Early response assessment through multiparametric MRI based endpoints in a phase II multicenter study evaluating the efficacy of DPX-Survivac, intermittent low dose cyclophosphamide (CPA) and pembrolizumab combination study in subjects with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14245-e14245
Author(s):  
Diana Roettger ◽  
Faiq Shaikh ◽  
Sotirios Bisdas ◽  
Lisa Diana MacDonald ◽  
Stephan Fiset ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Response Assessment ◽  
Early Response ◽  
Multiparametric Mri ◽  
Imaging Biomarkers ◽  
Accurate Assessment ◽  
Tumor Biopsy ◽  
Recist 1.1 ◽  
Patient Reported ◽  
Pre Treatment

e14245 Background: Accurate assessment of tumor response to immunotherapy is challenged by pseudoprogression that mimics true progression. Conventional imaging and RECIST assessment do not adequately distinguish between them given their inability to account for changes in the tumor microenvironment. DPX-Survivac is a novel T cell activating therapy that triggers immune responses against tumors expressing survivin and is being studied in this trial in combination with CPA and pembrolizumab in several solid tumors. Multiparametric MRI approaches - dynamic contrast-enhanced MRI and diffusion-weighted imaging MRI are useful for accurate assessment of structural, perfusion and vascular assessment of the lesion and may identify pseudoprogression and compare to the RECIST-based assessment. Methods: The study will enroll up to 226 evaluable subjects in 5 different cohorts: ovarian cancer, HCC, NSCLC, bladder cancer and MSI-H cancer. These subjects will undergo initial imaging 28 days prior to treatment, to be assessed based on RECIST 1.1, and a pre-treatment tumor biopsy for quantitation of survivin and PD-L1 expression and MSI analyses. Treatment for 35 cycles or until disease progression. All patients will have CT images for RECIST 1.1 and iRECIST assessment. A subset of subjects will undergo mpMRI to calculate advanced imaging biomarkers. Results: MRI, clinical and patient-reported outcomes will be analyzed. Conclusions: This study will provide important evidence on the utility of mpMRI + CT-based assessment of response to immunotherapy and use it as an adjunct to the CT-based RECIST criteria by providing insight on how tumor lesions are impacted by treatment.

scholarly journals The use of hyperpolarised 13C-MRI in clinical body imaging to probe cancer metabolism

2021 ◽  
Author(s):  
Ramona Woitek ◽  
Ferdia A. Gallagher
Keyword(s):  
Cancer Metabolism ◽  
Signal To Noise Ratio ◽  
Response Assessment ◽  
Early Response ◽  
Multiparametric Mri ◽  
Metabolic Reprogramming ◽  
Response To Treatment ◽  
Additional Information ◽  
Positron Emission ◽  
Breast And Prostate Cancer

AbstractMetabolic reprogramming is one of the hallmarks of cancer and includes the Warburg effect, which is exhibited by many tumours. This can be exploited by positron emission tomography (PET) as part of routine clinical cancer imaging. However, an emerging and alternative method to detect altered metabolism is carbon-13 magnetic resonance imaging (MRI) following injection of hyperpolarised [1-13C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised 13C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of 13C-pyruvate to 13C-lactate over time. The method has produced promising preclinical results in the area of oncology and is currently being explored in human imaging studies. The first translational studies have demonstrated the safety and feasibility of the technique in patients with prostate, renal, breast and pancreatic cancer, as well as revealing a successful response to treatment in breast and prostate cancer patients at an earlier stage than multiparametric MRI. This review will focus on the strengths of the technique and its applications in the area of oncological body MRI including noninvasive characterisation of disease aggressiveness, mapping of tumour heterogeneity, and early response assessment. A comparison of hyperpolarised 13C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique.

scholarly journals Induction of Micronuclei in Cervical Cancer Treated with Radiotherapy

2020 ◽  
Vol 10 (3) ◽  
pp. 110
Author(s):  
Daijiro Kobayashi ◽  
Takahiro Oike ◽  
Kazutoshi Murata ◽  
Daisuke Irie ◽  
Yuka Hirota ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Immune Responses ◽  
Solid Tumors ◽  
Clinical Evidence ◽  
Median Number ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Biopsy ◽  
Biopsy Specimens ◽  
Pre Treatment ◽  
Sting Pathway

Micronuclei (MN) trigger antitumor immune responses via the cyclic GMP-AMP synthase-signaling effector stimulator of interferon genes (cGAS-STING) pathway. Radiotherapy induces MN in peripheral blood lymphocytes. However, data for solid tumors are lacking. Here, we analyzed MN post-radiotherapy in solid tumor samples. Tumor biopsy specimens were obtained from seven prospectively recruited patients with cervical cancer, before treatment and after receiving radiotherapy at a dose of 10 Gy (in five fractions). The samples were stained with 4′,6-diamidino-2-phenylindole dihydrochloride, and 200 nuclei per sample were randomly identified and assessed for the presence of MN or apoptosis, based on nuclear morphology. The median number of MN-harboring nuclei was significantly greater in samples from patients treated with radiotherapy than in pre-treatment samples (151 (range, 16–327) versus 28 (range, 0–61); p = 0.015). No significant differences in the number of apoptotic nuclei were observed between pre-treatment and 10 Gy samples (5 (range, 0–30) versus 12 (range, 2–30); p = 0.30). This is the first report to demonstrate MN induction by radiotherapy in solid tumors. The results provide clinical evidence of the activation of antitumor immune responses by radiotherapy.

scholarly journals Feasibility of a multiparametric MRI protocol for imaging biomarkers associated with neoadjuvant radiotherapy for soft tissue sarcoma

BJR|Open ◽  
2021 ◽  
pp. 20200061
Author(s):  
Lucy Kershaw ◽  
Laura Forker ◽  
Darren Roberts ◽  
Benjamin Sanderson ◽  
Patrick Shenjere ◽  
...  
Keyword(s):  
Overall Survival ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Early Response ◽  
Imaging Biomarkers ◽  
Neoadjuvant Radiotherapy ◽  
Imaging Protocol ◽  
Enhancement Curve ◽  
Pre Treatment ◽  
Rare Malignancy

Objectives: Soft tissue sarcoma (STS) is a rare malignancy with a 5 year overall survival rate of 55%. Neoadjuvant radiotherapy is commonly used in preparation for surgery, but methods to assess early response are lacking despite pathological response at surgery being predictive of overall survival, local recurrence and distant metastasis. Multiparametric MR imaging (mpMRI) is used to assess response in a variety of tumours but lacks a robust, standardised method. The overall aim of this study was to develop a feasible imaging protocol to identify imaging biomarkers for further investigation. Methods: Fifteen patients with biopsy-confirmed STS suitable for preoperative radiotherapy and radical surgery were imaged throughout treatment. The mpMRI protocol included anatomical, diffusion weighted and dynamic contrast-enhanced imaging, giving estimates of apparent diffusion coefficient (ADC) and the area under the enhancement curve at 60 s (iAUC60). Histological analysis of resected tumours included detection of CD31, Ki67, HIF and calculation of a hypoxia score. Results: There was a significant reduction in T1 at visit 2 and in ADC at visit 3. Significant associations were found between hypoxia and pre-treatment iAUC60, pre-treatment ADC and mid-treatment iAUC60. There was also statistically significant association between mid-treatment ADC and Ki67. Conclusions: This work showed that mpMRI throughout treatment is feasible in patients with STS having neoadjuvant radiotherapy. The relationships between imaging parameters, tissue biomarkers and clinical outcomes warrant further investigation. Advances in knowledge : mpMRI based biomarkers have good correlation with STS tumour biology and are potentially of use for evaluation of radiotherapy response.

scholarly journals Imaging Biomarkers to Predict and Evaluate the Effectiveness of Immunotherapy in Advanced Non-Small-Cell Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying Liu ◽  
Minghao Wu ◽  
Yuwei Zhang ◽  
Yahong Luo ◽  
Shuai He ◽  
...  
Keyword(s):  
Predictive Accuracy ◽  
Response Assessment ◽  
Early Response ◽  
Imaging Biomarkers ◽  
Imaging Data ◽  
Predictive Capacity ◽  
Clinical Factor ◽  
Response Status ◽  
Expression Status ◽  
Radiomics Signature

ObjectiveWe aimed to identify imaging biomarkers to assess predictive capacity of radiomics nomogram regarding treatment response status (responder/non-responder) in patients with advanced NSCLC undergoing anti-PD1 immunotherapy.Methods197 eligible patients with histologically confirmed NSCLC were retrospectively enrolled from nine hospitals. We carried out a radiomics characterization from target lesions (TL) approach and largest target lesion (LL) approach on baseline and first follow-up (TP1) CT imaging data. Delta-radiomics feature was calculated as the relative net change in radiomics feature between baseline and TP1. Minimum Redundancy Maximum Relevance (mRMR) and Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression were applied for feature selection and radiomics signature construction.ResultsRadiomics signature at baseline did not show significant predictive value regarding response status for LL approach (P = 0.10), nor in terms of TL approach (P = 0.27). A combined Delta-radiomics nomogram incorporating Delta-radiomics signature with clinical factor of distant metastasis for target lesions had satisfactory performance in distinguishing responders from non-responders with AUCs of 0.83 (95% CI: 0.75–0.91) and 0.81 (95% CI: 0.68–0.95) in the training and test sets respectively, which was comparable with that from LL approach (P = 0.92, P = 0.97). Among a subset of those patients with available pretreatment PD-L1 expression status (n = 66), models that incorporating Delta-radiomics features showed superior predictive accuracy than that of PD-L1 expression status alone (P <0.001).ConclusionEarly response assessment using combined Delta-radiomics nomograms have potential advantages to identify patients that were more likely to benefit from immunotherapy, and help oncologists modify treatments tailored individually to each patient under therapy.

Validation of RECIST 1.1 for use with cytotoxic agents and targeted cancer agents (TCA): Results of a RECIST Working Group analysis of a 50 clinical trials pooled individual patient database.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2534-2534 ◽  
Author(s):  
Saskia Litière ◽  
Gaëlle Isaac ◽  
Elisabeth De Vries ◽  
Jan Bogaerts ◽  
Alice P. Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Solid Tumors ◽  
Response Assessment ◽  
Time Dependent ◽  
Tumor Shrinkage ◽  
Recist 1.1 ◽  
Patient Database ◽  
Mixed Responses ◽  
Landmark Analyses

2534 Background: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were derived from an international collaborative effort supported by data from clinical trials (16 studies, 9147 patients) on cytotoxic chemotherapy (CT), providing a standard tool for response assessment. RECIST’s role has been questioned for TCA. Using a pooled individual patient database (IPD) from clinical trials performed by industry and cooperative groups, we assessed whether modifications to RECIST are required to evaluate antitumor activity of TCA. Methods: Data were collected from phase 2 and 3 clinical trials testing TCA in solid tumors. To study the occurrence of mixed responses, the variability of response of lesions within patients was studied. Furthermore, response was correlated with survival through landmark analyses and time dependent Cox models. Results: Clinical data were obtained from 23,259 patients, mainly with lung (36%), colorectal (28%) or breast cancer (11%). 15,620 patients (67%) received a TCA, mainly transduction or angiogenesis inhibitors, either as single agent (37%) or combined with other TCAs (7%) or CT (56%); 28% received CT only and 5% best supportive care or placebo. Within-patient variability reduced as the number of lesions used for response assessment increased, and did so similarly for TCAs (+/- CT) and CT. Mixed responses seemed to occur similarly across these treatment categories as well. Landmark analyses showed improving overall survival by % tumor shrinkage and a clear distinction between the effect of tumor shrinkage and progressive disease (PD) according to RECIST 1.1. This was confirmed by time dependent analysis. In addition target lesion growth showed no marked improvement in overall survival prediction over and above the other components of RECIST 1.1 PD (new lesions, non-target PD), regardless of treatment (TCA, CT or both) received. Similar results were seen focusing on major tumor types and classes of TCA. Conclusions: Using a large IPD dataset we demonstrated that RECIST 1.1 performs equally well for response assessment of TCA as for CT. No modifications are required.

Response criteria for intratumoral immunotherapy in solid tumors: ItRECIST.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3141-3141
Author(s):  
Gregory V. Goldmacher ◽  
Anuradha D. Khilnani ◽  
Robert H. I. Andtbacka ◽  
Jason J. Luke ◽  
F. Stephen Hodi ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Evaluation Criteria ◽  
Response Assessment ◽  
Target Lesion ◽  
Tumor Burden ◽  
Therapeutic Modality ◽  
Overall Response ◽  
Recist 1.1 ◽  
Trial Protocols ◽  
Systemic Responses

3141 Background: The approval of intratumoral (IT) immunotherapy for metastatic melanoma and the active development of numerous novel IT drugs have created a need for standardized evaluation of response to this unique treatment strategy. The Response Evaluation Criteria in Solid Tumors (RECIST) is not suitable for assessing responses separately for injected and noninjected tumors. Building on RECIST concepts, we propose an IT immunotherapy RECIST (itRECIST) to capture data and assess local and systemic responses in a standardized fashion for clinical trials involving IT immunotherapies. Methods: itRECIST will address the unique needs of IT immunotherapy trials but, where possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject but provides guidelines for collecting data and assessing response as treatment evolves. Results: itRECIST enables overall response assessment, separate response assessments in injected and noninjected lesions, and continued assessment following modifications of therapy at initial progression. At baseline, lesions are classified into 4 categories: target injected, target noninjected, nontarget injected, and nontarget noninjected. After baseline, lesions can be reclassified from noninjected to injected if the investigator decides to change the lesions to inject, but target and nontarget designations never change. Overall response at each assessment is based on target lesion response (injected and noninjected), nontarget lesion response, and absence/appearance of new lesions. Noninjected lesion response is determined by comparing tumor burden with baseline and nadir values. Injected lesion assessment is based on visit-to-visit changes in the lesions injected during treatment and on a combined assessment once the patient is off treatment. A new response category is defined to capture progression that would be “confirmed” per iRECIST even though injected lesions are responding and therapy continues. Multiple examples have been created to aid in training and adoption. Conclusions: itRECIST is an important step toward a standardized method of response assessment for this promising and evolving therapeutic modality. The proposed guidelines can be adopted into trial protocols and routine clinical practice without the need for complex additional assessments by treating physicians. Until there is evidence to support wider use, itRECIST is intended only to support standardized collection of data and to facilitate exploratory analysis. Authors G.V.G. and A.D.K. contributed equally to this work.

Alpha-T: An innovative decentralized (home-based) phase 2 trial of alectinib in ALK-positive (ALK+) solid tumors in a histology-agnostic setting.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3155-TPS3155
Author(s):  
Razelle Kurzrock ◽  
Amy R. MacKenzie ◽  
Adham Adel Jurdi ◽  
Basem Goueli ◽  
Walter Bordogna ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Locally Advanced ◽  
Fusion Partner ◽  
Phase 2 ◽  
Anaplastic Lymphoma ◽  
Recist 1.1 ◽  
Home Based ◽  
Patient Reported ◽  
Tumor Types

TPS3155 Background: Anaplastic lymphoma kinase ( ALK) fusions are found in 3–8% of non-small cell lung cancers (NSCLC) and ̃0.2% of other tumor types. Alectinib is a selective, CNS-active ALK tyrosine kinase inhibitor approved as first-line treatment for adults with advanced ALK fusion-positive ( ALK-fp) NSCLC based on the phase 3 ALEX trial (NCT02075840; PMID 28586279). Preliminary evidence supports investigation of alectinib in a tumor-agnostic setting. ALK inhibitors have shown efficacy in ALK-fp tumor types other than NSCLC (PMIDs 29685646; 28977547; 30591488), with alectinib showing efficacy irrespective of ALK fusion partner and against ALK-activating mutations (PMIDs 29642598; 29559559). Methods: Alpha-T is a phase 2 open-label, single-arm trial (NCT04644315) with an innovative home-based remote design, currently enrolling adults with histologically confirmed, locally advanced/metastatic solid tumors (except lung cancer and cancers of unknown primary) harboring ALK fusions or selected mutations ( ALK-mut; R1275Q, F1245C, F1174X). The decentralized design permits enrollment regardless of location, allows most assessments to be home-based and maintains the relationship between patients (pts) and their treating oncologist. Key inclusion criteria: no alternative or unsuitable to receive standard therapy; ECOG PS 0–2; adequate hematologic, renal and hepatic functions; no prior ALK inhibitor; measurable solid tumor (RECIST 1.1) or primary brain tumor (RANO); asymptomatic or stable CNS metastases permitted. Pts are identified via the Foundation Medicine Inc. (FMI) Precision Enrollment service. For any solid tumor identified as ALK+ (fusion/selected mutation) by next-generation sequencing in tissue/blood (F1 CDx/F1L CDx, FMI), the ordering oncologist is given trial details and can liaise with a Science 37 investigator. Pts receive 600mg oral alectinib twice a day with food until radiological PD, unacceptable toxicity, withdrawal of consent or death. Home-based assessments (eg, physical examination, blood sampling, questionnaire completion) are conducted in-person by a mobile nurse at baseline and every 4 weeks, with remote support from the Science 37 investigator via their telemedicine platform. Tumor assessments at screening and every 8 weeks are performed at a local radiology facility. Primary endpoint: confirmed ORR by investigator in pts with ALK-fp tumors (RECIST 1.1). Secondary endpoints: ORR by independent review facility (IRF); DoR and PFS; intracranial ORR and DoR (IRF); OS and safety. Descriptive analyses are planned for pts with ALK-mut tumors and primary brain tumors. Pharmacokinetics and biomarkers will be evaluated. Patient-reported outcomes will be assessed via the EORTC QLQ-C30 and EuroQoL EQ-5D-5L questionnaires. Target enrollment is 50 pts with ALK-fp tumors evaluable by RECIST. As of 9 Feb 2021, 1 pt is in screening. Clinical trial information: NCT04644315.

scholarly journals Current status of ctDNA in precision oncology for hepatocellular carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yan Li ◽  
Yuanyuan Zheng ◽  
Liwei Wu ◽  
Jingjing Li ◽  
Jie Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Diagnostic Technique ◽  
Response Assessment ◽  
Selection Response ◽  
Circulating Tumor Dna ◽  
Current Status ◽  
Precision Oncology ◽  
Tumor Biopsy ◽  
Non Invasive

AbstractThe conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.

scholarly journals 18F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing tyrosine kinase or checkpoint inhibitor therapy: preliminary results

2020 ◽  
Author(s):  
L. M. Mittlmeier ◽  
M. Unterrainer ◽  
S. Rodler ◽  
A. Todica ◽  
N. L. Albert ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Treatment Response ◽  
Renal Cell ◽  
Systemic Treatment ◽  
Response Assessment ◽  
Recist 1.1 ◽  
Psma Pet ◽  
Pet Ct

Abstract Introduction Tyrosine kinase (TKI) and checkpoint inhibitors (CI) prolonged overall survival in metastatic renal cell carcinoma (mRCC). Early prediction of treatment response is highly desirable for the individualization of patient management and improvement of therapeutic outcome; however, serum biochemistry is unable to predict therapeutic efficacy. Therefore, we compared 18F-PSMA-1007 PET imaging for response assessment in mRCC patients undergoing TKI or CI therapy compared to CT-based response assessment as the current imaging reference standard. Methods 18F-PSMA-1007 PET/CT was performed in mRCC patients prior to initiation of systemic treatment and 8 weeks after therapy initiation. Treatment response was evaluated separately on 18F-PSMA-PET and CT. Changes on PSMA-PET (SUVmean) were assessed on a per patient basis using a modified PERCIST scoring system. Complete response (CRPET) was defined as absence of any uptake in all target lesions on posttreatment PET. Partial response (PRPET) was defined as decrease in summed SUVmean of > 30%. The appearance of new, PET-positive lesions or an increase in summed SUVmean of > 30% was defined as progressive disease (PDPET). A change in summed SUVmean of ± 30% defined stable disease (SDPET). RECIST 1.1 criteria were used for response assessment on CT. Results of radiographic response assessment on PSMA-PET and CT were compared. Results Overall, 11 mRCC patients undergoing systemic treatment were included. At baseline PSMA-PET1, all mRCC patients showed at least one PSMA-avid lesion. On follow-up PET2, 3 patients showed CRPET, 3 PRPET, 4 SDPET, and 1 PDPET. According to RECIST 1.1, 1 patient showed PRCT, 9 SDCT, and 1 PDCT. Overall, concordant classifications were found in only 2 cases (2 SDCT + PET). Patients with CRPET on PET were classified as 3 SDCT on CT using RECIST 1.1. By contrast, the patient classified as PRCT on CT showed PSMA uptake without major changes during therapy (SDPET). However, among 9 patients with SDCT on CT, 3 were classified as CRPET, 3 as PRPET, 1 as PDPET, and only 2 as SDPET on PSMA-PET. Conclusion On PSMA-PET, heterogeneous courses were observed during systemic treatment in mRCC patients with highly diverging results compared to RECIST 1.1. In the light of missing biomarkers for early response assessment, PSMA-PET might allow more precise response assessment to systemic treatment, especially in patients classified as SD on CT.

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