eISSN: 2081-2841
ISSN: 1689-832X
Journal of Contemporary Brachytherapy
Current Issue Archive Supplements Articles in Press Journal Information Aims and Scope Editorial Office Editorial Board Register as Author Register as Reviewer Instructions for Authors Abstracting and indexing Subscription Advertising Information Links
SCImago Journal & Country Rank

vol. 11
Original paper

Adjuvant interstitial three-dimensional pulse-dose-rate-brachytherapy for lip squamous cell carcinoma after surgical resection

Artur Jan Chyrek, Grzegorz Mikołaj Bielęda, Wojciech Maria Burchardt, Adam Chicheł, Piotr Andrzej Wojcieszek

J Contemp Brachytherapy 2019; 11, 2: 116–121
Online publish date: 2019/04/30
Article file
- adjuvant.pdf  [0.39 MB]
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero


Lip cancer is a rare malignancy among the global population, with an incidence of 0.3 cases per 100,000 per year [1,2]. There are regions where a number of cases are higher than average. It may be linked to sun exposure, combined with specific skin phenotype (e.g., Spain, Australia) or with increased consumption of tobacco and alcohol (e.g., Central and Eastern Europe) [1]. Other factors include male sex and low level of education. The decrease in the incidence of lip cancer may be associated with educational activities, an increase of self-consciousness, and a drop in tobacco use in the last 20 years [1,2]. Ninety-five per cent of lip malignancies are squamous cell carcinomas [3].
Radical surgery, with or without lymphadenectomy, is the first choice and gold standard of treatment [4,5,6,7,8,9]. However, if surgery is subtotal (i.e., positive or close margins), which is not unusual, there is a need for adjuvant irradiation to decrease the risk of a recurrence [10,11]. Recommendations for adjuvant treatment following non-radical lip cancer surgery seem to be imprecise. Positive margins or perineural invasion are mentioned as the indications for irradiation; a panel of experts issued no opinion on close margins proceedings, but they added that every squamous cell carcinoma (SCC) case should be treated individually [5,10,12].
There are data available on brachytherapy regarding the treatment of lip cancer [13,14,15,16,17,18,19,20,21,22,23]. Results reported in these studies are encouraging, with five-year local control of 77-100%, and mostly good cosmetic outcomes and no grade 4 late toxicities. However, these publications analyzed heterogeneous groups of patients, with either primary tumors, local relapses, or after non-radical surgery, treated with low-dose-rate brachytherapy (LDR-BT), pulse-dose-rate brachytherapy (PDR-BT), or high-dose-rate brachytherapy (HDR-BT). There is no recommendation on adjuvant brachytherapy after surgical excision. Interstitial PDR-BT is preferred for lip cancer management in our center. We aim to analyze the efficacy and toxicity of adjuvant PDR-BT retrospectively after insufficient surgery in the management of lip cancer.

Material and methods

Twenty lip cancer patients, with a median age of 66.5 years (range, 45-94 years) were treated from January 2012 to September 2016. There were three women and 17 men in the analyzed group. Most of them had lower lip (95%) involvement. Primary treatment included surgery with or without reconstruction, 75% and 25%, respectively. Moreover, 70% of patients underwent neck dissection. Either bilateral lymphadenectomy (40%; with suprahyoid bilateral neck dissection, 35%) or selective neck dissection (30%) were performed. All patients were diagnosed with squamous cell carcinoma, while most of the tumors were pT1 (60%, according to UICC/AJCC TNM version 7, 2009). One patient had micrometastasis in a node of IA group. Patients were qualified for adjuvant PDR-BT due to positive or close post-operative margins (< 5 mm). Patients characteristics are summarized in Table 1.
Brachytherapy procedures were completed after post-operative wound healing (median of 62 days; range, 40-96 days). Plastic catheters (flexible implant tubes by Nucletron, an ELEKTA company, ELEKTA AB, Stockholm, Sweden) were implanted, with insertion needles into the tumor bed under local anesthesia in the operating theatre. Median of three plastic tubes were implanted (range, 1-5). A free-hand technique was used. After the implantation, computed tomography scanning without contrast was done, with maximum slices of 1.2 mm (Figure 1). Treatment planning was completed with the OncentraBrachy system (Nucletron, an ELEKTA company, ELEKTA AB, Stockholm, Sweden). Two PDR-BT treatments with two separate implantations were scheduled for every patient, with a gap of median 13 days (range, 6-17 days). Patients were connected to microSelectron PDR (Nucletron, an ELEKTA company, ELEKTA AB, Stockholm, Sweden) afterloader (192Ir stepping source, with nominal activity 1 Ci) for whole treatment session and could be disconnected on demand between pulses. The presence of physician and qualified nurse on the ward during the procedure was required but their presence in the afterloader control room was not – the patient was continuously observed via audio-visual system. The planned dose was 0.8-1 Gy per pulse to total dose from two PDR-BT treatments of 50 Gy. A physician defined clinical target volumes (CTV) after every implantation (median, 3.95 ml; range, 1.4-12.83 ml), which was a scar with margins adapted to the initial tumor volume, location, and pathological report; the total margin of surgery and PDR-BT should be at least 1 cm. The transversal plane was used for catheters reconstruction. Source step was 2.5 mm, while no active positions were allowed outside the CTV. An initial plan was prepared with inverse planning simulated annealing algorithm for dwell time deviation constraint of 0.3. In the next step, the treatment plan was graphically optimized by a physicist. A final plan was chosen according to 90% isodose coverage of CTV (D90) and volumes of 100% and 150% isodoses (V100, V150). Maximal dose and volume of 200% isodose were reported. Maximal dose on the skin surface (Dmax skin) was investigated retrospectively for this analysis.
Eleven patients (55%) received 1 Gy per pulse and four patients (20%) 0.8 Gy per pulse, while for five patients (25%), 1 Gy per pulse was prescribed for the first PDR-BT and 0.8 Gy per pulse for the second treatment due to logistic reasons. Every treatment contained 25 to 32 pulses, given every 50-60 minutes. Median total dose from two fractions was 50 Gy (range, 49.8-50.6 Gy). Utilizing / = 10 Gy and sublethal damage repair halftime T1/2 = 1 h for squamous cell carcinoma for early effects, and / = 3 Gy and T1/2 = 1.5 h for late effects biologically effective dose (BED) formula were used to compare scheduled doses and dose-volume parameters (Table 2):
BED = nd [1 + dg/(/], where
n – number of pulses, d – pulse dose, ,  – coefficients determining the death of cells as a result of the passage of one or more radiation quanta, g – repair function
k = e–μx , y = 1 – e–μt, where
μ - repair constant (In/T1/2), t – pulse time, x – time between pulses
No shields were used during the treatment. Patients were discharged after catheters removal. First follow-up visit was planned four weeks after the treatment and then, patients were evaluated every 3-6 months. Follow-up time was counted from the last day of treatment to the last control visit in our center. Early and late toxicities were assessed with RTOG scale after clinical examination. The intensity of acute adverse-events was evaluated until the first visit, while late events were defined as occurring four months after PDR-BT.

Statistical analysis

Data was collected in a spreadsheet (MS Excel). Statistical analysis was performed using Statistica 12.0 (StatSoft, Inc. Tulsa, USA). Students unpaired t-test was applied to determine the significance of the differences for continuous variables between the two-sample means. The Mann-Whitney test was used for ordinal and continuous variables without normal distribution. DFS survival was calculated using the Kaplan-Meier method. Statistical significance was considered if p-value was lower than 0.05.


Average follow-up was 34.7 months (median, 34.5 months; range, 12.7-67.6). Local control at last follow-up was 100%. There was no difference between three- and five-year estimated disease-free survival, which was 95% (Figure 2). One patient suffered from regional relapse in the submental region (IA lymph node group).
The same patient was diagnosed with micrometastasis in the pathological examination after the neck dissection; however, due to the extension of the surgery, multi-disciplinary tumor board resigned from adjuvant elective radiotherapy to the neck lymph nodes.
Acute toxicity was grade 2 or below. Skin erythema or dry desquamation (grade 1) or wet desquamation (grade 2) were observed in 13 patients (65%) and one patient (5%), respectively. Six patients presented no acute toxicity. Moreover, there were no complications involving lip mucosa.
All patients had grade 1 soft tissue fibrosis in the irradiated area, besides that, late toxicity included only skin complications: five patients (25%) reported grade 1 depigmentation, three patients (15%) had mild telangiectasia (grade 2), and two patients suffered from skin ulceration (grade 4). The female patient had diagnosed systemic lupus erythematosus a few months after PDR-BT was finished. The male patient denied medical recommendations during and after PDR-BT, he also was a heavy smoker. Both cases were treated successfully with surgical excision.
There were no significant factors associated with skin late toxicity ≥ grade 2; however, a tendency was observed for higher Dmax skin BED3. Statistical analysis is presented in Table 3.


Even though interstitial brachytherapy is invasive, this irradiation technique seems to be favorable for patients with lip cancer [22]. Due to brachytherapy dosimetric advantages and high conformity, it is eligible for local treatment [24,25,26].
Our study confirmed that interstitial PDR-BT for patients after non-radical lip cancer surgery is efficient and safe. It is in agreement with other brachytherapy studies; however, data on adjuvant brachytherapy in lip cancer management are scarce and limited. Grabenbauer et al. presented head and neck cancer patients treated with adjuvant LDR-BT [14]. Although investigated group included 318 patients diagnosed with oral cavity or oropharynx cancer (a primary or a recurrent tumor; staged from I to IV), only 19 patients (6%) suffered from lower lip cancer. Similarly, Strnad et al. showed large head and neck cancer patient group of 385 patients treated with PDR-BT, but only 19 (3.6%) patients suffered from lip cancer [15]. Ten patients (11%) had adjuvant LDR-BT due to positive margins (6 patients) or relapse after surgery (4 cases), among 89 lip cancer patients described by Rio et al. [16]. In a study, Guinot et al. [17] presented the results of a cohort including 102 patients with lip cancer, out of which, twenty cases (20%) were treated with post-operative HDR-BT. Johansson et al. reported long-term results of PDR-BT in the management of lip cancer in 43 patients, but only 11 patients (26%) were treated because of positive margins [18].
Despite the heterogeneous groups comprising either primary or adjuvant approach, the efficacy of post-operative brachytherapy is excellent. Our results showed 100% local control at last follow-up. Patients from other studies had a similar outcome. Large PDR-BT head and neck study showed no significant differences between anatomical sites, with local control of 86% estimated for 5 years [15]. Another PDR-BT study presented 5-year local control of 95% after median follow-up of 54 months (telephone interviews included) [18]. Loco-regional failure (second head and neck tumor, no lip recurrence) was observed in one (2%) post-operative PDR-BT patient. Also, LDR-BT showed its efficiency, with at least 77% of 5-year local control in combination with external-beam radiotherapy [14]. The same study reported 5-year local control of 89% for post-operative brachytherapy alone. A different study on LDR-BT in lip cancer estimated 100% local control after five years, but all patients treated with excision combined with brachytherapy were staged as T1 [16]. HDR-BT study demonstrated 100% local control after a median follow-up of 45 months; however, two nodal relapses were observed in this group [17].
The GEC-ESTRO recommends interstitial brachytherapy for primary lip cancer treatment [22]. The 2017 update of the GEC-ESTRO ACROP recommendations advise the use of brachytherapy also in the adjuvant option for head and neck tumors, but without any suggestions for dose scheduling [27]. While the interstitial insertion of catheters was consistent among reported groups, treatment schedules varied. Physical prescribed doses are hard to compare, particularly among PDR-BT, LDR-BT, and HDR-BT [13,14,15,16,17,18,19,21]. Nevertheless, biologically effective doses were between 57-73 Gy (tumor / = 10 Gy), which was similar to our group (median, 65 Gy; range, 62-65 Gy). Patients assessed in this paper received total physical dose between 49.8-50.6 Gy, which was less than reported PDR-BT patients (range, 55-57 Gy) [15,18]. However, similar BED was achieved with higher pulse doses, 0.8-1 Gy every 1 hour versus 0.55 Gy/h or 0.834 Gy every 2 hours, even though efficacy and side effects were comparable. Evaluation of available brachytherapy regimens are summarized in the Table 4.
Interstitial brachytherapy as a local adjuvant treatment yields mild toxicity with good cosmetic results. In our group, 90% of patients developed late side effect of grade 2 and below. This is comparable with other PDR-BT groups. Severe complications were reported in 2 up to 10% of lip cancer and head and neck cancer patients [15,18]. Also, some LDR-BT and HDR-BT studies showed low toxicity, with no grade 4 late complications [16,17]. Other LDR-BT head and neck cancer study reported 7.5% of persistent ulcers, with or without osteonecrosis [14].
These results show that even patients with close margins (i.e. < 5 mm) should be considered as candidates for PDR-BT due to its low toxicity and short treatment time. The National Comprehensive Cancer Network’s (NCCN) recommendations of minimal margins of 5 mm in the surgical management of lip cancer are based on two publications [5]. Although both presented worse outcome for surgical patients with margin < 5 mm, one (Looser et al.) presented only two lip cancer patients in the 62 head and neck cancer patients group, while other (Scholl et al.) investigated tongue cancer patients only [11,28]. Moreover, the NCCN recommends that locally advanced lip cancer (> pT2) should be treated with adjuvant radiotherapy, according to Babington et al. [5,10]. This retrospective analysis reported 130 patients with lip cancer (96% ≤ pT2) divided into three groups. Patients were treated with surgery alone (51 patients), radiotherapy alone (62 cases), or a combination of surgery followed by radiotherapy (17 patients). Positive or close margins (≤ 2 mm) were reported in 27% of patients treated with surgery alone, and 96% in the group of combined treatment. The loco-regional failure was presented after surgery or its combination with radiotherapy in 53% and 6% of patients, respectively. Authors concluded that minimal margins should exceed 2 mm with ideal margins of 4-5 mm, but if this goal is not achieved, adjuvant radiotherapy can provide an excellent local control.
As mentioned above, the evidence on the adjuvant lip cancer brachytherapy is limited. One of the most significant problems is small patients’ groups reported in larger datasets including primary tumors and/or other head and neck patients. Moreover, recommendations do not contain guidelines who, how, and when should be treated after lip cancer surgery with interstitial brachytherapy. This should be addressed in a modern digital approach with the use of data collection systems. One of these is the Consortium for Brachytherapy Data Analysis (COBRA), which is used by the GEC ESTRO Head and Neck Working Group [29,30].


PDR-BT in the adjuvant treatment of lip cancer yields high local control with low toxicity. It is advisable to pay significant attention in using maximum dose to the skin; it may be linked to higher complications probability.
Although further studies with larger groups of patients are required, digital tools as the COBRA may be used to find guidelines and recommendations required.


Authors would like to thank Mrs Joanna Koszewska for her contribution in data collection.


Authors report no conflict of interest.


1. Perea-Milla López E, Minarro-Del Moral RM, Martinez-Garcia C et al. Lifestyles, environmental and phenotypic factors associated with lip cancer: a case-control study in southern Spain. Br J Cancer 2003; 88: 1702-1707.
2. Shield KD, Ferlay J, Jemal A et al. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin 2017; 67: 51-64.
3. Veness M. Lip cancer: important management issues. Australas J Dermatol 2001; 42: 30-32.
4. Kerawala C, Roques T, Jeannon JP et al. Oral cavity and lip cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016; 130: S83-S89.
5. NCCN. National Comprehensive Cancer Network. Head and Neck Cancer 2, 2018.
6. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992; 27: 241-248.
7. Campbell JP. Surgical management of lip carcinoma. J Oral Maxillofac Surg 1998; 56: 955-961.
8. Cruse CW, Radocha RF. Squamous cell carcinoma of the lip. Plast Reconstr Surg 1987; 80: 787-791.
9. De Visscher JG, Gooris PJ, Vermey A et al. Surgical margins for resection of squamous cell carcinoma of the lower lip. Int J Oral Maxillofac Surg 2002; 31: 154-157.
10. Babington S, Veness MJ, Cakir B et al. Squamous cell carcinoma of the lip: is there a role for adjuvant radiotherapy in improving local control following incomplete or inadequate excision? ANZ J Surg 2003; 73: 621-625.
11. Looser KG, Shah JP, Strong EW. The significance of “positive” margins in surgically resected epidermoid carcinomas. Head Neck Surg 1978; 1: 107-111.
12. Zitsch RP 3rd, Park CW, Renner GJ et al. Outcome analysis for lip carcinoma. Otolaryngol Head Neck Surg 1995; 113: 589-596.
13. 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.
14. Grabenbauer GG, Rodel C, Brunner T et al. Interstitial brachytherapy with Ir-192 low-dose-rate in the treatment of primary and recurrent cancer of the oral cavity and oropharynx. Review of 318 patients treated between 1985 and 1997. Strahlenther Onkol 2001; 177: 338-344.
15. Strnad V, Lotter M, Kreppner S et al. Interstitial pulsed-dose-rate brachytherapy for head and neck cancer--Single-institution long-term results of 385 patients. Brachytherapy 2013; 12: 521-527.
16. Rio E, Bardet E, Mervoyer A et al. Interstitial brachytherapy for lower lip carcinoma: global assessment in a retrospective study of 89 cases. Head Neck 2013; 35: 350-353.
17. 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: 1737-1742.
18. Johansson B, Karlsson L, Hardell L et al. Long-term results of PDR brachytherapy for lip cancer. J Contemp Brachytherapy 2011; 3: 65-69.
19. Lebioda A, Makarewicz R, Terlikiewicz J et al. Results of interstitial HDR brachytherapy for cancer of the lower lip. Rep Pract Oncol Radiother 2005; 10: 203-207.
20. Orecchia R, Rampino M, Gribaudo S et al. Interstitial brachytherapy for carcinomas of the lower lip. Results of treatment. Tumori 1991; 77: 336-338.
21. Serkies K, Ziemlewski A, Sawicki T et al. Pulsed-dose-rate brachytherapy of lip cancer. J Contemp Brachytherapy 2013; 5: 144-147.
22. Mazeron JJ, Ardiet JM, Haie-Meder C et al. GEC-ESTRO recommendations for brachytherapy for head and neck squamous cell carcinomas. Radiother Oncol 2009; 91: 150-156.
23. Nag S, Cano ER, Demanes DJ et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2001; 50: 1190-1198.
24. Akiyama H, Major T, Polgar C et al. Dose-volume analysis of target volume and critical structures in computed tomography image-based multicatheter high-dose-rate interstitial brachytherapy for head and neck cancer. J Contemp Brachytherapy 2017; 9: 553-560.
25. Akiyama H, Pesznyak C, Bela D et al. Image guided high-dose-rate brachytherapy versus volumetric modulated arc therapy for head and neck cancer: A comparative analysis of dosimetry for target volume and organs at risk. Radiol Oncol 2018; 52: 461-467.
26. Sresty NV, Ramanjappa T, Raju AK et al. Acquisition of equal or better planning results with interstitial brachytherapy when compared with intensity-modulated radiotherapy in tongue cancers. Brachytherapy 2010; 9: 235-238.
27. 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.
28. Scholl P, Byers RM, Batsakis JG et al. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue. Prognostic and therapeutic implications. Am J Surg 1986; 152: 354-360.
29. Tagliaferri L, Budrukkar A, Lenkowicz J et al. ENT COBRA ONTOLOGY: the covariates classification system proposed by the Head & Neck and Skin GEC-ESTRO Working Group for interdisciplinary standardized data collection in head and neck patient cohorts treated with interventional radiotherapy (brachytherapy). J Contemp Brachytherapy 2018; 10: 260-266.
30. Tagliaferri L, Kovacs G, Autorino R et al. ENT COBRA (Consortium for Brachytherapy Data Analysis): interdisciplinary standardized data collection system for head and neck patients treated with interventional radiotherapy (brachytherapy). J Contemp Brachytherapy 2016; 8: 336-343.

Received: 15.02.2019
Accepted: 29.03.2019
Published: 29.04.2019
Copyright: © 2019 Termedia Sp. z o. o. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe