10 General Aspects of Head and Neck Brachytherapy

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SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE HEAD AND NECK 10 General Aspects of Head and Neck Brachytherapy Rafael Martínez-Monge, José Luis Guinot, Christine Haie-Meder

Editors Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

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General Aspects of Head and Neck Brachytherapy Rafael Martínez-Monge, José Luis Guinot, Christine Haie-Meder

1. SUMMARY

4 4 4 6 6 6 7 7 8 8 8 8 8

2. GENERALITIES

3. HEAD AND NECK BRACHYTHERAPY TODAY: AN HISTORICAL PERSPECTIVE

4. TOPOGRAPHY OF THE MAIN BRACHYTHERAPY SITES

4.1 Implantability

4.2 Special anatomical hazards

5. STAGING

5.1 Local and regional assessment

5.2 Metastatic workup

5.3 Non-oncological assessment

6. CLINICAL INDICATIONS OF HN BT

6.1 Brachytherapy alone

6.2 Brachytherapy combined with external irradiation or chemoradiation

6.3 Brachytherapy combined with surgery

10 10 10 10 10 10 10 11 11 12 12 13 13 13 13 13 14 14 14 14 14 14 14 15 15 15 15 15 15 15 16 16 16 16

6.4 Brachytherapy combined with surgery and external irradiation or chemoradiation

7. IMPLANTATION

7.1 Staff

7.2 Techniques and rules

8. PLANNING

8.1 Timing and characteristics of the CT/MRI study

8.2 Target definition

8.3 OAR definition and tissue sparing devices

8.4 Catheter reconstruction

8.5 Dose prescription and dose evaluation

8.6 Dose calculation

8.7 Treatment Recording and Reporting 9. BRACHYTHERAPY MODALITIES

9.1 LDR 9.2 PDR 9.3 HDR

10. BRACHYTHERAPY IN PREVIOUSLY IRRADIATED CASES AND OTHER SPECIAL SCENARIOS

10.1 Types of previously irradiated cases

10.2 Special considerations on dose-volume parameters 11. PATIENT CARE DURING BRACHYTHERAPY

11.1 Nursing control

11.2 Implant check and treatment delivery

11.3 Medication and nutrition

12. IMPLANT REMOVAL

12.1 Safety concerns 12.2 Technique 12.3 Discharge orders

13. FOLLOW-UP 13.1 Schedule

13.2 Basic follow-up assessment 13.3 The follow-up team

14. KEY MESSAGES 15. REFERENCES

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1. SUMMARY

Brachytherapy alone or combined with other treatment modalities is a highly selective treatment option in the management of squamous cell tumors head and neck region. The physical properties of the radioactive sources provide an advantageous conformation of the clinical target volume (Treated Volume) compared to other radiation techniques due to the rapid dose fall-off into the surrounding normal tissues. PDR and HDR brachytherapy with stepping sources and CT-based planning have replaced LDR brachytherapy as the new standard of care although the implantation and planning rules generated during the LDR era must be used as a reference. Brachytherapy alone yields local control rates above 90% in a) T1 and small T2 tumours with low risk of node involvement arising in areas of functional or cosmetic importance as well as in b) selected advanced lip tumors. Brachytherapy alone should also be considered under c) medical contraindication for radical surgery or in cases of d) small lesions arising in previously irradiated areas. Combined EBRT and brachytherapy yields local control rates in excess of 80% in patients e) unfit for surgery with cT1-2N0 tumors that require node irradiation or in f) advanced T3-4 and/or N + tumors that would require resections with functional or cosmetic impact or in g) patients who may require high radiation doses that are precluded by the proximity to dose-sensitive structures. Adjuvant brachytherapy can also be used after surgery in h) accesible lesions if the surgical pathology reveals that the neck is negative and that there is an indication for postoperative irradiation of the primary tumor bed. Similarly, adjuvant brachytherapy can be used in combination with external chemoirradiation for i) dose escalation in well-defined areas of the surgical bed such as those with positive margins or extracapsular spread.

2. GENERALITIES

(ACR), initiated practice guidelines aimed to normalize clinical indications and treatment parameters.The gradual implementation of these recommendations into routine clinical practice will probably allow in the near future the integration of standardized brachytherapy treatments intomultidisciplinary clinical trials. [1,2]

Scope Head and Neck Cancer Brachytherapy (HN BT) refers to the use of radioactive implants, alone or combined with other treatment modalities, in the management of squamous cell tumors and their variants arising in lip, oral cavity, oropharynx, nasopharynx, larynx and hypopharynx as well as cervical lymph nodes metastases of cutaneous or unknown origin. Proof of Concept Brachytherapy remains an important treatment option in the armamentarium of the radiation oncologist treating head and neck cancer. The physical properties of the radioactive sources provide an unparalleled conformation of the clinical target volume (TreatedVolume) due to the rapid dose fall-off into the surrounding normal tissues (Figure 1). Unlike other anatomical areas, HN BT is extremely demanding due to the number and importance of the normal tissue structures that constrain accessibility and dose delivery. Evidence Practice guidelines usually categorize the recommendations for HN BT as NCCN 2A (there is uniform consensus based on low levels of evidence including clinical experience, that the recommendation is appropriate) or NCCN 2B (there is no uniform consensus -even though no important disagreement- about the appropriateness of the recommendation). The scientific evidence that supports HNBT is limited because the majority of the published data has been produced at single expert institutions. This carries the disadvantage of limited sample size and reproducibility and makes difficult a cross-comparison of results between centers as well as the implementation of standards of treatment. During the 1990s, several scientific societies like the American Brachytherapy Society (ABS), the Groupe Européen de Curiethérapie of the European Society for Radiotherapy and Oncology (GEC-ESTRO) and the American College of Radiology

3. HEAD AND NECK BRACHYTHERAPY TODAY: AN HISTORICAL PERSPECTIVE

HNBT emerged as a formidable oncological solution in the middle part of the XXth century. In an era of non-functional head and neck surgery and rudimentary external beam irradiation (EBRT), HN BT soon became a main player in the HN arena. HN BT proved effective andmuch less traumatic than other treatment options. In addition, patients unsuitable for radical surgery could still benefit from HN BT due to a shorter anesthetic time, a less problematic post-procedure status and a faster recovery after treatment. The implementation of technical developments such as 192 Ir hairpins and afterloading catheters facilitated the implementation of HNBT that was incorporated into the armamentarium of both radiation oncology and surgical teams. In addition, the design of systems that directed the source geometry placement and dose calculation such as the Paris [3] andManchester systems notably strengthened the quality of the treatment in an era without computer aids. In the last quarter of the XXth century, the developments in anesthesia, surgical resection with immediate reconstruction and postoperative care began to widen the indications for functional surgery and increased the number of patients considered to be good surgical candidates. As a result, surgery and HN BT started to compete for the same case load. The complete pathological information derived from a comprehensive surgical procedure was rapidly acknowledged as the main source of information in an era of otherwise limited medical imaging. Hence, HN BT was progressively relegated as a treatment of frail patients and poor surgical candidates. On the other hand, the development in EBRT with the implementation of 3D treatment planning

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Fig 1. Typical CTV of a pT2N0 squamous cell carcinoma of the left border of the tongue treated with a wide excision and found to be candidate for postoperative irradiation due to close surgical margins. Left image: typical double-plane 192 Ir HDR implant with 8 afterloading catheters covers the CTV with the 150% (white), 100% (red), 50% (yellow) and 25% (blue) isodose lines. Right image: Volumetric Arc Radiation Therapy (V-MAT) with the 100%, 50% and 25% isodose lines using the same color panel as in the former case (Prepared by Haizea Etxebarria, RTT & Dosimetrist, University of Navarre).

Fig 2. Anatomy of the Oral Cavity. Taken from http://anatomymedicalook.com

Fig 3. Sagittal View of the Anatomy of the Oral Cavity and Oropharynx. Taken from http:// anatomymedicalook.com

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systems (TPS) during the 1990´s allowed to generate and deliver more conformal treatment plans in anatomical areas where HN BT was more technically demanding and hazardous such as the oropharynx. The widespread availability of 3DCRT prompted a decrease in the use of HN BT in traditional locations such as base of the tongue, tonsil, soft palate, etc. As a result, former active HN BT schools disappeared or were reduced to a minimum and more importantly, the number of HN BT experts gradually decreased, leaving HN BT teaching at risk. However, the decline inHNBT during the late 90´s has been halted to some extent with the implementation of the brachytherapy 3D TPS and the replacement of the former LDR technology by modern stepping source PDR or HDR equipment. In spite of this, HN BT is today an endangered species and needs to find its place in the world of multidisciplinary oncology. Awareness of strengths and weaknesses is essential. Return to the old days of performing HN BT procedures based solely on clinical grounds with limited imaging workup is no longer possible. Modern HN BT should adopt the quality standards required by other state-of-the-art radiation oncology specialities. Optimal case selection is mandatory and requires accurate determination of the gross extension of the tumor through comprehensive clinico-radiological workup in cases primarily managed with brachytherapy alone or combined with EBRT. In those cases treated in combination with surgery, optimal case selection requires complete surgicopathological information. Finally, HN BT lacks the necessary standards in CTV definition, dose prescription and OAR constraints that are mandatory in modern brachytherapy. It must be recognized, however, that the heterogeneity and complexity of HN BT in terms of distinct anatomical scenarios, diverse implantation and brachytherapy techniques surely represent an obstacle towards the required uniformity. However, further progress in HN BT requires the development of a common methodology similar to that already implemented by different groups of experts in other brachytherapy specialities (i.e, gynaecological or breast brachytherapy).

of the desired location. Buttons at the entry and exit points are required in most locations to avoid catheter displacement.

4.1.2. Oropharynx Anatomical Description

The oropharynx follows the oral cavity, extending from the plane of the hard palate to the hyoid bone (Figure 3). The oropharynx includes the faucial arch (soft palate, uvula, tonsils and anterior and posterior pillars of the tonsils), the base of tongue, and the pharyngeal walls [4]. Accessibility Many oropharyngeal locations are implantable. The degree of technical expertise ranges fromhigh to very high. Oropharyngeal locations are usually accessed through the posterior submental route close to the mandibular angle in a way similar to the oral cavity sites although the degree of maneuverability is limited. Buttons at the entry and exit points are required inmost locations to avoid catheter displacement. Neck locations usually refer to the implantation of lymph node metastases from head and neck sites present in the nodal groups Ib to V. Neck lymph node metastases fromother sites draining into the neck such as the skin of the head and face are usually included within this disease category. The vascular and neural networks of the neck can be seen in figure 4. Accessibility Nowadays most neck implants are performed after surgical resection, and therefore, there are no anatomical limitations to the placement of brachytherapy catheters into the surgical bed. Catheters are usually placed along the neck structures using single- leader tubes but can also be placed across the neck structures using button-ended tubes. Lesions adjacent tomajor vessels carry the risk of vascular damage. This can occur during implantation or at removal (procedural damage) ormonths to years after the implant (late radiation damage). Procedural vascular damage should always be kept in mind when dealing with posterior and lateral lesions located close to the carotid artery and its branches, especially the lingual arteries. In closed-cavity implants (i.e, intact tumors or postoperative implants) anatomical references or palpation may help to determine the location of the carotid artery. Doppler US can be sometimes used. In open-cavity implants (i.e, intraoperatively placed catheters), the vessels are visible and direct damage is unlikely. In these cases, placement of catheters directly over the vessels must be avoided to minimize the risk of mechanical trauma resulting fromprolonged catheter stay. Although the risk of procedural vascular damage is low (1-2%)[5], implants close to large vascular structures must be placed and removed with a surgical teamon-call. Airway protection with a temporary tracheostomy may be necessary. 4.1.3. Neck Anatomical Description 4.2. Special Anatomical Hazards 4.2.1. Vascular Damage

4. TOPOGRAPHY OF THE MAIN BRACHYTHERAPY SITES

4.1. Implantability 4.1.1. Oral Cavity Anatomical Description

The oral cavity begins at the lips (vermilion border) and ends at a virtual plane defined by the soft palate, the anterior pillar of the tonsil, and the posterior limit of the mobile tongue (Figure 2). The oral cavity includes the posterior part of the lips and the commissure, the floor of mouth, the mobile tongue, the buccal mucosa, and the alveolar ridges [4]. Accessibility The vast majority of tumors of the oral cavity are implantable. The degree of technical expertise required ranges from low tomoderate. Lip locations are implanted through the adjacent normal mucosa or skin with entry and exit points lateral to the lesion. Oral cavity locations are usually implanted through the submental route with entry points in the submental skin and exit points at the surface

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damage can be minimized with preimplantion dental care, proper case selection, adequate implant technique, intensive treatment planning with appropriate optimization [7] and bone shielding during treatment (Figure 10). Tumors invading bone tissue are usually advanced cases not suitable for brachytherapy alone or combined with EBRT. However, smaller lesions adjacent to the bone can be treated with brachytherapy provided that there is a minimal space of a few millimeters between the CTV and the cortical bone. In lesions closer to the bone, the general rule is that no more than 2 catheters should be placed in contact with the mandible. Alternative options in case of closer proximity to the mandible include narrowing the catheter interspacing to minimize high dose regions extending into the cortical bone tissue. This is especially important in bones with a high mechanical stress such as the mandible, namely in the area adjacent to the mandibular angle.

Fig 4. Neurovascular anatomy of the neck. Taken from http://pinterest.com

5. STAGING

Radiation vascular damage can be minimized by using a shorter intercatheter distance in the area of the CTV occupied by the vessels and by placing the catheters alongside the vessels rather than directly over the vessels. This allows to decrease the volume of the high-dose region as well as to displace the high-dose regions (V 150 ) towards less vulnerable areas, such as those that have not been surgically dissected. Vessel stumps are more vulnerable than intact vessels to high-dose irradiation and should be identified at implantation and during dosimetry [6]. If catheters need to be placed on the vessels, a narrow sheet (1-2 mm) of biodegradable material or tissue (i.e, fat, muscle, etc.) should be interposed to avoid vessel wall exposure to very high dose regions (V 200 ). 4.2.2. Bone Damage Lesions adjacent to themandible carry the risk of osteoradionecrosis (Figure 5). In addition, bone absorption of the 192 Ir photons is much higher due to the predominance of the photoelectric effect at low radiatiion energies that is proportional to the atomic number (Z 3 ) instead of Compton or Pair production that is the most frequent absorption mechanism at high radiation energies such as megavoltage EBRT. Bone damage in other head and neck sites treatedwith brachytherapy such as the upper maxilla, hard palate, etc. is infrequent. Bone

5.1. Local and Regional assessment 5.1.1. Local

A thorough ENT examination is crucial to determine which tumors are suitable candidates for HN BT. In general, good candidates for brachytherapy in the head and neck area are not essentially different from ideal candidates in other anatomical sites. Unifocal, well-defined lesions of ≤ 3cm of diameter that are technically implantable and without fixation to neurovascular structures or bone should be considered. Direct assessment with bimanual palpation and with inspection is crucial in all accessible lesions. ENT endoscopy is necessary for the examination of the naso-, oro- and hypopharyngeal structures that cannot be done through direct vision as well as to rule out multifocality and/or second primary tumours. In case the tumour is treated with a combination of EBRT and brachytherapy, the tumour limits may be tattooed or indicated by clips. Finally, clinical palpation and visual findings requires a comprehensive interpretation with CT or MRI imaging that may better delineate the full extension of the GTV in most head and neck sites. MRI is more sensitive at detecting muscle infiltration and at showing invasion of the medullary space of the mandible and tumour spread along the inferior alveolar nerve.

Fig 5. Osteoradionecrosis of the left mandible. Oral view (left); Bone fragment removed (middle); X-ray (right). Courtesy Prof.D.Peiffert.

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5.1.2. Regional Nodal status should be determined in all cases. Clinical examination and CT/MRI imaging is helpful in classifying patients into a group of clinically-negative (cN0) and clinically-positive necks (cN+). Since the predictive ability of clinical-radiological assessment is limited, the majority of cN0 patients with deeply invasive lesions will require a surgical assessment of nodal status. A few cN0 cases may be spared froma surgical exploration if the tumor is superficial (i.e, invasion beyond the lamina propria of 2mm or less) or if the probability of nodal spread calculated as a function of location, size and grade is minimal (i.e, <5%).

be evaluated by an experienced anesthesiologist in the clearance visit prior to implantation. Precautions to maintain the patency of the airway in case of bleeding at insertion, at removal or due to postimplant edema are mandatory. Since most implants are performed under general anesthesia in an anesthesiologist-controlled scenario, bleeding during catheter insertion should rarely compromise the airway. However, extensive implants located in the posterior oral cavity or the oropharynx can cause life-threatening edema and bleeding during the postimplant period or at removal and precautionary measures such as a temporary tracheostomymay be required. Some radiation oncologists use an individual silk thread tied to each of the catheters implanted and secured with tape at the patient´s lip commissure to facilitate implant removal in case of emergency. 6.1. Brachytherapy alone Brachytherapy alone remains an acceptable mode of treatment in a) intact T1 and small T2 tumours with low risk of lymph node involvement that are located in areas of functional importance (lip, commisure, vestibulumnasi ,etc.) or b) cosmetic relevance such as the periorificial zone (eyelids, pinna, ears, etc.). Ninety percent of the cases described above are locally controlled after LDR/PDR doses of 60–70 Gy with hourly doses in the 0.4–0.7 Gy range [9] . These results underline the similar efficacy of brachytherapy compared to surgery in node-negative T1-T2 cancers. In addition, c) exclusive HN BT can also be a reasonable option for advanced lip tumors. Brachytherapy alone should also be considered when there exists a d) medical contraindication for radical surgery or e) in cases of small lesions (< 3cm) arising in a previously irradiated field with dose and volume adjustments aimed to minimize potential complications derived from cumulative dose. The combination of EBRT or chemoradiation and brachytherapy for HN tumors follows the same principles applied in other tumor sites treated with combined modality therapy such as advanced cervical cancer. Brachytherapy is used as a boost one or two 2 weeks after the completion of EBRT or cisplatin-based chemoradiation. If brachytherapy is used as a boost, the overall treatment time should be kept similar to that elapsed with external irradiation alone (preferrably within 7 weeks). Combined EBRT and brachytherapy is an acceptable mode of treatment in a) patients unsuitable for surgery with intact clinical T1-2N0 tumors that present a substantial risk of lymph node involvement or in b) advanced T3-4 and/or N+ tumors that would require surgical resections with functional or cosmetic impact (i.e. cheek, base of tongue, etc.) provided that the residual lesion after EBRT is accessible and can be adequately covered with a HN BT implant. Combined EBRT and brachytherapy may also be a reasonable treatment option in c) patients who may require high radiation doses that are precluded by the proximity of the lesion to dose-sensitive structures such as the swallowing apparatus [10]. In these later cases, a benefit of a brachytherapy boost over an EBRT 6.2.BrachytherapycombinedwithExternal Irradiation or Chemoradiation 6. CLINICAL INDICATIONS OF HN BT

5.2. Metastatic workup 5.2.1. Baseline assessment

Most tumors considered for HNBT alone (cT1, 2-N0) will require at least a chest CT to rule out lung metastases or a second cancer. Patients withmore advanced disease (cT3, 4 and/or N+) in whom HN BT is being considered as a boost after EBRT or patients with recurrent lesions may require a more extensive workup including FDG-PET/CT.

5.3. Non-oncological assessment 5.3.1. Dental care

An evaluation of oral hygiene and dental status should always be made by a odontologist well trained in head and neck oncology. Mandibular panoramic radiographs or CT are indicated and provide information about the height and the structure of the mandible as well as radiographic evidence of bone destruction [8]. Teeth with caries should be restored. Teeth with deep caries or poor periodontal support must be removed and complete healing obtained before starting radiotherapy, although this would require at least two weeks and must be counterbalanced with the oncological status of the patient. 5.3.2. Nutritional assessment An evaluation of the patient nutritional status needs to be made by a nutritionist before HN BT as in any other head and neck patient that is being evaluated to receive irradiation. Some patients may have a recent history of weight loss induced by tumor-related dysphagia. In the most severe cases, a high calorie hypercaloric diet, dietary supplements and hyperhydration must be done before brachytherapy. Parenteral feeding may be an option in severe cases of malnourishment. In average cases, care must be taken in scheduling an adequate oral/feeding tube intake during the duration of brachytherapy and during the subsequent weeks until the swallowing function returns to normal. Percutaneous gastrostomy may be an option to allow outpatient management in patients who do not tolerate feeding tubes and in whom return to adequate oral intake is presumably long. 5.3.3. Airway assessment and protection As mentioned before, HNBT requires a preimplantation evaluation of the status of the airway due to anesthetic needs, risk of hemorrhage during catheter insertion or at removal and risk of postimplant edema leading to impaired ventilation. Most implants in the head and neck area benefit fromnasotracheal intubation because traditional orotracheal intubation, although manageable, may limit maneuverability within the oral cavity and the oropharynx. If this is the case, nasotracheal intubation must

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Fig 6. Three pairs of non-looping loops after removal.

Fig 7. (A) Contrast-enhanced MRI showing the recurrent lesion (arrows); (B) Customized mold. Note the curvature of the catheters in the surface of the intracavitary extent of the mold; and (C) Axial CT scan showing the intraoral mold in place with the prescription isodose of 4 Gy (blue) covering most of the ggross tumor volume (outlined in red). Taken from Ciérvide et al [13].

Fig 8. Six free-hand catheters implanted after a resection of a T2N0 squamous cell carcinoma of the leftborderof the tongue.Cathetersenter the tumorbed through theskinof the ipsilateralneck.The tipof thecathetersendat5 to10mmover the tonguesurface toavoidunderdosageof the tumorbed.

Fig 9. An implant with 8 rigid needles and templates in a big lip carcinoma, shows a dosimetry with very high homogeneity. High doses per fraction can be used.

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boost derived from a better dose distribution has been described (figure 1) [11]. Finally, combined EBRT and brachytherapy may also be used in d) patients with tumors with a poor regression after EBRT and in whom dose escalation is advisable and in e) patients with lesions subjected to position uncertainty in spite of restraint devices (i.e, anterior tongue). Local control rates in excess of 80% are commonly reported in different tumor sites treated with a standard combination of 45- 50 Gy of EBRT and 15-20 Gy of LDR brachytherapy (or PDR/ HDR equivalent). 6.3. Brachytherapy combined with surgery Exclusive brachytherapy can be used after surgery when there is a well-delineated and accessible CTV. Oral cavity tumor stages cT1, cT2, N0 that are managed primarily with surgery can be treated with adjuvant brachytherapy alone if the surgical pathology reveals that the neck is negative and that there is indication for postoperative irradiation of the primary tumor bed due to close or positive margins, lymphovascular space involvement or perineural invasion. Implant can be performed postoperatively, 4 to 6 weeks after surgery (postoperative brachytherapy) once the patient has recovered from the surgical procedure or intraoperatively (perioperative brachytherapy) in those cases in which the need for adjuvant treatment is presumed due to the characteristics of the tumor. Brachytherapy can be used as a boost in patients selected for combined treatment with surgery and external irradiation or chemoradiation.The areas selected for brachytherapy boost should be those with a higher probability of residual disease such as the tumor bed (close or positive surgical margins) and large metastatic nodes (extracapsular spread). Unirradiated local or regional recurrences can also be treated through this treatment approach. The treatment sequence may be quite variable but in general, it is preferable to performHNBT at the time of surgery in patients who require neck brachytherapy because neck implantation is easier when performed intraoperatively rather than postoperatively. Hence, if surgery is performed first and the neck needs to be implanted, HN BT boost can be done perioperatively followed by external irradiation or chemoradiation postoperatively. However, if external irradiation or chemoradiation is done first and surgery is planned for residual disease (i.e, large metastatic neck nodes), HN BT should be postponed until surgical resection is planned. 6.4. Brachytherapy combined with Surgery and External Irradiation or Chemoradiation

some difficult oropharyngeal locations, the assistance of the ENT surgeon may be required. In all cases, an ENT surgeon should be on-call during implantation and at removal. The medical team is completed by specialized anesthesiology, radiation oncology and in-patient nursing staff to take care of the patient while in the recovery room, in the radiation facility or during hospital stay. 7.2. Techniques and rules Interstitial brachytherapy using the submental route is the most frequently used technique in patients treated with afterloading techniques.The submental approach allows access to the oral cavity and the oropharynx. In general, HN BT area is usually delivered through fixed applicators (plastic tubes or steel needles) inserted with amargin of 5–10mmaround the CTV. Former techniques that involved the use of loops have been gradually replaced by variants of the loop technique such as the non-looping loop technique [12] than can be seen in figure 6. Permanent implants are only rarely used in this setting and will not be discussed here. Other techniques used for afterloading include intraoral mold brachytherapy, perioperative mold brachytherapy and hand-free perioperative brachytherapy. In mold brachytherapy, the implant is built into a mold (figure 7) that is placed intraorally onto shallow lesions arising in non-mobile areas such as the hard palate or the gum [13]. In perioperative mold brachytherapy, custom-made molds are placed in the surgical bed to deliver perioperative brachytherapy such as in the AMORE protocol for advanced and recurrent non- orbital rhabdomyosarcoma of the head and neck. In perioperative brachytherapy, free-hand catheters are placed through the skin into the tumor bed at the time of surgery (Figure 8). We recommend that catheter geometry and intercatheter distance according to specific rules belonging to a system should be always kept in mind at the time of implantation. Although the use of modern TPS has reduced the need for rigid geometrical rules that cannot always be applied in HNBT due to anatomical constraints, it is always wise to followwhen possible reproducible implantation and dosimetric rules with proven results over decades such as those of the Paris system [3]. (Figure 9) 8.1. Timing and characteristics of the CT/MRI study CT planning should be done in all cases. In patients in whom severe CT artifacts are produced by the presence of reconstruction plates, teeth implants, etc. a return to the old orthogonal film techniquemay be the only option to obtain a reasonable dosimetry. Nowadays, we also have the possibility to perform a MRI which can be helpful to delineate the tumor limits and can be fused with CT images.The CT study should be done as soon as possible once the patient is stable and ready for transportation. There is no reason to delay the CT due to the risk of infection andmechanical trauma associated with the implant. A CT scan slice thickness of 3 to 5 mm is adequate in most cases. Intravenous contrast is useful in defining the vascular structures and should be used whenever possible, especially in lesions recurrent after prior irradiation. 8. PLANNING

7. IMPLANTATION

7.1. Staff HN BT should be performed by an experienced Radiation Oncologist with advanced brachytherapy skills assisted by an anesthesiologist. Although local anesthesia or local anesthesia with sedation can be used in some cases, general anesthesia usually provides the level of comfort and safety required by the patient and the medical staff during HN BT. The radiation oncologist should perform HN BT with at least one assistant although in

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8.2. Target Definition The Gross Tumor Volume (GTV) is the visible or palpable primary tumor volume (GTV-T) ormetastatic lymph nodes (GTV-N) defined at diagnosis by clinical examination and imaging techniques. The GTV should be precisely recorded, especially if external beam irradiation or chemoradiation is delivered before brachytherapy. Placement of radioopaque markers (e.g. clips, seeds, etc.) or tattoos can be very helpful in delineating the tumor volume before any shrinkage occurs. Gold seeds also aid in subsequent external irradiation if image-guided radiation therapy (IGRT) is used. The Clinical Target Volume (CTV) is the tissue volume presumed to containmicroscopic disease at a certain probability level.There is always a CTV around each of the GTVs (generated by asymmetrical expansion of 5-10 mm) and as many CTVs as areas felt to contain microscopic disease. In the postop setting, tumor bed clips are very useful in defining the post-resection CTV corresponding to the tumor bed. The ABS [1,14] and the GEC-ESTRO [2,15] guidelines do not detail specific CTV definition rules applicable to different disease scenarios such as the CTV definition for tumors treated with Brachytherapy alone (Section 6.1.), CTV definition for tumors treated with HN BT after External irradiation or chemoradiation (Section 6.2.) or CTV definition for tumors treated with surgery and adjuvant HN BT (Sections 6.3. and 6.4.). The Planning Treatment Volume (PTV) is the margin provided around the CTV to account for organ motion and setup errors that guarantees that the CTV actually receives the prescribed dose. It has traditionally assumed that in HN BT the effect of organ motion and setup errors is negligible and, therefore, that a PTV is unnecessary [2]. Due to the lack of recommendations for target definition, the leading Brachytherapy Societies should create a task force aimed to produce target definition guidelines for tumors treated with HN BT alone (Section 6.1.), tumors treated treated with HN BT after External irradiation or chemoradiation (Section 6.2.) or tumors treated with surgery and adjuvant HN BT (Sections 6.3. and 6.4.). It is important to note that the adaptative target definition concept should be considered in the HN BT boosting after external irradiation/chemoradiation in a similar way to that used in gynaecological brachytherapy. 8.3. OAR definition and Tissue Sparing Devices Standardized Organ at Risk (OAR) dose–volume constraints in HN brachytherapy are lacking. It is wise, however, to keep the dose in bone, nerves, vessels and other dose-limiting organs as low as possible provided that the CTV coverage is adequate. Adoption of OAR constraints used for other highly conformal radiation techniques such as IMRT or V-MAT is a prudent alternative in the absence of HN BT-specific OAR constraints. The spinal cord should be contoured in all the cases. Although the spinal cord will receive very low doses from the HN BT implant, this may be sometimes used in the management of locally recurrent tumors after prior irradiation in whom the spinal cord tolerance has already been reached during the first course of irradiation. The mandible should be contoured to evaluate and minimize the risk of osteonecrosis, especially in implants adjacent to the jaw or in patients with recurrent disease after prior irradiation. A prosthesis including lead shielding should be made when brachytherapy of

Fig 10. A custom-designed dental shield lined with lead. A dental cast is used to make the shield. Courtesy Prof.D.Peiffert.

Fig11.3DPlanningofaperioperativeHDRbrachytherapyafterresectionofapreviously irradiated, recurrent squamous cell cancer of the left border of the tongue with level Ib positive nodes. Structures delineated include mandible (orange), carotid artery (green) and spinal cord (yellow). CTV-T (magenta) is delineated by the 100% isodose line of 4Gy (traslucid green) produced by 9 afterloading catheters.

Fig 12. DVH Planning of a perioperative HDR brachytherapy after resection of a previously irradiated, recurrent squamous cell cancer of the left border of the tongue with level Ib positive nodes. Structures delineated include mandible (orange), carotid artery (green) and spinal cord (yellow). CTV-T (magenta) and CTV-N (red).

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8.5. Dose Prescription and Dose Evaluation The different steps involved in dose prescription and dose evaluation should be always carried out in a Dose Volume Histogram scenario with careful attention to small details; this includes a triple assessment of the dose to the CTV, doses at OARs and dose inhomogeneity. The prescription dose is usually the minimumdose received by the CTV or a CTV surrogate (i.e., the D 90 ≥ 100%, V 100 ≥ 90%) and the total dose administered will depend on the clinical indication of HN BT (Section 6). The former LDR 192 Ir-wire schedules remain the reference standard because most clinical data on HN BT was produced with that methodology and technology. Therefore, the current fractionation PDR and HDR schedules should aim to be to be at least biologically equivalent to the reference LDR programs. The LQ (Linear-Quadratic) model with an α/β ratio of 10 Gy and a repair half-time of 1.5 h can be used to calculate equi-effective doses of different fractionation schedules [15]. The EQD2 concept that is used to normalize any given fractionation to 2-Gy equi-effective doses should always be used with caution in brachytherapy because the calculation does not take into account the time effect on repopulation and the implications that this may have in extremely short treatment schedules. As a result, EQD2 calculations for HNBT schedules result in rather low values (i.e, 32 Gy in bifractionated 8 x 4 Gy in 4 days yields an EQD2 of 37.3Gy) as compared to classical fractionation where 66Gy results in the same EQD2 of 66Gy. However, the clinical results produced are much better than the predicted by such low EQD2 values and are comparable with data obtained from accelerated external beam radiation schedules. For instance, the CHART schedule of 54Gy in 36 fractions of 1.5Gy delivered over 10 days is clinically equivalent to a normofractionated regimen of 66 Gy in 6.5 weeks [17] in spite of a calculated EQD2 of only 51.7 Gy. Similarly, the EORTC acceleration study showed a 13% local control advantage (p=0.02) with accelerated 72 Gy in 5 weeks (EQD2 of 69.6Gy) compared to 70 Gy delivered with standard fractionation (EQD2 of 70Gy) [18]. Also the data from Dobrowski [19] of 55.3Gy in 33 fractions of 1.67Gy (EQD2 =53.7Gy) in are in line with the above data showing that accelerated radiotherapy produces equivalent results with lower EQD2 values. In addition to the time-effect limitation, the EQD2 formalismdoes not incorporate inhomogeneity indices, and therefore, the calculated dose values underestimate the clinical biological effect [20]. The impact of inhomogeneities can be calculated by complex dose integrating formulas such as EUD calculations [21] or by simpler dose inhomogeneity surrogate indices as DNR (=V 150 /V 100 ) or other relevant indices. Finally the higher RBE attributed to lower energy irradiation (1,3-fold for 192 Ir) should also be taken into account to explain the low EQD2 values related to short BT regimens. Efforts should be made to develop an EQD2 adapted formalism that incorporate these crucial parameters into the model to improve comparability with external beam schedules. As long as such comprehensive model is not available, we recommend despite the well recognized shortcomings nevertheless to record and report physical doses as well as EQD2 values to allow for comparison between the effects of different dose rates and fraction sizes since this is the currently major accepted model. During dose evaluation, the inhomogeneities need to be minimized following general rules such as those derived from the Paris system [3] with additional optimization if needed, mainly by geometrical

the lips, the mobile tongue, and the floor of mouth, is planned, to reduce the dose to the mandible and prevent osteoradionecrosis [15].This shielding system is made of 2mm thick lead encompassed by plastic protection (figure 10). It must be taken into account that dose absorption in the bone is proportional to the atomic number (Z 3 ) which is until now included in the TG 43 formalism. The Erlangen group has shown an increased risk for osteoradionecrosis using PDR brachytherapy for a Prescription Dose greater than 64.2 cGy/pulse (p = 0.028) and a High Dose greater than 80.3 cGy/ pulse (p = 0.037)[16]. The carotid vessels should be contoured if the implant has been placed very close to the vessel wall (i.e, neck implant) as well as in patients who have been previously irradiated, due to the risk of vessel rupture.The preimplant CT/MRI as well as the atherosclerotic plaques (if present) are helpful in defining the location of the carotid artery and its main branches. The use of intravenous contrast is obviously preferable for vessel definition but may not be feasible in the immediate post-implant or postoperative period. The definition of other organs such as the parotid glands, hard palate, lens, swallowing muscles, eyes, etc. depends on the location of the implant and the special characteristics of the patient. Due to the paucity of data relating dosimetric parameters and toxicity it is important that the leading Brachytherapy societies issue guidelines to create a panel of normal tissues to be contoured in all head and neck cases. This information can be shared among treatment groups to generate dose volume constraints. For instance, the Rotterdam group1 described doses to the 5 main swallowing muscular groups (SCM, MCM, ICM, CPM, OI) and found that the mean dose to the SCM and MCM correlated with dysphagia in a group of patients treated with HN Boost or IMRT boost. The HN BT subset had a lower rate of dysphagia derived from a lower dose (that was a consequence of smaller volumes). Figures 11 and 12 describe the 3D view and DVH obtained with modern TPS. 8.4. Catheter Reconstruction Catheter reconstruction is an important step in the planning process of HN BT. Catheters must be well visible in the image set and need to be distinguished from other foreign objects such as clips, seeds, drains, etc. Depending on the catheter manufacturer, these may appear as low or high-signal linear structures. The use of thin metal wires to enhance the visibility of plastic catheters is rarely required nowadays buymay be a practical solution in difficult cases. A CT slice thickness of 0.2–0.3 cm (in small tumors 0.1 cm) should be adequate to accurately reconstruct each individual catheter. Numbering of catheters in the treatment planning system must always be done following a diagram or a picture of the numbering of the actually implanted catheters. Numbered buttons at the catheter entry site are the most practical and reliable way to avoid confusion. Institutional standards in the numbering of the catheters (i.e, numbering left to right referenced to the hands of the operator manipulating the implant, lower row first, upper row last, etc. ) may help to minimize treatment misadministration.

- 1In lovingmemoryofProfessorPeterLevendagwhopassedawayduring thewritingof thischapter.

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and graphical methods [7] which is possible in stepping source systems. A cautionary measure is to keep the hyperdose sleeves (200% isodose volumes) as thin as possible and not confluent with other 200%hyperdose sleeves [3]. Dose Non-uniformity Ratio (DNR = V 150 /V 100 ) should be equal to or lower than 0.36 [22]. However, optimal DNR values may not always be obtained in HN BT due to the anatomical constraints of the HN area that reduce the number of catheters implanted compared with other disease sites such as breast, prostate or soft tissue sarcomas. All these limitations may lead to an inadequate geometry with DNR values in the 0.35 - 0.50 range that can be acceptable in small CTVs but not in large volumes. The University of Navarra group showed that Grade ≥3 and ≥4 complications increased with TV 150 values of 13cm 3 or greater (p = 0.032) in a series of patients treated with PHDRB. No specific constraints could be obtained for the different OARs analyzed. The Erlangen group showed a correlation between soft tissue necrosis and V85 (tissue volume encompassed by the 85% isodose line) [16]. Dose through the skin should be avoided if possible - except when using surface molds or tumors with skin involvement [2]. Although clear surrogates of OAR damage are lacking in HN BT, it is reasonable to keep the dose in the neighbouring dose-limiting organs as low as possible. Adoption of OAR constraints used for HN IMRT or V-MAT is a prudent alternative in the absence of HN BT-specific OAR constraints (Section 8.4). 8.6. Dose Calculation The dose calculation in brachytherapy is typically performed using the TG-43 formalism [24]. Nevertheless, this highly standardized dose calculation method does not take into account tissue inhomogeneities or finite patient dimensions. Since a few years model-based dose calculation algorithms became commercially available in brachytherapy [25]. So far it seems that for head and neck HDR techniques the impact of the dose calculation algorithm on dose distributions of the CTV is limited [26]. 8.7. Treatment Recording and Reporting The ICRU report No. 58 [27] describes general recommendations for reporting interstitial therapy. This report substitutes the basal dose from the Paris system by the mean central dose (MCD) while the reference dose of the Paris system (85% of the basal dose) is substituted by the minimal target dose (MTD) that does not necessarily matches with the reference isodose from the Paris System. In the absence of more-specific recommendations, these general concepts could be followed in HN BT: a. To describe the clinical volumes, such as the size of the GTV and CTV and the criteria used in their definition. b. To describe the technique used for implantation. c. To specify the source (or sources used) in HN BT including the RAKR (Reference Air Kerma Rate) and TRAK (Total Reference Air Kerma). d. To describe the time-dose pattern. e. To describe the clinically meaningful dose coverage indices such as the CTV D 100 , D 98 , D 90 ,… (Minimal dose received by at least 100%, 98%,90% of the CTV, etc.). The CTVD 90 has become of particular relevance in different brachytherapy sites such as prostate and cervical cancer and should be used as the reference standardwhen reporting brachytherapy doses.The reporter should give preference to those parameters that have been consistently related with clinical outcomes.

f. To describe the OARs, including size and criteria used in their delineation (contrast enhancement, etc.) g. To describe clinically meaningful OAR constraints such as D2cc, etc. (minimal dose received the most exposed 2cm 3 of that particular OAR). h. The absorbed dose for target volumes and OARs should be given per fraction, and EQD2 should be calculated for the dose per fraction as well as for the total dose. i. To describe quality indices such as: Dose Homogeneity Index (DHI) = (V 100 – V 150 ) / V 100 Dose Non-uniformity Ratio (DNR) = V 150 / V 100 Where V 100 is the volume of CTV encompassed by the prescription 150 is the volume of CTV encompassed by 150% isodose and V

of the prescription isodose.

Conformity Index (CI) = CTV/TV

Where TV= Tissue Volume encompassed by the prescription isodose and CTV = Target volume.

9. BRACHYTHERAPY MODALITIES.

9.1. LDR LDR is defined as a dose rate lower than 1Gy/h. LDR was usually delivered by temporary sources (i.e, the sources were placed and removed after a specified time) in the formof continuous irradiation (no pulses). The majority of the temporary LDR implants used 192 Ir, although 125 I implants have also been occasionally used. The typical dose rate was 0.5Gy/h. Permanent seeds are a special type of LDR brachytherapy in which there is not implant removal and will not be discussed here. The largest series of HN BT were reported with LDR. 9.2. PDR The shortage of iridium wires as well as radiation safety concerns led to the use of other dose rates such as PDR brachytherapy. In PDR brachytherapy the continuous delivery of LDR irradiation is replaced by hourly pulses of irradiation delivered at a higher dose rate lasting a fewminutes. PDR has the advantage to be equivalent to LDR under the conditions of one hourly pulse, treatment 24 pulses per day and a dose-rate of 0.5 Gy/hour. [28] The total recommended dose for PDR is the same as for LDR brachytherapy. PDR brachytherapy doses of 25-30Gy are customarily used in combination with 45-50Gy of EBRT. If PDR brachytherapy is used alone, a total dose of 65-70Gy is recommended. Because of local logistics some authors have chosen a PDR schedule with less than 24 pulses per day (i.e, 12 daily pulses). With this schedule, a 15% reduction in the total dose is usually recommended i.e. 60Gy when brachytherapy alone is performed. These recommended doses are subject tomodifications, depending on tumor size, location and dose constraints. For instance, a tumor located in the lip can be treated with higher doses than a tumor of the floor of mouth, where the proximity of the mandible limits the total dose that can be safely reached.

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