Hendrik P. Bijl

Accelerated Radiotherapy With Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial

PURPOSE To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer. PATIENTS AND METHODS Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. RESULTS From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity. CONCLUSION Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.

Predictive modelling for swallowing dysfunction after primary (chemo)radiation: Results of a prospective observational study

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 6 months 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 6 months 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 >65 years), 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 >65 years). 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.

Unexpected changes of rat cervical spinal cord tolerance caused by inhomogeneous dose distributions.

PURPOSE The effects of dose distribution on dose-effect relationships have been evaluated and, from this, iso-effective doses (ED(50)) established. METHODS AND MATERIALS Wistar rats were irradiated on the cervical spinal cord with single doses of unmodulated protons (150 MeV) to obtain sharp lateral penumbras, using the shoot-through technique, which employs the plateau of the depth-dose profile rather than the Bragg peak. Two types of inhomogeneous dose distributions have been administered: (1) 2 4-mm fields with 8- or 12-mm spacing between the center of the fields (referred to as split-field) were irradiated with variable single doses and (2) cervical spinal cord was irradiated with various combinations of relatively low doses to a large volume (20 mm) combined with high doses to a small volume (4 mm) (referred to as bath and shower). The endpoint for estimating the dose-response relationships was paralysis of the fore or hind limbs. RESULTS The split-field experiments (2 x 4 mm) showed a shift in the dose-response curves, giving significant higher ED(50) values of 45.4 Gy and 41.6 Gy for 8- and 12-mm spacing, respectively, compared with the ED(50) of 24.9 Gy for the single 8 mm (same total tissue volume irradiated). These values were closer to the ED(50) for a single 4-mm field of 53.7 Gy. The bath and shower experiments showed a large decrease of the ED(50) values from 15-22 Gy when compared with the 4-mm single field, even with a bath dose as low as 4 Gy. There were no histologic changes found in the low dose bath regions of the spinal cord at postmortem. CONCLUSIONS Not only the integral irradiated volume is a determining factor for the ED(50) of rat cervical spinal cord, but also the shape of the dose distribution is of great importance. The high ED(50) values of a small region or shower (4 mm) decreases significantly when the adjacent tissue is irradiated with a subthreshold dose (bath), even as low as 4 Gy. The significant shift to lower ED(50) values for induction of paralysis of the limbs by adding a low-dose bath was not accompanied by changes in histologic lesions. These observations may have implications for the interpretation of complex treatment plans and normal tissue complication probability in intensity-modulated radiotherapy.

Delineation of organs at risk involved in swallowing for radiotherapy treatment planning

BACKGROUND AND PURPOSE Radiotherapy, alone or combined with chemotherapy, is a treatment modality used frequently in head and neck cancer. In order to report, compare and interpret the sequelae of radiation treatment adequately, it is important to delineate organs at risk (OARs) according to well-defined and uniform guidelines. The aim of this paper was to present our institutional Computed Tomography (CT)-based delineation guidelines for organs in the head and neck at risk for radiation-induced swallowing dysfunction (SWOARs). MATERIAL AND METHODS After analyses of the human anatomy of the head and neck area and literature review, CT-based guidelines for delineation of the most relevant SWOARs were described by a panel of experts. RESULTS AND CONCLUSIONS This paper described institutional guidelines for the delineation of potential SWOARs, accompanied by CT-based illustrations presenting examples of the delineated structures and their corresponding anatomic borders. This paper is essential to ensure adequate interpretation of future reports on the relationship between dose distribution in these SWOARs and different aspects of post-treatment swallowing dysfunction.

Dose-volume effects in the rat cervical spinal cord after proton irradiation

PURPOSE To estimate dose-volume effects in the rat cervical spinal cord with protons. METHODS AND MATERIALS Wistar rats were irradiated on the cervical spinal cord with a single fraction of unmodulated protons (150-190 MeV) using the shoot through method, which employs the plateau of the depth-dose profile rather than the Bragg peak. Four different lengths of the spinal cord (2, 4, 8, and 20 mm) were irradiated with variable doses. The endpoint for estimating dose-volume effects was paralysis of fore or hind limbs. RESULTS The results obtained with a high-precision proton beam showed a marginal increase of ED50 when decreasing the irradiated cord length from 20 mm (ED50 = 20.4 Gy) to 8 mm (ED50 = 24.9 Gy), but a steep increase in ED50 when further decreasing the length to 4 mm (ED50 = 53.7 Gy) and 2 mm (ED50 = 87.8 Gy). These results generally confirm data obtained previously in a limited series with 4-6-MV photons, and for the first time it was possible to construct complete dose-response curves down to lengths of 2 mm. At higher ED50 values and shorter lengths irradiated, the latent period to paralysis decreased from 125 to 60 days. CONCLUSIONS Irradiation of variable lengths of rat cervical spinal cord with protons showed steeply increasing ED50 values for lengths of less than 8 mm. These results suggest the presence of a critical migration distance of 2-3 mm for cells involved in regeneration processes.

POTENTIAL BENEFITS OF SCANNED INTENSITY-MODULATED PROTON THERAPY VERSUS ADVANCED PHOTON THERAPY WITH REGARD TO SPARING OF THE SALIVARY GLANDS IN OROPHARYNGEAL CANCER

PURPOSE To test the hypothesis that scanned intensity-modulated proton therapy (IMPT) results in a significant dose reduction to the parotid and submandibular glands as compared with intensity-modulated radiotherapy with photons (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for oropharyngeal cancer. In addition, we investigated whether the achieved dose reductions would theoretically translate into a reduction of salivary dysfunction and xerostomia. METHODS AND MATERIALS Ten patients with N0 oropharyngeal carcinoma were used. The intensity-modulated plans delivered simultaneously 70 Gy to the boost planning target volume (PTV2) and 54 Gy to the elective nodal areas (PTV1). The 3D-CRT technique delivered sequentially 70 Gy and 46 Gy to PTV2 and PTV1, respectively. Normal tissue complication probabilities were calculated for salivary dysfunction and xerostomia. RESULTS Planning target volume coverage results were similar for IMPT and IMRT. Intensity-modulated proton therapy clearly improved the conformity. The 3D-CRT results were inferior to these results. The mean dose to the parotid glands by 3D-CRT (50.8 Gy), IMRT (25.5 Gy), and IMPT (16.8 Gy) differed significantly. For the submandibular glands no significant differences between IMRT and IMPT were found. The dose reductions obtained with IMPT theoretically translated into a significant reduction in normal tissue complication probability. CONCLUSION Compared with IMRT and 3D-CRT, IMPT improved sparing of the organs at risk, while keeping similar target coverage results. The dose reductions obtained with IMPT vs. IMRT and 3D-CRT varied widely per individual patient. Intensity-modulated proton therapy theoretically translated into a clinical benefit for most cases, but this requires clinical validation.

The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study.

Abstract Background. Predictive models for swallowing dysfunction were developed previously and showed the potential of improved intensity-modulated radiotherapy to reduce the risk of swallowing dysfunction. Still the risk is high. The aim of this study was to determine the potential of swallowing-sparing (SW) intensity-modulated proton therapy (IMPT) in head and neck cancer (HNC) for reducing the risk of swallowing dysfunction relative to currently used photon therapy. Material and methods. Twenty-five patients with oropharyngeal (n = 21) and hypopharyngeal (n = 4) cancer received primary radiotherapy, including bilateral neck irradiation, using standard (ST) intensity-modulated photon therapy (IMRT). Prophylactic (54 Gy) and therapeutic (70 Gy) target volumes were defined. The dose to the parotid and submandibular glands was reduced as much as possible. Four additional radiotherapy plans were created for each patient: SW-IMRT, ST-IMPT, 3-beam SW-IMPT (3B-SW-IMPT) and 7-beam SW-IMPT (7B-SW-IMPT). All plans were optimized similarly, with additional attempts to spare the swallowing organs at risk (SWOARs) in the SW plans. Probabilities of swallowing dysfunction were calculated with recently developed predictive models. Results. All plans complied with standard HNC radiotherapy objectives. The mean parotid gland doses were similar for the ST and SW photon plans, but clearly lower in all IMPT plans (ipsilateral parotid gland ST-IMRT: 46 Gy, 7B-SW-IMPT: 29 Gy). The mean dose in the SWOARs was lowest with SW-IMPT, in particular with 7B-SW-IMPT (supraglottic larynx ST-IMRT: 60 Gy, 7B-SW-IMPT: 40 Gy). The observed dose reductions to the SWOARs translated into substantial overall reductions in normal tissue complication risks for different swallowing dysfunction endpoints. Compared with ST-IMRT, the risk of physician-rated grade 2–4 swallowing dysfunction was reduced on average by 8.8% (95% CI 6.5–11.1%) with SW-IMRT, and by 17.2% (95% CI: 12.7–21.7%) with 7B-SW-IMPT. Conclusion. SWOAR-sparing with proton therapy has the potential to substantially reduce the risk of swallowing dysfunction compared to similar treatment with photons.

The potential benefit of swallowing sparing intensity modulated radiotherapy to reduce swallowing dysfunction: An in silico planning comparative study

PURPOSE To apply recently developed predictive models for swallowing dysfunction to compare the predicted probabilities of swallowing dysfunction for standard intensity modulated radiotherapy (ST-IMRT) and swallowing sparing IMRT (SW-IMRT). MATERIALS AND METHODS Thirty head and neck cancer patients who previously underwent radiotherapy for the bilateral neck were selected for this study. For each patient, ST-IMRT and SW-IMRT simultaneous integrated boost treatment plans were created. ST-IMRT treatment plan optimisation aimed at obtaining adequate target volume coverage and sparing of the parotid and submandibular glands as much as possible. Objectives for SW-IMRT were similar, with additional objectives to spare the organs at risk related to swallowing dysfunction (SWOARs). Dose-volume data with ST-IMRT and SW-IMRT and normal tissue complication probabilities for physician-rated and patient-rated swallowing dysfunction were calculated with recently developed predictive models. RESULTS All plans had adequate target volume coverage and dose to critical organs was within accepted limits. Sparing of parotid glands was similar for ST-IMRT and SW-IMRT. With SW-IMRT, the mean dose to the various SWOARs was reduced. Absolute dose values and dose reductions with SW-IMRT differed per patient and per SWOAR and depended on N stage and tumour location. The mean reduction in predicted physician-rated Radiation Therapy Oncology Group (RTOG) grade 2-4 swallowing dysfunction was 9% (range, 3-20%). Mean reductions of the probability of patient-rated moderate to severe complaints with regard to the swallowing of solid food, soft food, liquid food and choking when swallowing were 8%, 2%, 1% and 1%, respectively. CONCLUSIONS New predictive models for swallowing dysfunction were applied to show potential reductions in physician and patient-rated swallowing dysfunction with IMRT that was specifically optimised to spare SWOARs.

Radiation-induced hypothyroidism in head and neck cancer patients: A systematic review

PURPOSE To review literature on the relationship between the dose distribution in the thyroid gland and the incidence of radiation-induced hypothyroidism in adults. MATERIAL AND METHODS Articles were identified through a search in MEDLINE, EMBASE and the Cochrane Library. Approximately 2449 articles were screened and selected by inclusion- and exclusion criteria. Eventually, there were five papers that fulfilled the eligibility criteria to be included in this review. RESULTS The sample sizes of the reviewed studies vary from 57 to 390 patients. The incidence of hypothyroidism was much higher (23-53%) than would be expected in a non-irradiated cohort. There was a large heterogeneity between the studies regarding study design, estimation of the dose to the thyroid gland and definition of endpoints. In general, the relationship between thyroid gland volume absorbing 10-70Gy (V10-V70), mean dose (Dmean), minimal dose (Dmin), maximum dose (Dmax) and point doses with hypothyroidism were analysed. An association between dose-volume parameters and hypothyroidism was found in two studies. CONCLUSIONS Hypothyroidism is frequently observed after radiation. Although the results suggest that higher radiation doses to the thyroid gland are associated with hypothyroidism, it was not possible to define a clear threshold radiation dose for the thyroid gland.

Development of a multivariable normal tissue complication probability (NTCP) model for tube feeding dependence after curative radiotherapy/chemo-radiotherapy in head and neck cancer

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 (TUBEM6) 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. TUBEM6 was scored prospectively in a standard follow-up program. To design the prediction model, the penalized learning method LASSO was used, with TUBEM6 as the endpoint. RESULTS The prevalence of TUBEM6 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 TUBEM6 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.