A Review of the Clinical Rationale and Evidence-Based Research in Support of a Decision to Build a National Proton Therapy Institute in Israel

by Albert Schlocker, MS

Contents
Introduction .................................................................................................................................................. 5 Types of Studies ............................................................................................................................................ 8 Dosimetric Plan Comparison ..................................................................................................................... 8 Retrospective Studies ............................................................................................................................... 9 Prospective Studies ................................................................................................................................... 9 Randomized Clinical Trials (RCT) ............................................................................................................. 10 Materials and Methods............................................................................................................................... 11 Clinical Trials ............................................................................................................................................... 12 Dosimetric Study of Pelvic Proton Radiotherapy for High-Risk Prostate Cancer................................ 12 Comparative Analysis of Second Malignancy Risk in Patients Treated with Proton Therapy versus Conventional Photon Therapy ............................................................................................................ 12 Risk of Secondary Malignant Neoplasms From Proton Therapy and Intensity-Modulated X-Ray Therapy for Early-Stage Prostate Cancer ............................................................................................ 13 A Phase III Trial Employing Conformal Photons with Proton Boost in Early-stage Prostate Cancer: Conventional Dose (70.2 GyE) Compared to High-dose Irradiation (79.2 GyE): Long-term Updated Analysis of Proton Radiation Oncology Group (PROG)/American College of Radiology (ACR) 9509 14 DoseVolume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer ................................................................................................................................................. 15 Combined Proton and Photon Conformal Radiotherapy for Intracranial Atypical and Malignant Meningioma ........................................................................................................................................ 16 Proton Radiotherapy for Childhood Ependymoma: Initial Clinical Outcomes and Dose Comparisons ............................................................................................................................................................ 16 Proton Radiotherapy for Pediatric Central Nervous System Germ Cell Tumors: Early Clinical Outcomes ............................................................................................................................................ 17 Intensity-Modulated Proton Therapy Reduces the Dose to Normal Tissue Compared With IntensityModulated Radiation Therapy or Passive Scattering Proton Therapy and Enables Individualized Radical Radiotherapy for Extensive Stage IIIB Non-Small-Cell Lung Cancer: A Virtual Clinical Study 18 Analysis of Vision Loss Caused by Radiation-Induced Optic Neuropathy After Particle Therapy for Head-and-Neck and Skull-Base Tumors Adjacent to Optic Nerves..................................................... 19 Effectiveness and Safety of Spot Scanning Proton Radiation Therapy for Chordomas and Chondrosarcomas of the Skull Base: First Long-Term Report ............................................................ 19 Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas . 20 Postoperative Spot-Scanning Proton Radiation Therapy for Chordoma and Chondrosarcoma in Children and Adolescents: Initial Experience at Paul Scherrer Institute ............................................ 21 2

A Prospective Study of Hypofractionated Proton Beam Therapy for Patients With Hepatocellular Carcinoma ........................................................................................................................................... 21 Four-Dimensional Computed TomographyBased Treatment Planning for Intensity-Modulated Radiation Therapy and Proton Therapy for Distal Esophageal Cancer ............................................... 22 Proton Beam Radiotherapy for Uveal Melanomas at Nice Teaching Hospital: 16 Years' Experience 23 Dosimetric Comparison of Three Different Involved Nodal Irradiation Techniques for Stage II Hodgkin's Lymphoma Patients: Conventional Radiotherapy, Intensity-Modulated Radiotherapy, and Three-Dimensional Proton Radiotherapy ........................................................................................... 23 Early Outcomes From Three Prospective Trials of Image-Guided Proton Therapy for Prostate Cancer ............................................................................................................................................................ 24 Predicted Rates of Secondary Malignancies From Proton Versus Photon Radiation Therapy for Stage I Seminoma ......................................................................................................................................... 25 Proton Radiotherapy for Parameningeal Rhabdomyosarcoma: Clinical Outcomes and Late Effects 26 Dosimetric Comparison of Three-Dimensional Conformal Proton Radiotherapy, Intensity-Modulated Proton Therapy, and Intensity-Modulated Radiotherapy for Treatment of Pediatric Craniopharyngiomas ........................................................................................................................... 26 Using a Reduced Spot Size for Intensity-Modulated Proton Therapy Potentially Improves Salivary Gland-Sparing in Oropharyngeal Cancer............................................................................................. 27 On the Benefits and Risks of Proton Therapy in Pediatric Craniopharyngioma ................................. 28 Long-Term Quality of Life Outcome After Proton Beam Monotherapy for Localized Prostate Cancer ............................................................................................................................................................ 29 Proton Radiotherapy for Pediatric Ewings Sarcoma: Initial Clinical Outcomes ................................. 29 Dosimetric Comparison of Combined Intensity-Modulated Radiotherapy (IMRT) and Proton Therapy Versus IMRT Alone for Pelvic and Para-Aortic Radiotherapy in Gynecologic Malignancies............... 30 Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma .................. 31 Rationale for and Preliminary Results of Proton Beam Therapy for Mediastinal Lymphoma............ 32 Prospective Study of Reirradiation for Soft Tissue Sarcoma: Early Outcomes and Morbidity ........... 32 Intensity-modulated radiotherapy of nasopharyngeal carcinoma: a comparative treatment planning study of photons and protons............................................................................................................. 33 Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy ....................................................................................................................................... 34 RapidArc, intensity modulated photon and proton techniques for recurrent prostate cancer in previously irradiated patients: a treatment planning comparison study ........................................... 34 Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger ............................................................................. 35 3

Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer .................................................................................................................... 36 Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma .................... 37 Cardiac sparing with proton therapy in consolidative radiation therapy ........................................... 38 for Hodgkin lymphoma: Letter to the Editor ...................................................................................... 38 Proton versus photon radiotherapy for common pediatric brain tumors: Comparison of models of dose characteristics and their relationship to cognitive function ...................................................... 39 Other Uses for Proton Beam Therapy......................................................................................................... 40 Lack of Evidence Based Medicine ............................................................................................................... 40 Skeptics ................................................................................................................................................... 41 Suggestions for Clinical Trials ...................................................................................................................... 41 Retrospective non-randomized clinical trials ......................................................................................... 41 Prospective non-randomized clinical trials ............................................................................................. 41 Prospective randomized clinical trials .................................................................................................... 42 Conclusion ................................................................................................................................................... 42 References .................................................................................................................................................. 44

Introduction
The historical use of charged particles, and in particular protons, in the radio-therapeutic treatment of cancer is well documented. In fact, surprisingly, well over a thousand journal articles on the topic have been published dating back to the early 1950s. And the current research efforts on the proton therapy experience are widely covered in nearly every oncology journal. For example, the International Journal of Radiation Oncology Biology and Physics (aka Red Journal) published four articles on proton therapy in January 2012,1 2 3 4 another seven in February,5 6 7 8 9 10 11 and will publish four more in this years March12 13 14 15 edition. The preponderance of clinical data on the use of protons, however, began in the early 1990s when proton therapy emerged from the research bunker and into a well-established commercial medical environment. It was initially hypothesized and then proven that the use of an accelerated stream of protons could be carefully controlled and directed with a high degree of precision into a cancerous tumor target for the express purpose of strategically irradiating the tumor to the exclusion of surrounding, otherwise normal, healthy tissue. The superior physics of proton beams for radiotherapy compared to photons (x-rays) are uncontested and the details of the physics will not be discussed in this review. This review does not deal with the historical aspects of proton therapy, and skips-over the nearly 20 years of medical research and clinical outcomes that have brought proton therapy to the forefront of medical radiotherapy technology today. This review will not discuss the economics of proton therapy, and does not ask the question, What is the cost of proton therapy, and is the cost worth it? Recently, the New York Times16 published commentary on this question and the burgeoning construction of proton therapy centers in the United States. In nearly every popular article written for the nonscientific audience, proton irradiation of the prostate is singled-out to draw attention to the higher cost and lack of clinical difference between protons and lower-cost therapies. In most reports however, the lack of a significant difference in survival statistics between proton therapy and IMRT for prostate cancer is extrapolated to other cancers, and the inferred negative conclusion is that proton therapy is an unjustified expense on the health systems limited resources. Clearly this discussion takes on political dimensions that are beyond the scope of this report. By choosing to ignore the quality-of-life issues, a significant component in the aftermath of any medical procedure, reports such as one by Ezekiel Emanuel seek to turn the medical discussion into a purely economic one. It is valuable to note however that even though the long-term disease-free survival rates for prostate patients irradiated with protons are comparable to other therapeutic procedures for prostate (i.e., IMRT17and brachytherapy18), patients who have undergone proton therapy for prostate cancer overwhelmingly recommend proton therapy, and their personal reports (and the reports of their significant-other) seem to indicate a high level of satisfaction and tolerance for the minimal short and long-term side-effects such as erectile dysfunction, genitourinary irritation, and gastrointestinal irritation.19 The clinical, political, and economic motivations of hospital administrators and cancer center developers will also not be topics of discussion in this review. However an amusing opportunity to glean insight into 5

the debate and the perspective from a US-based commercial proton therapy developer can be found at http://runningahospital.blogspot.com/2011/05/dear-cms-stop-proton-beam-arms-race.html. It is critical to differentiate the conditions that exist between the U.S. for example where commercial for-profit proton therapy prostate-mills can be developed on a whim, and in Israel, where even purely motivated developers seeking to enjoin the forces of every radiation oncology department in the country, who have a stated goal of treating only complex cases, with a vision of social responsibility that is reflected in their business model and economic plans, face significant obstacles. There is no question that those physicians and researchers who treat patients in centers with proton therapy believe in it and are outspoken about its clinical superiority over other forms of radiation therapy for certain cancers. There is no question that an informed patient, given a choice to receive proton therapy or photon therapy, where insurance or financial concerns are not at issue, will choose the proton option. There is no debate that a side-by-side evaluation of proton vs. photon treatment plan dosimetry will conclude that proton therapy allows for more conformal, higher tumoricidal doses to a cancerous target with simultaneously lower overall integral radiation dose to the patient.20 This observation is not merely anecdotal. It is evidence for the superiority of proton therapy over other forms of external beam therapy. The fact is, historically, most of the advancements in modern radiation therapy have relied on similar observational and equally quantifiable evidence for their acceptance. In particular the use of 3D conformal treatment planning, multi-leaf collimators (MLC) with all of their inherent inter-leaf leakage and variability across the treatment field, and the relatively more expensive therapy modalities like Intensity Modulated Radiotherapy (IMRT), Fractionated Stereotactic Radiotherapy (FSR) and Stereotactic Body Radiotherapy (SBRT) have been widely accepted for clinical use on similar merits as are sincerely offered for the acceptance of protons for radiotherapy. None of these treatment methods have been accepted into clinical practice on the basis of phase III clinical trial data.21 It is also fairly obvious to those interested in the field, that those physicians who do not have access to proton therapy, especially those practicing medicine in proximity to centers with proton therapy, have found opportunities to muddy the clinical-effectiveness issue with socio-economic concernsand this has been a very effective strategy in portraying proton therapy in a negative light, especially in an economically-difficult environment where health-care spending and health-care legislation is in the daily press. Never-the-less, the purpose of this treatise is to present clinical evidence and rationale in support of the medical effectiveness of proton therapy. The material presented here is culled from the most recent research and published articles dating from 2008-2012. The limitation of these dates is intentional. In any field, improvements in technique and advanced functionality develop over time. This is especially true in modern radiotherapy that is so heavily dependent on computer software such as dose calculation algorithms, and software-regulated controls that drive every aspect of the mechanical and radiation producing components of the beam delivery systems. It should be noted however, that in any long-term follow-up of patient disease progression and survival, that the statistics that are reported today are the result of treatments given several years priorwe are always evaluating yesterdays 6

technology and therapeutic processes. Likewise, the most recent advancements in technology and dose prescriptions can only be reported in short-term studies. The advancements in technology are not the only factors that contribute to successful and improving medical applications. The skills of the technical staff and clinician that are acquired over time, and the clinical intuition that develops in the physician through the natural processes of decision-making and patient follow-up, contribute significantly to the improved patient-care experience. It would be expected that this experience can only be reflected in the most recent research and journal articles. The acute observer will note some irony in the status of our current research publications. Todays most prestigious, academic, hospital-based proton therapy institutions, tend to be the most highly-regarded in terms of expertise, and are accordingly, the most prolific. However these centers were developed nearly 15 years ago, outfitted with the prevailing technology of the time. The 10+ year diseaseprogression and survival statistics that are published today are the result of fledgling proton technology, dose prescriptions, and treatment planning strategies. As a result we do not always see perfect agreement and interpretation of the statistics for every prospective study as compared to research being published by newer institutions. Even so, the majority of results are remarkable. The introduction of spot-scanning technology and more accurate collimation and dose calculation algorithms for protons has transformed the field of proton therapy from one of heavy industry to hitech. It is no longer necessary to create patient-customized, machine-milled brass collimators and Lucite dose-compensators for every treatment field as is required in passive-scattering and in single and double-scattering techniques. The advent of spot-scan technology has the added benefit of nearly eliminating the unwanted and otherwise-ignored and unaccounted-for production of neutrons. As a result, superficial dose (skin dose) and integral body dose with spot scanned protons is 10 times lower than with IMRT.22 Unfortunately however, time is not on the side of these advancements. Though there are a few recent publications on the use of spot scan technology, particularly those that compare spot-scanning to scattering techniques, the long-term follow-up and clinical outcomes results for spot scanning are limited. As a result, what can be surmised from the published results can only be expected to get better with long-term follow-up of patients treated with spot-scanning techniques. The evidence for proton therapy indicates that protons in general are superior to x-ray photons, but the question of how much better? cannot always be deduced. Most comparative trials between protons and photons aim to keep the target prescription the same. In these tests, the overall exposure of the patient to extraneous radiation is significantly reduced in the proton arm. The advantage of protons then would likely be in the reduced incidence of late normal-tissue complications. This type of damage is difficult to quantify, varies considerably within the treated population, and as the name implies, requires long follow-up times. Dose-escalation studies have also been designed. These trials allow for an increased normal-tissue complication (higher integral dose) in order to evaluate the tumoricidal effect of increased dose to the tumor. Acute sequelae are expected to increase as a trade-off for benefit at the target. Most proton vs. proton trials fall under this category, and could reasonably be designed as randomized controlled studies. Large scale, well designed clinical trials are ongoing, and should be

encouraged. It is the stated objective of the Israel Proton Therapy Initiative that every patient accepted for treatment would be enrolled in one or more clinical trials.

Types of Studies
The analysis of the relevant publications on proton therapy indicates that the clinical research may be classified into one of several major categories:

Dosimetric Plan Comparison

Dosimetric comparisons, the physics of radiation therapy, specifically the comparison and analysis of proton vs. photon computer simulated three-dimensional treatment plans, make up the majority of articles written to validate and prognosticate on the benefits of proton therapy. These plans may be prospective or retrospective and utilize mathematical modeling for interpretation and estimation of long term side-effects, secondary malignancies, cost benefits, etc. In most instances, computed radiation doses are calculated and displayed on identical Computed Tomography studies (CT) containing contour definitions of target tumor, various planning volumes and organs-at-risk (healthy tissues). The plans are optimized for each specific radiation modality and then a Dose Volume Histogram (DVH) or other dosimetric evaluation criteria are analyzed for the target and normal tissues and organs. This type of research is the most common because it is relatively easy to perform. Generally the patient has already undergone one or the other radiation therapy and the alternative modality is calculated for comparative purpose. The patients decision to proceed with one or the other therapies was not influenced by this trial. These types of trials are significant simply because this replicates the process that radiation oncology physicians and medical physicists have used to evaluate novel radiation therapy protocols and innovations in the past. In fact, this method of dose evaluation is by far the most important tool utilized in external beam radiation therapy today in the decision-making process for optimizing beam arrangements that maximize dose to the target volume and minimize dose to the organs-at-risk. Radiation oncologists and medical physicists are accustomed to evaluating virtual radiation dose in this form and have developed complex protocols for dose prescriptions. Patient treatment plans are rejected, improved and approved based upon these computerized simulations. In any treatment plan evaluation, the goal is to ensure that the target volume receives at least the minimum prescription dose and that the otherwise healthy surrounding tissues are protected as much as possible from extraneous radiation, and when extra-target dose is unavoidable it is allocated to anatomical regions with higher tolerance for side-effects whenever possible. This is the strategy of all radiation therapy and has been the motivation behind all efforts and ingenuity to improve technology in the field of radiation oncology. There is unequivocally accepted agreement based on years of clinical trials, that increased therapeutic tumor response is correlated with increased radiation dose. As technology has improved the ability to 8

more conformally direct radiation to the target volume without a significant increase in toxicity, the outcomes have improved and the medical establishments standard of care has responded accordingly. Concurrently, there is never a situation where higher dose to the surrounding healthy tissue and organs is considered beneficial to the patient. In fact, the tolerance dose for organs-at-risk is often a limiting factor in the clinicians ability to apply the maximal tumoricidal dose to the target. It is worth pointing out that photon IMRT does not reduce the integral dose to the patients healthy tissue, it simply spreads it around. The question of whether it is better to give less stray dose to a larger volume of healthy tissue, or a higher dose to a smaller volume of healthy tissue is an ongoing debate amongst oncologists. In any case, proton therapy clearly reduces the extraneous dose to healthy tissue as compared to IMRT and every other form of photon radiotherapy. With some tongue-in-cheek, this difference is hardly insignificant, If it were, since the improvement in integral dose that modern treatment machines and techniques offer over cobalt-60 teletherapy machines is even less, it would make economic and clinical sense to revert to the use of cobalt-60 machines for radiation therapy.23 Clearly this is not what we are suggesting, but for many of these reasons, we believe it is appropriate to consider comparative treatment plans as evidence in the relative estimation of benefit, expected short and long-term side-effects, and chance of secondary malignancy resulting from various radiation therapy techniques.

Retrospective Studies
These study results are derived from the historical evaluation of patient outcomes and reported sequelae for patients who received either proton therapy or some other form of radiotherapy (conventional photon, IMRT, brachytherapy, etc.) or a combination. Most often, the patient data cited in a study has been collected by a single center, and rarely from various treatment centers over a specified time period with similar staging and inclusion and exclusionary parameters. In most cases, the study compares this data to some other previously published data. The studies typically draw conclusions about the efficacy of proton therapy compared to some other therapy in terms of diseasefree survival, reported side effects, overall survival. Most real-patient experiences are captured in this type of research publication. Significant variability in the patients care resulting from subjective staging criterion, inter-practitioner variability, differences in cancer center protocols, researcher bias, and often the lack of complete medical history reported for each patient, introduces some uncertainty into the studys outcome statistics. Never-the-less, this type of study can be useful for drawing conclusions that a particular therapy or treatment protocol is worthy of further investigation with a more tightly controlled clinical trial.

Prospective Studies
Prospective, observational, case-controlled studies should assess local tumor control, morbidity, quality of life, and cost-effectiveness. Bias is a risk in these studies, both due to possible systematic differences in the patient populations, and because patients who have researched and sought out what they judge to be a superior treatment are often very satisfied with the outcome even when it is functionally poor.24 9

Clearly local tumor control and overall survival are important endpoints and they are generally relatively easy to measure. The quantification of normal tissue complications is equally important. It is likely that patients treated with protons will suffer fewer acute side effects than patients treated with photons. However because late effects can be more deleterious, and the main difference between the two modalities may lie in the much larger dose-bath delivered by photons, including IMRT, it is likely they will be more important. Late normal tissue damage is very difficult to quantify and even identify, and require very long follow-up times. Measures of quality-of-life, made over long periods of time are likely to be useful. Multi-institutional cooperation can be leveraged to collect a larger and less biased set of prospective, long-term data.

Randomized Clinical Trials (RCT)

The randomized distribution of patients, into one of multiple arms of a research trial is practically nonexistent in the realm of proton therapy. Because randomization involves the assignment of some patients into a research arm with previously recognized harmful attributes, medico-ethical considerations must be debated. Radiation therapy clinical trials are unlike clinical trials for pharmaceuticals and some other therapies. In appropriately designed RCTs, the two or more arms of the trial are considered, at least initially by the researcher, to be essentially balanced in terms of expected clinical benefit and risks. From the perspectives of both the physician and patient, there is no dilemma as to which arm the patient is stratified because the new treatment is not known to be better (or worse) than the current standard. For radiation therapy, and in particular proton therapy, the testable aspects of the trial are in fact based on well-established, and understood criterion that are evident at the trials onset. These factors include: superior dose distributions attainable with protons, a lack of biologic difference between protons and high-energy x-rays, and the extensive clinical evidence of a dose-response relationship for normal tissues and tumors. As an example, consider a trial between protons and photons where the protons deliver the same dose to the target as the photons. The tumor control probability (TCP) would be essentially the same, but in this scenario, the protons would deliver an overall lower dose to the normal tissue outside the target than the photons resulting in a predictably lower normal tissue complication probability (NTCP). As a result, many radiation oncologists have come to the conclusion that it is medically un-ethical to refer a patient to the standard-of-care trial arm when a better therapy is obviously available to their patient. The medical code of ethics does not allow a physician to intentionally harm his patient. Accordingly, a patient to whom was made a full disclosure of the risks and potential benefits of the trials arms, would not willingly accept enrollment in the trial knowing ahead of time that he could potentially be subjected to the therapeutic arm that offered additional and unnecessary radiation to parts of his otherwise healthy anatomy and without any additional benefit of tumor control. It is for this reason that proton therapy centers find it nearly impossible to conduct this type of head-to-head randomized clinical trial. The pressure to conduct RCTs in proton therapy stems primarily not from academic curiosity but from financial concerns about its costs. Trials in which one arm of the trial is deemed likely to be superior to 10

the other and the question asked is whether the improvement is worth the cost can not appear balanced from the patients point of view. Few patients would be willing to be randomized if this was clearly explained. How many advocates of RCTs would volunteer to unnecessarily receive the 30-to-50 Gy photon dose bath in order to help determine just how deleterious it was?25 It is valuable to point out that the ubiquitous acceptance of photon IMRT for clinical practice was made without the randomized clinical trials of the sort that most critics of proton therapy advocate. IMRT was adopted on the basis of a substantial number of *nonrandomized+ clinical studiesthat strongly suggested a decrease in clinical toxicity.26

Materials and Methods

It is fair to state that the intention of this treatise is to bolster the initiative to bring a proton therapy institute to Israel and as a defense against those who maintain that the evidence for proton therapy is either insufficient or inconclusive. An arbitrary decision was made to seek out only current articles, defined as 2008-2012, for inclusion. The amount of material available on this topic is mind-boggling so it was necessary to reject for inclusion research material if the specific indication was over-represented (eg, prostate). A literature search was carried out in various oncology and cancer-related medical journals using the search profile: proton and therapy for the dates Jan, 2008 to March, 2012. Identified articles were assessed for relevancespecifically outcomes and evidence of clinical benefit from proton therapy, but no articles were excluded due to negative statistics or bias. The reviewed journal articles and the subsequent references gleaned from them included dosimetric comparisons, prospective and retrospective studies, and articles specific to the issue of RCTs in the debate surrounding proton therapy. The mass of collected articles was reviewed, evaluated for relevance and if found to be worthy and interesting, the abstract was included in this report.

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Clinical Trials
Dosimetric Study of Pelvic Proton Radiotherapy for High-Risk Prostate Cancer Int J Radiat Oncol Biol Phys. 2009;75(4):994-1002.
Bhishamjit S. Chera, M.D., Carlos Vargas, M.D Christopher G. Morris, M.S.,
Purpose To compare dose distributions in targeted tissues (prostate, seminal vesicles, pelvic regional nodes) and nontargeted tissues in the pelvis with intensity-modulated radiotherapy (IMRT) and forward-planned, double-scattered, three-dimensional proton radiotherapy (3D-PRT). Methods and Materials IMRT, IMRT followed by a prostate 3D-PRT boost (IMRT/3D-PRT), and 3D-PRT plans were created for 5 high-risk prostate cancer patients (n = 15 plans). A 78-CGE/Gy dose was prescribed to the prostate and proximal seminal vesicles and a 46-CGE/Gy was prescribed to the pelvic nodes. Various dosimetric endpoints were compared. Results Target coverage of the prostate and nodal planning target volumes was adequate for all three plans. Compared with the IMRT and IMRT/3D-PRT plans, the 3D-PRT plans reduced the mean dose to the rectum, rectal wall, bladder, bladder wall, small bowel, and pelvis. The relative benefit of 3D-PRT (vs IMRT) at reducing the rectum and rectal wall V5-V40 was 53% to 71% (p < 0.05). For the bladder and bladder wall, the relative benefit for V5 to V40 CGE/Gy was 40% to 63% (p < 0.05). The relative benefit for reducing the volume of small bowel irradiated from 5 to 30 CGE/Gy in the 3D-PRT ranged from 62% to 69% (p < 0.05). Use of 3D-PRT did not produce the typical low-dose bath of radiation to the pelvis seen with IMRT. Femoral head doses were higher for the 3D-PRT. Conclusions Use of 3D-PRT significantly reduced the dose to normal tissues in the pelvis while maintaining adequate target coverage compared with IMRT or IMRT/3D-PRT. When treating the prostate, seminal vesicles, and pelvic lymph nodes in prostate cancer, proton therapy may improve the therapeutic ratio beyond what is possible with IMRT.

Comparative Analysis of Second Malignancy Risk in Patients Treated with Proton Therapy versus Conventional Photon Therapy Int J Radiat Oncol Biol Phys. 2008;72(1):S8.
Chung CS, Keating N, Yock TI, Tarbell NJ.
Background Compared to photon radiation, proton radiation improves dose distribution to the target and decreases dose to adjacent normal tissues. The most common method of delivering proton radiation involves passive scattering. However, passive scattering produces secondary low-dose neutrons, which may induce late radiation-induced malignancies. The magnitude of

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second cancer risk in patients treated with proton radiation compared to photon radiation therapy has not been reported to date. Purpose/Objective(s) To quantify the risk of a second malignancy associated with the use of proton radiation therapy compared to photon radiation therapy. Materials/Methods Matched retrospective cohort study of 1,450 patients treated with proton radiation therapy from 1974-2001 at the Harvard Cyclotron in Cambridge, MA, and patients treated with photon therapy in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. We matched patients by age at radiation treatment, year of treatment, cancer histology, and site of treatment. We restricted the study to patients with 1 year of follow-up. The primary endpoint was the risk of a second malignancy in any site after radiation therapy. Results We matched 503 Harvard Cyclotron proton patients with 1591 photon patients from the SEER registry. 6.4% of proton patients (32 patients) developed a second malignancy, while 12.8% of photon patients (203 patients) developed a second malignancy. The median duration of follow-up was 7.7 years in the proton cohort and 6.1 years in the photon cohort. The median age at treatment was 56 years in the proton cohort and 59 years in the photon cohort. After adjusting for gender and the age at treatment, treatment with photon therapy was significantly associated with an increased risk of a second malignancy (Adjusted Hazard Ratio 2.73, 95% CI 1.87 to 3.98, p < 0.0001). Conclusion The results of our preliminary analysis indicate that the use of proton radiation therapy is associated with a significantly lower risk of a second malignancy compared to photon radiation therapy. Additional analyses are required, and ongoing close surveillance of these patients is necessary, given the prolonged latency period for the development of second cancers.

Risk of Secondary Malignant Neoplasms From Proton Therapy and Intensity-Modulated XRay Therapy for Early-Stage Prostate Cancer Int J Radiat Oncol Biol Phys. 2009;74:616-622.
Jonas D. Fontenot, Andrew K. Lee, Wayne D. Newhauser
Purpose To assess the risk of a secondary malignant neoplasm (SMN) from proton therapy relative to intensity-modulated radiation therapy (IMRT) using X-rays, taking into account contributions from both primary and secondary sources of radiation, for prostate cancer. Methods and Materials A proton therapy plan and a 6-MV IMRT plan were constructed for 3 patients with early-stage adenocarcinoma of the prostate. Doses from the primary fields delivered to organs at risk of developing an SMN were determined from treatment plans. Secondary doses from the proton therapy and IMRT were determined from Monte Carlo simulations and available measured

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data, respectively. The risk of an SMN was estimated from primary and secondary doses on an organ-by-organ basis by use of risk models from the Committee on the Biological Effects of Ionizing Radiation. Results Proton therapy reduced the risk of an SMN by 26% to 39% compared with IMRT. The risk of an SMN for both modalities was greatest in the in-field organs. However, the risks from the in-field organs were considerably lower with the proton therapy plan than with the IMRT plan. This reduction was attributed to the substantial sparing of the rectum and bladder from exposure to the therapeutic beam by the proton therapy plan. Conclusions When considering exposure to primary and secondary radiation, proton therapy can reduce the risk of an SMN in prostate patients compared with contemporary IMRT.

A Phase III Trial Employing Conformal Photons with Proton Boost in Early-stage Prostate Cancer: Conventional Dose (70.2 GyE) Compared to High-dose Irradiation (79.2 GyE): Longterm Updated Analysis of Proton Radiation Oncology Group (PROG)/American College of Radiology (ACR) 9509 Int J Radiat Oncol Biol Phys. 2009:S11.
Zietman A.L, Bae K, Rossi C, J.D. Slater
Purpose/Objective(s) Randomized trial to test the hypothesis that increasing radiation dose to men with early-stage prostate cancer above conventional levels improves clinical outcomes. Materials/Methods Patients with T1bT2b prostate cancer and a PSA of <15 ng/mL were randomized to receive a boost to the prostate alone using conformal protons (either lateral or perineal fields) of either 19.8 or 28.8 Gray equivalent (GyE). All patients then received 50.4 Gy at 1.8 Gy per fraction using 3D conformal photons to the prostate, seminal vesicles, and periprostatic tissues. No patient received androgen suppression with their radiation. Local failure (LF), biochemical failure (BF) defined by ASTRO consensus or Phoenix definitions, and overall survivals (OS) were used as outcomes. The Kaplan-Meier estimation with logrank test was used for the OS rate and the cumulative incidence estimation with Gray's test was used for LF and BF rates. Results Of a total of 391 eligible patients with median follow-up of 8.9 years, 197 received 70.2 GyE (conventional dose) and 196 79.2 GyE (high dose). Median age at diagnosis was 67 years and median PSA 6.3. A total of 75.3% had Gleason scores of 6 or less, 15.3% GS 7, and 8.4% GS 810. A total of 61.2% had T1c tumors. Men in the high-dose arm were less likely to have LF than the conventional arm with hazard ratio of 0.57 (95% CI, 0.43, 0.74). Ten-year ASTRO BF rates (with backdating) were 35.3% (95% CI, 27.9, 43.6) for conventional dose and 16.3% (95% CI, 9.8, 22.7) for high dose (p = 0.0001). For low risk disease (n = 227, 58% of total): 10-year BF rate was 29.0% in the conventional dose arm and 6.1% in the high dose arm (p < 0.0001). There was a trend in the same direction for the smaller group of intermediate risk patients (n = 144, 37% of total; 44.6 vs. 28.6; p = 0.06). Eleven percent of the patients subsequently required androgen deprivation for recurrence in the conventional dose arm compared with 6% in the high-dose arm (p = 0.047). There remains no difference in OS between the arms (83.4 [high-dose] vs. 78.4; p = 0.41). A total of 2.1% of patients in the both arms experienced late urinary or rectal toxicity Grade 3. The cumulative incidence

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of any Grade 2 late toxicity was 29.4% and 39.4%, respectively, (p = 0.045). Parallel quality of life studies have shown similar levels of satisfaction with bowel and urinary function in both arms. Conclusions This RCT shows a long-term advantage in terms of freedom from biochemical failure for men with low and intermediate risk prostate cancer receiving high dose vs. conventional dose conformal radiation delivered with mixed proton and photon beams. This advantage was achieved without any associated increase in Grade 3 late urinary or rectal morbidity.

DoseVolume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer Int J Radiat Oncol Biol Phys. 2008;70(3):744-751.
Carlos Vargas, Amber Fryer, Chaitali Mahajan
Purpose The contrast in dose distribution between proton radiotherapy (RT) and intensity-modulated RT (IMRT) is unclear, particularly in regard to critical structures such as the rectum and bladder. Methods and Materials Between August and November 2006, the first 10 consecutive patients treated in our Phase II low-risk prostate proton protocol (University of Florida Proton Therapy Institute protocol 0001) were reviewed. The double-scatter proton beam plans used in treatment were analyzed for various dosimetric endpoints. For all plans, each beam dose distribution, angle, smearing, and aperture margin were optimized. IMRT plans were created for all patients and simultaneously analyzed. The IMRT plans were optimized through multiple volume objectives, beam weighting, and individual leaf movement. The patients were treated to 78 Gray-equivalents (GE) in 2-GE fractions with a biologically equivalent dose of 1.1. Results All rectal and rectal wall volumes treated to 1080 GE (percentage of volume receiving 1080 GE [V10V80]) were significantly lower with proton therapy (p < 0.05). The rectal V50 was reduced from 31.3% 4.1% with IMRT to 14.6% 3.0% with proton therapy for a relative improvement of 53.4% and an absolute benefit of 16.7% (p < 0.001). The mean rectal dose decreased 59% with proton therapy (p < 0.001). For the bladder and bladder wall, proton therapy produced significantly smaller volumes treated to doses of 1035 GE (p < 0.05) with a nonsignificant advantage demonstrated for the volume receiving 60 GE. The bladder V30 was reduced with proton therapy for a relative improvement of 35.3% and an absolute benefit of 15.1% (p = 0.02). The mean bladder dose decreased 35% with proton therapy (p = 0.002). Conclusion Compared with IMRT, proton therapy reduced the dose to the dose-limiting normal structures while maintaining excellent planning target volume coverage.

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Combined Proton and Photon Conformal Radiotherapy for Intracranial Atypical and Malignant Meningioma Int J Radiat Oncol Biol Phys. 2009;75(2): 399-406.
Christos Boskos, Lois Feuvret, Georges Noel, et al.
Purpose To evaluate retrospectively the efficacy of conformal fractionated radiotherapy combining proton and photon beams after primary surgery for treatment of atypical and malignant meningiomas. Patients and Methods Between September 1999 and October 2006, 24 patients (12 male, 12 female) with histopathologically proven meningioma (atypical 19, malignant 5) received postoperative combined radiotherapy with a 201-MeV proton beam at the Centre Protontherapie d'Orsay and a high-energy photon beam. Six patients underwent gross total resection and 18 a subtotal resection. Median gross tumor volume and clinical target volume were 44.7 cm3 and 153.3 cm3, respectively. Mean total irradiation dose was 65.01 CGE (cobalt gray equivalent), with a mean proton total dose of 34.05 CGE and a mean photon total dose 30.96 CGE. Results The median (range) follow-up interval was 32.2 (172) months. The overall mean local relapse-free interval was 27.2 (1050) months, 28.3 (1050) months for atypical meningioma and 23 (1333) months for malignant meningioma. Ten tumors recurred locally. One-, 2-, 3-, 4-, 5-, and 8- year local control rates for the entire group of patients were 82.9% 7.8%, 82.9% 7.8%, 61.3% 11%, 61.3% 11%, 46.7% 12.3%, and 46.7% 12.3%, respectively. One-, 2-, 3-, 4-, 5-, and 8- year overall survival rates were 100%, 95.5% 4.4%, 80.4% 8.8%, 65.3% 10.6%, 53.2% 11.6%, and 42.6% 13%, respectively. Survival was significantly associated with total dose. There was no acute morbidity of radiotherapy. One patient developed radiation necrosis 16 months after treatment. Conclusions Postoperative combination of conformal radiotherapy with protons and photons for atypical and malignant meningiomas is a well-tolerated treatment producing long-term tumor stabilization.

Proton Radiotherapy for Childhood Ependymoma: Initial Clinical Outcomes and Dose Comparisons Int J Radiat Oncol Biol Phys. 2008;71(4):979-986.
Shannon M. MacDonald, Sairos Safai, Alexei Trofimov, et al.
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.

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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 dosevolume 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.

Proton Radiotherapy for Pediatric Central Nervous System Germ Cell Tumors: Early Clinical Outcomes Int J Radiat Oncol Biol Phys. 2009;75(3);S509-S510.
S. MacDonald, A. Trofimov, S. Safai
Purpose/Objective(s) To report early clinical outcomes for pediatric patients treated with proton beam radiation for pediatric central nervous system (CNS) germ cell tumors (pure germ cell tumors (GCT) & non-germanomatous germ cell tumors (NGGCT)). To compare the dose distributions of intensity modulated radiation therapy with photons (IMRT), broad field proton radiation, and proton radiation with pencil beam scanning (IMPT) for whole ventricular radiation. Materials/Methods All children with pure GCT or NGGCT confined to the CNS who were treated at the Francis H. Burr Proton Facility and Harvard Cyclotron between 1998 and 2007 were included in this study. Proton, photon (IMRT) plans and IMPT plans were generated with similar clinical constraints for a representative case. Tumor and normal tissue dose volume histograms were calculated and compared. Results Twenty-two patients were treated with broad field proton radiotherapy. At a median follow-up of 28 months, there were no CNS recurrences; one patient had a distant recurrence outside the CNS. Local control, progression free, and overall survival was 100%, 95%, and 100%, respectively. We compared treatment plans for whole ventricle radiation. Comparable tumor volume coverage was achieved with proton scanning, scattered proton therapy, and IMRT. Substantial normal tissue sparing was seen with the proton therapy plan as compared to IMRT. The use of IMPT allowed for additional sparing of some critical structures if the pencil beam sigma was less than 5 mm.

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Conclusions Preliminary disease control with proton therapy compares favorably to the literature. Dosimetric comparisons demonstrate the advantage of proton radiation as compared to IMRT in the treatment of whole ventricle radiation. Superior dose distributions were accomplished with fewer beam angles with the use of broad beam and scanned protons. IMPT may improve dose distribution for whole ventricle radiation, but meaningful differences are seen in this case only if small sigma (< 5 mm) can be achieved.

Intensity-Modulated Proton Therapy Reduces the Dose to Normal Tissue Compared With Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy and Enables Individualized Radical Radiotherapy for Extensive Stage IIIB Non-Small-Cell Lung Cancer: A Virtual Clinical Study Int J Radiat Oncol Biol Phys. 2010;77(2):357-366.
Xiaodong Zhang, Yupeng Li, Xiaoning Pan, et al.
Purpose To compare dose volume histograms of intensity-modulated proton therapy (IMPT) with those of intensity-modulated radiation therapy (IMRT) and passive scattering proton therapy (PSPT) for the treatment of stage IIIB non-small-cell lung cancer (NSCLC) and to explore the possibility of individualized radical radiotherapy. Methods and Materials Dose volume histograms designed to deliver IMRT at 60 to 63 Gy, PSPT at 74 Gy, and IMPT at the same doses were compared and the use of individualized radical radiotherapy was assessed in patients with extensive stage IIIB NSCLC (n = 10 patients for each approach). These patients were selected based on their extensive disease and were considered to have no or borderline tolerance to IMRT at 60 to 63 Gy, based on the dose to normal tissue volume constraints (lung volume receiving 20 Gy [V20] of <35%, total mean lung dose <20 Gy; spinal cord dose, <45 Gy). The possibility of increasing the total tumor dose with IMPT for each patient without exceeding the dose volume constraints (maximum tolerated dose [MTD]) was also investigated. Results Compared with IMRT, IMPT spared more lung, heart, spinal cord, and esophagus, even with dose escalation from 63 Gy to 83.5 Gy, with a mean MTD of 74 Gy. Compared with PSPT, IMPT allowed further dose escalation from 74 Gy to a mean MTD of 84.4 Gy (range, 79.488.4 Gy) while all parameters of normal tissue sparing were kept at lower or similar levels. In addition, IMPT prevented lower-dose target coverage in patients with complicated tumor anatomies. Conclusions IMPT reduces the dose to normal tissue and allows individualized radical radiotherapy for extensive stage IIIB NSCLC.

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Analysis of Vision Loss Caused by Radiation-Induced Optic Neuropathy After Particle Therapy for Head-and-Neck and Skull-Base Tumors Adjacent to Optic Nerves Int J Radiat Oncol Biol Phys. 2009; 75(5):1487-1492.
Demizu Y, Murakami M, Miyawaki D, et al.
Purpose To assess the incident rates of vision loss (VL; based on counting fingers or more severe) caused by radiation-induced optic neuropathy (RION) after particle therapy for tumors adjacent to optic nerves (ONs), and to evaluate factors that may contribute to VL. Methods and Materials From August 2001 to August 2006, 104 patients with head-and-neck or skull-base tumors adjacent to ONs were treated with carbon ion or proton radiotherapy. Among them, 145 ONs of 75 patients were irradiated and followed for greater than 12 months. The incident rate of VL and the prognostic factors for occurrence of VL were evaluated. The late effects of carbon ion and proton beams were compared on the basis of a biologically effective dose at / = 3 gray equivalent (GyE3). Results Eight patients (11%) experienced VL resulting from RION. The onset of VL ranged from 17 to 58 months. The median follow-up was 25 months. No significant difference was observed between the carbon ion and proton beam treatment groups. On univariate analysis, age (>60 years), diabetes mellitus, and maximum dose to the ON (>110 GyE3) were significant, whereas on multivariate analysis only diabetes mellitus was found to be significant for VL. Conclusions The time to the onset of VL was highly variable. There was no statistically significant difference between carbon ion and proton beam treatments over the follow-up period. Based on multivariate analysis, diabetes mellitus correlated with the occurrence of VL. A larger study with longer follow-up is warranted.

Effectiveness and Safety of Spot Scanning Proton Radiation Therapy for Chordomas and Chondrosarcomas of the Skull Base: First Long-Term Report Int J Radiat Oncol Biol Phys. 2009;75(4):1111-1118.
Carmen Ares, Eugen B. Hug, Antony J. Lomax
Purpose To evaluate effectiveness and safety of spot-scanning-based proton radiotherapy (PT) in skull-base chordomas and chondrosarcomas. Methods and Materials Between October 1998 and November 2005, 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22) were treated at Paul Scherrer Institute with PT using spot-scanning technique. Median total dose for chordomas was 73.5 Gy(RBE) and 68.4 Gy(RBE) for chondrosarcomas at 1.82.0 Gy(RBE) dose per fraction. Local control (LC), disease specific survival (DSS), and overall survival (OS) rates were calculated. Toxicity was assessed according to CTCAE, v. 3.0.

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Results Mean follow-up period was 38 months (range, 1492 months). Five patients with chordoma and one patient with chondrosarcoma experienced local recurrence. Actuarial 5-year LC rates were 81% for chordomas and 94% for chondrosarcomas. Brainstem compression at the time of PT (p = 0.007) and gross tumor volume >25 mL (p = 0.03) were associated with lower LC rates. Five years rates of DSS and OS were 81% and 62% for chordomas and 100% and 91% for chondrosarcomas, respectively. High-grade late toxicity consisted of one patient with Grade 3 and one patient with Grade 4 unilateral optic neuropathy, and two patients with Grade 3 central nervous system necrosis. No patient experienced brainstem toxicity. Actuarial 5-year freedom from high-grade toxicity was 94%. Conclusions Our data indicate safety and efficacy of spot-scanning based PT for skull-base chordomas and chondrosarcomas. With target definition, dose prescription and normal organ tolerance levels similar to passive-scattering based PT series, complication-free, tumor control and survival rates are at present comparable.

Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas Int J Radiat Oncol Biol Phys. 2009;74(3):732-739.
Thomas F. Delaney, Norbert J. Liebsch, Francis X. Pedlow
Purpose Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of 66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. Methods and Materials Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. Results A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. Conclusions Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

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Postoperative Spot-Scanning Proton Radiation Therapy for Chordoma and Chondrosarcoma in Children and Adolescents: Initial Experience at Paul Scherrer Institute Int J Radiat Oncol Biol Phys. 2008;71(1):220-225.
Hans Peter Rutz, Damien C. Weber, Gudrun Goitein, Carmen Ares, Alessandra Bolsi, Antony Lomax, Eros Pedroni, Eugen Hug Purpose To evaluate postoperative spot-scanning proton radiation therapy (PT) and intensity-modulated PT (IMPT) for chordoma and chondrosarcoma in pediatric patients. Methods and Materials Between 2000 and 2005, 10 patients (six male patients, four female patients; six chordomas, four chondrosarcomas), aged 10 20 years (median, 16 years), were treated at our institute. Tumor sites were in the brain (one case), skull base (five cases), cervical (three cases), and lumbar spine (one case). Three children had complete resections. In seven children, resection was incomplete, leaving residual tumor behind (range, 2.346.3 mL). PT was delivered using spot scanning, with (three patients) or without (seven patients) IMPT. Total dose was 74.0 cobalt Gray equivalents (CGE) for chordoma, and 63.268.0 CGE for chondrosarcoma (median, 66.0), depending on histopathological grading and whether the patient had concurrent chemotherapy. Results Median follow-up time was 36 months (range, 877 months). Radiation treatment was well tolerated. All patients remained failure-free at their last follow-up. Late adverse events were reported in three patients and were mild (neurosensory in one patient; alopecia and hypoaccusis in one patient) to moderate (one patient, Grade 2 pituitary insufficiency). Conclusions Postoperative spot-scanning PT, delivered in combination with and without IMPT, for chordoma and chondrosarcoma in children and adolescents was tolerated without unacceptable adverse event and initial outcome is perfectly satisfactory in this small cohort. Longer follow-up time and larger cohort are needed to more fully assess tumor control, adverse events, as well as functional and cosmetic outcome.

A Prospective Study of Hypofractionated Proton Beam Therapy for Patients With Hepatocellular Carcinoma Int J Radiat Oncol Biol Phys. 2009;74(3):831-836.
Fukumitsu N, Sugahara S, Nakayama H, et al.
Purpose To evaluate the efficacy and safety of hypofractionated proton beam therapy for patients with hepatocellular carcinoma (HCC). Methods and Materials Between September 2001 and August 2004, 51 patients with HCC greater than 2 cm away from the porta hepatis or gastrointestinal tract were treated with proton beam therapy to 66 Gy-equivalents (GyE) in 10 fractions.

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Results Overall survival rates were 49.2 and 38.7% at 3 and 5 years after treatment. Local control rates were 94.5 and 87.8% at 3 and 5 years after treatment. Posttreatment serum -fetoprotein values were significantly reduced when compared with pretreatment values (p < 0.0001). Patients experienced only minor acute reactions of Grade 1 or less, and 3 patients experienced late sequelae of Grade 2 or higher. However, there were no treatment-related deaths. Conclusions Hypofractionated proton beam therapy is safe and well-tolerated by patients with HCC located greater than 2 cm away from the porta hepatis or gastrointestinal tract and may be effective alternative to other modalities.

Four-Dimensional Computed TomographyBased Treatment Planning for IntensityModulated Radiation Therapy and Proton Therapy for Distal Esophageal Cancer
Int J Radiat Oncol Biol Phys. 2008;72(1):278-287. Zhang X, Zhao K, Guerrero TM, Cox J, Mohan R, et al.
Purpose To compare three-dimensional (3D) and four-dimensional (4D) computed tomography (CT)based treatment plans for proton therapy or intensity-modulated radiation therapy (IMRT) for esophageal cancer in terms of doses to the lung, heart, and spinal cord and variations in target coverage and normal tissue sparing. Methods and Materials The IMRT and proton plans for 15 patients with distal esophageal cancer were designed from the 3D average CT scans and then recalculated on 10 4D CT data sets. Dosimetric data were compared for tumor coverage and normal tissue sparing. Results Compared with IMRT, median lung volumes exposed to 5, 10, and 20 Gy and mean lung dose were reduced by 35.6%, 20.5%, 5.8%, and 5.1 Gy for a two-beam proton plan and by 17.4%, 8.4%, 5%, and 2.9 Gy for a three-beam proton plan. The greater lung sparing in the two-beam proton plan was achieved at the expense of less conformity to the target (conformity index [CI], 1.99) and greater irradiation of the heart (heart-V40, 41.8%) compared with the IMRT plan(CI, 1.55, heart-V40, 35.7%) or the three-beam proton plan (CI, 1.46, heart-V40, 27.7%). Target coverage differed by more than 2% between the 3D and 4D plans for patients with substantial diaphragm motion in the three-beam proton and IMRT plans. The difference in spinal cord maximum dose between 3D and 4D plans could exceed 5 Gy for the proton plans partly owing to variations in stomach gas filling. Conclusions Proton therapy provided significantly better sparing of lung than did IMRT. Diaphragm motion and stomach gas-filling must be considered in evaluating target coverage and cord doses.

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Proton Beam Radiotherapy for Uveal Melanomas at Nice Teaching Hospital: 16 Years' Experience Int J Radiat Oncol Biol Phys. 2010;78(1):98-103.
Caujolle JP, Mammar H, Chamorey E, Pinon F, Herault J, Gastaud P.
Purpose To present the results of uveal melanomas treated at Nice Teaching Hospital. Methods and Materials This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model. Results The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%) patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years. Conclusions We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy.

Dosimetric Comparison of Three Different Involved Nodal Irradiation Techniques for Stage II Hodgkin's Lymphoma Patients: Conventional Radiotherapy, Intensity-Modulated Radiotherapy, and Three-Dimensional Proton Radiotherapy Int J Radiat Oncol Biol Phys. 2009;75(4):1173-1180.
Bhishamjit S. Chera, Christina Rodriguez, Christopher G. Morris
Purpose To compare the dose distribution to targeted and nontargeted tissues in Hodgkin's lymphoma patients using conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and three-dimensional proton RT (3D-PRT). Methods and Materials

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CRT, IMRT, and 3D-PRT treatment plans delivering 30 cobalt Gray equivalent (CGE)/Gy to an involved nodal field were created for 9 Stage II Hodgkin's lymphoma patients (n = 27 plans). The dosimetric endpoints were compared. Results The planning target volume was adequately treated using all three techniques. The IMRT plan produced the most conformal high-dose distribution; however, the 3D-PRT plan delivered the lowest mean dose to nontarget tissues, including the breast, lung, and total body. The relative reduction in the absolute lung volume receiving doses of 416 CGE/Gy for 3D-PRT compared with CRT ranged from 26% to 37% (p < .05), and the relative reduction in the absolute lung volume receiving doses of 410 CGE/Gy for 3D-PRT compared with IMRT was 4865% (p < .05). The relative reduction in absolute total body volume receiving 430 CGE/Gy for 3D-PRT compared with CRT was 47% (p < .05). The relative reduction in absolute total body volume receiving a dose of 4 CGE/Gy for 3D-PRT compared with IMRT was 63% (p = .03). The mean dose to the breast was significantly less for 3DPRT than for either IMRT or CRT (p = .03) The mean dose and absolute volume receiving 430 CGE/Gy for the heart, thyroid, and salivary glands were similar for the three modalities. Conclusion In this favorable subset of Hodgkin's lymphoma patients without disease in or below the hila, 3D-PRT significantly reduced the dose to the breast, lung, and total body. These observed dosimetric advantages might improve the clinical outcomes of Hodgkin's lymphoma patients by reducing the risk of late radiation effects related to low-to-moderate doses in nontargeted tissues.

Early Outcomes From Three Prospective Trials of Image-Guided Proton Therapy for Prostate Cancer Int J Radiat Oncol Biol Phys. (82) 1, 213-221.
Mendenhall N., Zoufeng L., Hoppe B., et al.
Purpose To report early outcomes with image-guided proton therapy for prostate cancer. Methods and Materials We accrued 211 prostate cancer patients on prospective Institutional Review Board-approved trials of 78 cobalt gray equivalent (CGE) in 39 fractions for lowrisk disease, dose escalation from 78 to 82 CGE for intermediate-risk disease, and 78 CGE with concomitant docetaxel followed by androgen deprivation for high-risk disease. Minimum follow-up was 2 years. Results One intermediate-risk patient and 2 high-risk patients had disease progression. Pretreatment genitourinary (GU) symptom management was required in 38% of patients. A cumulative 88 (42%) patients required posttreatment GU symptom management. Four transient Grade 3 GU toxicities occurred, all among patients requiring pretreatment GU symptom management. Multivariate analysis showed correlation between posttreatment GU 2+ symptoms and pretreatment GU symptom management (p < 0.0001) and age (p = 0.0048). Only 1 Grade 3+ gastrointestinal (GI) symptom occurred. The prevalence of Grade 2+ GI symptoms was 0 (0%), 10 (5%), 12 (6%), and 8 (4%) at 6, 12, 18, and 24 months, with a cumulative incidence of 20 (10%) patients at 2 years after proton therapy.

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Univariate and multivariate analyses showed significant correlation between Grade 2+ rectal bleeding and proctitis and the percentage of rectal wall (rectum) receiving doses ranging from 40 CGE (10 CGE) to 80 CGE. Conclusions Early outcomes with image-guided proton therapy suggest high efficacy and minimal toxicity with only 1.9% Grade 3 GU symptoms and <0.5% Grade 3 GI toxicities.

Predicted Rates of Secondary Malignancies From Proton Versus Photon Radiation Therapy for Stage I Seminoma Int J Radiat Oncol Biol Phys. (82) 1, 242-249.
Simone C, Kramer K, OMeara W., et al.
Purpose Photon radiotherapy has been the standard adjuvant treatment for stage I seminoma. Single-dose carboplatin therapy and observation have emerged as alternative options due to concerns for acute toxicities and secondary malignancies from radiation. In this institutional review board-approved study, we compared photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities. Methods and Material Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ-specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors. Results Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p < 0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.225.01), large bowel (0.81; 95% CI, 0.391.01), and bladder (0.03; 95% CI, 0.010.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, 0.010.06). Conclusions For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients with a life expectancy of 40 years from the time of radiation treatment with protons instead of photons. Proton radiation therapy also allowed significant sparing of most critical structures examined and warrants further study for patients with seminoma, to decrease radiationinduced toxicity.

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Proton Radiotherapy for Parameningeal Rhabdomyosarcoma: Clinical Outcomes and Late Effects Int J Radiat Oncol Biol Phys. (82) 2, 635-642.
Childs S., Koazk K., Friedmann A.
Purpose To report the clinical outcome and late side effect profile of proton radiotherapy in the treatment of children with parameningeal rhabdomyosarcoma (PM-RMS). Methods and Materials Seventeen consecutive children with PM-RMS were treated with proton radiotherapy at Massachusetts General Hospital between 1996 and 2005. We reviewed the medical records of all patients and asked referring physicians to report specific side effects of interest. Results Median patient age at diagnosis was 3.4 years (range, 0.417.6). Embryonal (n = 11), alveolar (n = 4), and undifferentiated (n = 2) histologies were represented. Ten patients (59%) had intracranial extension. Median prescribed dose was 50.4 cobalt gray equivalents (GyRBE) (range, 50.456.0 GyRBE) delivered in 1.82.0-GyRBE daily fractions. Median follow-up was 5.0 years for survivors. The 5-year failure-free survival estimate was 59% (95% confidence interval, 3379%), and overall survival estimate was 64% (95% confidence interval, 3782%). Among the 7 patients who failed, sites of first recurrence were local only (n = 2), regional only (n = 2), distant only (n = 2), and local and distant (n = 1). Late effects related to proton radiotherapy in the 10 recurrence-free patients (median follow-up, 5 years) include failure to maintain height velocity (n = 3), endocrinopathies (n = 2), mild facial hypoplasia (n = 7), failure of permanent tooth eruption (n = 3), dental caries (n = 5), and chronic nasal/sinus congestion (n = 2). Conclusions Proton radiotherapy for patients with PM-RMS yields tumor control and survival comparable to that in historical controls with similar poor prognostic factors. Furthermore, rates of late effects from proton radiotherapy compare favorably to published reports of photon-treated cohorts.

Dosimetric Comparison of Three-Dimensional Conformal Proton Radiotherapy, IntensityModulated Proton Therapy, and Intensity-Modulated Radiotherapy for Treatment of Pediatric Craniopharyngiomas Int J Radiat Oncol Biol Phys. (82)2 643-652
Boehling N., Grosshans D., Bluett J.
Purpose Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared

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with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. Methods and Materials IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dosevolume histograms. Results The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3% ), dentate gyrus (27.3, 75.0% ), and subventricular zone (4.5, 57.8% ). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3 , 100.0% ; middle cerebral arteries, 25.9% , 100% ; anterior communicating arteries, 30.8 , 41.7% ; and carotid arteries, 51.5 , 77.6 ). Relative reduction of integral dose to the infratentorial brain (190.7 , 109.7% ), supratentorial brain without PTV (9.6, 26.8% ), brainstem (45.6, 22.4% ), and whole brain without PTV (19.4 , 34.4% ) were recorded with the use of proton therapy. ( Differences were significant based on Friedmans test with Bonferroni-Dunn correction, = 0.05) Conclusions The current study found that proton therapy was able to avoid excess integral radiation dose to a variety of normal structures at all dose levels while maintaining equal target coverage. Future studies will examine the clinical benefits of these dosimetric advantages.

Using a Reduced Spot Size for Intensity-Modulated Proton Therapy Potentially Improves Salivary Gland-Sparing in Oropharyngeal Cancer Int J Radiat Oncol Biol Phys. (82) 2, e313-e319
Van de Water T., Lomax T., Bijl H
Purpose To investigate whether intensity-modulated proton therapy with a reduced spot size (rsIMPT) could further reduce the parotid and submandibular gland dose compared with previously calculated IMPT plans with a larger spot size. In addition, it was investigated whether the obtained dose reductions would theoretically translate into a reduction of normal tissue complication probabilities (NTCPs). Methods Ten patients with N0 oropharyngeal cancer were included in a comparative treatment planning study. Both IMPT plans delivered simultaneously 70 Gy to the boost planning target volume (PTV) and 54 Gy to the elective nodal PTV. IMPT and rsIMPT used identical three-field beam arrangements. In the IMPT plans, the parotid and submandibular salivary glands were spared as much as possible. rsIMPT plans used identical dosevolume objectives for the parotid glands as those used by the IMPT plans, whereas the objectives for the submandibular glands were tightened further. NTCPs were calculated for salivary dysfunction and xerostomia. Results

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Target coverage was similar for both IMPT techniques, whereas rsIMPT clearly improved target conformity. The mean doses in the parotid glands and submandibular glands were significantly lower for three-field rsIMPT (14.7 Gy and 46.9 Gy, respectively) than for three-field IMPT (16.8 Gy and 54.6 Gy, respectively). Hence, rsIMPT significantly reduced the NTCP of patient-rated xerostomia and parotid and contralateral submandibular salivary flow dysfunction (27%, 17%, and 43% respectively) compared with IMPT (39%, 20%, and 79%, respectively). In addition, mean dose values in the sublingual glands, the soft palate and oral cavity were also decreased. Obtained dose and NTCP reductions varied per patient. Conclusions rsIMPT improved sparing of the salivary glands and reduced NTCP for xerostomia and parotid and submandibular salivary dysfunction, while maintaining similar target coverage results. It is expected that rsIMPT improves quality of life during and after radiotherapy treatment.

On the Benefits and Risks of Proton Therapy in Pediatric Craniopharyngioma Int J Radiat Oncol Biol Phys. (82) 2, e281-e287
Beltran C., Roca M., Merchant T
Purpose Craniopharyngioma is a pediatric brain tumor whose volume is prone to change during radiation therapy. We compared photon- and proton-based irradiation methods to determine the effect of tumor volume change on target coverage and normal tissue irradiation in these patients. Methods and Materials For this retrospective study, we acquired imaging and treatment-planning data from 14 children with craniopharyngioma (mean age, 5.1 years) irradiated with photons (54 Gy) and monitored by weekly magnetic resonance imaging (MRI) examinations during radiation therapy. Photon intensity-modulated radiation therapy (IMRT), double-scatter proton (DSP) therapy, and intensity-modulated proton therapy (IMPT) plans were created for each patient based on his or her pre-irradiation MRI. Target volumes were contoured on each weekly MRI scan for adaptive modeling. The measured differences in conformity index (CI) and normal tissue doses, including functional sub-volumes of the brain, were compared across the planning methods, as was target coverage based on changes in target volumes during treatment. Results CI and normal tissue dose values of IMPT plans were significantly better than those of the IMRT and DSP plans (p < 0.01). Although IMRT plans had a higher CI and lower optic nerve doses (p < 0.01) than did DSP plans, DSP plans had lower cochlear, 3 optic chiasm, brain, and scanned body doses (p < 0.01). The mean planning target volume (PTV) at baseline was 54.8 cm , and the mean increase in PTV was 11.3% over the course of treatment. The dose to 95% of the PTV was correlated with a change in 2 the PTV; the R values for all models, 0.73 (IMRT), 0.38 (DSP), and 0.62 (IMPT), were significant (p < 0.01). Conclusions Compared with photon IMRT, proton therapy has the potential to significantly reduce whole-brain and -body irradiation in pediatric patients with craniopharyngioma. IMPT is the most conformal method and spares the most normal tissue; however, it is highly sensitive to target volume changes, whereas the DSP method is not.

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Long-Term Quality of Life Outcome After Proton Beam Monotherapy for Localized Prostate Cancer Int J Radiat Oncol Biol Phys. (82) 2, e201-e209
Coen J., Paly J., Niemierko A.
Objectives High-dose external radiation for localized prostate cancer results in favorable clinical outcomes and low toxicity rates. Here, we report long-term quality of life (QOL) outcome for men treated with conformal protons. Methods QOL questionnaires were sent at specified intervals to 95 men who received proton radiation. Of these, 87 men reported 3and/or 12-month outcomes, whereas 73 also reported long-term outcomes (minimum 2 years). Symptom scores were calculated at baseline, 3 months, 12 months, and long-term follow-up. Generalized estimating equation models were constructed to assess longitudinal outcomes while accounting for correlation among repeated measures in an individual patient. Men were stratified into functional groups from their baseline questionnaires (normal, intermediate, or poor function) for each symptom domain. Long-term QOL changes were assessed overall and within functional groups using the Wilcoxon signed-rank test. Results Statistically significant changes in all four symptom scores were observed in the longitudinal analysis. For the 73 men reporting long-term outcomes, there were significant change scores for incontinence (ID), bowel (BD) and sexual dysfunction (SD), but not obstructive/irritative voiding dysfunction (OID). When stratified by baseline functional category, only men with normal function had increased scores for ID and BD. For SD, there were significant changes in men with both normal and intermediate function, but not poor function. Conclusions Patient reported outcomes are sensitive indicators of treatment-related morbidity. These results quantitate the long-term consequences of proton monotherapy for prostate cancer. Analysis by baseline functional category provides an individualized prediction of long-term QOL scores. High dose proton radiation was associated with small increases in bowel dysfunction and incontinence, with more pronounced changes in sexual dysfunction.

Proton Radiotherapy for Pediatric Ewings Sarcoma: Initial Clinical Outcomes Int J Radiat Oncol Biol Phys. (82) 3, 1142-1148
Rombi B., DeLaney T., MacDonald S.
Purpose Proton radiotherapy (PT) has been prescribed similarly to photon radiotherapy to achieve comparable disease control rates at comparable doses. The chief advantage of protons in this setting is to reduce acute and late toxicities by decreasing the amount of normal tissue irradiated. We report the preliminary clinical outcomes including late effects on our pediatric Ewings sarcoma patients treated with PT at the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital (Boston, MA).

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Methods and Materials This was a retrospective review of the medical records of 30 children with Ewings sarcoma who were treated with PT between April 2003 and April 2009. Results A total of 14 male and 16 female patients with tumors in several anatomic sites were treated with PT at a median age of 10 years. The median dose was 54 Gy (relative biological effectiveness) with a median follow-up of 38.4 months. The 3-year actuarial rates of event-free survival, local control, and overall survival were 60%, 86%, and 89%, respectively. PT was acutely well tolerated, with mostly mild-to-moderate skin reactions. At the time of writing, the only serious late effects have been four hematologic malignancies, which are known risks of topoisomerase and anthracyline exposure. Conclusions Proton radiotherapy was well tolerated, with few adverse events. Longer follow-up is needed to more fully assess tumor control and late effects, but the preliminary results are encouraging.

Dosimetric Comparison of Combined Intensity-Modulated Radiotherapy (IMRT) and Proton Therapy Versus IMRT Alone for Pelvic and Para-Aortic Radiotherapy in Gynecologic Malignancies Int J Radiat Oncol Biol Phys. (82) 3, e477-e484
Milby A., Both S., Ingram M., Lin L.
Purpose To perform a dosimetric comparison of intensity-modulated radiotherapy (IMRT), passive scattering proton therapy (PSPT), and intensity-modulated proton therapy (IMPT) to the para-aortic (PA) nodal region in women with locally advanced gynecologic malignancies. Methods and Materials The CT treatment planning scans of 10 consecutive patients treated with IMRT to the pelvis and PA nodes were identified. The clinical target volume was defined by the primary tumor for patients with cervical cancer and by the vagina and paravaginal tissues for patients with endometrial cancer, in addition to the regional lymph nodes. The IMRT, PSPT, and IMPT plans were generated using the Eclipse Treatment Planning System and were analyzed for various dosimetric endpoints. Two groups of treatment plans including proton radiotherapy were created: IMRT to pelvic nodes with PSPT to PA nodes (PSPT/IMRT), and IMRT to pelvic nodes with IMPT to PA nodes (IMPT/IMRT). The IMRT and proton RT plans were optimized to deliver 50.4 Gy or Gy (relative biologic effectiveness [RBE)), respectively. Dosevolume histograms were analyzed for all of the organs at risk. The paired t test was used for all statistical comparison. Results The small-bowel V20, V30, V35, andV40 were reduced in PSPT/IMRT by 11%, 18%, 27%, and 43%, respectively (p < 0.01). Treatment with IMPT/IMRT demonstrated a 32% decrease in the small-bowel V20. Treatment with PSPT/IMRT showed statistically significant reductions in the body V520; IMPT/IMRT showed reductions in the body V515. The dose received by half of both kidneys was reduced by PSPT/IMRT and by IMPT/IMRT. All plans maintained excellent coverage of the planning target volume.

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Conclusions Compared with IMRT alone, PSPT/IMRT and IMPT/IMRT had a statistically significant decrease in dose to the small and large bowel and kidneys, while maintaining excellent planning target volume coverage. Further studies should be done to correlate the clinical significance of these findings.

Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma Int J Radiat Oncol Biol Phys. (82) 3, e529-e535
Mizumoto M., Okumura T., Hashimoto T.
Purpose Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials The subjects were 259 patients treated with PBT at the University of Tsukuba between January 2001 and December 2007. We evaluated the ChildPugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the ChildPugh score of 1 or more was defined as an adverse event. Results Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of ChildPugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of ChildPugh score, 15 had a 1-point increase, and 10 had an increase of 2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

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Rationale for and Preliminary Results of Proton Beam Therapy for Mediastinal Lymphoma Int J Radiat Oncol Biol Phys.2011(81)1, 167-174.
Purpose To evaluate the potential of three-dimensional proton beam therapy (3D-PBT) for reducing doses to normal structures in patients with mediastinal lymphomas compared with conventional photon radiation therapy (RT). Methods and Materials We treated 10 consecutive patients with mediastinal masses from lymphomas with 3D-PBT between July 2007 and February 2009 to 30.650.4 cobalt-Gray equivalents (CGE). Of those patients, 7 had primary refractory or recurrent disease, and 8 had Hodgkin lymphoma. Dosimetric endpoints were compared with those from conventional RT plans. Results PBT delivered lower mean doses to the lung (6.2 vs. 9.5 Gy), esophagus (9.5 vs. 22.3 Gy), and heart (8.8 vs. 17.7 Gy) but not the breasts (5.9 vs. 6.1 Gy) than did conventional RT. Percentages of lung, esophagus, heart, and coronary artery (particularly the left anterior descending artery) volumes receiving radiation were consistently lower in the 3D-PBT plans over a wide range of radiation doses. Of the 7 patients who had residual disease on positron emission tomography before PBT, 6 (86%) showed a complete metabolic response. Conclusions In patients with mediastinal lymphomas, 3D-PBT produced significantly lower doses to the lung, esophagus, heart, and coronary arteries than did the current conventional RT. These lower doses would be expected to reduce the risk of late toxicities in these major organs.

Prospective Study of Reirradiation for Soft Tissue Sarcoma: Early Outcomes and Morbidity Advance review of Abstract submitted to PTCOG 2012
Abigail Berman Milby, Curtiland Deville, Stefan Both, Zelig Tochner, James Metz, MD

PURPOSE: The management of soft tissue sarcoma (STS) in the setting of previously-irradiated tissue is complex. Proton radiotherapy (PRT) is ideally suited to the problem of reirradiation by sparing further dose to previously-radiated surrounding organs. Our institution developed a prospective trial to assess the feasibility of using PRT for reirradiation of recurrent malignancies. We report our preliminary experience with reirradiation of STS. METHODS: Between March, 2010 and May, 2011, 11 patients with non-metastatic STS in or near prior treatment fields were enrolled on a prospective trial of PRT for reirradiation. The end of prior radiation was required to have completed at least 3 months before the start of PRT. The median prior dose to the recurrent area was 5040 cGy(5000-6480). The median time from end of treatment of the prior course to the start of the PRT was 56.3 months(17.2-274.2). STS was histopathologically confirmed, among whom 8 patients had recurrent sarcoma, and 3 had de novo sarcoma with prior radiation given for rectal (2) and prostate (1) adenocarcinoma. Histology was liposarcoma (4), spindle cell (2), myxofibrosarcoma (2), fibrosarcoma (1), pleomorphic sarcoma (1), and leiomyosarcoma (1). Four patients had tumors of the lower extremity, 4 of the pelvis, 2 of the retroperitoneum, and 1 of the thorax. Surgical resection of the recurrent tumor was

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performed in 6 patients, 4 pre-PRT and 2 post-PRT. At the time of recurrence, 5 tumors were greater than 5 cm and 9 were high 3 grade. Mean clinical target volume (CTV) size was 280 cm . Radiotherapy was administered as double scatter proton therapy alone in 9 patients and in combination with intensity modulated photon radiotherapy (IMRT) in 2 patients. The median total dose prescribed was 7000 cGy(RBE), 5000-7920; the dose for PRT given pre-operatively was 5000 cGy(RBE) and post-operatively was 5000-7560 cGy(RBE). One patient received adriamycin-based chemotherapy prior to PRT. RESULTS: The median follow-up was 15.7 months (range 2.9-19.6) from the end of retreatment, and no living patients were lost during follow-up. Mean age was 64.3, range 28 to 89.4. Median survival was not reached. Seven (64%) patients were alive without evidence of local recurrence (LR) or distant metastasis (DM). Four (36%) patients had evidence of LR and 2 developed DM. Two patients died, one of LR and one of LR and DM, at 2.7 and 11.7 months, respectively. There was one acute PRT-related grade 3 toxicity which was a skin infection. There was no acute grade 4 toxicity. Late grade 3 toxicity soft tissue necrosis was observed in one patient treated pre-operatively to the LLE, requiring flap reconstruction. No other grade 3 or 4 late toxicities were observed thus far. CONCLUSIONS: Preliminary results indicate that PRT for the reirradiation of soft tissue toxicity is associated with good early outcomes and moderate toxicity. Further follow up on these patients is needed to assess the long-term utility of PRT reirradiation in STS.

Intensity-modulated radiotherapy of nasopharyngeal carcinoma: a comparative treatment planning study of photons and protons Radiation Oncology 2008;3:4.
Taheri-Kadkhoda Z, Bjrk-Eriksson T, Nill S, et al.
Background The aim of this treatment planning study was to investigate the potential advantages of intensity-modulated (IM) proton therapy (IMPT) compared with IM photon therapy (IMRT) in nasopharyngeal carcinoma (NPC). Methods Eight NPC patients were chosen. The dose prescriptions in cobalt Gray equivalent (GyE) for gross tumor volumes of the primary tumor (GTV-T), planning target volumes of GTV-T and metastatic (PTV-TN) and elective (PTV-N) lymph node stations were 72.6 GyE, 66 GyE, and 52.8 GyE, respectively. For each patient, nine coplanar fields IMRT with step-and-shoot technique and 3D spotscanned three coplanar fields IMPT plans were prepared. Both modalities were planned in 33 fractions to be delivered with a simultaneous integrated boost technique. All plans were prepared and optimized by using the research version of the inverse treatment planning system KonRad (DKFZ, Heidelberg). Results Both treatment techniques were equal in terms of averaged mean dose to target volumes. IMPT plans significantly improved the tumor coverage and conformation (P < 0.05) and they reduced the averaged mean dose to several organs at risk (OARs) by a factor of 23. The low-to-medium dose volumes (0.3313.2 GyE) were more than doubled by IMRT plans. Conclusion

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In radiotherapy of NPC patients, three-field IMPT has greater potential than nine-field IMRT with respect to tumor coverage and reduction of the integral dose to OARs and non-specific normal tissues. The practicality of IMPT in NPC deserves further exploration when this technique becomes available on wider clinical scale.

Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy Radiation Oncology 2011(6)58.
Benjamin J Moeller, Murali Chintagumpala, Jimmy J Philip, David R Grosshans
Background Hearing loss is common following chemoradiotherapy for children with medulloblastoma. Compared to photons, proton radiotherapy reduces radiation dose to the cochlea for these patients. Here we examine whether this dosimetric advantage leads to a clinical benefit in audiometric outcomes. Methods From 2006-2009, 23 children treated with proton radiotherapy for medulloblastoma were enrolled on a prospective observational study, through which they underwent pre- and 1 year post-radiotherapy pure-tone audiometric testing. Ears with moderate to severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis. Results The predicted mean cochlear radiation dose was 30 Co-Gy Equivalents (range 19-43), and the mean cumulative cisplatin dose was 303 mg/m (range 298-330). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P < 0.05). There was partial sparing of mean post-radiation hearing thresholds at low-to-midrange frequencies and, consequently, the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was favorable (5%). Ototoxicity did not correlate with predicted dose to the auditory apparatus for proton-treated patients, potentially reflecting a lower-limit threshold for radiation effect on the cochlea. Conclusions Rates of high-grade early post-radiation ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. The sparing of auditory threshold in the audible speech range with proton radiotherapy may eventually translate into improved communication skills, quality of life, social development, and cognitive development for these patients.
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RapidArc, intensity modulated photon and proton techniques for recurrent prostate cancer in previously irradiated patients: a treatment planning comparison study Radiation Oncology 2009 (4)34
Damien C Weber, Hui Wang, Luca Cozzi, et al

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Background A study was performed comparing volumetric modulated arcs (RA) and intensity modulation (with photons, IMRT, or protons, IMPT) radiation therapy (RT) for patients with recurrent prostate cancer after RT.

Methods Plans for RA, IMRT and IMPT were optimized for 7 patients. Prescribed dose was 56 Gy in 14 fractions. The recurrent gross tumor volume (GTV) was defined on F-fluorocholine PET/CT scans. Plans aimed to cover at least 95% of the planning target volume with a dose > 50.4 Gy. A maximum dose (DMax) of 61.6 Gy was allowed to 5% of the GTV. For the urethra, DMax was constrained to 37 Gy. Rectal DMedian was < 17 Gy. Results were analyzed using Dose-Volume Histogram and conformity index (CI90) parameters. Results Tumor coverage (GTV and PTV) was improved with RA (V95% 92.6 7.9 and 83.7 3.3%), when compared to IMRT (V95% 88.6 10.8 and 77.2 2.2%). The corresponding values for IMPT were intermediate for the GTV (V95% 88.9 10.5%) and better for the PTV (V95%85.6 5.0%). The percentages of rectal and urethral volumes receiving intermediate doses (35 Gy) were significantly decreased with RA (5.1 3.0 and 38.0 25.3%) and IMPT (3.9 2.7 and 25.1 21.1%), when compared to IMRT (9.8 5.3 and 60.7 41.7%). CI90 was 1.3 0.1 for photons and 1.6 0.2 for protons. Integral Dose was 1.1 0.5 Gy*cm *10 for IMPT and about a factor three higher for all photon's techniques.
3 5 18

Conclusion RA and IMPT showed improvements in conformal avoidance relative to fixed beam IMRT for 7 patients with recurrent prostate cancer. IMPT showed further sparing of organs at risk.

Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger Cancer 2012:1 Bradford Hoppe, Romaine C. Nichols, Randal H. Henderson, et al.
Abstract BACKGROUND:

We evaluated patient-reported health-related quality of life following proton therapy for prostate cancer in 262 men 60 years old.

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METHODS:

Between August 2006 and January 2010, 262 hormone-naive men 60 years old were treated with definitive proton therapy for prostate cancer. Before treatment and every 6 months after treatment, patients filled out the Expanded Prostate Index Composite (EPIC) and the International Index of Erectile Function (IIEF) questionnaires. Potency was defined as successful sexual intercourse in the prior month or an EPIC sexual summary (SS) score 60.

RESULTS:

Median follow-up was 24 months; 90% of men completed follow-up EPIC forms within the last year. For EPIC urinary, bowel, and hormone subscales, the average decline from baseline to 2 years was 5 points, except for bowel function (5.2 points). SS scores declined 12.6 points after 2 years. Potency rates declined by 11% from baseline at 2 years, but 94% of men were potent with a baseline IIEF > 21, body mass index < 30, and no history of diabetes. At 2 years after treatment, only 1.8% of men required a pad for urge incontinence. On multivariate analysis, factors associated with a significant decline in SS score were mean penile bulb dose 40 cobalt Gy equivalents (P = .012) and radiation dose 80 cobalt Gy equivalents (P = .017); only diabetes was significantly associated with impotence (P = .015).

CONCLUSIONS:

Young men undergoing proton therapy for treatment of prostate cancer have excellent outcomes with respect to erectile dysfunction, urinary incontinence, and other health-related quality of life parameters during the first 2 years after treatment. Longer follow-up is needed to confirm these findings.

Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer Cancer 2011:3
Joe Y. Chang, Ritsuko Komaki, Charles Lu, et al.
BACKGROUND:

Standard therapy for stage III nonsmall cell lung cancer, concurrent chemoradiation therapy with photon (x-raybased) therapy, is associated with significant toxicity and produces suboptimal local control. The authors sought to improve the toxicity of conventional concurrent chemoradiation therapy for stage III nonsmall cell lung cancer (NSCLC) by using proton-beam therapy to escalate the radiation dose to the tumor. They report early results of a phase 2 study of high-dose proton therapy and concurrent chemotherapy in terms of toxicity, failure patterns, and survival.

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METHODS:

Forty-four patients with stage III NSCLC were treated with 74 grays (radiobiologic equivalent) proton therapy with weekly carboplatin (area under the curve, 2 U) and paclitaxel (50 mg/m ). Disease was staged with positron emission tomography/computed tomography (CT), and treatments were simulated with 4-dimensional (4D) CT to account for tumor motion. Protons were delivered as passively scattered beams, and treatment simulation was repeated during the treatment process to determine the need for adaptive replanning.
2

RESULTS:

Median follow-up time was 19.7 months (range, 6.1-44.4 months), and median overall survival time was 29.4 months. No patient experienced grade 4 or 5 proton-related adverse events. The most common nonhematologic grade 3 toxicities were dermatitis (n = 5), esophagitis (n = 5), and pneumonitis (n = 1). Nine (20.5%) patients experienced local disease recurrence, but only 4 (9.1%) had isolated local failure. Four (9.1%) patients had regional lymph node recurrence, but only 1 (2.3%) had isolated regional recurrence. Nineteen (43.2%) patients developed distant metastasis. The overall survival and progression-free survival rates were 86% and 63% at 1 year.

CONCLUSIONS:

Concurrent high-dose proton therapy and chemotherapy are well tolerated, and the median survival time of 29.4 months is encouraging for unresectable stage III NSCLC. The authors found that concurrent chemotherapy and high-dose proton beam therapy was less toxic than conventional photon-based treatments and produced a total local failure rate of 20.5%.

Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma Cancer 2011:3

Frank Ciernik, Andrzej Niemerko, David Harmon, et al.
BACKGROUND:

The cohort of Massachusetts General Hospital patients with inoperable or incompletely resectable osteosarcoma treated with proton or combined photon/proton therapy was reviewed. A study was undertaken to assess clinical outcome and the role of proton therapy for local control of osteosarcoma (OSA).

METHODS:

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All patients who received proton therapy or mixed photon-proton radiotherapy from 1983 to 2009 at the Massachusetts General Hospital were reviewed. Criteria for proton therapy were the need for high dose in the context of highly conformal radiotherapy of unresected or partially resected OSA, positive postoperative margins, postoperative imaging studies with macroscopic disease, or incomplete resection as defined by the surgeon. The primary endpoint was local control of the site treated; secondary endpoints were disease-free survival (DFS), overall survival (OS), long-term toxicity, and prognostic factors associated with clinical outcome.

RESULTS:

Fifty-five patients with a median age of 29 years (range, 2-76 years) were offered proton therapy. The mean dose was 68.4 gray (Gy; standard deviation, 5.4 Gy). Of the total dose, 58.2% (range, 11%-100%) was delivered with protons. Local control after 3 and 5 years was 82% and 72%, respectively. The distant failure rate was 26% after 3 and 5 years. The 5-year DFS was 65%, and the 5-year OS was 67%. The extent of surgical resection did not correlate with outcome. Risk factors for local failure were 2 grade disease (P < .0001) and total treatment length (P = .008). Grade 3 to 4 late toxicity was seen in 30.1 % of patients. One patient died from treatment-associated acute lymphocytic leukemia, and 1 from secondary carcinoma of the maxilla.

CONCLUSIONS:

Proton therapy to deliver high radiotherapy doses allows locally curative treatment for some patients with unresectable or incompletely resected OSA. Local control could be achieved in >70% of cases with acceptable toxicity in most patients.

Cardiac sparing with proton therapy in consolidative radiation therapy for Hodgkin lymphoma: Letter to the Editor Leukemia & Lymphoma, 2010; 51(8) 1559-1562
Bradford Hoppe, Stella Flampouri, Zuofeng Li, Nancy Mendenhall
Standard therapy for Hodgkin lymphoma (HL) with anthracycline-based chemotherapy and consolidative radiotherapy (RT) produces excellent cure rates. Unfortunately, cardiovascular toxicity is responsible for the majority of non-malignant early deaths in survivors of HL. We report the case of a patient with HL requiring consolidative mediastinal RT after a high total dose of adriamycin (575 mg/m2). Involved nodal irradiation was recommended, and treatment plans were generated using conventional radiation therapy and proton therapy. The proton therapy plan substantially reduced the radiation dose to the non-targeted cardiac tissue without increasing the radiation dose to other critical structures. In addition to reducing the radiation dose to the heart, proton therapy may offer other benefits as well, such as potential reductions in risk for breast cancer and other second malignancies and, in some patients, potential reduction in risk for acute radiation pneumonitis and late pulmonary effects.

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Proton versus photon radiotherapy for common pediatric brain tumors: Comparison of models of dose characteristics and their relationship to cognitive function Pediatric Blood and Cancer 2008(51)1, 110-117.
Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U.
Background To determine whether proton radiotherapy has clinical advantages over photon radiotherapy, we modeled the dose characteristics of both to critical normal tissue volumes using data from patients with four types of childhood brain tumors. Procedures Three-dimensional imaging and treatment planning data, including targeted tumor and normal tissues contours, were acquired for 40 patients, 10 each with optic pathway glioma (OPG), craniopharyngioma (CR), infratentorial ependymoma (EP), or medulloblastoma (MB). Dosevolume data were collected for the entire brain, temporal lobes, cochlea, and hypothalamus from each patient. The data were averaged and compared based on treatment modality (protons vs. photons) using dosecognitive effects models. Outcomes were estimated over 5 years. Results Relatively small critical normal tissue volumes such as the cochlea and hypothalamus may be spared from radiation exposure when not adjacent to the primary tumor volume. Larger normal tissue volumes such as the supratentorial brain or temporal lobes receive less of the low and intermediate doses. When applied to longitudinal models of radiation dose-cognitive effects, these differences resulted in clinically significant higher IQ scores for patients with MB and CR and academic reading scores in patients with OPG. Extreme differences between proton and photon dose distributions precluded meaningful comparison of protons and photons for patients with EP. Conclusions Differences in the overall dose distributions, as indicated by modeling changes in cognitive function, showed that a reduction in the lower-dose volumes or mean dose would have long-term, clinical advantages for children with MB, CR, and OPG.

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Other Uses for Proton Beam Therapy

Protons may have particular usefulness in certain situations that are not site-specific. These include: treatment of tumors in situations of substantial anatomic complexity, unusually larger tumors, pregnant patients, elderly or frail patients, and re-irradiation of recurrences. Re-irradiation of local recurrences of tumors after treatment is a growing indication for proton therapy. As PET/CT gains acceptance as the main imaging modality for follow-up of cancer patients, we will see growing numbers of patients with local recurrence of tumors. For many of these patients for whom maximum threshold doses to normal tissues have already been delivered, conventional radiation will not be a possible. The use of protons in such situations is very likely to be beneficial, but may not readily lend itself to test by clinical trial.

Lack of Evidence Based Medicine

The lack-of-evidence-based medicine (LEBM) for proton therapy is cited by skeptics as evidence against the use of proton therapy. But the lack of evidence on protons is not evidence of the lack of benefit from protons. True, a large body of RCTs comparing protons to photons does not exist. And those who require RCTs for proof of the benefits will certainly not be convinceduntil the day (G-d forbid) they need to choose a therapy for themselves. S.M. Bentzen made the following point in the Journal of Clinical Oncology, There is no evidence from randomized controlled trials demonstrating the clinical benefit from widely adopted port films, simulators, CT-based treatment planning, and mega-voltage radiotherapy. Think of the profound health economic consequences if we got rid of all these unproven technologies! By the way, there are also no phase III trial data showing the benefit from sharp versus dull scalpels for surgery.27 The absence of level I evidence has been a convenient excuse to do nothing. For example, until recently, in the United Kingdom the National Institute for Health and Clinical Excellence (NICE) has relied on LEBM to restrict access to proton therapy in the National Health Service (NHS). In 2008/2009 the NHS approved proton therapy abroad for 11 British citizens. In 2009/2010 the figure rose to 20, and in 2010/2011, 50 patients were approved.28 These experiences have obviously had positive results. In 2011 the NHS decided to fund the creation of two national proton therapy centers (Manchester and London), and has given approval for a third private center to be built.

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Skeptics
Interestingly, an internet article was located29 that reported on a conference presentation by a radiation oncologist from Cleveland Clinic who reviewed the U.S. National Cancer Institute Medicare records (1991-2007) of 137,000 men who received some form of therapy for prostate cancer, external beam radiation, prostatectomy, or brachytherapy. The article cites toxicity rates and cost comparisons, and concluded that brachytherapy was the best value for the money. Unsurprisingly, further investigation revealed that this clinician heads the brachytherapy department at Cleveland Clinic. The same article was picked up by another medical news reporting service which then proceeded to criticize the high cost of proton therapy. It is worth noting that Cleveland Clinics top local rival, University Hospitals Case Medical Center has recently announced plans to construct a $30 million proton beam center.30 In a similarly related article31, a researcher from University of North Carolina also questions the benefits of treating prostate with proton therapy, citing increased complications as compared to patients who underwent conventional therapy, but the majority of the story focuses on the cost of proton therapy. UNC is located within the catchment area of the brand new Hampton University Proton Center in Virginia.

Suggestions for Clinical Trials

Retrospective non-randomized clinical trials
Retrospective trials can be designed for any tumor type, population, or cancer staging. It is certainly feasible to data-mine historical medical records for comparisons and survival statistics. It is critical however that the complete medical record and specific endpoint data for the historical patient are available. This control data is vital to the accurate portrayal of any retrospective trial. Such data include: normal tissue injury as a function of dose received and tissue volume, secondary underlying medical indications that could have effect on patient outcome and survival, baseline function (both physiological and physical). It would be particularly important to compare the normal-tissuecomplications of tissues that received the low-medium doses typical of extraneous photon dose found in tissues outside the intended target volume.

Prospective non-randomized clinical trials

It could certainly be possible for a cooperative study to be performed between two distant centers, one with proton therapy available for their patients and the other without protons. A trial of this type could be subject to various forms of bias and would therefore need coordination in dose protocol, patient selection and staging, to ensure some compatibility in the two arms of the trials. Building a proton center takes about three years. A novel approach for conducting clinical trials, that would benefit the development of a national consortium model in Israel and could be the impetus for a nurturing a collaborative environment, would be to establish protocols now and begin collecting data on 41

currently treated patients during the few years it takes to plan, develop and build the Israel proton center. This data would be the control group to which proton patient statistics would be evaluated in the future. The financial aspects of the radiotherapy and the ongoing medical costs related to the remediation of side-effects should be tracked for each patient as well. This approach would be relatively easy and relatively free of bias.

Prospective randomized clinical trials

The ethical suitability of any randomized trial must be given serious consideration. As discussed earlier, a head-to-head randomized trial between protons and photons, where the target dose was maintained in the two arms of the trial, the difference being only in the modality, the superior dose distribution of the proton plan would be expected to offer significantly lower morbidity. In a dose escalation trial the proton plan would be expected to offer better tumor control, and probably still maintain lower overall integral body dose. The ethics of this comparison has already been discussed. It is possible however to design randomized trials that could be ethical and informational. Possibilities include 1) a trial that compares protons to some other form of non-radiotherapeutic modality, such as protons versus surgical resection of liver tumors, 2) hypofractionation vs. conventional fractionation with protons in both arms, 3) dose escalation studies comparing two or more different prescription target doses, 4) various combinations of protons and/or photons with concurrent chemotherapeutic agents and different dose levels. With the increased utilization of low-dose chest CT for routine screening of high-risk population (mostly heavy smokers) the survival of the people being screened compared to similar population who do not get screened is a very important development in the fight against lung cancer. At MD Anderson in Houston, Texas, a new protocol has been designed to use stereotactic proton therapy for the treatment of early-diagnosed NSCLC in patients who are not good surgical candidates. In Israel where the number of smokers is very high we may see more early diagnosed lung cancer. Several protocols exist in Israel for the treatment of NSCLC. Many of these patients might be candidates for stereotactic proton therapy in the future. This could make for a very worthwhile RCT.

Conclusion
A proton therapy institute in Israel offers a rich opportunity for both clinical service and clinical research. While we all agree there is a need for critical health technology assessment, we must also acknowledge the reality that the fundamental dose-volume-effects from irradiation of tumors and normal tissues are established beyond reasonable doubt. Non-randomized, observational studies should be considered evidentiary along with other controlled trials of treatment outcome. By the time the medical profession has established the required evidence on clinical performance, the technology has developed further and we are left with todays evidence on yesterdays technology. To make progress, we need to move beyond the fixation on RCTs and get on with the business of designing, funding, and conducting largescale clinical studies using ethically defensible methodologies that would have the broad acceptance of 42

our patients. In the final analysis however, we need to provide the best possible care for the patient in front of us, even in the current absence of level I evidence. The chart below, based on data from the Particle Therapy Co-Operative Group website, indicates the acceptance and trend in development of proton therapy centers worldwide.32

70 60

Worldwide Particle Therapy Centers

Centers in Clinical Operation

50 40 30 20 10 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020

In Clinical Operation Scheduled to Open

Year

Of course it really is all about money. In the US, proponents of proton therapy frame the argument this way, Can anyone seriously believe that, if protons were cheaper than photons, there would such objection to their widespread use? Although we can understand the desire to rely on RCTs to establish the advantage of a superior therapy, we find it totally unacceptable to insist on unethical RCTs in order to establish the financial cost-effectiveness of an admittedly better technologynor would patients, if fully informed, consent to participate in such studies.33 Could anyone have even imagined that in Israel we would face the same argument even when the cost of protons and photons is the same?

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