Spatial fractionation of the dose in proton therapy: Proton minibeam radiation therapy

In radiation therapy, a renewed interest is emerging for the study of spatially fractionated irradiation. In this article, a few applications using spatial fractionation of the dose will be discussed with a focus on proton minibeam radiation therapy. Examples of calculated dose (1D profiles and 2D dose distributions) and biological evidence obtained so far will be presented for various spatially fractionated techniques GRID, micro- and minibeam radiation therapy. Recent results demonstrating that proton minibeam radiation therapy leads to an increase in normal tissues sparing will be discussed, which opens the door to a dose escalation in the tumour and a possibly efficient treatment of very radioresistant tumours.     

Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No

PURPOSE: Evaluate the rationale for the proposals that prior to a wider use of proton radiation therapy there must be supporting data from phase III clinical trials. That is, would less dose to normal tissues be an advantage to the patient? METHODS: Assess the basis for the assertion that proton dose distributions are superior to those of photons for most situations. Consider the requirements for determining the risks of normal tissue injury, acute and remote, in the examination of the data from a trial. Analyze the probable cost differential between high technology photon and proton therapy. Evaluate the rationale for phase III clinical trials of proton vs photon radiation therapy when the only difference in dose delivered is a difference in distribution of low LET radiation. RESULTS: The distributions of biological effective dose by protons are superior to those by X-rays for most clinical situations, viz. for a defined dose and dose distribution to the target by protons there is a lower dose to non-target tissues. This superiority is due to these physical properties of protons: (1) protons have a finite range and that range is exclusively dependent on the initial energy and the density distribution along the beam path; (2) the Bragg peak; (3) the proton energy distribution may be designed to provide a spread out Bragg peak that yields a uniform dose across the target volume and virtually zero dose deep to the target. Importantly, proton and photon treatment plans can employ beams in the same number and directions (coplanar, non-co-planar), utilize intensity modulation and employ 4D image guided techniques. Thus, the only difference between protons and photons is the distribution of biologically effective dose and this difference can be readily evaluated and quantified. Additionally, this dose distribution advantage should increase the tolerance of certain chemotherapeutic agents and thus permit higher drug doses. The cost of service (not developmental) proton therapy performed in 3-5 gantry centers operating 14-16 h/day and 6 days/week is likely to be equal to or less than twice that of high technology X-ray therapy. CONCLUSIONS: Proton therapy provides superior distributions of low LET radiation dose relative to that by photon therapy for treatment of a large proportion of tumor/normal tissue situations. Our assessment is that there is no medical rationale for clinical trials of protons as they deliver lower biologically effective doses to non-target tissue than do photons for a specified dose and dose distribution to the target. Based on present knowledge, there will be some gain for patients treated by proton beam techniques. This is so even though quantitation of the clinical gain is less secure than the quantitation of reduction in physical dose. Were proton therapy less expensive than X-ray therapy, there would be no interest in conducting phase III trails. The talent, effort and funds required to conduct phase III clinical trials of protons vs photons would surely be more productive in the advancement of radiation oncology if employed to investigate real problems, e.g. the most effective total dose, dose fractionation, definition of CTV and GTV, means for reduction of PTV and the gains and risks of combined modality therapy.     

Proton radiation therapy for head and neck cancer

Due to the close spatial relationship of head and neck and skull base tumors to numerous normal anatomical structures, conventional photon radiation therapy can be associated with significant acute and long-term treatment-related toxicities. Superior dose localization properties of proton radiation therapy allow smaller volumes of normal tissues to be irradiated than is feasible with any photon technique. Intensity-modulated proton therapy (IMPT) is a powerful delivery technique which results in improved dose distribution as compared to that of intensity-modulated radiation therapy (IMRT). Initial clinical experience with proton radiation therapy in treatment of head and neck and skull base tumors is promising. Prospective multi-institutional trials are underway to define the role of proton radiation therapy, particularly IMPT, in the treatment of head and neck and skull base tumors.     

Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons

PURPOSE: To report preliminary clinical outcomes for pediatric patients treated with proton beam radiation for intracranial ependymoma and compare the dose distributions of intensity-modulated radiation therapy with photons (IMRT), three-dimensional conformal proton radiation, and intensity-modulated proton radiation therapy (IMPT) for representative patients. METHODS AND MATERIALS: All children with intracranial ependymoma confined to the supratentorial or infratentorial brain treated at the Francis H. Burr Proton Facility and Harvard Cyclotron between November 2000 and March 2006 were included in this study. Seventeen patients were treated with protons. Proton, IMRT, and IMPT plans were generated with similar clinical constraints for representative infratentorial and supratentorial ependymoma cases. Tumor and normal tissue dose-volume histograms were calculated and compared. RESULTS: At a median follow-up of 26 months from the start date of radiation therapy, local control, progression-free survival, and overall survival rates were 86%, 80%, and 89%, respectively. Subtotal resection was significantly associated with decreased local control (p = 0.016). Similar tumor volume coverage was achieved with IMPT, proton therapy, and IMRT. Substantial normal tissue sparing was seen with proton therapy compared with IMRT. Use of IMPT will allow for additional sparing of some critical structures. CONCLUSIONS: Preliminary disease control with proton therapy compares favorably with the literature. Dosimetric comparisons show the advantage of proton radiation compared with IMRT in the treatment of ependymoma. Further sparing of normal structures appears possible with IMPT. Superior dose distributions were accomplished with fewer beam angles with the use of protons and IMPT.     

Treatment planning for conformal proton radiation therapy

Clinical results from various trials have demonstrated the viability of protons in radiation therapy and radiosurgery. This has motivated a few large medical centers to design and build expensive hospital based proton facilities based proton facilities (current cost estimates for a proton facility is around 100 million US dollars). Until this development proton therapy was done using retrofitted equipment originally designed for nuclear experiments. There are presently only three active proton therapy centers in the United States, 22 worldwide. However, more centers are under construction and being proposed in the US and abroad. The important difference between proton and x-ray therapy is in the dose distribution. X-rays deposit most of their dose at shallow depths of a few centimeters with a gradual decay with depth in the patient. Protons deliver most of their dose in the Bragg peak, which can be delivered at most clinically required depths followed by a sharp fall-off. This sharp falloff makes protons sensitive to variations in treatment depths within patients. Treatment planning incorporates all the knowledge of protons into a process, which allows patients to be treated accurately and reliably. This process includes patient immobilization, imaging, targeting, and modeling of planned dose distributions. Although the principles are similar to x-ray therapy some significant differences exist in the planning process, which described in this paper. Target dose conformality has recently taken on much momentum with the advent of intensity modulated radiation therapy (IMRT) with photon beams. Proton treatments provide a viable alternative to IMRT because they are inherently conformal avoiding normal tissue while irradiating the intended targets. Proton therapy will soon bring conformality to a new high with the development of intensity modulated proton therapy (IMPT). Future challenges include keeping the cost down, increasing access to conventional proton therapy as well as the clinical implementation of IMPT. Computing advances are making Monte Carlo techniques more accessible to treatment planning for all modalities including proton therapy. This technique will allow complex delivery configurations to be properly modeled in a clinical setting.     

Conformal radiation therapy for childhood CNS tumors

Radiation therapy plays a central role in the management of many childhood brain tumors. By combining advances in brain tumor imaging with technology to plan and deliver radiation therapy, pediatric brain tumors can be treated with conformal radiation therapy. Through conformal radiation therapy, the radiation dose is targeted to the tumor, which can minimize the dose to normal brain structures. Therefore, by limiting the radiation dose to normal brain tissues, conformal radiation therapy offers the possibility of limiting the long-term side effects of brain irradiation.In this review, we describe different approaches to conformal radiation therapy for pediatric central nervous system tumors including: A) three-dimensional conformal radiation therapy; B) stereotactic radiation therapy with arc photons; C) intensity-modulated radiation therapy; and D) proton beam radiation therapy. We discuss the merits and limitations of these techniques and describe clinical scenarios in which conformal radiation therapy offers advantages over conventional radiation therapy for treating pediatric brain tumors.     

A review of the impact of photon and proton external beam radiotherapy treatment modalities on the dose distribution in field and out-of-field; implications for the long-term morbidity of cancer survivors

The use of untraditional treatment modalities for external beam radiotherapy such as intensity modulated radiation therapy (IMRT) and proton beam therapy is increasing. This review focuses on the changes in the dose distribution and the impact on radiation related risks for long-term cancer survivors. We compare conventional radiotherapy, IMRT, and proton beam therapy based on published treatment planning studies as well as published measurements and Monte Carlo simulations of out-of-field dose distributions. Physical dose parameters describing the dose distribution in the target volume, the conformity index, the dose distribution in organs at risk, and the dose distribution in non-target tissue, respectively, are extracted from the treatment planning studies. Measured out-of-field dose distributions are presented as the dose equivalent as a function of distance from the treatment field. Data in the literature clearly shows that, compared with conventional radiotherapy, IMRT improves the dose distribution in the target volume, which may increase the probability of tumor control. IMRT also seems to increase the out-of-field dose distribution, as well as the irradiated non-target volume, although the data is not consistent, leading to a potentially increased risk of radiation induced secondary malignancies, while decreasing the dose to normal tissues close to the target volume, reducing the normal tissue complication probability. Protons show no or only minor advantage on the dose distribution in the target volume and the conformity index compared to IMRT. However, the data consistently shows that proton beam therapy substantially decreases the OAR average dose compared to the other two techniques. It is also clear that protons provide an improved dose distribution in non-target tissues compared to conventional radiotherapy and IMRT. IMRT and proton beam therapy may significantly improve tumor control for cancer patients and quality of life for long-term cancer survivors.     

Proton radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons

BACKGROUND: Over 85% of pediatric orbital rhabdomyosarcoma (RMS) are cured with combined chemotherapy and radiation. However, the late effects of photon radiation compromise function and cosmetic outcome. Proton radiation can provide excellent tumor dose distributions while sparing normal tissues better than photon irradiation. METHODS AND MATERIALS: Conformal 3D photon and proton radiotherapy plans were generated for children treated with proton irradiation for orbital RMS at Massachusetts General Hospital. Dose-volume histograms (90%, 50%, 10%) were generated and compared for important orbital and central nervous system structures. Average percentages of total dose prescribed were calculated based on the 3 dose-volume histogram levels for normal orbital structures for both the proton and photon plans. The percent of normal tissue spared by using protons was calculated. RESULTS: Seven children were treated for orbital rhabdomyosarcoma with proton irradiation and standard chemotherapy. The median follow-up is 6.3 years (range, 3.5-9.7 years). Local and distant controls compare favorably to those in other published accounts. There was an advantage in limiting the dose to the brain, pituitary, hypothalamus, temporal lobes, and ipsilateral and contralateral orbital structures. Tumor size and location affect the degree of sparing of normal structures. CONCLUSIONS: Fractionated proton radiotherapy is superior to 3D conformal photon radiation in the treatment of orbital RMS. Proton therapy maintains excellent tumor coverage while reducing the radiation dose to adjacent normal structures. Proton radiation therapy minimizes long-term side effects.     

Economic evaluation of proton radiation therapy in the treatment of breast cancer.

BACKGROUND AND PURPOSE: Proton beam therapy offers potential clinical advantages compared with conventional radiation therapy for many cancer patients. The benefits are mainly a result of a more favourable dose distribution. The treatment cost with proton radiation is higher than for conventional radiation, mainly due to the large investment cost of building a proton therapy facility. It is therefore important to evaluate whether the medical benefits of proton therapy are large enough to justify the higher treatment costs, compared with conventional radiation therapy. PATIENTS AND METHODS: The cost-effectiveness of proton therapy in the treatment of 55-year old women with left-sided breast cancer was assessed. A Markov cohort simulation model was used to simulate the life of patients diagnosed with breast cancers and treated with radiation. Cost and quality adjusted life years (QALYs) were the primary outcome measures. RESULTS: The study found a cost per QALY gained of 67,000 Euro for the base case analysis of an average breast cancer patient. The cost per QALY gained would, however, be considerably lower if a population with high-risk of developing cardiac disease was treated. Sensitivity analyses showed that the results were stable and that the risk of cardiac disease was the most important parameter. CONCLUSIONS: The results indicate that proton therapy for breast cancer can be cost-effective if appropriate risk groups are chosen as targets for the therapy.     

髓母细胞瘤X线与质子适形放射治疗计划比较

目的对髓母细胞瘤患者用X线和质子适形放射治疗计划进行比较,寻求髓母细胞瘤更好的放射治疗方法。方法采用Eclipsephoton光子治疗计划系统和Eclipseproton7.3.2质子治疗计划系统对5例髓母细胞瘤患者设计放射治疗计划并进行比较。全脑全脊髓剂量36Gy,后颅窝局部加量至54Gy。用剂量体积直方图(DVH)比较正常组织受照剂量的差异。结果X线与质子适形放射治疗计划相比,右侧耳蜗90%的体积平均受照剂量分别为后颅窝加量野的39%和1.6%,右颞颌关节90%体积平均受量分别为26.1%和0.4%,50%心脏平均受照剂量分别为脊髓野处方剂量的63.3%和0.8%,90%甲状腺平均受量分别为72.2%和0.5%。结论质子适形放射治疗髓母细胞瘤可明显减少正常组织的受照剂量,优于X线适形放射治疗。     

Number of patients potentially eligible for proton therapy

A group of Swedish radiation oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy in a facility where one of the principal aims is to facilitate randomized and other studies in which the advantage of protons can be shown and the magnitude of the differences compared with optimally administered conventional radiation treatment, also including intensity-modulated radiation therapy (IMRT) and brachytherapy, can be shown. The estimations have been based on current statistics of tumour incidence in Sweden, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours together with information on normal tissue complication rates. In Sweden, it is assessed that between 2200 and 2500 patients annually are eligible for proton beam therapy, and that for these patients the potential therapeutic benefit is so great as to justify the additional expense of proton therapy. This constitutes between 14-15% of all irradiated patients annually.     

The Meaningless Meaning of Mean Heart Dose in Mediastinal Lymphoma in the Modern Radiation Therapy Era

PurposeMean heart dose (MHD) correlates with late cardiac toxicity among survivors of lymphoma receiving involved-field radiation therapy (IFRT). We investigated MHD and cardiac substructure dose across older and newer radiation fields and techniques to understand the value of evaluating MHD alone.Methods and MaterialsAfter institutional review board approval, we developed a database of dosimetry plans for 40 patients with mediastinal lymphoma, which included IFRT (anterior-posterior and posterior-anterior), involved-site radiation therapy (ISRT) + 3-dimensional conformal radiation therapy (3DCRT), ISRT + intensity modulated radiation therapy, and ISRT + proton therapy plans for each patient. Each plan was evaluated for dose to the heart and cardiac substructures, including the right and left ventricles (RV, LV) and atria (RA, LA); tricuspid, mitral (MV), and aortic valves; and left anterior descending coronary artery (LAD). Correlation between MHD and cardiac substructure dose was assessed with linear regression. A correlation was considered very strong, strong, moderate, or weak if the r was ≥0.8, 0.6-0.79, 0.4-0.59, or <0.4, respectively.ResultsA very strong correlation was observed between MHD and the mean cardiac substructure dose for each plan as follows: IFRT—LV, RV, LA, MV and LAD; ISRT + 3DCRT—LV, RV, MV, TV, and LA; ISRT + intensity modulated radiation therapy—LV and RV; ISRT + proton therapy—none. The following strong correlations were observed: IFRT—RA; ISRT + 3DCRT—LAD, RA, AV; ISRT + IMRT—LA, RA, LAD, AV, TV, and MV; ISRT + proton therapy—LV only.ConclusionsIn the management of mediastinal lymphoma, more conformal treatment techniques can lead to more heterogeneous dose distributions across the heart, which translate into weaker relationships between mean heart dose and mean cardiac substructure doses. Consequently, models for assessing the risk of cardiac toxicity after radiation therapy that rely on MHD can be misleading when using modern treatment fields and techniques. Contouring the cardiac substructures and evaluating their dose is important when using contemporary RT.     

Compensation techniques in NIRS proton beam radiotherapy

Proton beam has the dose distribution advantage in radiation therapy, although it has little advantage in biological effects. One of the best advantages is its sharp fall off of dose after the peak. With proton beam, therefore, the dose can be given just to cover a target volume and potentially no dose is delivered thereafter in the beam direction. To utilize this advantage, bolus techniques in conjunction with CT scanning are employed in NIRS proton beam radiation therapy planning. A patient receives CT scanning first so that the target volume can be clearly marked and the radiation direction and fixation method can be determined. At the same time bolus dimensions are calculated. The bolus frames are made with dental paraffin sheets according to the dimensions. The paraffin frame is replaced with dental resin. Alginate (a dental impression material with favorable physical density and skin surface contact) is now employed for the bolus material. With fixation device and bolus on, which are constructed individually, the patient receives CT scanning again prior to a proton beam treatment in order to prove the devices are suitable. Alginate has to be poured into the frame right before each treatments. Further investigations are required to find better bolus materials and easier construction methods.     

Advanced radiation therapy technologies in the treatment of rectal and anal cancer: intensity-modulated photon therapy and proton therapy

Intensity-modulated photon radiation therapy (RT; IMRT) and proton therapy are advanced radiation technologies that permit improved conformation of radiation dose to target structures while limiting irradiation of surrounding normal tissues. Application of these technologies in the treatment of rectal and anal cancer is attractive, based on the potential reduction in radiation treatment toxicities that are frequently incurred in the pelvis and perineum. Furthermore, conformal RT might also allow for dose escalation to target areas, leading to improved tumor control. This review discusses the underlying principles of IMRT. In addition, the rationale and clinical data regarding the efficacy of radiation dose escalation for rectal and anal cancer will be highlighted, as well as tolerance of pelvic organs to RT and chemotherapy. Finally, preliminary results of IMRT in the treatment of lower gastrointestinal tract cancers will be reviewed. The potential and rationale for proton therapy in treatment of these malignancies are also discussed.     

Proton therapy for prostate cancer

Proton therapy has been used in the treatment of cancer for over 50 years. Due to its unique dose distribution with its spread-out Bragg peak, proton therapy can deliver highly conformal radiation to cancers located adjacent to critical normal structures. One of the important applications of its use is in prostate cancer, since the prostate is located adjacent to the rectum and bladder. Over 30 years of data have been published on the use of proton therapy in prostate cancer; these data have demonstrated high rates of local and biochemical control as well as low rates of urinary and rectal toxicity. Although before 2000 proton therapy was available at only a couple of centers in the United States, several new proton centers have been built in the last decade. With the increased availability of proton therapy, research on its use for prostate cancer has accelerated rapidly. Current research includes explorations of dose escalation, hypofractionation, and patient-reported quality-of-life outcomes. Early results from these studies are promising and will likely help make proton therapy for the treatment of prostate cancer more cost-effective.     

前列腺癌的外照射放疗进展

外照射放疗作为前列腺癌的主要治疗手段之一,随着放疗技术的进步、靶区认识的统一,已进入精确放疗时代.高剂量放疗的准确实施,使前列腺癌的疗效显著提高.而影像引导的放射治疗、质子放疗和低分割放疗则是疗效进一步提高的研究方向.     

Improving the therapeutic ratio in Hodgkin lymphoma through the use of proton therapy

The risk of serious late complications in Hodgkin lymphoma (HL) survivors has led to a variety of strategies for reducing late treatment effects from both chemotherapy and radiation therapy. With radiation therapy, efforts have included reductions in dose, reductions in the size of the target volume, and most recently, significant reductions in the dose to nontargeted normal tissues at risk for radiation damage, achieved by using the emerging technologies of intensity-modulated radiation therapy and proton therapy (PT). PT is associated with a substantial reduction in radiation dose to critical organs, such as the heart and lungs, and has the potential to improve not only the therapeutic ratio, but also both event-free and overall survival. This review addresses the rationale and evidence for--and the challenges, cost implications, and future development of--PT as an important part of the treatment strategy in HL.     

Proton beams in radiation therapy.

The rationale for study of proton radiation therapy is that, for some anatomic sites and tumors, the treatment volume is smaller; i.e., there is less irradiation of nontarget tissue while the target is included in three dimensions at each treatment session. As a result, the dose to the target can be raised. The consequence is that the tumor control probability improves and the frequency and severity of treatment-related morbidity decrease. These results come about from the physical fact that the proton range in tissue is finite; in comparison, absorption of photons is an exponential function and, hence, some dose is received for the full-beam path through the body. Accordingly, the dose deep to the target for proton treatments can be zero for each beam path. This situation provides a virtually certain means of improving the treatment outcome for selected categories of patients. Experience to date with proton radiation therapy has been quite limited. As of June 1991, the total number of proton radiation-treated patients was 11,763 from the various centers. Of that number, approximately 46% and 32% have been treated for small benign intracranial lesions (principally pituitary adenomas and arteriovenous malformations) and for tumors of the eye, respectively. Thus, only some 2500 patients have been treated for all other tumor types. The results from three centers and approximately 2800 patients with uveal melanoma are that the local control rate was 96% (for failures in-field, marginal, and in other parts of the eye). The local control results for chondrosarcomas and chordomas of the skull base are 91% and 65%, respectively. These percentages compare with some 35% achieved with conventional treatment. Experience with arteriovenous malformations indicates that control of bleeding and disappearance of the lesion are comparable to those achieved by other procedures. The developments from the proton therapy programs have contributed greatly to radiation treatment planning, e.g., the first three-dimensional treatment planning system put into regular clinical use (uveal melanoma), beam's eye view, digital-reconstructed radiograph, dose-volume histograms, and definitions of the uncertainty in dose around any defined point. The potential for clinical gains is high. In May 1991, the Proton Radiation Oncology Group was formed to design, supervise, and coordinate clinical trials and to assist in data analysis. The efficacy of proton radiation therapy will be compared with that of photon therapy of the very highest technology.     

Selection of patients for radiotherapy with protons aiming at reduction of side effects: The model-based approach

Most new radiation techniques, have been introduced primarily to reduce the dose to normal tissues in order to prevent radiation-induced side effects. Radiotherapy with protons is such a radiation technique that due to its superior beam properties compared to photons enables better sparing of normal tissues. This paper describes a stepwise methodology to select patients for proton therapy when the primary aim is to reduce side effects. This method has been accepted by the Dutch health authorities to select patients for proton therapy. In addition, an alternative method is described in case randomised controlled trials are considered not appropriate.     

Comparison of passive-beam proton therapy,helical tomotherapy and 3D conformal radiation therapy in Hodgkin's lymphoma female patients receiving involved-field or involved site radiation therapy

PurposeSecond cancers and cardiovascular toxicities are long term radiation toxicity in locally advanced Hodgkin's lymphomas. In this study, we evaluate the potential reduction of dose to normal tissue with helical tomotherapy and proton therapy for Hodgkin's lymphoma involved-field or involved-site irradiation compared to standard 3D conformal radiation therapy.Patients and methodsFourteen female patients with supradiaphragmatic Hodgkin's lymphoma were treated at our institution with 3D conformal radiation therapy or helical tomotherapy to a dose of 30 Gy in 15 fractions. A planning comparison was achieved including proton therapy with anterior/posterior passive scattered beams weighted 20 Gy/10 Gy.ResultsMean doses to breasts, lung tissue and heart with proton therapy were significantly lower compared to helical tomotherapy and to 3D conformal radiation therapy. Helical tomotherapy assured the best protection of lungs from doses above 15 Gy with the V_20 Gy equal to 16.4%, compared to 19.7% for proton therapy (P = 0.01) or 22.4% with 3D conformal radiation therapy (P < 0.01). Volumes of lung receiving doses below 15 Gy were significantly larger for helical tomotherapy than for proton therapy or 3D conformal radiation therapy, with respective lung doses V_10 Gy = 37.2%, 24.6% and 27.4%. Also, in the domain of low doses, the volumes of breast that received more than 10 Gy or more than 4 Gy with helical tomotherapy were double the corresponding volumes for proton therapy, with V_4 Gy representing more than a third of one breast volume with helical tomotherapy.ConclusionsHelical tomotherapy achieved a better protection to the lungs for doses above 15 Gy than passive proton therapy or 3D conformal radiation therapy. However, dose distributions could generally be improved by using protons even with our current passive-beam technology, especially allowing less low dose spreading and better breast tissue sparing, which is an important factor to consider when treating Hodgkin's lymphomas in female patients. Prospective clinical study is needed to evaluate the tolerance and confirm these findings.