First published online November 8, 2006
British Journal of Radiology (2007) 80, 121-125
© 2007 British Institute of Radiology
doi: 10.1259/bjr/69420116
A retrospective analysis of the use of brachytherapy in relation to early stage squamous cell carcinoma of the oropharynx and its relationship to second primary respiratory and upper digestive tract cancers
M Kishino, MD
1
H Shibuya, MD
1
R Yoshimura, MD
1
S M Miura, DDS
2 and
H Watanabe, DDS
2
1 Department of Radiology, 2 Department of Oral Radiology, Graduate School, Tokyo Medical and Dental University Hospital, Tokyo Medical and Dental University, Tokyo, Japan
Correspondence: Hitoshi Shibuya, MD, Department of Radiology, Graduate School, Tokyo Medical and Dental University Hospital, 5-45, Yushima 1-Chome, Bunkyo-Ku, Tokyo 113-8519, Japan
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Abstract
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The purpose of this study was to retrospectively evaluate brachytherapy for early stage squamous cell carcinoma of the oropharynx (SCO) in relation to second primary respiratory and upper digestive tract cancers (RUDT). Between 1976 and 2001, 111 previously untreated patients with stage I or II SCO were treated with Au-198 seed brachytherapy alone (36 cases) or Au-198 seed brachytherapy plus external irradiation (75 cases). Of the 111 patients, 28 patients had stage I disease and 83 patients had stage II disease. Each patient was evaluated for therapeutic efficacy, post-treatment quality of life (QOL) and a second cancer. The 5-year and 10-year cause-specific actuarial survival rates for stage I and II SCO were 87% and 86%, respectively. We found that the 5-year and 10-year survival rates for all SCOs combined with second primary RUDT cancers were 71% and 45%, respectively. 51 second primary RUDT cancers occurred successively in 41 patients following treatment for early stage oropharyngeal cancer and this was the sole prognostic factor by the multivariate analysis. Au-198 seed brachytherapy with or without ipsilateral external irradiation of up to 30 Gy was associated with fewer late complications in the oral cavity and salivary gland. We concluded that our treatment policy of brachytherapy with or without external irradiation for patients with early stage SCO was effective and acceptable from the standpoint of tumour control and post-treatment QOL.
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Introduction
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The excellence of brachytherapy has long been demonstrated by the preservation of structure and function [1–4]; however, even since the advent of new treatment methods for head and neck cancer, the concept of interstitial radiation has become a subject of discussion and even challenge. Selection of brachytherapy has come to be discussed in terms of treatment-related morbidity and the availability of alternative modalities. The therapeutic modality should be chosen based on success rates, complication rates, disadvantages following treatment and the availability of equipment. Several authors have reported a high incidence of osteoradionecrosis and have voiced concern regarding the selection of brachytherapy [1, 4, 6–9], but other authors have reported the results of Au-198 implantation for head and neck cancer, stressing both its effectiveness and reduced invasiveness with minimum symptomatic radiation damage [3, 9, 10]. Au-198 seeds can be implanted easily under local anesthesia into lesions at sites where a rigid linear source could not be used, and they can deliver a high dose of radiation only to the lesion [3].
Nevertheless, we have observed a high incidence of secondary primary cancers related to the second primary digestive tract (RUDT) that necessitate more invasive treatment in patients cured of early stage squamous cell carcinoma of the oropharynx (SCO), and we need to determine the complete post-treatment history and optimal treatment policy for early stage SCO [2, 12–14].
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Methods and materials
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Early stage (stage I and II) SCO cases treated with Au-198 seed brachytherapy with or without external radiation between April 1976 and July 2001 were analysed. A total of 111 patients, 98 males and 13 females, were included. Those were cases among 330 patients of SCO in the same period (Figure 1
) and most of the other 219 cases were advanced (stage III or IV ) and were treated by irradiation pre- or post-operatively, or with external irradiation with or without chemotherapy. Their ages ranged from 44 years to 83 years and the median age was 65 years. The shortest follow-up period was 3 years. Patients were staged according to the 2002 criteria of the International Union Against Cancer (UICC). There were 28 T1 lesions and 83 T2 lesions. 37 lesions were confined to the lateral wall (27 faucial arch and 10 tonsil), and 37 to the superior (soft palate) wall. The sites of the others cases extended from the faucial arch to the soft palate (37 cases).
The patients underwent brachytherapy with Au-198 seeds alone (36 patients) or brachytherapy with Au-198 seeds plus external irradiation (75 patients). Exophytic and/or bulky tumours with over 5 mm thickness (stage I: 11 cases; stage II: 64 cases) were treated with a combination of brachytherapy and teletherapy. The treatment planning and implantation techniques have been described previously [3]. The Au-198 seeds were inserted under local anaesthesia. The activity of each seed was 185 MBq, and single plane implants were performed routinely. After implantation, patients were cared for in a restricted area from 3–7 days until the total radiation activity decreased to a safe level of 111 MBq. The insertion of Au-198 was performed by two radiotherapists and radiation exposure of the operators was under 40 µSv each time. The most common tumour doses were 70 Gy in 7 days in the brachytherapy-alone cases and 62 Gy in 7 days in the combined brachytherapy plus external irradiation cases. The average external dose in the combined cases was 30 Gy in 3 weeks. The most common external radiation portal was the field ipsilateral of the oropharynx and upper neck. Death due to SCO or other causes was used as the endpoint to calculate survival. The criteria used for diagnosis were those suggested by the Surveillance, Epidemiology and End-result Program of the National Cancer Institute [15], according to which multiple primary lesions of the same histological type in different parts of the same organ are considered separate primary cancers if the second cancer is diagnosed after the first cancer. When the interval between the diagnosis of the SCO and neoplasm at the other site was less than 2 months, they were classified as synchronous; others were classified as metachronous [15]. "Local failure" refers to failure at the primary tumour site; "regional failure" refers to regional node failure. Distant metastasis occurred following neck metastasis in two cases. There were no deaths during the course of radiation treatment and patients were followed without chemotherapy after primary radiation therapy. The cause-specific survival rate was calculated by the Kaplan-Meier method. The statistical significance of differences between survival curves was assessed by the log-rank test. Cox's multivariate analysis was performed for potential prognostic factors, including age, gender, stage, local recurrence and neck node metastasis. A p value of less than 0.05 was considered indicative of a statistically significant difference.
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Results
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The retrospective cause-specific actuarial 5 year and 10 year survival rates for all early stage oropharyngeal cancer patients were 87% and 86% (Figure 2). The actuarial 5 year and 10 year survival rates for deaths related to early-stage oropharyngeal cancer alone and oropharyngeal cancer with all second primary cancers were 68% and 35% (Figure 3). The actuarial 5 year and 10 year survival rates for deaths related to oropharyngeal cancer and second primary RUDT cancers were 71% and 45% (Figure 4). Overall, the 5 year and 10 year survival rates were 50% and 23%.
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Figure 3. Cause-specific survival rates for early-stage oropharyngeal cancer alone and oropharyngeal cancer with all second primary cancers.
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Figure 4. Cause-specific survival rates for early-stage oropharyngeal cancer alone and oropharyngeal cancer with a second primary respiratory and/or upper digestive tract (RUDT) cancer.
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There were 9 local failures among 83 T2 lesions (9/83 = 115). Four patients were surgically salvaged and three patient were treated by external irradiation; all four patients who were operated on and two of the three radiated patients were successfully salvaged by each treatment. Another two patients refused all subsequent treatment and died with local failure. There was no local failure in the 28 T1 lesions.
There were 29 neck node metastases (5 metastases in the 36 T1 patients and 24 metastases in the 75 T2 patients). 16 out of 24 surgical cases and 1 out of 3 irradiated cases were controlled without any distant metastasis. Another two patients died of neck metastasis after refusing subsequent treatment. 2 of the 12 regional failures were associated with pulmonary metastasis, and these 2 patients died of distant metastasis.
There were no differences in incidence of primary and/or regional failure, gender, age, or external irradiation dose. There was no difference in the cause-specific survivals between T1N0 and T2N0. There was a large difference in the survival rate between patients without RUDT cancer and patients with a second primary RUDT cancer (p<0.001).
The difference between the results for local control with implant therapy alone and combined therapy was not significant. The most frequent post-treatment complication was transient radiation ulcers, found in 41 patients 1 year to 8 years after treatment (median 12 months), and the interval after treatment was 1 month to 18 months (median 5 months). The incidence of transient ulcers in the combined implantation plus external irradiation group was higher (26/75) than in the implant alone group (10/36), but the difference was not significant. There were four adverse effects of bone exposure. Two of these four cases developed radiation osteoradionecrosis and trismus 3 years and 4 years, respectively, after treatment. Both patients had received 80 Gy of brachytherapy following 40 Gy of teletherapy and both of them required surgery for osteoradionecrosis. Grade 1 salivary dysfunction developed in 11 patients, but none of the patients in either the brachytherapy-alone group or brachytherapy plus ipsilateral teletherapy with less than 30 Gy group complained of post-treatment salivary disorders.
The only significant prognostic factor identified by multivariate analysis was secondary RUDT cancers (p = 0.0001). Local recurrence, neck metastasis, gender, stage and age were not significant prognostic factors. There were 76 synchronous and/or successive second cancers in the 111 patients (Table 1), including 51 RUDT cancers in 41 patients. These 51 RUDT cancers included 19 oesophageal cancers and 12 lung cancers. 8 of the 31 oesophagus and lung cancers were surgically and/or endoscopically treated, and the other 19 cancers were treated by radiation or other modalities. 4 of 19 patients with a second cancer of the oesophagus (21%) and 1 of 12 patients with a second cancer of the lung (8%) were disease-free at the time of writing, but 26 patients had died of the second primary cancers of the oesophagus (15 patients) or lung (11 patients). Based on the total follow-up period of 709 person-years for all 111 patients, the incidence of RUDT cancer in the early oropharyngeal cancer cases was estimated to be 7.1% per year. The occurrence of second primary RUDT cancers increased linearly over the 10 years following treatment. There were no associations between the incidence and site of the second primary RUDT cancers and the type of treatment given. In addition to the second primary RUDT cancers, there were 17 patients with a history of cancer prior to the oropharyngeal cancer diagnosis. These 17 patients had 25 antecedent RUDT cancers, including 17 head and neck cancers and 6 oesophageal cancers. The six patients who had histories of previous operation on oesophageal cancer strongly desired less invasive treatment, and referred to our institution. The total incidence of RUDT cancers was 66 cancers in 55 patients.
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Discussion
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Surgical treatment of oropharyngeal carcinoma usually results in swallowing and speech disorders [16–17], and it is thus important to establish an optimal treatment method for early carcinoma of the oropharynx [2, 4–6, 9, 18–22]. Fletcher and Liedberg reported a failure rate by external radiation of 10% in retromolar trigone and soft palate T1 lesions and of 18% in T2 tumours; complications such as xerostomia, trismus and osteoradionecrosis were frequent [18]. Cheng et al reported a local recurrence rate of 7.4% for T1 and T2 tumours after external irradiation with doses of 60 Gy to 75 Gy, in contrast to 33% with 40 Gy to 45 Gy doses of external irradiation and radon seed implantation in the soft palate [6]. Mazeron and co-workers also found that local and overall survival rates were improved by brachytherapy [4]. Garret et al demonstrated a mandibular necrosis rate as low as 3% following primary radiation therapy for carcinoma of the tonsil, and reported that local was obtained in 77% of cases with 1700 ret [1]. Eshe et al recommended an interstitial dose of 70 Gy for Ir-192 wire alone and, for combined modality therapy, a dose of 25 Gy in T1 and 30–35 Gy in T2 primary tumours following external irradiation with 50 Gy [2]. Chao et al estimated the 4 year disease-free survival rate of oropharyngeal carcinoma patients treated by intensity-modulated radiation therapy to be 81% [23]. In view of these previous reports and our own data, our policy of treatment by brachytherapy alone or brachytherapy with less than 30 Gy external irradiation seems to have advantages in achieving good local control, preserving swallowing and salivary function, and a low risk of late complications.
Ir-192 wire and high dose-rate Ir-192 sources are now available worldwide, but because of an inadequate system for supplying the Ir-192 source we cannot always use sources with an optimal dose rate in Japan. Au-198 seeds with optimal activity, on the other hand, are supplied weekly on a routine basis and these can be easily implanted under local anaesthesia, including in physically disabled patients, without problems such as severe pain or discomfort and during a short hospital stay. Moreover, the exposure of the operating staff was low at less than 40 µSv per operation. Au-198 seed implantation has therefore been selected as a major treatment modality for oropharyngeal cancer in our institution [3]. Even when there is recurrence, curative surgery or boost radiotherapy can be chosen as a salvage treatment. The incidence of osteoradionecrosis was reduced by decreasing the implant dose to 70 Gy over 7 days in the brachytherapy-alone cases and to around 60 Gy in brachytherapy plus 30–40 Gy external irradiation cases. Large doses of bilateral portal external irradiation over 40 Gy should also be avoided to prevent salivary and mandibular complications (trismus). Our results also suggest that the rate of late complications is related not only to the radiation dose delivered and extent of the primary lesion, but to careful treatment of dental and soft tissue complications as well [19].
The improvement in the results of treatment of early carcinoma of the oropharynx has been associated with second primary RUDT cancers becoming a major post-treatment problem. Although the cause-specific 5-year and 10-year survival rates were 87% and 86%, respectively, when calculated for oropharyngeal cancer with second primary RUDT cancers, the actuarial 5-year and 10-year survivals were 71% and 45%, respectively. The actuarial incidence of second primary RUDT cancer following treatment was 7.1% per year in our cases. There was no cessation of second primary RUDT cancer and it occurred steadily year by year following treatment for oropharyngeal carcinoma. Eshe and colleagues reported an overall actuarial 5-year survival rate for 43 limited oropharyngeal cancer patients of 37%, and the leading cause of death was a second RUDT cancer, with an actuarial rate of occurrence of 7% per year [2]. Vikram et al found the incidence of a second malignant neoplasm to be approximately 6% per year in 114 advanced carcinomas of the oral cavity, pharynx, larynx, and hypopharynx [24]. In addition to the high incidence of second head and neck tumours, a majority (36 cases, 70%) of the second RUDT cancers were hypopharyngeal, lung, or oesophageal cancers refractory to all treatment. As the RUDT cancers at these sites require treatment by difficult major operations or chemoradiation, less invasive effective treatment should be recommended for patients with early oropharyngeal carcinoma. Brachytherapy with Au-198 seeds offers many patients with early carcinoma of the oropharynx the chance of a fair quality of life and avoidance of surgical procedures that are cosmetically and functionally debilitating. Early detection of a second primary carcinoma of the lung or oesophagus can provide a number of patients with a chance for less invasive treatment. Second primary RUDT cancers were detected long after treatment for the carcinoma of the oropharynx. Patients treated for carcinoma of the oropharynx must be closely followed to enable detection of second primary RUDT cancers in the early stage and achieve good treatment results.
A clonal relationship suggesting the concept of the field carcinogenesis has been reported in a subset of patients with head and neck cancers [25], and Carey et al have identified sequential genetic changes, indicating multifocal metachronous tumour progression in the same individual [26]. Research should be continued in order to ascertain the nature of multiple primary cancers in the RUDT region and to improve the QOL and life expectancy of patients with early oropharyngeal carcinoma.
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Conclusion
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The treatment policy consisting of interstitial brachytherapy with or without external irradiation for patients with early stage oropharyngeal carcinoma was effective and acceptable, and also had the advantage of preserving oral structure and function.
To the best of our knowledge, there have been no reports on the long-term prognostic factors in early stage oropharyngeal carcinoma. We were able to follow up 111 cases of early-stage oropharyngeal carcinoma to death and found a very high incidence of second primary oesophageal and lung cancers that resulted in a poor outcome.
We therefore recommend effective brachytherapy with or without external irradiation for early-stage oropharyngeal carcinoma.
Received for publication March 13, 2006.
Revision received July 22, 2006.
Accepted for publication July 28, 2006.
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Abstract
Introduction
