A review of Brachytherapy in head and Neck cancers

Here is a small review of brachytherapy in head and neck cancers that I wrote for a recently concluded conference.

Brachytherapy for Head and Neck Cancers

Dr S.C. Sharma and Dr S. Chakraborty

Department of Radiotherapy and Oncology, Regional Cancer Center, PGIMER, Chandigarh

Squamous cell carcinomas of the head and neck region present an unique challange to the radiation oncologist because of the close relationship of various structures in the region responsible for maintaining the aero-digetive functions of the body along with the inherently complex topography. The area begins at the vermilion border of the lip and extends posteriorly upto the pharynx . Superiorly it is limited by the nasopharynx and inferiorly continues into the thorax via the cervical structures. The mucosal lining is the site for origin of the majority of malignancies and it is served by an extensive system of lymphtics draining into various lymphatic groups of the neck, often with extensive contralateral drainage. Majority of malignancies originating in this area are squamous cell carcinomas which are moderately radiosensitive, spread through the lymphatics and by local invasion; with the exception of few undifferentiated carcinomas of the nasopharynx which are highly radiosensitive and have significant hematogenous spread.

Brachytherapy, the most conformal form of radiation therapy, provides the best therapeutic ratio in this senario (Table 1). The unique dosimetric characterisitcs of the sealed radioisotopes used, have allowed the practising radiation oncologist to give a high dose of radiation to the tumor bearing tissue while sparing the adjacent critical structures at the same time. The functional and cosmetic outcome of brachytherapy cannot be equalled by even the most conservative of surgeries or external beam radiotherapy. Brachytherapy also allows the oncologist to deliver curative doses of radiation to the tumor in a substantially shorter period of time as compared to external beam radiation therapy, amplifying the biological response in the process. In addition it eliminates errors due to setup inaccuracies to a significant extent and thus can minimize the irradiated volume by reducing the Planning Target Volume (PTV). All these characteristics make brachytherapy the ideal form of radiation therapy both biologically and physically. However the same advantages of conformality and high dose gradient around the irradiated volume, also limit the potential application of brachytherapy to small tumor bearing regions only. The skill of acheiving an optimal geometric coverage of the target volume is also one which is acquired through experience and practice.

Table 1: Advantages and disadvantages of brachytherapy

Advantages of Brachytherapy

High dose can be delivered in a short period of time. Rapid dose fall off towards the periphery allows excellent normal tissue sparing. Increased cure rates due to a higher biologically effective dose. Decreased volume of tissue irradiated as compared to external beam radiation leading to reduction in integral dose. Elimination of setup errors as the sources maintain fixed relationship to the target volume. Better cosmetic results due to reduced volume of tissue exposed to high dose of radiation. Acute radiation reactions are sharply localized and usually occur after treatment completion – thus treatment interruptions due to acute reactions are uncommon and radiation morbidity is limited.

Disadvantages of Brachytherapy

Usefulness primarily in leisons with small size in easily accessible areas. Chance of geographic miss high if not used properly. Nodal disease can't be covered simultaneously. Quality of implant is operator dependant. Invasive procedure often requiring anaesthesia.

Almost immediately after the path breaking discovery of Radium by the Curie couple in 1898, radiation oncologists had started using radium in the management of a variety of leisons encountered in the head and neck region with mixed results. This was in a large part consequent to large degree of empiricism in the design of the treatment schedules and doses delivered at that time. This aspect was reversed after the First World War when several of the leading institutions practicing brachytherapy in Europe distilled their experience and knowledge into so called “Schools of Brachytherapy”. Notable of these were the RadiumHemmet in Stockholm (1914) , the the Radium Institute in Paris by Regaud and Lacassagne (1919). However the most influential of these Schools was the Manchester School popularised by Paterson and Parker during the 1930s using Ra²²⁶. The specification of dose prescription points and volumes, radioisotope used and desirable implant geometry went a long way in standardizing brachytherapy. Perhaps the most important contribution of these systems was that the geometry of the implants designed using these system had a near optimal distribution with minimal hot and cold spots. This was important in an era where sources were primarily preloaded and optimization of the implant was not possible after the sources had been implanted. The invention of techniqes for production of artificial radionuclides in 1935 by Irene Curie allowed the development of a widely used system of brachytherapy known as the Paris System (Pierquin, Chassagne and Dutreix) using wires or ribbons of Ir¹⁹². The use of this form of source introduced new possibilites for implantations as a result of their flexibility and adaptability.

Traditionally brachytherapy has been classified based on dose rate as low dose rate brachytherapy (Dose rate 0.4 -2 Gy per hour; classically 50 – 60 cGy /hr), medium dose rate brachytherapy ( Dose rate 2 – 12 Gy per hour) and high dose rate brachytherapy ( Dose rate 12 Gy per hour or more). Low dose rate (LDR) brachytherapy involves the used radioactive sources with low specific activity like Radium (Ra²²⁶), Cesium (Cs¹³⁷) and Iridium (Ir¹⁹²). Clinical experience with this form of brachytherapy is extensive, spanning over a century. Low dose rate brachytherapy is also considered radiobiologically superior to the other forms of brachytherapy. The reason lies in the differential repair kinetics of the tumor and the normal cells. The repair half life for normal tissues (t_1/2 = 1.5 hrs) is lesser than that for tumors so giving a continuous low dose radiation allows healing of the radiation induced subleathal damage during the course of the radiation itself so that the therapeutic ratio between cell kill and normal tissue damage becomes more favourable. Despite the results produced by HDR brachytherapy, LDR brachytherapy is still considered potentially less toxic when it is necessary to reach the limits of the normal tissue toxicity for maximizing tumor control for example definitive treatment of small cancers of lip and tongue using brachytherapy alone.

The other extreme of therapy is HDR brachytherapy, using specially designed high activity, sealed radioactive sources like Ir¹⁹² and Co⁶⁰. HDR brachytherapy has allowed the radiation oncologist significant flexibility in planning the procedure and being an afterloading technique has eased radiation protection issues simultaneously. The small source diameter allows use of thinner channels, minimizing tissue trauma and facilitating application in difficult areas like the base of tongue and nasopharynx. The higher dose rate allows quick treatment, minimizing patient discomfort and allowing OPD based treatment unlike LDR brachytherapy where the treatment often took 6-7 days. The high dose rate however negates the biological advantage of LDR brachytherapy and therefore the treatment has to be administered in fractions. This actually has lead to a protraction of treatment time and a resultant increase in the overall treatment time for majority of head and neck cancer patients. Further the total dose delivered has to be “corrected” i.e. reduced in order to avoid excessive late toxicity. The exact magnitude of this correction remains an area of controversy with various experts recommending values between 45- 55% of the LDR doses. The dose per fraction is another contentious area and it has been observed that doses higher than 4.5 Gy per fraction in the head and neck region often lead to unacceptable rates of tissue necrosis. However some areas like the lip allow the delivery of higher doses per fraction owing to the limited volume of irradiated tissue and the higher radiation tolerance.

The diverse anatomy of the head and neck region has spurred the development of several types of applicators for delivery of radioactive sources inside the tissue intersitium (Interstitial Brachytherapy). The original Manchester system advocated the use of needles containing Ra²²⁶. These needles were available in different source strengths and implantation rules were designed to load a larger amount of radium to the periphery of the implanted volume with a aim to maximize the dose homogenity(± 10%). Later on with the introduction of the Ir¹⁹² wires, several other devices were introduced to facilitate manual afterloading. Examples include guide gutter for implantation of tongue and hypodermic syringes for the lip. Another special type of applicator used for areas like the buccal mucosa and palate was surface moulds where radioactive sources were placed on a platform at a fixed distance from a superficial tumors. The complex anatomy of the nasopharynx prompted the development of a new type of intracavitary brachytherapy using specialized catheter based applicators like the Rotterdam applicator. Due to the ease of use and flexibility offered, most of the modern day interstial implants are done using plastic catheters which are introduced under the guidance of hollow needles. The various forms in which brachytherapy can be used in different sites in head and neck region are detailed in Table 2.

Table 2: Types of Brachytherapy used in Head and Neck Region

Type	Location
Interstitial	Lips, Buccal Mucosa, Tongue, Tonsil, Soft Palate, Base of Tongue, Floor of mouth
Intracavitary	Nasopharynx, Maxilla
Surface Mould	Lip, Angle of mouth, Alveolus, Hard Palate, Pinna, Scalp
Intraluminal	Post cricoid

Brachytherapy can be delivered in several situations and in combination with other forms of therapy. In majority of the areas like the tongue, buccal mucosa and oropharynx brachytherapy is used as a adjuvant to external beam radiation. External radiation is delivered to a dose of 40 – 50 Gy over a period of 4-5 weeks followed by brachytherapy. This approach allows sterilization of the microscopic disease burden surrounding the tumor and also reduces the tumor volume helping to limit the implanted volume. The high chance of occult contralateral and ipsilateral neck node metastatsis also makes this a sensible policy. However the pretreatment volume should be clearly recorded as this volume is always implanted regardless of the size of the tumor at the time of brachytherapy. The dose of brachytherapy in this situation is 20 - 30 Gy by LDR (or equivalent by HDR) and brachytherapy should be started as soon as possible – ideally within 1-2 weeks. Results of LDR and HDR brachytherapy with EBRT in various sites are detailed in Table 3 and 4 respectively.

Table 3: Results of combined LDR Brachytherapy and EBRT

Series	Year	N	Site	Outome
Gerbault(1)	1992	269	Tongue	LC 49% ; 5 yr DFS 30%
Pernot(2)	1992	147	Tongue	LC 51% ; 5 yr DFS 35%
Shibuya(3)	1993	370	Tongue	LC 48%
Decorix(4)	1984	114	FOM	LC 57% ; 5 yr DFS 16-18% (T3-T4)
Bolla(5)	1983	239	FOM	LC 81% (T1) – 37% (T3); 5 yr DFS 65% - 30%
Gerbaulet(1)	1994	80	Buccal Mucosa	LC 52% (T1 -T3) ; 5 yr DFS 31%
Pernot(6)	1994	343	Tonsil	LC 80% ; 5 yr OS 53%
PGI*	1990	157	All Sites	T1 -T2 5 yr LC 86%

DR = Dose Rate; LC = Local Control; OS = Overall Survival; FOM = Floor of Mouth; * = unpublished

Table 4: Results of HDR brachytherapy after EBRT

Author (Yr)	Site (N)	EBRT	HDR	Results
Nose (2004)(7)	Oropharynx (83)	46 Gy	21 Gy / 3.5 # / 2 days	2 yr LC 89% (T1/2); 66% (T3/4) 2 yr OS 88% (T1/2); 64% (T3/4)
Chen (2007)(8)	Oropharynx (97)	50 Gy	24 Gy (median)	5 yr LC 83% - 64% (T1 -T4) 5 yr OS 55%
Nagy-Takaesi (2004)(9)	BOT (37)	50 – 60 Gy	18 – 28 Gy	4 yr LC 60%; OS 46%
Kakemoto (2003)(10)	Tongue (14)	12.5 – 60 Gy	32 – 60 Gy / 8 -10# / 5 - 7 days	5 yr LC 71%
PGI*	Tongue , lips	40 – 50 Gy	18 -24 Gy / 5-6 # / 3 days	Immediate LC 72%

EBRT = External Beam Radiotherpay;BOT = Base of Tongue; * = Unpublished

In selected areas like the lip, early tongue cancers (<> 5 mm distant from the mandible) brachytherapy can be used alone for the entire treatment. Evidence points that for these leisons brachytherapy may provide a better cure rate with lesser toxicity as compared to EBRT or EBRT with brachytherapy. Data from investigators like Mazeron, Gerbaulet etc. show that local control rates can be as high as 80 -90% in these situation, with minimal late toxicity. In particular the latter author has shown that using brachytherapy as the sole modality can almost double the local control rates for smaller leison of the oral tongue. When brachytherapy is used alone, doses of 66 – 70 Gy LDR equivalent are delivered to the primary tumor (GTV) with a safety margin which includes the potential area of microscopic spread (CTV). The margins choosen vary according to location, type of tumor and personal experience of the investigator concerned, but usually margins of 1-1.5 cm are choosen with care to avoid the mandible as far as possible. HDR doses need to be suitably corrected and the doses delivered usually range from 40 – 50 Gy in 3 – 4 Gy per fraction treating twice daily with a suitable interfraction interval (6 hours or more). Selected series of LDR and HDR brachytherapy alone in various sites are detailed in Table 5 and Table 6 respectively.

Table 5: Selected results of LDR Brachytherapy alone

Series	Year	N	Site	Outcome
Gerbaulet(11)	1978	316	Lip	95.8% 5 yr LC (T1 - T4)
Mazeron(12)	1983	1896	Lip	96.6% 5 yr LC (T1 - T4)
Van Limbergen*	1993	2794	Lip	94% 10 yr LC (T1 – T4)
Decorix(13)	1981	602	Tongue	76% 5 yr LC; DFS 80% (T1) – 25% (T3)
Pernot(2)	1992	147	Tongue	90% LC , 62% 5 yr DFS in T1
Lefebvre(14)	1994	146	FOM	91% LC (T1) – 53% (T3); 46% overall DFS
Gerbaulet(15)	1985	266	Buccal Mucosa	LC 81% ; DFS (64%)

FOM = Floor of Mouth;DFS = Disease Free Survival; LC = Local Control; DR = Dose rate

Table 6: Results of HDR brachytherapy alone in various sites

Author	Site (N)	HDR dose	Results
Guinot (2003)(16)	Lip (39)	40.5 – 40 Gy / 8 -10 # / 5 -7 days	5 yr LC – 88% ; CSS - 90%
Kakimoto (2006)(17)	Tongue (71)	54 – 60 Gy / 9 -10 # / 5 -7 days	5 yr LC – 85.9% ; OS - 80.3%
Lueng (2002)(18)	Tongue (19)	55 Gy / 10 # / 6 days	5 yr LC – 94.7%
Inoue (2001)(19)	Tongue (25)	60 Gy / 10 # / 1 week	4 yr LC – 87%
Yamazaki (2003)(20)	Tongue (58)	48 – 60 Gy / 8-10 # / 6 -7 days	5 yr LC – 84%
PGI*	Tongue	35 -42 Gy/ 10 -12 # / 6-7 days	4 month LC - 72%

LC = Local Control; OS = Overall survival; CSS = Cause specific surviavl; * = Unpublished

A special case of brachytherapy is that for nasopharyngeal cancers where commonly the technique popularised by Lavendag is used. The procedure is commonly indicated for boosting the nasopharynx selectively after completion of EBRT to a dose of 60-66 Gy provided there is a small residual disease confined to the nasopharynx (pretereatment T1 -T3) without parapharyngeal extension and nodal disease. A dose of 18 Gy in 6 fractions over 3 days (2 fractions per day, 6 hours apart) by HDR is recommeded. The risk of late neurotoxicity and nasal synachie should be kept in mind while planning this form treatment.

Superficial (less than 0.5 cm thick) tumors of the head-and-neck areas can be treated with brachytherapy using molds. Suitable sites for mold therapy include scalp, face, pinna, lip, buccal mucosa, maxillary antrum, hard palate, oral cavity, external auditory canal, and the orbital cavity after exenteration. A total dose equivalent to about 60 Gy LDR (prescribed at 0.5 cm depth) is recommended. Brachytherapy can also be used as a boost to 45 to 50 Gy EBRT, in which cases the doses are appropriately reduced to LDR equivalent doses of 15 to 30 Gy. Moulds should be prepared from a tissue equivalent material which can be easily moulded to the surface topography like dental acrylic or perspex.

Brachytherapy can be combined with surgery in various ways the most common situation being a planned neck dissection after the completion of brachytherapy. This is most commonly used for small leisons of the tongue or oropharynx where the risk of occult nodal metastatsis may be as high as 30%. Post operative brachytherapy is rarely indicated except in senarios where gross residual or recurrence is documented and EBRT can't be delivered safely. Most commonly this situation arises after resection of a recurrent tumor in a previously irradiated area. LDR brachytherapy doses of 50 to 60 Gy have for several decades been used for the treatment of patients with recurrent head-and-neck cancer, with 30–70% salvage rate and 30–40% complication rates. For HDR brachytherapy recommended doses range from 3–4.5 Gy per fraction in 8–18 fractions.

A more specialized application of brachytherapy is the use of Intraoperative brachytherapy (IOHDR) in paranasal sinuses and and other deep areas near the base of the skull are difficult to treat either by conventional brachytherapy or intraoperative (electron beam) radiation therapy(21). After maximal resection, the tumor bed is irradiated using surface applicators placed on the tumor bed. The advantages of IOHDR include ability to displace or shield normal tissues during the irradiation and its applicability in narrow, deep cavities.The ABS recommends 10–15 Gy IOHDR in conjunction with 45–50 Gy external beam irradiation for the treatment of microscopic disease in previously unirradiated patients. IOHDR alone (without supplementary EBRT) for recurrent tumors has achieved poor local control. The IOHDR dose is to be prescribed at 1 cm from the plane of catheters (0.5 cm from the applicator surface). This provides an additional advantage that a higher dose (up to 200%) can be given at the surface (i.e., the tumor bed or surgical margin at greatest risk of harboring residual microscopic disease).

Complications of brachytherapy depend to a significant extent on the volume irradiated and the dose inhomogenity. Transient soft tissue necrosis can be expected in 15 -20% patients which usually resolves spontaneously. In case of lip mild depigmentation and telengiectasias can be expected in 10 -15% patients. The incidence of Grade 3 cosmetic sequale was estimated to vary from 1 – 9% depending on the volume irradiated. Mandibular osteoradionecrosis can occur in 5 – 10% patients and if the area is 1 cm² then majority heal with conservative management. Unlike EBRT neural and salivary gland toxicity are unknown.

To conclude brachytherapy in it's various forms remains a excellent tool for acheiving control and cure for locally confined head and neck cancers. The high degree of conformality cannot be equalled even by modern day EBRT techniques like IMRT and IGRT. However proper patient selection, experience and skill are of utmost importance in ensuring the best outcome.

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7. Nose T, Koizumi M, Nishiyama K. High-dose-rate interstitial brachytherapy for oropharyngeal carcinoma: results of 83 lesions in 82 patients.. Int J Radiat Oncol Biol Phys. 2004 Jul;59:983-91.

8. Chen J, Pappas L, Moeller JH, Rankin J, Sharma PK, Bentz BG et al. Treatment of oropharyngeal squamous cell carcinoma with external beam radiation combined with interstitial brachytherapy.. Head Neck. 2007 Apr;29:362-9.

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17. Kakimoto N, Inoue T, Inoue T, Murakami S, Furukawa S, Yoshida K et al. High-dose-rate interstitial brachytherapy for mobile tongue cancer: influence of the non-irradiated period.. Anticancer Res. 2006 Sep-Oct;26:3933-7.

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20. Yamazaki H, Inoue T, Yoshida K, Yoshioka Y, Furukawa S, Kakimoto N et al. Brachytherapy for early oral tongue cancer: low dose rate to high dose rate.. J Radiat Res (Tokyo). 2003 Mar;44:37-40.

21. Nag S, Koc M, Schuller DE, Tippin D, Grecula JC. Intraoperative single fraction high-dose-rate brachytherapy for head and neck cancers.. Brachytherapy. 2005 ;4:217-23.