Initial clinical experience with scanned proton beams at the Italian National Center for Hadrontherapy (CNAO).

We report the initial toxicity data with scanned proton beams at the Italian National Center for Hadrontherapy (CNAO). In September 2011, CNAO commenced patient treatment with scanned proton beams within two prospective Phase II protocols approved by the Italian Health Ministry. Patients with chondrosarcoma or chordoma of the skull base or spine were eligible. By October 2012, 21 patients had completed treatment. Immobilization was performed using rigid non-perforated thermoplastic-masks and customized headrests or body-pillows as indicated. Non-contrast CT scans with immobilization devices in place and MRI scans in supine position were performed for treatment-planning. For chordoma, the prescribed doses were 74 cobalt grey equivalent (CGE) and 54 CGE to planning target volume 1 (PTV1) and PTV2, respectively. For chondrosarcoma, the prescribed doses were 70 CGE and 54 CGE to PTV1 and PTV2, respectively. Treatment was delivered five days a week in 35-37 fractions. Prior to treatment, the patients' positions were verified using an optical tracking system and orthogonal X-ray images. Proton beams were delivered using fixed-horizontal portals on a robotic couch. Weekly MRI incorporating diffusion-weighted-imaging was performed during the course of proton therapy. Patients were reviewed once weekly and acute toxicities were graded with the Common Terminology Criteria for Adverse Events (CTCAE). Median age of patients = 50 years (range, 21-74). All 21 patients completed the proton therapy without major toxicities and without treatment interruption. Median dose delivered was 74 CGE (range, 70-74). The maximum toxicity recorded was CTCAE Grade 2 in four patients. Our preliminary data demonstrates the clinical feasibility of scanned proton beams in Italy.

Rationale for carbon ion therapy in high-grade glioma based on a review and a meta-analysis of neutron beam trials.

PURPOSE: The standard treatment of high-grade glioma is still unsatisfactory: the 2-year survival after radiotherapy being only 10-25%. A high linear energy transfer (LET) ionising radiotherapy has been used to overcome tumour radioresistance. An overview of the field is needed to justify future prospective controlled studies on carbon ion therapy. MATERIALS AND METHODS: A meta-analysis of clinical trials on neutron beam therapy and a literature review of clinical investigations on light ion use in high-grade glioma were carried out. RESULTS: Four randomised controlled trials on neutron beam therapy were retained. The meta-analysis showed a non-significant 6% increase of two-year mortality (Relative risk [RR]=1.06 [0.97-1.15]) in comparison with photon therapy. Two phase I/II trials on carbon and neon ion therapy reported for glioblastoma 10% and 31% two-year overall survivals and 13.9 and 19.0 months median survivals, respectively. CONCLUSION: This meta-analysis suggests that neutron beam therapy does not improve the survival of high-grade glioma patients while there is no definitive conclusion yet regarding carbon therapy. The ballistic accuracy and the improved biological efficacy of carbon ions renew the interest in prospective clinical trials on particle beam radiotherapy of glioma and let us expect favourable effects of dose escalation on patients' survival.

Carbon-ion radiotherapy: clinical aspects and related dosimetry.

The features of relativistic carbon-ion beams are attractive from the viewpoint of radiotherapy. They exhibit not only a superior physical dose distribution but also an increase in biological efficiency with depth, because energy loss of the beams increases as they penetrate the body. This paper reviews clinical aspects of carbon-beam radiotherapy using the experience at the National Institute of Radiological Sciences. The paper also outlines the dosimetry related to carbon-beam radiotherapy, including absolute dosimetry of the carbon beam, neutron measurements and radiation protection measurements.

Expression of MMP-13 in osteoblast cells and rat tibia after exposure to gamma rays or accelerated carbon ions.

In past research, we found that carbon ion irradiation increased bone volume in rats, and a significant amount of cartilage remained inside the carbon ion-irradiated trabeculae. The amounts of matrix metalloproteinase 13 (MMP-13) mRNA in osteoblast-like MC3T3-E1 cells tended to decrease after carbon ion irradiation. The level of MMP-13 mRNA in non-irradiated cells was stable during the experimental period, but in gamma ray-irradiated cells it tended to increase. When localization of MMP-13 in locally irradiated experimental rats was investigated, it was found in the marginal trabeculae in both non-irradiated and gamma ray-irradiated animals. MMP-13 was detected in osteoid and neogenetic bone in the trabeculae surface. The trabeculae in carbon ion-irradiated bone remained cartilaginous. Carbon ion-irradiated rats exhibited weak expression of MMP-13 around the cartilage inside the trabeculae. We conclude that carbon ion irradiation reduced expression of MMP-13, thus suppressing both chondrocyte maturation and cartilage resorption. Increases in hyperplasia of the bone trabeculae and of bone volume were caused by ongoing bone addition and calcification in the absence of sufficient cartilage resorption.

High linear energy transfer carbon radiation effectively kills cultured glioma cells with either mutant or wild-type p53.

PURPOSE: A mutation in the p53 gene is believed to play an important role in the radioresistance of many cancer cell lines. We studied cytotoxic effects of high linear energy transfer (LET) carbon beams on glioma cell lines with either mutant or wild-type p53. METHODS AND MATERIALS: Cell lines U-87 and U-138 expressing wild-type p53 and U-251 and U-373 expressing mutant p53 were used. These cells were irradiated with 290 MeV/u carbon beams generated by the Heavy Ion Medical Accelerator in the National Institute of Radiologic Science or X-rays. A standard colony-forming assay and flow cytometric detection of apoptosis were performed. Cell cycle progression and the expression of p53, p21, and bax proteins were examined. RESULTS: High LET carbon radiation was more cytotoxic than low LET X-ray treatment against glioma cells. The effects of the carbon beams were not dependent on the p53 gene status but were reduced by G(1) arrest, which was independent of p21 expression. The expression of bax remained unchanged in all four cell lines. CONCLUSION: These results indicate that high LET charged particle radiation can induce cell death in glioma cells more effectively than X-rays and that cell death other than p53-dependent apoptosis may participate in the cytotoxicity of heavy charged particles. Thus, it might prove to be an effective alternative radiotherapy for patients with gliomas harboring mutated p53 gene.

The phase I/II clinical study of carbon ion therapy for cancer of the uterine cervix.

PURPOSE: The phase I/II clinical study of carbon beam therapy was undertaken for 31 cases of advanced cervical cancer of stages IIIB and IVA from June 1995 to November 1997. The main purpose was to determine clinically useful fraction doses without severe acute reaction of normal tissues and to assess tumor control dose levels achievable without significant normal tissue toxicity. PATIENTS AND METHODS: The treatment was given with four fixed fractions per week (24 fractions over 6 weeks) and was initiated with a fraction dose of 2.2 Gray equivalent (GyE), and the dose was increased as 2.4 GyE, 2.6 GyE, 2.8 GyE, and 3.0 GyE. Consequently, the total dose initiated was 52.8 GyE, to increase up to 72.0 GyE in 4.8-GyE increments in the dose-escalation fashion. Thirty patients with eligible advanced cervical cancers consisting of 27 squamous cell carcinomas and three adenocarcinomas were analyzed. RESULTS: Acute response of normal tissues was less than with photon treatment until fraction doses of 2.8 GyE were administered, and patients finished treatment with comfortable conditions. Severe late complications occurred in the two patients who received more than 67.2 GyE. The 2-year cumulative survival rate and the local control rate of 27 patients with squamous cell carcinoma were 61.5% and 59.3%, respectively. According to stages, the 2-year survival rates of stage IIIB and IVA patients were 54.4% and 75.0%, respectively. The 2-year local control rates of stage IIIB and IVA patients were 52.6% and 75.0%, respectively. DISCUSSION: These results indicated that the disease control seems to be relatively better for very advanced disease and with dose escalation treatment. Local control was not significantly correlated with total dose and tumor volume. The results of the present study, despite small numbers and short observation, suggest that an adequate fraction dose for pelvis fields is 2.8 to 3.0 GyE and that the carbon beam therapy might be advantageous for advanced cervical cancer.

A horizontal CT system dedicated to heavy-ion beam treatment.

A horizontal helical CT system to be used for 3-D treatment planning and for positioning verification of patients in seated position was installed in the treatment room with a fixed horizontal heavy-ion beam line. The system achieved the expected mechanical consistency and reliability.

High-dose-rate intracavitary irradiation using linear source arrangement for stage II and III squamous cell carcinoma of the uterine cervix.

PURPOSE: The purpose of this article is to evaluate fractionated high-dose-rate (HDR) intracavitary irradiation using linear source arrangement (LSA) for patients with squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS: The subjects consisted of 217 patients (71 patients with stage II and 146 with stage III disease) who received external beam therapy (EBT) followed by fractionated HDR intracavitary irradiation using LSA between January 1980 and June 1990. In EBT, 40 Gy in 20 fractions (40 Gy/20 Fr) or 39.6 Gy/22 Fr was delivered to the whole pelvis and an additional 10 Gy/5 Fr or 10.8 Gy/6 Fr was delivered to the parametrium. The intracavitary irradiation dose was 30 Gy/6 Fr or 35 Gy/7 Fr with a daily fraction size of 5 Gy and two fractions per week. During the intracavitary treatment, most patients were treated on an out-patient basis. RESULTS: Cause-specific 5-year survival rates were 77% for stage II and 50% for stage III. Pelvic failure rates were 13% for stage II and 36% for stage III. In multivariate analyses, improved cause-specific survival was significantly associated with stage II (P = 0.0003), higher pretreatment serum hemoglobin level (P = 0.0015), higher pretreatment serum total protein level (P = 0.0029), and shorter total treatment time (P = 0.0024). The rate of severe (grade 3 or 4) late complication was 2% for the rectum, 1% for the small intestine or sigmoid colon and 1% for the bladder. CONCLUSIONS: Fractionated HDR intracavitary irradiation using LSA is an effective treatment for patients with uterine cervical cancer without need for hospitalization.

MRI of mucosal malignant melanoma of the head and neck.

PURPOSE: The objective of this study was to determine the characteristic MR findings for mucosal malignant melanomas of the head and neck. METHOD: We retrospectively analyzed the MR images for six patients with this entity. T1-weighted SE images with and without gadolinium and T2-weighted fast SE images were obtained. MR images were analyzed qualitatively and quantitatively by comparing the signal intensity of the melanoma with that of muscle. RESULTS: On T1-weighted images, five melanomas were hyperintense and one was isointense. On T2-weighted images, five were of mixed intensity and one showed isointensity. The mean signal intensity ratio of the primary melanoma to muscle was 1.51 and 1.39 on T1-weighted images with and without gadolinium, respectively. These values were not statistically significant. CONCLUSION: Hyperintensity on T1-weighted images is characteristic of this entity, but not universal.

[Metabolic imaging of human brain tumors: H-1 chemical shift imaging and PET].

Positron Emission Tomography(PET) and Proton Chemical Shift Imaging(1H-CSI) has provided a cerebral metabolism. The glucose analog fluorine-18 fluorodeoxy-glucose(FDG) and amino acid analog 11C-L-methionine is the most commonly used PET tumor tracer. This time we compare with 1H-CSI and PET in gliomas and metastatic brain tumor with computer-assisted fusion images. We experienced some cases of the brain tumor. One case is metastatic brain tumor after radiation therapy, localized in right parietal hemisphere, with hemorrhage, and slightly accumulated Gd-DTPA in tumors. 11C-methionine PET demonstrates defects in tumors, but slight accumulated surrounding tumors. Accumulation of PET lesion is not elevated choline in CSI, but lactate is accumulated in tumors. Choline signal elevation seen in brain neoprasms, associated with increased cellular proliferation. Accumulation of PET and another accumulation of lactate in tumor are not demonstrate recurrence. Fusion image of PET and CSI is useful in understanding metabolism of brain tumor.

Fast-neutron radiotherapy of nonsmall cell-carcinoma of the lung.

To determine the efficacy of fast neutron (FN) for the treatment of non-small cell lung cancer, 112 patients with histologically proven adenocarcinoma or squamous cell carcinoma at a limited stage were studied to evaluate local control and survival, after treatment with either FNs or photons alone. The local control rate of adenocarcinoma in FN-treated patients attained 50%, which was significantly higher than that (<10%) of squamous cell carcinoma in FN-treated patients or that of both histological types of carcinoma in patients treated with photons alone. In accordance with this, the 5-year survival rate for the FN-treated patients with adenocarcinoma was significantly higher than that for FN-treated patients with squamous cell carcinoma or that for photon-treated patients with both histological types of disease. The present study clearly suggests the usefulness of FN in the treatment of adenocarcinoma of the lung, though it was a non-randomized trial.

Is postoperative radiotherapy beneficial in the management of stage I-II squamous-cell carcinoma of the uterine cervix with negative metastatic nodes and positive parametrial involvement?: A retrospective review of 70 patients.

Seventy patients having squamous-cell carcinoma of the uterine cervix FIGO Stage I-II with negative lymph nodes and positive parametrial involvement received postoperative radiotherapy following radical hysterectomy and pelvic lymphadenectomy. In 48 patients with microscopic parametrial invasion, the 5-year survival rate was 92%. The other 22 patients with macroscopic parametrial involvement had a 5-year survival rate of 75%. The overall recurrence rate was 13% (9 of 70). The sites of failure were 3 pelvic alone, 5 distant metastases alone, and 1 combined pelvis and para-aortic lymph node. All of those with recurrence were Stage-II cases. The absolute pelvic-control rate was 94.3% (66/70). Fifty-six percent of the patients experienced mild-to-moderate lymphedema. Severe complications requiring surgical intervention were observed in 6 patients (5 bowel obstructions and 1 femoral head fracture). A review of the literature suggests that early carcinoma can be successfully treated by surgery alone. Taking into consideration the risk and benefits involved, postoperative radiotherapy is not recommended for most cases with cervical carcinoma with negative lymph nodes and positive parametrial involvement in the present form, despite excellent local control. However, no definite conclusion can be drawn from this retrospective analysis.

Fast neutron therapy for malignant gliomas--results from NIRS study. National Institute of Radiological Sciences.

The results of combined radiotherapy with fast neutrons and photons for 39 malignant gliomas were analyzed. The patients consisted of 16 astrocytoma grade 3 and 23 glioblastoma multiforme. There were two kinds of combination methods which were either "boost therapy" or "mixed beam therapy" with a localized fast neutron field. The average dose of fast neutrons was 569 cGy (n, gamma) and that of photons was 36.86 Gy. The median survival of astrocytoma grade 3 was 15.5 months, and that of glioblastoma multiforme was also 15.5 months. With respect to the combination methods, there was no difference between the boost regimen and the mixed beam regimen. This result seems to have no impact on survival compared to other reports. Patients' ages, surgical debulking procedures, and photon doses were listed as significant prognostic factors, but doses of fast neutrons had no prognostic significance for survival. Because there were no moderate or severe complications for the brain except permanent epilation in all cases, neutron dose escalation study with a localized field will be recommended.

Results of prophylactic adjuvant chemotherapy for early stage non-Hodgkin's lymphoma of the head and neck.

Results were reviewed in 46 patients who had stage I and II head and neck non-Hodgkin's lymphoma, and received five to six cycles of CVP chemotherapy after regional irradiation. Disease-free survival, pattern of relapse, and time of relapse were compared with those of 64 patients, who received regional irradiation alone. Adjuvant, post irradiation CVP significantly improved five-year survival in stage I (and IE) disease, 49.6% to 81.9% (p less than 0.05), but was less successful in patients with heavier tumor burden, such as stage II disease or advanced loco regional disease in Waldeyer's ring (48.3% to 63.7%; p greater than 0.10 in stage II patients). In addition, in those who relapsed, the time and pattern of relapse were not altered by adjuvant CVP chemotherapy. This easily tolerated, mild adjuvant chemotherapy, we conclude, failed to prove significant in preventing relapse, especially in patients with heavier tumor burden.

Analysis of the dose-volume histogram in uterine cervical cancer by diagnostic CT.

The dose-volume histogram of the target volume during intracavitary irradiation in cases of uterine cervical cancer was calculated from diagnostic computed tomography data in order to study the correlation with prognosis. The minimum dose applied to the target volume was most closely related with the prognosis. However, for the actual planning of three-dimensional treatment, a dose of 80% of the volume of the dose-integration volume curve, on which the histogram was integrated in the order of high dose, was recommended as an index dose for dose optimization.

[Radiotherapy of carcinoma of the uterine cervix--high dose rate intracavitary irradiation using a linear source arrangement].

We analyzed the records of 339 patients with squamous cell carcinoma of the uterine cervix. The patients were treated by irradiation alone in the period of 1973-1985 with external and high-dose rate intracavitary irradiation using linear source arrangement. The reason for using the linear source arrangement was to ensure the position of source as well as to simplify the technique of intracavitary irradiation. First, external irradiation was performed mainly with a dosage of 50Gy/25f four times a week or 50.4Gy/28f five times a week. Intracavitary irradiation was then carried out mainly with a dose of 30Gy/6f two times a week or 35Gy/7f two times a week and dose was indicated at point A. The 5-year survival rate of all 330 patients were 51.4%, and 55.1% for stage I (N = 19), 66.7% for stage II (N = 88), 47.1% for stage III (N = 212), 33.7% for stage IV (N = 20). Of the patients followed up for 24 months and found to have recurrence, 21.8% (39/179) had a recurrence in the pelvis and 22.1% (39/175) were found to have a distant metastasis. Of the patients followed up for over 24 months, 21.5% 932/149) developed intestinal complications and 12.2% (18/149) developed bladder complications. However complications Grade 2-4 were 5.4% for intestinal complications and 2.0% for bladder complications. From these results high-dose-rate intracavitary irradiation using a linear source arrangement was considered to be an effective treatment of carcinoma of the uterine cervix and to produce a standard results of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Computed tomography of the kidney with diuretics--a method for avoiding artifacts due to nonionic contrast media].

We devised a method for avoiding beam-hardening artifacts, which interfere with enhanced CT images of kidney due to nonionic contrast medium. The radiographic effect and the frequency of beam-hardening artifacts on enhanced CT of kidney were studied by prospective comparison among three groups: a group of 20 patients examined with furosemide (f-d. CT), a group of 20 patients examined without diuretics (non-d. CT) and a group of 20 patients examined after water intake (w-d. CT). In all patients of f-d. CT group, the renal parenchyma from the cortex to the papilla was almost evenly enhanced, free from artifacts. The density of the renal papilla and pelvis in non-d. CT and w-d. CT groups was significantly higher than that in f-d. CT group, and artifacts were also observed in 14 (70%) of non-d. CT group and 12 (60%) of w.d. CT group, respectively. Satisfactory CT of kidney free from artifacts was obtained by f-d. CT, providing easy evaluation of renal pelvic or peripelvic lesions. In conclusion, this technique can be used in those pathologic cases of renal pelvis or peripelvic region, that are not clear on routine CT because of artifacts.