Modern Radiotherapy for Head and Neck Cancers: Benefits and Pitfalls-a Literature Review

1 University of Medicine and Pharmacy, Craiova, Romania 2 Regional Institute of Oncology, Iasi, Romania 3 „Gr. T. Popa” University of Medicine and Pharmacy, Iasi, Romania 4 „Sf. Spiridon” University Hospital, Iasi, Romania 5 EUROCLINIC Oncological Center, Iasi, Romania Corresponding author: Roxana Irina Iancu, Department of Pathophysiology, „Gr. T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115, Iasi, Romania. E-mail: rox_iancu@yahoo.com, riiancu@umfi asi.ro Abstract


REVIEW
luation of patients "reports of dry mouth syndrome" demonstrated the ability of the IMRT technique to protect the parotid glands compared to the 3D-CRT irradiation technique.However, avoiding the parotid glands to reduce xerostomia should be approached with caution in order not to aff ect the tumor target volume dosimetric coverage.Eisburuch et al. notes that an improvement in saliva production over time associated with dose reduction in the parotid glands may lead to a reduction in late xerostomia.Th e authors identify the average dose of the oral cavity as an independent predictor of xerostomia, stressing the need to reduce the doses received by the tumor-free oral cavity 2 .
However, the IMRT technique also has disadvantages, requiring quality assurance of the treatment plan by verifying it in the phantom or with the help of portal dosimetry and the large number of fascicles can increase the irradiation time with possible radiobiological consequences if the treatment time per fraction exceed 20 minutes.Th e large number of monitor units (MU) associated with the scattering of small doses into large volumes of tissue 3 .
Dysphagia associated with irradiation in patients receiving radiotherapy for HNSCC was defi ned as aspiration or stricture evidenced by video-fl uoroscopy or endoscopy, gastrostomy tube or aspiration pneumonia diagnosed at ≥12 months after treatment completion.Evaluation of this toxicity associated with IMRT treatment for multimodal patients treated for oropharyngeal cancer revealed an age-dependent incidence increasing from 5% to 20% for patients <50 years of age >70 years receiving a dose >60Gy per pharyngeal constrictor superior evaluated on volume dose histograms (DVH) 4 .
A systemic review analyzed the benefi t in terms of xerostomia, overall survival (OS) and quality of life (QOL) included patients from randomized controlled trials diagnosed with locally advanced, non-metastatic HNSCC who received radiotherapy with curative intent.Th e analysis included 1155 patients, s treated with conventional IMRT and 2D or 3D-CRT radiotherapy in HNSCC.Th e use of the IMRT technique has led to a relative reduction in the risk of 36% acute grade 2 xerostomia and the risk of late xerostomia compared

INTRODUCTION
Curative radiotherapy is part of the multimodal treatment of locally advanced squamous cell carcinoma of the head and neck (HNSCC) as a unique method of treatment or in combination with concurrent or sequential chemotherapy.Th e lasts decades have come with changes and a signifi cant progress in improving irradiation techniques and with the implementation of multidisciplinary treatments by combining induction or concurrent chemotherapy or Cetuximab based biological therapy.Th e goal of quality based radiotherapy is to improve the therapeutic ratio that establishes the effi cacy/toxicity ratio.IMRT technique has become a standard in the treatment of HNSCC following Phase III Intensity Modulated Radiation Th erapy (IMRT) versus conventional radiotherapy in head and neck cancer (PARSPORT trial).Th e purpose of this study was to demonstrate the advantage of the IMRT technique in the proportion of patients presenting xerostomia 2 or higher degree, 1 year after the completion of the treatment for head and neck cancers.Th e control group received radiotherapy by 3D-Conformal technique (3D-CRT) 1 .
Xerostomia associated with dry mouth syndrome is one of the complications that most severely aff ect the quality of life for radiotherapy and radio-chemotherapy treated patients for the head and neck cancers.Th e irradiation of the salivary glands region leads to changes in the glands volume, consistency and pH and composition of the secreted saliva.Th ese phenomena are also implicated in the pathogenesis of the tooth diseases that aff ect structure and resistance.Xerostomia is also related to infections of the oral cavity.

Intensity Modulated Radiation Therapy (IMRT) in HNSCC
Reducing the volume of parotid glands receiving a high dose of radiation has been shown to be a necessary condition for reducing severe xerostomia, but irradiation of level II lymph nodes makes it diffi cult by standard radiotherapy technique to spare parotid glands.Limiting doses to at least one parotid gland or if it is not possible to reduce the dose received by a sub-volume from the parotid glands is a purpose for reducing post-irradiation xerostomia.Th e severity of salivary gland damage depends on the total radiation dose and irradiated volume, recent studies being focused on the possibility of parotid glands sparing.Evaluation of salivary fl ow or salivary gland scintigraphy as well as subjective eva-

Intensity Modulated Volumetric Therapy (VMAT) in HNSCC
Volumetric Intensity Modulated Arc Th erapy (VMAT) is a newer radiotherapy technique than "step and shot" IMRT, based on the treatment is delivered while gantry of Linac performs a continuous rotation simultaneously with the modulation of the beam intensity using the multi-leaf collimator (MLC).Th e advantage of the technique is the increase in conformity of the treatment plan and the treatment dose delivery in a shorter time compared with the IMRT technique.Also some studies highlight the possibility of reducing the monitor units (MU) number and a better dose homogeneity compared to the plans obtained by the IMRT technique 3,5 .Verbakel et al. evaluated the potential advantages of VMAT technique over IMRT by comparing treatment plans for nasopharynx, oropharynx and hypopharynx cancers.Treatment plans based on 2 complete arcs used were superior in terms of dose delivery time and dose homogeneity, and in terms of organ at risk sparing (OAR), VMAT plans were similar to the plans IMRT 6 .
A study that included 222 patients diagnosed with oropharyngeal cancers (134 who received radiation therapy using the IMRT technique and 88 who were irradiated by the VMAT technique) analyzed dysphagia and xerostomia of degree 2 or greater.All the treatment plans were dosimetric compared.In the group of patients irradiated by VMAT technique, the toxicities were signifi cantly lower 7 .
Th e same superiority for VMAT technique in reducing the number of MU to 30% compared with IMRT radiotherapy is also demonstrated by a retrospective study by Fung-Kee-Fung and collaborators for concurrent radio-chemotherapy treated patients for head and neck cancer (stages II-IV) 8 .
Although the irradiation techniques have improved considerably, xerostomia remains a diffi cult problem to solve even in the era of modern techniques, the rate of xerostomia remaining high even when using new techniques.By retrospectively analyzing data from the dosimetry of 609 patients, the average dose and the average percentage of the volume of the salivary gland that received at least 26Gy (V26) evaluated for the contralateral parotid gland were 24.50Gy and 40.92% .Identifying an average dose of 48.18Gy for submandibular glands, the study authors conclude that even if the submandibular glands are not suffi ciently considered as OAR, the "level one" priority should be to target volume coverage target and the OAR protection associated with xerostomia remain only a "second level priority" 9 .
Late xerostomia may ocur at large intervals after IMRT irradiation with a decreasing tendency over time.Although the toxicities at large intervals after treatment are rare, Baudelet et al. reported an increase in the risk of dysphagia between 5 and 8 years after treatment, observing a non-linearity of the phenomenon, both for dysphagia and for fi brosis of the neck 10 .
Radiation superiority of IMRT technique in nasopharyngeal cancer has been demonstrated by a metaanalysis including 8 studies and 3570 patients, (1541 treated by IMRT technique and 2029 treated by 2D and 3D-CRT techniques).Th e authors compared the clinical results of the treatment regression free survival (PFS) and OS in both patients groups and the late toxicities of intensity modulated radiotherapy (IMRT) with those obtained with two-dimensional radiotherapy (2D-RT) or three-dimensional conformal radiotherapy (3D-CRT) in nasopharyngeal carcinoma.IMRT technique has shown superiority in OS but also in tumor control.Th ere was also a lower rate of trismus and temporal lobe neuropathy in the IMRT radiotherapy treated patients 11 .

CONCLUSIONS
Th e IMRT technique has become a therapeutic standard in curative treatment, proving the ability to reduce acute and late toxicity and superiority in survival and loco-regional control in nasopharyngeal cancer.Th e VMAT technique off ers a reduction of the irradiation time, avoiding the negative radiobiological consequences of the prolonged dose delivery time, and increasing the patient's comfort level and limiting the risk of ballistic errors in dose delivery by reducing the immobilization time.Combining the dosimetric qualities of the IMRT «step and shot» plan with the advantages in reducing the delivery time of the VMAT treatment could replace the IMRT method in the treatment of HNSCC.
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article.Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008 (5), as well as the national law.Informed consent was obtained from all the patients included in the study.