© 2004 Foundation for Promotion of Cancer Research
Hyperfractionated Radiation Therapy for Oropharyngeal Carcinoma in a Japanese Population
1 Department of Radiology and Radiation Oncology and 2 Department of Otolaryngology, Tokyo Metropolitan Komagome Hospital, Tokyo, 3 Deparment of Radiology, Kitasato University School of Medicine, Sagamihara, Kanagawa and 4 Department of Radiology, Nihon University Medical School, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Hyperfractionated radiation therapy is recognized to be a better treatment method, especially regarding local control, than conventional radiation therapy for oropharyngeal carcinoma. However, the survival benefit of hyperfractionated radiation therapy for oropharyngeal carcinoma has not been reported so far. Moreover, patient populations of previous studies were mostly white or African-American, and rarely included Orientals. Thus, the current study is designed to evaluate not only local control but the survival benefit of hyperfractionated radiation therapy for oropharyngeal carcinoma in a Japanese population.
Methods: The eligibility criteria were as follows. The patients were 20 years or older. Performance status ranged from 0 to 2. No patient with double carcinoma was included except those with superficial esophageal carcinoma or advanced carcinoma controlled for at least 2 years after treatment. In our radiation protocol, hyperfractionated radiation therapy was adopted using 1.2 Gy per fraction, two fractions per day (6 h apart), 5 days a week, for a total dose of 66 Gy or more.
Results: Complete response was achieved in all 14 patients with oropharyngeal lesions. In five patients with lymph node metastasis, complete response was achieved in four patients and partial response was achieved in the remaining one. The 3-year loco-regional control rate was 77% and the 3-year overall survival rate was 69%.
Conclusions: Treatment with hyperfractionated radiation therapy is considered superior to conventional radiation therapy with acceptable toxicity for Japanese patients with oropharyngeal carcinoma in terms of loco-regional control rate and overall survival rate.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Hyperfractionated radiation therapy is recognized as a better treatment method than conventional radiation therapy for patients with oropharyngeal carcinoma. However, previous studies have demonstrated its effect only on local control and did not show any benefits on overall survival (1,2). Moreover, previous studies have included only white or African-American patients, not Oriental populations, so there are no existing reports on Japanese populations.
The purpose of this study was to evaluate not only local control, but also the survival benefit of hyperfractionated radiation therapy for treating oropharyngeal carcinoma in a Japanese population.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Study Design
The current prospective study was designed with the consensus of radiation oncologists and head & neck surgeons at our hospital. Hyperfractionated radiation therapy was adopted in the current study using 1.2 Gy per fraction, two fractions per day (6 h apart), 5 days a week, for a total of 66 Gy or more. Moreover, the shrinking field technique was used. The initial radiation field covered the entire pharynx, supraclavicular lymph node area and neck. After 50 Gy, prophylactic nodal irradiation was stopped. After 60 Gy, the field was further reduced to the area of gross tumor volume (GTV) with a margin of 1–2 cm. To avoid excess spinal cord irradiation, 9–11 MeV electron was adopted to irradiate the posterior neck lymph node area after 40 Gy instead of 4 MV X-rays. Chemotherapy was added to treat stage III or IV disease if head & neck surgeons or radiation oncologists deemed it necessary.
Eligibility Criteria
The eligibility criteria were as follows. All patients in this study were at least 20 years or older. Performance status (PS) based on Eastern Cooperative Group (ECOG) was between 0 and 2. All patients had pathologically proven oropharyngeal carcinoma. No cases of double carcinoma were included except those with superficial esophageal carcinoma or advanced carcinoma controlled for at least 2 years after treatment.
Staging Evaluation
In the current study, physical examination, laryngofiberscopy, CT scan and MRI studies were performed to determine the tumor staging. All patients underwent tissue biopsy before treatment.
Radiation Response
Radiation response was evaluated from laryngofiberscopy, CT scan and MRI findings. The evaluation was made on the basis of WHO criteria (3).
Toxicity
Acute and late radiation toxicities were evaluated on the basis of the Acute Radiation Morbidity scoring criteria RTOG radiation morbidity criteria and RTOG/EORTC Late Radiation Morbidity Schema (4).
Statistical Analysis
Loco-regional control was defined in the current study as no evidence of recurrence within the irradiated field; thus, tumors controlled after salvage surgery were included as failures in the calculation of loco-regional control. Both local control rate and overall survival rate were calculated to construct survival curves using the Kaplan–Meier method.
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RESULTS |
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Patients
Fourteen patients with oropharyngeal carcinoma were treated with hyperfractionated radiation therapy between June 1998 and February 2003 at Tokyo Metropolitan Komagome Hospital, Japan. The median follow-up time was 30 months (range, 6–63 months). Patient characteristics are listed in Table 1. The median age was 64 years (range, 47–84 years). Regarding PS, four patients were PS0, seven were PS1 and three were PS2. According to the UICC-TNM staging classification (5), one patient was stage I, three were stage II, three were stage III and seven were stage IV. As for histopathology, 13 were squamous cell carcinoma and one was adenoidcystic carcinoma. Concerning subsites of oropharynx, six were tonsillar fossa, four were soft palate, three were base of tongue and the other one was posterior pharyngeal wall.
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Treatment Characteristics
Treatment characteristics are presented in Table 2. The median total dose was 72.0 Gy (range, 66.0–74.4 Gy). The median overall treatment time was 43.5 days (range, 38–65 days). Chemotherapy was conducted in four patients. They were all stage III or IV and their ages were all under 70 years. With respect to the regimen of chemotherapy, three patients underwent concurrent chemotherapy with low dose cisplatin (10–20 mg per week), totaling 40–100 mg. One patient underwent neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin.
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Response Rate
Table 3 shows the response rate of oropharyngeal lesions and lymph node metastases. Of the oropharyngeal lesions, complete response was achieved in all of the 14 patients (100%). Of the five patients with lymph node metastases, complete response was achieved in four patients (80%) and partial response was achieved in one patient.
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Loco-regional Control Rate
The loco-regional control rate of the oropharyngeal carcinoma is shown in Figure 1. The 1-year loco-regional control rate was 92%, and the 3-year loco-regional control rate was 77%. When the patients were stratified by T-stage and N-stage, the 3-year loco-regional control rate of the T1–2 stage (n = 6) was 100% and that of the T3–4 stage (n = 8) was 67%. The 3-year loco-regional control rate of the N0–1 stage (n = 10) was 100% and that of the N2 stage was 75% (n = 4). These results indicate that the loco-regional control rates of early stage tumors were better than those of advanced stage tumors in the both T-stage and N-stage. However, these differences were not statistically significant. As for the subsite of oropharynx, two loco-regional recurrent tumors originated from the tonsils and base of the tongue. Thus, no subsites of oropharynx showed any trend of frequent recurrence in the current study.
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Overall Survival
Figure 2 shows the overall survival rate of patients with oropharyngeal carcinoma. The 1-year overall survival rate was 100%, and the 3-year overall survival rate was 69%.
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Toxicity
Regarding acute toxicity, 10 patients experienced grade 1 and four experienced grade 2 in the skin. In the pharynx, one patient experienced grade 1, eight experienced grade 2 and five experienced grade 3. In the hematologic findings, six patients experienced grade 0, four experienced grade 1, two experienced grade 2 and two experienced grade 3. Regarding late toxicity, no patients of toxicity grade 3 or higher have been found so far.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Five-year local control and overall survival rates of oropharyngeal carcinoma treated with only conventional external radiation therapy in a Japanese population have been reported at 37 and 21%, respectively (6); however, these results are not satisfactory. On the other hand, hyperfractionated radiation therapy was considered to enable high dose without prolonging overall treatment time, which improves treatment results without increasing late toxicity (7–10). These rationales suggested that the treatment results of hyperfractionated radiation therapy might be superior to those of conventional external radiation therapy. Some randomized trials have indeed revealed the effectiveness of hyperfractionated radiation therapy for oropharyngeal carcinomas (1,2). Horiot et al. reported that the 5-year local control rate of intermediate advanced oropharyngeal carcinoma (T2–3, N0–1) treated with hyperfractionated radiation therapy totaling 80.5 Gy was 59%, and that with conventional radiation therapy totaling 70 Gy was 40%, the improvement being statistically significant (P = 0.02) (1). Fu et al. reported that 2-year local control rate of head and neck carcinoma treated with hyperfractionated radiation therapy totaling 81.6 Gy was 54.4%, while that with conventional radiation therapy totaling 70 Gy was 46.0%, the improvement also being statistically significant (P = 0.045). Furthermore, 59% of the patients in their study had oropharyngeal carcinoma (2). These results led to the conclusion that hyperfractionated radiation therapy was superior to conventional radiation therapy in the treatment of oropharyngeal carcinoma. However, these studies demonstrated no benefit in terms of overall survival, and neither included meaningful numbers of Oriental patients (only 1% of Orientals in Fu’s study; no mentioned figure, but probably a very low percentage, in Horiot’s study).
In the current study, the 3-year loco-regional control rate was 77%. This was a better result than that of conventional radiation therapy, which is consistent with the results of the Horiot and Fu reports. Moreover, the 3-year overall survival rate in the current study was 69%, which is far superior to that of conventional radiation therapy, namely 21%, previously reported in the Japanese population (6). No reported study of hyperfractionated radiation therapy for the treatment of oropharyngeal carcinoma has been previously performed in a Japanese population. Thus, no evidence for survival benefit of hyperfractionated radiation therapy for oropharyngeal carcinoma has actually existed, although it has been widely believed. However, the current study indicates that survival benefit from this therapy might exist in a Japanese population. This is the first clinical demonstration of such a benefit, although a larger number of patients are required to evaluate the precise survival benefit.
The total dose was defined as 66 Gy or more and the median dose was 72 Gy in the current study, which is about 10 Gy less than the Horiot and Fu studies. Smaller doses have achieved good results in a Japanese population. The reasons for this are still unclear. However, we decided on the total dose as 66 Gy or more for the following reasons. At the initiation of the current study, the total dose of hyperfractionated radiation therapy practically used in Japan was about 72 Gy (11). Moreover, Fu’s trial had not been completed at the initiation of the current study. Thus, we did not appreciate the impact of 81.6 Gy of hyperfractionation. Furthermore, in the current study, we included not only young patients but also elderly patients, which is where our study differed most from others. If higher dose irradiation had been performed we would have expected several elderly patients to suffer either treatment-related deaths or acute toxicity such as pharyngitis, which would have consequently caused swallowing difficulty and aspiration pneumonia and resulted in our having to stop treatment. These reasons were the basis for our decision to set the total dose at 66 Gy or more.
As for toxicity, late severe toxicity was not reported for any patients. As for acute toxicity, pharyngeal region was considered to be only slightly more severe than that from conventional radiation therapy, but was still within the limits of acceptability.
In conclusion, treatment with hyperfractionated radiation therapy is considered superior to conventional radiation therapy with acceptable toxicity for Japanese patients with oropharyngeal carcinoma in terms of loco-regional control rate and overall survival rate.
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FOOTNOTES |
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+ For reprints and all correspondence: Yuzuru Niibe, Department of Radiology, Kitasato University School of Medicine, 1-15-1, Kitasato, Sagamihara-shi, Kanagawa 228-8555, Japan. E-mail: joe-n{at}hkg.odn.ne.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Received January 16, 2004; accepted March 22, 2004
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