Intensity Modulated Radiotherapy ( IMRT ) in the Planning of Hypofractionated Treatment in Head and Neck Tumors

Head and neck cancer (HNCC) is the sixth most common cancer with an incidence of approximately 600,000 cases per year and 300,000 annual deaths worldwide. In Cuba, cancer of the larynx is the fourth cause in incidence, being the fourth cause of cancer death in men. Radiotherapy constitutes an important modality in the control of these tumors and the Intensity Modulated Radiotherapy (IMRT) is a new advance in this field. With it, it is possible to improve dose distribution, decreasing the dose in adjacent healthy tissues and escalating dose in tumor. In this work we present 33 patients of National Institute of Oncology and Radiobiology in Cuba (INOR), in whom the IMRT was used as a treatment technique with a hypofractionation of the dose. Their response was observed at the end of the treatment and one month later. 56% (19) of the patients had a complete response to treatment at the primary site of the tumor and neck. 10% (3) had no response, progressed. 11 of the patients had no response at the lymph node site at the end of treatment, 8 of these 11 had complete remission one month after radiotherapy ended.


Introduction
Head and neck cancer (HNCC) is the sixth most common cancer with an incidence of approximately 600,000 cases per year and 300,000 deaths per year worldwide [1] [2].
It preferentially affects male patients older than 50 years and its main risk International Journal of Clinical Medicine factors are smoking and excessive consumption of alcohol.However, an epidemiological transition is currently observed due to an increased incidence of head and neck cancer associated with human Papilloma virus infection.The most common histological type is Squamous, covering more than 90% of cases [1] [2].
In Cuba, laryngeal cancer is the fourth cause in incidence [3].
At the time of diagnosis, only 32% were in localized stage, 47% with regional commitment and 15% with remote commitment.The 5-year survival rate reaches 83% in localized tumors, 61% if there is regional commitment and 37% if there is distance commitment [4].
The treatment contemplates different alternatives, with the main surgery and radiotherapy associated or not with chemotherapy and/or biological therapies, depending on the tumor stage and the functional reserve of the patient [5].
Radiation therapy offers possible benefits by allowing the patient to heal, the preservation of organ functionality, and cost-effectiveness [6].
The evolution of the radiant methods from the conventional radiotherapy of the beginnings looks for to reduce to the minimum, the exhibition of healthy weaves neighbors to the tumor and to maximize the dose in the tumor weave.
The Intensity Modulated Radiotherapy (IMRT) is a technology consisting of the supply of tele-therapy beams with non-uniform fluency in the cross-section of the beam; calculated by computer programs with algorithms known as inverse planning; who seek to obtain the highly conformed distribution of radiation doses.In addition, it allows the treatment of various targets with different doses, at the same time radiation is minimized to critical structures not compromised with the disease [7] [8].
The hypofractionated radiotherapy uses fewer fractions with more doses for each of them.The typical dose values per fraction are in the range of 2.2 to 2.75 Gy, unlike conventional therapy with 2Gy fractions.The IMRT thus allows to decrease the time of treatment and also allows can obtain similar tumor response than conventional fractionation in tumors of the head and neck [9].
The waiting list of patients to start radiant treatment and what this implies for the patient, family member and society in general means that with a high level of evidence we incorporate them into these treatment regimens, optimizing more and more existing resources.

Materials and Methods
A prospective, observational study was carried out in which 33 patients diagnosed in the National Oncology and Radiobiology Institute (INOR) with loco-regional squamous cell carcinoma in pharynx, larynx and oral cavity (except nasopharynx, paranasal sinous, and stage I-II glottic carcinoma) were included in the period between 2014-2017.Prior surgical excision (except for biopsy purposes) is an exclusion criterion.2) Histopathological diagnosis of invasive squamous cell carcinoma at the primary site.

Inclusion Criteria
3) Age > 18 years.4) Informed consent according to the Helsinki declaration and local regulations.
5) The patient must be a candidate for external beam radical radiotherapy, and must be expected to complete the treatment.6) World Health Organization (WHO) performance status of 0 -2.
2) The patient should not be in a state or have major co-morbidity that could be expected to influence the outcome of treatment, or interfere with the assessment of treatment outcome at follow-up, or (apart from the present disease) considerably reduce the life expectancy.
3) Patients who test positive for human immunodeficiency virus (HIV).
6) The existence of synchronous multiple malignancies (not leukoplakia) or previous history of cancer.
7) The patient must not be pregnant.8) Socio-demographic or other factors that make it unlikely that the patient will be available for follow up of long term treatment outcome.
They received hypofractionated treatment with a daily dose of 2.75 Gy and 55 Gy as the total dose in the high-risk white tumor volume (CTV-Hi) while the low-risk tumor target volume (CTV-Lo) received a daily dose of 2.2 Gy.And 44 Gy as the total dose.These doses were delivered with the Modulated Intensity Technique (IMRT), performed in the radiotherapy planning system, Elekta Xio.
Patients were fitted with an Orfit type 5-point immobilization mask for simulation and a computerized axial tomography before planning.The equipment used for the treatments was an Elekta Synergy device, with a coupled conical tomographic image system (CBCT).The CBCT was used to carry out a weekly verification of the positioning of the system.

Results
The most frequent age group of patients included in the study was between 55 -64 years.Being the masculine sex the most frequent for a 94% and 79% with toxic habits (Table 1).
As the Figure 1 shows, the most frequent site of the primary tumor was the oropharynx (78%) and 93% of this patients were in advanced stage of the disease at diagnosis time, III and IVA.19 (56%) of the patients had complete response (CR) to treatment at the primary site of the tumor and neck at the end of treatment.3 (10%) had not response, progressed.At the same time 11 (33%) had a complete response at the site of the primary tumor but not at the lymph node; however, 8 of these 11 had complete remission one month after radiotherapy ended.In all, 27 of the 33 patients had CR after one month of treatment at the primary and regional tumor site (Figure 2).
A neck dissection was performed on patients who did not respond or with partial response of the lymph node site.As an interesting fact, it was proved that the results of the biopsies were negative to the tumor.
To date, 25 (83%) of the patients are controlled for their disease and 5 have died (17%) (Three who progressed, one due to metastatic disease and the other due to an accident).Three patients are in tumor relapse at the primary site.

Discussion
Many authors agree that radiotherapy with IMRT techniques for head and neck cancer is an excellent curative therapeutic tool.
The control rates of our patients are similar to those of Chao et al, who in 2003, presented their experience in a study conducted at the University of Washington in 126 patients with epidermoid carcinomas of the head and neck and intensity modulated radiotherapy technique (IMRT).They reported a loco-regional control rate of 85% at two years [10].
Similarly Dawson et al, in 2000, observed 58 patients with primary head and neck tumors treated with IMRT too and followed for a mean of 27 months.They reported a local control rate of 79% and 12 patients relapsed at 2 years [11].
Butler et al reported also, a study with 20 patients with primary head and neck tumors, showing 19 patients with a complete response to IMRT therapy [12].
Meta-analyses and collective data showed that loco-regional control may be improved at high level of evidence by concomitant chemo-radiotherapy, reason why 100% of our patients were treated with concurrent treatments [13].
At the same time, Di Nicola et al. showed in their study that both radiotherapy regimens (Conventional and hypofractionated) achieve similar results in terms of local control and complications [14].
The use of hypofractionated treatments in radiotherapy centers in low-income countries has become an attractive method to improve the probability of tumor control and maximize service productivity.In the meta-analysis of radiation therapy for head and neck carcinomas (MARCH), which included 15 phase III trials and 6515 patients, there was a global survival benefit of 3.4% at 5 years for altered fractionation versus conventional fractionation.However, there is still the possibility of not obtaining an answer as it happened in three of our six IVB staged patients who progressed despite the treatment.This result coincides with what was proposed by this collaboration group, where they express that the majority of patients with insane failure-regional were in the groups of stage III -IV with bulky node state in the initial presentation.This implies that patients with a large nodal load are likely to be less likely to benefit from hypofractionated treatment.This finding is well corroborated with the meta-analysis that demonstrated the effect of altered fractionation, being significantly more pronounced in the primary tumor than in the lymph node disease.Occurring the same with 3 out of four pts of the IVB state of our series [16].
Other authors such as: Sanghera et al. analyzed 81 patients with squamous cell cancer of the larynx, oropharynx, oral cavity and hypopharynx (International Union against Cancer Stages II-IV), who received hypofractionated radiotherapy with a dose of 55 Gy in 20 fractions with concurrent chemotherapy.The 2-year local control rate was 75.4%.The 2-year Global Survival rate was 71.6% and the 2-year Disease-free Survival rate was 68.6% [17].
A multi-institutional intensity modified hypofraction radiotherapy trial for early-stage oropharyngeal cancer showed that hypofractionated radiotherapy International Journal of Clinical Medicine without chemotherapy for early oropharyngeal cancer is feasible, achieving high rates of tumor control [18].
The Phase I dose increase trial without concurrent chemotherapy indicated that 2.36 Gy per fraction for a total of 70.8 Gy was the maximum tolerable dose delivered to the gross tumor volume while using an integrated simultaneous boost for head and neck cancers.With a median follow-up of 17 months, the LRC rate was almost similar for the hypofractionated group compared to a conventional group (76% vs. 80%).When analyzed by subgroups, the benefit of hypofractionation was probably more pronounced in patients with tumors of the oral cavity and cancer of the oropharynx.The differences in response observed were consistent with that experience [19]. Also

Conclusion
Epidemiologically Head and neck tumors in Cuba have a behavior similar to that reported in the literature.The use of radiotherapy techniques such as IMRT, allows us to concentrate and increase the dose at the tumor site and to protect the healthy organs as much as possible.Thus, different targets are used at the same time and hypofraction schemes are used with the same results as conventional treatments, as reported in the literature it's very advantageous in our environment due to the limited availability of radiotherapy equipment and the advanced diagnosis of these patients.

1 )
Tumor classified as stage I-IV located in oropharynx, hypopharynx, larynx International Journal of Clinical Medicine (not glottic stage I-II), or oral cavity according to the TNM classification of Malignant Tumors.
Source: Clinical History.
, Weissberg et al. compared the conventional fractionation (60 Gy to 70 Gy in 6 -7 weeks) with the hypofractionated (40 Gy to 48 Gy in 10/12 fractions at 400 cGy/fr) No significant differences were found in tumor control in 64 patients with surgically unresectable Squamous Cell carcinoma in stages III and IV [20].Saikat Das et al. conducted a study in 36 patients with locally advanced and inoperable head and neck cancer, who received doses of 40 Gy equivalents to 49.8 Gy in conventional fractionation and concluded that hypofractionated schemes are a viable option for these patients [21].