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Purpose To investigate the clinical features, prognostic factors, and toxicity of treatment for unresectable carcinomas of the nasal cavity and paranasal sinus (NCPS) treated with proton beam therapy (PBT). Methods and Materials Seventeen patients (13 men, 4 women) with unresectable carcinomas of the NCPS who underwent PBT at the University of Tsukuba between 2001 and 2007 were analyzed. The patients' median age was 62 years (range, 30–83 years). The tumors were located in the nasal cavity in 3 patients, the frontal sinus in 1, the ethmoid sinus in 9, and the maxillary sinus in 4. The clinical stage was Stage IVA in 5 cases, IVB in 10, and recurrent in 2. The tumors were deemed unresectable for medical reasons in 16 patients and because of refusal at a previous hospital 4 months earlier in 1 patient. All the patients received PBT irradiation dose of 22–82.5 GyE and a total of 72.4–89.6 GyE over 30–64 fractions (median 78 GyE over 36 fractions) with X-ray, with attention not exceeding the delivery of 50 GyE to the optic chiasm and brainstem. Results The overall survival rate was 47.1% at 2 years and 15.7% at 5 years, and the local control rate was 35.0% at 2 years and 17.5% at 5 years. Invasion of the frontal or sphenoid sinus was a prognostic factor for overall survival or local control. Late toxicity of more than Grade 3 was found in 2 patients (brain necrosis in 1 and ipsilateral blindness in 1); however, no mortal adverse effects were observed. Conclusion Proton beam therapy enabled a reduced irradiation dose to the optic chiasm and brainstem, enabling the safe treatment of unresectable carcinomas in the NCPS. Superior or posterior extension of the tumor influenced patient outcome.

Purpose To present the results of proton beam therapy for patients with esophageal cancer. Methods and materials This study reviewed 46 patients with esophageal cancer who were treated between 1985 and 1998 using proton beams with or without X-rays. All patients had locoregionally confined disease; all but one had squamous cell carcinoma. Of the 46 patients, 40 received combinations of X-rays (median, 48 Gy) and protons (median, 31.7 Gy) as a boost. The median total dose of combined X-ray and proton radiation for the 40 patients was 76.0 Gy (range, 69.1–87.4 Gy). The remaining 6 patients received only proton beam therapy (median, 82.0 Gy; range, 75–89.5 Gy). Results The 5-year actuarial survival rate for the 46 patients, patients with T1 ( n = 23), and those with T2–T4 ( n = 23) was 34%, 55%, and 13%, respectively. The 5-year disease-specific survival rate for the 46 patients, those with T1, and those with T2–T4 was 67%, 95%, and 33%, respectively. The 5-year local control rate for patients with T1 and T2–T4 lesions was 83% and 29%, respectively. The site of the first relapse was locoregional for 16 patients and distant organs for 2 patients. Conclusion The results suggest that proton beam therapy is an effective treatment for patients with locally confined esophageal cancer. Additional studies are required to determine the optimal total dose, fractionation schedule, and best combinations of protons and conventional X-rays with or without chemotherapy.

Purpose: To evaluate the clinical results of proton radiotherapy for patients with non–small-cell lung cancer (NSCLC). Methods and Materials: Between 1983 and 2000, 51 NSCLC patients were treated with proton beams at the University of Tsukuba. There were 28 patients in Stage I, 9 in Stage II, 8 in Stage III, 1 in Stage IV, and 5 with recurrent disease. Thirty-three patients had squamous cell carcinoma, 17 had adenocarcinoma, and 1 had large-cell carcinoma. Median fraction and total doses given were 3.0 Gy (range 2.0 – 6.0 Gy), and 76.0 Gy (range 49.0 –93.0 Gy), respectively. Results: The 5-year overall survival rate was 29% for all patients, 70% for 9 Stage IA patients, and 16% for 19 Stage IB patients, respectively (IA vs. IB: p < 0.05). The 5-year in-field local control rate was higher in patients with Stage IA (89%) when compared with those with Stage IB (39%). Forty-seven patients (92%) experienced acute lung toxicity of Grade 1 or less; 3 had Grade 2, 1 had Grade 3, and none experienced Grade 4 or higher. Patients in the present series showed very little late toxicity. Conclusion: Proton therapy is a very safe and effective treatment for patients with NSCLC, especially for those with early stages. The relative merit of proton therapy in comparison with stereotactic photon radiotherapy or three-dimensional conformal photon radiotherapy remains to be defined through future clinical trials. © 2003 Elsevier Inc.

Purpose : To determine the preserved functional capacity of the liver as a probable determinant of radiation tolerance in patients with cirrhosis and hepatocellular carcinoma, who underwent proton beam radiotherapy. Materials and Methods : We reviewed computed tomographic (CT) scans of 26 patients with cirrhosis and hepatocellular carcinoma during a period of 12–27 months after proton beam radiotherapy. Tumors were treated with focused proton beams with target doses of 140–186 TDF (time, dose, and fractionation). We measured the degree of hypertrophy of the untreated liver volume by measuring the total liver volume and the treated liver volume which was radiologically identified on contrast-enhanced CT scans. The risk of radiation-induced liver failure was estimated using the prediction score (PS) originally used for estimating posthepatectomy liver failure, substituting the planned treated liver volume for the resection liver volume. Results : The degree of hypertrophy ranged from —19% to 51%, and was significantly positively correlated with the ratio of the planned treated liver volume to the functional liver volume. The PS agreed well with observed radiation tolerance in 21 patients, but underestimated the tolerance in 5. This underestimation was diminished when the PS was recalculated using the identified untreated liver volume in lieu of the planned untreated liver volume. Conclusion : As in surgical treatment, radiation tolerance of the cirrhotic liver after focused treatement is closely related to the preserved functional capacity of the identified untreated liver volume, which shows compensatory hypertrophy following radiotherapy.

Purpose Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials The subjects were 259 patients treated with PBT at the University of Tsukuba between January 2001 and December 2007. We evaluated the Child–Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child–Pugh score of 1 or more was defined as an adverse event. Results Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child–Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child–Pugh score, 15 had a 1-point increase, and 10 had an increase of ≥2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

Purpose To investigate the geometric accuracy of proton beam irradiation to the liver by measuring the change in Hounsfield units (HUs) after irradiation. Methods and Materials We examined 21 patients with liver tumors who were treated with respiratory-gated proton beam therapy (PBT). The radiation dose was 66 GyE in 12 patients and 72.6 GyE in 9 patients. Image registration and reslicing of the computed tomography (CT) results obtained within 1 month before and 3 months after PBT was performed, referring to the planning CT image. The resliced CT images obtained after PBT were subtracted from the images obtained before PBT. We investigated whether the area of the large HU change was consistent with the high-dose distribution area using the location of the largest change in HU around the tumor (peak) on the subtracted CT image and the 90% dose distribution area of the planning CT image. Results The number of patients ( n = 20) whose left–right peaks were within the 90% dose distribution area was significantly larger than the number of patients whose anterior–posterior peaks and superior–inferior peaks were within the 90% dose distribution area ( n = 14, n = 13, p = 0.034, and p = 0.02, respectively). Twelve patients exhibited a peak within the 90% dose distribution area in all directions. Nine of the 11 patients with smaller 90% confidence intervals of the percent normalization of the beam cycle (BC; 90% BC) showed a peak within the 90% dose distribution area in six directions, and this percentage was higher than that among the patients with larger 90% BC (3/10, p = 0.03). Conclusion The geometric accuracy of proton beam irradiation to the liver was higher in the left–right direction than in the other directions. Patients with an irregular respiratory rhythm have a greater risk of a reduced geometric accuracy of PBT in the liver.

Background Our previous results for treatment of hepatocellular carcinoma (HCC) with proton beam therapy revealed excellent local control with low toxicity. Three protocols were used to avoid late complications such as gastrointestinal ulceration and bile duct stenosis. In this study, we examined the efficacy of these protocols. Methods and Materials The subjects were 266 patients (273 HCCs) treated by proton beam therapy at the University of Tsukuba between January 2001 and December 2007. Three treatment protocols (A, 66 GyE in 10 fractions; B, 72.6 GyE in 22 fractions; and C, 77 GyE in 35 fractions) were used, depending on the tumor location. Results Of the 266 patients, 104, 95, and 60 patients were treated with protocols A, B, and C, respectively. Seven patients with double lesions underwent two different protocols. The overall survival rates after 1, 3 and 5 years were 87%, 61%, and 48%, respectively (median survival, 4.2 years). Multivariate analysis showed that better liver function, small clinical target volume, and no prior treatment (outside the irradiated field) were associated with good survival. The local control rates after 1, 3, and 5 years were 98%, 87%, and 81%, respectively. Multivariate analysis did not identify any factors associated with good local control. Conclusions This study showed that proton beam therapy achieved good local control for HCC using each of three treatment protocols. This suggests that selection of treatment schedules based on tumor location may be used to reduce the risk of late toxicity and maintain good treatment efficacy.

Purpose To determine the role of proton therapy in patients with carcinoma of the uterine cervix. Methods and materials Between 1983 and 1991, 25 patients with squamous cell carcinoma of the uterine cervix (stages IIB–IVA) were treated with a curative intent by external photon irradiation to the pelvis, followed by proton irradiation to the primary tumor, delivering a median total tumor dose of 86 Gy (range 71 Gy/26 Fr–101 Gy/46 Fr), and were followed for a median period of 139 months (range 11–184 months). Results Ten-year overall survival rates for stages IIB and IIIB/IVA patients were 89% and 40%, respectively. Five-year local control rates for stages IIB and IIIB/IVA patients were 100% and 61%, respectively. Four percent of patients experienced severe (Grade 4 or more) late complications in the intestine or urinary bladder at 5 years. Conclusions External photon and proton therapy is effective for those who are not eligible for intracavitary irradiation, and who otherwise have a poor prognosis. The results show that tumor control, survival, and morbidity are similar to those after conventional therapy.

To evaluate clinical results of proton beam therapy for patients with skull base chordoma.Thirteen patients with skull base chordoma who were treated with proton beams with or without X-rays at the University of Tsukuba between 1989 and 2000 were retrospectively reviewed. A median total tumor dose of 72.0 Gy (range, 63.0-95.0 Gy) was delivered. The patients were followed for a median period of 69.3 months (range, 14.6-123.4 months).The 5-year local control rate was 46.0%. Cause-specific, overall, and disease-free survival rates at 5 years were 72.2%, 66.7%, and 42.2%, respectively. The local control rate was higher, without statistical significance, for those with preoperative tumors30 mL. Partial or subtotal tumor removal did not yield better local control rates than for patients who underwent biopsy only as the latest surgery.Proton beam therapy is effective for patients with skull base chordoma, especially for those with small tumors. For a patient with a tumor of30 mL with no prior treatment, biopsy without tumor removal seems to be appropriate before proton beam therapy.