Accepted 21 April 2014 Published online 11 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed.23715

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1 ORIGINAL ARTICLE Acute and late side effects to salivary glands and oral mucosa after head and neck radiotherapy in children and adolescents. Results of the Registry for the evaluation of side effects after radiotherapy in childhood and adolescence Tobias B olling, MD, 1,2* Julia Weege, 1 Hans Theodor Eich, MD, 1 Beate Timmermann, MD, 3,4 Frank-Michal Meyer, MD, 5 Christian R ube, MD, 6 Rolf-Dieter Kortmann, MD, 7 Karin Fischedick, MD, 8 Claus R odel, MD, 9 Raphael Koch, 10 Normann Willich, MD 1 1 Department of Radiotherapy, University Hospital of M unster, M unster, Germany, 2 Center for Radiotherapy Rheine/Osnabr uck, Osnabr uck, Germany, 3 Western German Proton Therapy Center, University Hospital of Essen, Essen, Germany, 4 Center for Proton Radiation Therapy, Paul Scherrer Institute, Villigen, Switzerland, 5 Department of Radiotherapy, Clinic Augsburg, Augsburg, Germany, 6 Department of Radiotherapy, University Hospital of Homburg/Saar, Homburg/Saar, Germany, 7 Department of Radiotherapy, University Hospital of Leipzig, Leipzig, Germany, 8 Department of Radiotherapy, University Hospital of Aachen, Aachen, Germany, 9 Department of Radiotherapy, University Hospital of Frankfurt, Frankfurt, Germany, 10 Institute of Biostatistics and Clinical Research (IBKF), University of M unster, M unster, Germany. Accepted 21 April 2014 Published online 11 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The registry for the evaluation of side effects after radiotherapy in childhood and adolescence (RiSK) was established to prospectively characterize radiation-associated side effects. The purpose of this analysis was to characterize side effects after radiotherapy to the head and neck in children and adolescents. Methods. Radiation doses have been collected across Germany since Acute and late side effects were characterized. Results. Until January 2010, 133 patients (median age, 12.7 years) were recruited who had received radiotherapy to the salivary glands. Toxicity evaluation was available for 114 patients (median follow-up, 2.9 years). Acute and late toxicity significantly depended on the maximum radiation dose to the salivary glands. An increase of the mean value of maximum dose of 1 Gray (Gy) to the submandibular glands resulted in an odds ratio of 1.04 (range, ; p 5.039) for acute toxicities of the salivary glands and 1.08 (range, ; p 5.001) for acute mucosal toxicities. Conclusion. These data can be used for an individual risk assessment in pediatric head and neck radiotherapy. VC 2014 Wiley Periodicals, Inc. Head Neck 37: , 2015 KEY WORDS: radiation, head and neck, salivary gland, childhood, adolescence INTRODUCTION The characterization of the effects of cancer therapy in children and adolescents has been of increasing interest because of the high cure rates of cancer using modern multimodal therapy. 1,2 Retrospective analyses on radiation-associated side effects have mainly been performed with unclear estimates of the radiation characteristics because of a lack of detailed organ dose documentation. Several study groups in a variety of countries have developed strategies to characterize different aspects of these late effects. The largest examination was performed in the United States using the Childhood Cancer Survivor Study (CCSS). The CCSS was established to retrospectively characterize the health status of 5-year survivors of childhood cancer. 3 In these studies, more than 12,000 patients were evaluated by questionnaires regarding their health status in comparison with their siblings. 2 Regarding radiation-associated late sequelae, studies within the CCSS setting cannot be based on detailed *Corresponding author: T. B olling, Center for Radiotherapy Rheine/Osnabr uck, Am Finkenh ugel 5, Osnabr uck, Germany. pd.dr.boelling@strahlenbehandlung.de Contract grant sponsor: The Deutsche Kinderkrebsstiftung, Bonn, Germany. information about radiation doses at organs at risk. The CCSS database includes radiotherapy treatment parameters, such as the first and last dates of treatment, the body region treated, the beam energy, the treatment field size, configuration and laterality, and the total treatment dose. 1 The acquisition of further data with retrospective reconstruction of doses at the organs at risk is described to be possible for special questions in subgroups of patients. 1 Although the approach of the CCSS has led to interesting analyses of many late sequelae, this approach may not be sufficient to answer open questions regarding the dosevolume-effect relationships of late effects in pediatric oncology patients treated with radiation. In Germany, the registry for the evaluation of side effects after radiation in childhood and adolescence (RiSK) has been established by the German Group of Pediatric Radiation Oncology, a working group of the German Society of Radiation Oncology, and the German Society of Pediatric Oncology and Hematology (GPOH). The purpose of this prospective multicenter registry was to evaluate radiation dose-effect relationships in organs and parts of organs after radiotherapy, including combined modality treatments with surgery and/or chemotherapy. The feasibility of RiSK has already been shown and initial results have been published. 4 8 The intention of the present analysis was to characterize salivary gland function and mucosa HEAD & NECK DOI /HED AUGUST

2 BÖLLING ET AL. TABLE 1. Overview about number of patients (percentage) with documented acute side effects, maximal late side effects and late side effects at the last documentation. No. of patients (%) by toxicity grade Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Mucosa Acute toxicity 52 (43) 30 (25) 25 (21) 11 (9) 2 (2) Maximal late toxicity 96 (90) 8 (7) 3 (3) 0 (0) 0 (0) Late toxicity last documentation 99 (93) 6 (5) 2 (2) 0 (0) 0 (0) Salivary glands Acute toxicity 84 (74) 22 (19) 5 (4) 3 (3) 0 (0) Maximal late toxicity 95 (90) 7 (7) 3 (3) 0 (0) 0 (0) Late toxicity last documentation 100 (95) 3 (3) 2 (2) 0 (0) 0 (0) toxicity in children and adolescents who had been irradiated to the head and neck region. PATIENTS AND METHODS The structure, study protocol, and original documentation forms for RiSK have already been published. 9 Briefly, documentation has been performed prospectively with detailed, standardized forms, which included radiation parameters, such as the irradiation technique used, the duration of the radiation, and the irradiation doses to all organs. The maximal radiation doses (as given in the treatment planning system) to the salivary glands (parotid and submandibular glands) were recorded based on the individual treatment planning using 3D treatment plans. However, complete dose volume histograms (DVHs) were not available. Doses to the salivary glands were recorded if at least 1 salivary gland was partly within the radiation fields. In case of intensity-modulated radiotherapy (IMRT), all patients with head and neck radiotherapy have been documented. Whether the entire salivary gland was included in the field of radiation was also recorded. During follow-up examinations, salivary gland function and mucosal status were evaluated according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Toxicity follow-up examinations were scheduled to be performed within 8 weeks after the end of radiotherapy for acute toxicities and at least once a year for late toxicities. The children and adolescents included in this analysis received radiotherapy in one of the therapy-optimizing study trials of the GPOH. The radiotherapy documentation was performed through local radiotherapists and the documentation forms were reviewed and collected in the study center. The study began in only a few centers in 2001, but, starting in 2004, documentation was performed all over Germany. Documentation and all statistical analyses were performed using the commercially available programs SPSS 20.0 (IBM, Armonk, NY) and SAS (SAS Institute, Cary, NC). In addition to descriptive analyses, the chi-square test, the exact Fisher test, and the Mann Whitney U test were used for univariate analyses. Box plot analyses helped to visualize data distribution. Multivariate analyses were performed using the binary logistic regression analysis. Inferential statistics were intended to be exploratory (hypothesis generating), not confirmatory, and were interpreted accordingly. The comparison-wise type I error rate was controlled instead of the experimentwise error rate. The local significance level was set to No adjustment for multiple testing was performed; therefore, an overall significance level was not determined and could not be calculated. RESULTS From June 2001 until January 2010, 1175 patients from 62 centers had been entered into the RiSK database. Of these, radiotherapy covered the salivary glands in 133 patients. The median age at radiotherapy was 12.7 years (range, years; 51.9% male). Most patients were diagnosed with Hodgkin lymphoma (n 5 66) and rhabdomyosarcomas (n 5 40), others had nasopharyngeal carcinomas (n 5 7), different sarcomas (n 5 5), and a variety of rare diseases (n 5 15). Radiotherapy was mainly performed using photon therapy (n 5 105); proton therapy (n 5 27), electrons (n 5 3), or cobalt therapy (n 5 2) were also used. Some patients (n 5 4) were treated using a combination of different techniques. The median prescribed target volume dose was 36 Gray (Gy; range, Gy), single doses showed a range from 1.0 (twice daily) to 2.5 Gy (once a day). The maximum doses to the parotid and submandibular glands were in median 20 Gy (range, 0 80 Gy and 0 67 Gy). For further analyses, the mean dose of the maximum doses for the right and left salivary glands were calculated. Almost all patients (94.7%) were given chemotherapy before radiotherapy; the therapy was performed within one of the therapy optimizing trials of the GPOH. One third of all patients (n 5 44) received simultaneous chemotherapy and radiation. Multiple different chemotherapy schedules have been used including vincristine, adriamycin, etoposide, cyclophosphamide, ifosfamide, procarbacine, and a variety of further agents, according to the corresponding treatment protocols. Follow-up information regarding salivary gland function and mucosa toxicity was available for 114 patients (85.7%) with a median follow-up time of 2.9 years (range, years). A detailed overview about acute, maximal toxicity, and toxicity at the last documentation is given in Table 1. The maximal late toxicity for mucosa and salivary glands was documented in a median of 1.16 years after radiotherapy (range, years). Information regarding radiation doses at the mucosa was not available. Calculations were performed with documented 1138 HEAD & NECK DOI /HED AUGUST 2015

3 SIDE EFFECTS AFTER HEAD AND NECK RADIOTHERAPY IN CHILDREN FIGURE 1. Box plot analyses of acute and maximal late toxicity to the salivary glands and mucosa dependent on the mean values of maximum doses to the parotid and submandibular glands. All differences are statistically significant: comparison of acute toxicity to salivary glands and mucosa with doses to submandibular and parotid gland, p <.001; maximal late effects to salivary glands, p 5.05 (parotid gland), p (submandibular gland); and maximal late effects to mucosa, p (parotid gland), p (submandibular gland). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] radiation doses at the salivary glands (for estimation) instead. Figure 1 shows box plot analyses regarding the distribution of mean values (of right and left parotid gland) of maximum doses to the salivary glands in view of acute toxicity, maximal late effects, and late toxicity at last documentation. Statistically significant differences can be observed with a clear dose effect relationship. In general, side effects were seen in patients who had received radiation doses to the salivary glands exceeding 20 Gy. In univariate analyses, age at radiotherapy, sex, and chemotherapy before or after radiation did not have any impact on toxicity. However, concurrent chemotherapy during radiation showed significant differences. For patients with and without concurrent chemotherapy, the odds ratios (ORs) were 3.64 (95% confidence interval [CI] ) and 8.28 (95% CI, ) in view of acute toxicity to salivary glands (p 5.005) and mucosa (p <.001). For late toxicities, a significant difference (p 5.026) could be observed for salivary gland function (OR, 5.15; 95% CI, ), whereas there was no significant difference for mucosa (p 5.065). A further differentiation of chemotherapy subgroups was not feasible because of the broad variety of chemotherapy schedules. The different diagnoses showed a significant difference in toxicities (p <.001) as they also represent the different radiation doses. Patients diagnosed with sarcomas were treated with higher radiation doses (resulting in higher radiation doses to the salivary glands) than patients diagnosed with Hodgkin lymphoma. A similar effect could be observed for the analysis of radiation techniques. In a univariate analysis comparing patients treated with protons to those treated with photons (without consideration of different radiation doses), children treated with protons had higher rates of mucosal toxicity. This effect also reflects the different radiation doses as children and adolescents treated with protons predominantly had been diagnosed with sarcomas. All patients diagnosed with Hodgkin lymphoma (who were treated with lower radiation doses) were treated with photons. Acute toxicity to the salivary glands and the late toxicities showed no significant difference between photon and proton therapy in univariate analyses. Multivariate analyses using a binary logistic regression model could be performed for acute toxicities. An increase of the mean value of a maximum dose of 1 Gy to the submandibular glands resulted in an OR of 1.04 (95% CI, ; p 5.039) for acute toxicities of the salivary glands and an OR of 1.08 (95% CI, ; p 5.001) for acute mucosal toxicities. No significant differences could be seen for parotid glands. Patients with concurrent chemotherapy during radiation had an OR of HEAD & NECK DOI /HED AUGUST

4 BÖLLING ET AL (p <.001) for acute mucosal side effects. The radiation techniques (photons vs protons) also showed significant differences. Patients treated with protons had an OR of 0.12 (95% CI, ; p 5.002) in view of acute side effects to the salivary glands. For acute mucosal toxicity, no significant difference could be observed. The reason for this result is discussed in detail. Because of the patient numbers, a multivariate analysis could not be established for late toxicities. DISCUSSION Xerostomia and mucosal damage are well known phenomena in adult patients with head and neck cancer. Several reports describe incidences of radiation-induced damages for several techniques. In a comprehensive review, Deasy et al 10 describe that severe xerostomia could usually be avoided if at least 1 parotid gland was spared to ameandoseof<20 Gy or if both glands were spared to <25 Gy. Tuan et al 11 report a xerostomia rate of 46% after a median follow-up time of 7.2 years in 796 patients conventionally irradiated for nasopharyngeal carcinoma. Different models have been established to try to predict the xerostomia risk in dependence on radiation dose and volume with consideration of innovative radiation techniques like IMRT. Beetz et al 12 investigated the ability of predictive models for patient-rated xerostomia after primary (chemo)radiation in patients with head and neck cancer treated with 3D-conformal radiotherapy to predict outcome in patients treated with IMRT. The 3D-based models turned out to be less valid for patients treated with IMRT. The authors concluded that models developed in a population treated with a specific technique cannot be generalized and extrapolated to a population treated with another technique without external validation. Buettner et al 13 presented novel dose response models taking the spatial distribution of the radiation dose into account. The radiation dose to the submandibular gland and other clinical factors were considered. They used a variable-selection algorithm to select the best dose response model. Beneficial dosepattern analysis demonstrated the importance of minimizing the dose to the lateral and cranial component of the parotid gland in order to avoid xerostomia. In contrast to a broad variety of analyses regarding radiation-induced xerostomia in adults, little is known about this side effect in children and adolescents. In 2000, Paulino et al 14 published an analysis regarding the long-term effects in 17 children receiving radiotherapy for head and neck rhabdomyosarcoma. Late effects of treatment were seen in all patients and included facial growth retardation in 11 and dental abnormalities in 7 patients. However, data regarding salivary gland function was not presented. Meazza et al 15 published a series of 90 pediatric patients diagnosed with head and neck rhabdomyosarcoma. Late toxicity analyses could be performed in 36 patients. The most common side effects were facial growth retardation and dental abnormalities. Xerostomia occurred in 38% of all patients. Analyses regarding radiation dose effect relationships were not performed. Our results regarding salivary function and mucosal damage after radiotherapy to the head and neck region in children and adolescents are in concordance with published data regarding adult patients. Clear dose effect relationships could be shown and individual risk estimations are made available. A multivariate analysis revealed significant differences in acute toxicity in patients treated with photons and protons independently of the mean values of maximum doses to the salivary glands. We do not think that this reflects different biological mechanisms but results from different DVHs for the parotid gland because of the dose gradient in proton therapy (with better organ sparing using proton therapy). The most limiting factor of our analysis was the absence of DVH parameters of the salivary glands. In the beginning of the development of the study design in the late 1990s, DVHs were not standard in all treatment institutions. Therefore, a more detailed documentation has not been performed. The difference between acute toxicities in patients treated with protons and photons may be explained by different DVHs with the same mean values of maximum doses. Therefore, the evaluation of new treatment approaches in pediatric patients diagnosed with tumors in the head and neck region will be of major interest. CONCLUSION Radiation-associated acute and late side effects in view of salivary gland function and mucosal status in childhood and adolescence show a clear dose-effect relationship that is comparable to those in adults. An increase of the mean value of the maximum dose of 1 Gy to the submandibular glands resulted in an OR of 1.04 for acute toxicities of the salivary glands. Concurrent chemotherapy during radiation highly increases the risk for acute as well as late salivary gland and mucosa toxicity. Proton therapy may have the potential to reduce side effects. However, this has to be proven in further clinical studies. Acknowledgments The authors acknowledge the financial support of the Deutsche Kinderkrebsstiftung, Bonn, Germany. The authors thank all persons who performed documentation for this study. Sincere thanks are given to the documentation staff in the RiSK study trial center and the Center for Clinical Trials at the University Hospital M unster. REFERENCES 1. 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