Early Evaluation Of Treatment Response Research Articles

Measurement of metabolite levels and treatment-induced changes in hepatic metastases of gastro-esophageal cancer using 7-T phosphorus magnetic resonance spectroscopic imaging.

Methods for early treatment response evaluation to systemic therapy of liver metastases are lacking. Tumor tissue often exhibits an increased ratio of phosphomonoesters to phosphodiesters (PME/PDE), which can be noninvasively measured by phosphorus magnetic resonance spectroscopy (31P MRS), and may be a marker for early therapy response assessment in liver metastases. However, with commonly used 31P surface coils for liver 31P MRS, the liver is not fully covered, and metastases may be missed. The objective of this study was to demonstrate the feasibility of 31P MRS imaging (31P MRSI) with full liver coverage to assess 31P metabolite levels and chemotherapy-induced changes in liver metastases of gastro-esophageal cancer, using a 31P whole-body birdcage transmit coil in combination with a 31P body receive array at 7 T. 3D 31P MRSI data were acquired in two patients with hepatic metastases of esophageal cancer, before the start of chemotherapy and after 2 (and 9 in patient 2) weeks of chemotherapy. 3D 31P MRSI acquisitions were performed using an integrated 31P whole-body transmit coil in combination with a 16-channel body receive array at 7 T, with a field of view covering the full abdomen and a nominal voxel size of 20-mm isotropic. From the 31P MRSI data, 12 31P metabolite signals were quantified. Prior to chemotherapy initiation, both PMEs, that is, phosphocholine (PC) and phosphoethanolamine (PE), were significantly higher in all metastases compared with the levels previously determined in the liver of healthy volunteers. After 2 weeks of chemotherapy, PC and PE levels remained high or even increased further, resulting in increased PME/PDE ratios compared with healthy liver tissue, in correspondence with the clinical assessment of progressive disease after 2 months of chemotherapy. The suggested approach may present a viable tool for early therapy (non)response assessment of tumor metabolism in patients with liver metastases.

Primary biliary cholangitis-response criteria of first-line treatment and perspectives of second-line therapy

Primary biliary cholangitis (PBC) is achronic cholestatic liver disease that can progress to liver cirrhosis if left untreated. Early diagnosis, initiation of therapy and, if necessary, adjustment of treatment are essential to prevent disease progression. The timing and thresholds for assessing adequate treatment response are inconsistently defined in the literature and can pose achallenge in clinical practice. In addition to providing aconcise overview of the guideline-based diagnostic work-up and first-line therapy, this study offers practical guidance for the evaluation of treatment response and options for second-line treatment in PBC. This article is based on the current European Association for the Study of the Liver (EASL) clinical practice guidelines for the management of PBC from 2017 as well as aliterature review of studies from 2017 to 2023, focusing on defining treatment response, assessing disease progression risk, and the approved and investigational agents for second-line therapy. There are varying definitions for asufficient response to ursodeoxycholic acid (UDCA). Therapeutic goals are tailored to the individual risk of disease progression. The lowest risk appears to be associated with normalization of alkaline phosphatase (AP) and serum bilirubin below 0.6 the upper limit of normal. Established second-line therapies include obeticholic acid and bezafibrate (off-label use), while other peroxisome proliferator-activated receptor (PPAR) agonists and combination therapies are under clinical investigation. Early evaluation of treatment response to UDCA is mandatory. In the case of insufficient treatment response, second-line therapy should be initiated according to the individual's risk profile.

The impact of the apparent diffusion coefficient for the early prediction of the treatment response after definitive radiotherapy in prostate cancer patients

PurposeWe assessed early changes in apparent diffusion coefficient (ADC) and serum prostate specific antigen (PSA) values after definitive radiotherapy (RT) without androgen deprivation treatment in low- and intermediate-risk prostate cancer (PC) patients. Materials and MethodsThe clinical data and ADC parameters of 229 PC patients were retrospectively evaluated. Pre-treatment and post-treatment serum PSA and primary tumor ADC values were calculated. Post-treatment DW-MRI was performed median 4.1 months after completion of definitive RT. The prognostic factors predicting freedom from biochemical failure (FFBF) and progression-free survival (PFS) were analyzed using univariable and multivariable analyses. ResultsWith a median follow-up time of 80.8 months, the 5-year FFBF and PFS rates were 95.9% and 89.3%, respectively. Eleven patients (4.8%) had PSA relapse, with a median of 34.4 months after the completion of RT. A statistically significant difference in post-treatment ADC values was noted between patients with and without recurrence (0.94 ± 0.07 vs. 1.10 ± 0.20 × 10-3 mm2/sec; p< 0.001). Patients with a Gleason score (GS) of 6 and low-risk disease had significantly higher post-treatment tumor ADC and PSA levels than patients with a GS of 7 and intermediate-risk disease. The 5-year FFBF rate in patients with tumor ADC ≤ 0.96 × 10-3 mm2/sec was significantly lower than patients with tumor ADC > 0.96 × 10-3 mm2/sec (85.5% vs. 100; p< 0.001). In the multivariable analysis, a lower ADC value, GS 4 + 3 and intermediate-risk disease were independent predictors of worse FFBF. In the multivariate analysis, a lower post-treatment ADC value and a GS of 4 + 3 were significant prognostic factors for a lower PFS. ConclusionThese findings suggest that the post-treatment tumor ADC value could be used for early treatment response evaluation after definitive RT in PC patients.

Utilizing CLL-1 Positive Leukemia Stem Cells As a Marker of Early Treatment Response in Acute Myeloid Leukemia

Background: Current methods to evaluate therapeutic response in Acute Myeloid leukemia (AML) rely primarily on morphological evaluation of leukemia blasts in bone marrow at end of treatment cycles, with complete remission (CR) defined as less than 5% bone marrow blast counts without leukemic phenotype. Measurable residual disease (MRD) has been shown highly prognostic for outcome. MRD by molecular methods is limited to subgroup of patients with defined genetic mutations. MRD detection by Multicolor Flow Cytometry (MFC) is still being standardized. Leukemia stem cells (LSC) has been established as source of treatment resistance and disease recurrence in AML. In this study, we aim to analyze change in LSC during treatment using immunophenotypically defined markers and examine whether information gained from LSC analysis could provide additional insights into disease course and assist management of AML under routine clinical practice setting. Methods: We analyzed flow cytometry data from bone marrow aspirate (BMA) and/or peripheral blood (PB) in patients with AML (excluding acute promyelocytic leukemia) before and after treatment. "Leukemic blasts” were identified by morphology and Leukemia-associated Immunophenotype by MFC. Hematopoietic stem cells (HSCs) gating was based on CD45dim/SSC and CD34+CD38low/- expression. Leukemic stem cells (LSC) fractional change was analyzed using CD371 (CLL-1), CD366 (TIM3), and CD45RA percent of positive over HSCs. A chart review was conducted to determine correlation between LSC fractional change and clinical outcome. Statistical analysis was performed using GraphPad Prism version 9. Results: Fifty AML cases with both pre- and post-treatment data from a single institution in the past 3 years were included in this study. Consistent with published literature, patients with significant reduction in LSC subsets was associated with longer remission, while patients with no significant decrease in the LSC subsets demonstrated no or only a temporary remission. Intriguingly, several patients with drastic reduction in LSC after induction chemotherapy achieved complete remission, despite initial post-treatment bone marrow showing persistence of ">5% leukemia blasts” indicating possibly failed induction therapy. In contrast, in patients with persistently high or increased LSC fraction post-treatment, overt clinical relapse occurred quickly despite "absence” or <1% of leukemia blast differential counts in initial bone marrow. In a series of patients who received allogeneic stem cell transplant (Allo-SCT), rise of LSC fraction post Allo-SCT was associated with early AML relapse (within 6 months), while the decrease of LSC fraction was associated with prolonged remission (Representative patient cases shown in Figure 1). Lastly, among the three LSC-specific markers analyzed, the changes in LSC characterized by CLL-1 expression showed the best correlation with clinical course. In addition, the LSC fraction measured by CLL-1 in the peripheral blood is highly correlated with that of the bone marrow (R2=0.93, P<0.0001). Conclusion: This retrospective study explored the value and applicability of LSC detection in routine clinical practice. Importantly, conventional methods relying on evaluating leukemic blast counts in post-treatment bone marrow can sometimes over- or under- estimate the benefit of certain treatment regimen, leading to inappropriate continuation of the same treatment or switch of a potentially effective treatment regimen. In those groups of patients, the change in LSC fraction provides additional information for early treatment response evaluation, refines outcome prediction, and helps with treatment regimen selection. Trending LSC fractional change identifies impending relapse in post Allo-SCT. LSC fractional change determined by CLL-1 showed the best clinical correlation and should be incorporated into routine evaluation for AML patient in clinical practice, and possibly for those participating in investigational trials. Future studies will focus on collecting more data to validate above findings, determining the thresholds of LSC fractional change which constitute potential treatment response vs failure and testing the feasibility of tracking LSC subsets non-invasively in peripheral blood during treatment to predict therapeutic outcome and potentially guide treatment decisions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Functional imaging for evaluation of cancers and biologically conformal radiotherapy: Past-history and present-day perspectives.

Over the past twenty years, nuclear medicine has enhanced the role of functional imaging in cancerology. A major milestone was achieved in the early 2000s with widespread availability of the positron emitter tracer 18F- deoxyglucose (FDG) and the introduction of hybrid imagers, i.e. positron imagers coupled with an X CT, providing anatomical landmarks and potently contributing to attenuation and scatter correction of the images. Other technical advances have progressively increased the quality of positron images. To date, the most widely used tracer remains FDG, which is highly beneficial in terms of sensitivity and specificity in detection of tumor sites, also providing biological information on tumors and early evaluation of treatment response for most cancers. Other highly specific tracers have been developed and are now routinely used for pheochromocytoma and paraganglioma, neuroendocrine tumors, and prostate cancer.Biological Radiotherapy has two aspects: Internal radiotherapy consisting in administration of a tumor-specific molecule radiolabeled with an isotope delivering an adequate radiation dose to the targeted tumor sites (on the model of thyroid cancer treated with radioiodine) and external radiotherapy designed to determine tumor volume, assess response and to dose radiation according to the tumor characteristics shown by functional imaging.

Evaluation of Early Treatment Response Utilizing the MAS-ALL18 Adapted Management Guideline in Four “Mexico in Alliance with St. Jude” (MAS) Member Hospitals

Introduction: Acute lymphoblastic leukemia (ALL) represents approximately 50% of all childhood cancers in Latin America. Mexico is not the exception. The impact of ALL survival on overall childhood cancer survival is significant. According to government data, five-year survival is about 52%. Mexico in Alliance with St. Jude (MAS) is a multi-site, intersectoral collaboration. The collaborative network has explored and reported on factors associated with this suboptimal outcome and have identified challenges with ALL risk group classification as a leading cause. For example, as many as 82% of children diagnosed with ALL in Mexico receive high-risk treatment and the tendency for higher-risk group assignment often occurs in response to limited access to cytogenetic testing and minimal residual disease (MRD) testing. This leads to higher intensity treatment and may explain the high rate of treatment-related death (TRD) (12%) documented during the induction but also subsequently. In our previous case series, only 75% of patients were alive at the end of the first year of treatment. These findings, led MAS to develop a consensus-derived standardized diagnosis and treatment schema (MAS-ALL18), which takes into account clinical, cytogenetic, and MRD results. Diagnostic testing is performed in a centralized laboratory. Although centred on delivery of standard of care, this experience represents is the first prospective multi-site cooperative group effort in Mexico. We report on early treatment (first 90 days) clinical and implementation outcomes utilizing the MAS-ALL18 adapted management guideline (AMG) in four member hospitals of the MAS collaboration network.Results: From June 2019 to June 2020, 137 patients received treatment utilizing the MAS-ALL18 AMG in four publicly funded hospitals in Mexico. B-cell ALL represented 91.9% of the cases, 20.4% of patients were older than 9 years of age, 25.5% had a white blood cell count greater than 50,000 at diagnosis and 58.3% were male. Complete remission at the end of the induction was achieved in 90.6% of patients. TRD during the induction phase was 8%. MRD at Day 15 in 123 patients with B-cell ALL, 84.5% of them had MRD <1% and 7.3% had MRD ≥5%. MRD at Day 29 was assessed for the 10 patients diagnosed with T-cell ALL, 4 patients had MRD <0.01%, 2 had 0.02%, and 4 died during the induction phase. MRD was also assessed during consolidation (at Day 84) in 99 patients, 94.9% had MRD <0.01% and 5 patients MRD ≥0.01%, from which 3 had MRD at day 15 >1% and none registered an MRD result <0.5%. Utilizing the MAS-ALL18 risk group stratification, 50% of patients were assigned to a favorable risk group at the end of the consolidation. In 34 patients, the risk group was reclassified following the standardized algorithm; 30 reclassification events happened at the end of the induction and four at the end of the consolidation. Only two events were reassigned to a lower risk group, while the rest of the reclassifications were conducted to assign patients to a higher risk group due to unfavorable cytogenetics or an inadequate early response to treatment. High-risk treatment was ultimately assigned to 30% of patients using the MAS-ALL18 risk classification schema.Conclusion: It is feasible to implement a standardized multi-site adapted management guideline for ALL risk group stratification and treatment allocation in Mexico in the context of a collaborative network. TRD remains high during the induction phase, nevertheless, this number shows an improvement (8%) compared to the 2015 data report (12%). The ALL risk group classification is transitioning from a rigid scheme that placed 80% of patients in a high-risk group to a dynamic classification system that considers cytogenetic testing and MRD conducted in a centralized and externally validated laboratory that serves as reference for all the participating hospitals. The standardized MAS-ALL18 approach allowed us to classify 50% of patients in a favorable risk group during and at the end of the induction phase, which implies receiving a lower intensity treatment with a high probability of cure and a lower risk of TRD. The implementation of MAS-ALL18 risk classification scheme reduced the number of children requiring high-risk treatment in the participating hospitals. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Value of 18F-FDG PET/MR Imaging in the Early Evaluation of Treatment Response following Radiofrequency Ablation of Liver Cancer in a Rabbit Model

PurposeTo test the hypothesis that 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging can detect early residual tumor following radiofrequency (RF) ablation of liver cancer using a VX2 tumor model. Materials and MethodsTwenty-four rabbits with VX2 liver tumors were randomly divided into 3 groups (n = 8/group): Group 1 without RF ablation treatment, Group 2 with complete ablation, and Group 3 with partial ablation. An 18F-FDG PET/MR imaging scan was obtained within 2 hours after RF ablation. The maximum standardized uptake values (SUV) of the nontreated liver tumor, benign periablational enhancement (BPE), residual tumor, ablated tumor, and adjacent liver parenchyma and mean SUV of the normal liver were measured. The ratios of maximum SUV for these targets to the mean SUV of the normal liver (TNR) were calculated and compared. ResultsThe mean TNR of the nontreated liver tumors in Group 1 was significantly greater than that of the adjacent liver parenchyma (8.68 ± 0.71 vs 1.89 ± 0.26, P < .001). In Group 2, the mean TNR of BPE was significantly greater than that of the adjacent liver parenchyma (2.85 ± 0.20 vs 1.86 ± 0.25, P < .001). In Group 3, the mean TNR of the residual tumor was significantly greater than that of BPE (8.64 ± 0.59 vs 2.78 ± 0.23, P < .001), which was significantly greater than that of completely ablated tumor (2.78 ± 0.23 vs 0.50 ± 0.06, P < .001). Conclusions18F-FDG PET/MR imaging may serve as a promising imaging tool for the early detection of viable residual tumors due to incomplete tumor ablation.

Early evaluation of treatment response to transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The role of dynamic three-dimensional contrast-enhanced ultrasound.

Dynamic three-dimensional contrast-enhanced ultrasound (3D-CEUS) with quantitative analysis is available in recent years. It can reduce the quantitative sampling error caused by the inconsistency of different sections in order to evaluate local treatment response of hepatocellular carcinoma (HCC) accurately. To investigate the value of dynamic 3D-CEUS in evaluating the early response to transarterial chemoembolization (TACE) treatment in patients with advanced HCC lesions. In this prospective study, both two-dimensional (2D) CEUS and dynamic 3D-CEUS were performed on 40 HCC patients who scheduled for TACE at baseline (T0) and 1-3 days (T1) after treatment. Tumor microvascular perfusion changes were assessed by CEUS time-intensity curve (TIC) and quantitative parameters. According to contrast-enhanced computed tomography (CT) and magnetic resonance (MR) imaging 1 month after treatment results, patients were divided into responders and non-responders groups. The changes of perfusion parameters of both 2D-CEUS and 3D-CEUS were compared between responders and non-responders groups before and after TACE treatment. Before and after TACE treatment, no significant difference in maximum diameter of HCC lesions between the two groups could be found. There were more significant differences and ratios of perfusion parameters in 3D-CEUS quantitative analysis than in 2D-CEUS. The mutual significant differences and ratios of 2D-CEUS and 3D-CEUS included peak intensity (PI) difference, PI ratio, ratio of area under the curve (A), ratio of area under the wash-out part (AWO) and slope (S) difference. The former 4 corresponding parameters were better on 3D-CEUS than on 2D-CEUS. Dynamic 3D-CEUS can be used as a potential imaging method to evaluate early treatment response to TACE in advanced HCC patients.

The value of dynamic contrast enhanced ultrasound (DCE-US) in monitoring treatment effect of high-intensity focused ultrasound (HIFU) in locally advanced pancreatic cancer (LAPC).

To evaluate the feasibility of dynamic contrast enhanced ultrasound (DCE-US) in predicting treatment response of high-intensity focused ultrasound (HIFU) in patients with locally advanced pancreatic cancer (LAPC) lesions. In this prospective study, 10 patients with pathologically confirmed LAPC lesions (7 men, 3 women; average age, 61.13±5.80 years) were prospectively enrolled. All patients received HIFU treatment with peak intensity at 12000 W/cm2. Contrast enhanced ultrasound (CEUS) was performed with an ACUSON Oxana 2 ultrasound equipment and a 6 C-1 transducer (1-6 Hz). A dose of 2.4 ml SonoVue was injected for each examination. Time intensity curves (TICs) were generated and quantitative analyses were performed by SonoLiver software. B mode ultrasound (BMUS) features, CEUS enhancement patterns, TICs, CEUS quantitative parameters and serum carcinoma antigen 19-9 (CA19-9) levels were compared before and 4 weeks after HIFU treatment. Statistical analyses were performed with SPSS Version 20.0 and GraphPad Prism 5. While comparing before and after HIFU, no significant difference was obtained on mean size of lesion, BMUS or CEUS features. After HIFU treatment, TICs showed decreased and delayed enhancement. Among all CEUS quantitative parameters, significant decrease could be found in maximum intensity (MI) (60.66±23.95% vs 41.31±26.74%) and mean transit time (mTT) (76.66±47.61 s vs 38.42±28.35 s). CA19-9 level decreased significantly after HIFU (2747.92±4237.41 U/ml vs 715.08±1773.90 U/ml) (P = 0.05). DCE-US combining with quantitative analysis might be a useful imaging method for early treatment response evaluation of HIFU in LAPC lesions.

Early Serum Free Light Chain Response after High-Dose Melphalan and Stem Cell Transplantation Predicts Hematologic Response in AL Amyloidosis

Introduction Immunoglobulin light chain (AL) amyloidosis is a rare disease caused by a clonal plasma cell dyscrasia producing monoclonal light chains that misfold and form amyloid fibrils which can deposit in a variety of tissues and organs. This deposition of amyloid fibrils can lead to progressive organ impairment, multi-organ failure, and death if left untreated. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is known to improve patient outcomes with hematologic complete responses (CR) rates of 25-67%. Hematologic CR is currently defined as the absence of monoclonal protein in serum and urine by immunofixation electrophoreses and normal serum free light chain ratio (FLCR). Studies have shown that even among patients achieving a normal FLCR after initial therapy with HDM, persistent elevation of the involved FLC (hiFLC) predicts poor prognosis. Serum half-life of FLCs is approximately 2-6 hours, even with diminished glomerular filtration rates, and could be a tool for early treatment response evaluation. We sought to determine the extent to which early FLC responses after HDM/SCT predict hematologic complete response (CR) at 6 months. Methods We analyzed patients with AL amyloidosis who underwent HDM/SCT from 2012-2019 at Boston Medical Center. Exclusion criteria included death within 100 days, lack of FLC data at any time point, pre-SCT normal FLC concentrations and ratio, and chronic renal insufficiency (serum creatinine &amp;gt;1.3 mg/dL) with a normal FLC ratio. All subjects received a total of 140-200 mg/m2 melphalan IV in equally divided doses on days -3 and -2. Stem cells were infused on day 0. FLC measurements were obtained early in the peri-SCT period (&amp;lt; 1 month), at 6 months, and at 12 months after HDM/SCT. The patients were evaluated for response according to the consensus response criteria at 6 months. Statistical analysis to compare CR at 6 months and early post-SCT free light chain levels was performed by Chi-square with significance considered at p&amp;lt;0.05. Results Of the 113 patients with AL amyloidosis treated with HDM/SCT during the specified time period, 32 were excluded (4 died within 100 days of SCT, 15 had normal FLCs pre-SCT, 5 lacked data, and 8 had chronic renal insufficiency (Cr &amp;gt;1.3 mg/dL) with normal FLCR. A total of 81 subjects (females=30) were analyzed. Median follow-up from SCT was 27.6 months (range, 6-145). Median time of early post-SCT FLC measurement was 8 days (range, 7-30). Median age at diagnosis was 58 years (range 30-79) and the iFLC was lambda in 81.5% (n = 66) of patients. Median number of bone marrow plasma cells was 10% (range, 1-50). The mean absolute involved FLC was 196 mg/L ±221 prior to SCT, 60 mg/L ± 77 in the early post-SCT period, 92 mg/L ± 152 at 6 months post-SCT. In early post-SCT period, 39.5% (n=32) had iFLC &amp;lt;20 mg/L, 28% (n=16/57) had dFLC&amp;lt;10 mg/L, and 84% (n=48/57) had normal FLCR. Early post-SCT dFLC &amp;lt;10 mg/dL and early post-SCT iFLC &amp;lt;20 mg/L were statistically associated with prediction of hematologic CR at 6 months (p=0.025 and p=0.001, respectively). However, early post-SCT normal FLCR was not associated with predicting hematologic CR at 6 months. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of early post-SCT iFLC &amp;lt;20 mg/L, dFLC &amp;lt;10 mg/L and normal FLCR to predict hematologic CR at 6 months are presented in table 1. Conclusion This study concludes that achievement of dFLC &amp;lt;10 mg/L and iFLC &amp;lt;20 mg/L in the early post-SCT period is associated with prediction of hematologic CR at 6 months. Early post-SCT dFLC &amp;lt;10 mg/L could be considered a tool for early evaluation of treatment response following HDM/SCT in AL amyloidosis. Key words: immunoglobulin light chains; AL amyloidosis, HDM/SCT Disclosures Sarosiek: Spectrum: Research Funding. Sanchorawala:Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents &amp; Royalties; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding.

P10 Clinical and pathologic tumor response following response-guided neoadjuvant chemotherapy for locally advanced breast cancer in the Philippine General Hospital – Breast Care Center

Background and purpose Neoadjuvant chemotherapy is recommended for locally advanced breast cancer (LABC) to improve surgical options and to provide an in-vivo assessment of response to treatment. The Philippine General Hospital (PGH) Breast Care Center has adopted a protocol of response-guided approach to allow for tailoring of the chemotherapy regimen being administered. This study aims to describe the clinical and pathologic tumor response of LABC patients after response-guided neoadjuvant chemotherapy. Methods This is a retrospective cohort of 128 patients with LABC who underwent neoadjuvant chemotherapy at the PGH Breast Care Center using sequential doxorubicin/cyclophosphamide-docetaxel (AC-T) regimen from July 2013 to June 2018. Clinical and pathologic response rates were obtained. Patients were categorized into either good or poor responders and were analyzed according to specific clinicopathologic factors. Results The mean clinical tumor response was at 80% with 14 patients (11%) achieving a pathologic complete response (PCR). The Her2 enriched subtype had the highest PCR rate (23.5%). Interestingly, 2 patients who initially had poor response to AC but had good response upon shifting to T attained PCR. A comparison of the clinicopathologic variables in patients with good or poor response to chemotherapy showed that there are significantly more patients with good response to the AC regimen if the patient is pre-menopausal (p=0.04), those with ductal histology (p=0.03), those with a triple negative subtype (p=0.002) and those with HR+HER2+ subtype (p=0.03). Intrinsic subtype did not appear to be a significant factor for a better response in those who received Docetaxel. A Spearman’s Rho score of 0.69 (p-value <0.0001) indicates a strong association between the pathologic and clinical responses. Conclusion Neoadjuvant chemotherapy allows direct and early evaluation of treatment response. This promotes personalized treatment and may justify early shifting to another chemotherapy regimen for non-responders as in response-guided neoadjuvant chemotherapy. 1. von Minckwitz, et. al. Response-Guided Neoadjuvant Chemotherapy for Breast Cancer. J Clin Oncol 31:3623-3630. DOI: 10.1200/JCO.2012.45.09402. Kim S.I, et. al. Molecular subtypes and Tumor Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer. Oncology 2010;79:324-330. http://doi.org/10.1159/000322192

Early response evaluation using primary tumor and nodal imaging features to predict progression-free survival of locally advanced non-small cell lung cancer.

Prognostic biomarkers that can reliably predict early disease progression of non-small cell lung cancer (NSCLC) are needed for identifying those patients at high risk for progression, who may benefit from more intensive treatment. In this work, we aimed to identify an imaging signature for predicting progression-free survival (PFS) of locally advanced NSCLC.Methods: This retrospective study included 82 patients with stage III NSCLC treated with definitive chemoradiotherapy for whom both baseline and mid-treatment PET/CT scans were performed. They were randomly placed into two groups: training cohort (n=41) and testing cohort (n=41). All primary tumors and involved lymph nodes were delineated. Forty-five quantitative imaging features were extracted to characterize the tumors and involved nodes at baseline and mid-treatment as well as differences between two scans performed at these two points. An imaging signature was developed to predict PFS by fitting an L1-regularized Cox regression model.Results: The final imaging signature consisted of three imaging features: the baseline tumor volume, the baseline maximum distance between involved nodes, and the change in maximum distance between the primary tumor and involved nodes measured at two time points. According to multivariate analysis, the imaging model was an independent prognostic factor for PFS in both the training (hazard ratio [HR], 1.14, 95% confidence interval [CI], 1.04-1.24; P = 0.003), and testing (HR, 1.21, 95% CI, 1.10-1.33; P = 0.048) cohorts. The imaging signature stratified patients into low- and high-risk groups, with 2-year PFS rates of 61.9% and 33.2%, respectively (P = 0.004 [log-rank test]; HR, 4.13, 95% CI, 1.42-11.70) in the training cohort, as well as 43.8% and 22.6%, respectively (P = 0.006 [log-rank test]; HR, 3.45, 95% CI, 1.35-8.83) in the testing cohort. In both cohorts, the imaging signature significantly outperformed conventional imaging metrics, including tumor volume and SUVmax value (C-indices: 0.77-0.79 for imaging signature, and 0.53-0.73 for conventional metrics).Conclusions: Evaluation of early treatment response by combining primary tumor and nodal imaging characteristics may improve the prediction of PFS of locally advanced NSCLC patients.

89Zr-PET imaging of DNA double-strand breaks for the early monitoring of response following α- and β-particle radioimmunotherapy in a mouse model of pancreatic ductal adenocarcinoma

Rationale: The evaluation of early treatment response is critical for patient prognosis and treatment planning. When the current methods rely on invasive protocols that evaluate the expression of DNA damage markers on patient biopsy samples, we aim to evaluate a non-invasive PET imaging approach to monitor the early expression of the phosphorylated histone γH2AX in the context of pancreatic cancer targeted radionuclide therapy. Pancreatic ductal adenocarcinoma has a poor patient prognosis due to the absence of curative treatment for patients with advanced disease. There is therefore a critical need for the fast clinical translation of new therapeutic options. In line with these observations, our group has been focusing on the development of radiotheranostic agents based on a fully human monoclonal antibody (5B1) with exceptional affinity for CA19.9, an antigen overexpressed in PDAC. Two on-going clinical trials resulted from these efforts, one with 89Zr (diagnosis) and one with 177Lu (β-particle therapy). More recently, we successfully developed and evaluated in PDAC mouse models a targeted α-therapy strategy with high clinical translation potential. We aim to expedite the clinical translation of the developed radioimmunotherapy approaches by investigating the early therapeutic response and effect of radiation therapy in a PDAC mouse model via PET imaging.Methods: Mice bearing BxPC3 tumor xenografts were treated with α- and β-particle pretargeted radioimmunotherapy (PRIT), external beam radiotherapy (EBRT), or sham-treated (vehicle). The phosphorylated histone γH2AX produced as a response to DNA double strand breaks was quantified with the PET radiotracer, [89Zr]Zr-DFO-anti-γH2AX-TAT.Results: PET imaging studies in BxPC3 PDAC mouse models demonstrated increased uptake of [89Zr]Zr-DFO-anti-γH2AX-TAT (6.29 ± 0.15 %IA/g) following β-PRIT in BxPC3 PDAC xenografts as compared to the saline control group (4.58 ± 0.76 %IA/g) and EBRT control group (5.93 ± 0.76 %IA/g). Similarly, significantly higher uptake of [89Zr]Zr-DFO-anti-γH2AX-TAT was observed in tumors of the 225Ac-PRIT and EBRT (10 Gy) cohorts (7.37 ± 1.23 and 6.80 ± 1.24 %IA/g, respectively) compared to the negative control cohort (5.08 ± 0.95 %IA/g). Ex vivo γH2AX immunohistochemistry and immunofluorescence analysis correlated with in vivo 89Zr-anti-γH2AX PET/CT imaging with increased γH2AX positive cell and γH2AX foci per cell in the treated cohorts. When α-PRIT resulted in prolonged overall survival of treated animals (107.5 days) as compared to β-PRIT (73.0 days), no evidence of difference in [89Zr]Zr-DFO-anti-γH2AX-TAT uptake at the tumor site was observed, highlighting that DNA damage is not the sole radiobiology paradigm and that off-targeted (bystander) effects should be considered.Conclusions: PET imaging studies with [89Zr]Zr-DFO-anti-γH2AX-TAT following α- and β-particle PRIT in a BxPC3 PDAC subcutaneous xenograft mouse model allowed the monitoring of tumor radiobiological response to treatment.

Multiparametric PET/MR (PET and MR-IVIM) for the evaluation of early treatment response and prediction of tumor recurrence in patients with locally advanced cervical cancer

To assess the value of 18F-FDG PET and MR-IVIM parameters before and during concurrent chemoradiotherapy (CCRT) for evaluating early treatment response and predicting tumor recurrence in patients with locally advanced cervical cancer (LACC) using a hybrid PET/MR scanner. Fifty-one patients with LACC underwent pelvic PET/MR scans with an IVIM sequence at two time-points (pretreatment [pre] and midtreatment [mid]). Pre- and mid-PET parameters (SUVmax, MTV, TLG) and IVIM parameters (D, F, D*) and their percentage changes (Δ%SUVmax, Δ%MTV, Δ%TLG, Δ%D, Δ%F, Δ%D*) were calculated. We selected independent imaging parameters and built a combined prediction model incorporating imaging parameters and clinicopathological risk factors. The performance of the combinative evaluation for tumor early shrinkage rates (TESR) and the prediction model for tumor recurrence was assessed. Thirty-two patients were classified into the good response (GR) group with TESR ≥ 50%, and 19 patients were categorized into the poor response (PR) group with TESR < 50%. Δ%D (p = 0.013) and Δ%F (p = 0.006) are independently related to TESR with superior combined diagnostic ability (AUC = 0.901). Pre-TLG, Δ%D, and suspicious lymph node metastasis (SLNM) were selected for the construction of the combined prediction model. The model for identifying the patients with high risk of tumor recurrence reached a moderate predictive ability and good stability with c-index of 0.764 (95% CI, 0.672-0.855). The combined prediction model based on pretreatment PET metabolic parameter (pre-TLG), IVIM-D percentage changes, and LNs status provides great potential to identify the LACC patients with high risk of recurrence at early stage of CCRT. • PET/MR plus IVIM offers various complementary information for LACC. • IVIM-D and IVIM-F percentage changes are independently related to tumor early shrinkage rates. • The combined prediction model can help identify the LACC patients with high risk of tumor recurrence.

Persistent Head and Neck Cancer Following First-Line Treatment.

Background: Following first-line treatment of head and neck cancer (HNC), persistent disease may require second-line treatment. Methods: All patients with HNC treated between 2008 and 2016 were included. Second-line treatment modalities and survival of patients were analyzed. Results: After first-line therapy, 175/741 patients had persistent disease. Of these, 112 were considered eligible for second-line treatment. Second-line treatment resulted in 50% complete response. Median overall survival of patients receiving second-line therapy was 24 (95% CI: 19 to 29) months; otherwise survival was 10 (9 to 11; p < 0.0001) months. Patients receiving second-line surgery had a median overall survival of 45 (28 to 62) months, patients receiving second-line radiotherapy had a median overall survival of 37 (0 to 79; p = 0.17) months, and patients receiving systemic therapy had a median overall survival of 13 (10 to 16; p < 0.001) months. Patients with persistent HNC in the neck had a better median survival (45 months; 16 to 74 months; p = 0.001) than patients with persistence at other sites. Conclusion: Early treatment response evaluation allows early initiation of second-line treatment and offers selected patients with persistent disease a realistic chance to achieve complete response after all. If possible, surgery or radiotherapy are preferable.

Evaluation of early treatment response to radiotherapy for HCC using pre- and post-treatment MRI

BackgroundStereotactic body radiation therapy is an emerging treatment option for patients with unresectable advanced hepatocellular carcinoma (HCC). Because liver parenchyma neighboring the tumor ...

Value of early evaluation of treatment response using 18F-FDG PET/CT parameters and the Epstein-Barr virus DNA load for prediction of outcome in patients with primary nasopharyngeal carcinoma.

To determine the value of early evaluation of response to concurrent chemoradiotherapy (CCRT) using 18F-FDG PET-derived parameters and the Epstein-Barr virus (EBV) DNA titre in outcome prediction in patients with primary nasopharyngeal carcinoma (NPC). Sixty patients with primary NPC were prospectively enrolled. All patients underwent 18F-FDG PET/CT before and during CCRT. The plasma EBV DNA titre was measured along with the PET/CT-derived parameters. Changes in EBV DNA titre and PET/CT-derived parameters during CCRT were analysed in relation to response to treatment, recurrence-free survival (RFS) and overall survival (OS). A total lesion glycolysis (TLG) reduction ratio of ≤0.6 and a detectable EBV DNA titre during CCRT were predictors of an unfavourable response to treatment, RFS and OS. In multivariate analysis, a TLG reduction ratio of ≤0.6 predicted incomplete remission (p = 0.002) and decreased RFS (p = 0.003). The proportion of patients with a TLG reduction ratio of >0.6 who achieved a complete response was more than twice that of patients with a TLG reduction ratio of ≤0.6. A detectable EBV DNA titre, a TLG reduction ratio of ≤0.6 and older age were independently associated with a poorer OS (p = 0.037, 0.009 and 0.016, respectively). A scoring system was developed based on these independent predictors of OS. Patients with a score of 1 and 2/3 had poorer survival outcomes than those with a score of 0 (hazard ratio 4.756, p = 0.074, and hazard ratio 18.973, p = 0.001, respectively). This scoring system appeared to be superior to the traditional TNM staging system (p < 0.001 versus p = 0.175). Early evaluation of response to CCRT using 18F-FDG PET-derived parameters and the EBV DNA titre can predict outcome in patients with primary NPC. A combination of interim PET parameters and the EBV DNA titre enables better stratification of patients into subgroups with different survival rates.

Bimodality Imaging of Primary Cervical Tumors Before and During Concurrent Chemoradiation Therapy Suggests Association Between Changes in Tumor Blood Volume and Treatment Response

To investigate changes of FDG-PET and perfusion CT parameters in cervical cancer patients before and during CCRT and to correlate these parameters and their changes with metabolic response evaluated post CCRT. Pretreatment perfusion CT and PET/CT were performed on 20 patients, of whom 19 also underwent during treatment imaging after 4 weeks of CCRT. Stage distribution was as follows: 1 IIA1, 2 IIA2, 11 IIB, 1 IIIA, 5 IIIB. Three-dimensional co-registered parametric maps of SUV, Blood Flow (BF), Blood Volume (BV), and Permeability (PMB) were generated. Summary statistics for these and other parameters were calculated within 3 regions: primary tumor, healthy muscle receiving prescription dose, and muscle in a peripheral low dose region. Baseline values and their changes were examined for association with therapy outcome as evaluated by FDG-PET/CT 3 months post-CCRT in 17 patients (14 with complete metabolic response (CMR) and 3 with new distant disease). In tumors, during- versus pre- treatment values decreased significantly for the following parameters: volume (66.2 +/- 65.1 vs. 17.4+/-15.0 ml, P = 0.0015), SUVmax (11.0 +/- 3.9 vs. 6.7 +/- 3.7, P = 0.0002), and SUVmean (5.1 +/- 1.7 vs. 3.5 +/-1.6, P = 0.0010). BVmean (10.9 +/- 2.6 vs. 12.1 +/- 3.4 ml/100ml, P = 0.0013) and PMBmean (18.8 +/- 5.3 vs. 25.4 +/- 7.2 ml/100 ml/min, P < 0.0001) increased significantly. Coefficients of variation for BF, BV, PMB, and SUV decreased significantly (P < 0.003) indicating therapy-induced improvement in the homogeneity of perfusion and FDG uptake. In muscle pre-treatment perfusion values were significantly lower (P < 0.0001) than the corresponding values in tumors: BFmean (22.3 +/- 13.6 ml/100 ml/min), BVmean (2.9 +/- 1.8 ml/100 ml), and PMBmean (2.9 +/- 2.4 vs. ml/100 ml/min). For both muscle locations pre- and during treatment BFmean and BVmean were not significantly different indicating that BVmean changes in tumors reflected tumor- specific vasculature response to radiation. On univariate analysis FDG-PET and CT perfusion baseline values were not associated with treatment outcome. Among the examined parameters both absolute and relative differences in BVmean were significantly associated with treatment outcome. In patients with CMR BVmean increased by 32.4% +/- 25.8%, whereas in patients with new disease BVmean decreased by 20.8% +/- 10.9% (P < 0.01). CCRT significantly changes both PET and perfusion values in cervical tumors but not in healthy muscle. In our patient cohort blood volume increase during treatment was associated with complete metabolic response to therapy, a finding in line with observations from serial dynamic MRI studies. This suggests a potential role for perfusion CT in early evaluation of treatment response to chemoradiotherapy for cervical patients.

FLT-PET for early response evaluation of colorectal cancer patients with liver metastases: a prospective study

BackgroundFluoro-L-thymidine (FLT) is a positron emission tomography/computed tomography (PET/CT) tracer which reflects proliferative activity in a cancer lesion. The main objective of this prospective explorative study was to evaluate whether FLT-PET can be used for the early evaluation of treatment response in colorectal cancer patients (CRC) with liver metastases. Patients with metastatic CRC having at least one measurable (>1 cm) liver metastasis receiving first-line chemotherapy were included. A FLT-PET/CT scan was performed at baseline and after the first treatment. The maximum and mean standardised uptake values (SUVmax, SUVmean) were measured. After three cycles of chemotherapy, treatment response was assessed by CT scan based on RECIST 1.1.ResultsThirty-nine consecutive patients were included of which 27 were evaluable. Dropout was mainly due to disease complications. Nineteen patients (70%) had a partial response, seven (26%) had stable disease and one (4%) had progressive disease. A total of 23 patients (85%) had a decrease in FLT uptake following the first treatment. The patient with progressive disease had the highest increase in FLT uptake in SUVmax. There was no correlation between the response according to RECIST and the early changes in FLT uptake measured as SUVmax (p = 0.24).ConclusionsNo correlation was found between early changes in FLT uptake after the first cycle of treatment and the response evaluated from subsequent CT scans. It seems unlikely that FLT-PET can be used on its own for the early response evaluation of metastatic CRC.

Abstract 2868: 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal therapy

Abstract Aim: Nanoparticle-assisted photothermal therapy is a new promising therapeutic strategy that utilizes photo-absorbing nanoparticles irradiated with near infrared light to generate a local temperature increase in tumor tissue. Here we used small animal 18F-FDG PET/CT to evaluate the treatment response of silica-gold nanoshell (NS)-assisted photothermal therapy in human tumor xenografts in mice. Method: NMRI nude mice had ~ 106 human neuroendocrine tumor cells (H727) inoculated into the left flank. After 4-5 weeks, animals were divided into three groups: one receiving NS and laser irradiation (NS group, n = 9), one receiving saline and laser irradiation (saline group, n = 9), and one receiving NS but no laser irradiation (sham group, n = 5). All animals were PET scanned with 18F-FDG one day before treatment (baseline), followed by iv administration of either NS or saline. Approximately 24 hours after injection, the animals were placed on a laser treatment platform and the tumors were irradiated with an 807 nm diode laser for 5 minutes using a laser intensity of 1.8 W/cm2. During irradiation, the temperature at the surface of the tumor was measured using thermographic imaging. The mice were 18F-FDG PET scanned again at day 1 after treatment and tumor growth was followed by caliper measurements with the humane endpoint defined as a tumor volume of 1,000 mm3. PET and CT images were co-registered, and regions of interest were manually drawn on whole tumor regions. 18F-FDG uptake was quantified as mean percentage of injected dose per grams of tissue (%ID/g) and the treatment response was evaluated based on the reduction in tumor uptake of 18F-FDG between baseline and day 1. Results: Thermographic imaging showed that the tumor surface on average reached 49.2 ± 3.3 °C in the NS group. In comparison, the average temperatures reached 44.5 ± 1.9 °C in the saline group and 33 ± 1.0 °C in the sham group. This was consistent with an overall inhibited tumor growth, as well as improved survival in the NS group compared to the sham and saline groups. The tumor accumulation of 18F-FDG uptake was comparable between groups at baseline but PET imaging revealed a significant reduction in tumor uptake at day 1 in the NS group ( 84 ± 8 % (day 1/baseline)) compared to the saline (= 108 ± 21 %; p &amp;lt; 0.01) and sham (= 110 ± 11 %; p &amp;lt; 0.05) groups. Moreover, the change in 18F-FDG tumor uptake (day 1/baseline), was used to stratify animals into responders and non-responders, where the responding group matched inhibited tumor growth and improved survival. Conclusion: In this study we showed that 18F-FDG PET could be used for early response monitoring of the therapeutic outcome of nanoparticle-assisted photothermal therapy in human tumor xenografts in mice. Based on this, we suggest that PET can also be used for optimization of therapy, both for guiding treatment planning and early identification of non-responders for which the treatment strategy should then be changed. Citation Format: Jesper Tranekjaer Joergensen, Kamilla Norregaard, Marina Simón Martín, Fredrik Melander, Lotte K. Kristensen, Pól Martin Bendix, Thomas L. Andresen, Lene B. Oddershede, Andreas Kjaer. 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2868. doi:10.1158/1538-7445.AM2017-2868