Table of Contents

Original ArticlesOptimal Management of Acute Lymphoblastic Leukemia (ALL) in Adult Patients During the Novel Coronavirus Disease 2019 (COVID-19) Pandemic ...........................................................................................................................07Ahmad Alhuraiji, Saleem Eldadah, Feras Alfraih, Ramesh Pandita, Ahmad Absi, Amr Hanbali, Mahmoud Aljurf, Riad El Fakih

Combined Intraoperative Radiotherapy (IORT) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with Cytoreduction Surgery (CRS) as a Novel Approach in the Management of Resectable Pancreatic Cancer ....................................19Ayman Zaki Azzam, Tarek Mahmoud Amin

Peritoneal Carcinomatosis of Colorectal origin in Cyclosporine Immunosuppressed Rats .....................................................................27Elie Rassy, George Hilal, Viviane Track-Smayra, Joseph Kattan, Riad Sarkis, Aline Khazzaka

A Comparative Study of Uninterrupted Treatment by Radiotherapy versus Standard Gap Correction after Interruptions in Oropharyngeal Cancer .............................................................................................................................................31Satya Narayan, Neeti Sharma, Sweta Soni, Rajkumar Niwan

The Frequency and Specific Features of Rare Epidermal Growth Factor Receptor Mutations in Moroccan Patients with Lung Adenocarcinoma whose Tumors harbor positive EGFR mutations ..........................................................40Hind El Yacoubi, Mohamed Lemine Sow, Meryem El Ghouti, Fouad Kettani, Lamia Gamra, Amina Mestari, Lamia Jabri, Ibrahim Elghissassi, Hassan Errihani

Dosimetric Evaluation and Comparison Between Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) Plan in Head and Neck Cancers ..............................................................................45Murugaiyan Nagarajan, Ramesh Banu, Balraj Sathya, Thangavel Sundaram, Thirumalai Palanichamy Chellapandian

Mode of Presentation of Laryngeal Cancer: A Single Radiotherapy Institute Experience in Iraq ............................................................51Shkar Othman Arif, Yousif Ibrahem Al Chalabi, Hiwa Asaad Abdul Kareem, Karzan Marif Murad, Jalil Salih Ali, Sazgar Star Majeed, Shwan Ali Mohammed, Nyan Othman Saeed, Bamo Mohammed Muhsin, Ayah Said, Layth Mula-Hussain

Factors Affecting Survival in Glioblastoma: A 10-year Single-Center Experience from Saudi Arabia ...................................................58Abdullah Azab, Nasser Alsayegh, Omar Kashkari, Suliman Hanbazazah, Yazid Maghrabi, Fahad Alghamdi, Rolina Al-Wassia, Saleh S. Baeesa

Prognostic Impact of Alpha Fetoprotein at Diagnosis on Overall Survival of Single Small Hepatocellular Carcinomas ........................64N. Lahmidani, FZ. Hamdoun, M. Lahlali, H. Abid, M El Yousfi, DA .Benajah, M. El Abkari, SA. Ibrahimi

Clinical Outcomes of Head and Neck Cancer Patients Treated with Palliative Oral Metronomic Chemotherapy at a Tertiary Cancer Center in Kerala, India .......................................................................................................................68Vinin NV, Geetha Muttath, Joneetha Jones, Kalpita Shringarpure, Karthickeyan Duraisamy, Vanitha Priya Deenathayalan, Priya Rathi

Case ReportPrimary Squamous Cell Carcinoma of the Trachea: Two Cases Report ....................................................................................................75Amany Hussein, Khaled Al-Saleh, Mustafa El-Sherify, Hamdy Sakr, Jitendra Shete, Marwa Nazeeh

Bilateral Vocal Cord Immobility After Chemoradiotherapy For Nasopharyngeal Carcinoma ...................................................................80Selvamalar Vengathajalam, Thevagi Maruthamuthu, Nik Fariza Husna Nik Hassan, Irfan Mohamad

Toxic Leukoencephalopathy: An unusual Presentation by 5-Fluorouracil Infusion .................................................................................84Virendra Kumar Meena, Punnet Pareek, Satya Narayan, Sweta Soni

Transformation of Grade I Follicular Lymphoma to Anaplastic Large Cell Lymphoma CD30+ ALK1 - with Complete Response to Brentuximab Vedotin and High-Dose Methotrexate ................................................................................87Mubarak Al-Mansour, Hatim Al-Maghraby, Bader Shirah

Conference Highlights/Scientific Contributions• News Notes .............................................................................................................................................................................................91

• Scientific events in the GCC and the Arab World for 2020 ...................................................................................................................95

45

Abstract

Aim: To evaluate and compare the dosimetric parameters between volumetric modulated arc therapy (VMAT) and Intensity modulated radiotherapy (IMRT) in head and neck cancers (HNCs).

Material and Methods: A total of 30 patients newly diagnosed with Head and Neck cancers planned for radiotherapy were enrolled in the study. Two plans were made for each patient, one VMAT plan with two complete arcs (one clockwise and another counter clockwise ranging from 181° to 179° (clockwise) and 179° to 181° (counter clockwise) and other seven field IMRT dynamic Plan with beam angles at 0°, 50°, 100°,150°, 210°, 260°, 310°. All plans were generated with 6 MV photons. Optimization and calculations were done in Varian Eclipse planning system .

Results: VMAT plan achieved a better Conformity Index 95% with value of 1.016 ± 0.014 compared to

1.033±0.012 in IMRT. D2%, D5%, D50% were higher in VMAT compared to IMRT. Homogeneity Index was higher for the plans in IMRT with value of 0.035 ± 0.003 compared to 0.058 ± 0.008 with VMAT. The dose to the surrounding organs-at-risk (OARs) are better in VMAT and in particular for brainstem and spinal cord (statistically significant). The monitor units were significantly lower with VMAT (610±70) compared to IMRT (1079± 149).

Conclusion: VMAT achieved acceptable planning target volume coverage with high conformity to the primary tumor and better sparing effect on organs-at-risk particularly spinal cord and brain stem. Statistically significant reduction in monitor units was achieved in VMAT than in IMRT. VMAT should be preferred wherever feasible with due consideration to cost and availability.

Keywords: IMRT, VMAT, Head and Neck Cancers , dosimetry, comparison

Original Article

Dosimetric Evaluation and Comparison Between Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) Plan in Head and

Neck CancersMurugaiyan Nagarajan1,2, Ramesh Banu2, Balraj Sathya2, Thangavel Sundaram2, Thirumalai Palanichamy

Chellapandian2

1 Valvadi Narayanaswamy Cancer Centre, Coimbatore, Tamil Nadu, India

2 G. Kuppuswamy Naidu Memorial Hospital, Coimbatore, Tamil Nadu, India

Corresponding author: Murugaiyan Nagarajan, Director, Research and Development and HOD

Radiation Oncology, Valvadi Narayanaswamy Cancer Centre, G. Kuppuswamy Naidu Memorial Hospital,

Coimbatore, Tamil Nadu, India. Email: mnr81@yahoo.com

IntroductionOverall, 57.5% of global Head and Neck cancers occur

in Asia especially in India and it accounts for 30% of all cancers. In India, 60 to 80% of patients present with advanced disease as compared to 40% in developed countries.[1] Radiotherapy is the cornerstone of treatment for head and neck cancers both as primary modality and as adjuvant treatment.[2]

Radiotherapy treatment planning for advanced head and neck cancer is difficult due to the complex shape of target volumes and the need to spare normal critical organs. The treatment techniques of radiotherapy have evolved from conventional, 3-Dimensional conformal radiotherapy (3D-CRT) to Intensity modulated radiation

therapy (IMRT). IMRT in recent past has established itself as a gold standard in its efficiency in dose conformity to irregular target volume and reduce dose to organs at risk (OAR) and better tumour control.

Disadvantages of the IMRT are increased treatment delivery time and increased monitor units.[3] To avoid drawbacks offered by IMRT, a new approach Volumetric

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Comparison of dosimetry parameters between VMAT and IMRT, Murugaiyan Nagarajan, et. al.

Modulated Arc Therapy (VMAT) has been implemented. VMAT plans have been reported to have faster delivery times, use less monitor units and have superior dose distributions compared to clinical IMRT plans. [4-6] Hence there is strong need to conduct studies comparing the dosimetry of VMAT with IMRT.

Materials and Methods 30 patients with newly diagnosed Head and Neck

cancers (oral cavity, oropharynx, larynx, hypopharynx) were included in the study. After pretreatment evaluation and subsequently consented for IMRT plan, patients underwent CT simulation in Siemens Somatom scope power 16 – slice CT simulator. CT simulation was done in supine position with patients immobilized using a head and neck thermoplastic mask. CT images were taken at 3mm slice thickness using intra–venous contrast. These CT scan images were transferred to the Eclipse treatment planning system version 11.0.31 (Varian Medical Systems, Palo Alto, US).

Target volume delineation: The following structure sets were delineated in the treatment planning system according to RTOG guidelines: Gross tumour volume (GTV), nodal volume (NV), clinical target volume (CTV), planning target volume (PTV) and organs-at-risk (OAR). ICRU-50, ICRU-62 and ICRU-83 reports were used to define tumour volumes. [7,8]

Two clinical target volumes (CTV-1 and CTV-2) are defined as follows: High-dose clinical target volume (CTV-1) is a volume or fields encompassing the GTV with a margin of at least 1 cm and any high-risk regions that need a high dose of radiation. In the case of involved palpable lymph nodes, the neighboring (more caudal) lymph node group were included in the clinical target volume area. Low-dose clinical target volume (CTV-2) is a volume including the lymph node levels that need elective irradiation. Planning target volumes (PTV 66, PTV 60, PTV 54) were generated by expanding corresponding clinical target volumes by 3mm.

Dose and fractionation: The prescribed dose was 66 Gy in 33 fractions (2 Gy per fraction) to PTV 66 leading to simultaneous integrated prescription of 60Gy at 1.8 Gy per fraction to PTV 60 and 54 Gy at 1.63Gy per fraction to PTV 54 .

Radiotherapy treatment planning: Eclipse version 11 (Varian Medical systems, Palo Alto, US) was used to create plans. Dose Volume Optimizer (DVO, version 11.0.31) and Progressive Resolution Optimizer (PRO, version 11.0.31) were used for Dynamic IMRT and VMAT (Rapid Arc, Varian Medical systems, Palo Alto, US) respectively. Analytical Anisotropic Algorithm (AAA, version 11.0.31) was used for

final calculations.3mm calculation grid was adopted for all plans.

For Rapid Arc Planning, two complete arcs (one clockwise and another counter clockwise ranging from 181° to 179° (clockwise) and 179° to 181° (counter clockwise) were used. Dynamic IMRT plan was done using seven fields with fixed beam angles at 0°, 50°, 100°, 150°, 210°, 260°, 310°. Beam arrangements were designed and optimization of dose distribution was done using inverse planning IMRT simultaneous integrated boost technique. Non-fixed jaw arrangement was employed for all plans in this study. Minimum monitor units per beamlet was fixed at 3 MU. All plans were generated with beam energy of 6 MV photons. All plans were normalized such that 95% volume of PTV is covered by prescribed dose of 66Gy.

Plan evaluation parameters: The planning objectives were optimized to achieve the following parameters. For OAR, the maximum dose constraints of 45Gy, 54Gy and 70Gy were used for spinal cord, brain stem and mandible respectively. Mean dose of less than 26Gy were used to spare combined parotids wherever possible. In all other cases, less than 20 Gy was used to spare the contralateral gland. Plan evaluation was done using isodose lines superimposed on CT slices, 3D surface dose displays, and dose-volume histograms (DVHs). The DVH for PTV coverage, parotid, spinal cord and brain stem were generated. D98% and D2% in Gray were recorded. In line with ICRU-83 report, homogeneity index (HI) was calculated using the equation D2%-D98% / D50% (difference between the dose to 2% and 98% volume divided by dose to 50% volume) for PTV 66. The conformity index-95% (CI) is defined as the ratio between the patient volume receiving at least 95% of the prescribed dose and the volume of PTV. Total monitor units in both groups were also documented.

IMRT/VMAT Quality Assurance (QA): All plans in this study were subjected to pre-treatment QA using both absolute and relative dosimetry. In absolute dosimetry, dose verification at appropriate point using Scanditronix-Wellhofer thorax slab phantom was carried out for all plans and compared with planning system calculated doses. A pass criteria of ±3 was used. In case of relative dosimetry, fluence measurements using either Electronic Portal Imaging Device (EPID, Varian Medical Systems, Palo, Alto, US) or ImatriXX (Scanditronix-Wellhofer) was employed for all plans in this study. All measured fluences were compared with treatment planning system evaluated fluences using EPID software in ECLIPSE version 11.0.31(Varian Medical systems, Palo Alto, US) planning system. Gamma evaluation parameters of 3 mm translational distance and 3% dose difference were employed for fluence analysis.

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Statistical analysis: The mean values along with standard deviation (mean ± SD) of all dosimetric parameters were compared across VMAT and IMRT. Independent sample t-test was used to assess statistical significance. ‘p’ value less than 0.05 was considered statistically significant.

ResultsPlanning Target Volume: Clinically acceptable VMAT

and IMRT plans were generated in all 30 patients. All the treatment plans were evaluated using dose volume histogram (DVH). Since the plans were normalized, it resulted in similar D95% values (p=0.398) as is evident in Table 1. D2%, D5% and D50% were consistently higher in VMAT and is considered as inherent capability of the technique though statistically significant (p<0.005). This has resulted in undesirable, but acceptable high homogeneity index value of 3.192 ± 0.452 compared to a better value of 2.116 ± 0.203 in IMRT. But the conformity index was better in VMAT (1.016 ± 0.014) than in IMRT (1.033±0.012).

Organs-at-risk:

Right, Left and Combined Parotids: For right parotid gland, the mean ± SD value was 22.24 ± 5.52 in VMAT and is marginally better than IMRT group (23.04 ± 5.82). The same is the case with left parotid (22.06± 5.20 against 22.80 ± 5.67). This has resulted in statistically insignificant ‘p’ values (0.588 and 0.598) as shown in Table 2.

Parameter VMAT (Gy) IMRT (Gy) p-value

D2% 69.81 ± 0.453 68.59 ± 0.218 <0.001

D5% 69.45 ± 0.574 68.53 ± 0.533 <0.001

D95% 66.34 ± 0.136 66.31 ± 0.089 0.4

D50% 68.05 ± 0.454 67.23 ± 0.242 <0.001

D98% 65.80 ± 0.166 66.12 ± 0.068 <0.001

CI95% 1.016 ± 0.014 1.033 ± 0.012 <0.001

TARGET HI 3.192 ± 0.452 2.116 ± 0.203 <0.001

Monitor

Units

610 ± 70 1070 ± 149 <0.001

Table 1. Dose-volume parameters and indices for PTV 66 along with Monitor Units• Dx% refers dose to x% volume of PTV-66 in Gy• p value less than 0.05 is considered statistically significant.• All values were reported as mean ± SD of all 30 patients

Parameter VMAT(Gy)

IMRT (Gy)

p-value

Brain Stem (max) 29.07 ± 15.06 32.68 ± 16.42 0.379

Spinal cord (max) 40.92 ± 2.04 43.47 ± 1.340 <0.001

Mandible (max) 65.83 ± 4.740 66.34 ± 3.032 0.622

Right Parotid (mean) 22.24 ± 5.525 23.04 ± 5.822 0.588

Left Parotid (mean) 22.06 ± 5.200 22.80 ± 5.671 0.598

Table 2. Dosimetric Results for Organs at risk (OAR)

Figure 1. Shows combined Dose volume histograms for VMAT and IMRT with axial Isodose distributions

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Comparison of dosimetry parameters between VMAT and IMRT, Murugaiyan Nagarajan, et. al.

In addition to mean dose for right and left glands, dose-volume parameters viz. D100, D66 and D33 were also evaluated for combined parotids. Mean ± SD values of D100, D66 and D33 values were 4.79 ± 1.84 Gy, 12.98 ± 4.97 Gy and 26.21 ± 8.35 Gy respectively in VMAT (RapidArc, Varian Medical Systems, Palo Alto, US) plans. The corresponding values were 4.79 ± 3.29 Gy, 13.20 ± 5.49 Gy and 25.74 ± 7.05 Gy respectively in IMRT plans.

Brain Stem: Considering serial nature, maximum dose was evaluated for brain stem. Maximum dose was non-negligibly low in VMAT (29.07±15.06) compared to IMRT (32.68±16.42). Nevertheless, it is not statistically significant (p = 0.379).

In addition to Dmax, D1%, D0.1cc and D1cc were also evaluated. In this study, significant reductions were evident in VMAT plans than in IMRT plans. These values in VMAT (Rapid Arc, Varian Medical Systems, Palo Alto, US) plans were 26.70 ± 14.39 Gy, 26.94 ± 14.59 Gy and 20.21 ± 1350 Gy respectively. Corresponding values in IMRT were 30.65 ± 17.05 Gy, 30.24 ± 16.72 Gy and 23.80 ± 17.77 Gy, a reduction of 3.95 Gy, 3.30 Gy and 3.59 Gy when compared with IMRT.

Spinal Cord: Spinal cord maximum doses were consistently less in VMAT than in IMRT. This has resulted in statistically significant reductions VMAT (p < 0.001) as shown in Table 2.

Mandible: The mean ± SD value in VMAT was 65.83 ± 4.740 Gy. The corresponding value in IMRT was 66.34 ± 3.032 Gy. It is statistically insignificant as is evident from Table 2.

Monitor Units: The mean monitor units 610 ± 70 with VMAT and against 1070 ± 149 with IMRT. The difference in mean between the two groups was statistically significant (p value <0.001).

Discussion Radiotherapy treatment planning for advanced head

and neck cancer is complicated because of the structural complexity. Many new delivery radiotherapy techniques have evolved since their introduction and tried to address the disadvantages of old techniques. Intensity modulated radiation therapy (IMRT) has been the most widely used radiotherapy method across the globe which provide a uniform dose to the target volume and a minimum dose to normal tissues. [10,11]

IMRT provides an advantage of sparing the important vital structures such as salivary gland, optic nerve, cochlea, pharyngeal constrictors, brain stem and spinal cord. There are various studies showing the advantages of IMRT in reducing the dose to OAR. An IMRT multi-

centered study has compared parotid gland sparing with conventional radiotherapy of pharyngeal cancer has shown significant reduction of xerostomia (40%) in one-year post radiotherapy. It is evident from this study that IMRT also spares the oral and hypopharyngeal muscles which help in normal deglutition hence reduces radiation-induced dysphagia. The ability of IMRT to spare cochlea reduces the incidence of radiation-induced loss of hearing.[12]

But IMRT is associated with some disadvantages. To avoid drawbacks offered by IMRT, a new approach Volumetric Modulated Arc therapy is gaining its prominence.

Relevant works have largely demonstrated that Rapid Arc compared to IMRT is capable of creating analogous or better dose distributions while attaining a reduction in treatment time and monitor units. [13-15]

Stieler F et al conducted a comparative study on several modulated radiotherapy techniques for head and neck cancer and concluded that all treatment paradigms produced plans of good quality and dosimetric accuracy with IMRT providing best OAR sparing and the most effective treatment option among treatment plans with high complexity for VMAT.[16]

In 2011 Wiezorek T et al has conducted a multi-institutional planning study to compare rotational IMRT techniques to fixed gantry IMRT and tomotherapy. As per the study findings, IMRT delivery technologies with their associated treatment planning system (TPS) provided plans with best target coverage and also satisfying the defined OAR criteria. Compared to step and shoot IMRT, target dose homogeneity was better in Sliding window IMRT, RapidArc, and Tomo techniques.[17]

A prospective study was conducted by Fung et al to compare volumetric intensity modulated arc therapy and conventional intensity modulated radiation therapy in treating the advanced head and neck cancer. A total of 20 patients with advanced tumors of the larynx, nasopharynx, oropharynx, and hypopharynx were selected for the study. Planning target volume (PTV), OAR and dose volume histograms (DVH) were compared between IMRT and VMAT plans. IMRT and VMAT plans were compared for dose conformity and homogeneity. There were no differences in sparing organs at risk. As per the study findings, VMAT plans used only one-third of the MUs, had shorter treatment times compared to IMRT, but both were similar sparing of OAR and dose homogeneity but less conformity in PTV irradiation was provided by VMAT than IMRT. This difference in conformity was not clinically significant.[18]

In our study both VMAT and IMRT plans were normalized such that at least 95% volume of PTV receives the prescribed dose of 66Gy. Our study results were consistent

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with the study of Vanetti E et al where mean PTV66 D2% in IMRT plan was 105.4±1.1, 106.2±1.4 in the RA1 plan and 104.9±1.2 in the RA2 plan. Mean difference was showing statistically significant association (p < 0.05). Mean PTV66 D98% was 92.4±1.2 in IMRT plan, 91.7±1.6 in RA1 plan and 93.2±1.5 in RA2 plan . Mean difference among the plans was showing a statistically significant association.[19]

In this study the mean PTV66 Conformity Index 95% was 1.016 ± 0.014 for VMAT and 1.033±0.012 in IMRT plan respectively and the mean difference was statistically significant (p < 0.001). Few existing studies in literature by Jeong Y et al have also reported similar results. [20]

Further, good agreement was noted between this study and a study by Syam Kumar SA et al where conformity was good in RA 2 plan (CI=1.01±0.025) compared to IMRT conformity (CI=1.06±0.068).[21]

Regarding OAR doses, in this study the mean value for maximum dose to brain stem was 29.07± 15.06 with VMAT compared to 32.68±16.42 in IMRT. Similar results were reported by Nithya L et al where the mean maximum dose to brain stem was less with VMAT. [22,23]. Further concerning brain stem, D1cc may also be a good representative value instead of Dmax for hot spots. In order of quantitative evaluation of endpoint necrosis infarction, D1cc is a good representative because of its non-negligible clinically relevant volume. Considerable reductions in D1%, D0.1cc and D1cc values of 3.95 Gy, 3.30 Gy and 3.59 Gy is clearly evident in VMAT plans, as stated elsewhere. This led to statistically significant differences between VMAT and IMRT plans (p < 0.05).

It is clearly evident from Table 2 that VMAT results in better parotid mean values than IMRT, though statistically insignificant. Similar results were found in the study of Teoh M et al in which mean dose to contralateral parotid was 29.0 for Rapid arc plan whereas 29.9 Gy for IMRT plans however with statistically significant association (p=0.01).[24] As far as combined parotid is concerned, the absolute dose differences in D100%, D66% and D33% values of 0.00 cGy, 22.06 cGy and 46.43 cGy (correct to two decimal places) between VMAT and IMRT is very narrow. Thus, it is evident from the analysis of these dose-volume parameters that there is no statistical significance (p > 0.05) observed.

In this study, the mean ± SD of monitor units was 610±70 for VMAT and 1070±149 for IMRT. The mean difference was statistically significant. This was consistent with results of Fung-Kee-Fung SD et al where the mean monitor units of VMAT was 542.85 whereas 1612.58 with IMRT plan with statistically significant association .[18] In most cases, the doses to organs-at-risk are better and

to some extent consistent as evident in VMAT than in IMRT group (Table 2). This is attributed to higher degree of freedom like real time dose rate adjustments, multiple control points and arc-mode gantry angles etc. However, for PTV, statistically significant improvements are observed in IMRT with the exception of conformity index. This is attributed to the inherent characteristics of both techniques. The marginal offset in VMAT is compensated by much improved OAR dose distributions.

ConclusionVMAT achieved acceptable planning target volume

coverage with high conformity to the primary tumor and better sparing effect on organs-at-risk. In particular, doses to brain stem and spinal cord are consistently less in VMAT. Another important advantage that was noted is the much less monitor units in VMAT than IMRT. In addition, though treatment time (patient setup, mechanical motions in linear accelerator, beam-on time) was not documented in this study, it is well-known that VMAT outweighs IMRT in increasing patient throughput. Hence, VMAT should be preferred wherever feasible with due consideration to above points in addition to cost and infrastructure availability. However, IMRT continues to be a safe alternative in centers lacking VMAT facility

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