This study demonstrates that, through increased doses to hypoxic or potentially hypoxic low-CBF subvolumes, dose painting with 3D-ASL-defined subvolumes can feasibly be accomplished without increasing the dose delivered to the OARs. This technique holds the potential to achieve better control of BM than can be achieved with traditional RT.
BM is a significant health problem whose incidence is increasing, and the median survival time is only 1–2 months without treatment[1,19−21]. Numerous studies have indicated that increasing the dose of RT significantly improves the local control of BM, and some patients have achieved long-term survival [22, 23]. Therefore, RT is an irreplaceable treatment for BM[3, 4, 22, 23]. However, an increased radiation dose, particularly to vascular endothelial cells and glial cells, is associated with increased toxicity and reduced tolerance to treatment. Thus, dose escalation without guidance is associated with a high risk of radiation damage to brain tissue. Targeted dose escalation in specific locations at risk for radiation resistance can effective improve on the safety of RT. BM is highly heterogeneous tumors whose radiation-resistant regions consist mainly of hypoxic or potentially hypoxic tissue.
Some studies have shown that BM has highly heterogeneous biological characteristics according to their pathological sources or even their sites of pathological origin. Hypoxia is one of the most important aspects of tumor heterogeneity.
The blood flow in hypoxic tissue is slower than that in normal tissue and cannot satisfy the oxygen requirement of the rapidly proliferating tumor cells because of highly irregular tumor vessels, arteriovenous shunts, blind ends, an incomplete basement membrane of vascular epithelial cells and other factors. Hence, due to the uneven distribution of blood flow and cancer cells, BM tumors appear as RT-sensitive regions with high perfusion, hypoxia radiation-resistant regions with low perfusion, and necrotic regions. Furthermore, the isoeffective dose can be up to three times higher under hypoxic conditions than under normoxic conditions. However, the group-based uniform dose given under a conventional plan cannot guarantee a sufficient dose for radiation-resistant regions, which eventually leads to further tumor progression and recurrence; local control failures are not uncommon under conventional treatment. Accurate and comprehensive identification of hypoxic regions is crucial.
Perfusion-weighted MR can be used for quantitative analysis of blood flow parameters, which is useful for identifying hypoxic regions[14, 15, 17, 28]. The noninvasive technology of 3D-ASL reflects angiogenesis and other functional features of the tumor microvascular system, rather than reflecting only morphology as CT and conventional MR; 3D-ASL provides quantitative information for the diagnosis and treatment of brain tumors from the perspectives of morphology and function . Yukie et al. demonstrated that the area under the curve (AUC) value of ASL for the recognition of hypoxic areas reached 0.830 based on the hypoxia tracer 18F-fluoromisonidazole. Our previous studies also demonstrated that the CBF variations of brain tissue and BM following radiation dose gradients could be quantified by 3D-ASL. With the development of IMRT, a dose escalation method called SIB can implement dose escalation for specific tumor subvolumes. Dose painting aims to apply relatively high radiation doses to hypoxic, radiation-resistant regions to improve tumor control without damaging OARs, and both 3D-ASL and SIB-IMRT are feasible methods for dose painting. Thus, in the present study, SIB-IMRT was used to achieve dose escalation in hypoxic subvolumes that were recognized and segmented by 3D-ASL.
Tumors tend to grow rapidly, showing a hypoxic state of low blood flow, if the growth rate of tumor cells exceeds the production rate of intratumoral blood vessels. Interestingly, 49.09% of the GTV was within a region of low blood flow. Our results showed that an extensive hypoxic subvolume existed within BM and that a dose-painting approach using 3D-ASL is feasible for BM treatment.
Dose painting for hypoxic regions based on various PET tracers has been widely studied in head and neck tumors, but the application of PET is indisputably limited at present because of its invasiveness and high price[11, 12]. In the present study, the results of dose escalation based on 3D-ASL demonstrated that the two boost plans significantly increased the dosimetric indices compared with the conventional plan of 60 Gy. However, there were two trends. On the one hand, the maximum doses of the three classes of PTVs all took on ascend trend among the conventional plan, the constrained boost plan and the unrestricted one. On the other hand, the constrained boost plan had better average and minimum doses than the other two plans, and this was the case for all three classes of PTVs. Thorwarth et al. noted that doses of up to 82 Gy may be applied to head and neck tumors without increasing toxicity, but constraints for normal tissue were not stated in their work.
Our results indicated that the dose delivered to OARs was increased less than 4.10% (2.19%-4.08%) except for the right eye (5.27%; 0.47 Gy) when the prescription dose for hypoxic subvolumes was increased by 20%. Undoubtedly, the absolute dose was still far below the dose constraint. In addition, the constrained boost plan outperformed the unconstrained plan in terms of OAR protection.
The conventional plan and both boost plans achieved target coverage of more than 98%, which indicated that the boost plans met the clinical dose requirement. Likewise, the constrained boost plan had better target coverage than the unconstrained boost plan and the conventional plan. Reducing the uniformity of the radiation dose is beneficial for dose escalation and OAR protection. The HI of the PTVH increased from 0.04 to 0.05 in Plan 2, suggesting that this boost plan achieved a well-targeted dose distribution. Meanwhile, it is necessary to confirm CI because the shape of the hypoxic subvolume as defined by blood flow is often irregular. In this work, the CI of the hypoxic subvolume was effectively improved through the boost plans with a minor sacrifice in terms of the HI, which further demonstrated the feasibility of our experimental method.
This study demonstrated that hypoxic subvolume delineation and dose escalation based on low CBF are potentially feasible and useful. There are still some limitations in this study. First, post-labeling delay(PLD) is one of the important parameters for accurate evaluation of CBF. However, in practice, it is difficult to ensure that PLD is set according to the specific conditions of patients to adapt to the arrival time of labeled arterial blood. Second, the effect of boost plans for BM still needs to be confirmed in clinical practice. Relevant research is under way.
In summary, hypoxia is one of the main reasons for the poor effect of RT on BM. It is feasible to delineate hypoxic subvolumes and escalate their radiation doses under the guidance of CBF distribution based on the quantitative method of 3D-ASL. An increased dose is targeted to the hypoxic subvolume without increasing the dose delivered to OARs. This approach provides an effective individualized dose-painting strategy for patients with BM.