Stereotactic central/core ablative radiation therapy: results of a phase I study of a novel strategy to treat bulky tumor

Purpose Bulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART. Methods and materials We defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV’s border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents. Results 21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14–85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009). Conclusion SCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials.

Patients undergo CT-based simulation using 2mm thin-slice CT for treatment planning.Contrast-enhanced CT, MRI, and PET/CT scans are routinely acquired and fused with the simulation CT to assist in tumor and organ at risk (OAR) delineation and contouring.The Gross Target Volume (GTV) is defined as the visibly bulky disease, while the Clinical Target Volume (CTV) coincides with the GTV and is not specifically highlighted in this study.The Stereotactic Treatment Volume (STV) is precisely defined as the region inside the GTV that receives the ablative dose during SCART treatment.

Design STV:
In the SCART planning, STV, but not the whole GTV nor TTV, is the true target of ablation and is pre-defined at the core of GTV prior to the planning optimization.In our design as Figure 1, the maximum opening of radiation arc is limited as the size of STV.These radiation fields only converge at STV, but not at TTV, and this arrangement will generate the highest possible dose gradient in TTV, the region between STV and GTV border.Using VMAT, the Stereotactic Treatment Volume (STV) is typically positioned at the center of the GTV, exhibiting a shape akin to the GTV in axial view and resembling a spindle in the superior-inferior (SI) view.

Defining Stereotactic Treatment Volume (STV) Dimensions in SCART
Determining the appropriate dimensions for the STV poses a challenge, as the dose gradient at the Transitional Treatment Volume (TTV) is intricately linked to the size of the STV.A delicate balance must be struck, considering that a larger STV results in a larger radiation field, slowing down the dose falloff in the surrounding area.Conversely, a larger STV leads to a smaller TTV, offering less space for the dose to attenuate.The goal is to identify the optimal STV dimensions, where the ablative prescription dose at the STV's edge precisely falls off to the tissue constraints dose at the GTV's edge.This ideal STV configuration is crucial for maximizing the elimination of hypoxic and radioresistant cancer cells in the tumor core and enhancing the likelihood of triggering a tumorimmune response.
Methodology for Dimension Determination: Using a SCART prescription dose of 15Gyx3 and a tissue constraints dose of 3Gyx3, hypothetical 10cm spherical tumors were employed for testing.The circular STV in axial view was incrementally increased by 1mm from 1cm, and each new STV was re-planned as the SCART target in VMAT treatment planning.The largest STV that maintained sufficient prescription dose coverage without violating tissue dose constraints was identified as the optimal STV dimension, determined to be around 2.1 cm (21% of the sphere tumor's size in axial view).
STV/GTV Independence from GTV Dimension: Extending the tests to nine hypothetical spherical tumors ranging from 4cm to 20cm in diameter revealed a consistent proportionality between the dimension of the STV and GTV (approximately 20~22%, as detailed in the Table 1).This finding suggests that the STV dimension remains relatively independent of the GTV dimension across a range of tumor sizes, reinforcing the consistency of the proposed SCART methodology.After STV being designed and cation will be added to review and edit it, if necessary, to avoid its overlapping with the serial organs, such as vessel or tracheal that resides inside of the tumor.

Optimized SCART Treatment Planning and Delivery
In the meticulous process of devising Stereotactic Core Ablative Radiation Therapy (SCART), we implemented a comprehensive treatment planning and beam arrangement strategy, ensuring precision and efficacy in every facet.
• As the exploration of non-coplanar beams enhances the dose gradient, we judiciously integrated non-coplanar beams or arcs whenever feasible.
• Heterogeneity corrections applied in order to enhance dosimetry accuracy.
• To refine optimization and minimize critical structure exposure, non-anatomical dose constraining ring structures were strategically incorporated.
Notably, intracranial targets, with their superior access to non-coplanar beams, resulted in a slightly larger/fatter STV in comparison to coplanar-only VMAT plans, attributing to its spindle-shaped nature.
• Delivery: • SCART sessions were scheduled every other day until the intended dose level was achieved or discontinued due to toxicity.
• Cone beam (CBCT) image guidance was meticulously employed in each treatment session, ensuring precision.
On average, 5302 monitor units (MU) were delivered in a streamlined 15-minute treatment time slot with average machine beam-on time of 8.9 min each fraction.
Figure 1 a.Illustration of VMAT arc irradiates the STV from 360 degrees.The maximum radiation field opening from various angels are limited to the projection of STV.These fields intersect at SSTV and the dose intensity falls off quickly at TTV, the surrounding region of GTV, to a modest dose level at the edge of GTV, which is safe to the surrounding tissue.1.b Dose cloud of a hypothetical elliptic GTV and a elliptic SST in axial view, along with the spindle shape of SST in SI direction (Sagittal and Coronal view)

Table 1 .
The appropriate STV dimension and volume were listed in the nine hypothetical spherical tumors ranging from 4cm to 20cm in diameter.It is found that, regardless the tumor's dimension, there is a consistent proportionality between the dimension of the STV and GTV.
To illuminate this intricate dynamic, we conducted targeted tests using a 10cm spherical tumor.Across four distinct prescription doses ranging from 15Gyx3 to 24Gyx3 and two tissue dose constraints (3Gyx3 or 5Gyx3), we observed a clear correlation listed in Table2.The proportionality between STV and GTV appears to be significantly influenced by the prescription dose and tissue dose constraints.It is also found that STV/GTV proportionality is approximately same as Tissue Constrain Dose/SCART Prescription Dose proportionality.

Table 2 :
The list of STV and GTV proportion with the escalated prescription doses

GTV dimension * Tissue Dose Constrains / Prescription Dose In SI direction, STV
is slight shorter of GTV and the STV typically looks like spindle in the sagittal and coronal view.