European Organization For Research And Treatment Of Cancer Criteria Research Articles

Response evaluation in nuclear medicine : Criteria, results and pitfalls

Established criteria to categorize metabolic tumor response to cytotoxic chemotherapies may not be suited to capture the effects of therapy with immune checkpoint inhibitors (ICI) or with kinase inhibitors (KI), such as BRAF or MEK inhibitors. To assess the metabolic response to cytotoxic chemotherapy by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG), the criteria of the European Organization for Research and Treatment of Cancer (EORTC) and the positron emission tomography response criteria in solid tumors (PERCIST) were conceived. The salient features of both criteria are detailed in acomparative way. To date only retrospective data exist for the evaluation of therapies with either ICI or KI. They show that response to ICI cannot be reliably determined using the established criteria. Employing the EORTC criteria the responses to KI can be adequately ascertained so that the metabolic tumor response in FDG-PET is regarded as asurrogate marker for the efficacy of these drugs. Tumor response to therapy with ICI cannot at present be assessed with FDG-PET. Responses to BRAF and MEK inhibitors are, however, assessable using the criteria that were originally developed to evaluate responses to cytotoxic chemotherapy.

Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point18F-FDG PET/CT Imaging in Patients with Advanced Melanoma

The purpose of this study was to evaluate 18F-FDG PET/CT scanning as an early predictor of response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: Twenty patients with advanced melanoma receiving ICI prospectively underwent 18F-FDG PET/CT at 3 scan intervals: before treatment initiation (SCAN-1), at days 21-28 (SCAN-2), and at 4 mo (SCAN-3). This study was approved by the institutional review board, and informed consent was received from all patients who were enrolled between April 2012 and December 2013. Tumor response at each posttreatment time point was assessed according to RECIST 1.1, immune-related response criteria, PERCIST (PERCIST 1.0), and European Organization for Research and Treatment of Cancer (EORTC) criteria. Performance characteristics of each metric to predict best overall response (BOR) at ≥ 4 mo were assessed. Results: Twenty evaluable patients were treated with ipilimumab (n = 16), BMS-936559 (n = 3), or nivolumab (n = 1). BOR at ≥ 4 mo included complete response (n = 2), partial response (n = 2), stable disease (n = 1), and progressive disease (n = 15). Response evaluations at SCAN-2 using RECIST 1.1, immune-related response criteria, PERCIST, and EORTC criteria demonstrated accuracies of 75%, 70%, 70%, and 65%, respectively, to predict BOR at ≥ 4 mo. Interestingly, the optimal PERCIST and EORTC threshold values at SCAN-2 to predict BOR were >15.5% and >14.7%, respectively. By combining anatomic and functional imaging data collected at SCAN-2, we developed criteria to predict eventual response to ICI with 100% sensitivity, 93% specificity, and 95% accuracy. Conclusion: Combining functional and anatomic imaging parameters from 18F-FDG PET/CT scans performed early in ICI appears predictive for eventual response in patients with advanced melanoma. These findings require validation in larger cohorts.

Predictive and Prognostic Value of Early Disease Progression by PET Evaluation in Advanced Non-Small Cell Lung Cancer

Objective: To assess the predictive and prognostic value of progressive metabolic disease (PMD) by the use of early ¹⁸Fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) in patients with clinical stage IV non-small cell lung cancer (NSCLC) treated with first-line chemotherapy. Methods: An ¹⁸FDG-PET performed following the first cycle of chemotherapy (PET-1) was compared with a pretreatment ¹⁸FDG-PET (PET-0) and a computed tomography (CT) scan after the third cycle (CT-3). The primary endpoint was the positive predictive value (PPV) of PMD. Secondary endpoints included the prognostic value of PMD. Results: Eleven of 38 patients (29%) had a PMD by PET-1, and 15 (39%), including all patients with a PMD, experienced a progressive disease by CT-3. The PPV of PMD was 100% according to both the European Organization for Research and Treatment of Cancer (EORTC) criteria and the PET Response Criteria In Solid Tumors (PERCIST) (p value for both, <0.0001). Patients with a PMD by PET-1 had a median overall survival of 7.0 months versus 14.0 months for those without a PMD (p = 0.04, according to the EORTC criteria). Conclusions: Early ¹⁸FDG-PET assessment deserves further investigation for the identification of NSCLC patients who do not benefit from first-line chemotherapy.

TLG-S criteria are superior to both EORTC and PERCIST for predicting outcomes in patients with metastatic lung adenocarcinoma treated with erlotinib

In this retrospective review of prospectively collected data, we sought to investigate whether early FDG-PET assessment of treatment response based on total lesion glycolysis measured using a systemic approach (TLG-S) would be superior to either local assessment with EORTC (European Organization for Research and Treatment of Cancer) criteria or single-lesion assessment with PERCIST (PET Response Criteria in Solid Tumors) for predicting clinical outcomes in patients with metastatic lung adenocarcinoma treated with erlotinib. We also examined the effect of bone flares on tumor response evaluation by single-lesion assessment with PERCIST in patients with metastatic bone lesions. We performed a retrospective review of prospectively collected data from 23 patients with metastatic lung adenocarcinoma treated with erlotinib. All participants underwent FDG-PET imaging at baseline and on days 14 and 56 after completion of erlotinib treatment. In addition, diagnostic CT scans were performed at baseline and on day 56. FDG-PET response was assessed with TLG-S, EORTC, and PERCIST criteria. Response assessment based on RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) from diagnostic CT imaging was used as the reference standard. Two-year progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. We identified 13 patients with bone metastases. Of these, four (31%) with persistent bone uptake due to bone flares on day 14 were erroneously classified as non-responders according to the PERCIST criteria, but they were correctly classified as responders according to both the EORTC and TLG-S criteria. Patients who were classified as responders on day 14 based on TLG-S criteria had higher rates of 2-year PFS (26.7% vs. 0%, P = 0.007) and OS (40.0% vs. 7.7%, P = 0.018). Similar rates were observed in patients who showed a response on day 56 based on CT imaging according to the RECIST criteria. Patients classified as responders on day 14 according to the EORTC criteria on FDG-PET imaging had better rates of 2-year OS than did non-responders (36.4% vs. 8.3%, P = 0.015). TLG-S criteria may be of greater help in predicting survival outcomes than other forms of assessment. Bone flares, which can interfere with the interpretation of treatment response based on PERCIST criteria, are not uncommon in patients with metastatic lung adenocarcinoma treated with erlotinib.

Independent prognostic impact of tumour-infiltrating macrophages in early-stage Hodgkin's lymphoma.

Although patients with early-stage Hodgkin's lymphoma have a high rate of cure, a portion of these are resistant to or relapse after standard treatment. Current prognostic criteria based on clinical and laboratory parameters at diagnosis do not allow to accurately identify the subset of patients with less favourable clinical outcome. An increased number of tumour-infiltrating macrophages was found to be associated with shortened survival in patients with classic Hodgkin's Lymphoma. The aim of this study was to assess the clinical significance of the proportion of CD68-positive infiltrating macrophages in patients with early-stage classic Hodgkin's lymphoma. By using immunohistochemistry technique, we evaluated for CD68 expression diagnostic biopsies of 106 patients affected by supradiaphragmatic early-stage classic Hodgkin's lymphoma treated at our institution since 2000 to 2010. All patients were treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed by radiotherapy in the majority. The 2-year overall survival and progression-free survival (PFS) in the entire cohort were 97% and 83% respectively. The 2-year PFS was statistically different between patients with favourable and those with unfavourable prognosis according to the European Organisation for Research and Treatment of Cancer (EORTC) risk criteria (96% vs 79%, p = 0.039) and between patients having less than 25% of CD68-positive infiltrating macrophages and those with more than 25% (85% vs 67%, p = 0.012). All patients with favourable EORTC criteria had CD68 expression lower than 25%. Within those with unfavourable EORTC criteria, patients with a CD68+ count greater than 25% had a worse 2-year PFS than patients having values lower than 25% (64% vs 82%, p = 0.03). Moreover, in multivariate analysis, after adjusting for CD68+ macrophages count and EORTC score, only CD68+ macrophages count higher than 25% retained a prognostic effect on PFS (hazard ratio = 2.8, 95%CI: 1.1-7.6, p = 0.038). Our data show that a proportion of tumour-infiltrating macrophages greater than 25% is associated with unfavourable clinical outcome in patients with early-stage Hodgkin's lymphoma Copyright © 2016 John Wiley & Sons, Ltd.

Evaluation of factors affecting tumor response and survival in patients with primary and metastatic liver cancer treated with microspheres.

Radioembolization with the yttrium-90 (Y-90) microspheres is being used increasingly more often in the treatment of patients with primary or metastatic liver cancer. Although technetium-99m macroaggregated albumin (Tc-99m MAA) scintigraphy performed following diagnostic angiography has an important role in predicting the effectiveness of treatment and in dose estimation, the number of studies using quantitative assessment of Tc-99m MAA scintigraphy is limited in this field. In the present study, the aim was to assess whether a tumor dose is required to obtain objective tumor response and to check whether this threshold value is predictive in terms of tumor response, survival, and liver toxicity by using Tc-99m MAA single-photon emission computed tomography (SPECT) images. Overall, 54 patients (20 women and 34 men; median age: 60 years) who underwent Y-90 Resin (SIR-Spheres) and Glass (TheraSphere) microsphere treatment with a diagnosis of unresectable liver cancer between August 2010 and April 2013 were included in the study. The mean doses to normal liver and tumor were estimated for each patient using Tc-99m MAA SPECT images and the medical internal radiation dosimetry method. The responses were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Kaplan-Meier survival curves and univariate Cox regression analysis were used in survival analysis. The relationship between treatment response and other parameters included was assessed using logistic regression analysis. The variables with a P value less than 0.01 in univariate analysis were assessed with multivariate analysis. Fifty-four Y-90 microsphere treatments (eight by using a Y-90 glass microsphere and 46 by using a Y-90 resin microsphere) were performed. In the multivariate analysis, the only parameter related to response was tumor dose (P<0.01). With a tumor dose of 280 Gy or higher, objective tumor response was observed in 59 and 77% of the patients according to RECIST and EORTC criteria, respectively, and the tumor control rate was found to be 95% according to both criteria. In addition, it was found that only tumor dose was correlated with progression-free survival (PFS) (P<0.001) and overall survival (OS) (P=0.018). When the tumor dose was 280 Gy or higher, median PFS increased from 2 to 10.7 months (P<0.001), whereas median OS increased from 9 to 17.6 months (P=0.018). However, reversible ≥ G2 liver toxicity was observed in 3.7% (2/54) of the patients within 3 months after radioembolization with a median normal liver dose of 40 Gy (10-102 Gy). There was reversible ≥ G3 liver toxicity in 3.7% (2/54) of patients, but no G4 liver toxicity was observed. Clinical radiation hepatitis and treatment-induced liver failure were not observed in any of these patients. Tc-99m MAA SPECT has a predictive value in terms of response to radioembolization, PFS, and OS. Dosimetry based on Tc-99m MAA SPECT images can be used in the selection of patients and, in particular, to adaptation of treatment plan in selected patients.

Feasibility and performance of an adaptive contrast-oriented FDG PET/CT quantification technique for global disease assessment of malignant pleural mesothelioma and a brief review of the literature.

Treatment of malignant pleural mesothelioma (MPM) remains very challenging. Assessment of response to treatment is necessary for modifying treatment and using new drugs. Global disease assessment (GDA) by implementing image processing methods to extract more information out of positron emission tomography (PET) images may provide reliable information. In this study we show the feasibility of this method of semi-quantification in patients with mesothelioma, and compare it with the conventional methods. We also present a review of the literature about this topic. Nineteen subjects with histologically proven MPM who had undergone fluoride-18-fluorodeoxyglucose PET/computed tomography ((18)F-FDG PET/CT) before and after treatment were included in this study. An adaptive contrast-oriented thresholding algorithm was used for the image analysis and semi-quantification. Metabolic tumor volume (MTV), maximum and mean standardized uptake volume (SUVmax, SUVmean) and total lesion glycolysis (TLG) were calculated for each region of interest. The global tumor glycolysis (GTG) was obtained by summing up all TLG. Treatment response was assessed by the European Organisation for Research and Treatment of Cancer (EORTC) criteria and the changes of GTG. Agreement between global disease assessment and conventional method was also determined. In patients with progressive disease based on EORTC criteria, GTG showed an increase of 150.7 but in patients with stable or partial response, GTG showed a decrease of 433.1. The SUVmax of patients before treatment was 5.95 (SD: 2.93) and after the treatment it increased to 6.38 (SD: 3.19). Overall concordance of conventional method with GDA method was 57%. Concordance of progression of disease based on conventional method was 44%, stable disease was 85% and partial response was 33%. Discordance was 55%, 14% and 66%. Adaptive contrast-oriented thresholding algorithm is a promising method to quantify the whole tumor glycolysis in patients with mesothelioma. We are able to assess the total metabolic lesion volume, lesion glycolysis, SUVmax, tumor SUVmean and GTG for this particular tumor. Also we were able to demonstrate the potential use of this technique in the monitoring of treatment response. More studies comparing this technique with conventional and other global disease assessment methods are needed in order to clarify its role in the assessment of treatment response and prognosis of these patients.

Role of FDG PET/CT in assessing response to targeted therapy in metastatic lung cancers: Morphological versus metabolic criteria.

Introduction:Targeted therapeutic agents are indicated in metastatic lung cancers. These being receptor specific therapies, manifestation of response can be best assessed by estimating the metabolic activity of tumor, rather than the size. This retrospective analysis studied metabolic and morphological response on Positron Emission Tomography (PET) and Computed Tomography (CT), respectively to these agents.Materials and Methods:Thirty-one patients (23 males, 8 females with an age range of 42–77 years) with Epidermal Growth Factor Receptor (EGFR) positive metastatic lung cancer on Gefitinib, who underwent PET/CT, at baseline and at 4–6 weeks, were assessed by Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 and European Organization for Research and Treatment of Cancer (EORTC) criteria.Results:Concordance between RECIST 1.1 and EORTC was seen in 26 (83.7%) patients. Discordance was seen in 5 (16.3%) patients. In patients with discordance, the results were confirmed by follow-up imaging. Metabolic EORTC criteria changed the disease status from stable disease to partial response (3 out of 5) and progressive disease (2 out of 5) in these five patients.Conclusions:Metabolic criteria using PET/CT could accurately predict response as well as disease progression early in the course of targeted therapy, compared to morphologic criteria. In addition, early metabolic response assessment can predict refractoriness of therapy.

Phase III development of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire module for women undergoing breast reconstruction

Comprehensive outcome assessments after breast reconstruction (BRR) require surgery-specific patient-reported outcome measures. The aims of this study were to assess the relevance, acceptability and redundancy of questions/items (phase III pretesting) of a new BRR questionnaire evaluating patients' health-related quality of life before and after BRR. Phase III occurred in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) following earlier development phases that identified 31 items. The EORTC BRR subgroup applied decision-making rules to each question according to eight EORTC criteria. A total of 197 patients (from the UK, Austria, Belgium, Italy and Sweden) were recruited. Forty-seven patients completed pre- and post-BRR questionnaires prospectively, and 150 reported post-BRR questionnaires only retrospectively. Qualitative debriefing interviews were undertaken in 189 patients. Preliminary psychometric analyses were performed. Thirty-one items fulfilled 'relevance', with none producing 'difficulties'. Ten items were not a priority for 10 per cent of respondents. Of these, two questions concerning muscle twitching in the affected breast and problem with donor-site swelling were deleted. Three redundant items were deleted: weakness in arm, which correlated significantly to the Quality of Life Questionnaire (QLQ) BR23 breast questionnaire, and shape and colour of the affected nipple. Descriptive statistics reduced the module to 26 items conceptualized into three provisional scales (disease treatment/surgery-related symptoms, sexuality and cosmetic outcome) within the newly completed questionnaire, EORTC QLQ-BRR26. The QLQ-BRR26 is available for psychometric validation in a large-field international sample. The intended use for QLQ-BRR26 is alongside EORTC QLQ-C30 and QLQ-BR23, in women treated by mastectomy for breast cancer and undergoing all types of BRR.

Abstract P2-19-08: Phase III development of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) module for women undergoing breast reconstruction: The EORTC QLQ-BRR26

Abstract Introduction: Comprehensive outcome assessments after breast reconstruction (BRR) require surgery- specific Patient Reported Outcomes Measures (PROMS). Completion of early Phases I-II development resulted in a 31-item questionnaire comprising 5 hypothesised scales and (numbers of items) : Treatment /surgery related symptoms (4), body image (3), sexuality (4), cosmetic outcomes (breast, n = 7, donor site, n = 5, nipple, n = 6) and overall satisfaction (2). Current evidence shows no BRR-specific PROM, with the further validation of the BREAST-Q, currently the only PROM. The aim of this study was Phase III pre-testing of a BRR questionnaire assessing patients’ health related quality of life (HRQL) before and after BRR, in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC). Pre-testing assessed the relevance, acceptability and redundancy of questions in all types of BRRs. This PROM is intended for use alongside the EORTC QLQ-C30, and QLQ-BR23 in women treated for breast cancer before and after mastectomy and all BRR types. Methods: The EORTC BRR HRQL subgroup applied decision-making rules to each question according to eight EORTC criteria comprising 1. priority, 2. relevance and 3. difficulty /consistency across five European languages and cultures. Descriptive statistics used HRQL score criteria: 4. mean &amp;gt;1.5, 5. range &amp;gt;2, 6. floor and ceiling effects &amp;gt;10%, 7. prevalence ratios &amp;gt;30% and 8. compliance &amp;gt;95%. 197 patients (UK, Austria, Belgium, Italy, Sweden) were recruited: 47 prospectively completing pre- and post-BRR questionnaires, and 150 retrospectively reporting only post-BRR questionnaires. 189 patients underwent qualitative debriefing interviews. Preliminary psychometric analyses performed multi-trait scaling using EORTC QLQ-C30 and QLQ- BR23 that were used in final decisions on items and scales. Results: 31 questions /items fulfilled ‘relevance’, with none producing ‘difficulties’. Ten items were not a ‘priority’ in 10% of respondents. Of these, two questions comprising ‘muscle twitching in affected breast’ and ‘problem with donor site swelling’ were deleted, fulfilling less than 5 out of 8 criteria. Deletions of three redundant items comprised ‘weak arm’, which correlated significantly to QLQ-BR23; and ‘shape’ and ‘colour’ of affected nipple with similarities to ‘overall nipple appearance’. Descriptive statistics and clinical judgment reduced the module to 26 items conceptualized into three scales (and items): Disease Treatment /Surgery related symptoms (2), Sexuality (5), and Cosmetic outcomes (breast, n = 10, donor site, n = 4, nipple, n = 4) within the EORTC QLQ-BRR26. The body image and overall satisfaction scales were dropped, with their respective items incorporated into other scales. Discussion: The QLQ-BRR26 has completed phase III development and is available for psychometric validation in a large field international sample that aims to recruit 450 patients across 17 European centres. Psychometric testing will be finalised in Phase IV including the evaluation of the questionnaires’ responsiveness to the effects of BRR subgroups with comparisons to the BREAST-Q. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-19-08.

Prospective study of a panfungal PCR assay followed by sequencing, for the detection of fungal DNA in normally sterile specimens in a clinical setting: a complementary tool in the diagnosis of invasive fungal disease?

We prospectively analyzed 34 clinical biopsy samples from 23 patients with a suspected invasive fungal infection by fungal culture, histology and a panfungal PCR followed by sequencing. Results were compared to the composite diagnosis according the European Organization for Research and Treatment of Cancer (EORTC) criteria. In 34 samples, culture, histology and panfungal PCR were positive in 35%, 38% and 62%, respectively. On the sample level the panfungal PCR revealed a sensitivity of 69% and a specificity of 62.5% compared to proven IFI according postoperative EORTC criteria. On patient level, the sensitivity of the PCR approach was 100%, specificity 62.5%.

Comparison of EORTC Criteria and PERCIST for PET/CT Response Evaluation of Patients with Metastatic Colorectal Cancer Treated with Irinotecan and Cetuximab

The study aim was to compare European Organization for Research and Treatment of Cancer (EORTC) criteria with PET Response Criteria in Solid Tumors (PERCIST) for response evaluation of patients with metastatic colorectal cancer treated with a combination of the chemotherapeutic drug irinotecan and the monoclonal antibody cetuximab. From 2006 to 2009, patients with metastatic colorectal cancer were prospectively included in a phase II trial evaluating the combination of irinotecan and cetuximab every second week, as third-line treatment. (18)F-FDG PET/CT was performed between 1 and 14 d before the first treatment and after every fourth treatment cycle until progression was identified by CT with Response Evaluation Criteria in Solid Tumors (RECIST). Response evaluation with (18)F-FDG PET/CT was retrospectively performed according to both EORTC criteria and PERCIST, classifying the patients into 4 response categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Individual best overall metabolic response (BOmR) was registered with both sets of criteria, as well as survival within response categories, and compared. A total of 61 patients and 203 PET/CT scans were eligible for response evaluation. With EORTC criteria, 38 had PMR, 16 had SMD, and 7 had PMD as their BOmR. With PERCIST, 34 had PMR, 20 had SMD, and 7 had PMD as their BOmR. None of the patients had CMR. There was agreement between EORTC criteria and PERCIST in 87% of the patients, and the corresponding κ-coefficient was 0.76. Disagreements were confined to PMR and SMD. Median overall survival (OS) in months with EORTC criteria was 14.2 in the PMR group and 7.2 in the combined SMD + PMD group. With PERCIST, it was 14.5 in the PMR group and 7.9 in the SMD + PMD group. Response evaluation with EORTC criteria and PERCIST gave similar responses and OS outcomes with good agreement on BOmR (κ-coefficient, 0.76) and similar significant differences in median OS between response groups. Compared with EORTC criteria, we find PERCIST unambiguous because of clear definitions and therefore more straightforward to use.

Therapy response evaluation with FDG-PET/CT in small cell lung cancer: a prognostic and comparison study of the PERCIST and EORTC criteria

Introduction: Small cell lung cancer (SCLC) is an aggressive form of lung cancer with poor prognosis. Adequate staging and therapeutic evaluation is necessary for therapy planning. Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has been shown to be useful for staging and therapy response evaluation. The European Organization for Research and Treatment of Cancer (EORTC) and Positron Emission Tomography Response Criteria In Solid Tumors (PERCIST) criteria were compared in the evaluation of response assessment and prognostic factors were defined in a cohort of SCLC patients. Methods: Twenty-nine consecutive patients with SCLC were included in this study. Sixteen patients had extensive disease and 13 had limited disease. All patients had chemotherapy, 21 had thoracic radiotherapy. FDG-PET/CT scans were performed before and after therapy to evaluate treatment response. Metabolic responses were assessed using the EORTC criteria and PERCIST criteria. Univariate and multivariate analysis were performed using a Cox model to investigate the association between progression-free and overall survival time with a number of covariates. Results: There was perfect concordance between the EORTC and PERCIST criteria. Eight patients had a complete metabolic response (CMR), 9 had a partial metabolic response (PMR), 5 had stable metabolic disease (SMD) and 7 had progressive metabolic disease (PMD). Overall survival time in patients with CMR was significantly longer compared with patients who did not have CMR. The initial or delayed CMR and post-therapeutic standardized uptake value corrected for lean body mass were significantly associated with overall survival. Conclusion: CMR on post-therapeutic FDG-PET/CT in patients with SCLC is an important prognostic factor and may help decision making for therapeutic management.

Validation of EORTC Prognostic Factors for Adults With Low-Grade Glioma: A Report Using Intergroup 86-72-51

A prognostic index for survival was constructed and validated from patient data from two European Organisation for Research and Treatment of Cancer (EORTC) radiation trials for low-grade glioma (LGG). We sought to independently validate this prognostic index with a separate prospectively collected data set (Intergroup 86-72-51). Two hundred three patients were treated in a North Central Cancer Treatment Group-led trial that randomized patients with supratentorial LGG to 50.4 or 64.8 Gy. Risk factors from the EORTC prognostic index were analyzed for prognostic value: histology, tumor size, neurologic deficit, age, and tumor crossing the midline. The high-risk group was defined as patients with more than two risk factors. In addition, the Mini Mental Status Examination (MMSE) score, extent of surgical resection, and 1p19q status were also analyzed for prognostic value. On univariate analysis, the following were statistically significant (p<0.05) detrimental factors for both progression-free survival (PFS) and overall survival (OS): astrocytoma histology, tumor size, and less than total resection. A Mini Mental Status Examination score of more than 26 was a favorable prognostic factor. Multivariate analysis showed that tumor size and MMSE score were significant predictors of OS whereas tumor size, astrocytoma histology, and MMSE score were significant predictors of PFS. Analyzing by the EORTC risk groups, we found that the low-risk group had significantly better median OS (10.8 years vs. 3.9 years, p<0.0001) and PFS (6.2 years vs. 1.9 years, p<0.0001) than the high-risk group. The 1p19q status was available in 66 patients. Co-deletion of 1p19q was a favorable prognostic factor for OS vs. one or no deletion (median OS, 12.6 years vs. 7.2 years; p=0.03). Although the low-risk group as defined by EORTC criteria had a superior PFS and OS to the high-risk group, this is primarily because of the influence of histology and tumor size. Co-deletion of 1p19q is a prognostic factor. Future studies are needed to develop a more refined prognostic system that combines clinical prognostic features with more robust molecular and genetic data.

FDG PET/CT (FDG PET) in evaluation of response in patients with multiple myeloma (MM) treated with bortezomib, pegylated liposomal doxorubicin, and dexamethasone

8533 Background: In a high risk population of pts with newly diagnosed or primary refractory MM, we prospectively studied FDG PET imaging to determine the value of PET/CT in assessing therapeutic response. Methods: Forty pts with high-risk MM defined as ISS II, ISS III or presence of extramedullary plasmacytoma have been enrolled on study and treated using a combination of bortezomib, pegylated liposomal doxorubicin hydrochloride (Doxil), and dexamethasone (BDD) for 3 cycles followed by 2 cycles of thalidomide and dexamethasone for patients achieving at least PR. Pts were assessed using serial FDG PET imaging: at baseline (BL), after 3 cycles of BDD and at end of study (EOS). FDG PET response was determined using European Organization for research and treatment of cancer (EORTC) recommendations. MM disease response was assessed according to the International Myeloma Working Group (IMWG) criteria. Results: Median age of pts enrolled was 59 yrs (range 41–80), 62% male, 38% ISS II, 47% ISS III, and 15% ISS I with soft-tissue disease. Thirty-five percent (14/40) had soft-tissue involvement with MM. At completion of protocol therapy, the ORR was 79%, with 44% of pts achieving CR/nCR and 59% ≥ VGPR. Ninety FDG PET scans were performed in 40 pts; 25 pts were evaluable for FDG PET response. The other pts are as follows: 2 had negative FDG PET at BL, 6 were taken off study (5 for toxicity and 1 with CR), 1 FDG PET was unable to be compared due to technical differences and 6 pts have not completed treatment. Seventeen of the 25 pts had PR by FDG PET, 5 had SD and 3 PD; none of the pts had CR. There was little agreement between MM disease response and FDG PET responses (Kappa statistic, 0.05). Three pts with PD by FDG PET, had PR (n=2) or CR (n=1) by IMWG criteria. One had granulomatous disease rather than MM at biopsy. In 1 pt with progression of disease with a progressive skull-based plasmacytoma, FDG PET was scored as PR by EORTC criteria. Conclusions: There was poor agreement between FDG PET response and MM disease response by IMWG criteria. Serial FDG PET did not provide additional information for therapeutic response assessment in pts with newly diagnosed or primary refractory MM. [Table: see text]

Validity of the modified RECIST criteria and EORTC PET criteria evaluated based on the pathologic findings for patients with resectable malignant pleural mesothelioma

e11639 Background: The unique growth pattern of malignant pleural mesothelioma (MPM) presents challenges for clinical investigators evaluating the responses to chemotherapy, which is an important surrogate endpoint for patient benefit, particularly in clinical trials. In patients with resectable MPM, multicenter clinical trials of neoadjuvant chemotherapy followed by extrapleral pneumonectomy (EPP) and subsequent radiotherapy have been attempted around the world. The applicability of modified RECIST based on the findings on CT images and EORTC (European Organization for Research and Treatment of Cancer) criteria based on the findings on FDG-PET images to resectable MPM would be challenging and significant, but their validity has never been examined. Methods: Between May 2006 and November 2008, 13 consecutive patients with resectable pathologically proven MPM were included in this study. All were initially treated with combination chemotherapy including cisplatin. EPP was successfully performed in all the patients. In addition to modified RECIST (CR vs PR vs SD vs PD), FDG uptake by the tumor on PET was also evaluated according to the EORTC PET criteria (CMR vs PMR vs SMD vs PMD). Also, pathologic findings (NT; no viable tumor vs MR; minimal residual vs GR; gross residual) were reviewed. Results: According to modified RECIST, in which the definition of measurable lesions is ≥10mm in diameter, 7 of the 13 patients investigated had no measurable lesion. Even when the definition of measurable lesions was changed to ≥5mm, 2 patients had no measurable lesion and 4 had only one lesion. In regard to the response, 4 of 11 patients with any measurable lesions were classified as PR, and 7 were classified as SD, while 8 patients were classified as PMR and 3 were classified as SMD according to the PET findings. Eight patients were classified as GR and 5 as MR. Kappa statistics suggested potential variation between the CT response and the pathologic findings (κ=0.214, 95% CI=-0.377 ∼ 0.806) and between the PET response and the pathologic findings (κ=0.286, 95% CI=-0.049 ∼ 0.620). Conclusions: Our data raise doubts about the validity of applying the modified RECIST criteria as well as EORTC PET criteria to resectable MPM. No significant financial relationships to disclose.

18F]Fluorodeoxyglucose Positron Emission Tomography Correlates With Akt Pathway Activity but Is Not Predictive of Clinical Outcome During mTOR Inhibitor Therapy

Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models. Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1. Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression. FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.

F-18 FDG PET and PET/CT Evaluation of Response to Chemotherapy in Bone and Soft Tissue Sarcomas

F-18 FDG PET has been used to grade sarcomas and assess response to therapy in advanced disease. Certain chemotherapy agents are thought to induce an inflammatory response in the tumor bed that can make interpretation of post-therapy FDG PET scans difficult. A review of our experience with PET in assessing therapy response in osseous and soft tissue sarcomas (OSTS) is presented. This is a retrospective study (January 1999 to December 2004) of 14 patients with histologic diagnosis of OSTS, who had 2 consecutive PET examinations for evaluation of chemotherapy response. The group included 8 men and 6 women, with age range of 18 to 56 years (average, 36 +/- 14). Semiquantitative assessment of FDG uptake was performed by calculating maximum standard uptake value (SUVmax) before and after treatment. The response to therapy was assessed independently by tumor necrosis at post-therapy surgery and according to European Organization for Research and Treatment of Cancer (EORTC) criteria for PET. The follow-up PET examinations were performed at an interval of 28 to 166 days (average, 90 +/- 45). All patients ended the ifosfamide regimen at 7 to 36 (average, 16 +/- 9) days before the follow-up PET scans. Five of them received methotrexate, adriamycin, and/or cisplatin as well. Based on the EORTC criteria alone, 3 patients (21.4%) had progression of disease (increase in SUVmax of 29%-69%; mean, 48% +/- 20%), 5 patients (35.7%) had stable disease, and 6 patients (42.8%) had partial response (decrease in SUVmax of 27%-84%; mean, 62% +/- 23%). Across all patients, the tumor necrosis postchemotherapy ranged from 5% to 100% (mean, 64% +/- 34%). In 8 patients (57.1%) the tumor necrosis correlated with the SUVmax changes. However, for 3 patients, the SUVmax changes indicated partial response despite necrosis of fewer than 90% of the surgical specimens, whereas 3 patients with >90% tumor necrosis had SUVmax changes indicative of stable disease. The pathologically determined degree of necrosis postneoadjuvant chemotherapy was concordant with PET-assessed EORTC classification of response in 57.1% of the cases. However, a significant number of patients had discrepancies, which may be in part explained by chemotherapy-induced inflammation. The latter should be considered during post-therapy PET interpretation in OSTS.

Adding 11C-methionine PET to the EORTC prognostic factors in grade 2 gliomas

The management of adult patients with grade 2 gliomas remains a challenge for the clinical neuro-oncologist. Several clinical prognostic factors appear to be as important as treatment factors in determining outcome. From the European Organisation for Research and Treatment of Cancer (EORTC) trials 22844 and 22845, a prognostic scoring system has been proposed based on the presence of unfavourable prognostic factors. The aim of the present study was to assess the additional prognostic value of (11)C-methionine (MET) measured by positron emission tomography (PET) in the setting of the EORTC prognostic scoring system. In this retrospective review, 129 patients with supratentorial grade 2 gliomas were subjected to a PET study as part of the pre-treatment tumour investigation. One hundred and three cases were classified as low-risk patients (0-2 unfavourable factors) and 26 cases as high-risk patients (3-5 unfavourable factors) according to the EORTC criteria. MET PET was evaluated as an extra prognostic factor in both groups. In the high-risk group, patients with high MET uptake had a worse outcome than patients with low MET uptake. A similar trend was found for the low-risk group in patients with oligodendrocytic tumours. Our findings further strengthen the role of MET PET as an important prognostic tool in the management of this group of patients.

Year Book of Dermatology

The objective of this study was to assess the safety, dosimetry, and efficacy of the ¹⁷⁷Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo (D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (¹⁷⁷Lu-DOTA-LM3) in patients with metastatic neuroendocrine neoplasms (NENs). <b>Methods:</b> Fifty-one patients (age 27–76, mean 51.6±13.9 years) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1±0.88 GBq (range 2.8–7.4 GBq). ⁶⁸Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after ¹⁷⁷Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed in 11 patients and compared with the SSTR agonist ¹⁷⁷Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. <b>Results:</b> Higher uptake and a longer effective half-life of ¹⁷⁷Lu-DOTA-LM3 was found for whole-body as well as kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses as compared to the agonist ¹⁷⁷Lu-DOTA-TOC. All patients tolerated therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 (9.8%) patients; no other symptoms were reported. The most severe delayed adverse event was CTC-3 thrombocytopenia in 3 (5.9%) patients. Neither CTC-4 thrombocytopenia nor CTC-3-4 anemia or leukopenia was observed after treatment. No significant decline in renal function was observed, nor was hepatotoxicity. According to RECIST 1.1, disease control could be reached in 40 patients (disease control rate, 85.1%) of 47 patients monitored after ¹⁷⁷Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 (14.9%) patients had progressive disease, and by EORTC criteria, complete remission in 2 (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%) patients. <b>Conclusion:</b> “Antagonist PRRT” with ¹⁷⁷Lu-DOTA-LM3 could be administered without severe adverse effects and was well tolerated by the majority of patients, with thrombocytopenia occurring only in a few patients. No other severe adverse effects were observed, particularly no nephrotoxicity. The SSTR antagonist ¹⁷⁷Lu-DOTA-LM3 appears to be very promising for PRRT, provides favorable biodistribution and higher tumor radiation doses than SSTR agonists, and was very effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients.