Balancing benefits and limitations of linear energy transfer optimization in carbon ion radiotherapy for large sacral chordomas.

Background and Purpose: A low linear energy transfer (LET) in the target can reduce the effectiveness of carbon ion radiotherapy (CIRT). This study aimed at exploring benefits and limitations of LET optimization for large sacral chordomas (SC) undergoing CIRT. Materials and Methods: Seventeen cases were used to tune LET-based optimization, and seven to independently test interfraction plan robustness. For each patient, a reference plan was optimized on biologically-weighted dose cost functions. For the first group, 7 LET-optimized plans were obtained by increasing the gross tumor volume (GTV) minimum LETd (minLETd) in the range 37-55 keV/µm, in steps of 3 keV/µm. The optimal LET-optimized plan (LETOPT) was the one maximizing LETd, while adhering to clinical acceptability criteria. Reference and LETOPT plans were compared through dose and LETd metrics (D x , L x to x% volume) for the GTV, clinical target volume (CTV), and organs at risk (OARs). The 7 held-out cases were optimized setting minLETd to the average GTV L98% of the investigation cohort. Both reference and LETOPT plans were recalculated on re-evaluation CTs and compared. Results: GTV L98% increased from (31.8 ± 2.5)keV/µm to (47.6 ± 3.1)keV/µm on the LETOPT plans, while the fraction of GTV receiving over 50 keV/µm increased on average by 36% (p < 0.001), without affecting target coverage goals, or impacting LETd and dose to OARs. The interfraction analysis showed no significant worsening with minLETd set to 48 keV/µm. Conclusion: LETd optimization for large SC could boost the LETd in the GTV without significantly compromising plan quality, potentially improving the therapeutic effects of CIRT for large radioresistant tumors.

Dose averaged linear energy transfer optimization for large sacral chordomas in carbon ion therapy.

BACKGROUND: Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose-averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. PURPOSE: The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)-weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). METHODS: Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV-HD) larger than 250 cm 3 $250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE-weighted median dose prescription with the local effect model (LEM) was D RBE , 50 % = 73.6 Gy $\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ , L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and L min = 100 keV / µ m $\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$ . To compare the LETd optimized against reference plans, LETd and RBE-weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios ( ± 3.5 % $\pm 3.5\%$ range uncertainty and ± 3 mm $\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). RESULTS: The optimization method with L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) in the CTV-HD by 8.9 ± 1.5 keV / µ m $8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ ( 27 % $27\%$ ) (and 6.9 ± 1.3 keV / µ m $6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ ( 17 % $17\%$ )), without significant difference in the RBE-weighted dose. By allowing ± 5 % $\pm 5\%$ over- and under-dosage in the target, the LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) can be increased by 11.3 ± 1.2 keV / µ m $11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ ( 34 % $34\%$ ) (and 11.7 ± 3.4 keV / µ m $11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ ( 29 % $29\%$ )), using the optimization parameters L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ . The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. CONCLUSIONS: Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE-weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE-weighted dose robustness and acquiring more in-room images remain crucial and inevitable aspects during treatment.

Dose-averaged LET optimized carbon-ion radiotherapy for head and neck cancers.

This feasibility study confirmed the initial safety and efficacy of a novel carbon-ion radiotherapy (CIRT) using linear energy transfer (LET) painting for head and neck cancer. This study is the first step toward establishing CIRT with LET painting in clinical practice and making it a standard practice in the future.

The LET trilemma: Conflicts between robust target coverage, uniform dose, and dose-averaged LET in carbon therapy.

BACKGROUND: Linear energy transfer (LET) is closely related to the biological effect of ionizing radiation. Increasing the dose-averaged LET (LETd ) within the target volume has been proposed as a means to improve clinical outcome for hypoxic tumors. However, doing so can lead to reduced robustness to range uncertainty. PURPOSE: To quantify the relationship between robust target coverage, target dose uniformity, and LETd , we employ robust optimization using dose-based and LETd -based functions and allow varying amounts of target non-uniformity. METHODS AND MATERIALS: Robust carbon therapy optimization is used to create plans for phantom cases with increasing target sizes (radii 1, 3, and 5 cm). First, the influence of respectively range and setup uncertainty on the LETd in the target is studied. Second, we employ strategies allowing overdosage in the clinical target volume (CTV) or gross tumor volume (GTV), which enable increased LETd in the target. The relationship between robust target coverage and LETd in the target is illustrated by tradeoff curves generated by optimization using varying weights for the LETd -based functions. RESULTS: As the range uncertainty used in the robust optimization increased from 0% to 5%, the near-minimum nominal LETd decreased by 17%-29% (9-21 keV/µm) for the different target sizes. The effect of increasing setup uncertainty was marginal. Allowing 10% overdosage in the CTV enabled 9%-29% (6-12 keV/µm) increased near-minimum worst case LETd for the different target sizes, compared to uniform dose plans. When 10% overdosage was allowed in the GTV only, the increase was 1%-20% (1-8 keV/µm). CONCLUSIONS: There is an inherent conflict between range uncertainty robustness and high LETd in the target, which is aggravated with increasing target size. For large tumors, it is possible to simultaneously achieve two of the three qualities range robustness, uniform dose, and high LETd in the target.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist's viewpoint (Part 3): Chapter 3. Clinical research, Chapter 4. Future challenges, Chapter 5. Discussion, and Conclusion.

Clinical studies of ion beam therapy have been performed at the Lawrence Berkeley Laboratory (LBL), National Institute of Radiological Sciences (NIRS), Gesellschaft für Schwerionenforschung (GSI), and Deutsches Krebsforschungszentrum (DKFZ), in addition to the development of equipment, biophysical models, and treatment planning systems. Although cancers, including brain tumors and pancreatic cancer, have been treated with the Bevalac's neon-ion beam at the LBL (where the first clinical research was conducted), insufficient results were obtained owing to the limited availability of neon-ion beams and immaturity of related technologies. However, the 184-Inch Cyclotron's helium-ion beam yielded promising results for chordomas and chondrosarcomas at the base of the skull. Using carbon-ion beams, NIRS has conducted clinical trials for the treatment of common cancers for which radiotherapy is indicated. Because better results than X-ray therapy results have been obtained for lung, liver, pancreas, and prostate cancers, as well as pelvic recurrences of rectal cancer, the Japanese government recently approved the use of public medical insurance for carbon-ion radiotherapy, except for lung cancer. GSI obtained better results than LBL for bone and soft tissue tumors, owing to dose enhancement enabled by scanning irradiation. In addition, DKFZ compared treatment results of proton and carbon-ion radiotherapy for these tumors. This article summarizes a series of articles (Parts 1-3) and describes future issues of immune ion beam therapy and linear energy transfer optimization.