Volumetric variations and the effects of these differences on dosimetry during the course of volumetric modulated arc therapy for head and neck cancer

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1 Page 1 of 6 Medical & Radiation Oncology Volumetric variations and the effects of these differences on dosimetry during the course of volumetric modulated arc therapy for head and neck cancer S Ozdemir 1*, Y Coban 1, A Bakır 1, O Uzel 1 Abstract Introduction To observe the changes in the patients anatomy and the effects of these differences on dose distribution throughout the treatment in order to design an optimal adaptive plan and to find the optimal time for replanning in head and neck cancer patients who receive primary radiotherapy or chemoradiotherapy. Materials and Methods Fifteen head and neck cancer patients were evaluated prospectively. VMAT plan with simultaneous integrated boost or sequential technique was performed. The last CBCT of the 3th and 5th week were fusioned deformably with planning CT. Initial plans were adapted to these CBCT images. An adaptive plan was generated during the week when normal tissues overdosed more than 5% or the target volume underdosed more than 5%. The volumetric changes and dosimetric differences in target volumes, parotid glands and spinal cord were compared between planning CT and CBCT images. Also adaptive plan doses were compared with delivered doses in terms of target volumes, parotid glands and spinal cord. Results While there was no significance at the comparison of the volumes in GTV and PTV70 between the planning CT and 3rd week CBCT, it became significant at the 5th week. Primary and lymph node GTVs reduced by 44.8% and 70.9% respectively. Parotid glands and spinal cord doses increased in the 3rd week as well as; it rose a significant level for the ipsilateral parotid and spinal cord in the 5th week. Adaptive plan was needed in 10 patients. Adaptive plan provided a 1 Gy dose reduction in contralateral parotid glands, 1.4 Gy in ipsilateral parotid glands and 1 Gy in the spinal cord. Conclusion Significant changes were observed in the volume of target and parotid glands despite it not being reflected much in dosimetry. A new CT scan can be recommended to evaluate for an adaptive plan in 5th week in the absence of clinically usable online correction methods. *Corresponding author drsozdem@hotmail.com 1 Istanbul University, Cerrahpasa Medical Faculty, Department of Radiation Oncology, Istanbul, Turkey Introduction During the utilization of IMRT, sharp dose decline may allow dose reduction to target volume and dose escalation to surrounding normal tissues 1,2,3,4. Modifications of daily anatomy and changes in the shape and position of the target volume may cause significant differences between the planned and delivered dose. Therefore, adaptive radiotherapy (ART) requirement which means creation of a new plan during radiotherapy occurs. Head and neck cancers can benefit from ART because of weight loss, organ deformation, volume reduction, shrinkage of the tumour and/or involved lymph nodes depending on dose response in the course of the treatment. This study aimed to observe the changes in the patients anatomy and the effects of these differences on dose distribution throughout the treatment in order to design an optimal adaptive plan in head and neck cancer patients who receive primary radiotherapy or chemoradiotherapy. In addition, to find the optimal time for an adaptive plan. Materials and Methods Istanbul University Faculty of Medicine Clinical Research Ethics Review Board approval was obtained before the study. This prospective study included 15 nonmetastatic head and neck cancer patients who received radical radiotherapy or chemoradiotherapy between January 2012 and September Inclusion and exclusion criteria are shown in Table 1. Pretreatment evaluation included medical history, physical examination, panendoscopy, complete blood count and serum chemistry panel. GFR was measured in patients who received chemoradiotherapy. All cases were asked to undergo PET-CT in treatment position with treatment mask and a contrast enhanced MRI of the head and neck. Patients were evaluated by a dentist, if there was a need for dental treatment, it was performed before radiotherapy. Table 1: Inclusion / Exclusion criteria. Inclusion criteria Newly diagnosed Between years old Patients with radiologically visible mass. Karnofsky Performance Scale (KPS) 70 Exclusion criteria Radiotherapy and/or chemotherapy received previously < 18 years old Patients with severe malnutrition KPS <70 T1 ve T2 glottic tumor Patients with recurrence, metastasis

2 Page 2 of 6 Table 2: Patient and tumor characteristics F: Female, M:Male, H: Hypopharynx, TB: Base of tongue, N: Nasopharynx, L: Larynx, T: Tonsil, *:gain weight. Case Sex Age Localization Stage Concurrent Chemotherapy Weight Loss (%) Adaptive plan Adaptive fraction 1 M 63 H 4a M 62 B.T 4a M 60 B.T 4a M 67 H 4a M 60 N M 50 N M 40 N M 34 N M 47 N 3 + Patient immobilization Immobilization of patients was provided with a thermoplastic head and neck mask. An appropriate pillow was used to support the patients neck during the treatment. Planning CT Imaging was performed from the top of the head to the lower part of the sternoclavicular joint with 2.5 mm sliced images. Contouring PET-CT and MRI images were fusioned with planning CT for all patients. Target volumes and critical organs were delineated on 2.5 mm sliced planning CT according to RTOG atlas by a single physician. The gross tumour volume (GTV70) was defined as primary tumour and involved lymph nodes considering physical examination, endoscopic findings, CT, PET-CT, and magnetic resonance imaging (MRI). The clinical target volumes (CTVs) were created as; CTV70: GTV+ 5mm margin, CTV60: high risk area and CTV54: low risk area. Planning target volumes (PTV) was formed by giving a safety margin of 3 mm at all directions to CTV. The eyes, lenses, optic nerves, chiasm, pituitary gland, mandible, temporal lobes, brain stem, spinal cord, parotid glands, submandibular glands, oral cavity, temporomandibular joints, larynx, thyroid gland, cochleas, pharynegeal muscles and the brachial plexus were delineated as organs at risk. Planning All of the treatments were planned with the Eclipse (ver. 8.6) treatment planning system by using VMAT plans. IMRT was administered using the simultaneous integrated boost (SIB) technique in 14 patients. The doses to the planning target volumes of the primary tumour and involved lymph nodes (PTV70), high risk (PTV60), and low risk (PTV54) lymph node regions were 70 Gy, 60 Gy, and 54 Gy delivered simultaneously over 33 fractions for 11 patients. PTV 70 and PTV 54 volume have been identified for 3 other patients with the SIB technique over 33 fractions. One patient was treated sequentially; 70 Gy in 35 fractions, to gross tumour and lymphadenopathy, and 50 Gy in 25 fractions to electively irradiated neck nodes. Treatment Treatment was implemented with Varian DHX OBI linear accelerator. Patients were treated with IGRT and treatment positions were confirmed by daily kv-cbct imaging (Varian On-Board Imaging version 1.5, Varian Medical Systems, Palo Alto, CA) according to the clinical protocol. Follow up during the treatment Weight of the patients was measured and recorded per week throughout the treatment. Oral nutritional support was provided to patients. Supportive care was applied for acute side effects. Figure 1: The change of the GTV volume during the treatment course for patient 10 (fusion of adaptive CT and planning CT). Plan adaptation The last CBCT of the 3 rd and 5 th week were fusioned deformably with planning CT in the Velocity AI (version 2.8.1) device. Initial plans were adapted to these CBCT images. An adaptive plan was generated during the week when normal tissues overdosed more than 5% or the target volume underdosed more than 5%. The volumetric changes and dosimetric differences in target volume, parotid glands and spinal cord were compared between planning CT and CBCT images. Also adaptive plan doses

3 Page 3 of 6 Table 3: Comparison of tumor and parotid gland volumes between planning CT, 3rd and 5th week CBCT * Values are given as mean ± standard deviation Wilcoxon Signed Rank Test p: 0,05. Volume Reduction (cc) Planning CT 3 rd week CBCT p Planning CT 5 th week CBCT p GTV 37,7 ± 24, ± ,7 ± 24,3 20,8 ± 10, GTV Lymph node 48,7 ± 69,7 31,5 ± 62,3 0,018 48,7 ± 69, ± ,028 PTV ,4 ± 79, ± , ,4 ± 79, ± ,007 PTV ,4 ± 264,9 562,1 ± 239,1 0, ,4 ± 264,9 342,4 ± 138,7 0,005 Ipsilateral parotid 32,6 ± 12, ± 8.5 0,2 32,6 ± 12, ± 8.3 0,169 Contralateral parotid 34,2 ± 13, ± ,199 34,2 ± 13, ± ,169 Table 4: Target volume dose coverage and normal tissue dose comparison between planning CT, 3rd and 5th week CBCT * Values are given as mean ± standard deviation Wilcoxon Signed Rank Test p:0,05. Planning CT 3 rd week CBCT p Planning CT 5 th week CBCT p PTV70 (mean) 72.4 ± ± ± ± PTV 70 (D%95) 70.2 ± ± ± ± İpsilateral parotid (mean) 30.7 ± ± ± ± Contralateral parotid (mean) 26.7 ± ± ± ± Spinal cord (max) 44.7 ± ± ± ± were compared with delivered doses in terms of target volume, parotid glands and spinal cord. Treatment gain which was achieved in the presence of an adaptive plan was evaluated. Imaging methods like MRI and PET-CT were not used during treatment. Chemotherapy Concurrent cisplatin chemotherapy (100 mg/m 2 ), was administered to 12 patients on the first, twenty second and forty third days of treatment. The remaining 3 patients did not receive chemotherapy. Statistical analysis Wilcoxon Test was used to compare the volumes and doses between planning CT and CBCTs (taken during week 3 and 5) and to compare the doses between adaptive plan and absence of an adaptive plan. Results Thirteen (87.7%) cases were male and 2 (13.3%) cases were female. Mean age was 62 years. Tumour localization was as follows; nasopharynx in 9 patients, hypopharynx in 2 patients, base of tongue in 2 patients, tonsil in 1 patient and larynx in 1 patient. Patients and tumour-related characteristics are given in Table 2. Changes in the parameters of the patient and the tumour during treatment None of the patients were hospitalized during treatment. Insertion of the nasogastric feeding tube, parenteral nutritional support or PEG insertion were not required for any patients. All patients were able to complete the whole course of irradiation without treatment interruption. CBCT images of a patient could not be recorded due to technical failure; the patient was not evaluated for the adaptive plan. Mean weight loss was 7.2% (+2.9% -12.5%). One patient gained weight during treatment (Table 2). While mean weight loss was 9.5% for 10 patients who had an adaptive plan and it was 3.2% for other 5 patients. Volumetric comparisons While there was no significance at the comparison of the volumes in GTV and PTV70 between the planning CT and 3rd week CBCT, it became significant at the 5th week. Primary and lymph node GTVs reduced by 44.8% and 70.9% respectively (Figure 1). Ipsilateral and contralateral parotid gland volumes reduced by median 16.8% and 18.4%, respectively. Comparison of changes in target volumes and parotid volumes between the planning CT and CBCTs is summarized in Table 3. Average 4.7 mm ( mm) replacement was determined from the centre for both parotid glands. Dosimetric comparisons There were 3.6 Gy and 12.6 Gy dose escalations in contralateral and ipsilateral parotid glands in the 5th week respectively. When we consider the spinal cord, there was 2.6 Gy dose escalations in the 5th week. Parotid glands and spinal cord doses increased in the 3 rd week as well as; it raised a significant level for the ipsilateral parotid and spinal cord in the 5th week (Table 4). Adaptive plan was needed in 10 patients. Comparison of dosimetric changes in target volumes, parotid glands and spinal cord between adaptive plan and delivered doses is summarized in Table 5.

4 Page 4 of 6 Table 5: Target volumes dose coverage and normal tissue dose comparison between delivered and adaptive plans Delivered dose: dose without an adaptive plan *Values are given as mean ± standard deviation Wilcoxon Signed Rank Test p:0,05. Delivered Dose Adaptive plan p Plan summation PTV70 (mean) 71.8 ± ± ± 0.46 PTV 70 (D%95) 70.2 ± ± ± 0.49 İpsilateral parotid (mean) 43.3 ± ± ± 6.08 Contralateral parotid (mean) 30.3 ± ± ± 3.55 Spinal cord (max) 47.3 ± ± ± 1.02 Discussion In the treatment of head and neck cancer, treatment planning and implementation of radiotherapy must be optimal due to the adjacent important structures such as the spinal cord, eyes, optic nerve, optic chiasm, brain, brain stem, temporomandibular joint, salivary glands, thyroid gland, pituitary gland, larynx, oral and oropharyngeal mucosa in terms of late morbidity 5,6. Weight loss, tumour shrinkage, deformation and modification of shape in normal tissues may be observed during radiotherapy 7. These changes are dose-dependent and specific to the patient. And they may lead to clinically significant changes in dosimetry. Thus, 'Image Guided Radiotherapy' (IGRT) methods were developed which evaluated the accuracy of radiotherapy with 2 or 3-dimensional imaging during treatment 8. However, IGRT do not include treatment planning and it is not capable of correcting dosimetric errors and potential changes in delivered dose. The aim of ART is; to equalize planned dose distribution with delivered dose distribution, by measuring changes during treatment 9. Barker and colleagues examined GTV changes in head and neck cancer patients treated with IMRT 10. GTV decreased median 0.2 cc ( cc) per day and the last day of treatment median reduction was 70% (10% - 92%). Castadot and colleagues reported significant volumetric and positional changes in 10 locally advanced pharyngolaryngeal cancer patients treated with concurrent chemoradiotherapy 11. They have detected 3.2% and 2.2% average daily reduction in primary tumour volume and in nodal GTV respectively. In our study, average cc (44.5%) reduction in GTV was observed between planning CT and adaptive CT. Ahn et al. planned the first prospective dosimetric ART study in head and neck cancer, and they generated a new plan after 11, 22 and 33 fractions to 23 locally advanced head and neck cancer patients. They applied IGRT to all patients. Most important changes were found between second and 4 th CT 12. An average 17.2% reduction on GTV was determined ultimately. Dose homogenity increased from CT1 to CT4. PTV coverage increased 61% and 65% of patients benefited from adaptive plan in terms of dose distribution. However, no significant difference was observed between planning CT, 3 rd and 5 th week CBCTs and adaptive plan in terms of target volume coverage in the present study. Most head and neck cancer patients experienced parotid gland shrinkage and displacement during treatment. Barker and colleagues found 0.6% reduction in median parotid gland volume per day, and reported an average 3.1 mm ( mm) medial shift for both parotid glands at the end of treatment 10. Lee and colleagues found 1.61 mm shift from the centre per day, and 4.36% volume exchange, using megavoltage CT with similar data 13. In the present study, average 4.7 mm ( mm) replacement was determined from the centre for both parotid glands during treatment. In another study, with 82 head and neck cancer patients, authors reported that; mean parotid gland volume reduction on 3 rd week of treatment, at the end of the treatment and second month after treatment were 20%, 26.9%, and 27.2% respectively 14. They observed that gland volume shrinkage was associated with average dose and increased with higher doses of irradiated parotid (> 30 Gy) (P<0.001). The current study detected a similar reduction rate for both parotid gland volumes. Xerostomia is the most common late side effect in head and neck cancer radiotherapy. The reduction or loss of salivary secretion; will result with speech, swallowing and dental problems 15,16,17. Several studies showed that salivary gland dysfunction was consistent with the average parotid dose 18,19,20,21,22,23. If the average parotid gland dose is 26 Gy, the function will be protected, the decrease in salivary secretion will be recovered and xerostomia will be prevented. Minimum parotid gland dysfunction was seen at doses less than Gy 24. Hypofunction was seen dramatically after 40 Gy and increased at 20 to 40 Gy gradually 22. In the first year, salivary secretion has been reduced by 25% and 15% after an average of 35 Gy and 20-Gy parotid gland irradiation respectively 22. In the PARSPORT study which was a multicentre phase 3 randomised studies with locally advanced cancers of the oropharynx and hypopharynx; conventional RT was compared with IMRT. IMRT reduced the ratio of grade 2 xerostomia (p < 0.01). Average contralateral parotid gland doses (25.4 Gy in IMRT and 60.0 Gy in conventional RT group) were found to be consistent in the reduction of salivary secretion 20. Toledeno et al. ( GORTEC) indicated that, the rate of grade 2 xerostomia increased by 3% and 7% per 1 Gy if the parotid gland mean dose excessed 28 Gy and 33 Gy respectively 24. All of these results showed that; 1 Gy dose fall off on parotid gland tolerance dose; may be clinically effective on xerostomi. In a study, which was included in 11 head and neck cancer patients treated with IMRT, a significant enhancement was

5 Page 5 of 6 observed in the parotid gland doses without an adaptive plan. The authors stated that, 3% reduction of the parotid gland dose with an adaptive plan, 5% reduction with two plans and 8% reduction with six plans 25. O'Daniel et al. investigated the differences between the planned and delivered doses in the parotid gland and target volume in head and neck cancer patients treated with IMRT. IMRT plan was calculated on the repeated CT images. Parotid gland doses were found 5-7 Gy higher in 45% of patients. Parotid gland doses fell (median 2 Gy) in 91% of patients with IGRT. The delivered dose to the parotid gland was higher than the planned dose due to the displacement and contraction of parotid volume 26. Lee et al. found that, daily parotid gland average dose was 15% different from the original plan, in patients performed a deformable fusion 13. They observed an escalation of more than 102% per parotid gland dose in 3 of 10 patients at the end of the treatment. A prospective study from M.D. Anderson Cancer Center with locally advanced cancers of the oropharynx, a dose reduction of 0.6 Gy was observed in the contralateral parotid gland and 1.3 Gy in the ipsilateral parotid gland, in the IGRT group 27. In the current study, while delivered doses to the ipsilateral and contralateral parotid glands were increased 12.6 Gy and 3.6 Gy, this difference decreased 11.2 Gy and 2.6 Gy thus with an adaptive plan. Therefore 1.4 Gy and 1 Gy dose reduction were found respectively. Also, an escalation of 1.4 Gy was observed in the ipsilateral parotid gland and 2.9 Gy in the contralateral parotid gland dose in the 3rd week. It may be imported for the function of the parotid glands. And when we consider the spinal cord, 1 Gy dose reduction was provided by an adaptive plan. Weight loss has been reported in most of the patients during treatment 10. Median 7.1% (+5.2%, -13.0%) weight loss was observed during treatment in a Barker and colleagues study 10. It has been suggested that reduction in body contour was associated with weight loss. However we had a deficiency in our study. We could not compare the group of patients who had an adaptive plan and who did not, due to insufficient number of patients. Therefore we could not show an exact association between weight loss and requirement of an adaptive process. Conclusion Significant changes were observed in the volume of target and parotid gland despite it s not reflected much in dosimetry. Adaptive radiotherapy may be helpful in improving the dose to the parotid glands and spinal cord. A new CT scan can be recommended to evaluate for an adaptive plan in the 5 th week in the absence of clinically usable online correction methods. References 1.Hong TS, Tome WA, Harari PM. Intensity-modulated radiation therapy in the management of head and neck cancer. Curr Opin Oncol : Studer G, Huguenin PU, Davis JB, Kunz G, Lütolf UM, Glanzmann C. 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