Radiation treatment for patients with lung cancer represents a balancing act, particularly if malignant lesions are centrally located near to critical structures. The radiation may destroy the tumour, but vital organs may be seriously damaged as well.
The standard treatment for non-small cell lung cancer (NSCLC) is stereotactic ablative body radiotherapy (SABR), which delivers intense radiation doses in just a few treatment sessions and achieves excellent local control. For ultracentral lung legions, however – defined as having a planning target volume (PTV) that abuts or overlaps the proximal bronchial tree, oesophagus or pulmonary vessels – the high risk of severe radiation toxicity makes SABR highly challenging.
A research team at GenesisCare UK, an independent cancer care provider operating nine treatment centres in the UK, has now demonstrated that stereotactic MR-guided adaptive radiotherapy (SMART)-based SABR may be a safer and more effective option for treating ultracentral metastatic lesions in patients with histologically confirmed NSCLC. They report their findings in Advances in Radiation Oncology.
SMART uses diagnostic-quality MR scans to provide real-time imaging, 3D multiplanar soft-tissue tracking and automated beam control of an advanced linear accelerator. The idea is to use daily online volume adaptation and plan re-optimization to account for any changes in tumour size and position relative to organs-at-risk (OAR). Real-time imaging enables treatment in breath-hold with gated beam delivery (automatically pausing delivery if the target moves outside a defined boundary), eliminating the need for an internal target volume and enabling smaller PTV margins.
The approach offers potential to enhance treatment precision and target coverage while improving sparing of adjacent organs compared with conventional SABR, first author Elena Moreno-Olmedo and colleagues contend.
A safer treatment option
The team conducted a study to assess the incidence of SABR-related toxicities in patients with histologically confirmed NSCLC undergoing SMART-based SABR. The study included 11 patients with 18 ultracentral lesions, the majority of whom had oligometastatic or olioprogressive disease.
Patients received five to eight treatment fractions, to a median dose of 40 Gy (ranging from 30 to 60 Gy). The researchers generated fixed-field SABR plans with dosimetric aims including a PTV V100% (the volume receiving at least 100% of the prescription dose) of 95% or above, a PTV V95% of 98% or above and a maximum dose of between110% and 140%. PTV coverage was compromised where necessary to meet OAR constraints, with a minimum PTV V100% of at least 70%.
SABR was performed using a 6 MV 0.35 T MRIdian linac with gated delivery during repeated breath-holds, under continuous MR guidance. Based on daily MRI scans, online plan adaptation was performed for all of the 78 delivered fractions.
The researchers report that both the PTV volume and PTV overlap with ultracentral OARs were reduced in SMART treatments compared with conventional SABR. The median SMART PTV was 10.1 cc, compared with 30.4 cc for the simulated SABR PTV, while the median PTV overlap with OARs was 0.85 cc for SMART (8.4% of the PTV) and 4.7 cc for conventional SABR.
In terms of treatment-related side effects for SMART, the rates of acute and late grade 1–2 toxicities were 54% and 18%, respectively, with no grade 3–5 toxicities observed. This demonstrates the technique’s increased safety compared with non-adaptive SABR treatments, which have exhibited severe rates of toxicity, including treatment-related deaths, in ultracentral tumours.
Two-thirds of patients were alive at the median follow-up point of 28 months, and 93% were free from local progression at 12 months. The median progression-free survival was 5.8 months and median overall survival was 20 months.
Acknowledging the short follow-up time frame, the researchers note that additional late toxicities may occur. However, they are hopeful that SMART will be considered as a favourable treatment option for patients with ultracentral NSCLC lesions.
“Our analysis demonstrates that hypofractionated SMART with daily online adaptation for ultracentral NSCLC achieved comparable local control to conventional non-adaptive SABR, with a safer toxicity profile,” they write. “These findings support the consideration of SMART as a safer and effective treatment option for this challenging subgroup of thoracic tumours.”
The SUNSET trial
SMART-based SABR radiotherapy remains an emerging cancer treatment that’s not available yet in many cancer treatment centres. Despite the high risk for patients with ultracentral tumours, SABR is the standard treatment for inoperable NSCLC.
The phase 1 clinical trial, Stereotactic radiation therapy for ultracentral NSCLC: a safety and efficacy trial (SUNSET), assessed the use of SBRT for ultracentral tumours in 30 patients with early-stage NSCLC treated at five Canadian cancer centres. In all cases, the PTVs touched or overlapped the proximal bronchial tree, the pulmonary artery, the pulmonary vein or the oesophagus. Led by Meredith Giuliani of the Princess Margaret Cancer Centre, the trial aimed to determine the maximum tolerated radiation dose associated with a less than 30% rate of grade 3–5 toxicity within two years of treatment.
All patients received 60 Gy in eight fractions. Dose was prescribed to deliver a PTV V100% of 95%, a PTV V90% of 99% and a maximum dose of no more than 120% of the prescription dose, with OAR constraints prioritized over PTV coverage. All patients had daily cone-beam CT imaging to verify tumour position before treatment.
At a median follow-up of 37 months, two patients (6.7%) experienced dose-limiting grade 3–5 toxicities – an adverse event rate within the prespecified acceptability criteria. The three-year overall survival was 72.5% and the three-year progression-free survival was 66.1%.
In a subsequent dosimetric analysis, the researchers report that they did not identify any relationship between OAR dose and toxicity, within the dose constraints used in the SUNSET trial. They note that 73% of patients could be treated without compromise of the PTV, and where compromise was needed, the mean PTV D95 (the minimum dose delivered to 95% of the PTV) remained high at 52.3 Gy.
As expected, plans that overlapped with central OARs were associated with worse local control, but PTV undercoverage was not. “[These findings suggest] that the approach of reducing PTV coverage to meet OAR constraints does not appear to compromise local control, and that acceptable toxicity rates are achievable using 60 Gy in eight fractions,” the team writes. “In the future, use of MRI or online adaptive SBRT may allow for safer treatment delivery by limiting dose variation with anatomic changes.”
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