Proton therapy: the current status of the clinical evidences – by Dongryul Oh

Precision and Future Medicine 2019

Proton Therapy Clinical Evidences – Dongryul Oh

The dosimetric advantages of proton therapy—compared with photon therapy—have been clearly defined in many comparison studies involving various tumor sites. There are now accumulating clinical data demonstrating that this dosimetric advantage can lead to better outcomes such as reduced RT toxicity and improved treatment outcomes. 

Pediatric Tumors

RT has an important role in treating pediatric tumors including central nervous system (CNS) tumors, extra-cranial sarcomas, neuroblastoma, and hematopoietic tumors. Long-term toxicities, including secondary malignancies, neurocognitive dysfunctions, growth and musculoskeletal problems, and cardiac problems, are major concerns in pediatric patients who undergo RT. There have been many efforts to reduce the RT dose and volume to avoid these RT-related toxicities.

Proton therapy is one of the best options to reduce unnecessary irradiation dose and volume in pediatric patients.

More than 30 pediatric tumor types were treated, mainly with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors

Head and Neck Tumors

Retrospective data have demonstrated better local control (LC) and overall survival (OS) with proton therapy than with photon therapy including IMRT and stereotactic body radiation therapy (SBRT).

Proton therapy has also demonstrated better survival rates in nasal cavity and paranasal sinus tumors.

In oropharyngeal cancers, proton therapy can reduce toxicity to normal tissues.

Proton therapy can also reduce toxicities in unilateral irradiation, such as in cases involving major salivary gland tumor and oral cavity cancers, because the exit dose of the proton beam is essentially negligible

CNS tumors

Cognitive impairment has been one of major concerns following RT for CNS tumors. Proton therapy has a potential benefit to reduce the irradiated dose to normal brain tissue to prevent cognitive dysfunction. In addition, a dose escalation could be possible in radioresistant brain tumors such as high-grade gliomas.

Gastrointestinal tumors

Proton therapy can spare the surrounding normal tissues when it is used to treat gastrointestinal tumors. In the management of hepatocellular carcinoma (HCC), it is very important to spare liver function. Because the liver is an organ with parallel functional subunit in the model of radiation response of normal tissues, liver toxicity is more sensitive to irradiated volume. Proton therapy has a major advantage in reducing the irradiated volume of remnant liver when irradiating the tumor. In many retrospective trials, proton therapy resulted in favorable outcomes.


Proton therapy has the advantage of irradiating the target while reducing the dose to the surrounding normal tissues; thus, it has a potential benefit in re-irradiation. Many retrospective studies investigating re-irradiation in various tumor sites have been reported.

Non-Small Cell Lung Cancer

Low-dose shower is a major risk for radiation pneumonitis (RP) when treating non-small cell lung cancer (NSCLC) with photon therapy. If the lateral beam placement is avoided to reduce the lung dose, the irradiated dose to heart is consequently increased and results in increased cardiac death in long-term follow-up. In many dosimetric studies, proton therapy demonstrated advantages in lung and heart dose compared with photon therapy. Several clinical studies have reported treatment outcomes and toxicities of proton therapy in early-stage disease, locally advanced disease, re-irradiation, and in postoperative settings 

Indications for Proton Therapy

American Society for Radiation Oncology (ASTRO)  has updated the recommendations for insurance coverage. The ASTRO recommendation is based on four selection criteria:

  1. a decrease in dose inhomogeneity in a large treatment volume is required to avoid an excessive dose “hotspot” within the treated volume to lessen the risk for excessive early or late normal tissue toxicity;
  2. the target volume is in close proximity to ≥1 critical structure(s), and a steep dose gradient outside the target must be achieved to avoid exceeding the tolerance dose to the critical structure(s);
  3. a photon-based technique would increase the probability of clinically meaningful normal tissue toxicity by exceeding an integral dose-based metric associated with toxicity;
  4. and, finally, the same or an immediately adjacent area has been previously irradiated, and the dose distribution in the patient must be carefully modelled to avoid exceeding the cumulative tolerance dose to nearby normal tissues.

Based on the above medical necessity requirements and published clinical data, group 1, which is recommended coverage is listed as follows:

  • ocular tumors, including intraocular melanomas;
  • skull base tumors, primary or metastatic tumors of the spine, where spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated;
  • hepatocellular cancer;
  • pediatric tumors;
  • patients with genetic syndromes making total volume of radiation minimization crucial;
  • malignant and benign primary CNS tumors;
  • advanced and/or unresectable H&N cancers;
  • the paranasal sinuses and other accessory sinuses cancers;
  • non-metastatic retroperitoneal sarcomas;
  • and cases requiring re-irradiation.

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Advantage of proton-radiotherapy for pediatric patients and adolescents with Hodgkin’s disease

a Areas in which the VMAT / IMRT plans will deliver more dose to organs at risk or the body compartment. b Areas in which the proton plan delivers more dose to organs at risk or the body compartment compared to the VMAT / IMRT plant

“Proton therapy for mediastinal lymphoma reduces significantly the dose to organs at risk and the integral body dose. It might lead to reduced late toxicities and secondary malignancies. This is especially important for children and young adults. It should be considered for both sexes, as both male and female patients benefit from the unique features of particle irradiation. Whenever proton for mediastinal lymphoma is not available or technical not feasible the alternative photon concepts have to be chosen carefully. Depending on the used technique certain organs at risk, i.e. the breasts in young females, can be spared with higher priority. However, with all photon techniques that comes at the cost of higher doses to the other organs at risk. If available, proton therapy should be the standard pattern of care for mediastinal lymphoma for young adults below 30 years of age, no matter if male or female.”

S. Lautenschlaeger, G. Iancu, V. Flatten, K. Baumann, M. Thiemer, C. Dumke, K. Zink, H. Hauswald, D. Vordermark, C. Mauz-Körholz, R. Engenhart-Cabillic & F. Eberle
Radiation Oncology volume 14, Article number: 157 (2019)

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Montefiore Study May Help Establish Patient Criteria for Proton Therapy

N. Patrik Brodin, PhD

Data supporting the efficacy of proton therapy are robust for pediatric cancers, brain and base-of-skull tumors, and complex-shaped tumors near critical structures (…)

Proton therapy has emerged as an attractive option for patients with head and neck cancer. This is due to proton therapy beam technology, which precisely destroys cancers with an unmatched ability to stop at precise locations within the body.

Protons also have significantly fewer adverse effects (AEs) and toxicities than most other cancer therapies, because of the protons’ unique ability to sculpt radiation doses according to the shapes and sizes of tumors. This is particularly important for head and neck cancers, which frequently are close to or impeding on vocal cords, air passageways, swallowing muscles, salivary glands, and the oral mucosa. The opportunity to preserve healthy tissue is considerable.

AEs estimated to be significantly less prominent include swallowing difficulties, inflammation of the esophagus, and reduced saliva production. For people suffering from head and neck cancer and their families, the ability to avoid these types of complications makes an overwhelmingly important difference in QoL.

Younger patients, non-smokers, and patients with HPV p16- positive tumors will most likely benefit from proton therapy (…)

The highest expense in cancer therapy involves the regrowth of cancer—large sums are required to prolong survival and maintain QoL. By increasing cure rates and improving patients’ QoL, we can increase cost-effectiveness.

It is important for healthcare providers not only to educate our patients and their families about each treatment’s ability to destroy cancers, but also to manage expectations about different treatments and what life may look like “post cancer.”

Proton therapy is one of the most modern therapies available, and its ability to minimize AEs such as trouble swallowing, reduced ability to eat, dental problems, and difficulty digesting food can’t be understated for some of our patients (…) By increasing cure rates and improving patients’ Quality of Life, we can increase cost-effectiveness.

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Dosimetric studies show that proton therapy can reduce the low/intermediate radiation dose to uninvolved tissue in children with low-grade glioma (LGG).

Outcomes Following Proton Therapy for Pediatric Low-Grade Glioma Indelicato, Daniel J. et al. International Journal of Radiation Oncology • Biology • Physics , Volume 104 , Issue 1 , 149 – 156.

Low-grade gliomas (LGGs) are the most common brain tumors in children, with approximately 800 cases diagnosed each year in the United States. Management of these tumors depends on several elements, including host factors (eg, patient age and comorbidities) and disease characteristics (eg, tumor location and histologic subtype). With a long-term survival rate that exceeds 90%, therapy selection involves careful consideration of minimizing late toxicity from surgery, chemotherapy, and irradiation. Treatment side effects can be permanent or life threatening and include neurocognitive impairment, neurologic deficits, neurovascular compromise, neuroendocrine deficiency, and second malignancies.

Surgery, radiation therapy, and chemotherapy may be used as solitary therapies or in combination, offering different therapeutic ratios depending on the setting. As a result, establishing the ideal treatment choice and sequencing has historically been an area of controversy, presenting challenges that are further complicated by the emergence of molecular targets.

Several studies have attempted to mitigate the impact of late radiation toxicity through selective radiation avoidance, systematic reduction in the size of target volumes, and the use of advanced radiation techniques. Of these radiation techniques, proton therapy is particularly promising because it allows for reductions in the low and intermediate radiation dose to normal tissue outside of the target volume. Accordingly, LGGs in children are considered a “Group 1” indication for proton therapy according to the United States American Society for Radiation Oncology Model Policy, and they have become the third most common pediatric brain tumor type treated with proton therapy worldwide.

Compared with modern photon series, proton therapy reduces the radiation dose to developing brain tissue, diminishing acute toxicities without compromising disease control.

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What is the best therapeutic approach to a pediatric patient with a deep-seated brain Arteriovenous Malformations ?

Meling TRPatet G

Proton Therapy offers promising results with a more accurate radiation that avoids the surrounding tissue

Although brain arteriovenous malformations (bAVMs) account for a very small proportion of cerebral pathologies in the pediatric population, they are the cause of roughly 50% of spontaneous intracranial hemorrhages. Pediatric bAVMs tend to rupture more frequently and seem to have higher recurrence rates than bAVMs in adults. Thus, the management of pediatric bAVMs is particularly challenging. In general, the treatment options are conservative treatment, microsurgery, endovascular therapy (EVT), gamma knife radiosurgery (GKRS), proton-beam stereotactic radiosurgery (PSRS), or a combination of the above. In order to identify the best approach to deep-seated pediatric bAVMs, we performed a systematic review, according to the PRISMA guidelines. None of the options seem to offer a clear advantage over the others when used alone. Microsurgery provides the highest obliteration rate, but has higher incidence of neurological complications. EVT may play a role when used as adjuvant therapy, but as a stand-alone therapy, the efficacy is low and the long-term side effects of radiation from the multiple sessions required in deep-seated pediatric bAVMs are still unknown. GKRS has a low risk of complication, but the obliteration rates still leave much to be desired. Finally, PSRS offers promising results with a more accurate radiation that avoids the surrounding tissue, but data is limited due to its recent introduction. Overall, a multi-modal approach, or even an active surveillance, might be the most suitable when facing deep-seated bAVM, considering the difficulty of their management and the high risk of complications in the pediatric population.

Neurosurg Rev. 2019 Jun;42(2):409-416.

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Proton Therapy is associated with favorable outcomes for intelligence and processing speed

Improved neuropsychological outcomes following proton therapy relative to x-ray therapy for pediatric brain tumor patients

Jeffrey P Gross, Stephanie Powell, Frank Zelko, William Hartsell, Stewart Goldman, Jason Fangusaro, Rishi R Lulla, Natasha Pillay Smiley, John Han-Chih Chang, Vinai Gondi, Neuro-Oncology, , noz070,


Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent x-ray radiotherapy (XRT) versus proton radiotherapy (PRT).Methods

Pediatric patients who underwent either XRT or PRT and received post-treatment age-appropriate neuropsychological evaluation including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time.Results

Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%) or posterior fossa (53.6%) compartments received radiation and had post-treatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated socioeconomic status and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs. 2.6 years, p<0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (=10.6, p=0.048) and processing speed (=14.4, p=0.007) relative to XRT, with trend toward higher verbal IQ (=9.9, p=0.06) and general adaptive functioning (=11.4, p=0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ, (p=0.01) and IQ (p=0.04) following PRT, with trend toward improved processing speed (p=0.09).Conclusions

PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.

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Proton therapy shows efficacy, low toxicity in large cohort of children with high-risk neuroblastoma.

Study supports expanded use of proton therapy to minimize radiation exposure to healthy, developing organs.

Researchers analyzed the largest cohort to date of pediatric patients with high-risk neuroblastoma treated with proton radiation therapy (PRT), finding both that proton therapy was effective at reducing tumors and demonstrated minimal toxicity to surrounding organs. “These data are extremely encouraging and could be a game-changer for a number of reasons,” said lead author Christine Hill-Kayser, MD, Chief of the Pediatric Radiation Oncology Service at Penn Medicine and an attending physician at CHOP. “Not only did we observe excellent outcomes and minimal side effects that validate the use of PRT in high-risk neuroblastoma patients, we answered a lingering question about proton therapy — the concern that because it is so targeted, tumors may come back. Tumors mostly did not come back — suggesting PRT is effective, less toxic and a superior choice for our young patients who must endure intense treatment modalities in an effort to cure this high-risk cancer.”

ScienceDaily. ScienceDaily, 9 April 2019 <>.

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Are further studies needed to justify the use of proton therapy for paediatric cancers of the central nervous system? A review of current evidence

Myxuan Huynh, Loredana Gabriela Marcu, Eileen Giles, Michala Short, Donna Matthews, Eva Bezak


Clinical implementation of proton therapy demonstrated its potential to overcome some limitations of the more traditional, photon-based radiotherapy, due to physical and radiobiological advantages of protons. However, questions concerning the long-term effects of protons on paediatric patients need outcome analysis of the reported literature in order to be answered. The current paper has analysed the available clinical trials and comparative studies (protons vs photons) for paediatric cancers of the central nervous system (CNS) analysing the reported outcomes and follow-up times in order to evaluate the safety of proton therapy for this patient group.

Based on the literature analysis, proton therapy for treatment of paediatric cancers of the CNS was found to provide survival and tumour control outcomes comparable, and frequently superior, to photon therapy. Furthermore, the use of protons was shown to decrease the incidence of severe acute and late toxicities, including reduced severity of endocrine, neurological, IQ and QoL deficits. Most commonly, the reported median follow-up time was up to 5 years. Only a few studies reported promising, longer follow-up results. Considering that these patients are likely to survive many of the malignancies reported on, the incidence of long term sequellae impacting growth, development and quality of life into adulthood, should be viewed longitudinally for completeness.

The evidence surrounding proton therapy in paediatric tumour management supports its effectiveness and potential benefits in reducing the incidence of late-onset toxicities and second malignancies. For stronger evidence, it is highly desired for future studies to improve current reporting by (1) highlighting the paediatric patient cohort’s outcome (in mixed patient groups), (2) reporting the follow-up time, (3) clearly indicating the toxicity criteria used in their evaluation, and (4) identifying the risk group. With this suggested clarity of future reporting, meaningful data to support treatment choice may then be available.

Table 1 Compilation of comparative studies (protons vs photons) for paediatric CNS tumours (treatment planning comparison studies not included).

Full article

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A Road Map for Important Centers of Growth in the Pediatric Skeleton to Consider During Radiation Therapy and Associated Clinical Correlates of Radiation-Induced Growth Toxicity

Rao, Avani D. et al. International Journal of Radiation Oncology • Biology • Physics , Volume 103 , Issue 3 , 669 – 679

With the increasing use of advanced radiation techniques such as intensity modulated radiation therapy, stereotactic radiation therapy, and proton therapy, radiation oncologists now have the tools to mitigate radiation-associated toxicities. This is of utmost importance in the treatment of a pediatric patient. To best use these advanced techniques to mitigate radiation-induced growth abnormalities, the radiation oncologist should be equipped with a nuanced understanding of the anatomy of centers of growth. This article aims to enable the radiation oncologist to better understand, predict, and minimize radiation-mediated toxicities on growth. We review the process of bone development and radiation-induced growth abnormalities and provide an atlas for contouring important growth plates to guide radiation treatment planning. A more detailed recognition of important centers of growth may improve future treatment outcomes in children receiving radiation therapy.

  1. Introduction
  2. Complexities of a Standard Dose Constraint
  3. Assessment of Skeletal Maturity and Completion of Growth
  4. Anatomic Road Map of Important Growth Plates and Clinical Correlates of Radiation-Associated Growth Toxicity
    1. Whole-brain radiation therapy
    2. Craniofacial radiation therapy
      1. Facial hypoplasia
      2. Orbital defects
    3. Shoulder and arm radiation therapy
      1. Clavicular narrowing
      2. Slipped proximal humeral epiphysis
      3. Arm-length discrepancy
    4. Pelvic radiation therapy
      1. Slipped capital femoral epiphysis
      2. Osteonecrosis
      3. Leg-length discrepancy
    5. Spinal irradiation
      1. Reduced final height
      2. Scoliosis
  5. Conclusion and Future Directions
  6. Supplementary Data
  7. References

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Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study) : a population-based, cohort study

Chloe J Bright, PhD Raoul C Reulen, PhD David L Winter, HNC Daniel P Stark, MD Martin G McCabe, PhD Angela B Edgar, MD et al.

“A previous large case-control study showed a dose-response relation between radiotherapy and risk of lung cancer in breast cancer survivors diagnosed at any age (not AYA-specific). Existing literature suggests that chest radiotherapy and smoking are both likely contributors to the substantial number of excess neoplasms accounted for by lung cancer.

The bladder and bowel would be directly exposed if external-beam radiotherapy was used to treat cervical cancer. A large case-control study showed a dose-response relation between radiotherapy and the risk of both bladder and rectal cancers in cervical cancer survivors. Existing literature suggests that pelvic irradiation and smoking are likely contributors to the number of excess neoplasms accounted for by lung, colorectal, and bladder cancer. Clinical follow-up of survivors of AYA cervical cancer, particularly where pelvic irradiation is used, should focus on lung, bowel, and bladder cancers.

Treatment for testicular cancer can involve irradiating the para-aortic lymph nodes, which might explain the excess of subsequent primary neoplasms seen in abdominal sites (prostate, bladder, and colorectal). The excess of subsequent primary neoplasms observed in the abdomen is consistent with international studies of testicular cancer survivors. The excess of lung subsequent primary neoplasms might be caused by radiotherapy to the lungs, since previous studies have reported an increased risk of lung cancer in survivors of testicular cancer who were given chest radiotherapy. Clinical follow-up of survivors of AYA testicular cancer should focus on prostate, bladder, colorectal, and lung cancers.

The lungs would be directly exposed if external-beam radiotherapy was used to treat Hodgkin lymphoma; previous studies of Hodgkin lymphoma survivors have provided evidence of a dose-dependent increase in lung cancer risk with radiotherapy with or without chemotherapy.”

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