A novel method to address the association between received dose intensity and survival outcome: benefits of approaching treatment intensification at a more individualised level in a trial of the European Osteosarcoma Intergroup

PURPOSE: There is lack of consensus on the prognostic value of received high dose intensity in osteosarcoma survivorship. Many studies have not shown a clear survival benefit when dose intensity is increased. The aim of this study is to go beyond chemotherapy intensification by arm-wide escalation of intended dose and/or compression of treatment schedule, while conversely addressing the relationship between treatment intensity and survival at the patient level. The study focusses on the difference in outcome results, based on a novel, progressively more individualised approach to dose intensity. // METHODS: A retrospective analysis of data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma was conducted. Three types of post hoc patient groups are formed using the intended regimen: the individually achieved cumulative dose and time on treatment, and the increase of individual cumulative dose over time. Event-free survival is investigated and compared in these three stratifications. // RESULTS: The strata of intended regimen and achieved treatment yields equivalent results. Received cumulative dose over time produces groups with evident different survivorship characteristics. In particular, it highlights a group of patients with an estimated 3-year event-free survival much larger (more than 10%) than other patient groups. This group mostly contains patients randomised to an intensified regimen. In addition, adverse events reported by that group show the presence of increased preoperative myelotoxicity. // CONCLUSIONS: The manuscript shows the benefits of analyzing studies by using longitudinal data, e.g. recorded per cycle. This has impact on the drafting of future trials by showing why such a level of detail is needed for both treatment and adverse event data. The novel method proposed, based on cumulative dose received over time, shows that longitudinal treatment data might be used to link survival outcome with drug metabolism. This is particularly valuable when pharmacogenetics data for metabolism of cytotoxic agents are not collected

Nodular Fasciitis With Malignant Morphology and a COL6A2-USP6 Fusion: A Case Report (of a 10-Year-old Boy)

Nodular fasciitis is usually a benign lesion genetically characterized by ubiquitin-specific protease 6 (USP6) rearrangements. We present a case of a 10-year-old boy with a 1.5-week history of a painless mass on the right chest wall, which was excised. A histomorphologically malignant tumor with pronounced pleomorphism, atypical mitotic figures, and a myoid immunophenotype was observed. The methylation profile was consistent with nodular fasciitis and fluorescence in situ hybridization confirmed USP6 rearrangement. Using Archer Fusion Plex (Sarcoma Panel) and RNA sequencing, a collagen, type VI, alpha 2 (COL6A2)-USP6 gene fusion was subsequently identified. Furthermore, DNA clustering analysis also showed a match with nodular fasciitis. During the follow-up of 22 months, no recurrence or metastasis occurred. In conclusion, we describe a clinically benign, histomorphologically malignant mesenchymal neoplasm with a myoid immunophenotype, and a genetic and epigenetic profile consistent with nodular fasciitis. In such cases, molecular analysis is a useful adjunct to avoid unnecessary overtreatment

Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma

Abstract This report summarizes the proceedings of the 4th European Bone Sarcoma Networking Meeting, held in London, England, on 21 June 2017. The meeting brought together scientific and clinical researchers and representatives from sarcoma charities from 19 countries representing five networks across Europe, to present and discuss new developments on bone sarcoma. In view of the challenges is poses, the meeting focussed primarily on osteosarcoma with presentations on developments in our understanding of osteosarcoma genetics and immunology as well as results from preclinical investigations and discussion of recent and ongoing clinical trials. These include studies examining the efficacy of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, as well as those with molecular profiling to stratify patients for specific therapies. Discussion was centred on generation of new hypotheses for collaborative biological and clinical investigations, the ultimate goal being to improve therapy and outcome in patients with bone sarcomas

Intact interferon signaling in peripheral blood leukocytes of high-grade osteosarcoma patients

High-grade osteosarcoma has a poor prognosis with an overall survival rate of about 60 percent. The recently closed European and American Osteosarcoma Study Group (EURAMOS)-1 trial investigates the efficacy of adjuvant chemotherapy with or without interferon-α. It is however unknown whether the interferon-signaling pathways in immune cells of osteosarcoma patients are functional. We studied the molecular and functional effects of interferon treatment on peripheral blood lymphocytes and monocytes of osteosarcoma patients, both in vivo and ex vivo. In contrast to other tumor types, in osteosarcoma, interferon signaling as determined by the phosphorylation of signal transducer and activator of transcription (STAT)1 at residue 701 was intact in immune cell subsets of 33 osteosarcoma patients as compared to 19 healthy controls. Also, cytolytic activity of interferon-α stimulated natural killer cells against allogeneic (n = 7 patients) and autologous target cells (n = 3 patients) was not impaired. Longitudinal monitoring of three osteosarcoma patients on interferon-α monotherapy revealed a relative increase in the CD16-positive subpopulation of monocytes during treatment. Since interferon signaling is intact in immune cells of osteosarcoma patients, there is a potential for indirect immunological effects of interferon-α treatment in osteosarcoma

TThe ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24–25, 2015. Workshop Report

This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas

Causal inference with randomised clinical trials of chemotherapy: The importance of well-documented treatment side-effects

Introduction Randomised Controlled Trials (RCTs) are universally considered as the most reliable way to demonstrate and assess causal relationships between treatments and outcome; science-based medicine is rooted in them. Spurious relationships between the outcome and a timefixed treatment-variable are eliminated by randomising patients over two or more arms of the trial. Hence, the randomisation procedure initiates the process by which treatment and outcomes of interest should be interpreted in a causal way. However, treatment is not always administered as intended, not least because of the occurrence of side effects and adverse events. In RCTs of chemotherapy, for example, the treatment administered may differ from the intended one because of the application of either cycle delays or dose reductions. Background Opposite to the∗intention-to-treat approach∗, a statistical analysis based on actual treatment data might be problematic due to the presence of the so-called∗treatment-adjustment bias∗. Exposure to chemotherapy agents may in fact be reduced and/or delayed as a consequence of previous-treatment side-effects. In particular, both reductions and delays contribute to lowering the value of the so-called Received Dose Intensity. Methods Inverse Probability-of-Treatment Weighting (IPTW) is a general methodology for removing treatment-adjustment bias. Working under the hypothesis of∗No Unmeasured Confounding∗, it creates a pseudopopulation by weighting each patient with the inverse probability of observing a certain treatment administration given the past treatment and toxicity history. However, a review of data collected from RCTs on osteosarcoma suggests that treatment side-effects may not be sufficiently well-documented. The pseudo-population created by IPTW has the following two properties: 1. Pseudo-patients' past toxicity-history no longer predicts exposure to chemotherapy in the next cycle; 2. The causal effect of treatment modifications on outcome is the same in both original and pseudopopulations. Results Using data from Medical Research Council trial BO06 (European Organisation for Research and Treatment of Cancer trial 80931) we will illustrate the use of IPTW and Marginal Structural Models (MSMs) for estimating the causal effect of dose reductions on Event-free Survival (EFS). The use of IPTW and MSMs allows to move beyond intention-to-treat and unbiasedly estimate the effect of treatment modifications on EFS. Conclusions We demonstrate that, even with complex and entangled data such as those collected in a RCT of chemotherapy, constructing and estimating a causal model is possible, provided that side-effects are well documented. When this is not the case, the removal of treatmentadjustment bias via IPTW might be problematic, if not prevented at all by the presence of unmeasured confounder. As such, good-quality toxicity data should be regarded as important enablers of causal modelling in RCTs of chemotherapy

Causal inference with randomised clinical trials of chemotherapy: The importance of well-documented treatment side-effects

Introduction Randomised Controlled Trials (RCTs) are universally considered as the most reliable way to demonstrate and assess causal relationships between treatments and outcome; science-based medicine is rooted in them. Spurious relationships between the outcome and a timefixed treatment-variable are eliminated by randomising patients over two or more arms of the trial. Hence, the randomisation procedure initiates the process by which treatment and outcomes of interest should be interpreted in a causal way. However, treatment is not always administered as intended, not least because of the occurrence of side effects and adverse events. In RCTs of chemotherapy, for example, the treatment administered may differ from the intended one because of the application of either cycle delays or dose reductions. Background Opposite to the∗intention-to-treat approach∗, a statistical analysis based on actual treatment data might be problematic due to the presence of the so-called∗treatment-adjustment bias∗. Exposure to chemotherapy agents may in fact be reduced and/or delayed as a consequence of previous-treatment side-effects. In particular, both reductions and delays contribute to lowering the value of the so-called Received Dose Intensity. Methods Inverse Probability-of-Treatment Weighting (IPTW) is a general methodology for removing treatment-adjustment bias. Working under the hypothesis of∗No Unmeasured Confounding∗, it creates a pseudopopulation by weighting each patient with the inverse probability of observing a certain treatment administration given the past treatment and toxicity history. However, a review of data collected from RCTs on osteosarcoma suggests that treatment side-effects may not be sufficiently well-documented. The pseudo-population created by IPTW has the following two properties: 1. Pseudo-patients' past toxicity-history no longer predicts exposure to chemotherapy in the next cycle; 2. The causal effect of treatment modifications on outcome is the same in both original and pseudopopulations. Results Using data from Medical Research Council trial BO06 (European Organisation for Research and Treatment of Cancer trial 80931) we will illustrate the use of IPTW and Marginal Structural Models (MSMs) for estimating the causal effect of dose reductions on Event-free Survival (EFS). The use of IPTW and MSMs allows to move beyond intention-to-treat and unbiasedly estimate the effect of treatment modifications on EFS. Conclusions We demonstrate that, even with complex and entangled data such as those collected in a RCT of chemotherapy, constructing and estimating a causal model is possible, provided that side-effects are well documented. When this is not the case, the removal of treatmentadjustment bias via IPTW might be problematic, if not prevented at all by the presence of unmeasured confounder. As such, good-quality toxicity data should be regarded as important enablers of causal modelling in RCTs of chemotherapy

Method to measure the mismatch between target and achieved received dose intensity of chemotherapy in cancer trials: A retrospective analysis of the MRC BO06 trial in osteosarcoma

Objectives: In cancer studies, the target received dose intensity (tRDI) for any regimen, the intended dose and time for the regimen, is commonly taken as a proxy for achieved RDI (aRDI), the actual individual dose and time for the regimen. Evaluating tRDI/aRDI mismatches is crucial to assess study results whenever patients are stratified on allocated regimen. The manuscript develops a novel methodology to highlight and evaluate tRDI/aRDI mismatches. Design: Retrospective analysis of a randomised controlled trial, MRC BO06 (EORTC 80931). Setting: Population-based study but proposed methodology can be applied to other trial designs. Participants: A total of 497 patients with resectable high-grade osteosarcoma, of which 19 were excluded because chemotherapy was not started or the estimated dose was abnormally high (>1.25 × prescribed dose). Intervention(s): Two regimens with the same anticipated cumulative dose (doxorubicin 6×75 mg/m2 /week; cisplatin 6×100 mg/m2 /week) over different time schedules: every 3 weeks in regimen-C and every 2 weeks in regimen-DI. Primary and secondary outcome measures: tRDI distribution was measured across groups of patients derived from k-means clustering of treatment data. K-means creates groups of patients who are aRDI-homogeneous. The main outcome is the proportion of tRDI values in groups of homogeneous aRDI. Results: For nearly half of the patients, there is a mismatch between tRDI and aRDI; for 21%, aRDI was closer to the tRDI of the other regimen. Conclusions: For MRC BO06, tRDI did not predict well aRDI. The manuscript offers an original procedure to highlight the presence of and quantify tRDI/aRDI mismatches. Caution is required to interpret the effect of chemotherapy-regimen intensification on survival outcome at an individual level where such a mismatch is present. The study relevance lies in the use of individual realisation of the intended treatment, which depends on individual delays and/or dose reductions reported throughout the treatment

A novel method to address the association between received dose intensity and survival outcome : benefits of approaching treatment intensification at a more individualised level in a trial of the European Osteosarcoma Intergroup

Purpose: There is lack of consensus on the prognostic value of received high dose intensity in osteosarcoma survivorship. Many studies have not shown a clear survival benefit when dose intensity is increased. The aim of this study is to go beyond chemotherapy intensification by arm-wide escalation of intended dose and/or compression of treatment schedule, while conversely addressing the relationship between treatment intensity and survival at the patient level. The study focusses on the difference in outcome results, based on a novel, progressively more individualised approach to dose intensity. Methods: A retrospective analysis of data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma was conducted. Three types of post hoc patient groups are formed using the intended regimen: the individually achieved cumulative dose and time on treatment, and the increase of individual cumulative dose over time. Event-free survival is investigated and compared in these three stratifications. Results: The strata of intended regimen and achieved treatment yields equivalent results. Received cumulative dose over time produces groups with evident different survivorship characteristics. In particular, it highlights a group of patients with an estimated 3-year event-free survival much larger (more than 10%) than other patient groups. This group mostly contains patients randomised to an intensified regimen. In addition, adverse events reported by that group show the presence of increased preoperative myelotoxicity. Conclusions: The manuscript shows the benefits of analyzing studies by using longitudinal data, e.g. recorded per cycle. This has impact on the drafting of future trials by showing why such a level of detail is needed for both treatment and adverse event data. The novel method proposed, based on cumulative dose received over time, shows that longitudinal treatment data might be used to link survival outcome with drug metabolism. This is particularly valuable when pharmacogenetics data for metabolism of cytotoxic agents are not collected. Trial registration: ISRCTN86294690