Review Clinical Studies, News and Opinions on the Clinical Efficacy of Proton Therapy

Note about interpreting these references: Radiance 330 employs scanning proton beam technology. Almost all of the clinical studies referenced below were performed with scattered proton beams. Outcomes of cancer cases treated with scattered beams are very good; however, many expect the clinical benefits of proton therapy to be much more pronounced with scanning beams – a technology that is less mature in clinical practice – and these studies are just getting started. Scattered beam studies are not necessarily indicative of the results expected with scanned beams.

1. Foote RL, et al. The clinical case for proton beam therapy. Radiation Oncology 2012, 7:174 The Mayo Clinic reviews the clinical case for proton beam therapy and concludes “proton beam therapy is a technically advanced and promising form of radiation therapy”.


2. Chung CS, et al. “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) Supplement S8.

The authors matched a retrospective cohort study of 1,450 patients treated with proton radiation therapy from 1974-2001 at the Harvard Cyclotron and patients treated with photon therapy in the SEER cancer registry. Patients were matched by age at radiation treatment, year of treatment, cancer histology, and site of treatment. 6.4% of proton patients (32 patients) developed a second malignancy, while 12.8% of photon patients (203 patients) developed a second malignancy. 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).


3.  Ronson, BB, et al., Fractionated proton beam irradiation of pituitary adenomas. Int. J. Radiat. Oncol. Biol. Phys. (2006) 64:425–434. 3/abstract
Fractionated conformal proton-beam irradiation achieved effective radiologic, endocrinological, and symptomatic control of pituitary adenomas.

4.  Mizumoto, M., et al., Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 77, 98–105. 

This group demonstrated excellent median (21.6 months) and overall (@ 1 and 2 years were 71.1% and 45.3%) survival rates compared to historical controls.

5. Weber DC, et al., Spot-scanning based Proton Therapy for Intracranial Meningioma: Long-term Results from the Paul Scherrer Institute.  (2012) 83(3):865-71. 

Five-year actuarial local control and overall survival rates were 84.8% and 81.8%, respectively, for the entire cohort and 100% for benign histology. Cumulative 5-year Grade ≥3 late toxicity-free survival was 84.5%.  The authors concluded that proton therapy is a safe and effective treatment for patients with untreated, recurrent, or incompletely resected intracranial meningiomas.

6.  Ramaekers, B. L., et al., Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons. Cancer Treat. Rev. (2011) 37, 185–201. 

Authors demonstrate improved local control and survival for paranasal and sinonasal cancers with use of proton therapy compared to IMRT; toxicity tends to be lower for proton compared to IMRT.

7. Patel SH, et al., Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis.  The Lancet Oncology (2014) 15/9:1027-1038. 

Compared with photon therapy, the authors conclude, charged particle therapy could be associated with better outcomes for patients with malignant diseases of the nasal cavity and paranasal sinuses.

8. Ares C, et al., 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.

The authors report local control rates at 5 years of 81% (chordomas) and 94% (chondrosarcomas), with 94% rate of freedom from high-grade toxicity.

9. Miralbell R, et al., Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors, Int J Radiat Oncol Biol Phys. 2002:54(3):824-829

The potential for a significant reduction in secondary cancers with pediatric cancers due to improved dose distributions using proton beams in the treatment of RMS and MBD in children and adolescents represents an additional argument supporting the development of proton therapy for most radiotherapy indications in pediatric oncology.

10. Merchant TE, et al., Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function.  Pediatr. Blood Cancer (2008) 51, 110–117.

Authors demonstrated through dose–cognitive effects models that reduction in integral radiation dose to the pediatric brain could be expected to translate to reduction in IQ deficit long recognized to result from radiation for childhood brain tumors.

11. St Clair WH, et al., Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys. 58, 727–734.

Protons found to be superior to conventional X-ray and IMRT, with improved sparing of cochlea, pituitary, and heart.

12. Rombi B, et al., Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical outcomes. Int. J. Radiat. Oncol. Biol. Phys (2013) 82(3):1142-8. 

Authors report the preliminary clinical outcomes including late effects on 30 pediatric Ewing’s sarcoma patients treated at Massachusetts General Hospital. The chief advantage of protons in this setting is to reduce acute and late toxicities by decreasing the amount of normal tissue irradiated. The authors conclude that 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.

13. Moteabbed M, Yock TI, et al, The risk of radiation-induced second cancers in the high to medium dose region: a comparison between passive and scanned proton therapy, IMRT and VMAT for pediatric patients with brain tumors.  Phys. Med. Biol. (2014) 59 2883.

Today, around 80% of paediatric cancer patients survive long term, spurring concern over adverse radiotherapy-related late effects.  In this study, the authors quantified the risks of young patients developing secondary tumours in the vicinity of the primary radiation field (in this case, the skull and cranial soft tissues), where most second cancers occur.  Analysis of dose-volume histograms (DVHs) showed that in general, protons irradiated smaller volumes of healthy tissue than IMRT and VMAT.

14. Mailhot Vega RB, et al., Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma.  Cancer (2013) 119(24):4299-307.

By using current risk estimates and data on required capital investments, the current study indicated that proton therapy is a cost-effective strategy for the management of pediatric patients with medulloblastoma compared with standard of care photon therapy.   Results from the base case demonstrated that proton therapy was associated with higher quality-adjusted life years and lower costs; therefore, it dominated photon therapy. In 1-way sensitivity analyses, proton therapy remained the more attractive strategy, either dominating photon therapy or having a very low cost per quality-adjust life year gained. Probabilistic sensitivity analysis illustrated the domination of proton therapy over photon therapy in 96.4% of simulations.

15. MacDonald SM, et al., Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons.  Int J Radiat Oncol Biol Phys (2008) 71(4):979-86.

The authors 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. 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.

16. Moran BJ, et al., ACR Appropriateness Criteria® definitive external beam irradiation in stage T1 and T2 prostate cancer, Am J Clin Oncol, 2011. 34(6): p. 636-44.

The ACR expert panel examined available peer-reviewed literature on this topic and concluded that proton beam therapy is equally appropriate and beneficial to intensity-modulated radiation therapy (IMRT), 3-dimensional conformal X-ray therapy and brachytherapy in the treatment of Stage T1 and T2 prostate cancer.

17. Slater JD, Rossi CJ Jr, Yonemoto LT, et al., Proton therapy for prostate cancer: the initial Loma Linda University experience, Int J Radiat Oncol Biol Phys, 2004. 59:348-352.

Outcomes analyses on 1255 patients treated between October 1991 and December 1997 were performed primarily on biochemical relapse and toxicity. Conformal proton radiation therapy at the reported dose levels yielded disease free survival rates comparable with other forms of local therapy, and with minimal morbidity.

18. Coen JJ, et al.,  Comparison of High-Dose Proton Radiotherapy and Brachytherapy in Localized Prostate Cancer: A Case-Matched Analysis, Int J Radiat Oncol Biol Phys, 2012. 82(1):e25-e31

No difference in BFFS was demonstrated between the two groups; however, the authors note that no quality of life analysis was possible, and that brachytherapy has historically been associated with increase in obstructive voiding symptoms compared to external beam radiation (Chen et al., 2009).

19. Zeitman AL, et al., Randomized Trial Comparing Conventional-Dose With High-Dose Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term Results From Proton Radiation Oncology Group/American College of Radiology 95-09, JCO March 1, 2010 vol. 28 no. 7 1106-1111

The authors demonstrated a 49% reduction in BFFS with the use of dose escalation with only a 1% associated increase in acute or late urinary or rectal toxicity. No increase in patient-reported symptoms in the high-dose arm compared to the lower dose arm was reported in a separate quality of life analysis (Talcott JA, et al., JAMA. 2010;303(11):1046-1053.)

20. Nihei K, Ogino T, Onozawa M, et al. Multi-institutional phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities. Int J Radiat Oncol Biol Phys, 2011 Oct 1;81(2):390-6

A multi-institutional phase II study from Japan with a median follow-up of 43 months reported only 1% of patients developed grade > 3 GU toxicity, and 0% developed late grade > 3 GI toxicity.

21. Fontenot JD, Lee AK, Newhauser WD. Risk of secondary malignant neoplasms from proton therapy and intensity-modulated X-ray therapy for early-stage prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74:616-22.

An evaluation of the risk of secondary malignancies with IMRT compared with PT in patients with early-stage prostate cancer has shown that PT should reduce the risk of secondary malignancies by 26% to 39% compared with IMRT.

22. Gray, PJ, et al., Patient-reported Quality of Life in Prostate Cancer Patients Treated With 3D Conformal Intensity Modulated or Proton Beam Radiation Therapy.  Int J Radiat Oncol Biol Phys. 2012:84(3):S13.

Proton beam therapy appeared to be associated with better early bowel quality of life compared to 3D-CRT and IMRT.

23. Talcott JA, et al., Patient-Reported Long-term Outcomes After Conventional and High-Dose Combined Proton and Photon Radiation for Early Prostate Cancer.  Journal of the American Medical Association (2010) Vol. 303, No. 11.

Increased radiation doses improve prostate cancer control but also increase toxicity to adjacent normal tissue. The authors performed a post hoc cross-sectional survey of surviving participants in the Proton Radiation Oncology Group (PROG) 9509-a randomized trial comparing 70.2 Gy vs 79.2 Gy of combined photon and proton radiation for 393 men with clinically localized prostate cancer, with an objective to determine long-term, patient-reported, dose-related toxicity.  It is possible that proton radiation may attenuate adverse effects.  Among men with clinically localized prostate cancer, treatment with higher-dose radiation compared with standard dose was not associated with an increase in patient-reported prostate cancer symptoms after a median of 9.4 years.

24. Mendenhall NP, et al., Five-Year Outcomes from 3 Prospective Trials of Image-Guided Proton Therapy for Prostate Cancer.  Int J Radiat Oncol Biol Phys, (2014) 88:596 – 602

Proton therapy (PT) for low-, intermediate-, and high-risk prostate cancer patients is highly effective, minimally toxic, and associated with excellent patient-reported outcomes. PT compares favorably with other contemporary radiation modalities used in treating prostate cancer.

25. Colaco, RJ, et al., Rectal Toxicity After Proton Therapy For Prostate Cancer: An Analysis of Outcomes of Prospective Studies Conducted at the University of Florida Proton Therapy Institute.  Int J Radiat Oncol Biol Phys, (2014) [Article in Press – Published Online: November 05, 2014]

This study presents the largest prospective assessment of rectal toxicity to date in cases of localized prostate cancer treated solely with proton therapy (PT). A total of 1285 consecutive patients were treated with PT between August 2006 and May 2010.  Our results demonstrate that the most frequent physician-reported toxicity in prostate cancer treated with PT is transient rectal bleeding (RB). Our data show low rates of Grade 2 and Grade 3 RB (14.5% and 0.9%, respectively) compared with some previously reported 3-dimensional conformal RT (3DCRT) and IMRT and dose-escalated studies.

26. Harris E, et al., Late Cardiac Mortality and Morbidity in Early-Stage Breast Cancer Patients After Breast-Conservation Treatment.  JCO 24(25):4100-4106

Irradiation to the left breast is associated with an increased rate of diagnoses of coronary artery disease and myocardial infarction compared with right breast treatment.  [See also:

Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer]

27. Nilsson G, et al., Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer.  JCO 30(4):380-386

An increase of stenosis in mdLAD + dD in irradiated left-sided BC and an association between high-risk RT and stenosis in hotspot areas for radiation indicate a direct link between radiation and location of coronary stenoses.

Note:  The two investigations above have resulted in a new study, BRE008-12, “Proton Radiation for Stage III Breast Cancer” (NCT01758445).

This study specifically includes longitudinal follow up to assess the incidence of cardiac mortality and second malignant neoplasms at 10 and 15 years following proton therapy for complex irradiation in women with loco-regionally advanced breast cancer.

28. Bush DA, et al., Partial Breast Radiation Therapy With Proton Beam: 5-Year Results With Cosmetic Outcomes.  Int. J. Radiat. Oncol. Biol. Phys. (Published Online: July 30, 2014).

Authors demonstrated that proton beam therapy for PBI produced excellent ipsilateral breast recurrence-free survival with minimal toxicity.  Cosmetic results may be improved over those reported with photon-based techniques due to reduced breast tissue exposure with proton beam, skin-sparing techniques, and the dose fractionation schedule used in this trial.

29. Chang JY, et al., Phase II trial of proton beam accelerated partial breast irradiation in breast cancer. Radiotherapy and Oncology: Journal of the ESTRO (2013) S0167-8140(13)00284-3.

The authors concluded that proton beam accelerated partial breast irradiation (PB-APBI) consisting of 30 CGE in six CGE fractions once daily for five consecutive days can be delivered with excellent disease control and tolerable skin toxicity to properly selected patients with early-stage breast cancer; multiple-field PB-APBI may achieve a high rate of good-to-excellent cosmetic outcomes, and additional clinical trials with larger patient groups are needed.

30. MacDonald SM, et al., Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial.  Int. J. Radiat. Oncol. Biol. Phys. (2013) 86(3):484-90.  It is well established that postmastectomy radiation therapy (PMRT) improves disease-free survival and overall survival for locally advanced breast cancer. The challenge of delivering PMRT, especially for patients with left-sided disease, is to achieve a homogeneous therapeutic dose to target volumes while sparing healthy uninvolved tissues such as the heart and lungs. Standard external beam RT (EBRT) to the chest wall and regional lymphatics carries risks of cardiopulmonary toxicities, including radiation pneumonitis, pericardial disease, congestive heart failure, and coronary atherosclerosis.  The authors conclude that proton therapy for PMRT is feasible and well tolerated. This treatment may be warranted for selected patients with unfavorable cardiac anatomy, immediate reconstruction, or both that otherwise limits optimal RT delivery using standard methods.

31. Bush DA, et al., Partial breast irradiation delivered with proton beam: results of a phase II trial. Clinical Breast Cancer (2011) 11 (4): 241-5.

Proton partial breast radiotherapy appeared to be a feasible method of treatment and provided excellent disease control within the ipsilateral breast. Dose-volume histogram analysis showed near-complete elimination of dose to the contralateral breast, lung, and heart; treatment-related toxicity was minimal. The incidence of post-treatment complications may be less than that reported when using more invasive techniques; comparative trials should be considered.

32. Xu, Natalie, et al., Can Proton Therapy Improve the Therapeutic Ratio in Breast Cancer Patients at Risk for Nodal Disease?  American Journal Clinical Oncology (2014) 37(6): 568-574.

Regional node irradiation in patients with invasive breast cancer often results in increased radiation exposure to organs at risk. We evaluated the potential advantages of 3-dimensional conformal photon+proton therapy (3DCX+PT) in treating regional nodes versus photon-electron (3DCRT) or intensity-modulated radiotherapy (IMRT).  Ten left-sided breast cancer patients underwent radiation treatment planning. 3DCX+PT, 3DCRT, and IMRT plans were generated for each patient.  Regional node target coverage was inferior with 3DCRT compared with either IMRT or 3DCX+PT. Organs at risk were exposed to less radiation with 3DCX+PT compared with 3DCRT or IMRT. Proton treatment offered both improved coverage of the regional lymph nodes and decreased dose to the heart, lung, and contralateral normal tissue.

33. Nakayama H, et al., Proton beam therapy for patients with medically inoperable stage I non-small cell lung cancer at the University of Tsukuba. Int. J. Radiat. Oncol. Biol. Phys. 78, 467–471.

Hypofractionated, dose escalated, proton beam therapy was effective – resulting in rates of overall and progression-free survival of all patients and of local control of all tumors at 2 years of 97.8%, 88.7% , and 97.0%, respectively.  Treatment was well-tolerated:  two patients (3.6%) had deterioration in pulmonary function, and 2 patients (3.6%) had Grade 3 pneumonitis.

34. Grutters JPC, et al., Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother. Oncol. 95, 32–40.

In the treatment of stage I NSCLC, 5 year overall survival was 20% after conventional photon radiotherapy compared to 40–42% after proton therapy, carbon ion therapy, or stereotactic body irradiation.

35. Bush DA, Cheek G, Zaheer S, et al. High-dose hypofractionated proton beam radiation therapy is safe and effective for central and peripheral early-stage non-small cell lung cancer: results of a 12-year experience at Loma Linda University Medical Center. Int J Radiat Oncol Biol Phys 2013;86:964-8.  High-dose hypofractionated proton therapy achieves excellent outcomes for lung carcinomas that are peripherally or centrally located.

36. Gomez DR, Chang JY, Accelerated dose escalation with proton beam therapy for non-small cell lung cancer.  J Thorac Dis. 2014; 6(4): 348–355  Leading to further study:

The feasibility of hypofractionated dose-escalated PBT for NSCLC has been demonstrated by several groups at a variety of institutions. The evidence is stronger for early-stage disease, as more studies have focused solely on PBT. Dosimetric analyses have shown a benefit for PBT over 3D-CRT or IMRT in select cases, and this advantage can reasonably be extrapolated to the hypofractionated context.

37. Berman AT, et al., An in-silico comparison of proton beam and IMRT for postoperative radiotherapy in completely resected stage IIIA non-small cell lung cancer.  Radiation Oncology 2013, 8:144.   Intensity modulated proton therapy demonstrates a large decrease in dose to all organs at risk. Passively-scattered proton therapy, while reducing the low-dose lung bath, increases the volume of lung receiving high dose. Reductions are seen in dosimetric parameters predictive of radiation pneumonitis and cardiac morbidity and mortality. This reduction may correlate with a decrease in dose-limiting toxicity and improve the therapeutic ratio.

38. Hoppe BS, et al., Double-scattered proton-based stereotactic body radiotherapy for stage I lung cancer: a dosimetric comparison with photon-based stereotactic body radiotherapy.  Radiother Oncol. (2010) 97(3):425-30.  In a dosimetric comparison between photon and proton-based SBRT, protons resulted in lower doses to critical organs at risk and a smaller volume of non-targeted normal lung exposed to radiation.

39. Gomez D, et al., Predictors of high-grade esophagitis after definitive three- dimensional conformal therapy, intensity-modulated radiation therapy, or proton beam therapy for non-small cell lung cancer.  Int J Radiat Oncol  Biol Phys (2012) 84(4):1010-6

652 patients were treated: 405 with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade ≥3 radiotherapy-induced esophagitis (RE) were 8%, 28%, and 6%.  This risk of severe RE is underestimated by the authors’ model in patients receiving IMRT.

40. Westover KD, et al., Proton SBRT for medically inoperable stage I NSCLC.  Journal of Thoracic Oncology (2012) 7(6):1021-5  Fifteen consecutive patients with medically inoperable stage I NSCLC and 20 tumors were treated with proton SBRT to 42-50 Gy(RBE) in 3-5 fractions.  The authors conclude that proton SBRT is effective and well tolerated in this unfavorable group of patients, and that prospective clinical trials testing the utility of proton SBRT in stage I NSCLC are warranted.

41. Koay EJ, et al. Adaptive/Nonadaptive Proton Radiation Planning and Outcomes in a Phase II Trial for Locally Advanced Non-small Cell Lung Cancer.  Int J Radiat Oncol Biol Phys. (2012) 84(5):1093–1100.  

Adaptive planning can reduce normal tissue doses and prevent target misses, particularly for patients with large tumors that shrink substantially during therapy.  Adaptive planning generally improved sparing of the esophagus (median absolute decrease in V70, 1.8%; range, 0–22.9%) and spinal cord (median absolute change in maximum dose, 3.7 Gy; range, 0–13.8 Gy).  Adaptive plans seem to have acceptable toxicity and achieve similar local, regional, and distant control and overall survival, even in patients with larger tumors, versus non-adaptive plans.

42. Chang JY, et al., Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer.  The Oncologist (2011) 117(20):4707-13.  The authors sought to improve the toxicity of conventional concurrent chemoradiation therapy for stage III non-small cell lung cancer (NSCLC) by using proton-beam therapy to escalate the radiation dose to the tumor, and in this paper report early results of a phase II study of high-dose proton therapy and concurrent chemotherapy in terms of toxicity, failure patterns, and survival.  The authors conclude that concurrent high-dose proton and chemotherapy is well tolerated, and the median survival time of 29.4 months is encouraging for unresectable stage III NSCLC.

43. Sejpal S, et al., Early findings on toxicity of proton beam therapy with concurrent chemotherapy for non small cell lung cancer.  Cancer (2011)1; 117(13):3004-13.

Concurrent chemoradiation therapy, the standard of care for locally advanced nonsmall cell lung cancer (NSCLC), can cause life-threatening pneumonitis and esophagitis. X-ray based radiation therapy often cannot be given at tumoricidal doses without toxicity to proximal normal tissues. The authors hypothesized that proton beam therapy for most patients with NSCLC could permit higher tumor doses with less normal-tissue toxicity than 3D-CRT or IMRT.  The authors conclude that higher doses of proton radiation could be delivered to lung tumors with a lower risk of esophagitis and pneumonitis; a randomized comparison of IMRT versus proton therapy is underway.

44. Li J, et al., Rationale for and preliminary results of proton beam therapy for mediastinal lymphoma. Int J Radiat Oncol  Biol Phys 2011;81:167-174.

Proton therapy produced significantly lower doses to the lung, esophagus, heart, and coronary arteries than did conventional X-ray therapy. These lower doses would be expected to reduce the risk of late toxicities in these major organs.

45. Oeffinger, KC, et al., Chronic Health Conditions in Adult Survivors of Childhood Cancer.  N Engl J Med 2006; 355:1572-1582.

Hodgkin Lymphoma survivors are at highest risk of second malignancies and heart disease due to low doses of radiation in normal tissues.

46. Hoppe BS, et al., Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study.  Int. J. Radiat. Oncol. Biol. Phys. (2014) 89:1053–1059.

The phase II study showed that the use of proton therapy after chemotherapy in such patients has a similar success rate to the conventional treatments, with reduced radiation dose outside of the target area, potentially reducing the risk of radiation-induced late effects.

47. Bush DA, et al., The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial.  Cancer (2011); 117(13):3053-9.

Previous radiation techniques that could not limit the dose delivered to functional parts of the liver have caused a high incidence of radiation induced liver disease.  Proton radiotherapy differs from photon-based treatments in that low and moderate doses delivered to the untargeted portion of the liver are substantially decreased. The authors conclude that proton therapy delivered using the methods outlined in this study is well tolerated in terms of development of liver dysfunction due to treatment.

48. Fukumitsu N, et al., A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma.  Int J Radiat Oncol Biol Phys. (2009) 74(3):831-6.  The authors sought to evaluate the efficacy and safety of hypofractionated proton beam therapy for 51 patients with hepatocellular carcinoma (HCC).  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.  Patients experienced only minor acute reactions of Grade 1 or less, and 3 patients experienced late sequelae of Grade 2 or higher.  The authors concluded that the treatment 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.  It is also noted that the excellent conformality of proton radiotherapy offers the possibility of retreatment if new HCCs arise within the liver further away from the originally treated HCC.

49. Nichols, RC Jr, et al., Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity.  Acta Oncol. 2013 52(3):498-505.

Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification*, and possibly increased acceptance of preoperative radiotherapy for patients with resectable or marginally resectable disease.  (* important since currently, the majority of pancreatic cancer patients will ultimately have metastases and succumb to distant disease)

50. Ling, TC, et al., Analysis of Intensity-Modulated Radiation Therapy (IMRT), Proton and 3D Conformal Radiotherapy (3D-CRT) for Reducing Perioperative Cardiopulmonary Complications in Esophageal Cancer Patients.  Cancers 2014, 6(4); 2356-2368.

While neoadjuvant concurrent chemoradiotherapy has improved outcomes for esophageal cancer patients, surgical complication rates remain high. The most frequent perioperative complications after trimodality therapy were cardiopulmonary in nature. The radiation modality utilized can be a strong mitigating factor of perioperative complications given the location of the esophagus and its proximity to the heart and lungs. Comparing the three modalities, proton plans delivered lower heart doses compared to both the IMRT and 3D-CRT plans. The proton plans also resulted in less lung dose in comparison to the IMRT plans. The data suggests that proton radiotherapy may help improve the therapeutic ratio for patients receiving radiotherapy during multimodality esophageal cancer treatment.

51. Gragoudas ES, et al., Uveal melanoma: proton beam irradiation.  Ophthalmol Clin North Am. (2005)18(1):111-8

Over the past two decades, radiotherapy has replaced enucleation as the standard treatment for uveal melanoma. Although this method does not alter survival, preservation of the globe and, in some instances, visual function, is achieved. This article presents the authors’ and other investigators’ experience with proton therapy.

52. Due to normal tissue toxicity resulting from primary tumor irradiation with X-rays, retreatment with X-rays is rarely possible.  However, the lower toxicity profile of protons may offer new hope for some previously treated cancer patients.  Three institutions are conducting a study involving adults with non-CNS recurrent tumors who have been previously irradiated and have a tumor recurrence in or near prior radiation fields.  
53.  Chen CC, et al., Proton radiosurgery in neurosurgery.  Neurosurg. Focus 23, E5 (2007).  In this review, the authors will discuss the fundamental principles underlying photon- and proton-based stereotactic radiosurgery (SRS). The clinical efficacy of proton-based SRS in the treatment of arteriovenous malformations, vestibular schwannomas, and pituitary adenomas is reviewed.

54.  Zambarakji HJ, et al.,  Proton Beam Irradiation for Neovascular Age-Related Macular Degeneration.  Ophthalmology , Volume 113 , Issue 11 , 2012 – 2019

Proton radiation may be useful as an adjuvant therapy or as an alternative for patients who decline or are not appropriate for approved therapies.

55.  DeLaney, TJ, et al., 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.  High dose photon/proton radiation with resection or following only biopsy controls a high proportion of spine/paraspinal tumors. The 78% five-year actuarial local control (LC) figure is better than that achievable with lower radiation doses delivered with conventional photon techniques. Of particular interest is the extremely high LC in 34/36 (94%) primary tumors and 23/23 (100%) primary chordomas.
56.  Ciernik IF, et al., Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma.  Cancer (2011) 117(19):4522-30.

A study was undertaken to assess clinical outcome and the role of proton therapy for local control of osteosarcoma (OSA).  All patients who received proton therapy or mixed photon-proton radiotherapy from 1983 to 2009 at the Massachusetts General Hospital were reviewed.  The authors note that the current use of RT for OSA follows the concept that high doses of ionizing radiation may add to local control, as has been the case in the treatment of sarcomas in general, when wide surgical margins cannot be achieved.  Authors note that the reduction in integral radiation dose is likely to be of most importance to the young patient with a large tumor such as patients with pelvic disease.  The study concludes that proton therapy to deliver high radiotherapy doses allows locally curative treatment for some patients with unresectable or incompletely resected OSA.