Yuzuru Niibe 1, Katsuyuki Karasawa 1, Toshio Mitsuhashi 2 and Yoshiaki Tanaka 3 INTRODUCTION. Jpn J Clin Oncol 2003;33(9)

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1 Jpn J Clin Oncol 2003;33(9) Hyperfractionated Radiation Therapy for Hypopharyngeal Carcinoma Compared with Conventional Radiation Therapy: Local Control, Laryngeal Preservation and Overall Survival Yuzuru Niibe 1, Katsuyuki Karasawa 1, Toshio Mitsuhashi 2 and Yoshiaki Tanaka 3 1 Department of Radiology and Radiation Oncology and 2 Department of Otolaryngology, Tokyo Metropolitan Komagome Hospital, Tokyo and 3 Department of Radiology, Nihon University School of Medicine, Tokyo, Japan Received June 1, 2003; accepted August 8, 2003 Background: Recent randomized trials have revealed the effectiveness of hyperfractionated radiation therapy for treating head and neck carcinomas, especially in their local control. Because the hypopharynx is located near the larynx, increasing local control of hypopharyngeal carcinomas achieves greater laryngeal preservation, which is very important for patients quality of life. In consideration of this, our facility adopted hyperfractionated radiation therapy for hypopharyngeal carcinoma in In this study we compared the results of this therapy with those of conventional radiation therapy. Methods: Forty-two patients with hypopharyngeal carcinoma whose tumors were inoperable or who refused surgery were treated with curative intended radiation therapy between April 1975 and January 2002 at Tokyo Metropolitan Komagome Hospital. Of these patients, 23 were treated with hyperfractionated radiation therapy (the HF group) and 19 were treated with conventional fractionated radiation therapy (the CF group). In the HF group, the numbers of patients at each clinical stage were as follows: stage I, 2; stage II, 5; stage III, 6; stage IV, 10. The fraction size was 1.2 Gy and the mean total dose was 73.4 Gy (range, Gy). In the CF group, the corresponding numbers were as follows: stage I, 3; stage II, 1; stage III, 5; stage IV, 10. The fraction size was Gy and the mean total dose was 65.4 Gy (range, Gy). Results: The 3-year local control rates for the HF group and the CF group were 61.5 and 18.4%, respectively (P = 0.016). The 3-year pharyngolaryngectomy-free survival rates for the HF group and the CF group were 64.7% and 5.3%, respectively (P = ). The 3-year overall survival rates for the HF group and the CF group were 69.3 and 31.6%, respectively (P = 0.075). Conclusion: This study suggests that hyperfractionated radiation therapy for hypopharyngeal carcinoma is promising with a better local control rate, a greater laryngeal preservation rate and a relatively better overall survival rate. Key words: radiation therapy hyperfractionation conventional fractionation hypopharyngeal carcinoma laryngeal preservation time (1). Moreover, randomized clinical trials have revealed that hyperfractionated radiation therapy was superior to conventional radiation therapy for the treatment of head and neck carcinomas, especially in local control (2,3). However, few trials have examined its effectiveness in the head and neck region according to subsites. Because the hypopharynx is located near the larynx, increasing local control of hypopharyngeal carcinomas achieves greater laryngeal preservation by avoiding salvage surgery. Previous reports have indicated that the local control rate of hypopharyngeal carcinomas treated with conventional radiation therapy was from 24 to 47% (4 7). These results are con- INTRODUCTION Hyperfractionated radiation therapy is considered to be one of the techniques to achieve better treatment results than with conventional radiation therapy. Theoretically, this alternative could escalate the total radiation dose without increasing the incidence of late toxicities or prolonging the overall treatment For reprints and all correspondence: Yuzuru Niibe, Department of Radiology and Radiation Oncology, Kitasato University School of Medicine, Kitasato, Sagamihara-shi, Kanagawa , Japan. joe-n@hkg.odn.ne.jp 2003 Foundation for Promotion of Cancer Research

2 Jpn J Clin Oncol 2003;33(9) 451 Table 1. Patients characteristics HF group CF group No. of cases Mean age (range) (years) 65.0 (52 84) 64.4 (36 81) Gender (M:F) 22:1 15:4 Histology SqCC* SqCC* Stage I 2 3 Stage II 5 1 Stage III 6 5 Stage IV Table 2. Treatment characteristics HF group CF group Fraction size (Gy) Total dose (range) (Gy) 73.4 ( ) 65.4 (60 70) Overall treatment time (Days) 45.3 (41 63) 53.3 (40 68) Chemotherapy NA 5 3 C 3 3 NA + C 2 1 C + A 1 0 *SqCC: squamous cell carcinoma. sidered to reflect a compromised quality of life for the patients. In 1996, our institution adopted hyperfractionated radiation therapy for treating hypopharyngeal carcinomas for inoperable patients or those refused surgery to achieve further laryngeal preservation. The current study compares the results of this therapy with those of conventional radiation therapy. METHODS PATIENTS AND RADIATION METHODS Forty-two patients with hypopharyngeal carcinoma whose tumors were inoperable or who refused surgery were treated with curative intended radiation therapy ( 60 Gy) between April 1975 and January 2002 at Tokyo Metropolitan Komagome Hospital. Of these, 23 were treated with hyperfractionated radiation therapy between January 1996 and January 2002 (the HF group) and 19 were treated with conventional fractionated radiation therapy between August 1975 and December 1995 (the CF group). Patients in the HF group met the following criteria: tumor was inoperable or surgery was refused and yet curative treatment was intended; no double carcinoma except in those with superficial esophageal carcinoma or advanced carcinomas; two or more years controlled after the treatment. Patients in the CF group also met these criteria and received conventional fractionated radiation therapy of at least 60 Gy. Patients characteristics are presented in Table 1. The average age in the HF group was 65.5 years (range, years). According to the UICC-TNM staging classification (8), two cases were stage I, five cases were stage II, six cases were stage III and ten cases were stage IV. All cases were proven histologically to be squamous cell carcinoma. The average age in the CF group was 64.4 years (range, years). According to the UICC-TNM staging classification, three cases were stage I, one case was stage II, five cases were stage III and ten cases were stage IV. All cases were proven histologically to be squamous cell carcinoma. As for the staging modality, physical examination, laryngoscopy, laryngogram and barium swallow were used between NA, neoadjuvant; C, concurrent; A, adjuvant and March After April 1979 CT scanning was added to the staging modalities. After April 1993, MRI was added to the staging modalities. Treatment characteristics are shown in Table 2. Both groups received 4 MV X-rays and were treated by the following shrinking field technique. Radiation therapy was initially applied to a large field covering the entire pharynx, including the Rouvier lymph node area, supraclavicular lymph node area and neck. After 50 Gy, prophylactic nodal irradiation was finished; after 60 Gy, the field was further reduced; and finally, the field was 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 electrons were used to irradiate the posterior neck lymph node area after 40 Gy. In this study hyperfractionated radiation therapy consisted of 1.2 Gy per fraction, two fractions per day delivered 6 h apart, 5 days per week. The mean overall treatment time of the HF group was 45.3 days (range, days) and the mean total dose was 73.4 Gy (range, Gy). Conventional fractionated radiation therapy consisted of Gy per fraction, one fraction per day, 5 days per week. The mean overall treatment time of the CF group was 53.3 days (range, days) and the mean total dose was 65.4 Gy (range, Gy). Chemotherapy was administered in some cases in both groups. The ratio of combination of chemotherapy in the HF group was slightly higher than that in the CF group. However, neoadjuvant or concurrent chemotherapy was performed in most cases in both groups. Chemotherapy regimens were as follows: in the concurrent case, low-dose weekly cisplatin was administered in both groups up to mg ; in the neoadjuvant case, cisplatin + 5-fluorouracil + methotrexate was administered to three patients in the CF group and to one patient in the HF group. Cisplatin + 5-fluorouracil + methotrexate + leucovolin was administered to four patients in the HF group. In the adjuvant cases, cisplatin + 5-fluorouracil + methotrexate was administered to one patient in the CF group. Cisplatin + 5- fluorouracil + methotrexate + leukovolin was administered to one patient in the HF group.

3 452 Radiotherapy for hypopharyngeal carcinoma Table 3. Radiation response hypopharynx CR PR SD CR rate (%) HF group CF group Table 4. Radiation response lymph node CR PR SD CR rate (%) HF group CF group RADIATION RESPONSE Radiation response was evaluated by laryngoscopy, laryngogram, barium swallow, CT scan or MRI, on the basis of the WHO criteria (9). However, the evaluation modality was the same as the staging modality. TOXICITY Evaluation of acute and late radiation toxicities in both the HF and CF groups were conducted on the basis of the RTOG radiation morbidity criteria (10). STATISTICAL ANALYSIS The median follow-up times (MFT) of the HF group and that of the CF group were 19 and 16 months, respectively. Limited to survivors, MFT of the HF group and that of the CF group were 22 and 109 months, respectively. Local control in the current study was defined as the absence of relapse within the irradiated field. The Kaplan Meier method was used to calculate local control and overall survival rates of both the HF and CF groups and comparisons between groups were made using the log-rank test. Statistical significance was set at P RESULTS RESPONSE RATE Tables 3 and 4 show the response rates of hypopharynx lesions and lymph node metastasis at the end of radiation therapy. Regarding hypopharynx lesions, there were 19 CRs and four PRs in the HF group and 14 CRs, four PRs and one SD in the CF group. Thus, the CR rate in the HF group was 82.6% and that in the CF group was 73.7%. Regarding lymph node metastasis, there were four CRs and five PRs in the HF group and six CRs and six PRs in the CF group. Thus, the CR rate in the HF group was 44.4% and that in the CF group was 50.0%. LOCAL CONTROL RATE Fig. 1 indicates the groups local control rates for hypopharyngeal carcinoma. The 3-year local control rate of the HF group Figure 1. Local control rates of hypopharyngeal carcinoma treated with hyperfractionated radiation therapy (HF group) and conventional radiation therapy (CF group). was 62.3% and that of the CF group was 18.4%. This difference was statistically significant (P = 0.016), indicating that HF was superior to CF in the local control of hypopharyngeal carcinoma. When the cases were stratified by T-stage and N-stage, the HF group was superior to the CF group in both the early and advanced stages. The 3-year local control rate of T1 2 stage in the HF group was 91.7% and that in the CF group was 0.0%. The 3-year local control rate of T3 4 stage in the HF group was 58.9% and that in the CF group was 53.0% (Table 5). The 3- year local control rate of N0 2 stage in the HF group was 82.2% and that in the CF group was 51.1%. The 3-year local control rate of N3 stage was 0% for both groups (Table 6). LARYNGEAL PRESERVATION Laryngeal preservation is defined as the rate of pharyngolaryngectomy-free survival. The 3-year pharyngolaryngectomy-free survival rate of the HF group was 64.7%, significantly greater than that of the CF group, 5.3% (P = ; Fig. 2). OVERALL SURVIVAL As shown in Fig. 3, the 3-year overall survival rate of the HF group was 69.3% and that of the CF group was 31.6% (P = Table 5. Local control T-stage T1 2 T3 4 HF group 91.7 (n = 12) 58.9 (n = 11) CF group 0.0 (n = 8) 53.0 (n = 11) Table 6. Local control N-stage 3-year control rate (%) N0 2 N3 HF group 82.2 (n = 18) 0.0 (n = 5) CF group 51.1 (n = 15) 0.0 (n = 4)

4 Jpn J Clin Oncol 2003;33(9) 453 Figure 2. Pharyngolaryngectomy-free survival rates of hypopharyngeal carcinoma treated with hyperfractionated radiation therapy (HF group) and conventional radiation therapy (CF group) ). This result indicated that the patients in the HF group had a tendency to have a better overall survival rate than those in the CF group. TOXICITY No cases of toxicity grade 3 or higher was observed in the HF group and only one case of mucous membrane toxicity grade 4 occurred in the CF group. Regarding the acute toxicity, the HF group had a tendency to have more severe mucous membrane toxicities than the CF group. However, the skin and hematological toxicities were comparable between the groups (Table 7). DISCUSSION Many reports have suggested that dose escalation achieves improved local control in radiation therapy for various malignancies (11,12) An increased understanding of the physics and biology of radiation therapeutic techniques is required to achieve dose escalation. Advances in physics have led to threedimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) for the treatment of head and neck carcinomas, prostate carcinomas and lung carcinomas; dose escalation was achieved by improved dose distributions. (13 16) However, hypopharynx is complicatedly moving during swallowing. Both 3D-CRT and IMRT require precise planning target volume (PTV) settings, which makes them difficult to apply in the treatment of hypopharygeal carcinomas. On the other hand, advances in biology have led to altered fractionated radiation therapy, including hyperfractionated radiation therapy, which has been performed since the 1980s to escalate the total dose without prolonging the overall treatment time. Furthermore, some randomized trials have recently revealed the clinical effectiveness of altered fractionated radiation therapy for treating head and neck carcinomas, especially in their local control (2,3). Fu et al. (2) reported that the 2-year local control rate of hyperfractionation at 1.2 Gy per fraction totaling 81.6 Gy was 54.4%, a statistically significant Figure 3. Overall survival rates of hypopharyngeal carcinoma treated with hyperfractionated radiation therapy (HF group) and conventional radiation therapy (CF group). improvement on that of conventional fractionation at 2 Gy per fraction totaling 70 Gy, which was 46.0% (P = 0.045). In their study, further investigations were performed to compare two altered fractionated radiation therapies, accelerated fractionation according to the protocol of Wang et al. (17) and concomitant boost fractionation, with conventional fractionation. This comparison revealed that only concomitant boost fractionation was superior to conventional fractionation. However, concomitant boost fractionation had more severe late toxicity than that of conventional fractionation. These findings suggested that hyperfractionated radiation therapy was one of the best altered fractionated radiation therapies. However, few trials have studied its effectiveness in the head and neck region according to subsites. Local control of hypopharyngeal carcinomas is very important because it correlates with laryngeal preservation. If surgery such as pharyngolaryngectomy is performed, patients may subsequently suffer from difficulty in speaking and swallowing, which considerably undermines their quality of life. The present study was conducted for this reason. No statistically significant difference was observed in the initial response between the HF group and the CF group (Tables 3 and 4). However, the local control rate of the HF group was significantly higher than that of the CF group (P = 0.016; Fig. 1, Tables 5 and 6). These results suggest that in the HF group, if CR was achieved at the initial response, it was often maintained for a long time, whereas in the CF group, even if CR was achieved at the initial response, local relapse frequently occurred. Patients in the HF group received about 10 Gy more irradiation than those in the CF group and the overall treatment time for the former was about 1 week less Table 7. Acute radiation toxicity Skin Pharynx Hematological Grade HF group CF group

5 454 Radiotherapy for hypopharyngeal carcinoma than for the latter. It was obvious that an insufficient dose led to a decreasing effectiveness of killing malignant cells. Furthermore, prolonging the overall treatment time was reported to increase radioresistant cells (18,19). These results suggest that in the HF group, malignant cells were killed at the micro-level without leaving radioresistant cells, whereas in the CF group they were killed only at the macro-level leaving radioresistant cells. However, Table 5 raised the problem that the local control rate of T1 2 stage was worse than that of T3 4 stage in the CF group (0 % of T1 2 vs 53.0% of T3 4). The median total dose of T1 2 stage was 64 Gy, whereas that of T3 4 stage was 66 Gy. The median overall treatment time of T1 2 stage was 50 days and that of T3 4 stage was 53 days. These differences were not statistically significant. Hence the reason for this discrepancy was considered to be accidental because of the small number of patients. With respect to the overall survival rate, the HF group had a 3-year survival rate of 69.3%, compared with only 31.6% for the CF group (P = 0.075; Fig. 3). This result was consistent with the report of Fu et al. (2). Although the difference in local control rates was statistically significant, probably the difference in overall survival rates was not, because the pharyngolaryngectomy-free survival rate of the HF group was significantly superior to that of the CF group (P = ), which meant that the patients in the CF group were better salvaged by pharyngolaryngectomy than those in the HF group (Fig. 2). However, Akimoto et al. reported that altered fractionated radiation therapy was significantly superior to conventional radiation therapy, even in the overall survival rate of patients with hypopharyngeal carcinoma, although their altered fractionated radiation therapy was accelerated hyperfractionation, which causes more severe late toxicity than hyperfractionated radiation therapy (20). In any event, a longer follow-up period and a larger number of patients are required to evaluate the effectiveness of our method on the overall survival rate of patients with hypopharyngeal carcinoma. As for late toxicity, hyperfractionated radiation therapy was considered to prescribe high doses without increasing severe late toxicities. No cases of grade 3 or higher toxicities were found in the HF group, whereas one case of grade 4 (mucous membrane) toxicity was found in the CF group. These results indicated that severe late toxicity was not frequently observed and no statistically significant differences in late toxicities were found between the HF group and the CF group. Fu et al. reported that among patients with head and neck carcinoma, 26.8% of those who received 70 Gy of conventional radiation therapy and 28.0% of those who received 81.6 Gy of hyperfractionated radiation therapy experienced toxicities of grade 3 or higher (2). This was consistent with the current study with the same rate of late toxicities between the HF group and the CF group. However, their study reported a higher rate of severe late toxicities than was found in the our study, probably because they prescribed higher doses and studied fewer oriental patients than we did. These might influence the difference in the rates of late toxicity. However, a longer follow-up period is required to evaluate precise toxicity. As for acute toxicity, the HF group had a tendency to have more severe pharyngeal toxicity than the CF group. However, the skin and hematological toxicities were comparable between the groups (Table 7), which indicated that acute toxicity of the HF group was acceptable. However, further investigations are required to reduce both acute and late toxicities. In conclusion, this study demonstrated that hyperfractionated radiation therapy for treating hypopharyngeal carcinoma achieved better local control, greater pharyngeal preservation, relatively better overall survival rates and acceptable toxicity. With significantly better local control and greater pharyngeal preservation rates, hyperfractionated radiation therapy for hypopharyngeal carcinoma preserved patients quality of life by decreasing the incidence of local relapse and avoiding salvage surgeries such as pharyngolaryngectomy. 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