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Takeaway from BJR Proton Therapy special feature

Targeting cancer stem cells: protons versus photons – Dini et al.

👉 preclinical data suggest that protons and photons differ in their biological effects on cancer stem cells, with protons offering potential advantages, although the heterogeneity of cancer stem cells and the different proton irradiation modalities make the comparison of the results not so easy. 

Is there a role for arcing techniques in proton therapy ? – Carabe-Fernandez et al.

👉 although Proton Arc Therapy (PAT) may not produce better physical dose distributions than intensity modulated proton therapy, the radiobiological considerations associated with particular PAT techniques could offer the possibility of an increased therapeutic index.

Proton minibeams—a springboard for physics, biology and clinical creativity – Avraham Dilmanian et al.

👉 Proton minibeam therapy (PMBT) is a form of spatially fractionated radiotherapy wherein broad beam radiation is replaced with segmented minibeams—either parallel, planar minibeam arrays generated by a multislit collimator or scanned pencil beams that converge laterally at depth to create a uniform dose layer at the tumor. By doing so, the spatial pattern of entrance dose is considerably modified while still maintaining tumor dose and efficacy. Recent studies using computational modeling, phantom experiments, in vitro and in vivo preclinical models, and early clinical feasibility assessments suggest that unique physical and biological attributes of PMBT can be exploited for future clinical benefit

FLASH and minibeams in radiation therapy: the effect of microstructures on time and space and their potential application to protontherapy – Mazal et al.

👉 the combination of FLASH and minibeams using proton beams, in spite of their complexity, may help to optimize the benefits of several or all the reviewed aspects, through the following concepts:
(1)  the intrinsic advantages of protons to reduce the integral mid and low doses, will be volumetrically combined in synergy with the FLASH and minibeam effects as a whole;
(2)  to reduce mid and high equivalent doses in critical organs around the tumour volume using the FLASH effect with high dose rates achievable with proton beams, both with passive or pencil beam approaches;
(3) to reduce healthy tissue complications by the minibeams space modulation in every beam path, where protons can be focalized with a steep penumbra and hence a high peak to valley ratio;
(4) to deliver an homogeneous dose to the target at any depth using the multiple scattering of proton minibeams in depth, and/or with multiple fields, or even setting a controlled inhomogeneous “vertex” doses escalation approach, optimizing intensity modulated proton therapy with robust solutions;
(5) to modify present approaches of immunological responses by the combination of concentration of lattice doses in very short time with a slight increase in LET, and the microstructure in time and space of both effects and
(6) to deliver single or hypofractionated treatments in very short time per fraction, facilitating the treatment of moving organs, specially when using pencil beam approaches and the associated risk of interplay effects, as well as the optimal use of minibeams with minimal risk of movement during the fraction.
Proton beams have in consequence one of the highest potentials to optimize the use of FLASH and Minibeams effects in radiation therapy, individually or in a synergistic combination.

Re-irradiation with protons or heavy ions with focus on head and neck, skull base and brain malignancies – Seidensaal et al.

👉 Re-irradiation can offer a potentially curative solution in case of progression after initial therapy; however, a second course of radiotherapy can be associated with an increased risk of severe side-effects. Particle therapy with protons and especially carbon ions spares surrounding tissue better than most photon techniques, thus it is of high potential for re-irradiation. Irradiation of tumors of the brain, head and neck and skull base involves several delicate risk organs, e.g. optic system, brainstem, salivary gland or swallowing muscles. Adequate local control rates with tolerable side-effects have been described for several tumors of these locations as meningioma, adenoid cystic carcinoma, chordoma or chondrosarcoma and head and neck tumors.

Reduced radiation-induced toxicity by using proton therapy for the treatment of oropharyngeal cancer – Meijer et al.

👉 proton therapy results in lower dose levels in multiple organs at risk, which translates into reduced acute toxicity (i.e. up to 3 months after radiotherapy), while preserving tumour control. Next to reducing mucositis, tube feeding, xerostomia and distortion of the sense of taste, protons can improve general well-being by decreasing fatigue and nausea. Proton therapy results in decreased rates of tube feeding dependency and severe weight loss up to 1 year after radiotherapy, and may decrease the risk of radionecrosis of the mandible.

Photons or protons for reirradiation in (non-)small cell lung cancer: Results of the multicentric ROCOCO in silico study – Troost et al.

👉 IMPT was able to statistically significantly decrease the radiation doses to the OARs. IMPT was superior in achieving the highest tumour dose while also decreasing the dose to the organs at risk.

Paediatric proton therapy – Thomas et al.

👉 Along with high cure rates, the rate of (late) toxicities is reduced using this radiotherapy modality

Articles cited above and many more are available in Proton therapy special feature, The British Journal of Radiology 2020 93:1107 

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Takeaway from Multidisciplinary 2020 Head and Neck Cancers Symposium

A dosimetric comparison of proton versus photon irradiation for pediatric glomus tumor – Vidal et al.

👉 Most notable are the lower doses to ipsilateral (left) cochlea, right-sided structures, and expanded cord with the proton plan. The mean oral cavity dose was also significantly lower. 
Dosimetric superiority of protons in the skull base region is largely due to the absence of dose deposition distal to the target, or “exit dose”. This phenomenon is explained by the distinctive Bragg Peak that protons have which allows for a rapid fall-off of the irradiation dose beyond the target. Contralateral structures were significantly spared with the proton plan. As previously established, proton beam therapy remains the therapy of choice for pediatric patients given their long term survival and concerns for secondary malignancy, as well as lower doses to most if not all normal structures of interest.

Long-Term Update of Proton Beam Re-Irradiation for Recurrent Head and Neck Cancer – Lee et al.

👉 Proton Therapy re-irradiation of the head and neck provides effective tumor control with acceptable acute and late toxicity profiles, likely secondary to the decreased dose to surrounding normal, albeit previously irradiated tissue.

Proton Therapy for Non-Skull Base Head and Neck Adenoid Cystic Carcinoma – Lee et al.

👉 Proton Therapy is a feasible option for ACC for the non-skull based head and neck in the definitive and postoperative setting, offering low rates of acute and late toxicities. Patients with metastatic disease also had acceptable outcomes and local treatment was well tolerated.

Improved Outcomes by proton beam radiation for nasal cavity and paranasal sinus malignances – Fan et al.

👉 Proton Therapy offers durable local control and survival in patients with nasal cavity and paranasal sinus malignancy. Even patients with recurrent tumor or with prior radiation history could achieve encouraging outcomes.

Chemosensory Outcomes in Nasopharyngeal Cancer Patients Treated with Proton Beam Therapy: A Prospective Longitudinal Study – Slater et al.

👉 with Proton Therapy the long-term chemosensory outcomes are preserved.

Proton Therapy for Nasopharyngeal Cancer: A Matched Case-control Study of Intensity-Modulated Proton Therapy and Intensity-Modulated Photon Therapy – Li et al.

👉 IMPT showed dosimetry advantages over  IMRT and lower rates of acute toxicities while both had comparable  treatment outcomes.

Outcomes following Proton Therapy for Squamous Cell Carcinoma of the Larynx – Ausat et al.

👉 Proton Therapy for SCC of the larynx demonstrates a high rate of overall survival, local-regional control, and disease-free survival with low toxicity profile.

Outcomes of Major Salivary Gland Tumors Treated with Proton Beam Radiation Therapy – Zakeri et al.

👉 rates of locoregional control were high and treatment was well tolerated.

Intensity Modulated Proton Therapy (IMPT) to the Parotid
Gland: A Seven-Year Experience – Hanania et al.

👉 IMPT for treatment 724 of the parotid gland manifests in low rates of acute and chronic toxicity 725 while maintaining dosimetric coverage and high rates of biological control. 726 Skin V30 may predict for radiation dermatitis.

Redefine End-of-range RBE of Protons Based on Long-term Clinical Outcome – Zhan et al.

👉 RBE in brain is 1.18

Abstracts published in International Journal of Radiation Oncology • Biology • Physics, Volume 106, Issue 5, April 1, 2020

https://www.redjournal.org/issue/S0360-3016(20)X0004-6

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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.

Re-irradiation

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.

Read the full study on Precision and Future Medicine 2019

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Clinical Outcomes of Recurrent Intracranial Meningiomas Treated with Proton Beam Reirradiation.

Brandon S. Imber, Brian Neal, Dana L. Casey, Heba Darwish, Andrew L. Lin, Oren Cahlon, Brian Chon, Henry Tsai, Eugen Hug, Yoshiya Yamada, and T. Jonathan Yang (2019) International Journal of Particle Therapy: Spring 2019, Vol. 5, No. 4, pp. 11-22.

Proton beam radiation therapy (PBRT) offers a dosimetric advantage for reRT, especially for patients with multiple prior courses of RT, owing to improved ability to spare toxicity to nearby normal structures.

PBRT reRT may be a relatively efficacious strategy for recurrent meningiomas, a patient population lacking durable therapeutic options. Even with significant prior radiation exposure, radionecrosis rates appear low. We feel that prospective investigation of the modality is warranted to validate incremental improvement over traditional photon RT.

Proton and photon comparative dosimetry for a 72-year-old man with an anaplastic meningioma of the right cavernous sinus. (A) Original photon IMRT plan, which delivered 59.4 Gy in conventional fractionation. (B) Nodular area of T1 post contrast enhancement posterior to the right carotid artery suggestive of in-field recurrence (yellow arrow). (C) Proton reirradiation plan delivered to 60 Gy(RBE) in 2 Gy(RBE) fractions with 2 beams and uniform scanning. (D) Hypothetical comparison reirradiation plan using photon VMAT (not delivered). (E) Cumulative dose delivered by using proton beam radiation therapy. (F) Hypothetical cumulative dose delivered had photon VMAT plan been delivered. (G) Isodose lines in Gy for plans in (A), (C), and (D). (H) Cumulative isodose lines in Gy(RBE) for plans in (E) and (F). Abbreviations: IMRT, intensity-modulated radiation therapy; VMAT, Volumetric Modulated Arc Therapy.

https://theijpt.org/doi/10.14338/IJPT-18-00045.1