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Purpose: To benchmark and improve, through means of a targeted intervention, the quality of intensity modulated radiation therapy treatment planning for locally advanced head and neck cancer (HNC) in the Netherlands. The short and long-term impact of this intervention was assessed.Methods and Materials: A delineated computed tomography-scan of an oropharynx HNC case was sent to all 15 Dutch radiation therapy centers treating HNC. Aims for planning target volume and organ-at-risk (OAR) dosimetry were established by consensus. Each center generated a treatment plan. In a targeted intervention, OAR sparing of all plans was discussed, and centers with the best OAR sparing shared their planning strategies. Impact of the intervention was assessed by (1) short-term (half a year after intervention) replanning of the original case and (2) long-term (1 and 3 years after intervention) planning of new cases.Results: Benchmarking revealed substantial difference in OAR doses. Initial mean doses were 22 Gy (range, 15-31 Gy), 35 Gy (18-49 Gy), and 37 Gy (20-46 Gy) for the contralateral parotid gland, contralateral submandibular gland, and combined swallowing structures, respectively. Replanning after targeted intervention significantly reduced mean doses and variation, but clinically relevant differences still remained: 18 Gy (14-22 Gy), 28 Gy (17-45 Gy), and 29 Gy (18-39 Gy), respectively. One and 3 years later the variation remained stable.Conclusions: Despite many years of HNC intensity modulated radiation therapy experience, initial treatment plans showed surprisingly large variations. The simple targeted intervention used in this analysis improved OAR sparing, and its impact was durable; however, fairly large dose differences still continue to exist. Additional work is needed to understand these variations and to minimize them. A national radiation oncology platform can be instrumental for developing and maintaining high-quality planning protocols. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To retrospectively report changes in gross tumor volume (GTV) and organ-at-risk (OAR) doses after induction chemotherapy (IC) in oropharyngeal cancer using different contouring strategies. Materials and methods: GTV and OARs were delineated on pre- and post-IC planning CT. Two post-IC GTV contours were made: (1) a ‘consensus set’ using published guidelines (GTVconsensus), and (2) ‘visible set’, delineating only visible post-IC GTV (GTVvisible). Pre-IC interactively optimized volumetric modulated arc therapy plans were generated. The pre-IC planning constraints served as the starting point for both post-IC plans. Results reflect pooled data from all 10 patients. Results: Mean reduction in volume post-IC was 24% and 47% for consensus and visible primary tumor and 57% and 60% for consensus and visible nodes. Compared to pre-IC plans, average mean OAR dose for post-IC GTVconsensus plans was significantly lower for CL parotid. For GTVvisible plans both parotids, upper/lower larynx, inferior pharyngeal constrictor and cricopharyngeal muscles were significantly lower. However reductions compared with post-IC GTVconsensus plans were modest (1.6/1.5/1.2/3.7/5.9/2.6Gy, respectively). Conclusion: IC in patients with oropharyngeal carcinoma results in substantial reductions in GTVs. If post-IC GTVs are used, which is contrary to current consensus, statistically significant but relatively small OAR dose reductions are observed. [Copyright &y& Elsevier]

Summary: Background & aims: Weight loss is a frequently observed problem in patients with head and neck cancer (HNC) during radiotherapy. It is still to be assessed whether hypermetabolism is contributing to this problem. The aim of this study was to investigate hypermetabolism before radiotherapy, and changes in resting energy expenditure (REE) in HNC patients during radiotherapy. Methods: REE was measured by indirect calorimetry in 71 patients with HNC before radiotherapy, after 3 and 6 weeks of radiotherapy, and 3 months after radiotherapy. The association between REE and tumour stage, CRP, and prior tumour surgery was analyzed by linear regression analyses. Forty healthy control subjects were one-to-one matched to 40 patients by gender, age and fat free mass (FFM) index to compare REE. Results: Before radiotherapy, REE was not significantly different between patients and controls, neither in absolute values (1568 ± 247 vs. 1619 ± 244 kcal/d; p = 0.29), nor after weight-adjustment (22.1 ± 3.5 vs. 21.5 ± 3.3 kcal/kg, p = 0.42) or FFM-adjustment (31.5 ± 4.9 vs. 30.7 ± 4.5 kcal/kg, p = 0.38). REE was independent of tumour stage, CRP, and prior tumour surgery. REE (kcal/d) decreased during radiotherapy and thereafter by 9% from pre-radiotherapy (p < 0.01). Weight and FFM also decreased significantly over time (p < 0.001). REE adjusted for FFM decreased in the first 3 weeks of radiotherapy with 4% (B = −1.39 kcal/kg FFM, p < 0.01), increased at the end of radiotherapy and decreased again 3 months after radiotherapy (B = −1.31 kcal/kg FFM, p = 0.04). Conclusions: Head and neck cancer patients had normal REE before radiotherapy. During radiotherapy, REE decreased continuously with ongoing weight loss. However, weight loss is not the only explaining factor, since REE expressed per kg FFM showed a much more divergent course which is currently unexplained. [Copyright &y& Elsevier]

Purpose: Volumetric modulated arc therapy (RapidArc, Varian Medical Systems) permits the delivery of highly conformal dose distributions. We studied planning and delivery in patients who underwent RapidArc for locally advanced head-and-neck cancer (HNC). Methods and Materials: A total of 35 consecutive patients who completed RapidArc with concurrent chemotherapy for Stages III-IV tumors of the oro- and hypopharynx/larynx in our center were identified. All underwent bilateral neck irradiation and 21 patients had at least N2 disease. A simultaneous integrated boost (SIB) delivered 70 Gy (in 2 Gy/fraction) to the planning target volume (PTV)boost and elective nodal regions (PTVelect) received 57.75 Gy. A standard planning constraint set was used and constraints for parotid glands were individually adapted. Treatments were delivered using two arcs after all plans were verified in a solid water phantom using GafChromic External Beam Therapy films. Results: RapidArc planning generally took 1.5–2 h, which was faster than with our previous seven-field intensity-modulated radiotherapy sliding window technique. Film dosimetry revealed that 0.6% of films exceeded a combination of dose differences ≥3% or distance to agreement ≥2 mm. More than 99% of both PTVs received ≥95% of the prescription dose. Average plan conformity index was 1.13 and mean dose to ipsilateral and contralateral parotid glands were 31.4 Gy and 26.1 Gy, respectively. The mean beam-on time was <3 min and mean number of monitor units was 426. Conclusions: RapidArc achieved excellent target coverage and normal tissue sparing, with delivery completed in less than 3 min. RA is currently our standard intensity-modulated radiotherapy approach for advanced HNC. [ABSTRACT FROM AUTHOR]

Purpose: The purpose was to evaluate the contralateral nodal control (CLNC) in postoperative patients with oral and oropharyngeal cancer treated with ipsilateral irradiation of the neck and primary site. Late radiation-induced morbidity was also evaluated. Methods and Materials: The study included 123 patients with well-lateralized squamous cell carcinomas treated with surgery and unilateral postoperative irradiation. Most patients had tumors of the gingiva (41%) or buccal mucosa (21%). The majority of patients underwent surgery of the ipsilateral neck (n = 102 [83%]). The N classification was N0 in 73 cases (59%), N1 or N2a in 23 (19%), and N2b in 27 cases (22%). Results: Contralateral metastases developed in 7 patients (6%). The 5-year actuarial CLNC was 92%. The number of lymph node metastases was the only significant prognostic factor with regard to CLNC. The 5-year CLNC was 99% in N0 cases, 88% in N1 or N2a cases, and 73% in N2b cases (p = 0.008). Borderline significance (p = 0.06) was found for extranodal spread. Successful salvage could be performed in 71% of patients with contralateral metastases. The prevalence of Grade 2 or higher xerostomia was 2.6% at 5 years. Conclusions: Selected patients with oral or oropharyngeal carcinoma treated with primary surgery and postoperative ipsilateral radiotherapy have a very high CLNC with a high probability of successful salvage in case of contralateral metastases. However, bilateral irradiation should be applied in case of multiple lymph node metastases in the ipsilateral neck, particularly in the presence of extranodal spread. The incidence of radiation-induced morbidity is considerably lower as observed after bilateral irradiation. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Although patients with early stage (T1/T2) laryngeal cancer (LC) are thought to have a low incidence of malnutrition, severe weight loss is observed in a subgroup of these patients during radiotherapy (RT). The objective of this study was to evaluate weight loss and nutrition-related symptoms in patients with T1/T2 LC during RT and to select predictive factors for early identification of malnourished patients. Methods: Of all patients with T1/T2 LC, who received primary RT between 1999 and 2007, the following characteristics were recorded: sex, age, TNM classification, tumour location, radiation schedule, performance status, quality of life, weight loss, and nutrition-related symptoms. The association between baseline characteristics and malnutrition (>5% weight loss during RT) was investigated by Cox regression analysis. Results: The study population consisted of 238 patients. During RT, 44% of patients developed malnutrition. Tumour location, TNM classification, RT on the neck nodes, RT dose, nausea/vomiting, pain, swallowing, senses problems, trouble with social eating, dry mouth and the use of painkillers were all significantly associated with malnutrition. In the multivariate analysis, RTs on both the neck nodes (HR 4.16, 95% CI 2.62–6.60) and dry mouth (HR 1.72, 95% CI 1.14–2.60) remained predictive. Nevertheless, RT on the neck nodes alone resulted in the best predictive model for malnutrition scores. Conclusions: Patients with early stage laryngeal cancer are at risk of malnutrition during radiotherapy. Radiotherapy on the neck nodes is the best predictor of malnutrition during radiotherapy. Therefore, we suggest to offer nutritional counselling to all the patients who receive nodal irradiation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare intensity-modulated radiation therapy (IMRT) and three-dimensional conventional radiotherapy (3D-CRT) with regard to patient-rated xerostomia, Radiation Therapy Oncology Group (RTOG) acute and late xerostomia and health-related quality of life (HRQoL) among patients with head and neck squamous cell carcinoma (HNSCC). Methods and Materials: Included were 241 patients with HNSCC treated with bilateral irradiation ± chemotherapy. Since 2000, all patients treated with HNSCC were included in a program, which prospectively assessed acute and late morbidity according to the RTOG and HRQoL on a routine basis at regular intervals. Before October 2004, all patients were treated with 3D-CRT (N = 150). After clinical implementation in October 2004, 91 patients received IMRT. In this study, the differences regarding RTOG toxicity, xerostomia, and other items of HRQoL were analyzed. Results: The use of IMRT resulted in a significant reduction of the mean dose of the parotid glands (27 Gy vs. 43 Gy (p < 0.001). During radiation, Grade 2 RTOG xerostomia was significantly less with IMRT than with 3D-CRT. At 6 months, the prevalence of patient-rated moderate to severe xerostomia and Grade 2 or higher RTOG xerostomia was significantly lower after IMRT versus 3D-CRT. Treatment with IMRT also had a positive effect on several general and head and neck cancer–specific HRQoL dimensions. Conclusions: IMRT results in a significant reduction of patient- and observer-rated xerostomia, as well as other head and neck symptoms, compared with standard 3D-CRT. These differences translate into a significant improvement of the more general dimensions of HRQoL. [Copyright &y& Elsevier]

Abstract: Introduction: Recently, we found that swallowing dysfunction after curative (chemo) radiation (CH) RT has a strong negative impact on health-related quality of life (HRQoL), even more than xerostomia. The purpose of this study was to design a predictive model for swallowing dysfunction after curative radiotherapy or chemoradiation. Materials and methods: A prospective study was performed including 529 patients with head and neck squamous cell carcinoma (HNSCC) treated with curative (CH) RT. In all patients, acute and late radiation-induced morbidity (RTOG Acute and Late Morbidity Scoring System) was scored prospectively. To design the model univariate and multivariate logistic regression analyses were carried out with grade 2 or higher RTOG swallowing dysfunction at 6 months as the primary (SWALL6months) endpoint. The model was validated by comparing the predicted and observed complication rates and by testing if the model also predicted acute dysphagia and late dysphagia at later time points (12, 18 and 24 months). Results: After univariate and multivariate logistic regression analyses, the following factors turned out to be independent prognostic factors for SWALL6months: T3–T4, bilateral neck irradiation, weight loss prior to radiation, oropharyngeal and nasopharyngeal tumours, accelerated radiotherapy and concomitant chemoradiation. By summation of the regression coefficients derived from the multivariate model, the Total Dysphagia Risk Score (TDRS) could be calculated. In the logistic regression model, the TDRS was significantly associated with SWALL6months ((p <0.001). Subsequently, we defined three risk groups based on the TDRS. The rate of SWALL6months was 5%, 24% and 46% in case of low-, intermediate- and high-risk patients, respectively. These observed percentages were within the 95% confidence intervals of the predicted values. The TDRS risk group classification was also significantly associated with acute dysphagia (P <0.001 at all time points) and with late swallowing dysfunction at 12, 18 and 24 months (p <0.001 at all time points). Conclusion: The TDRS is a simple and validated measure to predict swallowing dysfunction after curative (CH) RT for HNC. This classification system enables identification of patients who may benefit from strategies aiming at prevention of swallowing dysfunction after curative (CH) RT such as preventive swallowing exercises during treatment and/or emerging IMRT techniques aiming at sparing anatomical structures that are involved in swallowing. [Copyright &y& Elsevier]

Abstract: Background and purpose: In the present study, prognostic values of several CT-based pre-treatment nodal and treatment-related characteristics were evaluated among patients with squamous cell head and neck cancer treated with non-surgical modalities. Patients and methods: Included were 79 patients with 210 pathological nodes, who underwent primary irradiation or chemoradiation. Several nodal characteristics were assessed on the planning CT scan. In addition, the 3D-dose distribution in the nodes was calculated by the planning system to allow for evaluation of underdosage in the pathological nodes and to correlate these results with control in the neck. Analysis was done on patient level (regional control) and node level (nodal control). Results: For regional control, total nodal volume and the use of chemotherapy in addition to radiation were significant prognostic factors. For nodal control, also the presence of central necrosis and radiological extranodal spread were of importance. In case of radiotherapy alone, a minimal dose <95% of the prescribed dose was associated with worse control. In case of combined modality treatment, the minimal radiation dose was of less importance. Conclusions: Nodal volume and chemotherapy are the most important prognostic factors to control pathological nodes in the neck. Radiological central necrosis and extranodal growth, nodal volume and chemotherapy were significant prognostic factors for nodal control. Additionally, it appears that regional control in patients treated with primary radiation alone or with chemoradiation in case of a total nodal volume of more than 3.0cm3 results in an unacceptable high risk on regional recurrence. [Copyright &y& Elsevier]

Summary: The objective of this study was to investigate the prognostic significance of the hemoglobin (Hb) levels at different timepoints in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Included were 111 patients. The hemoglobin levels were assessed before surgery (PreS-Hb), between surgery and radiotherapy (HbAAC), before postoperative radiotherapy (PreRT-Hb) and at the end of radiotherapy (EndRT-Hb). HbAAC takes into account the duration of anemia during the interval between surgery and radiotherapy. Higher HbAAC corresponds with lower Hb levels. Five year locoregional control (LRC) among patients with HbAAC⩾median was 72% and significantly worse as compared to the 88% in case of HbAAC < median (p =0.0097). Multivariate analysis for LRC showed that the HbAAC was a prognostic factor. Overall survival (OS) after 3 years was 77% in case of HbAAC < median and 34% in case of HbAAC⩾median (p <0.0002). Multivariate analysis for OS showed that the PreS-Hb and HbAAC were prognostic factors. Hb level between surgery and radiotherapy is an important prognostic factor for both LRC and OS among patients with SCCHN treated with surgery and postoperative radiotherapy. [Copyright &y& Elsevier]

Abstract: Background and Purpose: To investigate the association between the mean salivary gland and oral cavity dose, with patient-rated moderate and severe xerostomia and sticky saliva. Patients and methods: One hundred and fifty-seven patients treated with bilateral irradiation for head and neck cancer were included. The parotid and submandibular glands and the oral cavity were delineated on plannings-CT scans. At baseline and 6 and 12 months self-reported xerostomia and sticky saliva were assessed using the EORTC QLQ-H&N35 questionnaire. Results: At 6 months a significant association between the mean parotid (MDpar) and mean submandibular dose (MDsubm) and xerostomia was observed (OR−MDpar: 1.17; P=0.002 and OR−MDsubm: 1.08; P=0.02). Between MDpar and MDsubm, a significant interaction term was present. No significant association was found with the oral cavity dose. Xerostomia was reversible depending on MDpar and MDsubm. Considering Sticky saliva, a significant association was found at 6 and 12 months with MDsubm (OR: 1.03; P<0.001). The P50 for sticky saliva increased with elapsing time. Conclusions: Both MDpar and MDsubm influence the risk of xerostomia in irradiated patients at 6 months. This probability as a function of the mean parotid dose significantly depended on the mean dose in the submandibular glands. Sticky saliva mainly depends on MDsubm. [Copyright &y& Elsevier]

Objectives To identify patterns of long-term, radiation-induced swallowing dysfunction after definitive radiotherapy with or without chemotherapy (RT or CHRT) and to determine which factors may explain these patterns over time. Material and methods The study population consisted of 238 consecutive head and neck cancer patients treated with RT or CHRT. The primary endpoint was ⩾grade 2 swallowing dysfunction at 6, 12, 18 and 24 months after treatment. Cluster analysis was used to identify different patterns over time. The differences between the mean dose to the swallowing organs at risk for each pattern were determined by using dose maps. Results The cluster analysis revealed five patterns of swallowing dysfunction: low persistent, intermediate persistent, severe persistent, transient and progressive. Patients with high dose to the upper pharyngeal, laryngeal and lower pharyngeal region had the highest risk of severe persistent swallowing dysfunction. Transient problems mainly occurred after high dose to the laryngeal and lower pharyngeal regions, combined with moderate dose to the upper pharyngeal region. The progressive pattern was mainly seen after moderate dose to the upper pharyngeal region. Conclusions Various patterns of swallowing dysfunction after definitive RT or CHRT can be identified over time. This could reflect different underlying biological processes. [ABSTRACT FROM AUTHOR]

Background and purpose Different planning protocols may define varying planning target volume (PTV) dose criteria. We investigated the hypothesis that this could result in differences in organ-at-risk (OAR) sparing. Material and methods Volumetric modulated arc therapy plans were created for ten locally advanced head and neck cancer patients following PTV criteria specified by the RTOG, EORTC and institutional (VUmc) protocols. Resulting plans were evaluated on the basis of the homogeneity index, calculated for the boost/elective PTVs as HI B /HI E = 100% * (D2% − D98%)/D50% and mean dose to individual and composite salivary (comp sal ) and swallowing (comp swal ) OARs. Results RTOG plans were the most homogeneous, with mean HI B of 8.2 ± 0.9%, compared to 9.5 ± 1.0%/11.6 ± 1.5% for the VUmc/EORTC plans. EORTC plans provided most OAR sparing, with comp sal /comp swal doses of 24.6 ± 7.7/22.9 ± 4.2 Gy, compared to 32.2 ± 9.7/29.9 ± 4.2 Gy and 28.4 ± 8.1/24.7 ± 5.3 Gy for RTOG and VUmc, respectively. EORTC provided 7.2/7.7 Gy mean dose reductions to the contra/ipsilateral parotid glands compared to RTOG. Conclusions Different planning protocols resulted in different levels of PTV dose homogeneity. We observed differences of up to ⩾7 Gy in composite and individual mean OAR doses. This could influence rates of toxicity and should be taken into account when comparing clinical studies. A consensus should be reached between major trial groups on appropriate PTV parameters. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Retrospective studies indicate that larger tumour volume is a strong prognostic indicator for poor tumour control after (chemo)radiotherapy for laryngeal cancer. The impact of tumour volume on the outcome of patients treated within a prospective study comparing accelerated radiotherapy (AR)±carbogen breathing and nicotinamide (ARCON) was investigated. Methods and materials: Of 345 patients with cT2-4 laryngeal cancer, pre-treatment computed tomography (CT) scans of 270 patients were available for tumour volume calculation. Contouring of the primary tumour and involved lymph nodes was reviewed by one experienced head and neck radiation oncologist. Kaplan–Meier plots were used for analysis of outcome. Results: Of 137 AR and 133 ARCON patients, 57 and 80 versus 56 and 77 patients had glottic and supraglottic tumours, respectively. A correlation between primary tumour volume and T-stage was observed (Rs=.51, P <.01). In both treatment arms no correlation was detected between the primary tumour volume and local control (LC), regional control (RC) and metastasis-free survival (MFS). A strong correlation between total nodal volume and N-stage was found (Rs=.93, P <.01). Both in the AR and ARCON groups total nodal volume was not associated with poorer RC rate. However, based on individual lymph node analyses, nodal control was in favour of ARCON, irrespective of volume (P <.01). Conclusion: Neither primary tumour volume, nor total nodal volume is a prognostic factor for patients with cT2-4 laryngeal cancer treated with accelerated radiotherapy±carbogen breathing and nicotinamide. Additional analyses based on individual nodal volumes demonstrate an excellent regional control rate and a significant benefit of ARCON. [Copyright &y& Elsevier]

Purpose: To report the acute toxicity profile and compliance from a randomized Phase III trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen and nicotinamide (ARCON) in laryngeal cancer. Methods and Materials: From April 2001 to February 2008, 345 patients with cT2–4 squamous cell laryngeal cancer were randomized to AR (n = 174) and ARCON (n = 171). Acute toxicity was scored weekly until Week 8 and every 2–4 weeks thereafter. Compliance to carbogen and nicotinamide was reported. Results: Between both treatment arms (AR vs. ARCON) no statistically significant difference was observed for incidence of acute skin reactions (moist desquamation: 56% vs. 58%, p = 0.80), acute mucosal reactions (confluent mucositis: 79% vs. 85%, p = 0.14), and symptoms related to acute mucositis (severe pain on swallowing: 53% vs. 58%, p = 0.37; nasogastric tube feeding: 28% vs. 28%, p = 0.98; narcotic medicines required: 58% vs. 58%, p = 0.97). There was a statistically significant difference in median duration of confluent mucositis in favor of AR (2.0 vs 3.0 weeks, p = 0.01). There was full compliance with carbogen breathing and nicotinamide in 86% and 80% of the patients, with discontinuation in 6% and 12%, respectively. Adjustment of antiemesis prophylaxis was needed in 42% of patients. Conclusion: With the exception of a slight increase in median duration of acute confluent mucositis, the present data reveal a similar acute toxicity profile between both regimens and a good compliance with ARCON for clinical stage T2–4 laryngeal cancers. Treatment outcome and late morbidity will determine the real therapeutic benefit. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of xerostomia on overall quality of life (QoL) outcome and related dimensions among head and neck cancer patients treated with primary radiotherapy. Methods and Materials: A total of 288 patients with Stage I–IV disease without distant metastases were included. Late xerostomia according to the Radiation Therapy Oncology Group (RTOG-xerostomia) and QoL (European Organization for Research and Treatment of Cancer QLC-C30) were assessed at baseline and every 6th month from 6 months to 24 months after radiotherapy. Results: A significant association was found between RTOG-xerostomia and overall QoL outcome (effect size [ES] 0.07, p < 0.001). A significant relationship with global QoL, all functioning scales, and fatigue and insomnia was observed. A significant interaction term was present between RTOG-xerostomia and gender and between RTOG-xerostomia and age. In terms of gender, RTOG-xerostomia had a larger impact on overall QoL outcome in women (ES 0.13 for women vs. 0.07 for men). Furthermore, in women ES on individual scales were larger, and a marked worsening was observed with increasing RTOG-xerostomia. No different ES according to age was seen (ES 0.10 for 18–65 years vs. 0.08 for >65 years). An analysis of the impact of RTOG-xerostomia on overall QoL outcome over time showed an increase from 0.09 at 6 months to 0.22 at 24 months. With elapsing time, a worsening was found for these individual scales with increasing RTOG-xerostomia. Conclusions: The results of this prospective study are the first to show a significant impact of radiation-induced xerostomia on QoL. Although the incidence of Grade ≥2 RTOG-xerostomia decreases with time, its impact on QoL increases. This finding emphasizes the importance of prevention of xerostomia. [Copyright &y& Elsevier]

Abstract: Background and purpose: To investigate the association between radiation technique with patient-rated moderate and severe xerostomia and sticky saliva. Materials and methods: One hundred and fifty patients treated with bilateral or unilateral irradiation for head and neck cancer were included. The salivary glands and the oral cavity were delineated on plannings-CT scans. Xerostomia and sticky saliva were assessed using the EORTC QLQ-H&N35 questionnaire at baseline and 6 and 12 months. Results: At 6 months a significant association between radiation technique and the mean parotid dose (MDparb) and xerostomia was observed (Odds ratio (OR)-technique: 2.55; p =0.04 and OR-MDparb: 1.04; p =0.009). Considering the individual salivary glands, only the mean dose in the contralateral parotid gland (MDparcl) is associated with xerostomia (OR: 1.04; p <0.0001). Moreover, the threshold dose for a 50% probability (P50) on xerostomia increased from 21Gy with bilateral to 44Gy for unilateral irradiation. Conclusions: Both technique and MDparb influence the risk of xerostomia in irradiated patients. Of all individual salivary glands, only MDparcl is of utmost importance for xerostomia. The shift in the P50 observed for xerostomia suggests that sparing of the contralateral parotid gland is compensated by hyperfunction of the contralateral parotid gland. [Copyright &y& Elsevier]

Purpose The aim of this study was to clinically validate a multivariable normal tissue complication probability (NTCP) model for grade 2–4 swallowing dysfunction at 6 months after radiotherapy or chemoradiation (SWAL M6 ) in head and neck cancer patients treated with swallowing sparing intensity modulated radiotherapy (SW-IMRT) and to test if SW-IMRT resulted in a reduction of the prevalence of SWAL M6 . Materials and methods The primary endpoint was SWAL M6 . For all 186 patients, a standard IMRT (parotid sparing) and a SW-IMRT plan (additional constraints for swallowing organs at risk) was created. The difference in NTCP for SWAL M6 (ΔNTCP SWALM6 = NTCP standard − NTCP SW-IMRT ) was calculated. Patients were treated with SW-IMRT. The external validation of the NTCP model was analyzed by comparing performance measures. Results The mean ΔNTCP SWALM6 was 4.9% (range 0.01–17.3%), with a significant lower mean predicted NTCP SW-IMRT of 22.6% (95% CI 20.2–24.9%), compared to NTCP standard of 27.5% (95% CI 24.9–29.9%) ( p < 0.001). There was a perfect correspondence of NTCP SW-IMRT with the observed prevalence of SWAL M6 (22.6%). The overall model performance, discrimination and ‘goodness of fit’ were good. Conclusion We externally validated the multivariable NTCP model for SWAL M6 in SW-IMRT treated patients, showing reduced swallowing dysfunction by reducing the dose parameters included in this NTCP model. [ABSTRACT FROM AUTHOR]

Objectives: Patients with head and neck cancer (HNC) frequently encounter weight loss with multiple negative outcomes as a consequence. Adequate treatment is best achieved by early identification of patients at risk for critical weight loss. The objective of this study was to detect predictive factors for critical weight loss in patients with HNC receiving (chemo)radiotherapy ((C)RT).Materials and Methods: In this cohort study, 910 patients with HNC were included receiving RT (±surgery/concurrent chemotherapy) with curative intent. Body weight was measured at the start and end of (C)RT. Logistic regression and classification and regression tree (CART) analyses were used to analyse predictive factors for critical weight loss (defined as >5%) during (C)RT. Possible predictors included gender, age, WHO performance status, tumour location, TNM classification, treatment modality, RT technique (three-dimensional conformal RT (3D-RT) vs intensity-modulated RT (IMRT)), total dose on the primary tumour and RT on the elective or macroscopic lymph nodes.Results: At the end of (C)RT, mean weight loss was 5.1±4.9%. Fifty percent of patients had critical weight loss during (C)RT. The main predictors for critical weight loss during (C)RT by both logistic and CART analyses were RT on the lymph nodes, higher RT dose on the primary tumour, receiving 3D-RT instead of IMRT, and younger age.Conclusion: Critical weight loss during (C)RT was prevalent in half of HNC patients. To predict critical weight loss, a practical prediction tree for adequate nutritional advice was developed, including the risk factors RT to the neck, higher RT dose, 3D-RT, and younger age. [ABSTRACT FROM AUTHOR]

Background and purpose Curative radiotherapy/chemo-radiotherapy for head and neck cancer (HNC) may result in severe acute and late side effects, including tube feeding dependence. The purpose of this prospective cohort study was to develop a multivariable normal tissue complication probability (NTCP) model for tube feeding dependence 6 months (TUBE M6 ) after definitive radiotherapy, radiotherapy plus cetuximab or concurrent chemoradiation based on pre-treatment and treatment characteristics. Materials and methods The study included 355 patients with HNC. TUBE M6 was scored prospectively in a standard follow-up program. To design the prediction model, the penalized learning method LASSO was used, with TUBE M6 as the endpoint. Results The prevalence of TUBE M6 was 10.7%. The multivariable model with the best performance consisted of the variables: advanced T-stage, moderate to severe weight loss at baseline, accelerated radiotherapy, chemoradiation, radiotherapy plus cetuximab, the mean dose to the superior and inferior pharyngeal constrictor muscle, to the contralateral parotid gland and to the cricopharyngeal muscle. Conclusions We developed a multivariable NTCP model for TUBE M6 to identify patients at risk for tube feeding dependence. The dosimetric variables can be used to optimize radiotherapy treatment planning aiming at prevention of tube feeding dependence and to estimate the benefit of new radiation technologies. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To evaluate the course of health-related quality of life (HRQOL) from diagnosis to 2years follow-up in patients with head and neck cancer (HNSCC) treated with chemoradiation (CRT). Materials and methods: 164 patients completed the EORTC QLQ-C30 and QLQ-H&N35 questionnaires 1week before and 6weeks and 6, 12, 18, and 24months after CRT. Patients were compared to a reference group. A linear mixed-model analysis was used to assess changes in HRQOL over time, and whether this was associated with age, gender, comorbidity, and tumor sublocation. Results: Significant differences for the majority of HRQOL scales were observed between patient and reference group at baseline, and follow-up. The course of HRQOL was different for survivors compared to non-survivors. In survivors, improvement over time was observed (in global quality of life, physical, role, and social function, fatigue, pain, swallowing, speech, social eating, and social contacts), while in non-survivors the pattern over time was either no changes in HRQOL or a deterioration (in physical function, social eating and contacts). In both survivors and non-survivors, emotional functioning improved after treatment, but deteriorated in the longer term. Patients with comorbidity reported worse physical function, and patients with oral/oropharyngeal cancer (compared to hypopharyngeal/laryngeal cancer) reported more oral pain and sexual problems, but fewer speech problems. Conclusions: The course of HRQOL of HNSCC patients during the first 2years after CRT is different for survivors compared to non-survivors and is associated with comorbidity and tumor subsite. [Copyright &y& Elsevier]

Abstract: Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx. Patients (N =272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome. A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p =0.02) and disease-specific survival (92% versus 77% p =0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p =0.009). In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON. [Copyright &y& Elsevier]

Abstract: Background and purpose: In a phase III trial in patients with advanced stage laryngeal carcinoma comparing ARCON (accelerated radiotherapy with carbogen breathing and nicotinamide) to accelerated radiotherapy alone (AR) the prognostic and predictive value of CAIX, a hypoxia-associated protein, was investigated. Material and methods: 261 Paraffin embedded tumor biopsies and 79 fresh frozen biopsies from patients entered in the trial were immunohistochemically stained for CAIX. CAIX-fraction and CAIX expression pattern were related to tumor control and patient survival. Results: Low CAIX-fraction was prognostic for worse regional control and overall survival in patients treated with AR. Patients with a low CAIX-fraction treated with ARCON had better regional control and metastasis-free survival compared to AR (RC 97% vs 71%, p <0.01 and MFS 92% vs 69%, p =0.06). Patients with a perinecrotic CAIX staining pattern had a significantly worse local control, metastasis-free and overall survival compared to patients with a diffuse pattern (65% vs 84%, p =0.01, 70% vs 96%, p <0.01 and 42% vs 71%, p <0.01 respectively), and this could not be improved with ARCON. After multivariate analysis CAIX pattern and N-stage emerged as significant predictors for metastasis-free survival and overall survival. Conclusions: ARCON improves regional control and metastasis-free survival only in patients with low CAIX expression. The different patterns of CAIX expression suggest different mechanisms of upregulation and have important prognostic value. [Copyright &y& Elsevier]

Summary: Purpose: To evaluate long-term changes in health related quality of life (HRQOL) in oral/oropharyngeal cancer survivors and their need for and use of supportive care. Methods: Between 1999 and 2001, 80 advanced oral or oropharyngeal cancer patients treated with free-flap reconstruction and postoperative radiotherapy were included in a prospective study of whom 27 patients were long-term survivors (mean 9.2years, range 8–11years). The HRQOL of 26 patients (response rate 96%) was assessed with the EORTC QLQ-C30 and QLQ-H&N35 questionnaires at four points in time: pretreatment (baseline), and at 6months, 12months (short term) and 8–11years (long-term) follow up. A study specific questionnaire was developed to evaluate the need for and use of supportive care (allied health services, peer contact, psychosocial care, and complementary care) and was completed at the period of treatment and at long-term follow up. Results: A number of HRQOL domains worsened significantly (p <0.01) in the long-term: emotional functioning, social functioning, swallowing, speech, taste/smell, dry mouth, sticky saliva and coughing assessed by the mixed effects statistical model. At time of treatment, the need for supportive care was the highest for a dental hygienist (77%), a physical therapist (73%), a speech therapist (42%), a dietician (38%), and a special diet (62%). At long-term follow up, the need for supportive care was limited to a dental hygienist (46%) and a physical therapist (23%). Only small differences were observed between the perceived need for and actual use of supportive care. Conclusion: A range of HRQOL domains in head and neck cancer survivors were deteriorated in the long-term compared to baseline and to the first year after treatment. At time of treatment and less frequently at long-term follow up, patients reported needing and using a variety of supportive care services. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this multicentre prospective study was to develop multivariable logistic regression models to make valid predictions about the risk of moderate-to-severe patient-rated xerostomia (XERM6) and sticky saliva 6months (STICM6) after primary treatment with intensity modulated radiotherapy (IMRT) with or without chemotherapy for head and neck cancer (HNC). Methods and materials: The study population was composed of 178 consecutive HNC patients treated with IMRT. All patients were included in a standard follow up programme in which acute and late side effects and quality of life were prospectively assessed, prior to, during and after treatment. The primary endpoints were XERM6 and STICM6 as assessed by the EORTC QLQ-H&N35 after completing IMRT. Organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate-to-severe xerostomia or sticky saliva, respectively, at baseline were excluded. The optimal number of variables for a multivariate logistic regression model was determined using a bootstrapping method. Results: Eventually, 51.6% of the cases suffered from XERM6. The multivariate analysis showed that the mean contralateral parotid gland dose and baseline xerostomia (none vs. a bit) were the most important predictors for XERM6. For the multivariate NTCP model, the area under the receiver operating curve (AUC) was 0.68 (95% CI 0.60–0.76) and the discrimination slope was 0.10, respectively. Calibration was good with a calibration slope of 1.0. At 6months after IMRT, 35.6% of the cases reported STICM6. The mean contralateral submandibular gland dose, the mean sublingual dose and the mean dose to the minor salivary glands located in the soft palate were most predictive for STICM6. For this model, the AUC was 0.70 (95% CI 0.61–0.78) and the discrimination slope was 0.12. Calibration was good with a calibration slope of 1.0. Conclusions: The multivariable NTCP models presented in this paper can be used to predict patient-rated xerostomia and sticky saliva. The dose volume parameters included in the models can be used to further optimise IMRT treatment. [Copyright &y& Elsevier]

Abstract: Background and purpose: The purpose of this large multicentre prospective cohort study was to identify which dose volume histogram parameters and pre-treatment factors are most important to predict physician-rated and patient-rated radiation-induced swallowing dysfunction (RISD) in order to develop predictive models for RISD after curative (chemo) radiotherapy ((CH) RT). Material and methods: The study population consisted of 354 consecutive head and neck cancer patients treated with (CH) RT. The primary endpoint was grade 2 or more swallowing dysfunction according to the RTOG/EORTC late radiation morbidity scoring criteria at 6months after (CH) RT. The secondary endpoints were patient-rated swallowing complaints as assessed with the EORTC QLQ-H&N35 questionnaire. To select the most predictive variables a multivariate logistic regression analysis with bootstrapping was used. Results: At 6months after (CH) RT the bootstrapping procedure revealed that a model based on the mean dose to the superior pharyngeal constrictor muscle (PCM) and mean dose to the supraglottic larynx was most predictive. For the secondary endpoints different predictive models were found: for problems with swallowing liquids the most predictive factors were the mean dose to the supraglottic larynx and radiation technique (3D-CRT versus IMRT). For problems with swallowing soft food the mean dose to the middle PCM, age (18–65 versus >65years), tumour site (naso/oropharynx versus other sites) and radiation technique (3D-CRT versus IMRT) were the most predictive factors. For problems with swallowing solid food the most predictive factors were the mean dose to the superior PCM, the mean dose to the supraglottic larynx and age (18–65 versus >65years). And for choking when swallowing the V60 of the oesophageal inlet muscle and the mean dose to the supraglottic larynx were the most predictive factors. Conclusions: Physician-rated and patient-rated RISD in head and neck cancer patients treated with (CH) RT cannot be predicted with univariate relationships between the dose distribution in a single organ at risk and an endpoint. Separate predictive models are needed for different endpoints and factors other than dose volume histogram parameters are important as well. [Copyright &y& Elsevier]

Abstract: Purpose: The purpose of this multicentre prospective study was to investigate the significance of the radiation dose in the major and minor salivary glands, and other pre-treatment and treatment factors, with regard to the development of patient-rated xerostomia and sticky saliva among head and neck cancer (HNC) patients treated with primary (chemo-) radiotherapy ((CH)RT). Methods and materials: The study population was composed of 167 consecutive HNC patients treated with three-dimensional conformal (3D-CRT) (CH) RT. The primary endpoint was moderate to severe xerostomia (XER6m) as assessed by the EORTC QLQ-H&N35 at 6months after completing (CH)RT. The secondary endpoint was moderate to severe sticky saliva at 6months (STIC6m). All organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate to severe xerostomia or sticky saliva at baseline were excluded. The optimum number of variables for a multivariate logistic regression model was determined using a bootstrapping method. Results: The multivariate analysis showed the mean parotid dose, age and baseline xerostomia (none versus a bit) to be the most important predictors for XER6m. The risk of developing xerostomia increased with age and was higher when minor baseline xerostomia was present in comparison with patients without any xerostomia complaints at baseline. Model performance was good with an area under the curve (AUC) of 0.82. For STIC6m, the mean submandibular dose, age, the mean sublingual dose and baseline sticky saliva (none versus a bit) were most predictive for sticky saliva. The risk of developing STIC6m increased with age and was higher when minor baseline sticky saliva was present in comparison with patients without any sticky saliva complaints at baseline. Model performance was good with an AUC of 0.84. Conclusions: Dose distributions in the minor salivary glands in patients receiving 3D-CRT have limited significance with regard to patient-rated symptoms related to salivary dysfunction. Besides the parotid and submandibular glands, only the sublingual glands were significantly associated with sticky saliva. In addition, reliable risk estimation also requires information from other factors such as age and baseline subjective scores. When these selected factors are included in predictive models, instead of only dose volume histogram parameters, model performance can be improved significantly. [Copyright &y& Elsevier]

Abstract: Purpose: The purpose of this study was to investigate the ability of predictive models for patient-rated xerostomia (XER6M) and sticky saliva (STIC6M) at 6months after completion of primary (chemo)radiation developed in head and neck cancer patients treated with 3D-conformal radiotherapy (3D-CRT) to predict outcome in patients treated with intensity modulated radiotherapy (IMRT). Methods and materials: Recently, we published the results of a prospective study on predictive models for patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with 3D-CRT (3D-CRT based NTCP models). The 3D-CRT based model for XER6M consisted of three factors, including the mean parotid dose, age, and baseline xerostomia (none versus a bit). The 3D-CRT based model for STIC6M consisted of the mean submandibular dose, age, the mean sublingual dose, and baseline sticky saliva (none versus a bit). In the current study, a population consisting of 162 patients treated with IMRT was used to test the external validity of these 3D-CRT based models. External validity was described by the explained variation (R 2 Nagelkerke) and the Brier score. The discriminative abilities of the models were calculated using the area under the receiver operating curve (AUC) and calibration (i.e. the agreement between predicted and observed outcome) was assessed with the Hosmer–Lemeshow “goodness-of-fit” test. Results: Overall model performance of the 3D-CRT based predictive models for XER6M and STIC6M was significantly worse in terms of the Brier score and R 2 Nagelkerke among patients treated with IMRT. Moreover the AUC for both 3D-CRT based models in the IMRT treated patients were markedly lower. The Hosmer–Lemeshow test showed a significant disagreement for both models between predicted risk and observed outcome. Conclusion: 3D-CRT based models for patient-rated xerostomia and sticky saliva among head and neck cancer patients treated with primary radiotherapy or chemoradiation turned out to be less valid for patients treated with IMRT. The main message from these findings is that models developed in a population treated with a specific technique cannot be generalised and extrapolated to a population treated with another technique without external validation. [Copyright &y& Elsevier]

Abstract: Background and purpose: The relation between health-related quality of life (HRQOL) and survival was investigated at baseline and 6months in 80 patients with advanced oral or oropharyngeal cancer after microvascular reconstructive surgery and (almost all) adjuvant radiotherapy. Materials and methods: Multivariate Cox regression analyses of overall and disease-specific survival were performed including sociodemographic (age, gender, marital status, comorbidity), and clinical (tumor stage and site, radical surgical, metastasis, radiotherapy) parameters, and HRQOL (EORTC QLQ-C30 global quality of life scale). Results: Before treatment, younger age and having a partner were predictors of disease-specific survival; younger age predicted overall survival. At 6months post-treatment, disease-specific and overall survival was predicted by (deterioration of) global quality of life solely. Global health-related quality of life after treatment was mainly influenced by emotional functioning. Conclusion: Deterioration of global quality of life after treatment is an independent predictor of survival in patients with advanced oral or oropharyngeal cancer. [Copyright &y& Elsevier]

Abstract: Background and purpose: Reports on shoulder function after non-surgical treatment are not available. In the present study shoulder morbidity after surgical and non-surgical treatment of the neck is determined and compared. Materials and methods: In 100 head and neck cancer patients 174 neck sides were treated by surgery (n =51) or (chemo)radiation (n =123). Abduction, anteflexion, endorotation and exorotation were assessed. Subjective measurements were performed using the Visual Analogue Scale for pain, the Shoulder Disability Questionnaire (SDQ) and stiffness reporting. Results: Predictive factors for SDQ-score>0 (n =54) were VAS pain score, stiffness, abduction, anteflexion, physiotherapy, low shoulder position and surgical treatment. The SDQ, stiffness and pain scores were significantly higher in the surgically treated group than in the non-surgical group (p <0.01). Anteflexion, abduction and exorotation were less impaired in the non-surgically treated group than in the surgically treated group (p <0.01). No differences between neck dissection and neck dissection with post-operative radiotherapy, and radiotherapy and chemoradiation were found for these movements. Conclusions: Shoulder morbidity is often present after non-surgical treatment of the neck, but to a lesser extent compared to surgical treatment. Radiotherapy adds no morbidity to neck dissection and chemotherapy does not add extra morbidity to primary radiation. [Copyright &y& Elsevier]

Summary: Adult soft tissue sarcomas of the head and neck are rare and consist of a variety of histopathological subtypes and sites. The purpose of this study was to review patients treated for adult soft tissue sarcomas of the head and neck at our institute. The medical records of 41 adult patients treated for head and neck soft tissue sarcomas between 1983 and 2004 were reviewed. Thirty-six tumours were histologically reviewed. Histopathological revision showed that 7% of the original sarcomas were found not to be sarcomas and 39% of the sarcoma subtypes changed. Multivariate analysis showed that surgical margin status and lymph node metastases are the most important prognostic factors. Review of histopathological examination of tumours showed a change in subtype in a substantial number of head and neck sarcomas. Negative surgical margins are an important prognostic factor, but are difficult to obtain in head and neck sarcomas. [Copyright &y& Elsevier]