐IR functions, such as regulation of cell–cell and cell–matrix adhesion are also increasingly acknowledged. Here, on the model of breast cancer cells, we discuss how IGF‐IR‐dependent regulation of intercellular adhesion may affect cell survival, resistance to antiestrogens, and invasion.

Intensity-modulated radiotherapy for recurrent and second primary head and neck cancer in previously irradiated territory☆

PURPOSE To evaluate re-irradiation using IMRT for recurrent and second primary head and neck cancer in previously irradiated territory. MATERIALS AND METHODS Between 1997 and 2008, 84 patients with recurrent and second primary head and neck cancer were treated with IMRT to a median dose of 69 Gy. Median time interval between initial radiotherapy and re-irradiation was 49.5 (5.2-298.3) months. Salvage surgery preceded re-irradiation in 19 patients; 17 patients received concurrent chemotherapy. RESULTS Median follow-up of living patients was 19.8 (1.9-76.1) months. Five-year locoregional control and overall survival were 40% and 20%, respectively. Five-year disease-specific survival and disease-free survival were 29% and 15%, respectively. Stage T4 (p=0.015), time interval between initial treatment and re-irradiation (p=0.011) and hypopharyngeal cancer (p=0.013) were independent prognostic factors for worse overall survival in multivariate analysis. Twenty-six and 11 patients developed Grade 3 acute and late toxicity, respectively. No Grade 5 acute toxicity was encountered. There were 2 fatal vascular ruptures during follow-up. CONCLUSIONS High-dose IMRT for recurrent and second primary head and neck cancer in previously irradiated territory leads to approximately 20% long-term survival in a non-selected patient population. Identification of patients who would benefit most of curative IMRT is warranted.

Intensity-modulated radiotherapy for cervical lymph node metastases from unknown primary cancer

PURPOSE To compare the effectiveness of intensity-modulated radiotherapy (IMRT) and conventional (two-dimensional) radiotherapy in the treatment of cervical lymph node metastases from unknown primary cancer (UPC). METHODS AND MATERIALS Between February 2003 and September 2006, 23 patients with UPC of squamous cell carcinoma were treated with IMRT. Extended putative mucosal and bilateral nodal sites were irradiated to a median dose of 66 Gy. In 19 patients, IMRT was performed after lymph node dissection, and in 4 patients primary radiotherapy was given. The conventional radiotherapy group (historical control group) comprised 18 patients treated to a median dose of 66 Gy between August 1994 and October 2003. RESULTS Twenty patients completed treatment. As compared with conventional radiotherapy, the incidence of Grade 3 acute dysphagia was significantly lower in the IMRT group (4.5% vs. 50%, p = 0.003). By 6 months, Grade 3 xerostomia was detected in 11.8% patients in the IMRT group vs. 53.4% in the historical control group (p = 0.03). No Grade 3 dysphagia or skin fibrosis was observed after IMRT but these were noted after conventional radiotherapy (26.7%, p = 0.01) and 26.7%, p = 0.03) respectively). With median follow-up of living patients of 17 months, there was no emergence of primary cancer. One patient had persistent nodal disease and another had nodal relapse at 5 months. Distant metastases were detected in 4 patients. The 2-year overall survival and distant disease-free probability after IMRT did not differ significantly from those for conventional radiotherapy (74.8% vs. 61.1% and 76.3% vs. 68.4%, respectively). CONCLUSIONS Use of IMRT for UPC resulted in lower toxicity than conventional radiotherapy, and was similar in efficacy.

Short term toxicity profile for 32 sinonasal cancer patients treated with IMRT. Can we avoid dry eye syndrome

Intensity modulated radiation therapy (IMRT) was given for 32 patients with M0 sinonasal cancer, with a median follow-up of 15 months. Acute toxicity was mucositis grades 1-2 in 28 patients and grade 3 in four patients. No corneal injury was observed, except in one patient where it was present before the start of IMRT. Conjunctivitis and dry eye symptoms were mild (no grade 3-4 toxicity) and no evolution to dry eye syndrome was observed. We conclude that high dose conformality of IMRT results in mild acute toxicity and that IMRT allows avoiding dry eye syndrome by its ability to create concave dose distributions which avoid the main lacrimal glands. Follow-up it too short to evaluate local control, optic nerve or retinal toxicity.

Postoperative radiotherapy for adenocarcinoma of the ethmoid sinuses: treatment results for 47 patients

PURPOSE Ethmoid sinus cancer is a rare malignancy. Treatment results are mostly reported together with other sinonasal tumors, grouping a wide range of different histologies and treatment approaches. This study reports on the treatment outcome of 47 patients diagnosed with adenocarcinoma of the ethmoid sinuses and treated with surgery and high-dose postoperative radiation therapy. METHODS AND MATERIALS Between September 1985 and October 2001, 51 patients with adenocarcinoma of the ethmoid sinuses were referred to the Ghent University Hospital. Four patients were treated with low-dose palliative radiation because of very extended inoperable disease or distant metastasis at the time of diagnosis. They were not included in this analysis. The other 47 patients, all staged as N0M0, were treated with surgery and postoperative high-dose radiation therapy. The median follow-up was 32 months. The T-stages were T1 for 2, T2 for 17, T3 for 11, and T4 for 17 patients. All 47 patients were staged as N0M0. RESULTS The 3-year, 5-year, and 7-year overall survival are respectively 71%, 60%, and 38%. The 3-year and 5-year disease-free survival are respectively 62% and 36%. The 3-year and 5-year disease-free survival for T1-T2 stages are respectively 87% and 55%, for T3 stages 57% and 28%, and for T4 stages 41% and 25%. The locoregional tumor control was 70% and 59% at respectively 3 and 5 years. Patients presenting with intracranial tumor invasion at the time of diagnosis relapsed within 7 months after the end of radiotherapy. Radiation-induced severe dry eye syndrome and optic neuropathy was observed in respectively 7 and 2 of the 47 cases. CONCLUSION Postoperative radiotherapy for adenocarcinoma of the ethmoid sinuses is associated with good local control rates. Crucial for a favorable prognosis is the absence of intracranial invasion. The rarity of these tumors makes it difficult to evaluate new therapeutic advances.