Tumor Dose Response Research Articles

SBRT for Liver Tumors: What the Interventional Radiologist Needs to Know.

This review summarizes the clinical evidence supporting the utilization of stereotactic body radiotherapy (SBRT) for liver tumors, including hepatocellular carcinoma, liver metastases, and cholangiocarcinoma. Emerging prospective evidence has demonstrated the benefit and low rates of toxicity across a broad range of clinical contexts. We provide an introduction for the interventional radiologist, with a discussion of underlying themes such as tumor dose-response, mitigation of liver toxicity, and the technical considerations relevant to performing liver SBRT. Ultimately, we recommend that SBRT should be routinely included in the armamentarium of locoregional therapies for liver malignancies, alongside those liver-directed therapies offered by interventional radiology.

“Primer shot” fractionation with an early treatment break is theoretically superior to consecutive weekday fractionation schemes for early-stage non-small cell lung cancer

PurposeRadiotherapy is traditionally given in equally spaced weekday fractions. We hypothesize that heterogeneous interfraction intervals can increase radiosensitivity via reoxygenation. Through modeling, we investigate whether this minimizes local failures and toxicity for early-stage non-small cell lung cancer (NSCLC). MethodsPreviously, a tumor dose-response model based on resource competition and cell-cycle-dependent radiosensitivity accurately predicted local failure rates for early-stage NSCLC cohorts. Here, the model mathematically determined non-uniform inter-fraction intervals minimizing local failures at similar normal tissue toxicity risk, i.e., iso-BED3 (iso-NTCP) for fractionation schemes 18Gyx3, 12Gyx4, 10Gyx5, 7.5Gyx8, 5Gyx12, 4Gyx15. Next, we used these optimized schedules to reduce toxicity risk (BED3) while maintaining stable local failures (TCP). ResultsOptimal schedules consistently favored a “primer shot” fraction followed by a 2-week break, allowing tumor reoxygenation. Increasing or decreasing the assumed baseline hypoxia extended or shortened this optimal break by up to one week. Fraction sizes of 7.5 Gy and up required a single primer shot, while smaller fractions needed one or two extra fractions for full reoxygenation. The optimized schedules, versus consecutive weekday fractionation, predicted absolute LF reductions of 4.6%-7.4%, except for the already optimal LF rate seen for 18Gyx3. Primer shot schedules could also reduce BED3 at iso-TCP with the biggest improvements for the shortest schedules (94.6Gy reduction for 18Gyx3). ConclusionA validated simulation model clearly supports non-standard “primer shot” fractionation, reducing the impact of hypoxia-induced radioresistance. A limitation of this study is that primer-shot fractionation is outside prior clinical experience and therefore will require clinical studies for definitive testing.

Effects of Interfraction Dose Variations of Target and Organs at Risk on Clinical Outcomes in High Dose Rate Brachytherapy for Cervical Cancer.

Meeting dose prescription is critical to control tumors in radiation therapy. Interfraction dose variations (IDVs) from the prescribed dose in high dose rate brachytherapy (HDR) would cause the target dose to deviate from the prescription but their clinical effect has not been widely discussed in the literature. Our previous study found that IDVs followed a left-skewed distribution. The clinical effect of the IDVs in 100 cervical cancer HDR patients will be addressed in this paper. An in-house Monte Carlo (MC) program was used to simulate clinical outcomes by convolving published tumor dose response curves with IDV distributions. The optimal dose and probability of risk-free local control (RFLC) were calculated using the utility model. The IDVs were well-fitted by the left-skewed Beta distribution, which caused a 3.99% decrease in local control probability and a 1.80% increase in treatment failure. Utility with respect to IDV uncertainty increased the RFLC probability by 6.70% and predicted an optimal dose range of 83 Gy-91 Gy EQD2. It was also found that a 10 Gy dose escalation would not affect toxicity. In conclusion, HRCTV IDV uncertainty reduced LC probabilities and increased treatment failure rates. A dose escalation may help mitigate such effects.

Tumor Treatment Response Assessed During the Chemo-Radiotherapy for Locally Advanced NSCLC

To evaluate the capability of assessing intratumoral treatment response distribution with using FDG-PET/CT during the chemoradiotherapy of locally advanced NSCLC. Twelve of total 50 patients with stage III NSCLC were enrolled in the institutional protocol for concurrent chemoradiotherapy with treatment dose of 54-60 Gy in 27-30 fractions. For each patient, a pre-treatment FDG-PET/CT image (SUV0) and a mid-treatment image (SUVm) obtained within the treatment dose of 24 ∼ 46 Gy were obtained. Followed by deformable PET/CT registration between SUV0 and SUVm, the tumor voxel SUV reduction ratio was obtained to construct a tumor dose response matrix (DRM). Tumor SUVavid was also constructed by limiting tumor voxel SUVm > a given value. Spatial correlations of the tumor SUV0, SUVm, SUVavid and DRM were determined. The mean and coefficient variation (CV) of the SUV0, SUVm and DRM for all tumors were 6.56(64%), 2.82(59%) and 0.52(70%) (Table contains the individual data), which were like those on the SUVs and the mean DRM of head-neck HPV- patients reported previously, but much larger on the DRM variation. The inter-tumoral CVs of SUV0 and DRM were 17% and 43%, which were much smaller than those of the intra-tumoral CVs 61% and 55%. Meanwhile, the intra-tumoral variations on both SUV0 and DRM were much larger than those of head-neck HPV- patients. There was a weak correlation between SUV0 and SUVm with the correlation coefficient 0.32, a medium correlation of -0.51 between SUV0 and DRM; 0.58 between SUVm and DRM. It implies that the rule of tumor dose response DRM on treatment modification decision cannot be fully replaced by either SUV0 or SUVm. The spatial correlation between tumor DRM and SUVavid was 0.23 with SUVavid value > 3, which was getting weaker when increasing SUVavid value. Spatial dose response for NSCLC assessed using FDG-PET/CT feedback demonstrated high treatment resistant patterns, which had a large intra-tumoral variation. In addition, the medium correlations of DRM vs SUV0 and DRM vs SUVm imply that all these factors could be used to guide adaptive modification of NSCLC treatment.

Tumor Treatment Response Assessed During the Concurrent Chemoradiotherapy for Nasopharyngeal Patients

To evaluate intratumoral treatment response distribution with using FDG-PET/CT during the chemoradiotherapy of nasopharyngeal patients (NPC). A total of 5 of 30 patients with stage III-IVA NPC were enrolled in the institutional protocol for induction/concurrent chemoradiotherapy with radiation dose of 70 Gy in 33 fractions. For each patient, a pre-radiation treatment FDG-PET/MRI image (SUV0) and a mid-treatment image (SUVm) at the treatment dose of 31.8 Gy were obtained. Followed by deformable PET/MRI registration between SUV0 and SUVm, the tumor voxel SUV reduction ratio was obtained to construct a tumor dose response matrix (DRM). Tumor SUVavid was also constructed by limiting tumor voxel SUVm > a given value. Spatial correlations of the tumor SUV0, SUVm, SUVavid and DRM were determined. The mean and coefficient variation (CV) of the SUV0, SUVm and DRM for all tumors were 5.05 (52%), 2.72 (49%) and 0.64 (63%) (Table contains the individual data), which were smaller than those on the SUVs of head-n-neck HPV+ patients reported previously due to the induction chemotherapy, but had much larger DRM mean and CV. The inter-tumoral CVs of SUV0 and DRM were 29% and 27%, which were much lower than those of the intra-tumoral CVs 43% and 57%. Meanwhile, the intra-tumoral variations on SUV0 was smaller than the one of head-neck HPV+ patients, but the DRM intra-variation was much larger. There was a weak correlation between SUV0 and SUVm with the correlation coefficient 0.13, a medium correlation of -0.55 between SUV0 and DRM, but a strong correlation, 0.72, between SUVm and DRM. However, the spatial correlation between tumor DRM and SUVavid was getting weaker as the SUVavid value increasing and equal 0.47 with SUVavid value > 3. The spatial dose response DRM for NPC in the concurrent chemoradiotherapy was relatively high, while had relatively low baseline tumor metabolic activity SUV0. It was most likely due to the induction chemotherapy. In addition, the tumor dose response showed vary large intra-tumoral variation. The high correlations between DRM and SUVm imply that SUVavid could be used partially to guide adaptive modification of NPC treatment with carefully selected boundary value.

A Theranostic Approach to Imaging and Treating Melanoma with 203Pb/212Pb-Labeled Antibody Targeting Melanin.

Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several immunotherapeutic agents into the clinic over the past decade, inspiring the development of novel therapeutics and the exploration of combination therapies. Our investigations target melanin pigment with melanin-specific radiolabeled antibodies as a strategy to treat metastatic melanoma. In this study, a theranostic approach was applied by first labeling a chimeric antibody targeting melanin, c8C3, with the SPECT radionuclide 203Pb for microSPECT/CT imaging of C57Bl6 mice bearing B16-F10 melanoma tumors. Imaging was followed by radioimmunotherapy (RIT), whereby the c8C3 antibody is radiolabeled with a 212Pb/212Bi "in vivo generator", which emits cytotoxic alpha particles. Using microSPECT/CT, we collected sequential images of B16-F10 murine tumors to investigate antibody biodistribution. Treatment with the 212Pb/212Bi-labeled c8C3 antibody demonstrated a dose-response in tumor growth rate in the 5-10 µCi dose range when compared to the untreated and radiolabeled control antibody and a significant prolongation in survival. No hematologic or systemic toxicity of the treatment was observed. However, administration of higher doses resulted in a biphasic tumor dose response, with the efficacy of treatment decreasing when the administered doses exceeded 10 µCi. These results underline the need for more pre-clinical investigation of targeting melanin with 212Pb-labeled antibodies before the clinical utility of such an approach can be assessed.

Voxel-based dosimetry predicting treatment response and related toxicity in HCC patients treated with resin-based Y90 radioembolization: a prospective, single-arm study

BackgroundThere is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC).PurposeTo evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization.Materials and methodsThis correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral liver dose (NTLD) < 70 Gy for non-segmental therapies. Single compartment dose of 200 Gy was used for segmentectomies. Prescribed Y90 activity minus scout activity was administered for therapeutic Y90 followed by Y90-PET/CT. Sureplan® (MIM Software, Cleveland, OH) was used for dosimetry analysis. Treatment response was evaluated at 3 and 6 months. Receiver operating characteristic curve determined TD response threshold for objective response (OR) and complete response (CR) as well as non-tumor liver dose (NTLD) threshold that predicted AEs.ResultsN = 30 patients were treated with 33 tumors (19 segmental and 14 non-segmental). One patient died before the first imaging, and clinical follow-up was excluded from this analysis. Overall, 26 (81%) of the tumors had an OR and 23 (72%) had a CR. A mean TD of 253 Gy predicted an OR with 92% sensitivity and 83% specificity (area under the curve (AUC = 0.929, p < 0.001). A mean TD of 337 Gy predicted a CR with 83% sensitivity and 89% specificity (AUC = 0.845, p < 0.001). A mean NTLD of 81 and 87 Gy predicted grade 3 AEs with 100% sensitivity and 100% specificity in the non-segmental cohort at 3- and 6-month post Y90, respectively.ConclusionIn patients with HCC undergoing resin-based Y90, there are dose response and dose toxicity thresholds directly affecting outcomes.Clinical trial number: NCT04172714.

Using Deep Learning to Predict Treatment Response in Patients with Hepatocellular Carcinoma Treated with Y90 Radiation Segmentectomy.

Treatment of hepatocellular carcinoma (HCC) with Y90 radioembolization segmentectomy (Y90-RE) demonstrates a tumor dose-response threshold, where dose estimates are highly dependent on accurate SPECT/CT acquisition, registration, and reconstruction. Any error can result in distorted absorbed dose distributions and inaccurate estimates of treatment success. This study improves upon the voxel-based dosimetry model, one ofthe most accurate methods available clinically, by using a deep convolutional network ensemble to account for the spatially variable uptake of Y90 within a treated lesion. A retrospective analysis was conducted in patients with HCC who received Y90-RE at a single institution. Seventy-seven patients with 103 lesions met the inclusion criteria: three or fewer tumors, pre- and post treatment MRI, and no prior Y90-RE. Lesions were labeled as complete (n = 57) or incomplete response (n = 46) based on 3-month post treatment MRI and divided by medical record number into a 20% hold-out test set and 80% training set with 5-fold cross-validation. Slice-wise predictions were made from an average ensemble of models and thresholds from the highest accuracy epochs across all five folds. Lesion predictions were made by thresholding all slice predictions through the lesion. When compared to the voxel-based dosimetry model, our model had a higher F1-score (0.72 vs. 0.2), higher accuracy (0.65 vs. 0.60), and higher sensitivity (1.0 vs. 0.11) at predicting complete treatment response. This algorithm has the potential to identify patients with treatment failure who may benefit from earlier follow-up or additional treatment.

Dose Response of Bulky Tumors in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

<h3>Purpose/Objective(s)</h3> This study sought to assess whether there is a radiotherapy (RT) dose response for bulky tumors in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). <h3>Materials/Methods</h3> Patients with r/r DLBCL (age ≥18 years) treated with salvage- or palliative-intent RT (2008-2020) at a single institution were included. Course-level data were examined to assess in-field responses of index lesions. Courses used for either post-therapy consolidation, CNS or skin disease, and TBI conditioning were excluded. Index lesion size ≥7.5 cm was considered bulky. EQD2s (α/β = 10) were calculated to accurately compare biologic effective doses between conventional and hypofractionated (≥2.5 Gy/fraction) schemes. Post-treatment responses of index lesions were classified using Lugano Criteria. Objective response rates (ORR), defined as achieving either CR or PR, were compared between non-bulky and bulky tumors using Fisher's exact test. Freedom from local progression (FFLP) and overall survival (OS, patient-level data) from RT start date were recorded. Bulky disease impacts on FFLP and OS were assessed using Kaplan-Meier and multivariable-adjusted Cox proportional hazard regression analyzes. <h3>Results</h3> 151 r/r DLBCL patients underwent 183 RT courses (median follow-up time: 6 months, IQR: 2-17 months). Median age at RT was 67 years (IQR: 56-72 years) with a male/female ratio of 55%/45%. Non-bulky and bulky tumors were treated in 109 (60%) and 74 (40%) cases, respectively. Intent was classified as salvage or palliative in 68 (37%) and 115 (63%) cases, respectively. Median EQD2 was 33 Gy (IQR: 23-39 Gy) with hypofractionation used in 84 (46%) cases. Of those with post-RT imaging (n = 146, 80%), there was a trend towards lower ORR for bulky vs. non-bulky tumors (50% vs. 65%, p = 0.087; CR: 21% vs. 42%, PR: 29% vs. 23%, SD: 28% vs. 14%, PD: 22% vs. 22%). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs. >30 Gy: 27% vs. 64%, p = 0.014), whereas a lower EQD2 cut-off was sufficient for non-bulky tumors (<20 Gy vs. ≥20 Gy: 38% vs. 73%, p = 0.0076). In all courses, bulky tumors were significantly associated with shorter FFLP (median: 5.6 months vs. not reached, HR = 2.30, 95% CI: 1.24-4.26, p = 0.0079) and OS (median: 3.7 vs. 10.1 months, HR = 1.66, 95% CI: 1.06-2.58, p = 0.025). Amongst bulky tumors, there was a trend towards improved FFLP with RT regimens with higher EQD2s (20-30 Gy vs. <20 Gy - median: 4.2 vs. 2.3 months, HR = 0.38, 95% CI: 0.09-1.62, p = 0.19; >30 Gy vs. <20 Gy - median: not reached vs. 2.3 months, HR = 0.34, 95% CI: 0.11-1.01, p = 0.053). <h3>Conclusion</h3> In this study, bulky r/r DLBCL tumors were associated with less favorable outcomes in salvage and palliative settings. If durable local control of bulky tumors is needed, RT regimens using higher EQD2s (>30 Gy) should be considered, including cases where shortened, hypofractionated courses are opted for such as during the SARS-CoV-2 pandemic, bridging to CAR-T cell infusion, or prior to allogeneic stem cell transplantation.

Analysis of tumour dose-response data from animal experiments via two TCP models accounting for tumor hypoxia and resensitization.

To treat animal dose-response data exhibiting inverse dose-response behavior with two tumor control probability (TCP) models accounting for tumor hypoxia and re-oxygenation leading to resensitization of the tumor. One of the tested TCP models uses a modified linear-quadratic (LQ) model of cell survival where both α and β radiosensitivities increase in time during the treatment due to re-oxygenation of the hypoxic tumor sub-population. The other TCP model deals with two types of hypoxia-chronic and acute-and accounts for tumor re-sensitization via oxygenation of the chronically hypoxic and fluctuating oxygenation of the acutely hypoxic sub-populations. The two models are fit using the maximum likelihood method to the data of Fowler et al. on mice mammary tumors irradiated to different doses using different fractionated schedules. These data are chosen since as many as five of the dose-response curves show an inverse dose behavior, which is interpreted as due to re-sensitization. The p-values of the fits of both models to the data render them statistically acceptable. A performed comparison test shows that both models describe the data equally well. It is also demonstrated that the most sensitive (oxic) tumor component has no impact on the treatment outcome. The ability of the tested models to predict and describe the impact of re-sensitization on the treatment outcome is thus proven. It is also demonstrated that prolonged treatment schedules can be more beneficial than shorter ones. However, this may be true only for schedules with small number of fractions, i.e. for hypo-fractionated treatments only.

Abstract No. 244 Determination of tumor dose response threshold and implication on survival in patients with metastatic uveal melanoma to the liver undergoing yttrium-90 radioembolization

To evaluate the relationship between yttrium-90 (Y-90) tumor dose (TD) and response rate and its implication on overall survival (OS) in patients with metastatic uveal melanoma to the liver undergoing Y-90 radioembolization (Y-90-RE)

Reassessment of the lung dose limits for radioembolization.

Radioembolization, also known as selective internal radiation therapy (SIRT), is an established treatment for the management of patients with unresectable liver tumors. Advances in liver dosimetry and new knowledge about tumor dose-response relationships have helped promote the well-tolerated use of higher prescribed doses, consequently transitioning radioembolization from palliative to curative therapy. Lung dosimetry, unfortunately, has not seen the same advances in dose calculation methodology and renewed consensus in dose limits as normal liver and tumor dosimetry. Therefore, the efficacy of curative radioembolization may be compromised in patients where the current lung dose calculations unnecessarily limit the administered activity. The field is thus at a stage where a systematic review and update of lung dose limits is necessary to advance the clinical practice of radioembolization. This work summarizes the historical context and literature for origins of the current lung dose limits following radioembolization, that is, the 25-year-old, single institution, small patient cohort series that helped establish the lung shunt fraction and dose limits. Newer clinical evidence based on larger patient cohorts that challenges the historical data on lung dose limits are then discussed. We conclude by revisiting the rationale for current lung dose limits and by proposing a staged approach to advance the field of lung dosimetry and thus the practice of radioembolization as a whole.

Determination of Tumor Dose Response Thresholds in Patients with Chemorefractory Intrahepatic Cholangiocarcinoma Treated with Resin and Glass-based Y90 Radioembolization.

To compare the efficacies of glass and resin-based Yttrium-90 microspheres by comparing absorbed tumor dose (TD) with both tumor response (TR) and overall survival (OS) in patients with chemorefractory intrahepatic cholangiocarcinoma (ICC). Post-Y90 treatment bremsstrahlung SPECT/CT of 38 consecutive patients receiving 45 treatments (21 resin microspheres, 24 glass microspheres) were analyzed retrospectively. MIM software v6.9.4 (MIM Software Inc, Cleveland, OH) was used to calculate targeted tumors' dose volume histogram. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate tumor response 3months post-treatment. Kaplan Meier estimation was used for survival analysis. T-test was used to compare the devices on various dosimetric parameters. Thresholds for TD to predict TR with ≥ 80% specificity were as follows: mean TD (Resin: 78.9Gy; Glass: 254.7Gy), maximum TD (Resin: 162.9Gy; Glass: 591Gy), minimum TD (Resin: 53.7Gy; Glass: 149.1Gy). Microsphere type had no effect on survival from first Y90 (Resin: 11.2 mo; Glass 10.9 mo [p = 0.548]). In patients receiving resin microspheres, mean TD ≥ 75Gy or maximum TD ≥ 150Gy was associated with median OS of 20.2 mo compared to 6.5 mo for those receiving less (p = 0.001, 0.002, respectively). For patients treated with glass microspheres, those receiving a mean TD ≥ 150Gy had a median OS of 14.6 mo vs. 2.6 mo for those receiving less (p = 0.031). TD thresholds predictive of TR and OS differ significantly between glass and resin microspheres. However, microsphere type has no impact on survival in patients with chemorefractory ICC. Level 3, Retrospective Study.

Determination of tumour dose response threshold and implication on survival in patients with HCC treated with Y90 radiation segmentectomy: a simple semi-quantitative analysis.

To evaluate the relationship between Yttrium-90 (Y90) tumour dose and response rate in patients with hepatocellular carcinoma (HCC) who undergo Y90 radiation segmentectomy (Y90-RS) and to determine implication on overall survival (OS). Post Y90-RS Bremsstrahlung single-photon emission computed tomography/CT of 105 HCC patients with 110 treatments performed with glass microspheres was retrospectively analysed. The dose-volume histogram of the targeted tumour was determined with commercially available dosimetry software. Tumour response at 3 months was evaluated using modified Response Evaluation Criteria in Solid Tumours. Tumour dose thresholds associated with the objective response with 80% specificity were then used to evaluate implication on OS using Kaplan-Meier estimation and log-rank analysis. Tumour dose thresholds to predict objective response with 80% specificity were the following: maximum tumour dose (748 Gy), mean tumour dose (568 Gy), minimum tumour dose of 30% tumour volume (608 Gy), minimum tumour dose of 50% tumour volume (565 Gy), minimum tumour dose of 70% tumour volume (464 Gy) and minimum tumour dose of 100% tumour volume (213 Gy). These parameters all significantly predicted tumour response with areas under the ROC curve of >0.6. Mean tumour dose of ≥250 Gy predicted median OS of 43.67 vs. 17.87 months for others (P = 0.026). Minimum dose ≥180 Gy to 100% of tumour volume predicted median OS of 44.93 vs. 35.87 months for others (P = 0.043). In patients with HCC undergoing Y90-RS, mean tumour dose ≥250 Gy and minimum tumour dose of ≥180 Gy to 100% of tumour volume are both significantly correlated with higher objective tumour response and prolonged survival.

Lung shunt and lung dose calculation methods for radioembolization treatment planning.

Radioembolization, also known as selective internal radiation therapy (SIRT), is firmly established in the management of patients with unresectable liver cancers. Advances in normal and tumor liver dosimetry and new knowledge about tumor dose response relationships have helped promote the safe use of higher prescribed doses, consequently transitioning radioembolization from palliative to curative therapy. The lungs are considered a critical organ of risk for radioembolization treatment planning. Unfortunately, lung dosimetry has not achieved similar advances in dose calculation methodology as liver dosimetry. Current estimations of lung dose are dependent on a number of parameters associated with data acquisition and processing algorithms, leading to poor accuracy and precision. Therefore, the efficacy of curative radioembolization may be compromised in patients for whom the lung dose derived using currently available methods unnecessarily limits the desired administered activity to the liver. We present a systematic review of the various methods of determining the lung shunt fraction (LSF) and lung mean dose (LD). This review encompasses pretherapy estimations and post-therapy assessments of the LSF and LD using both 2D planar and 3D SPECT/CT based calculations. The advantages and limitations of each of these methods are deliberated with a focus on accuracy and practical considerations. We conclude the review by presenting a lexicon to precisely describe the methodology used for the estimation of LSF and LD; specifically, category, agent, modality, contour and algorithm, in order to aid in their interpretation and standardization in routine clinical practice.

Imputing radiobiological parameters of the linear-quadratic dose-response model from a radiotherapy fractionation plan

The objective in cancer radiotherapy is to maximize tumor-kill while limiting toxic effects of radiation dose on nearby organs-at-risk (OAR). Given a fixed number of treatment sessions, planners thus face the problem of finding a dosing sequence that achieves this goal. This is called the fractionation problem, and has received steady attention over a long history in the clinical literature. Mathematical formulations of the resulting optimization problem utilize the linear-quadratic (LQ) framework to characterize radiation dose-response of tumors and OAR. This yields a nonconvex quadratically constrained quadratic program. The optimal dosing plan in this forward problem crucially depends on the parameters of the LQ model. Unfortunately, these parameters are difficult to estimate via in vitro or in vivo studies, and as such, their values are unknown to treatment planners. The clinical literature is thus replete with debates about what parameter values will make specific dosing plans effective. This paper formulates this as an inverse optimization problem. The LQ dose-response parameters appear in the objective function, the left hand side, and the right hand side of the forward problem, and none of the existing generic methods can provide an exact solution of the inverse problem. This paper exploits the structure of the problem and identifies all possible parameter values that render the given dosing plan optimal, in closed-form. This closed-form formula is applied to dosing-plans from three clinical studies published within the last two years.

Favorable Initial Outcomes of Abdominopelvic Reirradiation Using Dose-Escalated Magnetic Resonance Image-Guided Radiation Therapy

Abdominopelvic re-irradiation (reRT) is associated with increased risk of potentially severe or fatal toxicity. To minimize the risk of such toxicity, prescribed reRT dose is routinely limited to 35-40 Gy in 2 Gy equivalent dose (EQD2), although higher doses would be preferred to improve local control (LC), if they could be delivered safely. Magnetic resonance image (MRI)-guided radiation therapy (MRgRT) may facilitate dose-escalated reRT through the use of reduced uncertainty margins, continuous intrafraction motion assessment, and daily on-table adaptive replanning. We retrospectively evaluated clinical outcomes of cancer patients from a single institution who received MRgRT on an MR Linac to a previously irradiated site. All patients were treated with continuous intrafraction monitoring. Tumors with significant respiratory motion were usually treated in mid-inspiration breath hold without an internal target volume (ITV). Toxicity was evaluated according to Common Terminology Criteria for Adverse Events, version 5.0. 12 consecutive patients who received reRT were evaluated. Median age was 65 years (range: 33-88) and ECOG performance status was 0-1 in nearly all (91.7%). No patient had >1 prior course of RT. ReRT was initiated after a median of 29.1 months (range: 7.6-153.9) from prior RT completion. Concurrent systemic therapy was delivered to 25%. Conventionally fractionated RT was used prior to reRT in 83.3% (median EQD2: 54.0 Gy) while stereotactic body radiation therapy (SBRT) was used in 16.7% (median EQD2: 61.7 Gy). The most commonly reirradiated sites were abdominopelvic nodes (33.3%) and pancreatic cancer (33.3%). ReRT was delivered with SBRT in 66.7% (median EQD2: 51.3 Gy) and hyperfractionation in 33.3% (median EQD2: 39.2 Gy). On-table adaptive replanning was performed for 3 patients, each receiving reRT in 5 fractions to a median 40 Gy (range: 33-50 Gy). With median follow-up of 7.4 months (range: 1.4-12.8 months) in-field LC was 83.3%; median EQD2 among the 2 patients with local progression was 31.8 Gy. The incidence of acute grade 2 toxicity was 8.3% (fatigue; n = 1). No patient had acute grade 3+ or late grade 2+ toxicity. These initial safety and efficacy outcomes of reRT delivered on an MR Linac, typically with the intent of dose escalation, are encouraging. Based on these data, a prospective study of dose-escalated MR-guided reRT is currently under development at our institution. The range of doses used will allow us to generate a tumor dose-response curve for reRT.

Inter/intra-tumoral dose response variations assessed using FDG-PET/CT feedback images: Impact on tumor control and treatment dose prescription

PurposeTo quantify inter/intra-tumoral variations of baseline metabolic activity and dose response. To evaluate their impact on tumor control and treatment dose prescription strategies. Methods and materialsTumor voxel baseline metabolic activity, SUV0, and dose response matrix, DRM, quantified using the pre-treatment and weekly FDG-PET/CT imaging feedback for each of 34 HNSCC patients (25 HPV+ and 9 HVP−) were evaluated. Inter/intra-tumoral variations of tumor voxel (SUV0, DRM) for each of the HPV− and HPV+ tumor groups were quantified and used to evaluate the variations of individual tumor control probabilities and the efficiency of uniform vs non-uniform treatment dose prescription strategies. ResultsTumor voxel dose response variation of all tumor voxels assessed using FDG-PET/CT imaging feedback had the mean(CV) = 0.47(47%), which was consistent with those of previously published in vitro tumor clonogenic assay. The HPV− tumors had the mean(CV) dose response, 0.53(49%), significantly larger than those of the HPV+ tumors, 0.45(43%). However, their baseline SUVs were opposite, 6.5(56%) vs 7.7(65%). Comparing to the inter-tumoral variations, both HPV−/+ tumor groups showed larger intra-tumoral variations, (53%, 58%) vs (20%, 31%) for the baseline SUV and (38%, 37%) vs (31%, 21%) for the dose response. Due to the large dose response variations, treatment dose to control the tumor voxels has very broad range with CV of TCD50 = 97% for the HPV− and 67% for the HPV+ tumor group respectively. As a consequence, heterogeneous prescription dose could potentially reduce the treatment integral dose for 92% of the HPV+ tumors and 78% of the HPV− tumors. ConclusionsThe study demonstrates that tumor dose response assessed using FDG-PET/CT feedback images had a similar distribution to those assessed conventionally using in vitro tumor clonogenic assay. Inter-tumoral dose response variation seems larger for HPV− tumors, but intra-tumoral dose response variations are similar for both HPV groups. These variations cause very large variation on the individual tumor control probability and limit the efficacy of dose escalation and de-escalation in conventional clinical practice. On the other hand, heterogeneous dose prescription guided by metabolic imaging feedback has a potential advantage in radiotherapy.

3:09 PM Abstract No. 23 Determination of tumor dose response threshold and implication on survival in patients with hepatocellular carcinoma treated with Y90 radiation segmentectomy using glass microspheres: a simple semiquantitative analysis

3:09 PM Abstract No. 23 Determination of tumor dose response threshold and implication on survival in patients with hepatocellular carcinoma treated with Y90 radiation segmentectomy using glass microspheres: a simple semiquantitative analysis

Intra-Arterial Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor Liver Metastases

Purpose Currently, peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-DOTATATE is used in patients with progressive neuroendocrine neoplasms (NEN) as salvage therapy. The standard treatment schedule consists of multiple cycles of intravenous (IV) administration. However, patients with liver metastases suffer from reduced tumor targeting and worse response and survival. This review provides an overview of the available evidence on the intra-arterial (IA) administration of radionuclide-labeled somatostatin analogues. Methods Databases of PubMed and Embase were searched systematically in May 2018 for studies that addressed IA PRRT. Included studies were original research publications focusing on absorbed tumor dose or tumor response after IA administration of PRRT for NEN. Publications on combined PRRT with other therapies or treatment of nonhepatic sites were excluded. Included publications were critically appraised on quality and their results reported accordingly. Results Seven publications were included in this review, including a total of 114 patients treated IA with different types of radiopeptides. Objective response was seen in 13 to 69% of the patients and disease stabilization in 18 to 52%. Disease progression occurred in 0 to 29% of the patients. IA administration resulted in a 1.06 to 9.2-fold increase in tumor-to-nontumor dose ratios in liver tumors, while normal liver and kidney doses remained within expected ranges. The incidence of adverse events was comparable to IV administration. Conclusion There is limited evidence that IA application of PRRT results in higher tumor-to-non-tumor dose ratios compared with IV infusion. IA administration of 177Lu-DOTATATE seems to be a promising new improvement in current clinical practice, achieving a higher absorbed tumor dose in patients with hepatic metastases of NEN.