11 Lip and buccal mucosa

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE 11 Lip and buccal mucosa Jose Luis Guinot, Vratislav Strnad, Erik Van Limbergen

Editors Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

Lip and buccal mucosa

3

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

11 Lip and buccal mucosa

Jose Luis Guinot, Vratislav Strnad, Erik Van Limbergen

1. Summary 2. Introduction

3 3 3 4 4 4 5 5

9. Treatment planning

7 7 8 8

10. Dose, Dose Rate, Fractionation

3. Anatomical topography

11. Monitoring

4. Pathology 5. Work up

12. Results

13. Adverse side effects 14. Key messages

11 13 14

6. Indications, contra-indications 7. Tumour and Target Volume

15. References

8. Technique

1. SUMMARY

Lip and buccal mucosa cancers can be managed with surgery, but at the high cost of impaired functional or cosmetic outcomes in some cases. Radiation therapy can be a good alternative. These tumours are well localized and have been treated with low dose rate (LDR) brachytherapy with excellent results for decades. Pulsed and high dose rate brachytherapy (PDR and HDR) are the current standard, but few papers have been published on results in these tumour locations. An optimal treatment scheme has not been agreed upon, but the results show that local control is at least as high as expected with LDR and the incidence of complications is probably lower than with the old techniques. Functional outcome and cosmesis is better than with surgery, especially for lip cancer. Therefore brachytherapy should be considered in most of these cancers.

2. INTRODUCTION

contributes to one third of cases and alcohol to 20% of them, but these aetiological factors are often underestimated.The proportion of females is higher than in other head-and-neck cancers: the sex ratio is 3 : 1 (males : females). Involvement of the buccal mucosa or lateral commissure is difficult to treat with surgery due to the great alteration of function. Radiation is a good alternative, and brachytherapy allows an increase in the local dose leading to higher rates of local control. There are a lot of references of cases treated with low-dose rate (LDR) techniques, with high rates of success [3], but nowadays LDR 192-Iridiumwires are no longer available in Europe. Therefore we have to use PDR or HDR stepping sources to treat these tumours. The fear of adverse effects when using high doses per fraction has led to HDR-BT less frequently being used to treat carcinoma of the lip, compared to other head and neck locations, but the published results show that functional, cosmetic and control outcomes are similar to the LDR experience, with fewer complications [4].

The vermilion of the lip forms a transition zone between skin and oral mucosa and therefore the risk for cancer is related both to sun exposure and classical etiological factors for oral cancer such as tobacco, alcohol and bad oral hygiene [1]. Farm labourers and fishermen have a higher risk of lip cancer, as they are likely to be exposed to these risk factors. The involvement of the outer lower lip is 40 times more prevalent than the upper lip [2]. Early detection is usually possible because of location and slow growth. The incidence is higher in men (ratio, 6:1). It is the most common cancer of the oral cavity, approximately 30%, as well as being the one with the highest survival. Cases will increase with aging population and increasing life span. Patients are often old (the mean age of a patient suffering from lip cancer is over 65 years) or have poor general condition, contraindicating major surgical excision and flap reconstruction. Surgery as well as external radiotherapy, and interstitial implants with radioactive sources are very successful in treating these lesions. Modern brachytherapy (BT) is a simple and effective treatment modality leading to excellent local control rates and cosmetic and functional results. Nevertheless, in some countries, few patients are considered for treatment with brachytherapy. Buccal mucosa carcinoma represents 3 to 5% of oral-cavity cancers in Europe and North America; it is much more frequent in South Asia and LatinAmerica.These differences are due to people chewing areca and betel nuts, tobacco leaves and coca leaves mixed with lime, since these are carcinogenic. In developed countries, tobacco

3. ANATOMICAL TOPOGRAPHY

Anatomically the lip can be divided in three different parts. The cutaneous lip goes over to the vermilion or dry mucosa of the lip, which forms a transition zone between the skin and the wet oral mucosa. Its lateral limits are about 1cm from the lip commissures:

Lip and buccal mucosa

4

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

the upper limits are the naso-labial groove at the skin and the gingivo-labial groove at the mucosa side; the lower limits are the mento-labial and the lower gingivo-labial groove. Its lymphatic drainage goes to the sub-mental, sub-mandibular and sub-digastric lymph nodes. The submandibular nodes are the most frequently involved (level IA and IB). In a study of 617 patients, the lymph node involvement was 7.9% in T1-2 and 27.9% in T3-4 [5]. All patients affected with tumours reaching the median line are at high risk for bilateral nodal involvement. The buccal mucosa is bounded by the lower and upper gum sulcus; the lip commissure constitutes its anterior limit; the posterior limit is the intermaxillar commissure and the retromolar trigone [6]. Lymphatic drainage is to the submandibular nodes or directly to the jugular nodes (level IB- IIA). Nodal involvement is found at the time of initial diagnosis in about 40% of patients. Critical organs for both, lip and cheek, are the mandibular bone, the gingiva and the tongue, but also, in the case of very infiltrating tumours, soft tissues such as muscles and skin [7-8]. The ease of brachytherapy depends on the exact position in the cheek and the commissure involvement. Most lip cancers are squamous cell cancers (90%). The remaining 10% are basal cell cancer (starting from the cutaneous area). Sarcomas, adenoid cystic carcinoma, melanomas are very rare. Pre-cancerous conditions, such as actinic cheilitis, leucoplakia, Bowen’s disease, are frequently associated. They often constitute a diagnostic and an additional therapeutic problem. In general these associated lesions can be adequately treated by radiotherapy but are a contraindication to limited surgery. Macroscopically, tumours may be exophytic, ulcerating, infiltrating or nodular or any combination. In buccal mucosa cancers, most tumours are squamous cell carcinomas. Other histopathological types are: glandular carcinomas, non-Hodgkin lymphomas, melanomas. Precancerous lesions are observed in one third of patients [6-9]. 4. PATHOLOGY

are often poorly defined. Associated lesions are far from rare and should actively be sought for and noted as well. Detailed drawings or photographs will help to document the exact size and localisation. From every tumour and any suspected extension adequate biopsies should be taken. For buccal mucosa tumours, clinical symptoms are discomfort, mass, pain, trismus, neck node [6]. The work-up is comparable to other cancers of the oral cavity, but the particular carcinogenetic and epidemiological factors must be evaluated [7]. Because of the frequent association of malignant and premalignant tumours, the tumour site must be accurately described by diagrams, biopsies, ultrasound, CT scan and MRI [10-11]. Tumour must be staged, according to the TNM staging system. T1 ≤ 2cm, T2 >2 ≤4cm, T3 >3cm, T4a involvement of bone, floor of mouth, alveolar rim, skin of nose or chin. Lymph node involvement is rare but can be bilateral in lip cancers. A bi-digital palpation with a finger inside the mouth is necessary to better estimate the nature of submandibular lymph nodes. In case of clinical doubt, fine-needle aspiration is a simple procedure to assess involvement. A CT-scan is usually employed to identify lymph nodes, that have been reported in 2% of T1, 6% of T2 and 15- 30% of T3 cases [12]. Lymph node involvement is more frequent when there is tumour extension to the wet mucosa [13], to the skin, to the lateral commissure and in tumours greater than 2cm, and an elective treatment of the neck should be considered in these cases [14]. The sentinel node technique is a good option for T1 to T2 tumours [15]. For buccal mucosa tumours, lymph node extension is unilateral. Lip cancer can be treated with brachytherapy in over 90% of cases, depending on the tumour size. A simple surgical wedge excision is indicated for superficial, small tumours less than 0.5 cm in their major axis. Different techniques of wedge surgery are currently being used, but the local recurrence rate, varies between 10 and 30% according to different authors [16-17]. Larger tumours (over 5 cm in their major axis) are treated by external beam radiation followed by brachytherapy, or surgical excision followed by reconstruction surgery with an Abbe-Estlander lip flap rotation or derived techniques. Tumours invading adjacent bone usually require surgery if feasible. All other cases of lip carcinoma from T1 to T3 can be successfully managed with brachytherapy alone. Postoperative brachytherapy is indicated after surgery with a positive or close margin or perineural involvement, at lower total doses, but may result in functional compromise due to previous surgery, and should include the whole surgical scar. For lesions of the anterior and central part of the buccal mucosa, interstitial brachytherapy is strongly indicated, for tumours < 40 mm, well-defined, located in the anterior two thirds of the buccal mucosa without involvement of the gingiva or intermaxillary commissure. For tumours ≥ 40 mm, or tumours involving the 6. INDICATIONS, CONTRA-INDICATIONS

5. WORK UP

An accuratemedical examination should always include a systematic examination of the head and neck region, of the skin and teeth as well as X-rays of chest andmandible when indicated. It is mandatory to carefully inspect and palpate the tumour area and the whole affected lip, the other lip and the commissural areas. The tumour itself may be exophytic, nodular, ulcerated, or infiltrating. These forms can sometimes co-exist. The size (inmm) and site of the tumour: (cutaneous lip, vermilion, wet mucosa), invasion of lip muscles or commissura should be carefully assessed and noted. Any infiltration of the wet mucosa significantly increases the risk of nodal metastases. Lip cancers

Lip and buccal mucosa

5

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

Source: http://elementsofmorphology.nih.gov/anatomy-oral.shtml and https://headandneckcancerguide.org/adults/introduction-to-head-and-neck-cancer/oral-cancers/buccal-cancer/anatomy

8. TECHNIQUE

posterior third of the buccal mucosa (without involvement of the intermaxillary commissure), a combination of external-beam radiation and brachytherapy boost is indicated [9]. If there is deep involvement of the gingivobuccal sulcus, brachytherapy is contraindicated as in floor of mouth carcinoma, because of the unacceptable risk of osteoradionecrosis to the mandible [8-9-18]. For the posterior third of the buccal mucosa, the closest area to the retromolar trigone, the indication for implant alone must be discussed case by case as it may be technically difficult to cover completely that area with interstitial implants [19]. Brachytherapy is followed, as for other oral-cavity carcinomas, by a cervical node dissection in selected cases. It can be performed the next week after the treatment of the primary tumour, due to the shortness of the brachytherapy duration. The clinical target volume for lip includes all visible and palpable tumour extensions with a safety margin of at least 5 mm in all directions. Because there is nomovement of interstitial implanted sources when adequately fixedwith templates or pieces of nasogastric tubes, the PTV corresponds to the CTV. The target volume for buccal mucosa is defined by intraoral examination completed by a bidigital palpation of the tumour; with one finger in the mouth and the other on the skin of the cheek. The projection of the gross tumour volume (GTV) should be drawn and the clinical target volume (CTV) mapped out on the surface of the skin. The CTV comprises the GTV plus a safety margin of 10 mm at the anterior and posterior parts of the tumour (GTV) and 5-10 mm at its upper and lower limits, in relation to the mandible and upper maxilla. If brachytherapy is used as a boost, the initial tumour volume must be marked with metallic clips, or projection onto the skin should be drawn. CT-scan or preferablyMRI can contribute to defining the tumour volume and consequently the target volume more accurately. MRI is used at the time of diagnosis but also after the plastic tubes are implanted to check the quality of the implant and to adjust the position of the radioactive sources, according to the target delineation. 7. TUMOUR AND TARGET VOLUME

8.1 Technique for lip carcinoma Brachytherapy has been classically performed with hypodermic needles, classic nylon tubes, silk threads, small vascular catheters, guide gutters, or a combination of these techniques in the same patient [20] (Fig 1,2). No LDR wires are available in Europe nowadays, and PDR or HDR 192Iridium stepping sources are used, through rigid needles or plastic tubes.The implant procedure follows the same guidelines used with LDR-BT. The implant can be performed under local or regional (mental nerve) anaesthesia and sedation, if needed. 8.1.1 Rigid needles technique Parallel metallic rigid closed hollow needles are inserted to cover the whole volume of the target. It is better to start with the posterior needle at the transition of the vermillion and the wet mucosa and measure adequate spacing to the anterior needle to cover the CTV. They can be arrayed in equilateral triangular templates of 10-12 mm side [4] (Fig. 3). In some cases, needles can be placed outside the tissue to provide coverage of protruding lesions. In these cases, bolus material is placed between the lesion and the external needles to improve dosimetry (Fig. 4). The rigid steel and template system is fixed with screws which avoids collapse of the sources due to the elasticity of the soft tissues, and allows for an optimal dose homogeneity. Templates with predrilled holes in a triangular configuration and with spacing of 10 to 12 mm should be available. 8.1.2 Plastic tubes technique This requires the use of open point hollow needles to be replaced by the plastic tubes with buttons on the extremes. They are more flexible, allowing a better adaptation to round surfaces (Fig 5). However it is more difficult to keep good parallelism between tubes over the whole length of the treated volume. Plastic tubes are therefore indicated for larger masses, or when the lateral commissure or cheek is involved. The treatment has sometimes to be delayed as long as necessary for regression of the post brachytherapy trauma and oedema. 8.1.3 Mould technique Some series with small number of patients have used moulds made with resin or acrylic material and embedded plastic tubes

Lip and buccal mucosa

6

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

Fig 2a-b: Interstitial implant with two inserted needles and one outside with bolus material for the time of the session.

Fig 1: Needle implant of the lip for HDR- / PDR-brachytherapy, in an equilateral triangular configuration with templates.

Fig. 4. Seven needle implant; only three were inserted; the oth- er needles were placed outside tissue just before each fraction, after bolus placement.

Fig. 3. Distribution of needles arrayed in templates with equilateral triangles.

Fig 5: Plastic tubes implant for HDR- or PDR-brachytherapy as a boost after EBRT.

Fig 9: A single plane horizontal implant as a HDR-BT boost after EBRT.

Fig 8: Carcinoma of the anterior part of the buccal mucosa with extension to the labial commissure. Two planes are necessary to cover the posterior part of the CTV, one only for the anterior part.

Fig 6: Plastic-tube technique: the dimensions of the tumour projected on the skin surface of the cheek are checked accord- ing to the positioning of the metallic needles.

Fig 10: Double plane implant with eight needles as exclusive HDR-BT.

Fig 7: Classical plastic tube implant: four lines equidistant and parallel maintained in position by a perforated catheter.

Lip and buccal mucosa

7

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

Fig 11: Planning CT with isodose curves with plastic tubes technique.

Fig 12: Measure of the distance from the tip with rigid needles tehnique.

Fig 13: Isodose curves in an equidistant implant of six rigid needles forming triangles.

9. TREATMENT PLANNING

surrounding the lip, for small tumours. It is more comfortable, but not so fixed as interstitial techniques 8.1.4 Protection device A custommade protection device can be used, if clinically indicated. Such a device should be prepared to shield the upper lip, the tongue and the lower gum. The protector consists of a 2mm lead shield placed between both lips and the mandible, contained in an acrylic mouthpiece, bended in an L-shape. This reduces the dose to the upper lip and lower gum by a factor of two. The advantage with HDR is that it can be placed only during the few minutes of each session. To make exact dosimetry possible, an identical dummy protector without lead shielding or removable lead plate can be made and used for dose planning. 8.2 Technique for buccal mucosa carcinoma Two implantation techniques were mainly used with LDR: guide gutters replaced by iridium hairpins for superficial, well limited, anterior lesions, close to the lip commissure, smaller than 20 mm in size. And plastic tubes for all other lesions, taking into account the thickness of the tumour and the anatomical characteristics of the cheek, whose thickness increases from the lip commissure to the intermaxillary commissure. The needles are implanted parallel to each other, parallel to the oral mucosa and parallel to the horizontal branch of the mandible. Under digital control, the lines are placed approximately 3-5 mm deep, under the buccal mucosa. They should cover the CTV, 10 mm of normal mucosa behind and in front of the lesion with a recommended spacing of 10-15 mm. A single plane is required to cover the target volume if the thickness of the tumour does not exceed 5 mm. Plastic spacers at both ends keep the tubes parallel. Retention buttons are fixed at both extremities (Fig 6, 7, 8). If the lesion is thicker than 5 mm, a second plane of tubes is implanted between the first one and the skin. A customized lead gutter inside the oral cavity is highly recommended to reduce the risk of osteoradionecrosis. The shielding system may reduce the thickness of the target volume by stretching the cheek and squeezing the tumour so irradiation is better adapted. In some cases rigid needles can be used directly, with a template. An oblique direction is used in cases of lateral commissure involvement. The loops used with LDR are no longer needed with HDR, due to the optimization (Fig 9, 10).

2D dose planning Most of classical implants with LDRwere calculatedwith orthogonal projection images to register the source positions. The prescribed dose to the Minimal Target Dose usually corresponds to 85% of the MCD (Paris System). It was sometimes complemented by CT scan and/or MRI, to determine as closely as possible both GTV and CTV. 3D dose planning Nowadays, a planning CT scan is mandatory for plastic tubes technique, with radiopaque markers around the tumour or on the scar in postoperative cases (fig 11). Different planes are chosen, perpendicular to the radioactive lines if possible: in the frontal plane when the lines are parallel to the buccal mucosa, in the sagittal plane when the lines are perpendicular to the buccal mucosa. GTV and CTV must be drawn, and the bone as organ at risk. The Stepping Source Dosimetry System (SSDS), a modified Paris system, is useful to optimize the isodose curves, finishing with amanual optimization.The dose to bone should not be greater than the prescription dose. For the rigid needles technique with template, the distance between needles is fixed, and the tumour is clearly visible, then the CTV is well defined. Therefore, a theoretical calculation can be done quickly by taking the distance from the tip of the needle to the beginning and the end of the CTV, drawn on the skin or the lip (fig 12). The calculation can be done without planning CT, and optimization is done to volume to the 90% isodose (Fig 13). The whole tumour must be inside that volume. ACT planning can help to delineate the CTV, but it is not mandatory. 3D dose planning with MRI is lacking.

10. DOSE, DOSE RATE, FRACTIONATION

The prescribed dose for LDR was 60-75 Gy at the 85% reference isodose, at dose rates between 45-80 cGy/h. This used to take 4 to 6 days to deliver a dose of 60-65 Gy for T1 and 65-70 for T2 [21]. Although doses up to 70-75 Gy can be given in some large tumours, without unacceptable sequelaes [13] the increase in

Lip and buccal mucosa

8

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

cosmetic radiation damage is greater than the gain in local control expected from a dose increase above 70 Gy. The total dose for LDR brachytherapy was 25-30 Gy when it was used as a boost after 45-50 Gy of external beam irradiation. With PDR, the dose per pulse is between 40-80 cGy every hour to administer a total of 55-65 Gy, in five days, similar to LDR [22-23]. With HDR two fractions per day, separated at least 6 hours are used. A dose per fraction between 4 and 5 Gy are the most common employed. With rigid needles, the homogeneity index is over 80% and a higher dose per fraction can be used without risk. A dose of 5 Gy x 9 fractions to a total dose of 45 Gy (EQD2: 56.25 Gy) in five days allows for starting the treatment on Monday and withdraw the needles on Friday, keeping the same 5-days period as required for LDR [24]. In postoperative cases, 4.5 Gy x 9 fractions (EQD2: 48.9 Gy) is enough. Higher doses per fraction, 5.3Gy or 5.7Gy have been used. For the plastic tube technique, same doses can be used, but the homogeneity is not so good, and there can be hot spots. In these cases the DNR should be less than 0.36, what means that one third of the volume is receiving 150% of the prescribed dose [25]. Therefore a lower dose per fraction may be advisable: 4 Gy x 10-12 fractions (EQD2: 46.6 – 56 Gy). The EQD2 concept should be used with caution in H&N brachytherapy because the calculated values for the equi-effective dose are often lower than expected for a curative tumour effect with EBRT. (see chapter on General Aspects of Head and Neck Brachytherapy).

than prescribed by Paris System rules [26]. Beauvois reported even that when the entire lip was treated (this was the treatment policy in Nancy after 1985) no contralateral lip recurrences were seen [16]. In the large 1993 GEC-ESTRO brachytherapy for lip cancer study (brachytherapy for lip cancer study 224 recurrences in 2794 patients were noted over a long follow up time (up to over 15 years) with an annual probability for recurrence rate of less than 1% [27]. The local disease free survival probability (DFS) at 5, 10 and 15 years follow-up was respectively 94% 90% and 89%. Significant higher local control rates were seen in lower lip cancers, and worse in commissural lesions (p=0.00001). A highly significant difference was noted between the local control rates according to T-stage (p=0.00001). For T1 tumours, the 5, 10 and 15 years DFS were respectively 95%, 91% and 90%; for T2, they were 91%, 89% and 86%; and for T3 in 82%, 78% and 78%. Local control rates were worse in poorly differentiated tumours: the 5 and 10 year local control rates being 97% and 95% for WHO I lesions, 95% and 80% for WHO II, and 80% and 77% inWHO III lesions. There were no differences in local control rates for patients treated with combined surgery and brachytherapy versus patients treated with BRT alone. Besides T size, the brachytherapy dose delivered is the major predictor for local control. The data suggest that 60 - 65 Gy is optimal to treat T1 (2 - 3% local failure at 5 years) and 65 - 70 Gy optimal to treat T2 lesions (3.1-4% local failure rate at 5 years). These local control rates compare favourably with surgical series (6 - 30% local failures) [13-16]. In addition, local recurrences can be salvaged in 80 % of cases by surgery [16-20-21]. 12.1.1 Local control with PDR There are some series that use pulsed dose rate brachytherapy (PDR), with sessions of 0.83 to 1 Gy repeated every hour, to achieve doses similar to those administered with low rate [22-23]. Results of HDR and PDR are shown in table 2. 12.1.2 Local control with HDR The first publication with HDR-BT in lip appeared in 2003 with 39 cases [24]. The average follow-up was short, 18 months, with two daily fractions of 5 to 5.3 Gy in 8 or 9 fractions, reaching a control of 95% in T 1 and T 2 and 74% in T 4. It was found that the acute and chronic effects were similar to those of low rate, maintaining good function. Another work, published in 2005 on 28 patients, used acrylic moulds with plastic tubes for superficial or contact brachytherapy [37]. A dose of 1.8 Gy per day five days per week, up to 60-65 Gy in small tumours and up to 75-80 Gy in bulky ones was used and no relapses were seen. Good or excellent aesthetic results were reported in 96% of cases, without complications. Another studywith 24 T1-2 patients, 18with exclusive brachytherapy and 6 after surgery, used an average dose per fraction of 5.7 Gy and an average of 7 fractions to obtain a mean total dose of 35 Gy, prescribed at 80% or 3 -5mm depth from the tumour. The average duration of the treatment was 12 days. With a follow-up of 32 months, control was achieved in 87.5% [38]. In 2010 21 lip cancer patients were reported treated with HDR, giving 45-50 Gy in 9 -10 fractions, with 32 months of median follow-up. It was concluded that HDR seems to be as good as LDR [39]. Another study includes 70 cases of LDR and 33 of HDR, with doses using different fractions, using plastic tubes, reporting a control rate of 93%with no difference between LDR andHDR [40].

11. MONITORING

Before the treatment check the dwell times, the length of the tubes or needles, and the separation between them. Daily control of the position of source carriers and protector device is mandatory. When rigid needles are fixed with a template outside the tumour, they can be placed again and removed after every session, for better comfort. A soft diet is better, but usually no feeding tube is required. Simple analgesics may be indicated. Acute side effects such as mucositis (in the second week) and epidermitis (in the third to fourth week) can be mild to severe and have to be treated symptomatically with topical applications.

12. RESULTS

12.1 Results in lip carcinoma 12.1.1 Local control with LDR

Overview of the literature shows local control rates of 90 - 95% at 5 years (Table 1) for Ir-192 LDR brachytherapy following the Paris system implantation rules. The results are somewhat better in T1 (0 - 5%) five year local failure rates than in T2 disease: 2.1% - 8.2% [13-21]. They seem to be worse when Paris system implantation rules are not followed: local recurrences were 1/21 (4.8%) when active source lengths were long enough for covering the PTV and were 7/51 (13.7%) when source lengths were shorter

Lip and buccal mucosa

9

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

Table 1: Local recurrence rate in lip carcinoma, LDR series [28-29-30-31-32-33-34-35-36]

Author [reference]

Year

Number

T

Isotope

Local recurrence

Gerbaulet (28)

1978

316

T1-4

Ra-Ir

4.2%

Pigneux (29)

1979

91

Ir

4.5%

Mazeron (3)

1983

1267

T1-4

Ir

3.4%

Cowen (30)

1990

248

Ir

4%

Orecchia (31)

1991

47

T1-2

Ir

6.4%

Van Limbergen (27)

1993

2794

T1-4

Ir/Cs

6%

Gerbaulet (7)

1994

231

Ir

5.6%

Beauvois (16)

1994

237

T1-4

Ir

5%

Fongione (32)

1994

69

T1-3

Ir

1.5%

Farrus (26)

1996

72

T1-3

Ir

11%

Tombolini (21)

1998

57

T1-3

Ir

10%

Arribas (33)

1998

99

T1-4

Ir

5%

Conill (34)

2007

54

T1-2

Ir

2%

Guibert (35)

2011

172

T1-2

Ir

9.9%

Río (36)

2013

89

T1-3

Ir

5%

Table 2: Local recurrence rate in lip carcinoma, series with PDR and HDR

Author [reference]

Year

Number modality

T

Fractionation Total dose

EQD2

Local failure

Johanson (22)

2011

43 PDR

T1-3

0.83 Gy

55-60Gy

49.4-53.9Gy

6%

Serkies (23)

2013

32 PDR

T1-4

1 Gy

60-70Gy

55-64Gy

3,5%

Guinot (24)

2003

39 HDR

T1-4

8/9x5-5.3 Gy

40.5-45Gy

54-56.2Gy

10%

T1-3 basal cell

Finestres (37)

2005

28 HDR moulds

1.8Gy

65-75Gy

63.7-74Gy

0

Lebioda (38)

2005

24 HDR

5.8 Gy

35Gy

45.8Gy

12.5%

100 LDR 21 HDR 70 LDR 33 HDR

60-70Gy 45-50Gy

Querejeta Ayerra (39)

2010

T1-4

4.5-5 Gy

54.4-62.5Gy

10%

Ghadjar (40)

2012

T1-2

4-5 Gy

7%

Guinot (4)

2013

104 HDR

T1-4

4.5-5 Gy

40.5-45Gy

48.9-56.2Gy

4.8%

Mut (41)

2016

68 HDR

T1-2

4.5-5 Gy

40.5-45Gy

48.9-56.2Gy

3.1%

Lip and buccal mucosa

10

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

Fig 14: Squamous cell lip cancer and cosmetic outcome five years after 75 Gy LDR-BT.

Fig 15: Bulky lip cancer at the lateral commissure extending in both upper and lower lip treated with LDR. Cosmetic outcome after 10 years.

Fig 16: T2N0 SCC plus sentinel node. HDR 5Gy x 9 fractions (EQD2: 56.2 Gy). Four needles inserted and three outside (Implant shown in technique section). Results at 7 years

Lip and buccal mucosa

11

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

Fig 17: SCC. HDR 5.3 Gy x 9 fractions (EQD2 60.8 Gy) plus elective neck EBRT. Eight needles. Results at 2 years.

Fig 18: Recurrence after surgery, commissure tumour involving buccal mucosa, treated with oblique rigid needles. HDR 5Gy x 9 fractions (EQD2: 56.2 Gy). Results at one year

The largest study, was published in 2013, with 104 patients treated with rigid needles, 45 Gy in 9 fractions [4]. The 7-year actuarial control was 100% in T1, 93.6% in T2 and 79% in T4. The most interesting data is that there were no cases of lip or bone necrosis, compared with 15% with LDR in the previous experience, and preserved function in 100% of cases. An update of 68 T1-2 cases achieved a control of 96.5% [41].

carcinoma (Table 3) [7-8-19-20-42-43]. In these different studies, patients were treatedwith brachytherapy alone (A) or with combined external-beam radiation and brachytherapy boost (B) in nearly 700 cases. When the two treatments are compared, survival and local-control rates are better for brachytherapy 60% versus 35% and 75% versus 60%, respectively. 12.2.2 Local control with HDR/PDR Few reports show the results of HDR or PDR in buccal mucosa carcinoma. The current practice is similar to lip carcinoma with no apparent differences regarding local control, compared with LDR, and fewer complications, due to the optimization of the dose, according to personal experience.

12.2 Results buccal mucosa 12.2.1 Local control with LDR

The largest multicentre study was done by the GEC (Groupe Européen de Curiethérapie) ESTRO [9]. Seven hundred forty-eight patients were treated for primary tumour with: brachytherapy alone (31%) (A), combination of external beam irradiation + brachytherapy (11%) (B), external beam irradiation alone (36%) (C), surgery often followed by radiation therapy (22%) (D). These different therapeutic approaches were adapted to prognostic factors: tumour size, tumour site, nodal status. (12) Five-year NED survival rate according to T stage was: T1 61%, T2 46%, T3 33%, T4 10%. For the various treatments, the local failure rate (including all primary tumours) was: 19% for brachytherapy alone, 35% for combination external beam irradiation + brachytherapy and for external beam irradiation alone, 22% for surgery ±- external beam irradiation. With the exception of the GEC ESTROmulticentre trial, few other reports have been published of brachytherapy in buccal-mucosa

13. ADVERSE SIDE EFFECTS

Since the lip is relatively radioresistent; severe complications are rare. Superficial necroses occur in 2.8 - 10.1% [27-28-30-31]. They heal spontaneously in 70% before six months or after hyperbaric oxygen therapy inmore than 95%, and require surgery in less than 5% of cases [30]. Lip ulceration depends strongly on total dose and dose rate. In the GEC-ESTRO overview 27 the incidence of lip ulceration was 0%with doses under 50 Gy, 4.8% for 50 - 60 Gy,

Lip and buccal mucosa

12

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

Table 3: Local recurrence rate in buccal mucosa carcinoma with LDR 20. A: brachytherapy alone, B: EBRT + brachytherapy, C: EBRT alone, D Surgery ± EBRT, IBT: interstitial brachytherapy.

Author (reference)

Year

Number

TNM

T

Brachy

Local recurrence

106 T1 210 T2 175 T3 257 T4

A 266 B 80 C 273 D 167

A 19% B 35% C 55% D 22%

LDR Ra, Au, Ir

Gerbaulet (9)

1985

748

23 T1 33 T2 23 T3 6 Tx

1994 2001

A B

A 26% B 48%

Gerbaulet (8)

84

LDR Ir

1995 1996

Parallel tubes Loops

42% 9% loops

Lapeyre (19) Pernot (18)

42

36 T1-3

LDR Ir

LDR Ir IBT Moulds

IBT: 6% Mould 45%

Sakai (42)

1998

55

T1-4

A, B, C, D

T1 8 T2 30 T3 7

Permanent implants Au, Rn

Shibuya (43)

1993

45

A, B

14%

6.3% for 60 - 70 Gy, 7.3% for 70 - 80 Gy, 7.7% for 80 - 100 Gy and in 3/8 patients treated with doses over 100 Gy. Ulceration also is dose rate dependent present in 2.5% at dose rates under 40 cGy/h, in 6% between 40 - 80 cGy/h, 6.9% between 80-120 cGy/h and 15.2% at dose rates over 120 cGy/h. Cosmetic outcome is good to excellent in 80%-95% [27-28-30] with usually only mild depigmentation in 2.5 - 17.3% [27-28-30], teleangiectasia in 15.2%, light oedema 4.4%, dyskeratosis in 4.8% or fibrosis in 8% [30]. In the GEC-ESTRO review good to excellent cosmesis was seen in 94.9% of T1, 84.3% of T2, 72.5% of T3 and 60% of T4 [27]. Poor outcome was noted in 1.3% of T1, 4.1% of T2, 10.1% of T3 and 20% of T4. Lip deformation and retraction is seen in 6% of cases and is seen more frequently after treatment of larger lesions and commissural lesions. Functional loss due to lip deformationwas noted in the GECESTROoverview in 0/126 upper lip, 0.5% of 1199 lower lip, and in 4.2% of 92 commissural cases [27]. Mazeron [12] reported grade 3 cosmetic and functional late effects in 1% of 393 T1, in 5% of 363 T2 and 9 % of 78 T3 lesions. Cosmetic outcome has also been related to dose and dose rate. In the GEC-ESTRO study cosmetic outcome was excellent or good in 96.5% under 50 Gy, 91% between 50 - 70 Gy and 85% for doses over 70 Gy. In T1 cases (when cosmetic damage due to T size is minimal) bad cosmesis was seen in 0%when dose was lower than 60cGy, 1.5% between 60-80 Gy, and 8.6% over 80 Gy. Very few data have been published on complication rates for buccal mucosa LDR- BT. They are estimated to be about 15 to 20% for brachytherapy alone and 25 to 30% for combined irradiation With HDR the adverse side effects are fewer than with LDR [4]. Hair loss, fibrosis, depigmentation, and small telangiectasia on long term follow up are recorded. With LDR it is difficult to maintain a labial protection during the entire time since the irradiation is continuous.The University of Turin published its results with LDR

brachytherapy in 47 T1-2 patients, administering doses between 60 and 80 Gy. They report a 10.6% incidence of mucosal necrosis. In a review of the Valencian Institute of Oncology comparing 99 cases treated with LDR until 1997 (24% treated with plastic tubes) and 104 patients with HDR (all with needles and external fixation with templates), the incidence of long-term complications went down from 16% to 0%. There were no cases of soft tissue or bone necrosis in patients treated with HDR-BT. Moreover, the aesthetic and functional effects were all G1 (normal appearance) or G2 (visible sequelae without functional alteration), with good buccal closure. There were no cases of microstomia, as happens in some cases with surgery.

Lip and buccal mucosa

13

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

14. KEY MESSAGES

• Lip carcinoma is well managed with brachytherapy

• Local control with LDR is more than 90%

• Functional results are better than with surgery in many cases, because microstomia is avoided.

• HDR and PDR brachytherapy can be safely used with similar results as LDR.

• Complications with HDR or PDR are probably fewer than with LDR due to dose optimization.

• With HDR a fractionation of 4-5Gy twice a day is recommended, for 8-10 fractions.

• Parallel rigid needles with templates or plastic tubes can be used.

• Buccal mucosa cancers can be treated with brachytherapy alone or as a brachytherapy boost after EBRT.

• Local control for buccal mucosa cancer is not as high as for lip carcinomas, but if brachytherapy is part of the treatment, outcome is better than with EBRT alone.

Lip and buccal mucosa

14

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

15. REFERENCES

23. Serkies K, Ziemlewski A, Sawicki T, Kamińska J, Dziadziuszko R. Pulsed dose rate brachytherapy of lip cancer. J Contemp Brachytherapy. 2013 Sep;5(3):144- 7 24. Guinot JL, Arribas L, Chust ML, et al. Lip cancer treatment with high dose rate therapy. Radiother Oncol 2003;69:13–5. 25. Kovacs G, Martinez-Monge R, Budrukkar A, et al. GEC-ESTRO ACROP recommendations for head & neck brachytherapy in squamous cell carcinomas: 1st update – Improvement by cross sectional imaging based treatment planning and stepping source technology. Radiother Oncol 2017; 122:248–254. 26. Farrús B, Pons F, Sánchez-Reyes A, et al. Quality assurance of interstitial brachytherapy technique in lip cancer: comparison of actual performance with the Paris System recommendations. Radiother Oncol 1996; 38: 145-51. 27. Van Limbergen E, Ding W, Haustermans K, et al. Lip cancer: local control results of low dose rate brachytherapy. The GEC-ESTRO 1993 survey on 2800 cases. (unpublished data presented at the annual GEC ESTRO meeting Venice 1993). 28. Gerbaulet A, Chassagne D, HayemM et al. L’épithélioma de la lèvre. Une série de 335 cas. J Radiol Electrol 1978; 59: 603-610. 29. Pigneux J, Richaud PM, Lagarde C. The place of interstitial therapy using 192 iridium in the management of the carcinoma of the lip. Cancer 1979;43:1073- 7. 30. Cowen D, Thomas L, Richaud P et al. Cancer des lèvres. Résultées du traitement de 299 patients. Ann Oto-Laryngol 1990; 107:121-126. 31. Orecchia R, Rampino M, Gribaudo S, Negri GL. Interstitial brachytherapy for carcinomas of the lower lip. Results of treatment. Tumori 1991; 77 (4): 336- 338. 32. Fongione S, Signor M, Beorchia A. Interstitial brachytherapy in carcinoma of the lip. Case histories and results. Radiologia Medica. 1994; 88(5):657-660. 33. Arribas L, Mengual JL, GMiragall E, et al. Tratamiento del cáncer de labio con braquiterapia. Actas Dermosifiligr. 1998; 89:56-60. 34. Conill C, Verger E, Marruecos J, Vargas M, Biete A. Low dose rate brachytherapy in lip carcinoma. Clin Transl Oncol. 2007 Apr; 9(4):251-4. 35. Guibert M, David I, Vergez S, et al. Brachytherapy in lip carcinoma: long-term results. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):839-43 36. Rio E, Bardet E, Mervoyer A, Piot B, Dreno B, Malard O. Interstitial brachytherapy for lower lip carcinoma: global assessment in a retrospective study of 89 cases. Head Neck. 2013 Mar;35(3):350-3 37. Finestres F, Guix B, Cloquell A, Chimenos E, Tello JL. Treatment of the carcinoma of the lip through high dose rate brachytherapy. Med Oral Patol Oral Cir Bucal 2005; 10 (21–4):17–20. 38. Lebioda A, Makarewicz R, Terlikiewicz J, Wronczewska A, Kabacinska R, Zuchora A. Results of interstitial HDR brachytherapy for cancer of the lower lip. Reports Pract Oncol Radiother. 2005; 10(4):203-207 39. Ayerra AQ, Mena EP, Fabregas JP, Miguelez CG, Guedea F. HDR and LDR Brachytherapy in the Treatment of Lip Cancer: the Experience of the Catalan Institute of Oncology. J Contemp Brachytherapy. 2010 Mar;2(1):9-13. 40. Ghadjar P, Bojaxhiu B, Simcock M, et al. High-dose-rate versus low-dose rate brachytherapy for lip cancer. Int J Radiat Oncol Biol Phys 2012; 83:1205–12. 41. Mut A, Guinot JL, Arribas L, et al. High dose rate brachytherapy in early stage squamous-cell carcinoma of the lip. Acta Otorrinolaringol Esp. 2016 Sep- Oct;67(5):282-7. 42. Sakai M, Hatano K, Sekiya Y, et al. Radiotherapy for carcinoma of the buccal mucosa: analysis of the prognostic factors. Nippon Igaku Hoshasen Gakkai Zasshi 1998; 98: 705-11. 43. Shibuya H, Takeda M, Matsumoto S, et al. Brachytherapy for non metastatic squamous cell carcinoma of the buccal mucosa. An analysis of forty-five cases treated with permanent implants. Acta Oncol 1993; 32: 327-30.

1. De Visscher JG, van der Waal I. Etiology of cancer of the lip. A review. Int J Oral Maxillofac Surg 1998; 27:199–203. 2. Czerninski R, Zini A, Sgan–Cohen HD. Lip cancer: incidence, trends, histology and survival: 1970–2006. Br J Dermatol 2010; 162:1103–1109 3. Mazeron JJ, Richaud P. Treatment of epidermoid epithelioma of the lip. 2363 cases. Presse Med. 1983; 12:2183. 4. Guinot JL, Arribas L, Tortajada MI, et al. From low dose rate to high dose rate brachytherapy in lip carcinoma: equivalent results with fewer complications. Brachytherapy. 2013; 12:528-34. 5. Vartanian JG, Carvalho AL, de Araujo Filho MJ, Junior MH, Magrin J, Kowalski LP. Predictive factors and distribution of lymph node metastasis in lip cancer patients and their implications on the treatment of the neck. Oral Oncol 2004; 40:223–227. 6. Urist MM, O’Brien CJ, Soong SJ, et al. Squamous cell carcinoma of the buccal mucosa:analysis of prognostic factors. Am J Surg 1987; 154: 411-4. 7. Gerbaulet A, Haie-Meder C, Marsiglia H, et al. Role of brachytherapy in the treatment of Head & Neck cancer. Ed: Mould RF, Battermann JJ, Martinez A, et al. In: Brachytherapyfrom radium to optimisation 1994; 101-20. 8. Gerbaulet A, Maher M. Brachytherapy in the treatment of head and neck cancer. In Joslin CAF, Flynn A, Hall EJ (eds.) Principles and practice of brachytherapy 2001; London: Arnold, 284-95 9. Gerbaulet A, Pernot M. Le carcinome epidermoide de la face interne de joue: à propos de 748 malades. J Eur Radiother 1985; 6: 1-4. 10. Bloom ND, Spiro RH. Carcinoma of the cheek mucosa. A retrospective analysis. Am J Surg 1980; 140 (4): 556-9. 11. Vegers JW, Snow GB, Van der Waal I. Squamous cell carcinoma of the buccal mucosa. A review of 85 cases. Ann Otolaryngol 1979; 105: 192-5. 12. Mazeron JJ, Richaud P. Compte Rendu de la XVIIIe réunion du Groupe Européen de Curietherapie. Padova, mai 1981 Sesion consacrée aux cancers de la lèvre. J Eur Radiother 1984; 5: 50-56. 13. Gerbaulet A, Grande C, Chirat E, et al. Braquiterapia intersticial con iridio 192 en el carcinoma del labia: analysis de 231 casos tratados en el Institut Gustave Roussy. Oncologia 1994; 17: 45-9. 14. Guinot JL, Arribas L, Vendrell JB, et al. Prognostic factors in squamous cell lip carcinoma treated with high-dose-rate brachytherapy. Head Neck . 2014; 36:1737-42. 15. Altinyollar H, Berbero_glu U, Celen O. Lymphatic mapping and sentinel lymph node biopsy in squamous cell carcinoma of the lower lip. Eur J Surg Oncol 2002; 28:72–74. 16. Beauvois S, Hoffstetter S, Peiffert D, et al. Brachytherapy for lower lip epidermoid cancer: tumoral and treatment factors influencing recurrences and complications. Radiother Oncol 1994; 33: 195-203. 17. Vukadinovic M1, Jezdic Z, Petrovic M, Medenica LM, Lens M. Surgical management of squamous cell carcinoma of the lip: analysis of a 10-year experience in 223 patients. J Oral Maxillofac Surg. 2007 Apr;65(4):675-9. 18. Pernot M, Hoffstetter S, Peiffert D, Aletti P. Role of interstitial brachytherapy in oral and oropharyngeal carcinoma: Reflection of a series of 1344 patients treated at the time of initial presentation. Otolaryngol Head Neck Surg 1996; 115: 519-26. 19. Lapeyre M, Peiffert D, Malissard L, et al. An original technique of brachytherapy in the treatment of epidermoid carcinoma of the buccal mucosa. Int J Radiat Oncol Biol Phys 1995; 33: 447-54. 20. Gerbaulet A, van Limbergen E. Lip cancer. In The GEC ESTRO Handbook of Brachytherapy. Gerbaulet A, Pötter R, Mazeron JJ, Meertens H, van Limbergen E. 21. Tombolini V, Bonanni A, Valeriani M, Zurlo A, Vitturini A.Brachytherapy for squamous cell carcinoma of the lip. The experience of the Institute of Radiology of the University of Rome "La Sapienza". Tumori. 1998 Jul- Aug;84(4):478-82. 22. Johansson B, Karlsson L, Hardell L, Persliden J. Long term results of PDR brachytherapy for lip cancer. J Contemp Brachytherapy. 2011 Jun; 3(2):65-69.

Lip and buccal mucosa

15

THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 10/05/2019

ACKNOWLEDGEMENTS The authors of this chapter are much indebted to Prof. Alain Gerbaulet, one of the authors of the original version on lip and buccal mucosa brachytherapy in the first edition of the GEC-ESTRO Handbook of Brachytherapy 2002.

AUTHORS José Luis Guinot, MD Head of Brachytherapy Department of Radiation Oncology Fundacion Instituto Valenciano de Oncologia (IVO) Valencia, Spain

Vratislav Strnad. MD Professor of Radiation Oncology University Hospital Erlangen Erlangen, Germany Erik Van Limbergen, MD, PhD Professor of Radiation Oncology University Hospital Gasthuisberg Leuven, Belgium