13 Head and Neck - Oropharynx

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE 13

Head and Neck - Oropharynx Ashwini Budrukkar, Gyoergy Kovacs, Rafael Martinez-Monge, Christine Haie-Meder, Erik Van Limbergen, Vratislav Strnad

Editors Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

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13 Head and Neck - Oropharynx

Ashwini Budrukkar, Gyoergy Kovacs, Rafael Martinez-Monge, Christine Haie-Meder, Erik Van Limbergen, Vratislav Strnad

1. Summary 2. Introduction

3 3 4 4 4 5 6 7

9. Treatment planning

15 16 17 17 21 22 23

10. Dose, dose rate and fractionation 11. Monitoring and posttreatment care

3. Anatomical topography 4. Pathology and staging

12. Results

5. Work up

13. Adverse side effects 14. Key messages

6. Indications, contra-indications 7. Tumour and target volumes

15. References

8. Techniques

1. SUMMARY

Radiation therapy with or without chemotherapy is the standard of care for oropharyngeal cancers. With excellent control rates and reduction in the toxicity with modern external beam radiotherapy, the use of brachytherapy in oropharyngeal cancers has become less common. Brachytherapy, however, has a potential to deliver high doses to the centre of the tumour which is also the most common site of relapse. Various brachytherapy series have shown excellent tumour control rates and reduction in normal tissue toxicity compared to external beam radiotherapy. It may therefore be advantageous to combine the two modalities and optimize the outcomes further in this modern era.

2. INTRODUCTION

Interstitial brachytherapy for oropharynx is challenging. While interstitial brachytherapy has been in use since many decades; with the advent of intensity modulated radiation therapy (IMRT) there has been a debate regarding use of IMRT or BT [15]. While BT has advantages of being a time-tested technique with excellent local control rates and acceptable toxicity, IMRT is promoted for its non-invasive nature. As both modalities result in very good outcomes combining the two modalities could result in further improvements in control rates and reduction in toxicities. Combined IMRT and BT has resulted in excellent local control rates [16]. Brachytherapy due to its rapid fall off of the dose has greater ability to reduce doses to the critical structures than IMRT. Important among these are reductions in the dose to parotids and to constrictor muscles [17,18]. Combined IMRT and BT has resulted in reduction in xerostomia and improved quality of life [16]. Brachytherapy has also resulted in decreased doses to the dysphagia aspiration related structures (DARS) and improved quality of life [19]. Brachytherapy has evolved from the era of preloaded applicators to low dose rate BT and now to pulse dose rate (PDR) and high dose rate (HDR) BT [20]. The planning has evolved from X ray based planning to three dimensional computerized tomography (CT) based planning with various optimization techniques [20]. This has resulted in the ability to reduce doses to critical structures close to the implant such as mandible thereby minimising the long term sequelae of BT [21].

There has been an increase in the incidence of oropharyngeal cancer in the last decade in the western world which has been attributed to the presence of human papilloma virus (HPV) [1]. Significantly improved clinical outcomes have been observed with radiotherapy for oropharyngeal cancers in HPV positive patients [2,3] compared to HPV negative cancers. This has resulted in the different staging system for HPV positive and negative cancers in the 8th UICC TNM staging [4]. A similar increase in the incidence has however not been observed in the Asian countries [5]. Management of oropharyngeal tumours is challenging due the important role of the oropharynx in speech and swallowing. Early stage disease is managed with single modality treatment either in the form of surgery or radiation and for advanced stage disease multimodality treatment in the form of chemoradiation is considered. Surgery for oropharyngeal tumours involves extensive resection which has an impact on speech and swallowing [6]. This results in increased treatment-related morbidity and impaired quality of life [6]. More recently there has been a resurgence in the surgical management especially in HPV positive tumours using robotic surgery [7]. Radiation therapy either external beam alone or combined with brachytherapy (BT) has resulted in excellent outcomes for oropharyngeal cancers [8–13]. Combined external beam radiation therapy (EBRT) and brachytherapy has resulted in improved local control rates as compared to either modality alone [14].

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Figure 1: Anatomy of oropharynx (from headneckcancer.org)

3. ANATOMICAL TOPOGRAPHY

5. WORK UP

The oropharynx communicates anteriorly with the oral cavity, above with the nasopharynx, and below with the hypopharynx and the larynx. Its walls are anteriorly formed by the base of tongue, laterally by the two tonsillar regions, above by the soft palate, and posteriorly by the posterior pharyngeal wall (Figure 1). A transverse plane passing through the lingual insertions of the palatoglossal folds, laterally by the glosso-tonsillar sulci, and posteriorly by the glosso-epiglottic sulcus or vallecula, limits the base of tongue anteriorly. The faucial arch is composed of the two tonsillar regions and the soft palate. The tonsil lies in a fossa formed by the anterior and posterior tonsillar pillars. This is separated from the tongue by the glosso-tonsillar sulcus. The two pillars merge and superiorly form the soft palate, which is anteriorly adherent to the hard palate and inferiorly supports the uvula. The oropharynx has a rich lymphatic plexus draining for the most part to the upper anterior cervical or sub digastric lymph nodes (Level II nodes) .

• Documentation of history in detail is important. History of smoking, alcohol, sexual practices and comorbidities is necessary as this can be of prognostic value [3] • Detailed clinical examination including inspection and palpation of the primary site and neck should be done. Fibreoptic endoscopic evaluation is necessary. Detailed documentation of all mucosal extensions is extremely important as these may not be well visualised on imaging. A clinical diagramdelineating the primary with all disease extensions is helpful for planning of BT (Figure 2). • It is recommended to place radio-opaque markers or tattoos at 4 edges of the tumour for improving the target volume delineation (Figure 3). • Wherever possible clinical photographs should be taken (Figure 4). These are helpful while planning insertions of BT catheters. • Routine blood investigations such as full blood count, liver and renal function tests, viral markers and electro-cardiogram. • Evaluation under anaesthesia for disease mapping is important. This is also helpful for BT planning. • Biopsy for histopathology. P16 evaluation with immunohistochemistry should be done. • Imaging: Contrast enhanced CT scan of the head and neck region with slice thickness of ≤ 5mm is considered standard. Magnetic resonance imaging (MRI) has been proved to be better for soft tissue delineation of oropharynx especially infiltration of muscles in the base of the tongue as well as soft tissue extensions in a soft palate primary. Positron emission tomography (PET) CT scan could be considered in selected cases. Role of PET CT in delineation of the target volume is evolving. • Imaging of thorax: CT scan of the thorax or chest X ray should be done. • Dental evaluation which includes fluoride gel application, scaling and management of caries is mandatory. [20]

4. PATHOLOGY AND STAGING

Squamous cell carcinoma accounts for 95% of the cancers of the oropharynx. Other uncommon histopathologies include lymphomas, sarcomas and minor salivary gland tumours. Brachytherapy is considered only for squamous cell carcinoma of the oropharynx.

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6. INDICATIONS, CONTRA-INDICATIONS

• Fibro-optic endoscopic evaluation of swallowing may be considered if facilities are available as oropharyngeal cancer and treatment can have impact on the swallowing. • PreRT video-fluoroscopic evaluation may also be considered for swallowing assessment if facilities are available. • Dietician evaluation and diet plan is necessary so as tomaintain the nutrition during the treatment. • Pre-anaesthetic evaluation for general anaesthesia for BT should be done. Staging of carcinoma of the oropharynx should be done as per the UICC TNM staging 8th edition [4]. For the first time different staging system for a single subsite has been adopted.The preference of HPV for the oropharynx may be related to the presence of transitional mucosa in the oropharynx similar to the cervical mucosa [22]. Another possibility lies in the genetic features of HPV16 whichmay facilitate its survival in the tonsillar crypts [23] . The differences in the prognosis of HPV positive and negative oropharyngeal cancers has led to the change in the UICC TNM staging. The details of TNM staging for HPV negative and HPV positive tumours is as shown in Table 1 and table 2 .

Tumours of up to 5 cm can be considered for BT. Due to the high propensity of nodal involvement the vast majority of the tumours are considered for combined EBRT with BT approach. Radical BT alone is considered for small up to 1 cm tumours of tonsil, soft palate and uvula [24]. All other tumours are considered for combined EBRT and BT. Generally BT is considered for patients with N0-1 nodal status. In situations where patients with bulky nodes are considered for BT, the neck has to be addressed with surgery after EBRT. Patients who are considered for a combined EBRT and BT approach receive EBRT first. Typically, the primary target and bilateral nodal volumes are treated to a dose of 46-50Gy in conventional fractionation. IMRT is the preferred modality for EBRT [25,26]. Small T1 lesions of tonsil and lateralized tumours of soft palate can be considered for ipsilateral nodal irradiation [27,28]. Attempts should be made to keep the overall treatment time similar to that of EBRT alone.

Figure 2: Clinical diagram showing 3x2.5 cm ulcero-proliferative growth involving left tonsil, anterior and posterior tonsillar pillar extending superiorly to soft palate just short of midline, uvula uninvolved. No neck nodes. Diagnosis: Ca Tonsil T2N0M0

Figure 3: Radio-opaque markers 0.6mm diameter and 2mm length used for marking 4 corners of the tumour

Figure 4a: Clinical photograph of a patient with carcinoma of uvula considered for radical brachytherapy

Figure 4b: Clinical photograph of a patient with carcinoma of right tonsil T1N0 M0 considered for brachytherapy

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TABLE 1 T stage as per 8 th UICC TNM staging for HPV Positive oropharyngeal cancer T Category T Criteria T0 No primary identified T1 Tumour 2 cm or smaller in greatest dimension T2 Tumour larger than 2 cm but not larger than 4 cm in greatest dimension T3 Tumour larger than 4 cm in diameter or extension to lingual surface of epiglottis T4 Moderately advanced disease

Tumour extends to larynx, extrinsic muscles of the tongue, medial pterygoid, hard palate or mandible or beyond

TABLE 2 T stage as per 8 th UICC TNM staging for HPV Negative oropharyngeal cancer T stage T Criteria Tx Primary tumour cannot be assessed Tis Carcinoma in situ T1 Tumour 2cm or smaller in greatest dimension T2 Tumour larger than 2 cm but not larger than 4 cm in greatest dimension T3 Tumour larger than 4 cm in diameter or extension to lingual surface of epiglottis T4 Moderately advanced or very advanced disease

Moderately advanced disease Tumour extends to larynx, extrinsic muscles of the tongue, medial pterygoid, hard palate or mandible Very advanced local disease Tumour invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

T4a

T4b

Brachytherapy is not considered when the disease is extending to retromolar trigone, close to or involving hyoid bone, reaching up to pterygoid plates or involving pterygoid muscles. Patients with inadequate mouth opening and those unfit for anaesthesia are also not considered suitable for BT.

by 5-10 mm. CTV to the GTV res may be defined as CTV high risk (CTV HR) and CTV to the initial disease may be defined as CTV intermediate risk (CTV-IR) analogous to the concept of cervical cancer (ICRU 89, 2016). The aimof the BT is to deliver dose to the pretreatment volume with or without margins i.e CTV-IR. With a stepping source afterloader it is now possible to give a higher dose to the CTV HR which can be considered as a boost in boost technique. There is no further PTV in BT as CTV=PTV. While these concepts of contouring have been well established in gynaecological cancer [29] similar data and supporting evidence is lacking in head neck cancer. More work is needed by the head and neck working groups to establish some guidelines for target volume delineation in head neck BT. Often delineation of GTV on the RT planning CT scan is very challenging. There could be change in the anatomy due to post- procedure oedema and also due to presence of catheters at the site of GTV. CT, MRI and PET fusion could also be very challenging in some situations due to these factors. In such situations catheters which are placed at the site of tumour will themselves act as a guide for GTVdelineation as the implant is based on the visualized disease and taking into account preimplant imaging. In some situations, in view of uncertainty in the GTV delineation loading of the reconstructed catheters could be decided directly based on clinical evaluation of the disease and margins.

7. TUMOUR AND TARGET VOLUMES

Gross tumour volume (GTV) is defined at the time of initial diagnosis (GTV init ) and at the time of BT (GTV res ). GTV init is defined based on the information from the clinical diagram, clinical photograph and imaging at the time of diagnosis. MRI is helpful for the soft tissue extensions of the disease. Tumour marker clips at the 4 corners placed before starting EBRT are also useful for delineation of the GTV init on the BT planning CT scan. Image fusion with MRI and PET CT scan may also be considered for improving the target volume delineation. In patients who are considered for EBRT followed by BT fusion with preEBRT imaging such as CT scan, MRI and PETCT is especially useful. In the post EBRT scenario residual disease as evaluated under anaesthesia at the time of BT and as visualised on a post EBRT contrast imaging (CT/MRI) is considered as residual GTV (GTV res ). Clinical target volume (CTV) takes into account the microscopic extensions of the tumour in all directions and typically is grown

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8. TECHNIQUES

8.1 General Aspects In patients who have received EBRT a gap of 1-3 weeks is given for acute reactions to settle down. If possible, it is advisable to minimise the gap to reduce the overall treatment time. Intraoperative implantationwith “boost first “method reduces the overall treatment time. Detailed evaluation of the tumour is done before subjecting patient to anesthesia.This involves information from clinical examination, clinical photographs, diagrams, and imaging withCT scan andMRI. The instruments for brachytherapy are shown in Figure 5. The procedure is done under general anaesthesia in supine position with neck extension (Figure 6). Nasal intubation preferably through the contralateral nostril is done to have access to the oropharynx. Nasogastric tube placement is considered in the majority of the patients to maintain nutrition as swallowing may be affected with implanted tubes. The majority of patients do not require tracheostomy. Especially in the case of base of tongue implants, the anterior positioning and fixation of the base of tongue with the implanted tubes keeps the airways open in the later course of the treatment. However, in rare situations where there is a possibility of airway compromise prophylactic temporary tracheostomy may be considered. After induction and painting and draping of the head and neck region, the mouth is kept opened using a jaw retractor. A tongue tie is placed to pull the tongue which facilitates adequate visualization of the lesion and enables manoeuvring during the implant. Evaluation under anesthesia (EUA) is an important step in which the complete extent of the lesion is palpated in all directions (Figure 7). The size, shape, thickness and distance from bone are noted. A note is also made of any unhealthy mucosa in the surrounding area which may have to be covered. In the case of a boost implant, the response of the lesion is noted and compared to the pre- EBRT volume. Radio-opaque markers are placed at the four corners of the macroscopic tumour wherever feasible. This is helpful in target volume delineation (Figure 3). 8.2 Base of the tongue (BOT) Insertion of the needles for BOT is done with a suprahyoid approach. The approach depends on the tumour extension. If the tumour extends to the glosso-epiglottic sulcus, then the approach can be infrahyoid. The projection of the tumour is marked on the skin of the submental region and a margin of 5-10mm is given. The area to be implanted is decided based on the CTV. While some radiation oncologists consider implantation of the entire base of the tongue, the tumour with 5-10mm margins is considered appropriate by many others. Classic loop technique[30] The posterior branch of the central loop is first implanted. A guide needle is inserted perpendicular in the skin above the hyoid bone. The needle is guided into the pharynx, in most cases into the vallecula, with the index fingertip. One leader of a double leader plastic tube is then introduced intraorally into the needle. Then the

Figure 5: Instruments for brachytherapy of oropharynx

Figure 6: Patient position for head neck brachytherapy

Figure 7: Evaluation under anaesthesia

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needle is removed and the plastic tube is pulled through the tissue. A second needle is implanted anteriorly into the base of tongue for creating the anterior leg of the loop – therefore distance and position of the needle related to the posterior insertion channel is important. It is advised, at the beginning of the learning curve, to implant both needles first and control the distance and parallelism of thembefore inserting the plastic tube leaders and pulling through the tissue and completing the loop. The ideal distance apart of the two legs is 25 mm. Less distance results in frequent kinking of the loop. The two or three other sagittal loops are implanted with the same method, paying great attention to keeping them parallel. It is important to keep both legs at least 10 cm distance over the skin surface in order to be able to use the second leg after opening it as a single channel if the loop kinks. Less than 10 cm distance makes the connection to the transfer tubes of the HDR/ PDR machine very difficult. Finally, the loops are secured with plastic buttons to the skin. When large tumours are implanted, the separation between the branches of the loops may exceed 25 mm in order to encompass the entire lesion. If the distance exceeds 30 mm, crossing loops (latero-lateral loops, perpendicular to the sagittal ones) need to be implanted to avoid underdosage between the legs of the loop. To prevent underdosage in the central area of the PTV, crossing frontal loops may be added, with their branches equidistant to those of the sagittal loops. The bridges of the frontal crossing loops are not activated to avoid dose hotspots (Figure 8). Non Looping loop technique [31] A hollow needle (12 gauge) is inserted in the upper neck. This is guided through one finger which is inside the mouth and palpating the base of tongue. The needle is pushed in the posterior and superior direction until it comes out of the base of tongue. Multiple needles are inserted parallel to each other in the sagittal plane until the target is covered (Figure 9). Afterloading catheters with one end sealed are inserted in all the needles. Outside the mouth silk thread is attached to each catheter. This is used for attaching the tubes to the non-looping loop catheter. The needles in the neck are withdrawn and the tubes are pulled from the neck carefully until the crossing catheter sits on the base of tongue. The tubes are well secured in the neck with plastic buttons. The non-looping loop may be allowed to protrude out from the mouth. Multiple such sagittal planes are made so as to cover the target adequately.

Modified Non Looping loop technique with beads [32] Generally the most central and posterior needle is inserted first. The needle is inserted perpendicular to the skin and is guided by bimanual palpation. The sharp end of the needle is guided into the vallecula and is brought into the oropharyngeal air cavity. A plastic tube with thin ends on both sides is taken. One of the thin ends is inserted inside the needle. The needle is pulled out from the neck so that one end of the tube is brought out through the neck. The other end of the tube comes out through the mouth. A second needle is inserted 10-15mm anterior to the first needle.This needle is brought out into the oropharyngeal air cavity. A tube with a bead with at one end and thin segment at the other end is used for this needle. The bead which is attached to the plastic tube has a central hole. The thin end of the tube is inserted into the needle till it comes out in the neck. The needle is then pulled out so that the thick end of the tube comes out. The thin end of the loop tube is now passed through the hole of the bead of the second tube. This tube is now pulled slowly till the bead sits on the base of the tongue. The first loop tube gets anchored to the second tube by this procedure. The third tube is inserted anterior to the second tube keeping 10-15mm distance and the same procedure is repeated. Multiple needles are used until the target volume is covered. By doing this the loop tube gets anchored into the bead (straight) tubes forming a crossing tube. The loop tube with its thin edge is still coming out from the mouth. The tube is cut at the thick end and another tube with a button at the end is inserted into this tube. The tube is then pulled from the neck by a railroad method so that the button tube replaces the loop tube. This forms the first plane. Three or 4 such planes are inserted to cover the target (Figure 10, 11,12). In practice it may be better to place all the most posterior needles (forming loop) of 3-4 planes first. The implant is done posterior to anterior rather than plane by plane as tongue movement becomes restricted after insertion of all needles in one plane. Silk threads are tied at the closed ends of the beads and button tubes, brought out through the mouth and well secured outside on the cheek with tape. These threads are useful for removal of the implant. Modified Non Looping loop technique with sutures [33] In this technique instead of using bead tubes, button tubes are used as straight tubes. These are anchored to the loop tubes with stitches (Figure 13).

Figure 8: Classic Loop technique of brachytherapy for the base of tongue cancer (with courtesy to M Pernot)

Figure 9: Non -looping loop technique for base of tongue cancer ( Bhadrasain et al) [31]

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Figure 10: Technique of Non-looping loop with beads

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11b

Figure 11a, b: Base of tongue brachytherapy with non-looping loop technique using beads Note: The silk threads attached to each tube are useful at the time of removal. 11a: Bhalavat et al [39].

Figure 12: 3D CT based planning showing axial, sagittal, coronal and 3D dose for a BOT implant done using nonlooping loop with beads technique.

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Figure 13: Non looping loop technique with sutures (Johanson et al) [33]

Figure 14: Straight tube technique for base of tongue brachytherapy

Figure 16: Pre and post EBRT+ Brachytherapy pictures in a case of carcinoma of base of tongue

Figure 15: Straight tube technique for BOT brachytherapy (Puthawala A et al) [34]

Figure 17: Pre and Post EBRT+ Brachytherapy imaging in a case of carcinoma of vallecula

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All the non-looping loop techniques are especially useful for stepping source PDR and HDR BT afterloaders as the curves of non-looping loops have wider angles and hence there is no difficulty in passing the source. Straight tube technique [34] Needle is inserted through the suprahyoid region and pushed straight down till it comes out of the oropharynx. Needle is then threaded with plastic catheter with button at one end. Multiple such tubes are placed at a distance of 10-12 mm to make multiple planes. Additional buttons may be placed to increase the dose to the dorsum of the tongue (Figure 14,15). Figure 16 shows preRT tumour in the base of tongue and post RT (EBRT+BT) MRI showing complete resolution of the disease with organ and function preservation. 8.3 Vallecula For vallecular lesions or tumours with epiglottis infiltration, the insertion of the posterior post needles have to be done through thyrohyoid membrane using infrahyoid approach. The procedure of needle insertion remains similar to the base of tongue BT. The epiglottis gets anchored into the loop as the posterior most needle comes out through or behind the epiglottis. In this situation temporary tracheostomy is required before starting the procedure. Figure 17 shows MRI of a vallecular cancer treated with EBRT+BT. Two parallel frontal loops 15 -20 mm apart are implanted to cover the whole or two thirds of the faucial arch (Figure 18). After palpation of the position of the hyoid bone and the carotid artery, the entrance points of the needles are marked on the skin. The entrance point for the needle is decided by the bimanual palpation. Typically, the anterior loop enters 10 mm above the hyoid and will pass through the anterior faucial pillar. The entrance point of the posterior loop is marked 10 mm beneath the hyoid and will pass through the posterior pillar (Figure 18). However, the entrance pointsmay vary depending on the anatomy of that particular patient. The posterior tube is positioned first. A 10 cm guide needle is introduced under the hyoid bone perpendicular to the skin and is then advanced posteriorly about 25 mm into the neck, towards the pharyngeal mucosa, guided by a palpating finger in the oropharynx. Then the needle is turned cranially, and it is gently manoeuvred through the tissues and along the posterior faucial pillar to emerge in the oropharyngeal cavity at the junction of the inferior border of the soft palate and the posterior faucial pillar. A leader of the double-sided plastic tube is pushed through the lumen of the needle and the needle is removed. AReverdin hook or a curved hollow bladder needle (30) is inserted at the junction of the inferior border of the soft palate and the left posterior faucial pillar, and it is manoeuvred along the free border until it penetrates the oropharyngeal cavity at the same point as the plastic tube. The second leader of the double-sided plastic tube is grasped with the Reverdin and pulled through the free border of soft palate. The plastic tube is then pulled into position. Curved hollow needles may also be used directly. A guide needle is introduced on the left side along the posterior faucial pillar, as described in point 2, to emerge in the oropharyngeal 8.4 Soft Palate, Uvula [35] Classical Pernot technique

cavity at the same point as the plastic tube. Another double-sided plastic tube leader is introduced into the oropharyngeal cavity through the needle and pushed through the lumen of the plastic tube until it emerges at the initial entry point on the right side of the neck. Traction on the legs brings the plastic tube into its final position, spanning the oropharynx from the right side to the left, without penetrating the oropharyngeal cavity. A second plastic tube is then introduced, parallel and anterior to the first. The tube enters and exits at the right and left sides of the neck, at the marked points above the hyoid bone. The needles are introduced into the skin at these points, advanced about 5 mmposteriorly, are turned cranially to follow the anterior faucial pillars, and exit in the soft palate, close to the border with the hard palate. A Reverdin needle or a curved hollow needle is again necessary to traverse the soft palate along the border with the hard palate. If curved needles are used one can reach almost up to uvula from either side. When the uvula forms part of the clinical target volume, it may be underdosed using the described technique. In that case, the extremity of the uvula may be either stitched to the soft palate or threaded with the posterior plastic tube or removed. In certain situation two loop tubes for the soft palate can be combined with the most superior tube that is inserted through the cheek. This needle is inserted from the cheek just anterior to the retromolar trigone (RMT) and enters the soft palate. The tube is exited through the contralateral side from the RMT into the cheek. Figure 19 shows 3D CT planning of soft palate brachytherapy. Latero-lateral implantation technique It is possible to implant the soft palate as well as the posterior pharyngeal wall with latero-lateral directed plastic tubes. The use of ultrasound control of the large vessel positions (especially the internal carotid artery) is helpful. For this technique the use of a long (>25 cm) insertion needle is necessary. The first plastic tube needs to be implanted at the level of the junction of the bony hard palate and the soft palate. The needle has to enter the skin of the neck immediately behind the mandible and oriented in the first approx. 3-5 cm a bit anteriorly in order to avoid puncturing the internal branch of the carotid artery. The finger on the junction of the soft/hard palate will guide further direction. Arriving with the needle in this region, this finger can press and guide the course of the needle within the soft palate. On the other side, after the needle tip leaves the target area, the space between the posterior margin of the mandibular and the level of the large vessels can be used for exiting through the skin. The procedure is repeated for each of the other tubes – usually three tubes cover the complete soft palate (Figure 20) . In the case of posterior pharyngeal wall implantations only the level of the insertion points differ as it needs to correlate to the site of the target. The first/last plastic tube should pass the prevertebral soft tissue approximatively 5 mm cranial/caudal to the macroscopic lesion. Poseidon Technique [30] This technique is used to treat lesions of the uvula and small central tumours of the soft palate. It also permits coverage of tumour extension to the mucosa of the oral cavity (hard palate). Three curved needles are implanted in a sagittal direction into the soft palate. They are inserted into the mucosa at the junction of the hard and soft palate and exit at the free border laterally and for the

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Figure 18: Technique of soft palate brachytherapy (Mazeron et al)

Figure 19: Three dimensional CT based planning of soft palate brachytherapy

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11b

Figure 20: Axial, Coronal and sagittal view of dose distribution for lateral to lateral technique for soft palate.

Figure 22: Cartoon showing plastic catheter tubes in the anterior tonsillar pillar, tonsillar fossa and posterior pillar in a typical tonsillar cancer primary. Extension of the implant to the base of tongue in the case of involvement of base of the tongue

Figure 21: Poseidon technique of brachytherapy for soft palate tumours (E. Van Limbergen [30])

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middle line, through the uvula. Then a loop is made joining the two lateral lines. Before making the loop, a larger piece of plastic tube is placed over the implantation tubes, to fix the loop to the central tube, which will perforate the piece of plastic. Loading of the sources may be extended to the hard palate region. In that case it is advised tomake a customisedmould, covering the hard palate and with predrilled holes in it, to contain the sources close against the hard- and soft palate mucosa. It is also possible to build in a layer of lead protection caudal to the tube level to minimize normal tissue irradiation (Figure 21). 8.5 Tonsil For tumours of the tonsil the entire tonsillar fossa on the involved side is considered as the target. The most posterior needle which is positioned in the posterior tonsillar pillar is inserted first. A hollow slightly curved or straight needle is used. The needle is inserted below the hyoid and is guided with bimanual palpation into the posterior tonsillar pillar. The needle is pushed until it reaches the junction of posterior tonsillar pillar and soft palate where it exits. Nylon tube with a button at the closed end is used. The thin end of the nylon tube is inserted into the needle and taken out through the neck. The tube is pulled out in the neck until the button sits on the soft palate.

Tonsillar fossa needle is slightly deeper and hence is inserted posteriorly in the neck. Care has to be taken while inserting this needle palpating the carotid and keeping the needle anterior to it. The needle is inserted with bimanual palpation. The needle is pushed into the fossa until it reaches the upper pole of the tonsil where it exits into the oropharyngeal cavity. This needle is then replaced with the nylon tube with a button at the closed end. Third needle is inserted above the hyoid bone. This needle goes into the anterior tonsillar pillar. With bimanual palpation the needle is guided into the anterior tonsillar pillar and is pushed until it reaches the junction of the anterior tonsillar pillar with the soft palate. The bevelled edge of the tube is then taken out into the oropharyngeal cavity. The needle is replaced with a button tube (Figure 22). Typically, three tubes form a triangle in the neck with the most anterior needle being the tube for the anterior tonsillar pillar. For tumours extending to the base of the tongue using additional loop or non-looping loops with or without modification or a straight tube can be used to cover that region (Figure 22). Figure 23 shows 3D CT based planning for tonsillar brachytherapy.

Figure 23: Axial, Coronal, sagital and 3D dose distribution for right tonsillar tumour with extension to tonsillolingual sulcus. Please note the additional base of tongue needles for improved coverage.

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8.6 Perioperative Brachytherapy Preoperatively, the surgeon decides jointly with the brachytherapy expert the best surgical approach for tumour resection in the individual case.The possible intraoperative implantation geometry of the target area sometimes needs unusual surgical approaches – this will be discussed. In the course of the operation, the surgeon demonstrates for the brachytherapy expert the subregion(s), where potentially micro-macroscopic residuals are or will be left. Using this target information, the interventional radiotherapy expert performs the implantation of the jointly defined target area to obtain an optimal applicator geometry. The tumour bed is the tissues left behind around the primary tumour and the tissue around the neck nodes with a substantial probability of extracapsular spread. In the oropharyngeal area it is essentially muscle and fat. In the neck, the tumour bed may contain large vessels and nerves, depending upon the location of the enlarged node(s). Most oropharyngeal implants can be undertakenwith button-ended catheters with the entry point in the skin of the neck and the exit point in the oral mucosa beyond the tumour bed. Catheters are usually inserted in the lower neck and then passed upwards into the oropharynx. This allows the neck nodes to be covered (if they need to be treated: multiple N+ or ECS+) and the primary tumour bed with a single set of catheters. If the neck does not need to be treated the entry point will usually follow the submental route. It is advisable to pass the catheters just below the surface of the tumour bed wherever possible at certain intervals (i.e, every 1-1.5 cm). This improves geometry, implant stability and speeds up the procedure avoiding the use of absorbable stitches. When the wound closure involves a huge tissue displacement the catheters are more stable in this way than left just lying in the bed. If there is a flap it will usually interfere with implant placement and therefore brachytherapy needs to be done before the flap (Figure 24). However, if a free flap is used, careful attention needs to be paid to catheters interfering with vascular anastomosis of the flap in the neck. If this is the case, the trajectory and location of all the catheters need to be discussed with the surgeon before catheter placement. In certain locations large or medium sized arterial vessels are part of the CTV and need to be irradiated. It is very important to avoid mechanical trauma from the catheters.This is usually accomplished by placing the catheters alongside the vessels and not perpendicular to them. In addition, it is important to locate hot spots outside the vessels by placing the catheters a couple of millimeters away from the vessel. If this is not possible it is advisable to create a muscle flap or a fat pad 2 to 3 mm thick to be interposed between the vessel wall and a catheter. If this is not possible then haemostatic material (i.e. Surgicel) can be used to create a biological spacer. If vessels are at risk, it is recommended that they are delineated during treatment planning to minimize the dose while keeping if possible, a reasonable CTV coverage. Figure 25 shows the dose distribution for perioperative implantation. The technique of permanent seed implantation for the oropharyngeal cancer is beyond the scope of this chapter.

Figure 24: Tumour bed after resection of a base of tongue tumour. Tumour bed implanted with button-ended catheters. Surgical defect reconstructed with a free flap

Figure 25: Dose distribution of perioperative brachytherapy (Martinez Fernandez et al)

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9. TREATMENT PLANNING

into account all the extensions of the disease and CTV. Hence in a way the planning process is initiated in the operation theatre itself. The details of contouring are given in the target volumes section. It is advisable to also contour the critical structures such as mandible, bilateral parotids, spinal cord, and submandibular glands similar to EBRT. Planning Loading of the sources is based on the contouring of the target. In situations where the target is not drawn the radiation oncologist decides the loading based on the clinical and radiological findings. Basal dose points can be generated as per the Paris system rules and normalization is done. The dose is prescribed on an isodose representing 85% of the mean basal dose rate (mean central dose rate,), calculated in the central plane. However sometimes while prescribing at 85%, the volume of the 150% and 200% isodoses may increase. Hence the prescription isodose is typically decided based on the target coverage, reducing the V150% and V200% to minimum. In the 3D era the prescription at 85% is replaced by a minimal target dose (MTD). Figure 26 shows 3D planning of brachytherapy to the soft palate in the coronal, sagittal and axial planes along with the 3D dose distribution.

CT scan After recovery from general anaesthesia the next step is treatment planning. Three-dimensional computed tomography (3DCT) based planning is recommended. Tubes are numbered and dummy catheters are inserted in each tube. A radiotherapy planning CT scan with 1-5 mm cuts is obtained in the supine position. Overlapping images of 2mm may result in better quality for 3D catheter reconstruction. In the case of smaller tumours thin cuts of 1mm may be taken in the area of interest. After the CT scan each tube in the implant is measured and recorded methodically. Catheter reconstruction Multiplanar reconstruction software is useful for accurate localization of the tubes. Reconstruction can be started from the tip end or connector end. The same should be used for all the tubes. The tip of the tube can be identified by the radiopaque buttons which are placed at the entry and exit of the catheters. Contouring It is advisable that contouring be done by the same oncologist who has done the BT implant. Typically the needle placement takes

Figure 26: Coronal, sagittal, axial and 3D dose distribution for a soft palate implant. Please note the superior-most tube is inserted via lateral-lateral technique just anterior to the mandible, while the other two tubes are inserted as loops.

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With stepping source after loaders and current planning systems there are options of geometric and graphical optimization which can be considered (Figure 27 a and b). Plan evaluation Plan evaluation is done by slice by slice evaluation of the target volume coverage and also with the use of dose volume indices. Typically the coverage index of the GTV init and GTV res , CTV-IR and CTV-HR is evaluated. For evaluation the GTV D98 for the GTV init and GTV res are documented. When the dose is prescribed on the CTV-IR, D98, D90 and D50 of the same are documented. The D2cc doses to critical structures such as mandible, parotid and spinal cord should also be documented. In the situationwhere a target volume is not delineated dose volume parameters related to the implant are documented. This includes V100, V150 and V200 for the implant volume. Quality indices such as Dose Homogeneity Index (DHI) described by (V100-V150)/V100 and Dose non-uniformity ratio (DNR) described by V150/V100 should be used where V100 is the volume in cc receiving 100%of the prescribed dose and V150 is the volume in cc receiving 150% of the prescribed dose.

For PDR brachytherapy total doses of 66Gy with pulse sizes of 50 to 60 cGy per hour is recommended in radical cases.

Boost Brachytherapy The majority of patients are considered for boost BT after 46-50Gy EBRT. In such a scenario a BT dose of 20-30Gy LDR equivalent is recommended. A dose per fraction ranging from3-6Gy per fraction has been used in the literature [36], however the recommended fraction size is 3.0-4.5Gy per fraction. The total dose of HDR ranges between 15-30Gy and depends on the EBRT dose which ranges from 45-60Gy. Typically used fractionation after EBRT of 50Gy is 21Gy/7# (EQD2:22.75, BED:27.3Gy). With PDR a total dose of 15-35 Gy with pulse sizes of 50 to 60 cGy per hour has been recommended for a boost after EBRT of 45-60Gy (30). Recurrent BT For BT to recurrent tumours LDR equivalent doses of 60Gy are recommended. Typical HDR doses are 3-4.5Gy per fraction BID for 10-12 fractions (EQD2:50-55Gy, BED:65Gy). For PDR doses of 54-60Gy with pulse sizes of 50 to 60 cGy per hour are recommended (30). Perioperative BT For perioperative brachytherapy a commonly used fractionation is 32Gy: 4Gy x 8 fractions (EQD2:37Gy, BED:44Gy) when there is an R0 resection and 40Gy: 4Gy x10 fractions (EQD2:47Gy, BED:56Gy) when there is an R1 resection. Postoperative BT For postoperative BT doses of 50Gy LDR equivalent are recommended. Typical HDR fractionations used are 4Gy bid delivering 10-11 fractions.

10. DOSE, DOSE RATE, FRACTIONATION

Radical Brachytherapy For radical BT dose per fraction ranging from 2-6 Gy per fraction ( at reference isodose) has been used in the literature. However recommended fractionation ranges between 3.5-4.5Gy per fraction.[6,36–39] Typically two fractions are given each day with a minimum gap of 6 hours. Minimum doses of 60-66Gy LDR equivalent are recommended. A common fractionation is 52Gy/13# (EQD2:60.67Gy, BED: 72.8Gy) .

Figure 27a: Target volume coverage of a base of tongue primary where the plan is optimized using geometrical optimization

Figure 27b: Target volume coverage of a base of tongue cancer where coverage has been improved using graphical optimization

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treatment is considered while for advanced disease combined chemoradiation is the standard of care. Radiation therapy can be EBRT alone or combined with BT. The role of surgery in oropharyngeal cancers has been controversial due to treatment relatedmorbidity [6]. However with the advent of robotic surgery there is a resurgence in the surgical option for early stage disease [7]. Surgery vs Brachytherapy Brachytherapy results in excellent organ and function preservation when compared to surgery. Levendag et al studied 248 patients who were treated with either brachytherapy or surgery for oropharyngeal cancer T1-3,N0/+[6]. Those who were suitable for BT were considered for EBRT to a dose of 46Gy in 23 fractions followed by BT and unsuitable patients were considered for surgery followed by postoperative RT. The 5 year local control (LC) for both BT and surgery were 88%. The 5 year overall survival (OAS) was 67% for BT vs 57% for surgery. The significant late sequelae in BT vs surgery were ulceration 39% vs 7% (p=0.001) and trismus 1% vs 21% (p=0.005). There was no statistically significant difference in the quality of life scores between the two groups. LDR LDRBT is awell-establishedmodality of treatment for oropharyngeal cancer (Table 3). Lusichini et al reported outcomes of 108 patients treated with LDR BT for oropharyngeal cancers [40]. The LC rates in their series were 85% for T1 and 50% for T2 and 69% for T3. Similar outcomes were also reported in other studies [41,42]. Crook et al observed a dose response relationship with LC of 79% with doses of ≥ 75Gy vs 50% for doses ≤ 70Gy [41]. Puthawala et al treated 70 patients of base of tongue with EBRT and BT [34]. The dose delivered for T1-2 was 20-25Gy and for T3-4 around 30-40Gy after EBRT. One of the largest series of LDR for velotonsillar region is by Pernot et al in which they studied 361 patients [35]. The LC rate was 80% at 5 years in their series. There was a statistically significant difference in the LC rates in patients who had node negative disease (LC=83%) as compared to node positive patients (55%, p=0.002). Similar outcomes were also shown in other studies [43,44]. PDR There is relative lack of data for the use of PDRBT for oropharyngeal cancers (Table 4). Haddad A et al in a case control study compared 36 patients with oral cavity and oropharynx tumours treated with PDR BT with 72 patients treated with LDR BT [45]. The 3 year actuarial locoregional recurrence free survival was 94% for PDR and 97% for LDR. The soft tissue necrosis rates were 19% in PDR and 31% in LDR. The osteoradionecrosis rates were 3% in PDR and 7% in LDR. This suggests that PDR results in similar LC rates as compared to LDR with lower toxicity due to the possibility of dose distribution modulation. One of the largest studies of oropharyngeal BT using PDR BT is by the Rotterdam group[16]. They studied 167 patients with oropharyngeal cancers who were treated with IMRT to a dose of 46Gy followed by PDR BT to a mean total dose of 22Gy delivered in 8 fractions per day at 3 hourly intervals. At a median follow up of 56 months, the 5 year actuarial LC rate was 94%. Five year DFS and OAS were 84% and 74% respectively. They observed grade 3 ulceration in 3% patients requiring hyperbaric oxygen therapy.

Figure 28: Removal of patients treated with non-looping loop technique (Bhadrasain et al)

As majority of the experience in head and neck BT is with LDR, typically dose equivalent of the same are considered while treating with HDR or PDR. Doses may also be documented in terms of EQD2 as in other sites. However in head neck cancers the EQD2 calculations of the radical and boost doses appear much lower and hence should be used very cautiously.

11. MONITORING AND POSTTREATMENT CARE

During treatment dressings should be checked daily. Before each treatment catheters should be checked for possible loosening and movement. Maintaining good oral hygiene is extremely important during the treatment. Patients are advised to use salt soda gargles at frequent intervals. Patients receive feeding via a nasogastric tube and pain medications, steroids in tapering doses and antibiotics as and when necessary. Removal Because of the risk of bleeding catheters should be removed in the operating theatre in the presence of at least two persons. An intravenous line should be secured before the removal. Silk threads which are tied to the closed end are very useful for removal of the implant. The tubes are cut at the open ends in the neck and are pulled through the mouth using the silk threads (Figure 28). If there is any bleeding bimanual compression should be used for 5-10 minutes. In the majority of cases bleeding stops with this procedure. The mouth is cleaned with cold saline gargles and a tight dressing with antiseptic is put on the neck. The patient is advised to take a soft diet after a few hours. Once comfortable with oral feeds the nasogastric tube is removed. The neck dressing is also removed in a day or two depending on the rate of healing. Mucositis develops 1 - 2 weeks after BT.The acute mucosal toxicity is maximal at 3 - 4 weeks, and heals progressively in 5 - 8 weeks. This is managed with mouth care, mouth washes and analgesics.

12. RESULTS

Radical radiotherapy remains the mainstay of treatment of oropharyngeal cancer. For early stage disease single modality