Volumetric and Dosimetric Inconstancy of Parotid Glands and Tumor in Head and Neck Cancer during IMRT

Abstract

The treatment of head and neck cancer using external beam radiotherapy is commonly done with three field techniques, which involves bilateral parallel opposed beams and one anterior lower neck field. Conventional treatment is based on 2D fluoroscopic images where there is no facility to shield the organs at risk like parotid. The most common side effect of such conventional radiotherapy treatment is xerostomia. The incidence of radiotherapy-related xerostomia varies depending on the specific radiotherapy technique used and the dose delivered to the parotid glands. Dosimetric variation in the tumor and normal tissue including parotid glands due to volume shrinkage during intensity modulated radiotherapy is the leading challenges in radiotherapy delivery in head and neck malignancy in terms of acute and late radiation related toxicities. Therefore if the planning target volume and normal tissue anatomy are changing with time during intensity modulated radiotherapy, it would be beneficial and acceptable to adapt our treatment delivery to minimize normal tissue toxicities where it really matters.

1. Introduction

One of the biggest challenges in radiotherapy delivery in head and neck cancer is radiation related acute and late toxicities. Symptoms of acute toxicities can be present for up to 3 months post-radiotherapy, and late toxicities, tend to persist several months or years after the completion of radiotherapy.

Xerostomia is considered to be a major concern in radiation related acute and late toxicity after head and neck radiotherapy.

2. Radiobiology of parotid glands

Salivary gland cells are slow dividing cells even though they are highly radiosensitive, factors attributing to this could be smaller number of cells in the functional subunit of acinar cells, slow recovery of acinar cells, depletion of stem cell population, pattern and rate of terminal differentiation of stem cells, proliferation rate of the stem cells, turn over or life time of acinar cells. If turn over or life time of cell is short there will be early appearance of symptoms of radiation injury and vice versa if the cell turn over or life time of cell is long.

In slowly dividing tissue radiation injury becomes more prominent when dose per fraction is increased, because at higher dose there are fewer division cycles that cells can successfully negotiate before their death. Therefore injury develops more quickly with increase in dose per fraction in late dividing tissue.

Various inter current insults e.g. chemotherapy, surgery, dental or mechanical trauma, hyperthermia, infection are also capable of precipitating the expression of radiation injury in slowly responding tissues.

3. Radiation techniques in head and neck cancers

The treatment of head and neck cancer (HNC) using external beam radiotherapy is commonly done with three field techniques, which involves bilateral parallel opposed beams and one anterior lower neck field. Conventional treatment is based on 2D fluoroscopic images where there is no facility to shield the organs at risk like parotid [1]. The most common side effect of such conventional radiotherapy treatment is xerostomia. This damage to salivary glands causes a reduction in saliva, dryness of mouth, difficulty in chewing, and speech alterations [2, 3]. Dental caries, which results in impaired nutrition, weight loss and significant degradation of quality of life, so their management and prevention is important for radiotherapy. The incidence of radiotherapy-related xerostomia varies depending on the specific radiotherapy technique used and the dose delivered to the parotid glands.

With the advancement in imaging and treatment planning techniques, CT-based conformal radiotherapy has come into existence which delivers radiation to the target with precision and gives minimal dose to the parotids. These techniques involve three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). The evolution of imaging methods from 2D portals to 3D-CBCT (Cone beam CT) has established the role of image-guided radiotherapy in improving the inter and intra-fractional variations during Radiotherapy of HNC [4]. These high precision techniques have led to an improvement in dose distribution and significant sparing of OARs (in this case parotid) and reduction in radiation-induced xerostomia [1]. The various radiotherapy treatment planning techniques in HNC have been discussed here.

4. Three-dimensional conformal radiotherapy (3D-CRT)

In the 3D-CRT technique for the treatment of HNC, usually, three fields are used. This consists of bilateral portals to treat the primary tumor and cervical lymph nodes and an anterior field to treat lower jugular chain and supraclavicular group of lymph nodes. A total dose of 70 Gy in 35 fractions is delivered in two to three phases in the definitive setting and 60–66 GY in 2 Gy per fraction in the adjuvant setting with or without concurrent chemotherapy depending on indications [5, 6]. Due to large hotspots arising in this technique, Field in field technique or field segmentation is generally used to reduce the hot spots. Monoisocentric technique is generally used where the bilateral and anterior fields have a common isocenter. This removes the problem of beam divergence and field abutment to avoid under dosing of tumor volume and overdosing of critical structures. However, despite the matching of the lower border of bilateral fields and the upper border of the anterior neck field, there is a chance of error in the junction dose due to various dosimetric and physical factors causing inhomogeneity in the dose distribution in that area. The dosimetric factors include field size, beam quality, penumbra etc., while the physical factors include the jaw alignment, isocenter accuracy etc. [7]. Despite, all such efforts, a significant amount of dose is received by OARs (organs at risk) like parotid causing treatment toxicity like xerostomia. This limits the ability of 3D-CRT to spare the OARs when there is a concave-shaped target in the head and neck. Therefore, the 3D-CRT technique is not helpful in parotid sparing and cannot be a replacement for higher precision techniques like IMRT.

5. Intensity-modulated radiotherapy (IMRT)

The 3D-CRT technique is based on the delivery of uniform fluence across the beam and involves less complex beam arrangements. Here, the parameters for planning such as beam directions, beam weights, wedges, etc. are based on the trial and error method making it a time-consuming process. To overcome these challenges, a more sophisticated method of conformal planning known as Intensity-modulated radiotherapy (IMRT) is used in HNC. Unlike the 3D-CRT method, here beams of non-uniform intensity are used. IMRT is based on the principle of inverse planning optimization and uses computed-controlled multi-leaf collimators to modulate the intensity of beams across the tumor. Intensity modulation allows the conformal dose coverage to the target and sharp dose fall-off beyond the target thus sparing the critical structures surrounding the target [8].

Due to the complex anatomy of the head and neck, and proximity of various critical structures with the target, IMRT is the better choice of treatment [9]. Multiple beams of non-uniform intensity deliver dose with high conformity to the irregularly shaped target and steep dose gradient at the boundary of target and organs at risk (OARs) minimize the dose to adjacent OARs like spinal cord, parotids.

Head and neck tumor configurations are usually concave in nature. With multiple organs such as the parotid glands, brainstem, spinal cord etc. surrounding such concave-shaped lesions, there is a need for concave-shaped dose distribution to avoid risking dose to these OARs [10]. Head and neck IMRT clearly offers such advantages of better normal tissue sparing, improved dose coverage to the target, giving multiple isodose levels in tumor volume, and dose -escalation to the tumor [11].

IMRT has given better results over 3D-CRT in head and neck cancer with a significant reduction in xerostomia, prevention of acute and late toxicities, and improved quality of life. Parotid-sparing IMRT has superior results over conventional 3D-CRT [12, 13, 14]. However, for successful results from IMRT, there is a requirement of precision in the patient setup, immobilization, and correct tumor volume delineation to avoid any marginal miss, proper plan evaluation, strict imaging protocols, and rigorous quality assurance tests. Owing to the tight margins of dose around the target, any negligence during the IMRT treatment can pose a serious risk to the patient and can impact the treatment outcome. Another concern that arises during IMRT treatment is the volumetric and spatial changes in tumor volume and OARs due to shrinking of tumor, weight loss, radiation-induced toxicities as well as variation due to physiological movements like breathing [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26](Table 1). One such change observed during treatment of HNC is the movement of parotid closer to high dose regions during the progress of treatment owing to the shrinkage in tumor volume, inducing high-grade xerostomia (even worse than predicted) [27]. To limit the dose variation due to these factors, there is a need to adapt to the varying treatment volume and OAR volumes changing during the course of treatment (Figures 1–4). This could be possible through a technique known as adaptive radiotherapy.

Reference	N	Imaging	Anatomic changes	Dosimetric changes
Ho et al. [15]	10	Weekly CBCT	Parotid: V ↓ 25%	Parotid, SC, BS: no change; Larynx, OC: no change
Robar et al. [16]	15	Weekly CT	Parotid: V ↓ 4.9%/week; 0.85 mm/week medial shift	Parotid: Dmean↑ 2.6% (L); SC: ↑ 0.2%; BS: ↑ 1.0%
Hunter et al. [17]	18	Daily CBCT	Parotid: V ↓ 13%	Parotid: Dmean↑ 0.9 Gy
Jin et al. [18]	10	Weekly CBCT	Parotid: 4.5-4.7%/week	Parotid: V26 ↑ 7.5% (R); V26 ↑ 8.8% (L)
Wu et al. [19]	11	Weekly CT	Parotid: V ↓ 15%; CTV: V ↓ 10%	Parotid:Dmean↑10%; CTV, BS, SC: No change
Bhide et al. [20]	20	Weekly CT		Parotid: Dmean↑ 7% (ipsi); SC: Dmax↑ 2%; BS: Dmax↑ 4%; PTV1: Dmin↓ 3%; PTV2: Dmin↓ 5%
Castadot et al. [21]	10	4 rpt CTs		Parotid: Dmean↑ 4%; SC: D2% ↑ 4.5%; CTV: No change
Nishi et al. [22]	20	Rpt CT	GTV: V ↓ 63% (primary); V ↓ 52% (nodal); Parotid: V ↓ 18%; 4.2mm medial shift	GTV: D98 ↑ 1% (primary); D98 ↓ 0.3% (nodal); Parotid: Dmean↑20%; SC: D2 ↑ 5%
Castelli et al. [23]	15	Weekly CT		Parotid: Dmean↑ 3.7 Gy (59% parotids)
Barker et al. [24]	14	3 CT per week	Parotid: V ↓ 8% (0.6%/day); 3.1 mm medial shift; GTV: V ↓ 70% (1.8%/day)
Lee et al. [25]	10	Daily MVCT	Parotid: V ↓ 21% (0.7%/day); 2.6 mm medial shift
Vásquez Osorio et al. [26]	10	Repeat CT	Parotid: V ↓ 17% (ipsi); V ↓ 5% (contra); SMG: V ↓ 20% (ipsi); V ↓ 11% (contra)

Table 1.

Summary of anatomic and dosimetric changes throughout treatment for head and neck radiotherapy.

Abbreviations: SC = spinal cord; BS = brainstem; SMG = submandibular gland; L = left; R = right; V = volume; ipsi = ipsilateral; contra = contralateral.

Figure 1.

Comparison between pre-treatment (CT1) [left] and per-treatment (CT4) [right] images of a patient. Coronal CT slices of a 57 years old male patient with carcinoma hypopharynx (T4aN2c). The decrease in volume of GTV primary (maroon) [from 30.426 cc in CT 1 to 5.964 cc in CT 4] and GTV nodal (pink) [from 10.005 cc in CT 1 to 4.638 cc in CT 4] can be appreciated along with decrease in volume of both right (brown) and left (light blue) parotid glands.

Figure 2.

Comparative DVH of a patient [(Ca hypopharynx T4N2c)] comparing CT1 (-------) and CT4 (––––). The mean dose to the right parotid (brown) has decreased in CT4 compared to CT1 whereas the mean dose to left parotid (light blue) has increased in CT4 compared to CT1.

Figure 3.

Comparison between pre-treatment (a) and per-treatment (b) images of a Patient undergoing IMRT-SIB. Coronal CT slices of a 55 years old male carcinoma pyriform fossa (T1N3b) patient. We can appreciate the decrease in GTV nodal (pink) volume by end of treatment along with decrease in volume of both right (brown) and left (light blue) parotid glands (b). The low dose isodose curves of 20 Gy (light yellow) and 30 Gy (light green) can be seen covering more areas of right parotid gland in (b) compared to (a).

Figure 4.

DVH comparison between start (A) [--------] and end of treatment (B) [–––––].

6. Adaptive radiotherapy

Adaptive radiotherapy is a technique in which any volumetric or spatial variations in tumor volume or OARs, the morphological changes are taken into account through re-planning of patients at certain defined intervals during the course of treatment. The re-planning helps in adapting to the anatomical changes in tumor and OARs such as parotids and optimizing the plan to provide adequate tumor coverage and minimize the dose to OARs [28]. These variations are corrected on a daily basis through modifications in the treatment plan with the help of image guidance. Routine in-room volumetric images are acquired and sent to the treatment planning system for re-planning. The contours of the daily in-room CT are superimposed with the reference planning CT to account for any variation in the anatomy or set up, through deformable image registration software. A new treatment plan conforming to the current changes in anatomy, if any, is generated through automated deformable registration software and the adapted plan is transferred to the machine for treatment. The new plan is implemented either in online mode after online correction or in offline mode, where the corrections are implemented after some time [29]. Adaptive radiotherapy has offered dosimetric benefits in HNC and its clinical benefits have also been proven by a few studies [30].

Therefore medical fraternity now has a better understanding of radiation related toxicities in head and neck cancers, so it is truly gratifying to deliver radiotherapy by such innovative techniques where it really matters.