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.

Neoadjuvant Modified Short-course Radiotherapy for Stage IV Rectal Cancer.

BACKGROUND/AIM: This study aimed to assess the clinical outcomes of neoadjuvant modified short-course radiotherapy (mSC-RT) for rectal metastatic adenocarcinoma. PATIENTS AND METHODS: Data from 14 patients who underwent mSC-RT followed by surgery for primary tumors were retrospectively analyzed. Twelve patients received systemic chemotherapy for 18 weeks. A 2.5 Gy dose twice daily, up to a total dose of 25 Gy in 10 fractions, over 5 consecutive days was administered through mSC-RT. Surgery for primary tumor was performed five weeks (range=3-7 weeks) after mSC-RT. Nine patients underwent adjuvant chemotherapy. The median follow-up was 38.5 months. RESULTS: No patients developed grade ≥3 toxicities before surgery. Three patients developed local failures and 10 died during the follow-up period. The 1-, and 3-year local control rates were 91.7% and 71.3%, respectively. The median overall survival (OS) was 45.1 months. The 1-, and 3-year OS rates were 85.7% and 56.3%, respectively. Patients with stage IVA showed significantly better OS than those with stage IVB disease. CONCLUSION: mSC-RT followed by delayed surgery was well-tolerated and led to good local control in patients with rectal metastatic adenocarcinoma. mSC-RT could be a treatment option for patients with rectal metastatic adenocarcinoma as it is less likely to lead to cessation of systemic chemotherapy.

Clinical results and risk factors of proton and carbon ion therapy for hepatocellular carcinoma.

BACKGROUND: The objective of this study was to evaluate the clinical outcome of proton and carbon ion therapy for hepatocellular carcinoma (HCC). METHODS: In total, 343 consecutive patients with 386 tumors, including 242 patients (with 278 tumors) who received proton therapy and 101 patients (with 108 tumors) who received carbon ion therapy, were treated on 8 different protocols of proton therapy (52.8-84.0 gray equivalents [GyE] in 4-38 fractions) and on 4 different protocols of carbon ion therapy (52.8-76.0 GyE in 4-20 fractions). RESULTS: The 5-year local control and overall survival rates for all patients were 90.8% and 38.2%, respectively. Regarding proton and carbon ion therapy, the 5-year local control rates were 90.2% and 93%, respectively, and the 5-year overall survival rates were 38% and 36.3%, respectively. These rates did not differ significantly between the 2 therapies. Univariate analysis identified tumor size as an independent risk factor for local recurrence in proton therapy, carbon ion therapy, and in all patients. Multivariate analysis identified tumor size as the only independent risk factor for local recurrence in proton therapy and in all patients. Child-Pugh classification was the only independent risk factor for overall survival in proton therapy, in carbon ion therapy, and in all patients according to both univariate and multivariate analyses. No patients died of treatment-related toxicities. CONCLUSIONS: Proton and carbon ion therapies for HCC were comparable in terms of local control and overall survival rates. These therapies may represent innovative alternatives to conventional local therapies for HCC.

Neoadjuvant Modified Short-Course Radiotherapy Followed by Delayed Surgery for Locally Advanced Rectal Cancer.

This study aimed to assess the clinical outcomes and predictive factors of neoadjuvant modified short-course radiotherapy (mSC-RT) for locally advanced rectal cancer (LARC). Data from 97 patients undergoing mSC-RT followed by radical surgery for LARC were retrospectively analyzed. A 2.5 Gy dose twice daily up to a total dose of 25 Gy in 10 fractions was administered through mSC-RT, and this was delivered with oral chemotherapy in 95 (97.9%) patients. Radical surgery was performed 6 (range, 3-13) weeks after mSC-RT. The median follow-up among surviving patients was 43 (8-86) months. All patients completed neoadjuvant radiotherapy with no acute toxicity grade ≥ 3. Three- and five-year local control rates were 96.3% and 96.3%, respectively. Three- and five-year overall survival (OS) rates were 92.7% and 79.8%, respectively. Univariate analyses revealed that poor OS was associated with no concurrent administration of capecitabine, C-reactive-protein-to-albumin ratio ≥ 0.053, carcinoembryonic antigen ≥ 3.4 ng/mL, and neutrophil-to-lymphocyte ratio (NLR) ≥ 1.83 (P = 0.045, 0.001, 0.041, and 0.001, respectively). Multivariate analyses indicated that NLR ≥ 1.83 was independently associated with poor OS (p = 0.018). mSC-RT followed by delayed surgery for LARC was deemed feasible and resulted in good clinical outcomes, whereas poor OS was associated with high NLR.

[Particle beam radiotherapy with a surgical spacer placement for unresectable sacral chordoma].

Sacral chordomas constitute more than half of all chordomas and have a slower local growth than other bone malignant tumors. Although complete radical resection produces a longer local control and disease-free survival at the initial visit, chordomas are already often too large for complete resection to be possible. Particle radiotherapy consisting of proton and carbon-ion is a promising new modality which has an inherent anti-tumor effect against many types of malignancies. However, the application of particle radiotherapy for tumors adjacent to the gastrointestinal tract like sacral chordoma is restricted because the tolerance dose of the intestine is extremely low. A novel two-step treatment was developed with surgical spacer placement and subsequent proton radiotherapy to administer particle radiotherapy with curative intent. This report presents a case of a patient with a huge sacral chordoma treated by this method. This new strategy may potentially be an innovative and standard therapy for unresectable sacral chordoma in the near future.

[Current status and future of particle radiotherapy at the Hyogo Ion Beam Medical Center].

The Hyogo Ion Beam Medical Center was established in May 2001, a leading project of the Hyogo Cancer Strategy . Its major feature is that both proton and carbon ion beams can be generated. Particle beam radiation therapy had been performed in 2,639 patients as of the end of March 2009. The diseases were prostate cancer, head and neck tumors, liver cancer, lung cancer, and bone soft tissue tumors, in decreasing order of frequency, and these 5 major diseases accounted for 87% of the cases. By beam-type therapy, 2,122 and 517 patients (80 and 20%) were treated with proton and carbon ion beams, respectively. The outcomes surpassed those of surgical therapy realizing cancer therapy without resection. Current problems of particle beam radiation therapy include the unclear effect of differential use of proton and carbon ion beams and the necessity of laying in large-scale equipment, which prevents its dissemination. We are now aiming at the development and clinical application of a laser-driven proton radiotherapy device in cooperation with the Japan Atomic Energy Agency.

[Ion beam treatment: a new medical treatment system].

Ion beam treatment consists of a device and form of medical treatment. The device is a comprehensive system that consists of an irradiation system, a treatment planning system and a treatment verification system. The medical system consists of treatment criteria and a clinical path including daily treatment and care for patients. On April 1, 2001, HIBMC was opened as the world's first facility to provide both proton and carbon-ion radiotherapy. We have treated more than 1,300 patients with a variety of malignant tumors including those of the skull base, head and neck, lung, liver and prostate. Excellent local control for these tumors has been obtained with minimum side effects. During the clinical trials and general practice, many tumors including radio-resistant tumors were treated with proton or carbon-ion. This autumn we will start the prospective randomized trial of two beams and we will analyze the difference between them. In future we would like to start new combination treatment with both beams.

Acute morbidity of proton therapy for prostate cancer: the Hyogo Ion Beam Medical Center experience.

PURPOSE: To investigate the incidence and influencing factors of acute genitourinary (GU) and gastrointestinal morbidities in patients with prostate cancer treated with proton therapy. METHODS AND MATERIALS: A total of 287 patients with histologically proven Stage cT1-T4N0M0 prostate cancer were treated with proton therapy between 2003 and 2004. Of these, 204 (71%) received neoadjuvant androgen suppression therapy. The patients were treated with 190-230-MeV protons using lateral-opposed techniques to a dose of 74 GyE. Dose-volume histogram analyses were performed. The incidence of acute morbidity was evaluated using the National Cancer Institute Common Toxicity Criteria, version 2.0. Clinical factors, including age, clinical target volume, initial prostate-specific antigen level, T stage, presence of diabetes mellitus, and the use of androgen suppression therapy, were investigated to determine whether those affected the incidence of acute GU morbidity. RESULTS: None developed Grade 2 or higher acute gastrointestinal morbidity. In contrast, 111 (39%) and 4 (1%) patients experienced acute Grade 2 and Grade 3 GU morbidities, respectively. However, 87% of the patients were successfully relieved by the administration of a selective alpha-1 blocker. Multivariate analysis showed that a larger clinical target volume (p = 0.001) and the use of androgen suppression therapy (p = 0.017) were significant factors for the prediction of acute Grade 2-3 GU morbidity. CONCLUSION: In our experience with proton therapy, a low incidence of acute gastrointestinal morbidity was observed. In contrast, the incidence of acute GU morbidity was similar to that in other reports of photon radiotherapy. Additional follow-up is warranted to elucidate the long-term safety and efficacy of proton therapy for prostate cancer.

Particle irradiation suppresses metastatic potential of cancer cells.

Particle radiotherapy such as proton and carbon ion has been producing promising clinical results worldwide. The purpose of this study was to compare metastatic capabilities of malignant tumor cells after irradiation with photon, proton, and carbon ion beams to clarify their ion beam-specific biological effects. We examined the biological properties of highly aggressive HT1080 human fibrosarcoma cells to assess their metastatic processes in terms of cell adhesion capability to extracellular matrix, expression of integrins, cell migration, cell invasive capability, and matrix metalloproteinase-2 activity in vitro. We then assessed the metastatic capabilities of LM8 mouse osteosarcoma irradiated with carbon ion or photon beam in the syngeneic mice. Both proton and carbon ion irradiation decreased cell migration and invasion in a dose-dependent manner and strongly inhibited matrix metalloproteinase-2 activity. On the other hand, lower X-ray irradiation promoted cell migration and invasion concomitant with up-regulation of alphaVbeta3 integrin. For cancer cells treated with carbon ion irradiation, the number of pulmonary metastasis was decreased significantly in vivo. These findings suggest that particle irradiation suppresses metastatic potential even at lower dose, whereas photon irradiation promotes cell migration and invasive capabilities at lower dose level, and provide preclinical evidence that ion beam radiotherapy may be superior to conventional photon beam therapy in possible preventive effects on metastases of irradiated malignant tumor cells.

A feasibility study of a hybrid breast-immobilization system for early breast cancer in proton beam therapy.

PURPOSE: We aimed to develop a new breast-immobilizing system for proton beam therapy (PBT) of early breast cancer (EBC) that would provide the optimum breast shape during the treatment as well as increased fixation reliability by reducing the influence of respiratory movement. METHODS: The breast-immobilizing system (HyBIS; hybrid breast-immobilizing system) consists of a whole body immobilization system (WBIS), position-converting device (to change patient position), photo-scanning system, breast cup (made using a three-dimensional printer), breast cup-fitting apparatus, breast cup-holding device (to ensure the breast remains lifted in the supine position), and dedicated stretcher fixed to the WBIS (to carry the patient). We conducted a phantom experiment to evaluate the effect of the HyBIS on breast immobilization during the respiratory cycle. Thirteen markers were embedded in the right breast of a female phantom that simulated respiratory thoracic movement at an amplitude of 15 mm, and their displacements on four-dimensional computed tomography were compared between conditions with and without immobilization by HyBIS. RESULTS: When immobilization was applied with the HyBIS, breast protrusion was maintained in the phantom in the supine treatment position. The mean values of the anteroposterior, superoinferior, lateral, and three-dimensional (3D) displacement of the markers were 2.7 ± 1.7, 0.3 ± 0.5, 0.9 ± 0.8, and 3.1 ± 1.6 mm with HyBIS, and 5.5 ± 2.9, 0.6 ± 0.8, 0.5 ± 0.4, and 5.6 ± 2.9 mm without HyBIS, respectively; thus, the anteroposterior (P = 0.014) and 3D (P = 0.007) displacements significantly improved with HyBIS. CONCLUSIONS: We demonstrated that the HyBIS can help retain the protruded breast shape in the supine position during treatment and can reduce the influence of respiratory movement. Thus, the HyBIS can help to reliably and precisely perform PBT for EBC.

Effect of Film Dressing on Acute Radiation Dermatitis Secondary to Proton Beam Therapy.

PURPOSE: Acute radiation dermatitis (ARD) is one of the most common adverse events of proton beam therapy (PBT), and there is currently no effective method to manage ARD. The purpose of this study was to examine the prophylactic effect of a film dressing using Airwall on PBT-induced ARD compared with standard skin managements. METHODS AND MATERIALS: A total of 271 patients with prostate cancer who were scheduled for PBT at our center were divided into 2 groups based on their own requests: 145 patients (53%) chose Airwall (group A) and 126 patients (47%) received standard treatments (group B). We evaluated irradiated skin every other day during PBT and followed up once a week for a month after completion of PBT. RESULTS: Grade 0, 1, 2, and 3 dermatitis were seen in 2, 122, 21, and 0 and 0, 65, 57, and 4 patients in groups A and B, respectively (P<.001). Numbers of days to grades 1 and 2 ARD development were 34.9 ± 14.3 and 54.7 ± 10.3 and 31.8 ± 11.3 and 54.4 ± 11.6 in groups A and B, respectively. There were no significant differences between the 2 groups. Eighteen patients (12%) in group A who experienced problems in the region covered with Airwall switched to standard skin care after peeling the film off. CONCLUSIONS: Film dressing using Airwall reduced the severity of ARD without delaying the response time of the skin to proton beam irradiation compared with standard skin management. Hence, film dressing is considered a promising measure for preventing ARD secondary to PBT.

Pacemaker malfunction associated with proton beam therapy: a report of two cases and review of literature-does field-to-generator distance matter?

It is well known that radiotherapy causes malfunctions of cardiac implantable electronic devices such as pacemaker (PM) and implantable cardioverter-defibrillator because of incidental neutron production. Here, we report our experience with two cases of PM reset among seven patients with PM who underwent proton beam therapy (PBT) from January 2011 to April 2015 at our centre. Our experience shows PM reset can occur also with abdominal PBT. In both cases, PM reset was not detected by electrocardiogram (ECG) monitoring but was rather discovered by post-treatment programmer analysis. Our cases suggest that PM malfunction may not always be detected by ECG monitoring and emphasize the importance of daily programmer analysis.

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.

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.

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.

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.

Cell biological basis for combination radiotherapy using heavy-ion beams and high-energy X-rays.

We investigated the biological effect of combining carbon-beam and X-ray in vitro. The results showed that when we employed Gray equivalent as the indication of therapeutic dose, the effects could be explained with simple additive way in the treatment plan. This fact provides important information about the combined therapy of carbon-beam and X-ray.

Ridge filter design for proton therapy at Hyogo Ion Beam Medical Center.

At the Hyogo Ion Beam Medical Center (HIBMC) we have developed a new design method for the bar ridge filter used in proton therapy, taking into consideration the scattering and nuclear interaction effects within the filter itself, which are introduced in the design. In our beam delivery system, the bar ridge filter is employed as the range modulator. It is combined with the wobbler system, and produces a three-dimensionally uniform spread-out Bragg peak (SOBP). The design program predicts the three-dimensional dose distribution. Ridge filters of 3-12 cm SOBP in 1 cm increments were designed in the maximum radiation field for 150 MeV and 190 MeV proton beams so that a uniform physical dose area is obtained in the SOBP region three-dimensionally. Measurements were performed with the constructed ridge filters to verify the uniformity and these were compared with the predictions of the design program. The predictions and measurements were found to be in agreement except for the 12 cm SOBP. The uniformities were better than +/- 3.0% for all SOBPs produced. The ridge filters are now clinically in use.