Proton Medical Research Center

Proton Radiotherapy at Tsukuba

Proton therapy has a long history dating back to the 1940s. Basic research on proton therapy started initially in the USA and then in Europe. As of January 2005, more than 46,000 patients have been treated at more than 20 facilities worldwide (1).

The University of Tsukuba started proton clinical studies in 1983 using a synchrotron constructed for physics studies at the High Energy Accelerator Research Organization (KEK) (Figure-1). A total of 700 patients were treated at this facility from 1983 to 2000.

Figure-1

In 2000, a new in-house facility, called Proton Medical Research Center (PMRC), was constructed adjacent to the University Hospital. PMRC is equipped with a synchrotron and two rotating gantries. Clinical treatment was started in September 2001 at this new facility　(Figure-2). The mission of this facility is to prove the clinical utility of proton beam therapy, to develop innovative treatment technologies and techniques, and to train personnel involved in particle radiotherapy.

Figure-2

From September 2001 to March 2007, 1046 patients were treated in this new facility. PMRC focuses mainly on cancers commonly found in Japanese people, such as liver cancer, lung cancer, prostate cancer, esophageal cancer and brain or skull base tumors. Arterio-venous malformation of the brain is one example of the benign conditions treated in our facility. The content of the total 1746 patients treated so far is shown in Figure-3, and the results of our clinical studies are indicated below.

Figure-3

Hepatocellular carcinoma

We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection. The patients in the present series were considered unsuitable for surgery for various reasons including hepatic dysfunction, multiple tumors, recurrence after surgical resection, or concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days.

The overall survival rate for all patients was 23.5% at 5 years. The local control rate at 5 years was 86.8% for the 137 patients with 166 HCCs. The degree of impairment of hepatic function attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For patients having the least-impaired hepatic functions and only solitary tumor, the survival rate at 5 years was 53.5%. The patients had few acute reactions to treatment and only a small number of late sequelae during and after the treatments.

Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic function, and co-existing intercurrent diseases.

Chiba T, Tokuuye K, Matsuzaki Y, Sugahara S, Chuganji Y, Kagei K, Shoda J, Hata M, Abei M, Igaki H, Tanaka N, Akine Y. Proton Beam Therapy for Hepatocellular Carcinoma: A Retrospective Review　of 162 Patients. Clinical Cancer Research.11:3799-3805, 2005

Hepatocellular Carcinoma with Portal Vein Tumor Thrombus

Treatment modalities for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) are limited and controversial; furthermore, the prognosis is extremely poor. We performed a retrospective review to determine the role of proton beam therapy in the treatment of HCC with PVTT.

Twelve HCC patients with tumor thrombus in the main trunk or major branches of the portal vein, cT3-4N0M0, were treated with proton beam therapy. The patient's ages at proton beam irradiation were 42 to 80 years (median 62) and the tumor size ranged from 40 to 110 mm (median 60) in maximum diameter. A total dose of 50-72 Gy (median 55) in 10-22 fractions was delivered to the tumors including PVTT.

All tumors treated with proton beam therapy were controlled at the median follow-up period of 2.3 years (range, 0.3-7.3). Of 12 patients, 10 had new liver tumors outside the irradiated volume 0.1-2.4 years after proton beam therapy and 3 also had distant metastases; consequently, 8 patients died of cancer and 2 were salvaged by further therapies. The remaining 2 patients were alive with no evidence of disease 4.3 and 6.4 years after proton beam therapy. The progression-free survival rates for patients with HCC with PVTT were 67% and 24% at 2 and 5 years, respectively. The median progression-free survival time was 2.3 years. Therapy-related toxicity of grade 3 or more was not observed.

Proton beam therapy for HCC with PVTT was feasible and effective. It appeared to have significantly improved survival and local control for the patients.

Hata M, Tokuuye K, Sugahara S, Kagei K, Igaki H, Hashimoto T, Ohara K, Matsuzaki Y, Tanaka N, and Akine Y. Proton Beam Therapy for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus. Cancer. 107:591-598, 2006

Lung Cancer

From 1983 through 2000, 51 non-small-cell lung cancer (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. Of all patients, 33 had squamous cell carcinoma, 17 had adenocarcinoma, and 1 had large-cell carcinoma. The median fraction dose and the median total dose were 3.0 Gy (range: 2.0-6.0 Gy), and 76.0 Gy (range: 49.0- 93.0 Gy), respectively.

The five-year overall survival rate was 29% for all patients, 70% for the 9 stage IA patients, and 16% for the 19 stage IB patients (IA vs. IB: p < 0.05). The five-year in-field local control rate was higher in patients with stage IA (89%) when compared to those with stage IB (39%). Regarding acute lung toxicity: 47 patients (92%) experienced grade 1 or less; 3 had grade 2; 1 had grade 3; 0 experienced grade 4 or higher. Patients in the present series showed very little late toxicity.

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 3-dimensional conformal photon radiotherapy remains to be defined through future clinical trials.

Shioyama Y, Tokuuye K, Okumura T, Kagei K, Sugahara S, Ohara K, Akine Y, Ishikawa S, Satoh H, Sekizawa K. Clinical evaluation of proton radiotherapy for non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 56:7-13, 2003

Carcinoma of the esophagus

We reviewed forty-six patients with esophageal cancer who were treated using proton beams with or without x-rays between 1985 and 1998. All patients had loco-regionally 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. A 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 six patients received proton beam therapy alone (75-89.5 Gy, median 82.0 Gy).

Five-year survival for the 46 patients, that for patients with T1 (n=23), and that for those with T2/3/4 (n=23) were 34%, 55%, and 13%, respectively. The five-year disease-specific survival for the 46 patients, that for those with T1, and that for those with T2/3/4 were 67%, 95%, and 33%, respectively. The five-year local control rates for patients with T1 and T2/3/4 lesions were 83% and 29%, respectively. Sites of the first relapse were loco-regional for 16 patients and distant organs for 2 patients.

These results suggest that proton beam therapy is an effective treatment for patients with locally confined esophageal cancer. Further studies are needed to determine the optimal total dose, fractionation schedules, and best combinations of protons and conventional x-rays with or without chemotherapy.

Sugahara S, Tokuuye K, Okumura T, Nakahara A, Saida Y, Kagei K, Ohara K, Hata M, Igaki H, Akine Y. Clinical results of proton beam therapy for cancer of the esophagus. Int J Radiat Oncol Biol Phys. 61:76-84, 2005

Head and Neck cancers

From 1983 to 2000, thirty three patients with head and neck malignancies but no history of surgical resection were treated with 250MeV protons with or without x-ray irradiation. This study　retrospectively evaluates the local control, survival, and treatment sequelae of these patients. The median total target dose using protons with or without x-rays was 76 Gy (ranging 42 - 99 Gy) and the median　proton fraction dose was 2.8 Gy (ranging 1.5 - 6.0 Gy).

Overall five-year survival and local control rates were 44% and 74%, respectively. One (3%) and six (18 %) patients suffered from treatment- related acute and late toxicity greater than grade 3 (RTOG/EORTC acute and late radiation morbidity scoring criteria). One patient with a history of radiotherapy suffered from acute toxicity greater than grade 3.

Proton therapy appeared to offer high local control rates with little toxicity relative to conventional radiotherapy. However, late toxicity was seen in areas where large radiation doses had been given.

Tokuuye K, Akine Y, Kagei K, Hata M, Hashimoto T, Mizumoto T, Ohshiro Y, Sugahara S, Ohara K, Okumura T, Kusakari J, Yoshida H, Otsuka F. Proton therapy for head and neck malignancies at Tsukuba. Strahlenther Onkol. 180:96-101, 2004

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 tumors <30 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 of <30 mL with no prior treatment, biopsy without tumor removal seems to be appropriate before proton beam therapy.

Igaki H, Tokuuye K, Okumura T, Sugahara S, Kagei K, Hata M, Ohara K, Hashimoto T, Tsuboi K, Takano S, Matsumura A, Akine Y. Clinical results of proton beam therapy for skull base chordoma.Int J Radiat Oncol Biol Phys. 60:1120-6, 2004