Clinical Investigations
HDR and LDR Brachytherapy in the Treatment of Lip Cancer: the Experience of the Catalan Institute of Oncology

Purpose
In the United States, lip cancer is among the most common type of head and neck skin cancers, with the annual incidence estimation of 1.8 cases per 100 000 inhabitants. Numerous etiological factors such as: alcohol intake, inadequate oral hygiene, tobacco use, sun exposure, and precancerous lesions, have been related to lip cancer, although tobacco use (especially pipes) and sun exposure have the strongest association with this disease. Most patients are men, with a median age of 65 [1]. In 95% of cases, the tumor is located on the lower lip. More than 90% of lip cancers are squamous cell carcinomas while approximately 10% are basal cell carcinomas. Other histological types are exceptional [2].
Lip cancer is a slow-growing, localized cancer often diagnosed at an early stage; as a result, survival rates are usually quite high. At diagnosis, only 5-10% of patients have nodal involvement, usually in cases with undifferentiated cells and advanced stages [3, 4]. Distant metastases are infrequent and associated with very large tumors that are not locally controlled. Prognosis depends on the size of primary lesion, nodal involvement, perineural and lymphovascular invasion, and age, with a worse prognosis in younger patients [5]. Five year survival is 90-95% for T1 tumors, and 75-85% for T2, with a drastic drop off in survival for patients at stage T3-T4 [6].
Treatment typically includes radiotherapy (brachythe-rapy in general) and/or surgery. For a long time, low dose rate (LDR) brachytherapy was the treatment of choice, although high dose rate (HDR) BT was recently introduced. Brachytherapy as a treatment modality is recommended in up to 90% of lip tumor cases, with excellent results in local control, survival, and cosmetic outcome [7-17] (Table 1). The main purpose of this retrospective study was to analyze our results in terms of local control and survival in brachytherapy patients treated at our institution between July 1989 and June 2008.

Material and methods
From July 1989 to June 2008, a total of 121 patients diagnosed with lip cancer were treated with brachytherapy, with a median follow up of 31.8 months (range 20-188 months). Tumor staging was determined by clinical history, physical examination, histological diagnosis, and metastatic extension of the disease. The patient and tumor characteristics and treatment of 121 patients are described in Table 2. Out of 121 patients in our series, 109 were males (90.1%) and 12 females (9.9%). The median age at the beginning of treatment was 67 years. The most common tumor type was squamous cell carcinoma (115 cases; 95%), followed by basal cell carcinoma (3 cases; 2.5%), and cystic adenoid carcinoma (1 case; 0.8%). In 2 cases (1.7%) histological results were not available. Most tumors were located on the lower lip (107 patients; 88.4%), followed by the upper lip (8 cases; 6.6%), and commissure of lip (4 cases; 3.3%). Tumor staging was performed according to the TNM classification system, with 5 patients (4.1%) at stage Tis, 62 cases (51.2%) at stage T1, 44 (36.4%) stage T2, 3 cases (2.5%) stage T4, and in 7 patients (5.8%) the stage was unknown. BT with guide needles was performed in most cases (109 patients; 90.1%) while the remaining 12 patients (9.9%) were treated with plastic tubes. A total of 21 patients (17.4%) received high dose rate (HDR) brachytherapy while 100 patients (82.6%) underwent low dose rate (LDR) procedures with Iridium-192 (I-192) as radionuclide. Dosimetry was adapted from the Paris System with some modifications depending on the location. The dose varied between 45 Gy and 50 Gy for HDR treatments and between 60 Gy and 70 Gy for LDR.

Results
Survival analysis was performed for the whole series. Differential analysis between LDR and HDR was not possible due to the limited number of patients treated by HDR. At 15 years, overall survival was 89.5%, cause-specific survival 97.8% and disease-free survival 86.6% (Figs. 1-3). Local, regional, and distant control, were 90%, 92%, and 98.8%, respectively (Figs. 4-6).
Toxicity was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scales. Grade 3 mucosal toxicity was observed in 23% of patients treated with LDR compared to 33% of the HDR group, and grade 4 mucosal toxicity in 9% of LDR cases versus 0% of HDR patients. HDR and LDR BT showed similar results in terms of chronic fibrosis, telangiectasias, chronic alopecia and atrophy, although HDR was slightly superior to LDR. None of these differences, however, were significant as only a small percentage of cases experience any of these alterations (Grade 1 or 2 in all cases).

Discussion
Lip cancer is a common malignancy of the head and neck region and is frequently diagnosed at an early stage. A number of modalities, including surgery, external radiotherapy, and brachytherapy are all very successful in treatment of these lesions. However, because numerous different treatments have shown to provide good results, considerable uncertainty exists with regards to the treatment of choice.
At present, brachytherapy is one of the most important therapeutic treatments for lip cancer, because it can be used as a monotherapy, after surgery, or as a localized boost after external beam radiation therapy. Experience has shown that a high tumor dose is required to achieve local control [18]. The main treatment aim is to achieve tumor control while limiting toxicity and preserving function to the maximum extent possible. In stage T2-T3 cancers, surgery does not always completely eliminate the tumor, even with a surgical margin of safety, as evidenced by the incidence of local recurrences described in various studies [19-23] (Table 1). Brachytherapy offers numerous advantages, including high localized dose with rapid fall-off, and short overall treatment duration. The primary tumor volume receives a total dose that cannot be delivered by external beam radiotherapy alone, and rapid fall-off allows sparing of critical normal tissues.
For lip cancer, especially in early stages, results show that brachytherapy is similar to surgery in terms of local control and survival. Considerable experience has been accumulated with LDR brachytherapy. Gerbaulet et al. [11] presented long-term results of 231 patients treated with LDR I-192 brachytherapy, reporting a 94.4% local control rate. Beauvois et al. [7] reviewed 237 patients treated with LDR and found a 95% local control rate at 5 years. Urraca et al. [15] performed a retrospective analysis of overall survival in 66 patients treated with LDR brachytherapy, reporting 2- and 5-year survival rates of 93% and 73%, respectively.
The use of HDR brachytherapy is becoming more popular in the treatment of lip cancer. It offers the advantage of optimizing dose distribution by varying dwell times. Guinot et al. [12] retrospectively evaluated 39 patients treated with HDR (40.5-45 Gy), with a mean follow-up of 18 months. These authors reported an overall survival of 91% and local control rates of 100% for stage T1 tumors, 83% in stage T2, and 75% in stage T4. The authors concluded that HDR is at least as effective and safe as LDR brachytherapy in treating small and intermediate lip carcinomas.
However, aside from the above-mentioned studies, rela-tively few investigations have been published concerning HDR lip cancer treatment. Those available include limited number of patients and lack long-term follow-up. In our study, only 21 patients (17.4%) received HDR brachytherapy, making it impossible to perform a differential analysis between LDR and HDR. The lack of large, long-term studies makes it difficult to define the effectiveness of HDR in terms of local control, survival, and cosmetic and functional results. Likewise, it is not yet possible to establish the optimal total dose, number of fractions, and dose per fraction.

Conclusions
In conclusion, the results of the present study confirm brachytherapy as an effective treatment for lip cancer with results comparable to other treatment modalities.
The results from our centre are in line with those published elsewhere. Moreover, HDR appears to be as good as LDR in treating lip carcinomas, however this can only be confirmed by more comprehensive long-term study.

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