INTRODUCTION MATERIALS AND METHODS. Chemotherapy

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1 ORIGINAL ARTICLE Predictors of mucositis in oropharyngeal and oral cavity cancer in patients treated with volumetric modulated radiation treatment: A dose volume analysis Rosario Mazzola, MD, 1,2 Francesco Ricchetti, MD, 1 Sergio Fersino, MD, 1 Alba Fiorentino, MD, 1 Niccolo Giaj Levra, MD, 1 Gioacchino Di Paola, MS, 3 Ruggero Ruggieri, PhD, 1 Filippo Alongi, MD 1 * 1 Department of Radiation Oncology, Sacro Cuore Don Calabria Hospital, Negrar-Verona, Italy, 2 Department of Radiation Oncology School, University of Palermo, Palermo, Italy, 3 Statistic Sciences Faculty, University of Palermo, Palermo, Italy. Accepted 16 April 2015 Published online 15 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to assess predictors of mucositis in oropharyngeal and oral cavity cancer after definitive or adjuvant volumetric modulated arc radiotherapy (VMAT) 1/2 chemotherapy. Methods. Fifty patients were evaluated. Statistical analysis was performed for the following parameters as potential predictors of mucositis G2: total oral mucosa and oral mucosa minus target high-low radiation dose regions (planning target volumes [PTVs]), mean dose (D mean ), maximum dose (D max ), chemotherapy, weight loss, and dysphagia. Results. Mucositis G2 was found to be statistically related to chemotherapy, weight loss, dysphagia G2, total oral mucosa D mean 50 Gy and D max 65 Gy, V 45 Gy >40%, V 50 Gy >30%, and V 55 Gy >20% of the oral mucosa minus target PTVs. A ratio between total oral mucosa and oral mucosa minus target PTVs >2.5 is related to G3 mucositis (p 5.03). Conclusion. New parameters were found as predictors of moderatesevere mucositis. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E815 E819, 2016 KEY WORDS: mucositis, head neck cancer, volumetric modulated arc radiotherapy (VMAT), organ sparing INTRODUCTION In 40% to 80% of patients undergoing radiotherapy (RT) and/or chemotherapy for head and neck cancer, mucositis affects quality of life and compliance to treatment. 1 Furthermore, the progression to ulceration may represent a pabulum for opportunistic and bacterial infections, with a high rate of complications. 2,3 Topic drugs, opioids, steroids, and, in several cases, hospitalization are required for recovery. 4 The subsequent treatment discontinuation or interruption have a detrimental effect on clinical outcomes and negatively influence the prognosis of patients. 5 7 Concerning RT, several factors can affect mucositis incidence and/or severity, including site of disease (especially oral cavity and oropharynx), 8 treated volume, type of fractionation, total dose, overall treatment time, and chemotherapy. 9 In the era of dose painting intensity-modulated radiation therapy, it becomes crucial to spare healthy structures to improve the patient s quality of life. Volumetric modulated arc therapy (VMAT) has been evaluated for patients with head and neck cancer showing that it is a fast, safe, and accurate technique. The purpose of the present study was to analyze dosevolume parameters of oral mucosa and correlation with *Corresponding author: F. Alongi, Department of Radiation Oncologist, Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. dott.filippoalongi@gmail.com acute mucositis in oropharyngeal and oral cavity cancers after VMAT with or without chemotherapy. MATERIALS AND METHODS For the purpose of this retrospective analysis, inclusion criteria were: age 18 years, histologically proven carcinoma of the oropharynx and oral cavity, no dysphagia at baseline, and radical and adjuvant treatment with VMAT (RapidArc; Varian Medical System, Palo Alto, CA). According to these criteria, 50 patients were selected, consecutively. Patients characteristics are shown in Table 1. Pretreatment patient assessment included: physical examination, direct flexible fiberoptic endoscopic examination, total body CT and/or MRI of the head and neck region, and/or 18 F-fluorodeoxyglucose-positron emission tomography. Chemotherapy In the radical and adjuvant settings, concurrent chemotherapy was prescribed as follow: (1) cisplatin 100 mg/ m 2 repeated every 21 days if Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) was 0 to 1, age <70 years, disease of any T classification (T)/N classification (N1) or T3 to T4/N0; (2) cisplatin 30 mg/ m 2 weekly if ECOG-PS was 2, age <70 years, disease of any T/N1 or T3 to T4/N0; (3) no chemotherapy if ECOG-PS was >2, age >70 years, or T1 to T2/N0 disease. HEAD & NECK DOI /HED APRIL 2016 E815

2 MAZZOLA ET AL. TABLE 1. Patient characteristics (no. of patients 5 50). Factors % No. of patients Sex Male Female Age, y Median 64 Range (44 86) Smokers Yes No Diabetic Yes 20 6 No Site of disease Oral cavity Oropharynx Histology Epidermoid Grading G G G T classification T T T T Positive neck nodes None 18 9 Levels nodal irradiation IA Unilateral 12 6 Bilateral IB II III IV V Chemotherapy Cisplatin - weekly Cisplatin - 3 weekly None Radiation treatment Definitive Adjuvant Radiotherapy planning Immobilization of each patient for simulation and during treatment was achieved with a thermoplastic headshoulder mask (Civco, Orange City, IA). A treatment planning CT with 3-mm slice thickness and intravenous contrast was acquired in the treatment position and matched with 18 F-fluorodeoxyglucose-positron emission tomography and/or MRI to better define target volumes and organs at risk (OAR). According to Radiation Therapy Oncology Group (RTOG) guidelines, 15 the following OAR were contoured for the pretreatment planning: spinal cord, brain stem, mandible, ipsilateral and contralateral parotid gland, constrictor muscles, cricopharyngeal muscle, upper esophagus, and larynx. In the radical setting, gross tumor volume was manually expanded to clinical target volume (CTV1) at the discretion of the radiation oncologist. The CTV1 was manually expanded to CTV2 to cover the high-risk regions around the primary tumor and nodal disease. The CTV3 covered low-risk lymph nodes. Planning target volumes (PTV1, PTV2, and PTV3) were generated with an isotropic expansion of 5 mm from CTV1, CTV2, and CTV3, respectively. A total dose of 70 Gy to PTV1, to 63 Gy to PTV2 and to 58.1 Gy to PTV3 were prescribed in 33 to 35 fractions, using simultaneous integrated boost technique. In the postoperative setting, CTV1, including the tumor bed (primary and involved nodes), and CTV2, including elective lymphatic areas, were defined. PTV1 and PTV2 were generated with an isotropic expansion of 5 mm from CTV1 and CTV2, respectively. A total dose of 60 Gy and 54 Gy in 30 fractions to PTV1 and PTV2, respectively, were prescribed using simultaneous integrated boost. Based on T and N classifications, neck nodal levels were electively irradiated according to international consensus guidelines The dose was prescribed to cover 95% of the PTV. Target dose homogeneity was assured by requiring V 107% prescription dose <3% and a maximum point dose (D max ) <110% prescription dose to the higher dose volume, while stressing dose homogeneity to the lower dose levels too. Planning objectives required PTV coverage of 95% to 107%. Concerning OAR, they were set as follows: spinal cord 5 D max in 0.1 cc <46 Gy; brain stem 5 D max in 0.1 cc <54 Gy; parotid glands 5 V30 < 45% and mean dose (D mean ) <26 Gy; and larynx 5 V40 <50%. All dose distributions were computed with the Anisotropic Analytical Algorithm (AAA, version , Varian Medical System, CA, USA) implemented in the Eclipse planning system (Varian Medical System, CA, USA) with a calculation grid resolution of 2.5 mm. All plans were performed with 4-arcs VMAT and nominal energy of 6 MV. During planning, the system was also forced to reduce doses to healthy structures outside the PTVs as much as possible with different strategies, including phantom structures when needed. However, oral mucosa was not previously considered as OAR during planning and no data of dose to oral mucosa were available. Thus, for the purpose of our analysis, oral mucosa (defined as total oral mucosa) was retrospectively contoured by a single observer and subsequently reviewed by another radiation oncologist. The oral mucosa limits were defined as follows: hard palate superiorly, cricoid cartilage inferiorly, the buccal mucosa around the teeth anteriorly, and the posterior pharyngeal wall posteriorly (Figure 1). The portion of oral mucosa minus target PTVs was defined. Absolute cumulative dose-volume histogram of the structures was extracted for each patient after the recontouring phase. Before each daily fraction, the patients were submitted to the image-guided radiotherapy procedure by means of E816 HEAD & NECK DOI /HED APRIL 2016

3 PREDICTORS OF MUCOSITIS IN OROPHARYNGEAL AND ORAL CAVITY CANCER received in 1 cc of each structure were also considered for the analysis. Logistic univariate analysis was performed considering the following clinical factors: age >70 years, smoking, diabetes, chemotherapy, primary site of disease, weight loss, ratio between total oral mucosa/oral mucosa minus target PTVs, total dose, neck irradiation, and overall treatment time (days). The dose response of the pharyngeal mucosa was evaluated considering swallowing disorders. Parameters statistically significant on univariate analysis were considered for a binary logistic regression analysis to develop a multivariate model of factors predicting mucositis grade 2. A p value inferior to.05 was considered significant. Statistical analyses were performed using R-software v FIGURE 1. Oral mucosa in CT planning (sagittal projection). a daily pretreatment kv cone-beam CT to check and correct setup errors. No adaptive RT was performed. Acute toxicity Toxicity occurring within 90 days from the beginning of RT was defined as acute. It was scored prospectively using the RTOG/European Organization for Research and Treatment of Cancer (EORTC) radiation morbidity score system, including mucositis and dysphagia for each patient. No patient presented dysphagia at baseline, neither in the postoperative group nor in the definitive treatment group. During RT, weekly examination was performed through transoral inspection of the oral cavity and the visualized oropharynx. Observer-assessed dysphagia was used as a surrogate for pharyngeal mucositis, according to Bhide et al. 19 No periodic endoscopy to score the degree of mucositis all the way down to the level of the cricoids was performed. Data analysis Concerning the dosimetric parameters, oral mucosa Vx (structure volume receiving at least the dose x) and Dy (an amount y of the structure volume receiving at least the dose D) values were recorded to be included in the overall statistical analysis. All the variables were analyzed with Pearson s chi-square or Fisher s exact tests. Using a sort of constraints-escalation from V5 increasing every 5 Gy until maximum dose reported in the dose-volume histogram, total oral mucosa and oral mucosa minus target PTVs were evaluated for statistical analysis with mucositis G2. The D mean and the D max RESULTS Oropharyngeal and oral cavity sites were equally distributed in the patients. All the study population received their RT treatment as planned. The median overall treatment time was 42 days (range, days). In 3 cases, a 25% reduction of cisplatin dose was adopted for G3 mucositis. Acute mucositis was recorded as follow: grade 0 (G0) in 4% of patients (n 5 2); G1 in 26% of patients (n 5 13); G2 in 50% of patients (n 5 25); and G3 in 20% of patients (n 5 10). No case of G4 toxicity was registered. The median week of onset was the third (range, second fourth week). Acute dysphagia was recorded as follows: G0 in 24% of patients (n 5 12); G1 in 32% of patients (n 5 16); G2 in 38% of patients (n 5 19); and G3 in 6% of patients (n 5 3). No case of G4 toxicity was registered. The median weight loss was 3 Kg (range, 0 7 Kg). Chemotherapy was related to mucositis G2 (p 5.006; 95% confidence interval [CI] ), with no significant difference between 3-weekly or weekly administration (p 5.09). A G3 mucositis was related to a 10% weight loss (p 5.03) and dysphagia G2 (p 5.001). No statistical correlation was found with other clinical parameters (see Data analysis paragraph). Dose volume analysis Median volume of total oral mucosa and oral mucosa minus target PTVs were 211 cc (range, cc) and 67 cc (range, cc), respectively. Total oral mucosa D mean was 51 Gy (range, Gy) and D max was 67.5 Gy (range, Gy). Oral mucosa minus target PTVs D mean was 36 Gy (range, Gy) and D max was 60 Gy (range, Gy). At statistical analysis, mucositis G2 was related to total oral mucosa D mean 50 Gy (p 5.02; 95% CI ) and D max 65 Gy (p 50.04; 95% CI ). At logistic regression, for D mean 50 Gy and D max 65 Gy, the risk of mucositis G2 increased around 4 times (p 5.04). Considering oral mucosa minus target PTVs, the following volumetric constraints were related to mucositis G2: V 45 Gy >40% (p 5.04; 95% CI ); V 50 Gy >30% (p 5.009; 95% CI ); and V 55 Gy >20% (p 5.003; 95% CI ). Table 2 summarizes the total oral mucosa and oral mucosa minus target HEAD & NECK DOI /HED APRIL 2016 E817

4 MAZZOLA ET AL. TABLE 2. The new proposed oral mucosa dose-constraint predictors of mucositis G2, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale toxicity. PTVs dose constraints and predictors of mucositis G2 according to RTOG/EORTC scale toxicity. At logistic regression, oral mucosa minus target PTVs V 45 >40, V 50 >30, and V 55 >20, the risk of mucositis G2 increased around 5 times (p 5.05). A ratio between total oral mucosa and oral mucosa minus target PTVs >2.5 is related to G3 mucositis (p 5.03; 95% CI ). The odds ratio associated for each variable and an assigned percentage of relative predicting risk for grade 2 mucositis are shown in Table 3. DISCUSSION Dose constraints Total oral mucosa Mean dose 50 D max * 65 Oral mucosa minus target PTVs V45 Gy >40% V50 Gy >30% V55 Gy >20% Abbreviations: PTVs, planning target volumes; Vx, structure volume receiving at least the dose x. * Maximum dose received in 1 cm 3 ; To our knowledge, the current study is the first that evaluated an oral mucosa dose-volume relationship in patients receiving simultaneous integrated boost-vmat technique 1/2 chemotherapy for oropharyngeal and oral cavity cancer. Although it is possible to obtain highly conformal dose distributions around the target volumes, while sparing the nearby sensitive structures using intensity-modulated radiation treatments, it is difficult to minimize the high dose to the mucosa inside the PTVs. During treatment for head and neck cancer, mucositis represents the most significant toxicity affecting quality of life, especially in patients with oropharyngeal and oral cavity cancer. 20 This is probably related to the small therapeutic index, with regard to oral mucosa reactions versus tumor control. 21 Two studies demonstrated that the onset and severity of mucositis depends on the rate of mucosa dose accumulation. 21,22 Available data on timedose factors influencing the healthy tissues repopulation, estimated that the mucosa recovery is around 9 Gy/week, when a conventional fractionation schedule was delivered. 22 After head and neck cancer treatment, the radiobiological response of oral mucosa has a peak during the treatment phase. For these reasons, in the present analysis, we considered only acute toxicity. In this setting, confluents mucositis affects patient s nutrition and compliance to treatment. 8 In the study population, a G3 mucositis was related to a 10% weight loss (p 5.03). In regard to dysphagia and weight loss, both analyzed in the present study, these variables may not be solely attributable to mucositis, but may be a result of a variety of other factors, including treatment-related dysfunction of the pharyngeal constrictors, location of the primary tumor, and the type of surgery performed. In the current series, the median mucositis week onset was the third (range, second fourth week). Interesting dose escalation studies showed that mucositis develops earlier in the accelerated schedule, around the second to third week from the beginning of RT. 23 Overall, treatment time and chemotherapy could influence the probability of mucositis. The purpose of the present study was to include both factors that are able to influence the severity of mucositis: (1) treatment time duration, different between postoperative and definitive setting; and (2) chemotherapy schedules, different between weekly and 3-weekly administration. In regard to overall treatment time (days), it was calculated for all patients, but no correlation was statistically found with mucositis 2. In the literature, a well-defined relationship of mucositis and different chemotherapy schedules are not reported. 24 However, when chemotherapy is added to RT to improve tumor control and survival, 25 an increasing oral mucosa biologically effective dose of 3 or 4 additional 2-Gy fractions was estimated. 17 It is known that concomitant systemic therapy increases the incidence of acute toxicity. 8 In a meta-analysis of chemotherapy trials, the relative risk of acute mucositis was nearly 3 times higher compared to RT alone. 26 In our series, although the administration of concomitant chemotherapy was a risk factor for moderate to severe mucositis (p 5.006) with an odds ratio of approximately 5, when we analyzed the 2 chemotherapy schedules, no differences were observed. In our analysis, other variables were related to mucositis onset and severity. A relationship between total oral mucosa and oral mucosa minus target PTVs was analyzed to identify a threshold value useful during RT planning as a predictor of severe mucositis. A ratio >2.5 influenced a 35% of mucositis rate G2. This relationship was probably related to the healthy mucosa rate involvement in the high-dose regions. At statistical evaluation, dose response of total oral mucosa correlated with toxicity. In a previous analysis, total oral mucosa D mean was found to be related to severe toxicity, especially if a portion >20% was in the high-dose regions. 17 In the present study, total oral mucosa D mean 50 Gy (p 5.02) and D max 65 Gy (p 5.04) increased the risk of moderate to severe toxicity around 4 times. In a retrospective analysis 27 considering only oral cavity mucosa, a significant correlation between the risk of TABLE 3. Risk of grade 2 mucositis according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale after oral mucosa recontouring. Variables p value 95% CI OR % risk Concomitant chemotherapy Total oral mucosa D mean D max Ratio total oral mucosa/ oral mucosa out of PTVs: 2.5 Oral mucosa out of PTVs V45 >40.04 V50 > V55 > Abbreviations: CI, confidence interval; OR, odds ratio; D mean, mean dose; D max, maximum dose; PTVs, planning target volumes; V45, volume % of oral mucosa exposed to at least 45 Gy; V50, volume % of oral mucosa exposed to at least 50 Gy; V55, volume % of oral mucosa exposed to at least 55 Gy. E818 HEAD & NECK DOI /HED APRIL 2016

5 PREDICTORS OF MUCOSITIS IN OROPHARYNGEAL AND ORAL CAVITY CANCER confluent mucositis and mucosa D mean was found. The definition of total oral mucosa, including the upper digestive tract, derives from a previous analysis in which a dose of 9.5 to 10 Gy/week in more than 50 to 60 cm was considered as a predictor of percutaneous endoscopic gastrostomy insertion during intensity-modulated radiation therapy treatment. 28 InastudybyBhideetal, 19 it was shown that there was a significant correlation between the length of the pharyngeal mucosatreatedto50gyand60gyandtheincidenceof grade 3 dysphagia. For the authors, observer-assessed acute swallowing symptoms (such as burning, dysphagia, and pain) were a surrogate of pharyngeal mucositis extension. Several authors investigated the role of the involvement of other anatomic structures (such as constrictor muscles) in the risk of developing swallowing disorders A general consensus is not well-defined because of methodological issues. In a recent dose-volume analyses, 35 after a recontouring of constrictor muscles according to Christianen et al 36 guidelines, the superior constrictor muscle did not show a statistical correlation with moderate to severe acute dysphagia. Although, in the current analysis, it was not possible to make a difference between oral and pharyngeal mucositis with objective methods, because of limitations of methodology, the volumetric and dosimetric constraints, summarized in Table 2, could be suggested for clinical practice. These parameters were used to develop a multivariate model of factors predicting mucositis grade 2, as shown in Table 3. It is necessary to validate their clinical application with the VMAT approach in future analyses. REFERENCES 1. Elting LS, Keefe DM, Sonis ST, et al. 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