Introduction
Lip and oral cancers are the 15th most common cancers worldwide, with two-thirds occurring in men [1]. Unlike other upper aerodigestive tract cancers, which are primarily caused by tobacco, sunlight exposure is a significant risk factor for lip cancers, particularly those on the lower lip, which are more common than upper lip cancers.
Due to its visible location, lip cancers are often detected early, allowing effective treatment with a single modality [2]. Early-stage lip cancers can be managed effectively with either radiotherapy or surgery, offering local control rates between 90% and 95% [3].
While surgery provides excellent disease control, reconstructing the lips, oral commissure, and mucosa defects post-tumor resection poses significant challenges [4]. Functionally, lips are crucial for oral competence during swallowing and play a key role in emotional and verbal communication. Aesthetically, they are a focal point of facial identity. Poor reconstructive approaches can lead to microstomia, disfigurement, loss of sensation, and issues with oral competence and natural oral angle [5]. Elderly patients face additional challenges in reconstruction due to complex medical histories, prolonged general anesthesia, issues of age-related tissue quality, and significant comorbidities like diabetes that delay wound healing [6]. External beam radiotherapy (EBRT) is another treatment modality for lip and buccal mucosa cancers. Still, it does not adequately spare adjacent normal tissues, such as the salivary glands and mandible, leading to undesirable late side effects [7].
Brachytherapy in lip and oral cavity cancers is an important alternative to surgery or conventional EBRT, aiming to preserve normal anatomy and enhance both cosmesis and functional outcomes. Moreover, the affordable cost, shorter treatment duration, and ability to provide high localized doses with rapid dose fall-off make it an excellent tool for delivering highly conformal therapy with fewer side effects than EBRT [8].
Traditionally low-dose-rate (LDR) brachytherapy was used to treat tumors in head and neck sites like lips, tongue, buccal mucosa, etc. However, it is being replaced by high-dose-rate (HDR), which gives similar local control, and functional and cosmetic outcomes [9]. Besides safety and convenience, HDR brachytherapy has added advantages like intensity modulation using varying dwell time and position. The introduction of 3-dimensional (3D) imaging modality for brachytherapy planning has refined the definition of target volume and organs at risk, enhancing overall treatment accuracy.
Despite its efficacy, the use of brachytherapy is declining in oral tumors due to the limited availability of data, insufficient dissemination of the technique, advancements in EBRT, and a lack of training and experience among healthcare professionals [10]. Given the technique's efficacy in cancer treatment, providing data on treatment outcomes and discussing the technique is crucial. This retrospective study aims to evaluate the outcomes of image-guided HDR brachytherapy as a sole treatment modality for lip and buccal cavity cancers, focusing on disease control, and organ and function preservation.
Materials and Methods
1. Patient selection
This retrospective study reviewed 10 consecutive patients with histologically confirmed squamous cell carcinoma of the lip (n = 6) or buccal mucosa (n = 4) treated with exclusive brachytherapy at our institution between May 2019 and December 2024.
Eligible patients included those with histologically confirmed early to moderately advanced squamous cell carcinoma (T1–T4 categories) who were considered suitable for brachytherapy as a sole treatment modality. Individuals with contraindications to surgery, such as advanced age, significant comorbidities, or personal unwillingness to undergo surgical intervention, were included in the study. Patients with a history of prior surgery, radiation therapy, or systemic chemotherapy in the same treatment area were excluded. All patients were assessed and approved as appropriate candidates for brachytherapy by a multidisciplinary tumor board.
Clinical staging of th T1 (n = 3), T2 (n = 6), and T4 (n = 1). Table 1 enumerates individual patients and tumor characteristics, dose fractionation, and outcome. A significant number of patients in our study had multiple health issues, including compulsive obstructive pulmonary disease, myocardial infarction, a second malignancy, and kidney transplantation. Additionally, two patients were over 90 years old, one of whom had suffered a myocardial infarction leading to poor cardiac function precluding general anesthesia.
All patients underwent comprehensive staging, including physical examination, a biopsy of the primary site, chest X-ray, and contrast-enhanced computed tomography (CT)/magnetic resonance imaging of the head and neck when necessary. An ultrasonogram of the neck was done in all cases. Positron emission tomography–CT was not done either due to early-stage disease or due to financial limitations. Baseline blood counts and biochemistry were obtained.
2. Implantation technique
All implants were performed under local anesthesia via nerve or field block. The implantation volume was defined as tumor plus a 1 cm margin of surrounding normal tissue to ensure adequate coverage. The tumor and planned needle track including entry and exit points were marked in the skin using clinical examination and imaging data (Fig. 1). Using tactile guidance, a hollow stainless steel guide needle was inserted along the predetermined entry and exit points. Flexible afterloading plastic catheters were threaded along the steel guide needle and the steel guide needle was removed. Catheters were then cut to the desired length and secured with buttons. The spacing between catheters was 8 mm to 1 cm. Most patients received single-plane implants, while one lower lip case required a two-plane implant which was performed following the Paris method.
To maintain the implant during the radiation therapy, catheters were secured in place using adhesive dressing and buttons to prevent displacement. Patients were provided with a soft or liquid diet, often using a straw to take liquid or semi-solid food, to avoid disturbing the implant and minimize irritation to the treatment area. Nutritional supplements were offered as needed to ensure adequate caloric intake.
Despite the use of rigid needles in some published studies for HDR brachytherapy, we always use plastic tubes. This preference enables CT-based planning, facilitates the contouring of clinical target volume (CTV), and allows for a 3D calculation of the isodose distribution and comfort to the patient.
3. Radiation planning and delivery
Simulation CT scans for dose specification were obtained on the second day of the implant using a 1 mm slice thickness at the implant region in a 16-slice CT Scanner (Toshiba Alexion, Otawara, Japan). Dwell positions and times were computer-optimized following Paris system rules. The aim was to cover 90% of the target volume with more than 90% of the prescription dose while minimizing the volume receiving 150% (V150) and 200% of the prescription dose (Fig. 2). The dosimetric parameters were recorded and a linear regression model was used to model the relationship between CTV and V150.
A personalized mold or spacer made from wax or thermoplastic was used, with lead shielding added during treatment to protect nearby healthy tissue, particularly the mandible and tongue.
HDR brachytherapy was delivered using an iridium-192 afterloader (Gammamed, Varian Inc., Palo Alto, CA, USA) with 40-44 Gy doses given in 4 Gy fractions twice daily over a median of 5 days (range, 5 to 6) [11]. The dose prescription was based on the CTV volume. Patients stayed in the hospital for logistical reasons throughout their HDR brachytherapy treatment. Anti-inflammatory medications, analgesics, and antibiotics were prescribed as needed. After the implant was removed, patients received post-procedure instructions and were discharged.
4. Follow-up and outcome measures
Patients were asked to visit the hospital for routine follow-up weekly for the first month, every 3 months for the first year, and every 6 months thereafter. Follow-up included clinical examinations and imaging studies including ultrasonogram and CT scan. The primary endpoint was local tumor control, defined as the absence of tumor growth at the primary site. Secondary endpoints included treatment-related toxicities and overall survival. Local recurrence was defined as tumor regrowth at the treated site, while regional recurrence referred to tumor involvement of lymph nodes in the head and neck region. Response to treatment was categorized as complete response, partial response, disease progression, or recurrence. Descriptive statistics were used to summarize patient characteristics and treatment parameters. Treatment-related toxicities were graded according to the Common Terminology Criteria for Adverse Events version 5.0.
Aesthetic and functional outcomes were assessed using standardized photography evaluated by a panel of five plastic surgeons and five ear, nose and throat surgeons with an average of 8.5 and 8 years of clinical experience, respectively. Outcomes were rated on a three-point scale: 1 (good result), 2 (moderate result), and 3 (poor result) [12].
Results
Brachytherapy was safely administered to all 10 patients without any severe pain, discomfort, or complications, such as bleeding or infection. After the treatment, all the patients achieved complete response and maintained their remission over the median follow-up period of 29 months (range, 16 to 68). All of the patients are still in follow-up.
One patient experienced regional nodal failure. All patients achieved complete remission and 100% local control in the implanted site, exhibiting good to excellent cosmetic results. Representative photographs of tumor sites before and after treatment are shown in Fig. 3. Dosimetric parameters are presented in Table 2. In two patients, surface catheters were added to improve dose coverage (sandwich technique) [13].
Regarding dosimetry, the median number of interstitial catheters used in the treatment was 3 (range, 3 to 7). The regression analysis demonstrated a correlation between the CTV and the V150 (R2 = 0.85, p < 0.001), as shown in Fig. 4.
Patients experienced some acute events during the procedure which were mild to moderate, with none beyond grade 3. The most common acute toxicities were pain, mucositis and dermatitis. For the late adverse events, the highest level of toxicity was grade 2 fibrosis in one patient. No late side effects, such as dry mouth (xerostomia), soft tissue damage, or bone necrosis, were observed in the patients (Table 3).
All patients maintained lip symmetry and projection during follow-up assessments, resulting in pleasing aesthetic outcomes. Out of the 100 individual ratings given by the panel of 10 doctors, 77 were scored as 1 (good), indicating high satisfaction with the outcomes. Twenty-two ratings were scored as 2 (moderate), and only one was scored as 3 (poor).
All patients exhibited adequate facial expressions. Clinical evaluations indicated normal mouth opening, pouting, lip control, and sensation. In cases involving lesions near the oral commissure or modiolus, oral competence was preserved without the development of a narrowing of opening (microstomia) or loss of angle of the mouth, demonstrating preservation of form and function.
Discussion and Conclusion
In the treatment of lips and perioral cancers, the objective is twofold: achieving adequate tumor control while concurrently preserving optimal functional and cosmetic outcomes. Specifically, it aims to maintain patency for adequate oral aperture and ensure satisfactory cosmesis.
In our study, we achieved excellent local control and preserved cosmesis using HDR brachytherapy as the sole treatment for lip and buccal mucosa cancers. The acute and late adverse events observed in the patients were manageable, with most patients experiencing only low-grade toxicities at the median prescribed dose of 40 Gy in 10 fractions twice daily.
Similarly favorable outcomes of HDR interstitial brachytherapy have been reported by Guinot et al. [14] in 102 patients of lip cancer with a local control rate of 94.6%, a nodal regional control rate of 88.6%, and a disease-free survival rate of 84.6%. Likewise, in a systematic review consisting of seven studies comprising 456 patients with early-stage oral cancers, Draghini et al. [15] observed 5-year local control rates ranging from 60% to 100%, disease-free survival rates between 82% and 91%, and overall survival rates between 50% and 84%.
In brachytherapy, most of the past literature was based on LDR and manual afterloading techniques [16]. Initially, when HDR was introduced, there were some concerns about the radiobiological effects and toxicity of HDR [17]. However, Ghadjar et al. [18] compared the treatment outcomes of HDR and LDR brachytherapy in 103 lip cancer patients and reported a 5-year regional recurrence-free survival of 90% with no significant difference between the two modalities. Another study by Guinot et al. [19] in a series of 203 lip cancer patients reports a comparable 95% local control between HDR brachytherapy and LDR brachytherapy in lip cancer but fewer complications and no bone or soft tissue necrosis associated with HDR brachytherapy. A meta-analysis of trials devoted to HDR vs. LDR brachytherapy for oral cancer concludes that HDR brachytherapy is a comparable alternative to LDR brachytherapy in the treatment of oral cancer, and it might become a standard treatment option in oral cancers [20].
Previous literature has reported various fractionation schedules for HDR brachytherapy in oral cancers [21]. Our median total dose of 40 Gy in 10 fractions of 4 Gy each resulted in an acute biologically effective dose (α/β ratio = 10 Gy) of 56 Gy and a late biologically effective dose (α/β ratio = 3 Gy) of 93.3 Gy. Guidelines recommend a total dose of 45–54 Gy, administered in 4–4.5 Gy fractions with two fractions per day spaced at least 6 hours apart, which is slightly higher than the dose we used in our study [22].
The dose nonuniformity ratio (DNR) of 0.64 observed in our study is slightly higher than recommended in some guidelines [22]. Higher DNR values have been observed when the gross tumor volume volume and number of catheters are small or brachytherapy is performed particularly in complex areas like the head and neck without a corresponding increase in toxicity [23,24].
However, more dosimetry studies would be needed as there is no clear consensus on the acceptable value of DNR.
In the treatment of head and neck cancer, several authors have proposed the concept of “in-field” and “out-of-field” toxicity for radiation-induced toxicity [24,25]. The adverse effect occurring right in the area of treatment with the prescribed dose of radiation is referred to as in-field toxicity while unintended radiation exposure to adjacent tissues other than the primary radiation area is referred to as out-field toxicity [26]. We used a personalized spacer made from wax or thermoplastic material during simulation, which was combined with lead shielding during treatment delivery. The use of custom shielding/spacer in our approach contributed to the improved results by reducing out-field toxicity.
Studies have reported acceptable acute and late adverse events with major toxicities of acute mucositis and skin reactions in the treatment of lip and buccal mucosa cancer with HDR brachytherapy [14]. Guinot et al. [14] reported acute reactions of grade 4 hemorrhaging mucositis in 50% of patients and grade 3 confluent mucositis in 50% of patients with no severe late events. Acute and late adverse events observed in our patients were minimal and manageable. We observed hypopigmentation in the needle entry point in some patients, where a high dose had to be delivered to the skin due to disease conditions [27].
High quality-of-life (QOL) scores and high satisfaction levels have been reported among patients undergoing interstitial brachytherapy, particularly in the periorificial face region [27,28]. Likewise, our excellent cosmetic and functional outcomes as assessed by the panel of experts, serve as evidence that HDR brachytherapy confers significant aesthetic and functional benefits to the patients. However, the lack of a commonly shared grading system adds challenges in standardizing assessments across studies. A consistent and widely adopted method of assessing functional and cosmetic outcomes would ensure consistent and objective evaluation.
Whether or not to address the neck nodes in lip cancer patients is a debatable issue. Management of the neck in brachytherapy as monotherapy has varied from watchful waiting to elective nodal irradiation and/or radical neck dissection [29]. In a study of 617 patients, the lymph node involvement was 7.9% in T1 to T2 and 27.9% in T3 to T4 and in another study by Cowen et al. [30] conducted with 299 patients, it was 5.6% in T1 to T2 and 17.6% in T3 [20-31]. In our series, a 90-year-old gentleman with a T2 tumor at the angle of the mouth suffered a nodal relapse in level Ib after 7 months of brachytherapy completion. The patient subsequently underwent a modified neck dissection for right lymph node recurrence. Pathological examination revealed malignancy in 1 out of 10 lymph nodes at level 1b and was subsequently kept in follow-up. Another young patient opted for upfront prophylactic neck dissection, while the primary lip tumor was treated with brachytherapy for a better cosmetic outcome.
This combined brachytherapy to primary and neck dissection approach can be a good strategy for younger lip or buccal mucosa cancer patients. However, most of the patients are older and have comorbidities, and ultrasound surveillance of the neck may be reasonable for them [32]. Since early-stage lip cancers, especially those limited to the lip itself, have a low risk of nodal spread, observation of the neck can be considered [33]. Sentinel node biopsy is another potentially less aggressive option than surgery or radiation and can be done on the same day of the procedure [34].
Our study demonstrates that HDR brachytherapy is an effective monotherapy for oral cancers, particularly for the lip and buccal mucosa. All patients achieved good functional outcomes. Despite significant comorbidities in many patients, treatments were successful, indicating the efficacy of HDR brachytherapy for lip and buccal mucosa cancer patients with diverse underlying conditions, especially among the elderly. Additionally, the minimally invasive nature, lack of general anesthesia requirement, curative approach, and short treatment duration of around one week make HDR brachytherapy particularly suitable for elderly patients [35].
This study encompasses several limitations including its retrospective nature, small patient number, single institute-based study, short follow-up period, and operator dependence. However, given the paucity of prior studies evaluating HDR brachytherapy for lip and buccal mucosa cancers in our region, our study adds significant additional information to the available body of knowledge on the use of HDR brachytherapy for treating these cancers
This study explores the procedure and outcomes of using HDR interstitial brachytherapy for treating lip and buccal mucosa cancers. Our approach of delivering a median dose of 40 Gy in 10 fractions of brachytherapy twice daily, has shown to be a safe and effective treatment in achieving excellent local control, cosmetic results, and function preservation. These findings underscore that interstitial brachytherapy with a dose fractionation regimen of 40-44 Gy effectively balances the need for robust local cancer control with QOL in cases of lip and buccal mucosa cancers.
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