Response Criteria For Clinical Trials Research Articles

Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC

AbstractThe number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Update on amino acid PET of brain tumours

The aim of this study was to give an update on the emerging role of PET using radiolabelled amino acids in the diagnostic workup and management of patients with cerebral gliomas and brain metastases. Numerous studies have demonstrated the potential of PET using radiolabelled amino acids for differential diagnosis of brain tumours, delineation of tumour extent for treatment planning and biopsy guidance, differentiation between tumour progression and recurrence versus treatment-related changes, and for monitoring of therapy. The Response Assessment in Neuro-Oncology (RANO) working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recently recommended the use of amino acid PET imaging for brain tumour management in addition to MRI at every stage of disease. With the introduction of F-18 labelled amino acids, a broader clinical application has become possible, but is still hampered by the lack of regulatory approval and of reimbursement in many countries. PET using radiolabelled amino acids is a rapidly evolving method that can significantly enhance the diagnostic value of MRI in brain tumours. Current developments suggest that this imaging technique will become an indispensable tool in neuro-oncological centres in the near future.

Imaging of amino acid transport in brain tumours: Positron emission tomography with O-(2-[18F]fluoroethyl)-L-tyrosine (FET).

The assessment of cerebral gliomas using magnetic resonance imaging (MRI) provides excellent structural images but cannot solve all diagnostic problems satisfactorily. The differentiation of tumour tissue from non-neoplastic changes may be difficult especially in the post-treatment phase. In recent years, positron emission tomography (PET) using radiolabelled amino acids has gained considerable interest as an additional tool to improve the diagnosis of cerebral gliomas and brain metastases. A key step for this advancement was the development of the F-18 labelled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) which has spread rapidly in the last decade and replaced carbon-11 labelled amino acid tracers such as 11C-methyl-L-methionine (MET) in many centres in Europe. FET can be produced with high efficiency and distributed in a satellite concept like 2-[18F]fluoro-2-deoxy-D-glucose (FDG). Furthermore, FET exhibits favourable properties such as high in vivo stability, high tumour to background contrast and tissue specific tracer kinetics, which provides additional information for tumour grading or differential diagnosis. The Response Assessment in Neuro-Oncology (RANO) working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recently recommended the additional use of amino acid PET imaging for brain tumour management. FET PET can provide important diagnostic information in crucial situations such as the definition of biopsy site, the delineation of cerebral gliomas for therapy planning, sensitive monitoring of treatment response and an improved differentiation of tumour recurrence from treatment-related changes. In this article the basic information, methodological aspects and the actual status of clinical application of FET PET are reviewed.

Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology committee.

Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), CSF cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined. We recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other Response Assessment in Neuro-Oncology recommendations, these need to now be prospectively validated in clinical trials.

Advances in neuro-oncology imaging.

Despite the fact that MRI has evolved to become the standard method for diagnosis and monitoring of patients with brain tumours, conventional MRI sequences have two key limitations: the inability to show the full extent of the tumour and the inability to differentiate neoplastic tissue from nonspecific, treatment-related changes after surgery, radiotherapy, chemotherapy or immunotherapy. In the past decade, PET involving the use of radiolabelled amino acids has developed into an important diagnostic tool to overcome some of the shortcomings of conventional MRI. The Response Assessment in Neuro-Oncology working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recommended the additional use of amino acid PET imaging for brain tumour management. Concurrently, a number of advanced MRI techniques such as magnetic resonance spectroscopic imaging and perfusion weighted imaging are under clinical evaluation to target the same diagnostic problems. This Review summarizes the clinical role of amino acid PET in relation to advanced MRI techniques for differential diagnosis of brain tumours; delineation of tumour extent for treatment planning and biopsy guidance; post-treatment differentiation between tumour progression or recurrence versus treatment-related changes; and monitoring response to therapy. An outlook for future developments in PET and MRI techniques is also presented.

Inclusion and response criteria for clinical trials in relapsed/refractory acute lymphoblastic leukemia and usefulness of historical control trials

We thank Paul Gaynon for his commentary on our international reference analysis of relapsed/refractory (R/R) adult acute lymphoblastic leukemia (ALL). The commentary highlights a certain lack of standardization with regard to inclusion criteria and endpoints of clinical trials for R/R ALL in adults

An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults

AbstractMyelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

Tumor response evaluation criteria for HCC (hepatocellular carcinoma) treated using TACE (transcatheter arterial chemoembolization): RECIST (response evaluation criteria in solid tumors) version 1.1 and mRECIST (modified RECIST): JIVROSG-0602

Background.Two standard sets of criteria are used to evaluate the tumor response of hepatocellular carcinoma (HCC): RECIST (Response Evaluation Criteria in Solid Tumors) and modified RECIST (mRECIST). The purpose was to compare two tumor response evaluation criteria, RECIST version 1.1 and mRECIST, for HCC treated using transcatheter arterial chemoembolization (TACE).Methods.The radiological findings of patients who underwent TACE for HCCs in a multicenter clinical trial were examined. Sixty-five lesions in 21 patients treated with TACE without mixing iodized-oil were evaluated. The tumor size was evaluated by measuring the entire lesion, including the necrotic part, using RECIST version 1.1, whereas only the contrast-enhanced part observed during the arterial phase was measured using mRECIST. Five radiologists independently measured each lesion twice. To evaluate the inter-criteria reproducibility, the complete response (CR) rate, the response rate, the kappa statistics, and the proportion of agreement (PA) for response categories were calculated. The same analyses were conducted for inter- and intra-observer reproducibility.Results. In the inter-criteria reproducibility study, the CR rate and the response rate obtained using mRECIST (56.9% and 79.7%) were higher than those obtained using RECIST version 1.1 (9.2% and 43.1%). In the inter- and intra-observer reproducibility study, mRECIST exhibited an ‘almost perfect agreement', while RECIST version 1.1 exhibited a ‘substantial agreement'.Conclusions. Considerable differences in the CR rate and the response rate were observed. From the viewpoint of the high inter- and intra-observer reproducibility, mRECIST may be more suitable for tumor response criteria in clinical trials of TACE for HCC.

Application of Novel Response/Progression Measures for Surgically Delivered Therapies for Gliomas

The Response Assessment in Neuro-Oncology (RANO) Working Group is an international, multidisciplinary effort to develop new standardized response criteria for clinical trials in brain tumors. The RANO group identified knowledge gaps relating to the definitions of tumor response and progression after the use of surgical or surgically based treatments. To outline a proposal for new response and progression criteria for the assessment of the effects of surgery and surgically delivered therapies for patients with gliomas. The Surgery Working Group of RANO identified surgically related end-point evaluation problems that were not addressed in the original Macdonald criteria, performed an extensive literature review, and used a consensus-building process to develop recommendations for how to address these issues in the setting of clinical trials. Recommendations were formulated for surgically related issues, including imaging changes associated with surgical resection or surgically mediated adjuvant local therapies, the determination of progression in the setting where all enhancing tumor has been removed, and how new enhancement should be interpreted in the setting where local therapies that are known to produce nonspecific enhancement have been used. Additionally, the terminology used to describe the completeness of surgical resections has been recognized to be inconsistently applied to enhancing vs nonenhancing tumors, and a new set of descriptors is proposed. The RANO process is intended to produce end-point criteria for clinical trials that take into account the effects of prior and ongoing therapies. The RANO criteria will continue to evolve as new therapies and technologies are introduced into clinical trial and/or practice.

Radiologists Urge FDA To Accept PET-Based Tumor Response Criteria in Clinical Trials

Radiologists Urge FDA To Accept PET-Based Tumor Response Criteria in Clinical Trials

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Evaluation of the effects of a supplementary diet containing chicken comb extract on symptoms and cartilage metabolism in patients with knee osteoarthritis

We aimed to investigate whether a supplementary diet containing chicken comb extract (CCE) rich in hyaluronic acid (HA) has an effect on pain and other symptoms, as well as cartilage type II collagen (CII) metabolism in patients with knee osteoarthritis (OA). A randomized double-blind placebo-controlled study was conducted in 43 subjects with knee OA (Kellgren/Lawrence grade, mainly 1-2) comprising 22 patients receiving concurrent exercise therapy (ET) and 21 without ET (referred as ET-receivers and ET-unreceivers, respectively). Subjects were randomized to a CCE-containing diet (active diet) group administered a dose of 1,800 mg/day (containing 630 mg of CCE and approximately 60 mg of HA) and a placebo group, and the intervention was continued for 16 weeks. Symptomatic efficacy was evaluated based on the Japanese Orthopaedic Association clinical trials response criteria (JOA response criteria) and Visual analog scales (VAS) before (baseline) and during the intervention. To further examine its effect on CII metabolism, the levels of two degradation biomarkers (CTX-II and C2C) and one synthesis biomarker (CPII) were measured using urine or serum samples. Nineteen subjects (10 ET-receivers and 9 ET-unreceivers) in the active diet group and 21 subjects (10 ET-receivers and 11 ET-unreceivers) in the placebo group were finally included in the study. Compared to the baseline, subscale scores of the JOA response criteria, i.e., 'pain/walking function', 'pain/step-up and -down function' and 'aggregate total symptoms' were more intensely improved in the active diet group than in the placebo group. Moreover, subgroup analyses of ET-receivers and ET-unreceivers indicated that significant improvements were restricted to ET-receivers of the active diet group. Furthermore, VAS assessment indicated that the 'pain on pressing' subscale was significantly improved in ET-receivers of the active diet group. In addition, analysis of CII biomarkers revealed that serum C2C and CPII levels, but not the urinary CTX-II level, were increased in the active diet group. Notably, both urinary CTX-II/serum CPII and serum C2C/serum CPII ratios were reduced in the active diet group (particularly ET-unreceivers), suggesting that CII synthesis was relatively increased compared to CII degradation in the active diet group. Finally, no diet-related side effects were observed. The CCE-containing diet is likely to be effective in relieving symptoms in patients with knee OA. In addition, it has the potential to improve the balance of CII degradation/synthesis in knee OA.

Selection of Response Criteria for Clinical Trials of Sarcoma Treatment

Soft tissue sarcomas are a heterogeneous group of malignancies arising from mesenchymal tissues. A large number of new therapies are being evaluated in patients with sarcomas, and consensus criteria defining treatment responses are essential for comparison of results from studies completed by different research groups. The 1979 World Health Organization (WHO) handbook set forth operationally defined criteria for response evaluation in solid tumors that were updated in 2000 with the publication of the Response Evaluation Criteria in Solid Tumors (RECIST). There have been significant advances in tumor imaging, however, that are not reflected in the RECIST. For example, computed tomography (CT) slice thickness has been reduced from 10 mm to < or =2.5 mm, allowing for more reproducible and accurate measurement of smaller lesions. Combination of imaging techniques, such as positron emission tomography with fluorine-18-fluorodeoxyglucose (18FDG-PET) and CT can provide investigators and clinicians with both anatomical and functional information regarding tumors, and there is now a large body of evidence demonstrating the effectiveness of PET/CT and other newer imaging methods for the detection and staging of tumors as well as early determination of responses to therapy. The application of newer imaging methods has the potential to decrease both the sample sizes required for, and duration of, clinical trials by providing an early indication of therapeutic response that is well correlated with clinical outcomes, such as time to tumor progression or overall survival. The results summarized in this review support the conclusion that the RECIST and the WHO criteria for evaluation of response in solid tumors need to be modernized. In addition, there is a current need for prospective trials to compare new response criteria with established endpoints and to validate imaging-based response rates as surrogate endpoints for clinical trials of new agents for sarcoma and other solid tumors.

Post-Hoc Analysis of a Head-to-Head Hyaluronic Acid Comparison in??Knee??Osteoarthritis Using the??2004??OMERACT-OARSI Responder??Criteria*

Several intra-articular hyaluronic acid products are available for treating osteoarthritis (OA) of the knee, including hylan G-F 20 and the bioengineered straight-chain hyaluronic acid (Bio-HA). A recently published study in patients with knee OA demonstrated non-inferiority with regard to efficacy, using the pain subscore of the Western Ontario and McMaster Universities Osteoarthritis Index (safety data favoured Bio-HA with regard to knee effusions). However, the Osteoarthritis Research Society International (OARSI) Standing Committee for Clinical Trials Response Criteria Initiative together with the Outcome Measures in Rheumatology (OMERACT) committee have published new response criteria for OA clinical trials. These criteria focus on change in pain and physical function. The aim of this study was to reanalyse the data from the original comparative study of hylan G-F 20 and Bio-HA in knee OA utilising the new OMERACT-OARSI response criteria. The original study was a prospective, multicentre, randomized, double-blind trial of 321 patients with knee OA who received hylan G-F 20 or Bio-HA via three intra-articular injections 1 week apart. This post-hoc analysis of the data using the modified OMERACT-OARSI responder criteria focused only on efficacy. Using the OMERACT-OARSI criteria, 112 of the 157 patients (71%) receiving Bio-HA were considered to have a response compared with 99 of the 158 patients (63%) receiving hylan G-F 20 (p = 0.10). Application of the new, standardized definition of a responder in OA clinical trials to the existing data reinforces that Bio-HA is non-inferior to hylan G-F 20 for knee OA. Both agents were similarly well tolerated, but Bio-HA was associated with a lower incidence of effusions, suggesting that Bio-HA has an improved risk-benefit profile compared with hylan G-F 20.

Tumour-associated epilepsy: clinical impact and the role of referring centres in a cohort of glioblastoma patients. A multicentre study from the Lombardia Neurooncology Group

Epilepsy in high-grade glioma patients is a major concern, mainly as regards indications to treatment and best choice; toxicities, and pharmocokinetic and pharmacodynamic interactions of drugs. All these generally unsolved problems complicate patients' quality of life and interfere with the evaluation of response criteria in clinical trials. A prospective, multicentre data collection on 132 adult newly diagnosed, histologically proven glioblastomas from 9 Lombardy hospitals collected in the same database during a one-year period was recently published. From this database we report epidemiological and clinical characteristics in epilepsy-symptomatic (31%) glioblastoma patients vs. the group with other presenting symptoms (69%). We analyse demographic and clinico-radiological features, timing of onset and the course of seizures, and modalities of treatment in the two groups of patients. No statistically significant differences were observed between the two groups as regards age, site of lesion(s), extent of surgery and survival in relation to anticonvulsant treatment status or pharmacokinetic properties of drugs.

Update on primary central nervous system lymphoma

Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin's lymphoma that is confined to the central nervous system and eye. Numerous studies examining this disorder have been published in the past 2 years. This review will discuss recent advances in the understanding of the pathology, radiographic appearance, and treatment of this disorder. Novel treatment regimens continue to be studied for newly diagnosed and recurrent primary central nervous system lymphoma. As overall survival improves, the burden of late neurotoxicity has become more apparent. Neuropsychological testing of patients treated with chemoradiation shows significant cognitive deficits that can be attributed to whole brain irradiation. Standardization of phase II clinical trials across individual institutions remains an important goal within the oncology community. The International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) has proposed guidelines for the baseline evaluation and response criteria for clinical trials of the disorder. In addition, series of patients with uncommon histological variants of primary central nervous system lymphoma have been published. In 2005, the optimal treatment for primary central nervous system lymphoma remains undefined. Treatment of newly diagnosed disease should include methotrexate-based chemotherapy but the role of irradiation and intrathecal chemotherapy remain unclear. Salvage therapy for progressive or recurrent primary central nervous system lymphoma is an area of active interest but no standard recommendations exist at the present time. Future studies on the biology of recurrent primary central nervous system lymphoma should help to clarify treatment options for these patients.

A comparison of the OARSI response criteria with patient's global assessment in patients with osteoarthritis of the hip treated with a non-pharmacological intervention

To compare the Osteoarthritis Research Society International (OARSI) response criteria for clinical trials with patient's global assessment in patients with osteoarthritis (OA) of the hip receiving a non-pharmacological intervention, i.e., manual therapy or exercise therapy. Data of a randomized clinical trial on manual therapy and exercise therapy in patients with OA of the hip (n = 109) were used. Change scores of measures of hip function, range of joint motion and pain were compared between patients who were differently classified by the OARSI response criteria and the patient's global assessment (using a t test, 95% CI). Furthermore, risk ratios (with 95% CI) were calculated for the contrast between treatment outcome, using the OARSI criteria or patient's global assessment. Few patients were classified as improved (i.e., responders) with the OARSI response criteria as compared to patient's global assessment. Significantly worse outcome for hip function and pain was observed in patients who were classified as non-responders (OARSI criteria), but who considered themselves as improved (patient's global assessment). Risk ratios for the contrast between the two treatment programs (manual therapy vs exercise therapy) were similar, when using the OARSI criteria or patient's global assessment. The validity of the OARSI response criteria has been previously demonstrated in OA patients treated with pharmacological interventions. The present study demonstrates the validity of the OARSI response criteria in OA patients treated with a non-pharmacological intervention, i.e., manual therapy and exercise therapy.

Response Assessments in Low-Risk and High-Risk Myelodysplastic Syndromes (MDS)

The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders that differ with regard to etiology, pathologic and clinical features, treatment, and outcomes. MDS are chronic, progressive diseases that may be broadly categorized into early phase ("low-risk") and late-phase ("high-risk") groups based on prognostic criteria and the differential pathologic and cytogenetic features that drive the MDS phenotype in these disease phases. Consequently, the goals for treatment and management options also differ for low-risk MDS compared with high-risk MDS. Alleviation of disease-related complications, including transfusion requirements, and hematologic improvement are key treatment goals in low-risk MDS. In contrast, altering the natural history of disease, including improvements in overall survival and progression-free survival, are the most important treatment goals in high-risk MDS. To address the heterogeneity of MDS in patient populations enrolled in clinical trials and to resolve problems resulting from variability in the quality and quantity of responses to treatment, the International Working Group has developed standardized response criteria for MDS that are relevant for both low-risk and high-risk categories. The application of the standardized International Working Group response criteria in clinical trials is enabling the comparison of results from various clinical trials in MDS. Furthermore, the International Working Group response criteria provide an important framework for clinical development of new treatments options that may be particularly appropriate for specific MDS subsets.

Contemporary chemotherapeutic approaches for the treatment of hormone-refractory prostate carcinoma.

The medical management of hormone-refractory prostate cancer remains difficult and largely palliative. The development of effective antineoplastic agents has been frustrated by difficulty in the establishment of satisfactory objective response criteria for clinical trials. Nevertheless, recent trials indicate that mitoxantrone and spindle toxins such as docetaxel do show activity. Estramustine-based regimens have also been promising, and such combination regimens are now being explored rigorously. Benefiting from new molecular-biologic insights into the pathobiology of prostate cancer, novel strategies targeting new molecular pathways of cell regulation and cell-cell interaction (such as angiogenesis) are also being actively pursued.