Hans Paul van der Laan

Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer

Avoiding irradiation of the region of the parotid gland containing stem cells reduces the risk of xerostomia (dry mouth). Preserving saliva flow after radiotherapy Radiotherapy for head and neck cancer may damage the salivary glands, resulting in reduced salivation with consequent xerostomia (dry mouth). Xerostomia affects the quality of life of patients with head and neck cancer. van Luijk and co-workers reported the location of salivary (parotid) gland stem cells in the mouse, rat, and human. Next, they showed in rat and human that irradiation of the salivary gland region containing the highest number of stem cells resulted in the greatest loss of saliva production after treatment. Finally, the authors showed that it is possible to avoid irradiation of this specific area during therapy, which may reduce the patient’s risk of developing post-radiotherapy xerostomia. Each year, 500,000 patients are treated with radiotherapy for head and neck cancer, resulting in relatively high survival rates. However, in 40% of patients, quality of life is severely compromised because of radiation-induced impairment of salivary gland function and consequent xerostomia (dry mouth). New radiation treatment technologies enable sparing of parts of the salivary glands. We have determined the parts of the major salivary gland, the parotid gland, that need to be spared to ensure that the gland continues to produce saliva after irradiation treatment. In mice, rats, and humans, we showed that stem and progenitor cells reside in the region of the parotid gland containing the major ducts. We demonstrated in rats that inclusion of the ducts in the radiation field led to loss of regenerative capacity, resulting in long-term gland dysfunction with reduced saliva production. Then we showed in a cohort of patients with head and neck cancer that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicted the function of the salivary glands one year after radiotherapy. Finally, we showed that this region of the salivary gland could be spared during radiotherapy, thus reducing the risk of post-radiotherapy xerostomia.

Current technological clinical practice in breast radiotherapy; results of a survey in EORTC-Radiation Oncology Group affiliated institutions

PURPOSE To evaluate the current technological clinical practice of radiation therapy of the breast in institutions participating in the EORTC-Radiation Oncology Group (EORTC-ROG). MATERIALS AND METHODS A survey was conducted between August 2008 and January 2009 on behalf of the Breast Working Party within the EORTC-ROG. The questionnaire comprised 32 questions on 4 main topics: fractionation schedules, treatment planning methods, volume definitions and position verification procedures. RESULTS Sixty-eight institutions out of 16 countries responded (a response rate of 47%). The standard fraction dose was generally 2Gy for both breast and boost treatment, although a 2.67 Gy boost fraction dose is routinely given in British institutions. The main boost modality was electrons in 55%, photons in 47% and brachytherapy in 3% of the institutions (equal use of photon and electron irradiation in 5% of the institutions). All institutions used CT-based treatment planning. Wide variations are seen in the definition of the breast and boost target volumes, with margins around the resection cavity, ranging from 0 to 30 mm. Inverse planned IMRT is available in 27% and breath-hold techniques in 19% of the institutions. The number of patients treated with IMRT and breath-hold varied per institution. Electronic portal imaging for patient set-up is used by 92% of the institutions. CONCLUSIONS This survey provides insight in the current practice of radiation technology used in the treatment of breast cancer among institutions participating in EORTC-ROG clinical trials.

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.

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.

Three-dimensional conformal hypofractionated simultaneous integrated boost in breast conserving therapy: Results on local control and survival

PURPOSE To report on local control and survival after breast conserving therapy (BCT) including three-dimensional conformal simultaneous integrated boost irradiation (3D-CRT-SIB) and on the influence of age on outcome. PATIENT AND METHODS For this study, 752 consecutive female breast cancer patients (stages I-III), treated with 3D-CRT-SIB at the University Medical Center Groningen from 2005 to 2008, were retrospectively identified. Median age was 58.4 (range 26-84) years. The SIB fractionation used was: 28×1.8Gy (whole breast) and 28×2.3Gy or 2.4Gy (tumour bed). Next to outcome, we estimated the effect of age on the recurrence-free period (RFP) by multivariate Cox regression survival analysis. RESULTS Median follow-up was 41 (range 3-65) months. Local control was 99.6% at 3 years (6 ipsilateral recurrences). The 3-year locoregional control, RFP and overall survival (OS) rates were 99.2%, 95.5%, and 97.1%, respectively. In multivariate analysis, tumours >2cm (hazard ratio (HR) 3.11; 95% confidence interval (CI) 1.57-6.17) and triple negativity (HR 3.03; 95% CI 1.37-6.67) and not age were associated with impaired RFP. CONCLUSIONS At 3 years, the 3D-CRT-SIB technique in BCT results in excellent local control and OS. Age was not a risk factor for any recurrence.

Development and evaluation of an online three-level proton vs photon decision support prototype for head and neck cancer – Comparison of dose, toxicity and cost-effectiveness

To quantitatively assess the effectiveness of proton therapy for individual patients, we developed a prototype for an online platform for proton decision support (PRODECIS) comparing photon and proton treatments on dose metric, toxicity and cost-effectiveness levels. An evaluation was performed with 23 head and neck cancer datasets.

Acute symptoms during the course of head and neck radiotherapy or chemoradiation are strong predictors of late dysphagia

PURPOSE To determine if acute symptoms during definitive radiotherapy (RT) or chemoradiation (CHRT) are prognostic factors for late dysphagia in head and neck cancer (HNC). MATERIAL AND METHODS This prospective cohort study consisted of 260 HNC patients who received definitive RT or CHRT. The primary endpoint was grade 2-4 swallowing dysfunction at 6 months after completing RT (SWALM6). During treatment, acute symptoms, including oral mucositis, xerostomia and dysphagia, were scored, and the scores were accumulated weekly and entered into an existing reference model for SWALM6 that consisted of dose-volume variables only. RESULTS Both acute xerostomia and dysphagia were strong prognostic factors for SWALM6. When acute scores were added as variables to the reference model, model performance increased as the course of treatment progressed: the AUC rose from 0.78 at the baseline to 0.85 in week 6. New models built for weeks 3-6 were significantly better able to identify patients with and without late dysphagia. CONCLUSION Acute xerostomia and dysphagia during the course of RT are strong prognostic factors for late dysphagia. Including accumulated acute symptom scores on a weekly basis in prediction models for late dysphagia significantly improves the identification of high-risk and low-risk patients at an early stage during treatment and might facilitate individualized treatment adaptation.

Swallowing-sparing intensity-modulated radiotherapy for head and neck cancer patients: treatment planning optimization and clinical introduction.

PURPOSE To report on the potential benefits of swallowing-sparing intensity-modulated radiation therapy (SW-IMRT) in the first 100 SW-IMRT treated patients, as well as on the factors that influence the potential benefit of SW-IMRT relative to standard parotid sparing (ST)-IMRT. MATERIAL AND METHODS One hundred consecutive head and neck cancer patients, scheduled for primary radiotherapy, were included in this prospective cohort study. For each patient, ST-IMRT and SW-IMRT treatment plans were created. All patients were eventually treated with SW-IMRT. Objectives for SW-IMRT were identical to those with ST-IMRT, with additional objectives to spare the swallowing organs at risk (SWOARs). After 20 patients, interim results were evaluated by a multidisciplinary committee. RESULTS The mean gain of SW-IMRT relative to ST-IMRT in the first 20 patients was less than expected based on our previous planning comparative study. A critical review of all plans revealed that the results with SW-IMRT could be improved by: (1) gaining experience and attempting to reduce SWOAR dose as much as possible; (2) accepting a moderate shift of dose to unspecified tissues; (3) maximizing SWOAR sparing while keeping PTV coverage exactly according to protocol. In the additional 80 patients, the mean dose to the various SWOARs was further reduced significantly compared to ST-IMRT. Dose reductions with SW-IMRT were largest for patients who received neck irradiation, had a tumour located in the larynx, oropharynx, nasopharynx or oral cavity, and had <75% overlap between SWOARs and PTVs. The mean absolute reduction in predicted physician-rated RTOG grade 2-4 swallowing dysfunction for patients numbered 21-100 was 6.1%, ranging from 0.0% to 17.2%. CONCLUSIONS The benefit of SW-IMRT depends significantly on neck radiotherapy, tumour site and the amount of overlap between SWOARs and PTVs. Optimal clinical introduction requires a detailed evaluation and comparison between the standard (ST-IMRT) and new technique (SW-IMRT) in order to fully exploit the potential benefits.

Dosimetric consequences of the shift towards computed tomography guided target definition and planning for breast conserving radiotherapy

BackgroundThe shift from conventional two-dimensional (2D) to three-dimensional (3D)-conformal target definition and dose-planning seems to have introduced volumetric as well as geometric changes. The purpose of this study was to compare coverage of computed tomography (CT)-based breast and boost planning target volumes (PTV), absolute volumes irradiated, and dose delivered to the organs at risk with conventional 2D and 3D-conformal breast conserving radiotherapy.MethodsTwenty-five patients with left-sided breast cancer were subject of CT-guided target definition and 3D-conformal dose-planning, and conventionally defined target volumes and treatment plans were reconstructed on the planning CT. Accumulated dose-distributions were calculated for the conventional and 3D-conformal dose-plans, taking into account a prescribed dose of 50 Gy for the breast plans and 16 Gy for the boost plans.ResultsWith conventional treatment plans, CT-based breast and boost PTVs received the intended dose in 78% and 32% of the patients, respectively, and smaller volumes received the prescribed breast and boost doses compared with 3D-conformal dose-planning. The mean lung dose, the volume of the lungs receiving > 20 Gy, the mean heart dose, and volume of the heart receiving > 30 Gy were significantly less with conventional treatment plans. Specific areas within the breast and boost PTVs systematically received a lower than intended dose with conventional treatment plans.ConclusionThe shift towards CT-guided target definition and planning as the golden standard for breast conserving radiotherapy has resulted in improved target coverage at the cost of larger irradiated volumes and an increased dose delivered to organs at risk. Tissue is now included into the breast and boost target volumes that was never explicitly defined or included with conventional treatment. Therefore, a coherent definition of the breast and boost target volumes is needed, based on clinical data confirming tumour control probability and normal tissue complication probability with the use of 3D-conformal radiotherapy.