Particle therapy for clinically diagnosed stage I lung cancer: comparison with pathologically proven non-small cell lung cancer.

BACKGROUND: The purpose of the present study was to present the treatment outcomes of particle therapy for indeterminate pulmonary nodules (IPNs) diagnosed as stage I non-small cell lung cancer, including a comparative analysis involving pathologically proven lung cancer (PPLC). MATERIAL AND METHODS: A total of 54 patients (57 lesions) who underwent particle therapy for IPNs were enrolled in this study. Median patient age was 76 (range 52-87) years. T-classification was: T1a, 30; T1b, 16; and T2a, 11. Particle therapy using protons or carbon ions was delivered at total doses of 52.8-80 Gy equivalent in 4-26 fractions. The PPLC cohort included 111 patients. RESULTS: The median follow-up time was 41 (range 7-90) months. For all IPN patients, the three-year overall survival, progression-free survival, local control and distant progression-free survival rates were 90%, 72%, 94% and 79%, respectively. Grade 2 toxicities were radiation pneumonitis (19%), dermatitis (9%), rib fracture (2%), chest wall pain (2%) and neuropathy (2%). No ≥grade 3 toxicities were observed. In univariate analysis, the IPN group showed significantly better survival relative to the PPLC group. However, after adjustment for baseline imbalances between these two groups in multivariate analysis, pathological confirmation did not correlate with survival. CONCLUSIONS: Particle therapy for IPNs provided favorable outcomes with minimal toxicities, which may be comparable to those for PPLC patients. Further studies are needed to clarify the optimal management of IPN patients.

Treatment outcomes of particle radiotherapy using protons or carbon ions as a single-modality therapy for adenoid cystic carcinoma of the head and neck.

BACKGROUND AND PURPOSE: The aim of this study was to retrospectively analyse the outcomes of cases of adenoid cystic carcinomas (ACCs) of the head and neck that were treated at a single institution with particle therapy consisting of either protons or carbon ions. METHODS AND MATERIALS: Between February 2002 and March 2012, 80 patients were treated with proton therapy (PT) or carbon ion therapy (CIT) alone. PT and CIT were employed in 40 (50%) patients each, and more than half of the patients received 65.0 GyE in 26 fractions (n=47, 59%). RESULTS: The median duration of follow-up was 38 months (range, 6-115 months). For all patients, the 5-year for overall survival (OS) rate, progression-free survival (PFS) rate, and local control (LC) rate were 63%, 39%, and 75%, respectively. No significant differences between PT and CIT were observed. The 5-year LC rates for T4 and inoperable cases were 66% and 68%, respectively. Twenty-one patients (26%) experienced grade 3 or greater late toxicities, including three patients who developed grade 5 bleeding from nasopharyngeal ulcers. CONCLUSIONS: Particle radiotherapy for ACC achieves favourable LC, and its efficacy in inoperable or T4 cases is promising. There were no significant differences between PT and CIT in terms of OS, PFS and LC.

A retrospective comparison of proton therapy and carbon ion therapy for stage I non-small cell lung cancer.

BACKGROUND AND PURPOSE: This retrospective study aimed to compare the clinical outcomes and late toxicities of proton therapy (PT) with those of carbon ion therapy (CIT) for stage I non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: A total of 111 patients who underwent particle therapy for stage I NSCLC between April 2003 and December 2009 were enrolled in this study. PT (n=70) and CIT (n=41) were delivered to total doses of 52.8-80 GyE in 4-26 fractions and 52.8-70.2 GyE in 4-26 fractions, respectively. The median follow-up time was 41 months. RESULTS: Differences in outcome between the PT and CIT groups regarding 3-year overall survival (72% and 76%, respectively), progression-free survival (44% and 53%, respectively), and local control (81% and 78%, respectively) were not statistically significant. In multivariate analysis, the type of treatment beam did not correlate with overall survival. The severity of late toxicities was comparable between the two groups. CONCLUSIONS: Clinical results in the PT group were comparable to those in the CIT group. However, this study was a retrospective analysis of a highly heterogeneous population. Consequently, more homogeneous prospective data, large multicentric databases and, ideally, randomized trials are warranted.

Long-term outcome of proton therapy and carbon-ion therapy for large (T2a-T2bN0M0) non-small-cell lung cancer.

INTRODUCTION: : Although many reports have shown the safety and efficacy of stereotactic body radiotherapy (SBRT) for T1N0M0 non-small-cell lung cancer (NSCLC), it is rather difficult to treat T2N0M0 NSCLC, especially T2b (>5 cm) tumor, with SBRT. Our hypothesis was that particle therapy might be superior to SBRT in T2 patients. We evaluated the clinical outcome of particle therapy for T2a/bN0M0 NSCLC staged according to the 7th edition of the International Union Against Cancer (UICC) tumor, node, metastasis classification. METHODS: : From April 2003 to December 2009, 70 histologically confirmed patients were treated with proton (n = 43) or carbon-ion (n = 27) therapy according to institutional protocols. Forty-seven patients had a T2a tumor and 23 had a T2b tumor. The total dose and fraction (fr) number were 60 (Gray equivalent) GyE/10 fr in 20 patients, 52.8 GyE/4 fr in 16, 66 GyE/10 fr in 16, 80 GyE/20 fr in 14, and other in four patients, respectively. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, Version 4.0. RESULTS: : The median follow-up period for living patients was 51 months (range, 24-103). For all 70 patients, the 4-year overall survival, local control, and progression-free survival rates were 58% (T2a, 53%; T2b, 67%), 75% (T2a, 70%; T2b, 84%), and 46% (T2a, 43%; T2b, 52%), respectively, with no significant differences between the two groups. The 4-year regional recurrence rate was 17%. Grade 3 pulmonary toxicity was observed in only two patients. CONCLUSION: : Particle therapy is well tolerated and effective for T2a/bN0M0 NSCLC. To further improve treatment outcome, adjuvant chemotherapy seems a reasonable option, whenever possible.

A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis.

PURPOSE: We conducted the study to assess the feasibility and efficacy of gemcitabine-concurrent proton radiotherapy (GPT) for locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Of all 50 patients who participated in the study, 5 patients with gastrointestinal (GI)-adjacent LAPC were enrolled in P-1 (50 Gy equivalent [GyE] in 25 fractions) and 5 patients with non-GI-adjacent LAPC in P-2 (70.2 GyE in 26 fractions), and 40 patients with LAPC regardless of GI-adjacency in P-3 (67.5 GyE in 25 fractions using the field-within-a-field technique). In every protocol, gemcitabine (800 mg/m(2)/week for 3 weeks) was administered concurrently. Every patient received adjuvant chemotherapy including gemcitabine after GPT within the tolerable limit. RESULTS: The median follow-up period was 12.5 months. The scheduled GPT was feasible for all except 6 patients (12%) due to acute hematologic or GI toxicities. Grade 3 or greater late gastric ulcer and hemorrhage were seen in 5 patients (10%) in P-2 and P-3. The one-year freedom from local-progression, progression-free, and overall survival rates were 81.7%, 64.3%, and 76.8%, respectively. CONCLUSION: GPT was feasible and showed high efficacy. Although the number of patients and the follow-up periods are insufficient, the clinical results seem very encouraging.

The effectiveness of particle radiotherapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus.

BACKGROUND: The prognosis of patients who have hepatocellular carcinoma (HCC) associated with inferior vena cava tumor thrombus (IVCTT) is very poor, and effective treatment modalities are extremely limited. The objective of this study was to determine the therapeutic efficacy of particle radiotherapy for HCC with IVCTT. METHODS: Between June 2001 and January 2009, 16 evaluable patients who had HCC with IVCTT were treated with particle radiotherapy. They were divided into 2 groups: 6 were treated with curative intent; 10 with palliative intent. The local tumor control rates, overall survival rates, and toxicities were evaluated. RESULTS: All tumors treated with particle radiotherapy remained controlled without local recurrence at the last follow-up. The overall survival rates for the 16 patients at 1 and 3 years were 61.1 and 36.7%, respectively. We observed a significant difference in the survival rates according to treatment policy. The median survival time was 25.4 months for patients treated with curative intent and 7.7 months for those treated with palliative intent. The one-year survival rates were 100.0 and 33.3%, respectively. No Grade 3 or higher treatment-related toxicities were observed. CONCLUSIONS: Particle radiotherapy is thought to be potentially effective and safe for HCC with IVCTT. Considering the current lack of effective and less-invasive local therapy for HCC with IVCTT, particle radiotherapy may therefore be an attractive new therapeutic approach for this type of HCC.

Charged particle radiotherapy at the Hyogo Ion Beam Medical Center: Characteristics, technology and clinical results.

The Hyogo Ion Beam Medical Center was constructed in 2001 as the world's first charged particle radiotherapy center where both proton and carbon-ion radiotherapy can be performed. From April 2001 to February 2007, more than 1,400 patients with a variety of cancers were treated. Most of the tumors except for prostate cancer were considered hard to cure with standard treatments such as surgery or conventional x-ray radiotherapy. The clinical results obtained so far are very encouraging, mainly due to the excellent dose localization to the tumor and strong cell killing effects of protons and carbon-ions. The good indications are localized tumors including skull base tumors, head and neck tumors, cancers of the lung, the liver, and the prostate, and bone and soft tissue sarcomas. Charged particle radiotherapy will significantly improve the quality of life of cancer patients and promote their speedy return to normal lives or work if it is used for early stage cancer.

A case of hepatocellular carcinoma initially treated by carbon ions, followed by protons for marginal recurrence with portal thrombus.

We report a case of hepatocellular carcinoma (HCC), initially treated by carbon ions, then subsequently by protons for marginal recurrence. A 52-year-old man with stage II HCC was enrolled in the clinical study for carbon ion therapy. A total dose of 52.5 GyE in 8 fractions was delivered through a right lateral port for 13 days. Dynamic CT performed 7 months after the initiation of carbon ion therapy showed a decrease in the size of the tumor. Dynamic CT performed 12 months after the therapy revealed marginal recurrence of HCC accompanied with portal vein tumor thrombus (PVTT). Proton therapy of 66 GyE in 22 fractions was delivered through posterior and right lateral ports for 33 days. Dynamic CT performed 3 months after the initiation of proton therapy showed a regression of the recurrent tumor and disappearance of the PVTT. No serious adverse effects were observed during or after these two treatments. He was free from further recurrence 27 months after the initiation of the first carbon ion therapy. Both carbon ions and protons were effective with minimal side effects.

Experience with conformal proton therapy for early prostate cancer.

A study was conducted to evaluate the use of proton beam therapy for the treatment of organ-confined prostate cancer. This is a preliminary assessment of treatment-related morbidity and tumor response. Sixteen patients with T1-T2b prostate cancer underwent proton beam therapy. Acute and late toxicity was scored according to the National Cancer Institute Common Toxicity Criteria Grading System (version 2.0, April 1999) and to the Radiation Therapy Oncology Group grading system, respectively. Local control was assessed using magnetic resonance imaging (MRI) and prostate-specific antigen (PSA) values. Although skin toxicity and bladder irritability were commonly observed, none of the patients developed grade III or IV toxicity. Of 9 patients in whom the primary lesion was detected by MRI, partial response and no change (NC) was observed in 6 (66.7%) and 3 (33.3%) patients, respectively. Four patients presented normal PSA value before treatment due to the previous endocrine therapy. However, the other 12 patients with elevated PSA value before treatment showed complete response. No patients showed PSA failure within the median follow-up period of 11.9 months. Although longer follow-up is necessary, minimum toxicity and good short-term clinical responses were observed following proton beam therapy in T1-T2 prostate cancer patients.

Status of the clinical work at Hyogo.

On April 1, 2001, the Hyogo Ion Beam Medical Center (HIBMC) was opened as the first facility in the world to provide ion beam therapy using 2 types of beams, protons and carbon-ions. We will introduce the HIBMC, and report the results of the clinical study and general practice.

Preclinical biological assessment of proton and carbon ion beams at Hyogo Ion Beam Medical Center.

PURPOSE: To assess the biologic effects of proton and carbon ion beams before clinical use. METHODS AND MATERIALS: Cultured cells from human salivary gland cancer (HSG cells) were irradiated at 5 points along a 190 MeV per nucleon proton and a 320 MeV per nucleon carbon ion beam, with Bragg peaks modulated to 6 cm widths. A linac 4 MV X-ray was used as a reference. Relative biologic effectiveness (RBE) values at each point were calculated from survival curves. Cells were also irradiated in a cell-stack phantom to identify that localized cell deaths were observed at predefined depth. Total body irradiation of C3H/He mice was performed, and the number of regenerating crypts per jejunal section was compared to calculate intestinal RBE values. For carbon ion and referential 4 MV X-ray beams, mouse right legs were irradiated by four-fractional treatment and followed up for skin reaction scoring. RESULTS: RBE values calculated from cell survival curves at the dose that would reduce cell survival to 10% (D10) ranged from 1.01 to 1.05 for protons and from 1.23 to 2.56 for carbon ions. The cell-stack phantom irradiation revealed localized cell deaths at predefined depth. The intestinal RBE values ranged from 1.01 to 1.08 for protons and from 1.15 to 1.88 for carbon ions. The skin RBE value was 2.16 at C320/6 cm spread-out Bragg peak (SOBP) center. CONCLUSION: The radiobiologic measurements of proton and carbon ion beams at Hyogo Ion Beam Medical Center are consistent with previous reports using proton beams in clinical settings and carbon ion beams with similar linear energy transfer (LET) values.

Patterns of Care Study quantitative evaluation of the quality of radiotherapy in Japan.

BACKGROUND: Quality assurance (QA) of clinical practice is important for any medical specialty. Programs based on the Patterns of Care Study (PCS) have been developed to compare the quality of radiotherapeutic care at individual institutions, with the national average representing the process and outcome of radiotherapy. The feasibility of these programs was analyzed. METHODS: Calculation programs for the national average and standard score were developed to evaluate quantitatively the process and outcome of radiotherapy at individual institutions as well as at the national level. The programs were used to evaluate the quality of radiotherapy for 561 esophageal carcinoma patients surveyed in the Japanese PCS. RESULTS: As a representative example of QA measurement, the national average for the 5-year survival rate for these patients in the nonsurgery group was 5%. The regional averages for those in academic and nonacademic institutions were 9% and 1%, respectively (P = 0.0142), showing a significant difference between these two institutional strata. The standard score compared with the national average for institution No.105, for example, was 16.3 (P < 0.0001), with the positive value indicating that the outcome at this institution was significantly higher than the national average. The corresponding figure compared with the regional average was -0.3 (P = 0.7391), with the negative value indicating the outcome is not superior to the regional average of academic institutions. CONCLUSIONS: These programs make it possible to compare quantitatively the quality of radiation therapy at individual institutions with the national and regional averages. They should also be useful for nationwide QA projects in radiation oncology as well as in other medical specialities.

Usefulness of positron-emission tomographic images after proton therapy.

PURPOSE: To examine the positron emission tomography (PET) image obtained after proton irradiation and investigate the usefulness of the image for confirmation of the irradiated volume in proton radiotherapy (RT). METHODS AND MATERIALS: A homogenous phantom was irradiated separately by carbon-ion and proton beams and the images obtained were compared. The PET images of cancer patients just after proton RT were then taken after informed consent. RESULTS: In the PET image produced by carbon-ion beams, the high pixel counts in the image corresponded to the Bragg peak; however, in that produced by proton beams, they were visible throughout the entire track of the proton beams and were not related to the Bragg peak. The PET image of patients treated with proton RT was similar to that of the phantom experiment. CONCLUSION: The PET image after proton RT was different from that of carbon-ion RT. It was found that the PET image was very useful in proton RT to verify treatment planning.

Subcutaneous fibrosis after whole neck irradiation.

PURPOSE: To identify the risk factors for moderate to severe subcutaneous fibrosis after whole neck irradiation. MATERIALS AND METHODS: We analyzed 233 cases of patients who had undergone whole neck irradiation with 4-MV X-ray or 8-10-MeV electrons, or both, and had been followed with regard to their skin condition for at least 1 year. The prescribed dose to the whole neck ranged from 19.2 to 72.4 Gy (median 50). The skin-absorbed dose was specified as that at a depth of 4.1 mm (d4.1-mm(depth)), and a biologically equivalent dose (BED) of d4.1-mm(depth) was also estimated (BED(1.8) 4.1-mm(depth)). RESULTS: Univariate analysis revealed that previous neck dissection, concurrent chemotherapy, corticosteroid administration as a part of chemotherapy, fractionation, and BED(1.8) 4.1-mm(depth) were significant prognostic variables. Multivariate analysis showed that BED(1.8) 4.1-mm(depth) and previous neck dissection were the only prognostic variables for moderate to severe subcutaneous fibrosis. CONCLUSION: A high dose to a 4.1-mm depth of the skin and a history of neck dissection were identified as the predominant risk factors for moderate to severe subcutaneous fibrosis after whole neck irradiation. A subcutaneous dose should be considered in radiotherapy treatment planning involving the whole neck, especially in cases in which patients have undergone previous neck dissection.

[Report on proton therapy according to good clinical practice at Hyogo Ion Beam Medical Center].

The Hyogo Ion Beam Medical Center(HIBMC) is a hospital-based charged particle treatment facility. Having two treatment ion beams(proton and carbon) and five treatment rooms, it is a pioneer among particle institutes worldwide. In May 2001, proton therapy was started as a clinical study for patients with localized cancer originating in the head and neck, lung, liver, and prostate. The aim of this study was to investigate the safety, effectiveness, and stability of the treatment units and systems based on the evaluation of acute toxicity, tumor response, and working ratio of the machine, respectively. Six patients, including liver cancer in three, prostate cancer in two, and lung cancer in one, were treated. There was no cessation of therapy owing to machine malfunction. Full courses of proton therapy consisting of 154 portals in all six patients were given exactly as scheduled. None of the patients experienced severe acute reactions of more than grade 3 according to NCI-CTC criteria. Tumor response one month post-treatment was evaluable in five of the six patients, and was CR in 1 (prostate cancer), PR in 2 (lung cancer: 1, liver cancer: 1), and NC in 2(liver cancer: 2). These results indicate that our treatment units and systems are safe and reliable enough for proton irradiation to be used for several malignant tumors localized in the body.