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.

Sacral-Nerve-Sparing Planning Strategy in Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy.

To minimize radiation-induced lumbosacral neuropathy (RILSN), we employed sacral-nerve-sparing optimized carbon-ion therapy strategy (SNSo-CIRT) in treating 35 patients with pelvic sarcomas/chordomas. Plans were optimized using Local Effect Model-I (LEM-I), prescribed DRBE|LEM-I|D50% (median dose to HD-PTV) = 73.6 (70.4-76.8) Gy (RBE)/16 fractions. Sacral nerves were contoured between L5-S3 levels. DRBE|LEM-I to 5% of sacral nerves-to-spare (outside HD-CTV) (DRBE|LEM-I|D5%) were restricted to <69 Gy (RBE). The median follow-up was 25 months (range of 2-53). Three patients (9%) developed late RILSN (≥G3) after an average period of 8 months post-CIRT. The RILSN-free survival at 2 years was 91% (CI, 81-100). With SNSo-CIRT, DRBE|LEM-I|D5% for sacral nerves-to-spare = 66.9 ± 1.9 Gy (RBE), maintaining DRBE|LEM-I to 98% of HD-CTV (DRBE|LEM-I|D98%) = 70 ± 3.6 Gy (RBE). Two-year OS and LC were 100% and 93% (CI, 84-100), respectively. LETd and DRBE with modified-microdosimetric kinetic model (mMKM) were recomputed retrospectively. DRBE|LEM-I and DRBE|mMKM were similar, but DRBE-filtered-LETd was higher in sacral nerves-to-spare in patients with RILSN than those without. At DRBE|LEM-I cutoff = 64 Gy (RBE), 2-year RILSN-free survival was 100% in patients with <12% of sacral nerves-to-spare voxels receiving LETd > 55 keV/µm than 75% (CI, 54-100) in those with ≥12% of voxels (p < 0.05). DRBE-filtered-LETd holds promise for the SNSo-CIRT strategy but requires longer follow-up for validation.

Validation of a deep-learning segmentation model for adult and pediatric head and neck radiotherapy in different patient positions.

Background and purpose: Autocontouring for radiotherapy has the potential to significantly save time and reduce interobserver variability. We aimed to assess the performance of a commercial autocontouring model for head and neck (H&N) patients in eight orientations relevant to particle therapy with fixed beam lines, focusing on validation and implementation for routine clinical use. Materials and methods: Autocontouring was performed on sixteen organs at risk (OARs) for 98 adult and pediatric patients with 137 H&N CT scans in eight orientations. A geometric comparison of the autocontours and manual segmentations was performed using the Hausdorff Distance 95th percentile, Dice Similarity Coefficient (DSC) and surface DSC and compared to interobserver variability where available. Additional qualitative scoring and dose-volume-histogram (DVH) parameters analyses were performed for twenty patients in two positions, consisting of scoring on a 0-3 scale based on clinical usability and comparing the mean (Dmean) and near-maximum (D2%) dose, respectively. Results: For the geometric analysis, the model performance in head-first-supine straight and hyperextended orientations was in the same range as the interobserver variability. HD95, DSC and surface DSC was heterogeneous in other orientations. No significant geometric differences were found between pediatric and adult autocontours. The qualitative scoring yielded a median score of ≥ 2 for 13/16 OARs while 7/32 DVH parameters were significantly different. Conclusions: For head-first-supine straight and hyperextended scans, we found that 13/16 OAR autocontours were suited for use in daily clinical practice and subsequently implemented. Further development is needed for other patient orientations before implementation.

Investigation on the physical dose filtered by linear energy transfer for treatment plan evaluation in carbon ion therapy.

BACKGROUND: Large tumor size has been reported as a predicting factor for inferior clinical outcome in carbon ion radiotherapy (CIRT). Besides the clinical factors accompanied with such tumors, larger tumors receive typically more low linear energy transfer (LET) contributions than small ones which may be the underlying physical cause. Although dose averaged LET is often used as a single parameter descriptor to quantify the beam quality, there is no evidence that this parameter is the optimal clinical predictor for the complex mixed radiation fields in CIRT. PURPOSE: Purpose of this study was to investigate on a novel dosimetric quantity, namely high-LET-dose ( D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ , the physical dose filtered based on an LET threshold) as a single parameter estimator to differentiate between carbon ion treatment plans (cTP) with a small and large tumor volume. METHODS: Ten cTPs with a planning target volume, PTV ≥ 500 cm 3 $\mathrm{PTV}\ge {500}\,{{\rm cm}^{3}}$ (large) and nine with a PTV < 500 cm 3 $\mathrm{PTV}<{500}\,{{\rm cm}^{3}}$ (small) were selected for this study. To find a reasonable LET threshold ( L thr $\textrm {L}_{\textrm {thr}}$ ) that results in a significant difference in terms of D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ , the voxel based normalized high-LET-dose ( D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) distribution in the clinical target volume (CTV) was studied on a subset (12 out of 19 cTPs) for 18 LET thresholds, using standard distribution descriptors (mean, variance and skewness). The classical dose volume histogram concept was used to evaluate the D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ distributions within the target of all 19 cTPs at the before determined L thr $\textrm {L}_{\textrm {thr}}$ . Statistical significance of the difference between the two groups in terms of mean D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ volume histogram parameters was evaluated by means of (two-sided) t-test or Mann-Whitney-U-test. In addition, the minimum target coverage at the above determined L thr $\textrm {L}_{\textrm {thr}}$ was compared and validated against three other thresholds to verify its potential in differentiation between small and large volume tumors. RESULTS: An L thr $\textrm {L}_{\textrm {thr}}$ of approximately 30 keV / µ m ${30}\,{\rm keV/}\umu {\rm m}$ was found to be a reasonable threshold to classify the two groups. At this threshold, the D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ were significantly larger ( p < 0.05 $p<0.05$ ) in small CTVs. For the small tumor group, the near-minimum and median D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ (and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) in the CTV were in average 9.3 ± 1.5 Gy $9.3\pm {1.5}\,{\rm Gy}$ (0.31 ± 0.08) and 13.6 ± 1.6 Gy $13.6\pm {1.6}\,{\rm Gy}$ (0.46 ± 0.06), respectively. For the large tumors, these parameters were 6.6 ± 0.2 Gy $6.6\pm {0.2}\,{\rm Gy}$ (0.20 ± 0.01) and 8.6 ± 0.4 Gy $8.6\pm {0.4}\,{\rm Gy}$ (0.28 ± 0.02). The difference between the two groups in terms of mean near-minimum and median D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ ( D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) was 2.7 Gy (11%) and 5.0 Gy (18%), respectively. CONCLUSIONS: The feasibility of high-LET-dose based evaluation was shown in this study where a lower D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ was found in cTPs with a large tumor size. Further investigation is needed to draw clinical conclusions. The proposed methodology in this work can be utilized for future high-LET-dose based studies.

Planning Strategy to Optimize the Dose-Averaged LET Distribution in Large Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy.

To improve outcomes in large sarcomas/chordomas treated with CIRT, there has been recent interest in LET optimization. We evaluated 22 pelvic sarcoma/chordoma patients treated with CIRT [large: HD-CTV ≥ 250 cm3 (n = 9), small: HD-CTV < 250 cm3 (n = 13)], DRBE|LEM-I = 73.6 (70.4-73.6) Gy (RBE)/16 fractions, using the local effect model-I (LEM-I) optimization and modified-microdosimetric kinetic model (mMKM) recomputation. We observed that to improve high-LETd distribution in large tumors, at least 27 cm3 (low-LETd region) of HD-CTV should receive LETd of ≥33 keV/µm (p < 0.05). Hence, LETd optimization using 'distal patching' was explored in a treatment planning setting (not implemented clinically yet). Distal-patching structures were created to stop beams 1-2 cm beyond the HD-PTV-midplane. These plans were reoptimized and DRBE|LEM-I, DRBE|mMKM, and LETd were recomputed. Distal patching increased (a) LETd50% in HD-CTV (from 38 ± 3.4 keV/µm to 47 ± 8.1 keV/µm), (b) LETdmin in low-LETd regions of the HD-CTV (from 32 ± 2.3 keV/µm to 36.2 ± 3.6 keV/µm), (c) the GTV fraction receiving LETd of ≥50 keV/µm, (from <10% to >50%) and (d) the high-LETd component in the central region of the GTV, without significant compromise in DRBE distribution. However, distal patching is sensitive to setup/range uncertainties, and efforts to ascertain robustness are underway, before routine clinical implementation.

Dosimetric analysis of intraocular hemorrhage in nonsquamous head and neck cancers treated with carbon-ion radiotherapy.

BACKGROUND AND PURPOSE: Carbon-ion radiotherapy is an attractive treatment option for unresectable/inoperable, nonsquamous cancers of the head and neck. Intraocular hemorrhage associated with carbon-ion radiotherapy for head and neck cancer is largely an unresearched area; hence, we investigated its incidence and predictive factors. MATERIAL AND METHODS: We evaluated 79 patients (i.e., 158 eyes) with nonsquamous cancers of the head and neck treated by carbon-ion radiotherapy with a follow-up period of ≥12 months. Dosimetric parameters such as Dmax, Dmean and Vd [volume irradiated with "d" Gy (RBE)] and age, gender, primary site, histology and comorbidities were analyzed as predictors of intraocular hemorrhage. RESULTS: Seven (8.9%) of 79 patients (158 eyes) developed intraocular hemorrhage with a median latent period of 24 months (range, 15-47 months). The 5-year cumulative incidence of intraocular hemorrhage was 6%. Dmax and V10-60 for eyeballs, retina and optic nerves were significantly higher in intraocular hemorrhage group than the rest (p <0.001 for Dmax and V10-60). On univariate analysis, V40 ≥0.83 cm3 and ≥0.66 cm3 (p = 0.001) and Dmax ≥54.75 Gy (RBE) and ≥54.58 Gy (RBE) (p = 0.002) for eyeball and retina, respectively, were predictors of intraocular hemorrhage. Additionally, maxillary primary (p = 0.025) and younger age (age <60 years, p = 0.048) were significant risk factors for intraocular hemorrhage. CONCLUSIONS: Dosimetric parameters such as V40 and Dmax for the eyeball, retina and maxillary sinus primary and younger age were significant predictors of intraocular hemorrhage following carbon-ion radiotherapy.

64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity.

Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.

Reporting of methodologies used for clonogenic assays to determine radiosensitivity.

Radiotherapy treatment strategies should be personalized based on the radiosensitivity of individual tumors. Clonogenic assays are the gold standard method for in vitro assessment of radiosensitivity. Reproducibility is the critical factor for scientific rigor; however, this is reduced by insufficient reporting of methodologies. In reality, the reporting standards of methodologies pertaining to clonogenic assays remain unclear. To address this, we performed a literature search and qualitative analysis of the reporting of methodologies pertaining to clonogenic assays. A comprehensive literature review identified 1672 papers that report the radiosensitivity of human cancer cells based on clonogenic assays. From the identified papers, important experimental parameters (i.e. number of biological replicates, technical replicates, radiation source and dose rate) were recorded and analyzed. We found that, among the studies, (i) 30.5% did not report biological or technical replicates; (ii) 47.0% did not use biological or technical replicates; (iii) 3.8% did not report the radiation source; and (iv) 32.3% did not report the dose rate. These data suggest that reporting of methodologies pertaining to clonogenic assays in a considerable number of previously published studies is insufficient, thereby threatening reproducibility. This highlights the need to raise awareness of standardization of the methodologies used to conduct clonogenic assays.

FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy.

Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

Radiosensitivity Differences between EGFR Mutant and Wild-Type Lung Cancer Cells are Larger at Lower Doses.

In the era of precision medicine, radiotherapy strategies should be determined based on genetic profiles that predict tumor radiosensitivity. Accordingly, pre-clinical research aimed at discovering clinically applicable genetic profiles is needed. However, how a given genetic profile affects cancer cell radiosensitivity is unclear. To address this issue, we performed a pilot in vitro study by utilizing EGFR mutational status as a model for genetic profile. Clonogenic assays of EGFR mutant (n = 6) and wild-type (n = 9) non-small cell lung carcinoma (NSCLC) cell lines were performed independently by two oncologists. Clonogenic survival parameters SF2, SF4, SF6, SF8, mean inactivation dose (MID), D10, D50, α, and ß were obtained using the linear quadratic model. The differences in the clonogenic survival parameters between the EGFR mutant and wild-type cell lines were assessed using the Mann-Whitney U test. As a result, for both datasets, the p values for SF2, SF4, D50, α, and α/ß were below 0.05, and those for SF2 were lowest. These data indicate that a genetic profile of NSCLC cell lines might be predictive for their radiation response; i.e., EGFR mutant cell lines might be more sensitive to low dose- and low fraction sized-irradiation.

Primary mediastinal seminoma; resistance and relapse: An aggressive entity.

Seminoma is one of the most radio and chemo sensitive tumors. Aggressive variant of primary mediastinal seminoma (PMS) are rarely described in the literature. We here discuss an interesting case of young male (22 years) presenting with superior vena cava syndrome due to PMS that showed poor response to conventional platinum based chemotherapy and radiotherapy. Furthermore, with a short disease free interval (one year) relapsed at unusual sites of bone and soft-tissue deposits in check. This emphasizes the importance of identifying methods to pre-screen such aggressive variants for more effective treatment options.

Unusual coexistence of a renal anomaly and germ cell tumor: An embryonal happenstance?

The germ cell lines and kidney develop in close proximity in a similar embronic period. The extragonadal germ cell tumors and horseshoe kidney both are the result of abnormal migration of two germ line cells. Apart from origin, the combined incidence of mediastinal germ cell tumor with renal anomaly is a therapeutic challenge. This case review is an effort to address the various issues ranging from delima in origin to management and follow-up.