Early Tumor Response Research Articles

Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: The role of dynamic contrast enhanced ultrasound

Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points. Twenty-eight HCC patients treated with sorafenib 400mg bid were prospectively enrolled. CEUS was performed at baseline (T0) and after 15 (T1) and 30 (T2) days of treatment. Tumor vasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software (Q-Lab, Philips). Variations between T1/T2 and T0 were calculated for five D-CEUS functional parameters (peak intensity, PI; time to PI, TP; area under the curve, AUC; slope of wash in, Pw; mean transit time, MTT) and were compared for responders and non-responders. The correlation between D-CEUS parameters, overall survival (OS), and progression-free survival (PFS) was also assessed. A p value <0.05 was considered statistically significant. The percentage variation at T1 significantly correlated with response in three D-CEUS parameters (AUC, PI and Pw; p=0.002, <0.001, and 0.003, respectively). A decrease of AUC (p=0.045) and an increased/unchanged value of TP (p=0.029) and MTT (p=0.010) were associated with longer survival. Three D-CEUS parameters (AUC, TP, Pw) were significantly associated with PFS. D-CEUS provides a reliable and early measure of efficacy for anti-angiogenic therapies and could be an excellent tool for selecting patients who will benefit from treatment.

Ultrasonic spectrum analysis for in vivo characterization of tumor microstructural changes in the evaluation of tumor response to chemotherapy using diagnostic ultrasound

BackgroundThere is a strong need for early assessment of tumor response to chemotherapy in order to avoid the adverse effects of unnecessary chemotherapy and to allow early transition to second-line therapy. The purpose of this study was to determine the feasibility of ultrasonic spectral analysis for the in vivo characterization of changes in tumor microstructure in the evaluation of tumor response to chemotherapy using diagnostic ultrasound.MethodsExperiments were approved by the regional animal care committee. Twenty-four MCF-7 breast cancer bearing nude mice were treated with adriamycin or sterile saline administered by intraperitoneal injection. Ultrasonic radio-frequency (RF) data was collected using a clinically available ultrasound scanner (6-MHz linear transducer). Linear regression parameters (spectral slope and midband-fit) regarding the calibrated power spectra from the RF signals were tested to monitor tumor response to treatment. The section equivalent to the ultrasound imaging plane was stained with hematoxylin and eosin to allow for assessment of the density of tumor cell nuclei.ResultsTreatment with adriamycin significantly reduced tumor growth in comparison with the control group (p = 0.003). Significant changes were observed in the ultrasonic parameters of the treated relative to the untreated tumors (p < 0.05). The spectral slope increased by 48.5%, from −10.66 ± 2.96 to −5.49 ± 2.69; the midband-fit increased by 12.8%, from −57.10 ± 7.68 to −49.81 ± 5.40. Treated tumors were associated with a significant decrease in the density of tumor cell nuclei as compared with control tumors (p < 0.001).ConclusionsUltrasonic spectral analysis can detect changes in tumor microstructure after chemotherapy, and this will be helpful in the early evaluation tumor response to chemotherapy.

Correction: Probing Early Tumor Response to Radiation Therapy Using Hyperpolarized [1-13C]pyruvate in MDA-MB-231 Xenografts

Correction: Probing Early Tumor Response to Radiation Therapy Using Hyperpolarized [1-¹³C]pyruvate in MDA-MB-231 Xenografts

Dynamic gadobutrol-enhanced MRI predicts early response to antivascular but not to antiproliferation therapy in a mouse xenograft model

Dynamic contrast-enhanced magnetic resonance imaging has been described as a method to assess tumor vascularity and, therefore, is discussed as a noninvasive biomarker for drug response prediction in tumor therapies. Because antiangiogenic and antiproliferative drugs are frequently combined for therapy, the aim was to investigate (1) the early response predictability and (2) the extent to which these therapy types influence dynamic contrast-enhanced magnetic resonance imaging with gadobutrol soon after therapy initiation. Mice bearing a KPL-4 tumor were treated with either bevacizumab as an antiangiogenic drug or trastuzumab as a cytotoxic anti-tumor drug. The gadobutrol-contrast agent exposure of the tumor was recorded before and at several time points after therapy initiation to examine the response prediction by dynamic contrast-enhanced magnetic resonance imaging. Both therapies resulted in significant tumor growth attenuation over 30 days of therapy, but the individual response to each therapy was different. Specifically, bevacizumab affected the dynamic gadobutrol-enhanced MRI-derived area under the curve at early time points (≤8 days), while trastuzumab did not. The area under the curve obtained from dynamic gadobutrol-enhanced MRI predicted early tumor response to the antiangiogenic drug bevacizumab, but not to the anti-tumor cell drug trastuzumab. This indicates that the area under the curve may be useful for assessing early antiangiogenic but not antiproliferative drug effects.

The Potential of PET/MRI Imaging in Oncology: a Comment to a Summary Report of the First PET/MRI Workshop in Tuebingen in 2012

The Potential of PET/MRI Imaging in Oncology: a Comment to a Summary Report of the First PET/MRI Workshop in Tuebingen in 2012

Trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid (anti-18F-FACBC) is a feasible alternative to 11C-methyl-L-methionine and magnetic resonance imaging for monitoring treatment response in gliomas

Amino acid PET tracers are promising for visualizing gliomas and evaluating radiochemotherapeutic effects. We compared the glioma detection and early response assessment utility between trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) by simultaneously analyzing their uptake by rat gliomas treated with and without temozolomide (TMZ) in vitro and in vivo. C6 rat gliomas were incubated with low-dose TMZ to induce chemoresistance. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated a significantly greater surviving fraction in the TMZ-resistant subline (C6R) than in drug-naive cells (C6). The anti-(14)C-FACBC and (3)H-Met uptakes were quantified using a triple-label accumulation assay to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation rate) in tumor cells. C6 and C6R cells were inoculated into the right and left basal ganglia, respectively, of rats. Efficacy of TMZ against the orthotopic gliomas was analyzed by MRI, Evans blue extravasation, anti-(14)C-FACBC and (3)H-Met autoradiography, and MIB-5 proliferation index. The (3)H-TdR accumulation rate and amino acid tracer (anti-(14)C-FACBC and (3)H-Met) uptake significantly decreased 48 and 72 h, respectively, after TMZ treatment in C6 but not C6R cells. Anti-(14)C-FACBC uptake correlated significantly with (3)H-Met uptake and the (3)H-TdR accumulation rate. In the intracerebral glioma model, anti-(14)C-FACBC and (3)H-Met autoradiography clearly delineated the tumor extent, which spread well beyond the high-T2-intensity and enhancing lesions visible on MRI and Evans blue extravasation. TMZ significantly decreased anti-(14)C-FACBC and (3)H-Met uptake and the MIB-5 index of C6 but not C6R tumors. TMZ inhibited tracer uptake and tumor proliferation before morphological changes on MRI. Anti-(14)C-FACBC, like (3)H-Met, was more sensitive than post-contrast T1-weighted MRI for detecting tumor extent and early tumor response to TMZ treatment. Anti-(18)F-FACBC should be a sensitive and precise imaging biomarker for tumor extent visualization and response assessment in glioma patients.

Specific detection of Epstein-Barr virus microRNAs in plasma samples from nasopharyngeal carcinoma patients: Correlation with tumor mass assessed by MRI.

6079 Background: Epstein-Barr virus (EBV) microRNAs of the BART family can be detected in the plasma of at least a fraction of nasopharyngeal carcinoma (NPC) patients. Our aim was to investigate the specificity of plasma BART detection in NPC patients and the correlation with viral DNA load and/or clinical characteristics. Methods: Hsa miR484 and 4 miR-BARTs (ebv-miR BART 2-5p, 5, 9 and 18) were assessed by RT-PCR following RNA extraction in 37 plasma samples including 20 NPC, 8 non-NPC head and neck squamous cell carcinoma (SCC) patients and 9 healthy EBV carriers. EBV DNA copy numbers (viral load) were measured in the same samples. To explore correlations of BART concentrations with tumor mass, MRI-based volume analysis was designed and performed on a subset of 13 patients with non metastatic NPC. In addition, longitudinal variations of BART concentrations were studied in 9 NPC patients for whom we had sequential plasma samples. Results: The cellular hsa miR-484 was detected in all plasma samples with a slightly higher average concentration in plasma samples from NPC and SCC patients. On the other hand, the miR-BARTs were undetectable or at a very low level in samples from SCC patients and healthy carriers contrasting with a high level in most NPC patients. There was an overall positive correlation between EBVDNA copy numbers and plasma concentrations of each miR-BART. However substantial amounts of plasmatic miR-BARTs were observed in several patients for whom no plasma EBV DNA was detected.Their concentration was apparently not correlated to the initial tumor volume but their longitudinal variations were parallel with clinical evolution in all but one case. Conclusions: To a large extent, detection of plasma miR-BART-2-5p, 5, 9, and 18 is specific of NPC patients. Their concentration does not seem to correlate with tumor mass, at least in localized NPC patients. In a fraction of patients without initial detection of plasma EBV DNA, the kinetics of plasma BARTs may provide informations on early tumor response under treatment and may have prognostic value.

Prognostic value of early objective tumor response (EOTR) to first-line systemic therapy in metastatic colorectal cancer (mCRC): Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database.

3520 Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values &lt;0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p&lt;.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p&lt;.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p&lt;.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p&lt;.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p&lt;0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p&lt;.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.

Assessment of early tumor response to induction chemotherapy (IC) in locally advanced squamous-cell carcinoma of head and neck (LASCCHN) with 18FDG PET-CT: A prospective trial.

6017 Background: Response to IC with triplet regimens adding taxanes to cisplatin and 5-fluorouracil (TPF), followed by chemoradiotherapy (CRT) for LASCCHN, is usually evaluated after 2 cycles of IC, based on bidimensional WHO or modified WHO criteria. Concerns regarding toxicity profile of TPF suggest a potential benefit of an early response evaluation approach that could select patients who would be spared from a toxic regimen and promptly started on an alternative treatment. The aim of this study is to assess the ability of evaluating early response after the first IC cycle based on a 40% decrease in standard-uptake value (SUV) measured by 18 FDG PET-CT on the 14th day. Methods: Patients with LASCCHN who underwent IC with TPF were prospectively evaluated. Staging procedure included locoregional and chest imaging, endoscopic examination and FDG PET-CT. At day 14 of first cycle, a second FDG PET-CT was performed and treating physicians were blinded for these findings. All cases were conducted according to the usual post-cycle 2 WHO or modified WHO criteria evaluation. Written informed consent was obtained from all recruited patients. Results: Between February 2010 and October 2012, 40 stage III/IV LASCCHN patients (34 oropharyngeal, 3 hypopharyngeal and 3 laryngeal) were recruited. With a median follow up of 11.4 months the actuarial 2 years overall (OS) and disease free survival (DFS) of all patients were 81.4% and 69.2%, respectively. Responders (any decrease of SUV) at day 14 PET CT had a better OS (90 vs. 27% - p&lt;0,001) and DFS (76 vs. 0% - p&lt;0,001) as compared to non-responders. Decrease of at least 40% in the SUV of primary tumor predicted a better DFS (100 vs. 51% - p=0,007). Conclusions: These results suggest a potential role of early response evaluation with 18 FDG PET-CT in patients with LASCCHN undergoing IC. A SUV decrease of at least 40% predicts better DFS. An increase in the SUV predicts a poor prognosis.

The prognostic value of quantitative parameters of 18F-FDG PET/CT in the evaluation of response to internal radiation therapy with yttrium-90 in patients with liver metastases of colorectal cancer

The aim of this study was to evaluate tumor response using fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients who received yttrium-90 selective internal radiation therapy (SIRT) for colorectal liver metastases. The initial and sixth-week tumor lesion glycolysis values were calculated to evaluate the success of the treatment and compare it with patient survival. Thirty-five patients (15 female, 20 male, mean age: 61.9 ± 9.0 years, range: 33-76 years) who received SIRT treatment for unresectable colorectal cancer liver metastases in our hospital between June 2008 and May 2011 were included in the study. All patients included in the study had liver-only or liver-dominant disease. The treatment response was evaluated by 18F-FDG PET/CT in the sixth week after treatment. Response was evaluated according to the change in total lesion glycolysis (ΔTLG). The ΔTLG was calculated using the following formula: ΔTLG=100 ×[standardized uptake value (SUV) mean1 × total functional tumor volumes (FTVs)1-SUV mean2 × FTV2]/SUV mean1 × FTV1. Mean FTV1 and FTV2 values were calculated to be 235.7 ± 203 and 107.3 ± 67 mm3, respectively (P=0.04). The mean ΔTLG was 43 ± 35 (range: 0-100). Mean overall survival time was 12.7 ± 8.0 months (range: 3-31 months). The cutoff value of ΔTLG was calculated to be 26.5 using receiver operating characteristic analysis (sensitivity 64%; specificity 85%; AUC=0.717 ± 0.087, P=0.034). Patients were allocated into those having values greater than the cutoff value (group 1) and those having values lower than the cutoff value (group 2) in order to calculate the effect of ΔTLG on survival. Survival was 11.32 ± 1.18 (95% CI 9.02-13.62) months in group 2 and 20.76 ± 2.71 (95% CI 15.46-26.06) months in group 1 (P=0.016). ΔTLG was found to be a significant factor in univariate analysis (P=0.01). An 18F-FDG PET/CT scan with calculation of ΔSUVmax3, ΔFTV, and ΔTLG before and at the sixth week after SIRT may play an important role in evaluating early tumor response and survival expectancy in these patients and help decide whether these patients should be referred to other treatment modalities or to follow-up.

A potential new enriching trial design for selecting non‐small‐cell lung cancer patients with no predictive biomarker for trials based on both histology and early tumor response: further analysis of a thalidomide trial

There are few predictive biomarkers for antiangiogenic trials in lung cancer. We examine a potential treatment strategy in which a patient group is enriched using both histology and an early assessment of response during standard chemotherapy, and where a new agent is given for the remainder of chemotherapy and as maintenance. We performed a retrospective analysis of 722 stage IIIB/IV non-small-cell lung cancer patients from a double-blind placebo-controlled trial of thalidomide or placebo 100–200 mg/day, combined with gemcitabine/carboplatin (for up to four cycles), then given as single agent maintenance therapy. There was a significant statistical interaction between treatment and histology, with a possible benefit among squamous cell cancer (SCC) patients. We examined 150 SCC patients who were “nonprogressors” (stable disease or complete/partial response) after completing the second chemotherapy cycle. Endpoints were progression-free survival (PFS) and overall survival (OS). Among the 150 patients nonprogressors after cycle 2 (thalidomide, n = 72; placebo, n = 78; baseline characteristics were similar), the hazard ratios (HRs) were: OS = 0.76 (95% CI: 0.54–1.07) and PFS = 0.69 (95% CI: 0.50–0.97). In 57 patients who had a complete/partial response, the HRs were: OS = 0.63 (95% CI: 0.34–1.15) and PFS = 0.50 (95% CI: 0.28–0.88). SCC patients who were nonprogressors after 2 cycles of standard chemotherapy showed evidence of a benefit from thalidomide when taken for the remainder of chemotherapy and as maintenance. This strategy based on histology and, importantly, early assessment of tumor response, as a means of patient enrichment, could be examined in other lung cancer studies. Such an approach might be suitable for trials where there are no predictive biomarkers.

Assessment of Early Tumor Response to Cytotoxic Chemotherapy With Dynamic Contrast-Enhanced Ultrasound in Human Breast Cancer Xenografts

Assessment of Early Tumor Response to Cytotoxic Chemotherapy With Dynamic Contrast-Enhanced Ultrasound in Human Breast Cancer Xenografts

Value of apparent diffusion coefficient (ADC) in evaluating response of carcinoma of the cervix treated with chemoradiotherapy

Objective: To determine whether the apparent diffusion coefficient (ADC) value obtained by diffusion-weighted magnetic resonance imaging (DW-MRI) can be used as a reliable detector of response of carcinoma of the cervix treated with chemoradiotherapy, compared with conventional T2-weighted MRI. Design: A prospective cohort study was performed. Setting: Department of Oncology, Universitas-National Hospital Complex, Bloemfontein. Subjects: Seventeen women with advanced cervical cancer, FIGO staging IIB - IVB, were selected for chemoradiation. Outcome measures: Patients underwent pelvic MRI before therapy, 14 days after onset of therapy, and in the last week of treatment (5th/6th week). Axial and sagittal conventional T2 was followed by DW-MRI in the axial plane from which a tumour region of interest (ROI) was manually drawn to calculate ADC values using b-values of 500 and 1 000 s/mm2. Results: ADC values for cervical carcinoma increased after treatment with chemoradiation. The most significant observation was seen 14 days after treatment was started. The mean ADC value increased with 20% (b=500 s/mm2) and 24% (b=1 000 s/mm2) (statistically significant, p&lt;0.05) compared with a decrease in tumour size of only 8%, which was not statistically significant (p=0.075). Responders showed a larger change in ADC values than non-responders. Conclusion: The study showed considerable promise in the ability of ADC to identify early tumour response to therapy. DW-MRI is a non-invasive functional imaging technique that may in future change management in oncology by early identification of non-responders, hence avoiding unnecessary treatment.

Multimodal imaging of tumor response to sorafenib combined with radiation therapy: comparison between diffusion‐weighted MRI, choline spectroscopy and 18F‐FLT PET imaging

The purpose of this study was to determine the value of different imaging modalities, that is, magnetic resonance imaging/spectroscopy (MRI/MRS) and positron emission tomography (PET), to assess early tumor response to sorafenib with or without radiotherapy. Diffusion-weighted (DW)-MRI, choline (1)H MRS at 11.7 T, and (18)F-FLT PET imaging were used to image fibrosarcoma (FSaII) tumor-bearing mice over time. The imaging markers were compared with apoptosis cell death and cell proliferation measurements assessed by histology. Anti-proliferative effects of sorafenib were evidenced by (1)H MRS and (18)F-FLT PET after 2 days of treatment with sorafenib, with no additional effect of the combination with radiation therapy, results that are in agreement with Ki67 staining. Apparent diffusion coefficient calculated using DW-MRI was not modified after 2 days of treatment with sorafenib, but showed significant increase 24 h after 2 days of sorafenib treatment combined with consecutive irradiation. The three imaging markers were able to show early tumor response as soon as 24 h after treatment initiation, with choline MRS and (18)F-FLT being sensitive to sorafenib in monotherapy as well as in combined therapy with irradiation, whereas DW-MRI was only sensitive to the combination of sorafenib with radiotherapy.

Value of apparent diffusion coefficient (ADC) in evaluating response of carcinoma of the cervix treated with chemoradiotherapy

Objective: To determine whether the apparent diffusion coefficient (ADC) value obtained by diffusion-weighted magnetic resonance imaging (DW-MRI) can be used as a reliable detector of response of carcinoma of the cervix treated with chemoradiotherapy, compared with conventional T2-weighted MRI.Design: A prospective cohort study was performed.Setting: Department of Oncology, Universitas-National Hospital Complex, Bloemfontein.Subjects: Seventeen women with advanced cervical cancer, FIGO staging IIB - IVB, were selected for chemoradiation.Outcome measures: Patients underwent pelvic MRI before therapy, 14 days after onset of therapy, and in the last week of treatment (5th/6th week). Axial and sagittal conventional T2 was followed by DW-MRI in the axial plane from which a tumour region of interest (ROI) was manually drawn to calculate ADC values using b-values of 500 and 1 000 s/mm2.Results: ADC values for cervical carcinoma increased after treatment with chemoradiation. The most significant observation was seen 14 days after treatment was started. The mean ADC value increased with 20% (b=500 s/mm2) and 24% (b=1 000 s/mm2) (statistically significant, p&lt;0.05) compared with a decrease in tumour size of only 8%, which was not statistically significant (p=0.075). Responders showed a larger change in ADC values than non-responders.Conclusion: The study showed considerable promise in the ability of ADC to identify early tumour response to therapy. DW-MRI is a non-invasive functional imaging technique that may in future change management in oncology by early identification of non-responders, hence avoiding unnecessary treatment.

Assessment of Early Tumor Response to Cytotoxic Chemotherapy with Dynamic Contrast-Enhanced Ultrasound in Human Breast Cancer Xenografts

There is a strong need to assess early tumor response to chemotherapy in order to avoid adverse effects from unnecessary chemotherapy and allow early transition to second-line therapy. This study was to quantify tumor perfusion changes with dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of early tumor response to cytotoxic chemotherapy. Sixty nude mice bearing with MCF-7 breast cancer were administrated with either adriamycin or sterile saline. CEUS was performed on days 0, 2, 4 and 6 of the treatment, in which time-signal intensity (SI) curves were obtained from the intratumoral and depth-matched liver parenchyma. Four perfusion parameters including peak enhancement (PE), area under the curve of wash-in (WiAUC), wash-in rate (WiR) and wash-in perfusion index (WiPI) were calculated from perfusion curves and normalized with respect to perfusion of adjacent liver parenchyma. Histopathological analysis was conducted to evaluate tumor perfusion, tumor cell density, microvascular density (MVD) and proliferating cell density. Significant decreases of tumor normalized perfusion parameters (i.e., nPE, nWiAUC, nWiR and nWiPI) were noticed between adriamycin-treated and control groups (P<0.01) 2 days after therapy. There were significant differences of tumor volumes between control and treated groups on day 6 (P<0.001) while there were no significant differences in tumor volume on days 0, 2 and 4 (P>0.05). Significant decreases of tumor perfusion, tumor cell density, MVD and proliferating cell density were seen in adrianycin-treated group 2 days after therapy when compared to control group (P<0.001). Dynamic CEUS for quantification of tumor perfusion could be used for early detection of cancer response to cytotoxic chemotherapy prior to notable tumor shrinkage.

Evaluation of the antitumor effects of rilotumumab by PET imaging in a U-87 MG mouse xenograft model

Dysregulation of the hepatocyte growth factor (HGF)/MET pathway has been implicated in various cancers. Rilotumumab is an investigational, fully human monoclonal antibody that binds and neutralizes HGF. The purpose of this study was to evaluate the efficacy of rilotumumab in a U-87 MG mouse xenograft tumor model using (18)F-FDG and (18)F-FLT PET. U-87 MG tumor-bearing nude mice received rilotumumab or control IgG2. In the dose response study, increasing doses of rilotumumab (10, 30, 100, 300, or 500 μg) were administered, and mice were evaluated with (18)F-FDG PET at baseline and 7 days post-treatment. In the time course study, 300 μg of rilotumumab twice per week was used for the treatment, and mice were evaluated over 7 days using (18)F-FDG and (18)F-FLT PET. In the dose response study, rilotumumab at doses of 300 and 500 μg was similarly effective against tumor growth. Treatment with 300 and 500 μg rilotumumab inhibited (18)F-FDG accumulation with significant decreases of -37% and -40% in the percent injected dose per gram of tissue (%ID/g), respectively. In the time course study, treatment with 300 μg rilotumumab inhibited (18)F-FDG and (18)F-FLT accumulation with a maximum %ID/g of -41% and -64%, respectively. No apparent differences between the use of either tracer to evaluate rilotumumab efficacy were observed. Rilotumumab inhibited (18)F-FDG and (18)F-FLT accumulation as early as 2 and 4 days after treatment, respectively, in a mouse tumor model. Further studies to evaluate (18)F-FDG PET imaging as an early tumor response marker for rilotumumab are warranted. Rilotumumab is currently being tested in patients with MET-positive, advanced gastric and gastroesophageal cancer.

Radiotherapy with volumetric modulated arc therapy for hepatocellular carcinoma patients ineligible for surgery or ablative treatments

The aim of this article is to report the dosimetric and clinical findings in the treatment of primary hepatocellular carcinoma (HCC) with volumetric modulated arc therapy (VMAT, RapidArc). A total of 138patients were investigated. Dose prescription ranged from 45-66Gy. Most patients (88.4 %) presented AJCC stage III or IV and 83 % were N0-M0. All were classified as Barcelona Clinic Liver Cancer (BCLC) stage A-C. All patients were treated using 10MV photons with single or multiple, coplanar or non-coplanar arcs, and cone-down technique in case of early response of tumors. The patients' median age was 66years (range 27-87years), 83 % were treated with 60Gy (12 % at 45Gy, 6 % at 66Gy), 62 % with cone-down, 98 % with multiple arcs. The mean initial planning target volume (PTV) was 777 ± 632cm(3); the mean final PTV (after the cone-down) was 583 ± 548cm(3). High target coverage was achieved. The final PTV was V98% > 98 %. Kidneys received on average 5 and 8Gy (left and right), while the maximum dose to the spinal cord was 22Gy; mean doses to esophagus and stomach were 23Gy and 15Gy, respectively. The average volume of healthy liver receiving more than 30Gy was 294 ± 145cm(3). Overall survival at 12months was 45 %; median survival was 10.3months (95 % confidence interval 7.2-13.3months). Actuarial local control at 6months was 95 % and 93.7 % at 12months. The median follow-up was 9months and a maximum of 28months. This study showed from the dosimetric point of view the feasibility and technical appropriateness of RapidArc for the treatment of HCC. Clinical results were positive and might suggest, with appropriate care, to consider RapidArc as an additional therapeutic opportunity for these patients.

Probing Early Tumor Response to Radiation Therapy Using Hyperpolarized [1-13C]pyruvate in MDA-MB-231 Xenografts

Following radiation therapy (RT), tumor morphology may remain unchanged for days and sometimes weeks, rendering anatomical imaging methods inadequate for early detection of therapeutic response. Changes in the hyperpolarized [1-13C]lactate signals observed in vivo following injection of pre-polarized [1-13C]pyruvate has recently been shown to be a marker for tumor progression or early treatment response. In this study, the feasibility of using 13C metabolic imaging with [1-13C]pyruvate to detect early radiation treatment response in a breast cancer xenograft model was demonstrated in vivo and in vitro. Significant decreases in hyperpolarized [1-13C]lactate relative to [1-13C]pyruvate were observed in MDA-MB-231 tumors 96 hrs following a single dose of ionizing radiation. Histopathologic data from the treated tumors showed higher cellular apoptosis and senescence; and changes in the expression of membrane monocarboxylate transporters and lactate dehydrogenase B were also observed. Hyperpolarized 13C metabolic imaging may be a promising new tool to develop novel and adaptive therapeutic regimens for patients undergoing RT.

Predicting tumour response to chemoradiotherapy in oesophageal cancer by early interim 18F-FDG PET: where do we stand and where should we go?

Oesophageal cancer is a disease with a dismal prognosis and high mortality. There were an estimated 482,000 new cases and 407,000 patients died of the disease worldwide in 2008 [1]. Concurrent chemotherapy and radiotherapy is now considered the neoadjuvant treatment of choice in patients with operable oesophageal cancer, as has been demonstrated by the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial [2]. However, not all patients benefit from this treatment. In the CROSS trial, as much as 39 % of patients had no histopathological tumour regression (tumour regression defined as <10 % viable tumour cells in the resected specimen). Yet, toxicity due to chemotherapy occurs in 11–90 % and there is also a risk of radiation-induced complications [2, 3]. In patients who respond insufficiently, inefficient chemoradiotherapy should be discontinued, and surgery should not be delayed. On the other hand, patients who respond favourably may benefit from additional preoperative treatment and surgery may be delayed or even refrained from. Therefore, there is a need for a method which can differentiate responders from nonresponders early in the course of neoadjuvant treatment. In clinical practice, integrated F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) already has a well-established role in the diagnosis and staging of oesophageal cancer [4]. The change in F-FDG uptake at PET performed before and after the start of neoadjuvant therapy may be used to predict which tumours respond to treatment. To date, there are only a few published prospective studies investigating the value of F-FDG PET in early prediction of tumour response to neoadjuvant therapy in oesophageal cancer. Two subsequent studies in independent study populations by researchers from Munich demonstrated that early metabolic tumour response, as measured by F-FDG PET, is correlated to histopathological response and better overall survival (OS) [5, 6]. However, these studies [5, 6] were performed in patients who only received neoadjuvant chemotherapy, whereas concurrent chemoradiotherapy is now considered the standard neoadjuvant treatment [2]. Increased F-FDG uptake caused by radiation-induced inflammation may limit the use of FFDG PET, because F-FDG PET is unable to distinguish whether tracer uptake is associated with inflammatory cells or residual viable tumour cells [7, 8]. To our knowledge, there are only three published prospective studies [7–9] in which the predictive value of early interim F-FDG PET in patients who received concurrent neoadjuvant chemoradiotherapy has been investigated. These studies all demonstrated an association between a decrease in tumour standardized uptake value (SUV) 14 days after start of neoadjuvant treatment and histopathological tumour response [7–9]. The study by Wieder et al. [7], in 38 patients with squamous cell carcinoma, also found an association between metabolic tumour response and OS. In contrast, the study by Malik et al. [8], in 37 patients with adenocarcinoma, did not find a significant association. The study by Cuenca et al. [10] in the present issue of the European Journal of Nuclear Medicine and Molecular Imaging adds further evidence that early interim F-FDG PET may be used to predict tumour response to chemoradiotherapy. Cuenca et al. [10] retrospectively analysed 59 patients with locally advanced oesophageal cancer (T3/T4, N1 M1a) who underwent an integrated F-FDG PET/CT scan before and 5 weeks after the beginning of chemotherapy This commentary refers to an article that can be found at doi 10.1007/ s00134-012-2325-3.