FLASH Proton Pencil Beam Scanning Irradiation Minimizes Radiation-Induced Leg Contracture and Skin Toxicity in Mice

Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.

Download Full-text

Commissioning of a clinical pencil beam scanning proton therapy unit for ultra‐high dose rates (FLASH)

Medical Physics ◽

10.1002/mp.14933 ◽

2021 ◽

Author(s):

Konrad P. Nesteruk ◽

Michele Togno ◽

Martin Grossmann ◽

Anthony J. Lomax ◽

Damien C. Weber ◽

...

Keyword(s):

Proton Therapy ◽

High Dose ◽

Pencil Beam ◽

Beam Scanning ◽

Dose Rates ◽

Pencil Beam Scanning

Download Full-text

Prognostic factors for spinal chordomas and chondrosarcomas treated with postoperative pencil-beam scanning proton therapy: a large, single-institution experience

Journal of Neurosurgery Spine ◽

10.3171/2019.11.spine1927 ◽

2020 ◽

Vol 32 (6) ◽

pp. 921-930

Author(s):

Fritz R. Murray ◽

James W. Snider ◽

Ralf A. Schneider ◽

Marc Walser ◽

Alessandra Bolsi ◽

...

Keyword(s):

Prognostic Factors ◽

Proton Therapy ◽

Tumor Control ◽

High Dose ◽

Low Grade ◽

Pencil Beam ◽

Beam Scanning ◽

En Bloc ◽

Pencil Beam Scanning

OBJECTIVEThe aim of this paper was to evaluate the prognostic factors in surgical and adjuvant care for spinal chordomas and chondrosarcomas after surgery followed by high-dose pencil-beam scanning proton therapy (PBS-PT).METHODSFrom 1997 to 2016, 155 patients (61 female patients; median age 55 years) with spinal (cervical, n = 61; thoracic, n = 29; lumbar, n = 13; sacral, n = 46; pelvic, n = 6) classic chordomas (n = 116) and chondrosarcomas (n = 39; most were low grade) were treated with maximal safe resection followed by PBS-PT (median dose prescribed: 74 Gy [relative biological effectiveness], range 48.6–77 Gy). The majority of patients (n = 153, 98.7%) had undergone at least 1 resection prior to PBS-PT (median 1, range 0–5; biopsy only, n = 2). Fewer than half (45.1%) of the surgeries were rated as gross-total resections (GTRs) prior to PBS-PT. Surgical stabilization (SS) was present in 39% of all patients (n = 60). Ninety-one patients (59%) presented with macroscopic tumor at the start of PBS-PT. The median follow-up duration was 64.7 months (range 12.2–204.8 months).RESULTSThe 5-year local tumor control, disease-free survival (DFS), and overall survival were 64.9% (95% CI 56.3%–73.5%), 59.4% (95% CI 50.6%–68.2%), and 77.9% (95% CI 70.6%–85.2%), respectively. In total, 63 patients (40.6%) experienced failure during the follow-up period: local only in 32 (20.6%), distal only in 7 (4.5%), local + distal in 19 (12.3%), surgical pathway failure (SPF) only in 2 (1.3%), local + SPF in 2 (1.3%), and distal + SPF in 1 (< 1%). Univariate analysis identified gross residual disease, the presence of SS, and treatment era prior to 2008 as highly significant for worse outcome, with all 3 remaining significant on multivariate analysis. The type of surgery (GTR or subtotal resection/biopsy) and whether GTR was achieved by en bloc or curettage did not show a significant prognostic effect. Surgical complications prior to PBS-PT were present in 42.5% of all surgically treated patients and were seen more commonly in patients with multiple surgical interventions (p = 0.005) and those operated on with the intent of en bloc resection (p = 0.006).CONCLUSIONSThe extent of resection and metallic stabilization substantially influenced clinical outcomes for patients with spinal chordoma or chondrosarcoma despite high-dose adjuvant PBS-PT. Optimal upfront surgical management of these tumors continues to include GTR, as possible, with prompt adjuvant proton therapy.

Download Full-text