Analysis of mandibular dose distribution in radiotherapy for oropharyngeal cancer: dosimetric and clinical results in 18 patients

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1 Radiotherapy and Oncology 66 (2003) Analysis of mandibular dose distribution in radiotherapy for oropharyngeal cancer: dosimetric and clinical results in 18 patients Barbara A. Jereczek-Fossa a,b, *, Cristina Garibaldi c, Gianpiero Catalano a, Alberto d Onofrio d, Tommaso De Pas e, Chiara Bocci f, Mario Ciocca g, Fiora DePaoli c, Roberto Orecchia a,h a Division of Radiation Oncology, European Institute of Oncology, via Ripamonti 435, 20141, Milan, Italy b Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland c Unit of Medical Physics, European Institute of Oncology, via Ripamonti 435, 20141, Milan, Italy d Division of Epidemiology and Biostatistics, European Institute of Oncology, via Ripamonti 435, 20141, Milan, Italy e Division of Medical Oncology, European Institute of Oncology, via Ripamonti 435, 20141, Milan, Italy f Department of Radiation Oncology, Fondazione Salvatore Maugeri I.R.C.C.S., Pavia, Italy g Division of Head and Neck Surgery, European Institute of Oncology, via Ripamonti 435, 20141, Milan, Italy h Faculty of Medicine, University of Milan, Milan, Italy Received 10 April 2002; received in revised form 14 July 2002; accepted 15 July 2002 Abstract Background and purpose: The relationship between the radiation dose and the risk of the osteoradionecrosis is well known. However, the dose to the mandible is not routinely assessed in the radiotherapy for head and neck cancer. The aim of our study was to analyze the mandibular dose distribution in the patients administered curative radiotherapy for squamous cell carcinoma of the oropharynx. Moreover, the clinical results have been analyzed. Material and methods: We examined the clinical records and treatment plans in 18 patients treated with bifractionated radiotherapy for stage II IV oropharyngeal cancer. In 17 patients, the total radiotherapy dose prescribed in the International Committee of Radiation Units and Measurements (ICRU) reference point was 74.4 Gy administered in 62 fractions (1.2 Gy twice daily with 6 h interfraction interval) and one patient received a dose of 75.6 Gy. The whole dose to the mandibular orophryngeal region was delivered with 6 MV photons. The mandible was contoured manually on computed tomographic scans and the point doses at the both mandibular condyles, ascending ramus, mental symphysis, molar and retromolar regions were assessed. Moreover, the cumulative dose volume histograms (DHVs) were evaluated. The median follow-up period for alive patients is 30 months (range, months). Results: Tumor remission was observed in 17 patients: in 11 cases, complete remission was achieved and in six cases, only partial remission was possible. One patient was lost to follow-up before the first response evaluation. The median survival for all patients is 22 months (range, months). Ten patients are alive and seven died. In six cases, the cause of death was head and neck tumor and in one died due to pancreatic cancer (second primary). No late bone post-radiation complication was seen. The highest radiotherapy doses were observed in the retromolar regions. The mean percentage doses at the right and left retromolar regions were ^ 3.8% (range, %) and ^ 2.5% (range, %), respectively. Lower doses were seen in ascending ramus (the mean percentage doses at right and left ascending ramus were 97.3 ^ 8.5% and 97.8 ^ 7.6%, respectively), the molar regions (the mean percentage doses at right and left molar regions were 86.0 ^ 13.5% and 88.1 ^ 12.9%, respectively), and at the mandibular condyles (the mean percentage doses at the right and left mandibular condyles were 72.6 ^ 18% and 77.0 ^ 16.5%, respectively). The volume of the mandible ranged from 60.1 to cm 3 (a mean of of 82.3 cm 3 ). In all patients, the maximum dose absorbed in the mandible was higher than the dose prescribed in the ICRU point and the mean maximum dose absorbed in the mandible was ^ 2.1% (range, %). The percentage of mandibular volume receiving a dose higher than prescribed was 28.6 ^ 14.9% (range %). The area underlying the DVH curve, the maximum mandibular doses and the retromolar doses did not appear to statistically depend on use of wedge or mandibular volume. Conclusions: Radiotherapy for oropharyngeal cancer is associated with high doses to the retromolar mandibular regions (the dose can be higher than prescribed in the ICRU reference point), ascending ramus and molar regions. Lower doses are absorbed at the condyles and mental symphysis. The single dose point (for example, the ICRU reference point) could be not used as a representative for the mandibular dose. In our small series of patients treated with hyperfractionated irradiation, these dose heterogeneities were not correlated to the patientand treatment-related factors and are not related to the increased risk of late bone complications. The clinical relevance of mandibular dose distribution remains to be established in larger series of patients treated with conventionally and unconventionally fractionated irradiation. q 2002 Elsevier Science Ireland Ltd. All rights reserved. * Corresponding author /02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. doi: /s (02)

2 50 B.A. Jereczek-Fossa et al. / Radiotherapy and Oncology 66 (2003) Keywords: Head and neck cancer; Mandible; Osteoradionecrosis; Hyperfractionated radiotherapy; Dosimetry; Dose volume histograms 1. Introduction Radiation-related late complications such as radionecrosis of the mandible can be a serious problem for patients treated for oropharyngeal cancer. In fact, about half of the patients who develop osteoradionecrosis will necessitate the surgical resection of the mandible [1,5,13,15]. This therapy is associated with an alteration of the shape and function of the oral cavity and the oropharynx. The published data on the incidence of osteoradionecrosis of the mandible vary from 4% to more than 50% [1,5,13,15,18,19,22,24], but there are relatively few data on the risk of mandibular necrosis after radiotherapy with new fractionation schedules and techniques [8,20,25]. The relationship between the radiation dose and the risk of the osteoradionecrosis is well known [7,8,11,18,19,25]. However, all analyses have related the risk of late bone complications just to the total dose prescribed in the reference point and only occasionally to the field size. Indeed, the dose to the mandible is neither routinely assessed in standard radiotherapy for head and neck cancer nor in the clinical trials. To the best of our knowledge, no dosimetric study on the mandibular dose in radiotherapy for head and neck cancer has been published so far. The aim of our study was to analyze the mandibular dose distribution using both point doses and dose volume histograms in patients administered definite radiotherapy for squamous cell carcinoma of the oropharynx. The correlation between patient- and treatment-related factors has been assessed. Additionally, we have reviewed the preliminary clinical results in these groups of patients. 2. Material and methods 2.1. Patient population We analyzed the clinical and physical records of 18 consecutive patients treated between February 1998 and January 2000 at the European Institute of Oncology of Milan, with curative bifractionated radiotherapy for stage II IV non-metastatic squamous cell carcinoma of the oropharynx (Table 1). The median follow-up period for alive patients is 30 months (range, months) Treatment Radiotherapy was delivered on an out-patient basis with two daily fractions of 1.2 Gy with an interfraction interval of 6 h, for 5 days a week without any planned interruptions. The planned total dose to the tumor/involved lymph nodes was 74.4 Gy in 62 fractions, prescribed in the International Committee of Radiation Units and Measurements (ICRU) reference point. Treatment was performed with 6 MV photon beams produced by a linear accelerator (Varian Clinac). Opposite equally weighted parallel lateral fields were used for the first 40.8 Gy, then reduced off the spinal cord up to 52.8 Gy. The final dose of 21.6 Gy was administered via smaller fields including clinically detectable tumor and/or involved lymph nodes with 2 3 cm margin (shrinking field technique) (Fig. 1). Bilateral electron beams (6 9 MeV) produced by a linear accelerator (General Electric Saturne) were used to boost the dose in the posterior cervical lymph nodes up to 52.8 Gy (in case of elective irradiation). The maximum total dose to the spinal cord was set at 42 Gy. The lower cervical and supraclavicular lymph nodes were treated with an anterior photon beam up to 50 Gy prescribed at the depth of 3 cm. Elective irradiation of supraclavicular and posterior cervical lymph nodes was administered with 2 Gy daily fractions. All but one patient received the Table 1 Patients characteristics a Male 15 Female 3 Age Mean (years) 62 Range (years) Performance status (WHO) Localization of primary tumor: Tonsillar region 12 Base of the tongue 4 Soft palate 2 Stage II 4 III 3 IV 11 T-stage T1 2 T2 8 T3 4 T4 4 N-stage N0 7 N1 2 N2 9 N3 0 RT alone 10 CT 1 RT 8 a Number of patients RT, bifractionated radiotherapy. CT 1 RT, neoadiuvant chemotherapy followed by bifractionated radiotherapy.

3 B.A. Jereczek-Fossa et al. / Radiotherapy and Oncology 66 (2003) Fig. 1. Simulator film of the boosted radiotherapy field for tonsillar cancer. planned dose. In one case, one fraction of 1.2 Gy was added (up to the total dose of 75.6 Gy) to compensate for the interruption of the therapy due to serious mucositis. In all patients, a custom mask for head immobilization was used. Simulation of all therapy phases and fields, orthogonal laser beams, computed tomography (CT)-based 3D treatment planning (Cadplan, Varian, release 3.1.1) was performed. Asymmetric jaws and multileaf collimator were used to define the irradiation fields. In vivo dosimetry (diodes calibrated for entrance dose measurements) and electronic portal imaging were employed as part of a Quality Assurance program for each patient. The measured dose on the central axis of the field was compared with the dose calculated by the treatment planning system at the depth of the maximum dose. Correction factors for field size, skin source distance and presence of wedge were applied to the diode reading. Treatment planning was performed using 5 mm stepped CT scans. Correction for tissue inhomogeneity (Modified Batho Power Law correction, hereafter referred to as Batho method) was employed for all patients. For three patients, dose distribution was also calculated applying the more accurate equivalent tissue air ratio (ETAR) inhomogeneity correction algorithm. The dose distribution within the irradiated volume was optimized in eight patients (44%) through the use of 158 wedge filters to compensate for the tissue missing in the transversal direction and/or in the cranio-caudal direction, according to the patient body outline. Eight patients received induction chemotherapy prior to irradiation. In six cases, ViFuP chemotherapy regimen was administrated. This regimen consists of vinorelbine 20 mg intravenously (i.v.) on days 1 and 3, cisplatin 60 mg/m 2 i.v. on day 1, both repeated every 3 weeks and 5-fluorouracil 200 mg/m 2 in continuous i.v. infusion over 10 weeks [21]. One patient was treated with cisplatin, ifosfamide and retinoic acid and one was administered single-agent carboplatin. Before the start of irradiation, all patients were given the guidelines about oral hygiene and alimentation during the therapy. When radiotherapy was administered, the patients were seen by a radiation oncologist at least once a week. Prophylactic antifungal and sodium bicarbonate mouthwashes were introduced from the beginning of the irradiation. All patients were supposed to be followed up by a multidisciplinary team including head and neck surgeons, radiation and medical oncologists. Clinical examination was performed at every follow-up visit, whereas

4 52 B.A. Jereczek-Fossa et al. / Radiotherapy and Oncology 66 (2003) radiological evaluation (CT scan, magnetic resonance imaging (MRI)) was undertaken 6 8 weeks after the completion of radiotherapy and every second visit thereafter. Radiolological evaluation of mandible (for example, pantomography) was undertaken only when any dental extraction or cure was planned or in case of suspicious bone complication Dosimetric analysis The mandible was manually contoured on all CT scans. Nine reference points were signed including left and right mandibular condyles, left and right ascending ramus, mental (mandibular) symphysis, left and right molar regions and left and right retromolar regions. These points were chosen on the basis of the following anatomical and radiological aspects: 1. Condyle: the center of the mandibular condyle, on the CT scan passing through the nasopharynx; 2. Ascending ramus: the point in the middle of the left right and ventral dorsal extension of the ramus, on the CT scan passing through the oral cavity, just below the hard palate, approximately at the level of the body of the second cervical vertebra; 3. Mental (mandibular) symphysis: the point in the middle of the left right and ventral dorsal extension of the symphysis, on the CT scan passing through the center of the mandibular symphysis; 4. Molar region: the point in the middle of the left right and ventral dorsal extension of the molar region, on the scan passing through the center of the mandibular symphysis; 5. Retromolar region: the most posterior point, close to the mandibular angle, in the middle of the left right extension of the region on the scan passing through the center of the mandibular symphysis. The percentage doses in these points were measured for each phase of the irradiation and the total absorbed doses were calculated. The cumulative dose volume histograms (DVH) were drawn for the summed treatment plans. The mean, maximum and minimum doses to the mandible were assessed Statistical methods For the statistical computations and the graphical representations, the software system Mathematica (release 4) was used [26]. We calculated the cumulative DVHs for the summed treatment plans for each patient. Minimum, maximum, mean, median, lower and upper quartiles of the DVH curves were obtained by calculating the minimum, maximum, mean, median and the quartiles, respectively, of the percentages of the mandible irradiated at each dose level. We assessed the relationships between the maximum mandibular dose (assessed with DVHs), the dose in the retromolar region, the area of DVH (i.e. the area underlying the DVH curve) and the mandibular volume using Pearson s correlation coefficient. The association between the use of a wedge (presence or absence) and doses or DVH area was tested using Fisher s exact test after dichotomizing dose and area at their median values. 3. Results 3.1. Clinical results Tumor remission was observed in 17 patients: in 11 cases, complete remission was achieved and in six, only partial remission was possible. One patient lost to follow-up could not be evaluated for response to therapy. Tumor progression was seen in eight cases: in all cases, it was loco-regional progression, in one case associated with distant metastasis. Median time to progression was 10 months (range, 4 16 months). Three cases of second primary have been observed (esophageal, breast and pancreatic tumors). Severe xerostomy was observed in three cases and two patients developed paradonthopathy. No late bone post-radiation complications were seen. The median survival for all patients is 22 months (range, months). Ten patients are alive and seven died. In six cases, the cause of death was head and neck tumor and one patient died due to pancreatic cancer (second primary). Two out of ten alive patients have tumor: one recurrent head and neck cancer and one esophageal cancer (second primary) Percentage point doses The highest doses were observed in the retromolar regions. The mean percentage doses at the right and left retromolar regions were ^ 3.8% (range, %) and ^ 2.5% (range, %), respectively (Table 2). The lowest doses were seen in ascending ramus, molar regions and mandibular condyles. The mean percentage doses at the right and left ascending ramus were 97.3 ^ 8.5% (range %) and 97.8 ^ 7.6%% (range %), respectively. The mean percentage doses at right and left molar regions were 86.0 ^ 13.5% (range %) and 88.1 ^ 12.9% (range %), respectively. The mean percentage doses at the right and left mandibular condyles were 72.6 ^ 18% (range %) and 77.0 ^ 16.5% (range %), respectively. The mean percentage dose to the mental symphysis was 11.4 ^ 10.4% (range %). No correlation was found between the doses in the retromolar regions and use of wedge (P. 0:1) or mandibular volume (P. 0:1). When comparing the dose distributions calculated with the Batho and the ETAR inhomogeneity correction algorithms, similar results were obtained. The Batho algorithm slightly overestimated the absorbed dose in the mandible with a mean value of 1.2% and a maximum value of 3.4%

5 B.A. Jereczek-Fossa et al. / Radiotherapy and Oncology 66 (2003) Table 2 Percentage point doses and maximum dose (with respect to the dose prescribed in the ICRU point) a Condyle Ramus ascendens Chin region Molar region Retromolar region Maximum dose in mandible Right Left Right Left Right Left Right Left D mean (%) SD (%) D max (%) D min (%) a D max /D min /D mean, Maximal/minimal/mean value. SD, standard deviation. observed in the retromolar region, where the bone was thinner Dose volume histograms The DHVs for all patients are shown in Fig. 2. The minimum, maximum, mean and median DVHs are shown in Fig. 3. In Fig. 4, the quartiles DVHs with the median DVH are presented: note that for each dose, the volume data are located in a strict range of values. The volume of the mandible ranged from 60.1 to cm 3 with a mean value of 82.2 cm 3. In nine patients, 50% of the mandibular volume received more than 88% of the prescribed dose. In all patients, the maximum dose absorbed in the mandible was higher than the dose prescribed in the ICRU point and the mean maximum dose absorbed in the mandible was ^ 2.1% (range %) (Table 2). The percentage of mandibular volume receiving a dose higher than the prescription dose was 28.6 ^ 14.9% (range, %). No correlation was detected between area under the DVH curve and the mandibular volume (P. 0:1) (Fig. 5) and use of wedge (P. 0:1). Similarly, no correlation was observed between maximum dose absorbed in the mandible and the mandibular volume (P. 0:1) or use of wedge (P. 0:1) (Table 3). 4. Discussion Few studies on the mandibular dose distribution in radiotherapy for oropharyngeal cancer have been published and only descriptive methods have been mainly employed to analyze the irradiated volume of the mandible. Therefore, due to the lack of dosimetrical data and established reference points, existing published clinical data were used in our analysis to choose the anatomical radiological reference points of the mandible. We identified molar and retromolar regions, condyle and ascending ramus and mandibular symphysis. Molar regions are the most common sites of mandible bone complications, whereas a condyle makes part of temporal mandibular articulation that can be affected by fibrosis and dysfunction after irradiation. Numerous clinical and physical factors reported to be associated with the risk of osteoradionecrosis include total radiotherapy dose [7,8,11,18,19,25], biologically effective dose [20], photon energy [11], brachytherapy dose rate [7,16], combination of external beam irradiation and interstitial brachytherapy [7,9,18], volume of brachytherapy overdosage or reference volume [6,16], field size [20], dose per fraction [8,20,25], short interval between fractions (but not hyperfractionated therapy by itself) [20,25], volume of the horizontal ramus of the mandible irradiated with a high dose [8], use of a single homolateral field [9], use of unilateral wedge arrangements [8], deep parodontitis [18], bone Fig. 2. Cumulative dose volume histograms (DVH) of 18 patients. Fig. 3. Mean, median, maximum and minimum cumulative dose volume histograms (DVH).

6 54 B.A. Jereczek-Fossa et al. / Radiotherapy and Oncology 66 (2003) Table 3 Fisher s table for the association between the presence or absence of the wedge and the maximum dose a Wedge Present Absent D max #Median 4 6.Median 4 4 a D max, maximum dose. Fig. 4. Median, lower and upper quartile dose volume histograms (DVH). surgery in case of post-operative irradiation [20], bad oral hygiene [14,17,18], alcohol and tabacco abuse [14], tumor size or tumor stage [1,4,9,18,19], association of the tumor with bone [8], anatomic tumor site [18,19], bone inflammation [12], dental extraction after radiotherapy [1,12,19], and dental status [19]. All these factors have not been found to be of significance in particular series, probably due to inadequate patient sample sizes and multiple clinical and physical factors that could cloud the results [8,16]. Fujita et al. [7] defined a dose threshold in patients undergoing combined external beam irradiation and interstitial brachytherapy. They observed a significant increase in the incidence of bone complications when 60 Gy of brachytherapy at the dose of 0.55 Gy/h or higher was combined with conventionally fractionated external beam irradiation at a dose of 30 Gy. According to Perez et al. [22], the tolerance dose of external beam fractionated radiotherapy for bone (whole organ) is higher than 70 Gy and has not been well established. Our study showed that in all patients, the dose in the mandible was higher than the prescribed dose, i.e Gy although this was confined to the small volume. Such a high dose has not been however associated with Fig. 5. Dose volume histograms (DVH) areas vs. the mandibular volumes. osteoradionecrosis (no late bone complication has been observed in our series). There are some possible explanations of these findings. First of all, number of patients is small. Use of modern radiotherapy techniques carries low risk of osteoradionecrosis (in the majority of recent series, the incidence is lower than 10%), therefore in a series of 18 patients about one or two cases of mandibular necrosis could be expected [13]. Similar limitation could be seen in the follow-up duration. Due to the long interval before occurrence of late bone complications (up to 12 years from the completion of radiotherapy) and their relatively low occurrence rate, prolonged follow-up and enlarging the study group is required to draw any definitive conclusion [3,22]. Another explanation of lack of late bone complications in patients with high mandibular doses is hyperfractionation employed in our series. Low a=b ratio for the mandible indicates high sensibility to the fraction size [13]. The maximum mandibular dose (110%), with use of 1.2 Gy per fraction was translated to 1.32 Gy per fraction leading to the protective effect of normal tissue. In the conventionally fractionated schedules, the same maximum dose (110%) would be translated to the dose of 2.2 Gy, which could have some clinical consequences. Therefore, the accurate evaluation of the clinical implications of our findings necessitates larger series of patients treated with conventionally and unconventionally fractionated irradiation, followed for a long period after the therapy. Such data could help to define the modern tolerance level for the mandible. The inhomogeneity correction-based algorithms like the Batho and the ETAR methods can lead to large inaccuracies in the dose distribution calculation in presence of interfaces of tissues having different atomic composition and density, due to their inability to account for the effect of electronic disequilibrium. This effect becomes more important in lowdensity tissue such as lung and at higher beam energies because of the increased effects of electron side and longitudinal scatter. Shabine et al. [23] have shown that the Batho and the ETAR algorithms underestimate the dose as much as 55% at interfaces adjacent to air cavities for 6 MV photons. Du Plessis et al. [2] found that the Batho and the ETAR methods can lead to inaccuracies of 20 70% in the dose distribution in the maxillary sinus region as compared to the Monte Carlo calculations. The Batho algorithm shows problems in calculating accurately the dose absorbed in the build-up regions in presence of inhomogeneity [23]. However, for the evaluation of the absorbed dose, we

7 B.A. Jereczek-Fossa et al. / Radiotherapy and Oncology 66 (2003) chose the points in the mandible that were all inside the bone and not in the proximity of the interface between soft tissue and bone and hence that the inaccuracies in the dose calculation due to the presence of the interfaces with lower density material should not be significant. Indeed, the differences between the Batho and the ETAR algorithms observed in our study were much less pronounced when compared to the series including the maxillary sinus region or lung, where the significantly higher accuracy of ETAR method has been reported [2]. We observed the highest doses in the area of the horizontal ramus of the mandible, especially in the retromolar regions, ascending ramus and molar regions. These findings correspond with the previous observations demonstrating molar and premolar region as the most common sites of necrosis [10]. In fact, this area superposes with both the oropharynx and regional lymph nodes and by definition is included in the boosted radiotherapy fields (Fig. 1). Furthermore, these parts of the mandible undergo the maximal load during mastication and are often subjected to dental extraction. These traumas, in connection with the high absorbed dose, could explain the typical localization of mandible bone complications after radiotherapy. We did not observe any correlation between mandible volume and the area of DVH, maximum mandibular doses or doses at the retromolar regions, and we did not find any published data addressing these issues. The only analyses of the volume have been very generic and included field size (calculation of the part of the mandible within the 100% isodose) [20], and the volume of the mandible included in the volume of the target dose [8]. Glanzman et al. [8] scored the irradiated mandible volume from 1 (radiotherapy field including only ramus ascendens) to 7 (whole ramus horizontalis, chin region and angle included in the radiotherapy field). Unifactorial analysis performed on the basis of this score showed that inclusion of more than half of the horizontal ramus increases the risk of necrosis significantly [8]. We did not observe any correlation between the use of wedge and the area of the DVH, maximum mandibular doses or doses at the retromolar regions. Similarly, Withers et al. [25] in the retrospective analysis of 676 head and neck patients did not observe any correlation between bone, muscle or mucosa late complications and the use of wedges or the proportion of the dose delivered with an electron beam boost. They observed a weak trend to a higher probability of late muscle and mucosa complications but not bone late effects with increase in T stage. Unfortunately, the correlation between dose distribution and T stage and site could not be assessed in our analysis due to small number of patients. 5. Conclusions Radiotherapy for oropharyngeal cancer is associated with high doses to the horizontal ramus of the mandible, and particularly to the retromolar mandibular regions (the dose can be higher than prescribed in the ICRU reference point). Lower doses are absorbed at the condyles and at mental symphysis. The single dose point (for example, the ICRU reference point) is not sufficient to be used as a representative dose for the mandibular region. In our small series of patients treated with hyperfractionated irradiation, these dose heterogeneities were not correlated to the patientand treatment-related factors and were not related to the increased risk of late bone complications. 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