{'fraction_non_alphanumeric': 0.03524177496780236, 'fraction_numerical': 0.018616087109237796, 'mean_word_length': 4.94019471488178, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The impact of involved node radiotherapy on organs at risk on treatment of limited stage Hodgkin lymphoma

Radiotherapy is an important component of the combined modality treatment of limited stage Hodgkin lymphoma. Using such combination resulted in high cure rates exceeding 90%. Unfortunately, long-term survivors are at increased risk of critical long-term morbidities including second malignancy, lung, and cardiac toxicities. Radiation induced toxicity is related to dose and field size. The concept of involved node radiotherapy (INRT) is to minimize the irradiated volume to cover only the primarily involved nodes, while maintaining high local control rates.


Introduction:
Hodgkin lymphoma (HL) is a rare B-cell lymphoid malignancy that affects about 8480 new cases in the United States each year (Siegel et al., 2020). It constitutes 0.6% of all the cancers diagnosed worldwide and 10% of all lymphomas (Siegel et al., 2016).
Its incidence has two peaks, the first is in young adults (15-30 years), and the second is in patients aged 55 years and older. The exact etiology for developing HL stills unknown. HL is a complex of related conditions that are mediated by infectious diseases, immune deficiency, and genetic susceptibilities. There is little evidence to suggest any other environmental factors to be involved in the etiology.

156
As a result, increased concern on long-term morbidities of HL treatment had emerged. Radiotherapy related complications include but not limited to cardiovascular diseases, lung toxicity, endocrinopathy, and secondary malignancies (Oeffinger et al., 2006).
In an attempt to decrease radiation related toxicity to adjacent normal tissues, further field reduction from IFRT to INRT including only the initially involved nodes in the target volume has been advocated (Campbell et al., 2012).
The aim of this study is to compare OARs dosemetric outcomes with INRT vs IFRT in treatment of limited-stage HL, using conventional radiotherapy techniques.

Patients and methods
Twenty patients with limited stage, supradiaphragmatic, pathologically confirmed HL after receiving combination chemotherapy (2 -4 cycles of ABVD), were planned to receive consolidation radiotherapy. For each patient two plans were generated IFRT and INRT. The radiotherapy dose used was 20 Gy over 10 fractions (2 Gy per fraction) + 10 Gy boost over 5 fractions (2 Gy per fraction) for unfavorable cases and/or residual disease. OARs including lungs, heart, breasts, and thyroid gland were delineated and different dosimetric parameters of both plans were compared.

Exclusion Criteria
Patients with advanced or infra-diaphragmatic Hodgkin's disease, patients diagnosed with nodular lymphocyte predominant subtype) (NLPHL), Patients with previous neck and chest irradiation and Pregnant or lactating women.

Study design
All patients were classified based on the classic EORTC clinical prognostic factors into favorable and unfavorable diseases. Unfavorable disease includes patients with: Clinically stage II with ≥ 4 nodal regions or patients aged≥50 years or mediastinal lymph nodes occupying>one third of the chest width or an ESR ≥ 50 (without Bsymptoms) or ESR ≥ 30 (with B symptoms).
Favorable disease includes patients without any of the above-mentioned criteria of unfavorable disease. The prescribed dose was 20 Gy with10 Gyboostto unfavorable and residual disease.
 IFRT plan was defined to include the initially involved nodal regions, covering the pre-chemotherapy involved lymph nodes plus contiguous nodal groups.
 INRT plan was defined to include only the initially involved lymph nodes.

Radiotherapy technique
CT simulation with slice thickness 2.5 mm or less with intravenous contrast, immobilization devices were used for proper implementation of involved node radiotherapy. CT scans and prechemotherapy PET-CT were performed more or less in the same treatment position. 3Dconformal radiotherapy based two plans were generated for every patient using IFRT and INRT techniques following the GHSG guidelines (Eich et al., 2008).
For INRT,Gross Tumor Volume (GTV): is the residual lymph node(s). Clinical Target Volume (CTV): is the primarily involved volume of lymph node(s) prior to chemotherapy, incorporating the initial location and extent of the disease. Planning Target Volume (PTV): equal CTV plus a margin to consider organ movement and set-up errors. 0.5 -1 cm safety margin was considered adequate. For IFRT, GTV:is the residual lymph node(s).CTV: Is the initial volume of the lymph nodes plus contiguous nodal groups according to the site of the individualized lymph nodes. PTV:equalCTV plus a margin to consider organ movement and set-up errors. 0.5 -1 cm safety margin was considered adequate.

Organs at Risk Delineation
The heart, Lungs, breasts, and thyroid gland were contoured as organs at risk (OARs). The heart delineation started from the branching of the pulmonary trunk, including all cardiac chambers. The thyroid gland was contoured based on the extent of the glandular tissue. Breasts were delineated from head of the clavicle superiorly, to the xiphoid process inferiorly, and from the sternal-rib junction medially to anterior border of latissimus dorsi laterally, and from skin anteriorly to pectoralis muscle posteriorly. (Weber et al., 2009).

Plan assessment
The target volume (PTV volume) in each plan was calculated.  Combined lungs: mean dose, V5, V10 and V20.
 Thyroid gland: mean dose, V5, V20 For eachplan, the mean doses and dose-volume metrics were calculated and compared to estimate the differences in radiation exposure for each OAR by IFRT and INRT plans.
The current study has been approved by the Ethics Committee of South Egypt Cancer Institute, Assiut University, Assiut, Egypt.

Statistical Analysis
Statistical analyses were performed using IBM SPSS Statistics version 20 (SPSS Inc., Chicago, IL, USA). Categorical data were presented as frequencies and percentages, while Chi-square test was used for comparisons between groups. Continuous data were reported as means ± standard deviations and students' T-test was used for comparisons between groups. For comparison between progression free survival (PFS), Kaplan-Mayer survival curve and logrank test were performed. In all statistical tests pvalue <0.05 was considered statistically significant.   al., 2012). These results are comparable to those of our study in which, mean dose to the heart (17.47/8.98 Gy), whereas mean doses to lung (11.5/7.3 Gy), breasts (left 3.1/1.8 Gy, and right 3.3/1.6 Gy) and mean dose to thyroid (17.5/7.1).

Results
Maraldo et al. conducted a study with 29 patients diagnosed with supradiaphragmatic, clinical Stage I-II HL, treated with chemotherapy and INRT to a dose 30-36 Gy and simulated a mantle field (MF) plan for each patient to a dose of 36 Gy. It showed a significant decrease in mean doses to the heart, coronary arteries and the four heart valves, for INRT instead of MF technique With INRT the mean doses for the heart were 7.7 Gy (SD 7.4). (Maraldo et al., 2012).This result is comparable to our results with mean heart dose 8.9 GY in INRT plan.
Murray et al, generated 4 radiotherapy plans (IFRT, ISRT, INRT and residual postchemotherapy volume) for 15 patients already treated with mediastinal irradiation. Rates of relative and absolute second malignancies were calculated with the use of the organ equivalent dose. Results showed significant increased doses to OARs including heart, lungs, breasts and thyroid in IFRT arm compared to those with IFRT arm (Murray et al., 2015). These results are in line with our results.
It was found that the risk of developing heart disease increased linearly with increasing the mean heart dose with a 2.5-fold increase in the risk of cardiac events in patients receiving a mean heart dose of 20 Gy (Swerdlow et al., 2007). In this study the mean heart dose significantly decreased from 17.47 GY in IFRT to 8.98 GY in INRT.
Reducing the irradiated volume from IFRT to INRT across different trials represented reduction in radiation induced acute and late toxicities. In our study, all OARs contoured showed a statistically significant decrease in received doses with the use of INRT plan.

Conclusion
Reducing the irradiated volume from IFRT to INRT can significantly reduce the unnecessary 160 radiation exposure of adjacent normal tissues. This is associated with decreasing serious late complications of radiotherapy including cardiac toxicity, second malignancy, endocrinopathy and pulmonary morbidities.