Fréderic Duprez

High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC institutes

OBJECTIVE Examination of the rate of grade III or grade IV radiation dermatitis during treatment of head and neck cancer (HNC) with radiotherapy (RT) and concurrent cetuximab in EORTC centres. MATERIALS AND METHOD A questionnaire was sent to all members of the EORTC Radiation Oncology Group and Head and Neck Group (111 institutions) to evaluate the widespread use of cetuximab and radiotherapy in HNC and to estimate the frequency of grades III and IV skin reactions in the radiation portals associated with this protocol. Co-morbidities, RT schedules and co-medications were also recorded. RESULTS We received responses from 28 institutions in 11 countries. A total of 125 HNC patients from 15 institutions were treated with cetuximab and concurrent RT. Information about the skin reactions was available from 71 patients. Of these 36 had no grade III/IV adverse effects in the RT field, 15 had a grade III and 20 had grade IV radiation dermatitis. No detectable relation of grades III and IV radiation dermatitis with co-morbidities such as liver insufficiency or renal dysfunction was found. CONCLUSION According to the results of the questionnaire, grade III/IV radiation dermatitis is observed in 49% of HNC patients treated with cetuximab and concurrent RT. A systematic clinical monitoring of cutaneous side effects during RT plus cetuximab is advised to ensure the safety of this protocol.

Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

PURPOSE To investigate the feasibility of adaptive intensity-modulated radiation therapy (IMRT) using dose painting by numbers (DPBN) for head-and-neck cancer. METHODS AND MATERIALS Each patients treatment used three separate treatment plans: fractions 1-10 used a DPBN ([(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography [(18)F-FDG-PET]) voxel intensity-based IMRT plan based on a pretreatment (18)F-FDG-PET/computed tomography (CT) scan; fractions 11-20 used a DPBN plan based on a (18)F-FDG-PET/CT scan acquired after the eighth fraction; and fractions 21-32 used a conventional (uniform dose) IMRT plan. In a Phase I trial, two dose prescription levels were tested: a median dose of 80.9 Gy to the high-dose clinical target volume (CTV(high_dose)) (dose level I) and a median dose of 85.9 Gy to the gross tumor volume (GTV) (dose level II). Between February 2007 and August 2009, 7 patients at dose level I and 14 patients at dose level II were enrolled. RESULTS All patients finished treatment without a break, and no Grade 4 acute toxicity was observed. Treatment adaptation (i.e., plans based on the second (18)F-FDG-PET/CT scan) reduced the volumes for the GTV (41%, p = 0.01), CTV(high_dose) (18%, p = 0.01), high-dose planning target volume (14%, p = 0.02), and parotids (9-12%, p < 0.05). Because the GTV was much smaller than the CTV(high_dose) and target adaptation, further dose escalation at dose level II resulted in less severe toxicity than that observed at dose level I. CONCLUSION To our knowledge, this represents the first clinical study that combines adaptive treatments with dose painting by numbers. Treatment as described above is feasible.

EGFr inhibitor toxicityHigh rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC institutes

OBJECTIVE Examination of the rate of grade III or grade IV radiation dermatitis during treatment of head and neck cancer (HNC) with radiotherapy (RT) and concurrent cetuximab in EORTC centres. MATERIALS AND METHOD A questionnaire was sent to all members of the EORTC Radiation Oncology Group and Head and Neck Group (111 institutions) to evaluate the widespread use of cetuximab and radiotherapy in HNC and to estimate the frequency of grades III and IV skin reactions in the radiation portals associated with this protocol. Co-morbidities, RT schedules and co-medications were also recorded. RESULTS We received responses from 28 institutions in 11 countries. A total of 125 HNC patients from 15 institutions were treated with cetuximab and concurrent RT. Information about the skin reactions was available from 71 patients. Of these 36 had no grade III/IV adverse effects in the RT field, 15 had a grade III and 20 had grade IV radiation dermatitis. No detectable relation of grades III and IV radiation dermatitis with co-morbidities such as liver insufficiency or renal dysfunction was found. CONCLUSION According to the results of the questionnaire, grade III/IV radiation dermatitis is observed in 49% of HNC patients treated with cetuximab and concurrent RT. A systematic clinical monitoring of cutaneous side effects during RT plus cetuximab is advised to ensure the safety of this protocol.

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.

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.

Single-nucleotide polymorphisms in DNA double-strand break repair genes: association with head and neck cancer and interaction with tobacco use and alcohol consumption.

We investigated the effect of different levels of smoking and drinking on the development of squamous cell carcinoma of head and neck (HNSCC) and performed analyses to evaluate possible differences in cancer susceptibility among the anatomical subregions of head and neck. Moreover, we investigated the association between 5 single nucleotide polymorphisms (SNPs) in the homologous recombination DNA repair pathway (XRCC3 c.-1843 A>G, XRCC3 c.562-14 A>G, XRCC3 c.722 C>T, Rad51 c.-3429 G>C, Rad51 c.-3392 G>T) and 4 SNPs in the non- homologous end joining DNA repair pathway (Lig4 c.26 C>T, Lig4 c.1704 T>C, Ku70 c.-1310 C>G and Ku80 c.2110-2408 G>A) on one hand and the risk of the development of HNSCC on the other hand in a case- control setting in a Caucasian population. The study population consisted out of 152 HNSCC patients and 157 healthy controls, matched for age and gender. Polymorphic regions were analysed using the PCR-RFLP and PCR-single base extension assays. Stratification of the populations according to smoking habits and alcohol consumption highlighted the importance of tobacco and alcohol as two risk factors for the development of HNSCC (OR=11.81, p<0.01 and OR=4.66, p<0.01 for high exposure to tobacco and alcohol respectively). A stratification according to the anatomical region of the tumour showed site specific differences in sensitivity to tobacco smoke, with an increase in cancer susceptibility from the oral cavity down to the pharynx and larynx (OR=6.86, p<0.01; OR=9.83, p<0.01 and 36.57, p<0.01 for >25PY). A significant positive association between the XRCC3 c.722 polymorphism and HNSCC was found, with an adjusted odds ratio (OR) of 1.96 (p=0.02). Both the Lig4 c.26 and the Rad51 c.-3429 polymorphisms were associated with a significant reduced risk for HNSCC (OR=0.43, p=0.01; OR=0.43, p=0.05 respectively). Analysis of the gene- smoking interaction revealed no differences in OR for XRCC3 c.722 among the smoking groups. The protective effect seen for the Rad51 c.-3429 and polymorphism was most prominent among the group of heavy smokers (>25 PY). No associations with risk for HNSCC were found for the other SNPs in genes of the DNA DSB repair pathways.

Three-phase adaptive dose-painting-by-numbers for head-and-neck cancer: initial results of the phase I clinical trial

PURPOSE To evaluate feasibility of using deformable image co-registration in three-phase adaptive dose-painting-by-numbers (DPBN) for head-and-neck cancer and to report dosimetrical data and preliminary clinical results. MATERIAL AND METHODS Between November 2010 and October 2011, 10 patients with non-metastatic head-and-neck cancer enrolled in this phase I clinical trial where treatment was adapted every ten fractions. Each patient was treated with three DPBN plans based on: a pretreatment 18[F]-FDG-PET scan (phase I: fractions 1-10), a per-treatment 18[F]-FDG-PET/CT scan acquired after 8 fractions (phase II: fractions 11-20) and a per-treatment 18[F]-FDG-PET/CT scan acquired after 18 fractions (phase III: fractions 21-30). A median prescription dose to the dose-painted target was 70.2 Gy (fractions 1-30) and to elective neck was 40 Gy (fractions 1-20). Deformable image co-registration was used for automatic region-of-interest propagation and dose summation of the three treatment plans. RESULTS All patients (all men, median age 68, range 48-74 years) completed treatment without any break or acute G≥4 toxicity. Target volume reductions (mean (range)) between pre-treatment CT and CT on the last day of treatment were 72.3% (57.9-98.4) and 46.3% (11.0-73.1) for GTV and PTV(high_dose), respectively. Acute G3 toxicity was limited to dysphagia in 3/10 patients and mucositis in 2/10 patients; none of the patients lost ≥20% weight. At median follow-up of 13, range 7-22 months, 9 patients did not have evidence of disease. CONCLUSIONS Three-phase adaptive 18[F]-FDG-PET-guided dose painting by numbers using currently available tools is feasible. Irradiation of smaller target volumes might have contributed to mild acute toxicity with no measurable decrease in tumor response.

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.

Reduction of the dose to the elective neck in head and neck squamous cell carcinoma, a randomized clinical trial using intensity modulated radiotherapy (IMRT). Dosimetrical analysis and effect on acute toxicity

BACKGROUND AND PURPOSE A randomized trial was initiated to investigate whether a reduction of the dose to the elective nodal sites and the swallowing apparatus delivered by IMRT would result in a reduction of acute and late side effects without compromising tumor control. The aim of this paper is to report on dosimetrical analysis and acute toxicity. MATERIALS & METHODS Two-hundred patients were randomized. In the standard arm, elective nodal volumes (PTVelect) were irradiated up to an equivalent dose of 50Gy. In the experimental arm an equivalent dose of 40Gy was prescribed to the PTVelect. The dose to the swallowing apparatus was kept as low as possible without compromising therapeutic PTV (PTVther) coverage. RESULTS No significant difference was seen between both arms concerning PTVther coverage. The median D95 of the PTVelect was significantly lower in the experimental arm (39.5 vs 49.8Gy; p<0.001). Concerning the organs at risk, the dose to swallowing structures and spinal cord was significantly reduced. There was no significant difference in acute toxicity. Three months after radiotherapy there was significantly less grade ⩾3 dysphagia in the experimental arm (2% vs 11%; p=0.03). With a median follow-up of 6months no significant differences were observed in locoregional control, disease free survival or overall survival. CONCLUSIONS Using IMRT we were able to significantly reduce the dose to the PTVelect and several organs at risk without compromising PTVther coverage. This resulted in a significant reduction of severe dysphagia 3months after radiotherapy. Further follow-up is necessary to investigate whether these observations translate into a benefit on late treatment related dysphagia without affecting treatment outcome.

A predictive model for dysphagia following IMRT for head and neck cancer: Introduction of the EMLasso technique

BACKGROUND AND PURPOSE Design a model for prediction of acute dysphagia following intensity-modulated radiotherapy (IMRT) for head and neck cancer. Illustrate the use of the EMLasso technique for model selection. MATERIAL AND METHODS Radiation-induced dysphagia was scored using CTCAE v.3.0 in 189 head and neck cancer patients. Clinical data (gender, age, nicotine and alcohol use, diabetes, tumor location), treatment parameters (chemotherapy, surgery involving the primary tumor, lymph node dissection, overall treatment time), dosimetric parameters (doses delivered to pharyngeal constrictor (PC) muscles and esophagus) and 19 genetic polymorphisms were used in model building. The predicting model was achieved by EMLasso, i.e. an EM algorithm to account for missing values, applied to penalized logistic regression, which allows for variable selection by tuning the penalization parameter through crossvalidation on AUC, thus avoiding overfitting. RESULTS Fifty-three patients (28%) developed acute ≥ grade 3 dysphagia. The final model has an AUC of 0.71 and contains concurrent chemotherapy, D2 to the superior PC and the rs3213245 (XRCC1) polymorphism. The models false negative rate and false positive rate in the optimal operation point on the ROC curve are 21% and 49%, respectively. CONCLUSIONS This study demonstrated the utility of the EMLasso technique for model selection in predictive radiogenetics.