Physics Contribution

Clinical Target Volume: The Third Front

Treatment planning in radiotherapy distinguishes three target volume concepts: the gross tumor volume (GTV), the clinical target volume (CTV), and the planning target volume (PTV). Over time, GTV definition and PTV margins have improved through the development of novel imaging techniques and better image guidance, respectively. CTV definition is sometimes considered the weakest element in the planning process. CTV definition is particularly complex since the extension of microscopic disease cannot be seen using currently available in-vivo imaging techniques. Instead, CTV definition has to incorporate knowledge of the patterns of tumor progression. While CTV delineation has largely been considered the domain of radiation oncologists, this paper, arising from a 2019 ESTRO Physics research workshop, discusses the contributions that medical physics and computer science can make by developing computational methods to support CTV definition. First, we overview the role of image segmentation algorithms, which may in part automate CTV delineation through segmentation of lymph node stations or normal tissues representing anatomical boundaries of microscopic tumor progression. The recent success of deep convolutional neural networks has also enabled learning entire CTV delineations from examples. Second, we discuss the use of mathematical models of tumor progression for CTV definition, using as example the application of glioma growth models to facilitate GTV-to-CTV expansion for glioblastoma that is consistent with neuroanatomy. We further consider statistical machine learning models to quantify lymphatic metastatic progression of tumors, which may eventually improve elective CTV definition. Lastly, we discuss approaches to incorporate uncertainty in CTV definition into treatment plan optimization as well as general limitations of the CTV concept in the case of infiltrating tumors without natural boundaries.

Previous literature suggests that the dose proximally outside the PTV could have an impact on the incidence of distant metastasis (DM) after SBRT in stage I NSCLC patients. We investigated this observation (along with local failure) in deliveries made by different treatment modalities: robotic mounted linac SBRT (CyberKnife) vs conventional SBRT (VMAT/CRT).

This study included 422 stage I NSCLC patients from 2 institutions who received SBRT: 217 treated conventionally and 205 with CyberKnife. The dose behavior outside the PTV of both sub-cohorts were compared by analyzing the mean dose in continuous shells extending 1, 2, 3, …, 100 mm from the PTV. Kaplan-Meier analysis was performed between the two sub-cohorts with respect to DM-free survival and local progression-free survival. A multivariable Cox proportional hazards model was fitted to the combined cohort (n = 422) with respect to DM incidence and local failure.

The shell-averaged dose fall-off beyond the PTV was found to be significantly more modest in CyberKnife plans than in conventional SBRT plans. In a 30 mm shell around the PTV, the mean dose delivered with CyberKnife (38.1 Gy) is significantly larger than with VMAT/CRT (22.8 Gy, $p<{10}^{-8}$). For 95% of CyberKnife plans, this region receives a mean dose larger than the 21 Gy threshold dose discovered in our previous study. In contrast, this occurs for only 75% of VMAT/CRT plans. The DM-free survival of the entire CyberKnife cohort is superior to that of the 25% of VMAT/CRT patients receiving less than the threshold dose ($\mathrm{VMAT}/{\mathrm{CRT}}_{<21\mathrm{Gy}}$), with a hazard ratio of 5.3 (95% CI: 3.0–9.3, $p<{10}^{-8}$). The 2 year DM-free survival rates were 87% (95% CI: 81%–91%) and 44% (95% CI: 28%–58%) for CyberKnife and the below-threshold dose conventional cohorts, respectively. A multivariable analysis of the combined cohort resulted in the confirmation that threshold dose was a significant predictor of DM(HR = 0.28, 95% CI: 0.15–0.55, $p<{10}^{-3}$) when adjusted for other clinical factors. CyberKnife was also found to be superior to the entire VMAT/CRT with respect to local control (HR = 3.44, CI: 1.6–7.3). The 2-year local progression-free survival rates for the CyberKnife cohort and the VMAT/CRT cohort were 96% (95% CI: 92%–98%) and 88% (95% CI: 82%–92%) respectively.

In standard-of-care CyberKnife treatments, dose distributions that aid distant control are achieved 95% of the time. Although similar doses could be physically achieved by conventional SBRT, this is not always the case with current prescription practices, resulting in worse DM outcomes for 25% of conventional SBRT patients. Furthermore, CyberKnife was found to provide superior local control compared to VMAT/CRT.

In an era where little is known about the “abscopal” (out-of-the-field) effects of lung SBRT, we investigated correlations between the radiation dose proximally outside the PTV and the risk of cancer recurrence after SBRT in patients with primary stage I non-small cell lung cancer (NSCLC).

This study included 217 stage I NSCLC patients across 2 institutions who received SBRT. Correlations between clinical and dosimetric factors were investigated. The clinical factors considered were distant metastasis (DM), loco-regional control (LRC) and radiation pneumonitis (RP). The dose (converted to EQD2) delivered to regions of varying size directly outside of the PTV was computed. For each feature, area under the curve (AUC) and odds ratios with respect to the outcome parameters DM, LRC and RP were estimated; Kaplan–Meier (KM) analysis was also performed.

Thirty-seven (17%) patients developed DM after a median follow-up of 24 months. It was found that the mean dose delivered to a shell-shaped region of thickness 30 mm outside the PTV had an AUC of 0.82. Two years after treatment completion, the rate of DM in patients where the mean dose delivered to this region was higher than 20.8 Gy₂ was 5% compared to 60% in those who received a dose lower than 20.8 Gy₂. KM analysis resulted in a hazard ratio of 24.2 (95% CI: 10.7, 54.4); p < 10⁻⁵. No correlations were found between any factor and either LRC or RP.

The results of this study suggest that the dose received by the region close to the PTV has a significant impact on the risk of distant metastases in stage I NSCLC patients treated with SBRT. If these results are independently confirmed, caution should be taken, particularly when a treatment plan results in a steep dose gradient extending outwards from the PTV.