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[Science and ethics of proton therapy].

Proton therapy delivers a conformed dose to the tumor, while reducing the dose to the surrounding tissues. Its relative biological effectiveness (RBE) is similar to that of conventional radiation, such as X-rays and gamma-rays. Proton therapy was first applied to humans in 1954. Thus for more than 19,000 patients have been treated. The distribution of the diseases to which it has been applied, however, has been quite limited. Although it is now performed at 17 institutions throughout the world, a hospital-based medically dedicated proton therapy system exists at only one institution. Therefore, proton therapy is considered to be an experimental treatment for most malignant diseases, and its equipment is also considered to be underdevelopment situation. In this paper, the project of proton treatment facility at the National Cancer Center (NCC, Kashiwa) is presented. Problems and future direction of our project are also discussed in this article.

Cancer Care Facilities↗

Proton therapy.

Proton therapy has become a subject of considerable interest in the radiation oncology community and it is expected that there will be a substantial growth in proton treatment facilities during the next decade. I was asked to write a historical review of proton therapy based on my personal experiences, which have all occurred in the United States, so therefore I have a somewhat parochial point of view. Space requirements did not permit me to mention all of the existing proton therapy facilities or the names of all of those who have contributed to proton therapy.

Health Physics↗

Proton radiography as a tool for quality control in proton therapy.

Proton radiography is investigated for its use as a quality control tool in proton therapy. Images were produced both with range and range uncertainty information of protons passing through phantoms (Alderson phantom and a sheep's head). With the range images the correct positioning of the patient with respect to the beam could be verified. The range uncertainty images were used to quantitatively detect range variations of protons passing through inhomogeneities in the patient. These measurements can be used to indicate critical situations during proton therapy or to determine the safety margin around the tumor volume. With the range information the precision of different calibrations of computer tomography Hounsfield values to relative proton stopping power, used for proton treatment planning, was determined. It is found that the precision in range can be improved by a detailed analysis of the calibration data obtained from tissue-substitute measurements, by a factor of 2.5. The resulting range errors are in the order of the positioning precision (approximately 1 mm).

Animals↗

Clinical applications of proton therapy.

Proton therapy offers considerable potential advantages in the management of poorly resectable, radio-resistent tumors close to critical anatomical structures. So far over 15,000 patients have been treated worldwide with two major indications: conservative management of ocular melanomas in which local control exceeds 95% at 5 years and curative irradiation of sarcomas at the base of the skull and cervical canal, with a survival rate between 84 and 94% at 5 years. The different protocols tested currently worldwide are discussed.

Adolescent↗

A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours.

BACKGROUND AND PURPOSE: In this work, the potential benefits and limitations of different treatment techniques, based on mixed photon-electron beams, 3D conformal therapy, intensity modulated photons (IM) and protons (passively scattered and spot scanned), have been assessed using comparative treatment planning methods in a cohort of patients presenting with advanced head and neck tumours. MATERIAL AND METHODS: Plans for five patients were computed for all modalities using CT scans to delineate target volume (PTV) and organs at risk (OAR) and to predict dose distributions. The prescribed dose to the PTV was 54 Gy, whilst the spinal cord was constrained to a maximum dose of 40.5 Gy for all techniques. Dose volume histograms were used for physical and biological evaluation, which included equivalent uniform dose (EUD) calculations. RESULTS: Excluding the mixed photon-electron technique, PTV coverage was within the defined limits for all techniques, with protons providing significantly improved dose homogeneity, resulting in correspondingly higher EUD results. For the spinal cord, protons also provided the best sparing with maximum doses as low as 17 Gy. Whilst the IM plans were demonstrated to be significantly superior to non-modulated photon plans, they were found to be inferior to protons for both criteria. A similar result was found for the parotid glands. Although they are partially included in the treated volume there is a clear indication that protons, and to a lesser extent IM photons, could play an important role in preserving organ functionality with a consequent improvement of the patient's quality of life. CONCLUSIONS: For advanced head and neck tumours, we have demonstrated that the use of IM photons or protons both have the potential to reduce the possibility of spinal cord toxicity. In addition, a substantial reduction of dose to the parotid glands through the use of protons enhances the interest for such a treatment modality in cases of advanced head and neck tumours. However, in terms of target coverage, the use of 3D conformal therapy, although somewhat inferior in quality to protons or IM photons, has been shown to be a reasonable alternative to the more advanced techniques. In contrast, the conventional technique of mixed photon and electron fields has been shown to be inferior to all other techniques for both target coverage and OAR involvement.

Carcinoma, Squamous Cell↗

Proton therapy for base of skull chordoma: a report for the Royal College of Radiologists. The Proton Therapy Working Party.

Chordomas of the base of the skull are rare. They are locally infiltrative and frequently arise close to radiosensitive structures, which limits the ability to deliver a high dose of radiotherapy. Complete surgical excision is not usually possible. Conventional postoperative radiotherapy can result in approximately 50% 5-year survival and effective palliation, but long-term local control and cure are rare. The well-defined Bragg peak of protons allows planning with a sharp cut-off outside the target volume. This permits a higher dose of radiotherapy to be delivered to the tumour while avoiding excessive irradiation to radiosensitive structures. Outcome after proton irradiation is superior to that reported for conventional photon irradiation. Radiotherapy schedules involving a mixed schedule of protons and photons have achieved an approximately 60% local control rate at 5 years. Some of this improvement may have resulted from better surgical techniques. Proton irradiation is also effective for base of skull chondrosarcomas. Protons of sufficient energy to treat base of skull tumours are not available in the UK. Patients have been referred to the proton facilities at the Harvard cyclotron, and at Orsay, France. They will continue to require referral abroad for proton therapy for base of skull tumours. Proton therapy has become standard treatment for ocular melanoma and this is available at the Douglas cyclotron at Clatterbridge Hospital. Proton therapy has the potential for improved dose distribution compared with conformal photon radiotherapy. This may be exploited effectively to irradiate target volumes close to radiosensitive structures such as the spinal cord. There is a need for further clinical research to evaluate proton therapy for tumours such as spinal and paraspinal sarcomas, and paediatric brain tumours.

Chordoma↗

The clinical potential of intensity modulated proton therapy.

Intensity Modulated Proton Therapy (IMPT) differs from conventional proton therapy in its ability to deliver depth-shifted, arbitrarily complex proton fluence maps from each incident field direction. As the individual Bragg peaks delivered from any field can be distributed in three-dimensions throughout the target volume, IMPT provides many more degrees of freedom for designing dose distributions than IMRT or conventional proton therapy techniques. So how can the flexibility of IMPT best be exploited? Here we argue that IMPT has two main advantages over photon IMRT and conventional proton therapy: the ability to better 'sculpt' the dose to the target and around neighbouring critical structures, and the ability to find clinically acceptable solutions whilst simultaneously reducing the sensitivity of the treatments to potential delivery errors. The concept of IMPT as a tool for generating 'safer' plans opens an interesting new avenue of research from the point of view of plan optimisation, the potential of which is only just beginning to be explored.

Humans↗

A beam intensity monitor for the Loma Linda cancer therapy proton accelerator.

A beam intensity monitor was tested in a 230-MeV proton beam at the Loma Linda Proton Therapy Accelerator during its commissioning at Fermi National Accelerator Laboratory. The intensity monitor was designed to regulate the beam intensity extracted from the proton synchrotron. The proton beam is tunable between 70 and 250 MeV with an adjustable intensity between 10(10) and 10(11) protons per spill. A beam spill is typically 1 s long with a 2-s repetition period. The intensity monitor must be radiation hard, expose minimum mass to the beam, and measure intensity to 1% in 1-ms time intervals. To this end, a 5-cm-thick xenon gas scintillator optically coupled to a photomultiplier tube (PMT) was tested to measure its response to the proton beam. The gas cell was operated at 1.2 atm of pressure and has 12.7-microns-thick titanium entrance and exit foils. The total mass exposed to the beam is 0.14 g/cm2 and is dominated by the titanium windows. This mass corresponds to a range attenuation equal to 1.4 mm of water. The energy lost to the xenon gas is about 70 keV per proton. Each passing proton will produce approximately 2000 photons. With a detection efficiency on the order of 0.05% for this UV light, one would anticipate over 10(10) photoelectrons per second. In a 1-ms time bin there will be approximately 10(7) photoelectrons. This yields a resolution limited by systematics. For unregulated 0.4-s proton spills, we observe a response bandwidth in excess of 10(4) Hz. While signal-to-noise and linearity were not easily measured, we estimate as few as 10(3) protons can be observed suggesting a dynamic range in excess of 10(5) is available.

Humans↗

[Cooperation of proton therapy and chemotherapy].

Proton therapy was developed as one of the most promising radiation therapy techniques and it has shown remarkable improvement of the local cure rate of cancer lesions and decrease of late injury. However, cooperation with chemotherapy is to be considered as a reasonable way to further improve the radical cure rate, because the indication of proton therapy is limited to a single primary lesion. Thereupon, combined chemotherapy before or after completion of the proton therapy of the primary lesion to control latent metastases of lung cancer, esophageal cancer, to control multicentric lesions of liver cancer, urinary bladder cancer, or to diminish the size of the lesions with too much volume, could well contribute to improved clinical results.

Combined Modality Therapy↗

[Initial results of proton therapy in choroidal melanoma at the d'Orsey Center for Proton Therapy; the first 464 cases].

PURPOSE: Retrospective analysis of the treatment of choroidal melanoma with protontherapy at the Centre de protonthérapie d'Orsay, France. PATIENTS AND METHODS: Between September 1991 and September 1995, 612 patients presenting with choroidal melanoma were treated by protontherapy in Orsay. Following initial management of the first 464 patients, results were analyzed, as were results after a 1-year follow-up for 305 patients, a 2-year follow-up for 169 patients, and a 3-year follow-up for 59 patients. RESULTS: Univariate analysis showed that the actuarial local recurrence rate was 5%, the 3-year survival rate 88%, and the overall metastasic rate 5%. The initial tumor volume was the most significant predictive factor for visual results and metastases. Multivariate analysis revealed that visual results were significantly related to the initial tumor volume, initial retinal detachment, and total dose delivered to the optic nerve and macula. CONCLUSION: Protontherapy of choroidal melanoma allows in most cases conservation of the eye without modification of survival. Visual results mainly depend on the site and size of the tumor.

Choroid Neoplasms↗

A treatment planning comparison of intensity modulated photon and proton therapy for paraspinal sarcomas.

PURPOSE: A comparative treatment planning study has been undertaken between intensity modulated (IM) photon therapy and IM proton therapy (IMPT) in paraspinal sarcomas, so as to assess the potential benefits and limitations of these treatment modalities. In the case of IM proton therapy, plans were compared also for two different sizes of the pencil beam. Finally, a 10% and 20% dose escalation with IM protons was planned, and the consequential organ at risk (OAR) irradiation was evaluated. METHODS AND MATERIALS: Plans for 5 patients were computed for IM photons (7 coplanar fields) and protons (3 coplanar beams), using the KonRad inverse treatment planning system (developed at the German Cancer Research Center). IMPT planning was performed assuming 2 different sizes of the pencil beam: IMPT with a beam of full width at half-maximum of 20 mm, and IMPT with a "mini-beam" (IMPT(M), full width at half-maximum = 12 mm). Prescribed dose was 77.4 Gy or cobalt Gray equivalent (CGE) for protons to the gross tumor volume (GTV). Surface and center spinal cord dose constraint for all techniques was 64 and 53 Gy/CGE, respectively. Tumor and OAR dose-volume histograms were calculated. Results were analyzed using dose-volume histogram parameters, inhomogeneity coefficient, and conformity index. RESULTS: Gross tumor volume coverage was optimal and equally homogeneous with both IM photon and IM proton plans. Compared to the IM photon plans, the use of IM proton beam therapy leads to a substantial reduction of the OAR total integral dose in the low-level to mid-dose level. Median heart, lung, kidney, stomach, and liver mean dose and dose at the 50% volume level were consistently reduced by a factor of 1.3 to 25. Tumor dose homogeneity in IMPT(M) plans was always better than with IMPT planning (median inhomogeneity coefficient, 0.19 vs. 0.25). IMPT dose escalation (to 92.9 CGE to the GTV) was possible in all patients without exceeding the normal-tissue dose limits. CONCLUSIONS: These results suggest that the use of IM photon therapy, when compared to IM protons, can result in similar levels of tumor conformation. IM proton therapy, however, reduces the OAR integral dose substantially, compared to IM photon radiation therapy. As a result, tumor dose escalation was always possible with IM proton planning, within the maximal OAR dose constraints. In IM proton planning, reducing the size of the proton pencil beam (using the "mini-beam") improved the dose homogeneity, but it did not have a significant effect on the dose conformity.

Humans↗

Does electron and proton therapy reduce the risk of radiation induced cancer after spinal irradiation for childhood medulloblastoma? A comparative treatment planning study.

The aim of this treatment planning comparison study was to explore different spinal irradiation techniques with respect to the risk of late side-effects, particularly radiation-induced cancer. The radiotherapy techniques compared were conventional photon therapy, intensity modulated x-ray therapy (IMXT), conventional electron therapy, intensity/energy modulated electron therapy (IMET) and proton therapy (IMPT).CT images for radiotherapy use from five children, median age 8 and diagnosed with medulloblastoma, were selected for this study. Target volumes and organs at risk were defined in 3-D. Treatment plans using conventional photon therapy, IMXT, conventional electron therapy, IMET and IMPT were set up. The probability of normal tissue complication (NTCP) and the risk of cancer induction were calculated using models with parameters-sets taken from published data for the general population; dose data were taken from dose volume histograms (DVH). Similar dose distributions in the targets were achieved with all techniques but the absorbed doses in the organs-at-risk varied significantly between the different techniques. The NTCP models based on available data predicted very low probabilities for side-effects in all cases. However, the effective mean doses outside the target volumes, and thus the predicted risk of cancer induction, varied significantly between the techniques. The highest lifetime risk of secondary cancers was estimated for IMXT (30%). The lowest risk was found with IMPT (4%). The risks associated with conventional photon therapy, electron therapy and IMET were 20%, 21% and 15%, respectively. This model study shows that spinal irradiation of young children with photon and electron techniques results in a substantial risk of radiation-induced secondary cancers. Multiple beam IMXT seems to be associated with a particularly high risk of secondary cancer induction. To minimise this risk, IMPT should be the treatment of choice. If proton therapy is not available, advanced electron therapy may provide a better alternative.

Child↗

Beam optics design of compact gantry for proton therapy.

A new proton therapy facility for the treatment of deep-seated tumours is being assembled. The proton beam will be applied to the patient under computer control, using dynamic scanning of a focused proton pencil beam to produce a complete three-dimensional conformation of the dose to the target volume. The beam will be applied to the supine patient using a compact isocentric gantry for protons. By combining the scanning of the beam with the beam optics and by mounting the patient couch eccentrically on the gantry, the diameter of the rotating structure can be reduced to 4 m, which is the smallest diameter designed so far for a proton gantry. The paper describes the project especially from the point of view of the optics of the beam transport system of the gantry, including the beam line used to inject the beam into the gantry.

Dose-Response Relationship, Radiation↗

Margins for treatment planning of proton therapy.

For protons and other charged particles, the effect of set-up errors on the position of isodoses is considerably less in the direction of the incident beam than it is laterally. Therefore, the margins required between the clinical target volume (CTV) and planning target volume (PTV) can be less in the direction of the incident beam than laterally. Margins have been calculated for a typical head plan and a typical prostate plan, for a single field, a parallel opposed and a four-field arrangement of protons, and compared with margins calculated for photons, assuming identical geometrical uncertainties for each modality. In the head plan, where internal motion was assumed negligible, the CTV-PTV margin reduced from approximately 10 mm to 3 mm in the axial direction for the single field and parallel opposed plans. For a prostate plan, where internal motion cannot be ignored, the corresponding reduction in margin was from 11 mm to 7 mm. The planning organ at risk (PRV) margin in the axial direction reduced from 6 mm to 2 mm for the head plan, and from 7 mm to 4 mm for the prostate plan. No reduction was seen on the other axes, or for any axis of the four-field plans. Owing to the shape of proton dose distributions, there are many clinical cases in which good dose distributions can be obtained with one or two fields. When this is done, it is possible to use smaller PTV and PRV margins. This has the potential to convert untreatable cases, in which the PTV and PRV overlap, into cases with a gap between PTV and PRV of adequate size for treatment planning.

Humans↗

Proton therapy of cancer: potential clinical advantages and cost-effectiveness.

Proton therapy may offer potential clinical advantages compared with conventional radiation therapy for many cancer patients. Due to the large investment costs for building a proton therapy facility, however, the treatment cost with proton radiation is higher than with conventional radiation. It is therefore important to evaluate whether the medical benefits of proton therapy are large enough to motivate the higher costs. We assessed the cost-effectiveness of proton therapy in the treatment of four different cancers: left-sided breast cancer, prostate cancer, head and neck cancer, and childhood medulloblastoma. A Markov cohort simulation model was created for each cancer type and used to simulate the life of patients treated with radiation. Cost and quality adjusted life years (QALYs) were used as primary outcome measures. The results indicated that proton therapy was cost-effective if appropriate risk groups were chosen. The average cost per QALY gained for the four types of cancer assessed was about pounds 10,130. If the value of a QALY was set to pounds 55,000, the total yearly net benefit of treating 925 cancer patients with the four types of cancer was about pounds 20.8 million. Investment in a proton facility may thus be cost-effective. The results must be interpreted with caution, since there is a lack of data, and consequently large uncertainties in the assumptions used.

Aged↗

[Dose-volume histogram analysis of patients with hepatocellular carcinoma regarding changes in liver function after proton therapy].

Seventy-five patients with hepatocellular carcinoma were treated with proton beams from 1983-1993 at the Proton Medical Research Center, University of Tsukuba. For the purpose of confirming the feasibility of proton therapy for hepatocellular carcinoma, we investigated the influence of proton therapy on liver function and also tried to evaluate the possibility of optimization using dose-volume histogram (DVH) analysis. The results indicated that proton therapy did not cause clinically symptomatic damage in liver function and the only notable change after proton therapy was the transient increase of transminase. DVH analysis showed that this transient increase of transaminase was well correlated to the normal tissue complication probability (NTCP). These results indicate that localized high dose radiation using proton beams is feasible for the treatment of liver cancers and optimization of this treatment may be possible using DVH analysis.

Adult↗

[3-unit complex for proton therapy].

Since 1969 proton beam therapy of patients with different types of diseases using the ITEP synchrotron proton beam with the energy up to 200 MeV has been conducted in a number of Moscow medical centers. These irradiations employing a specially formed beam are used on a routine basis and are performed in parallel with the program of physical research. Two additional channels as well as two new procedure rooms have been in operation since 1982. A special setup of equipment including clinical dosimetry devices, equipment for patients' irradiation (4 special units), and computer-controlled systems have been installed at the facility. By the present time over 1300 patients have been irradiated. The authors describe physical and dosimetric equipment and irradiation techniques. A summary table containing data on the patients is provided.

Facility Design and Construction↗