Clinical studies of PBS protons
Cynthia E Keen | MedicalPhysicsWeb | July 19, 2016 | See Original Here
Switzerland’s Paul Scherrer Institute (PSI) developed the technique of pencil-beam scanning (PBS) proton therapy 20 years ago and continues to be a pioneering global leader in its use. In newly published studies, researchers at PSI’s Center for Proton Therapy report that this technology has produced excellent outcomes in children with rhabdomyosarcomas (RMS), and is and effective and safe for treatment of patients with skull-base tumours.
RMS, a cancer that normally develops in skeletal muscles, is the most common soft-tissue sarcoma in children. Paediatric patients with RMS are typically treated with surgery, chemotherapy and/or radiotherapy. Damien Weber, head and chairman of the Center for Proton Therapy, and co-authors conducted a study of all children with RMS who received PBS proton therapy at PSI (Radiother. Oncol. doi: 10.1016/j.radonc.2016.05.013; Pediatric Blood & Cancer doi: 10.1002/pbc.25864).
The study included 83 of 91 children treated between January 2000 and December 2014, 51.8% of whom had parameningeal RMS (PR-RMS, which represents approximately 15% of all RMS in children). In addition to proton therapy, all patients also received chemotherapy. Treatment plans were optimized to maximize gross tumour volume (GTV) coverage and not exceed organ-at-risk (OAR) dose constraints. A combination of single-field uniform dose (SFUD), intensity-modulated proton therapy (IMPT) and SFUD+IMPT plans were used. Patients received a median dose of 54 Gy(RBE), administered in a median of 30 fractions over 30 to 59 days.
Patients with PM-RMS initially underwent 3D planning with co-registered CT and MRI, and had subsequent CT scans throughout their treatment. These patients had positioning checked before the delivery of every 1.8–2 Gy(RBE) fraction to the primary tumour and involved lymph nodes. The median planning target, a 1-cm extension of the GVT, received a dose of 50.4–55.8 Gy(RBE). Dose constraints to OARs were determined as maximum of 54 Gy(RBE) to the brainstem, 50.4 Gy(RBE) to the spinal cord, 54 Gy(RBE) to the optic chiasm and optic nerves, and mean dose to at least one cochlea of 36 Gy(RBE).
Twelve patients developed grade 3 acute toxicities, none of which required radiotherapy interruption. There were 16 events of grade 3 late toxicities in 15 patients. Twelve of these patients, nine of whom had orbital RMS, developed radiation-induced cataracts that required subsequent surgery. One patient developed a unilateral hearing impairment. All patients who developed grade 3 late toxicities also experienced tumour recurrence.
Local failure occurred in 16 patients (19.3%) during a median follow-up period of 55.5 months. The majority of these had local recurrence within one year of radiotherapy. Tumour location and size, and group/stage were significant predictors for local failure. Fourteen patients died from tumour progression, nine of whom had PR-RMS. The five-year local control and overall survival rates were 78.5% and 80.6% respectively.
A quality-of-life survey determined that the children were quite resilient. Baseline surveys were low, but improved two months after completion of radiotherapy. After two years, patients were comparable with a healthy control group. The team concluded that PBS proton therapy led to excellent outcomes in children with RMS, with minimal late non-ocular toxicity and good quality of life.
At PSI, PBS proton therapy is also used to treat skull-base tumours, including chordoma and chondrosarcoma (ChSa). Chordoma is a rare tumour characterized by local aggressive growth and local recurrence; ChSa is a rarer bone tumour. A study of 151 chordoma patients and 71 patients with low-grade ChSa treated between October 1998 and October 2012 evaluated long-term tumour control and toxicities (Radiother. Oncol. doi: 10.1016/j.radonc.2016.05.011).
All patients underwent surgery before proton therapy. Their mean GTV following surgical resection was 35.7 cm3, and nearly one third of patients had a postoperative tumour abutting the brainstem or optic apparatus. Prescribed doses were 74 Gy(RBE) for chordoma and 70 Gy(RBE) for ChSa, with an administered mean fraction of 1.8–2.0 Gy(RBE).
Patients were followed for up to nearly 15 years. During this time, 29 patients died from their disease, nine of whom from local progression. Local failures were experienced by 15.7% (30 chordoma and five ChSa patients), half of which occurred within two and three years, respectively, following treatment. The estimated five- and seven-year local control rates for chordoma patients were 75.8% and 70.9%, respectively. ChSa patients had a local control rate of 93.6% for both time frames.
The only distant failures that occurred were in eight chordoma patients who also had local tumour recurrence. Metastasis-free survival for chordoma patients at seven years was 91.6%. The majority of patients (87.2%) did not experience any high-grade late toxicities within the first seven years following proton therapy treatment. Eighteen patients had 25 grade 3 or 4 events. While no patients experienced brainstorm toxicities, two patients had grade 4 bilateral optic neuropathy and one patient had a grade 4 spinal cord necrosis.
Weber and colleagues reported that compression of the optic apparatus of the brainstem, histology and a GTV greater than 25 cm3 were significant independent prognostic factors for both local tumour control and overall survival. They noted that OARs constrain the delivered dose to the target volumes and that tumours located in the direct vicinity of OARs create radiation inhomogeneities.
Concluding that PBS proton therapy is an effective treatment for skull-base tumours, the authors recommended that such patients should have brain MRI scans twice yearly during the first three years following treatment, annually for the next four years, and every two to three years thereafter.
About the author
Cynthia E Keen is a freelance journalist specializing in medicine and healthcare-related innovations.