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Abstract Aim We seek to characterize how faster tumour shrinkage rate (k) can lead to paradoxically shorter Response Evaluation Criteria in Solid Tumors (RECIST) time to progression ('TTP20' – tumour size exceeding its minimum by 5 mm and 20%) [1] and, therefore, progression-free survival (PFS). Specifically, we investigate under what conditions this paradoxical behaviour occurs, what fraction of patients satisfy these conditions, whether this phenomenon can invert population-level PFS hazard ratio, and consistency of an alternative time-to-event benefit metric with k. Methods We use a mathematical model treating tumour burden as decreasing drug-sensitive and increasing drug-resistant cell subpopulations. We fit this model to data from several clinical trials with different indications [2]. We simulated a more effective treatment and recorded whether patients' TTP20 increased or decreased. We performed a study-level analysis to compare the relationship of speed and depth of response with TTP20 for both the administered 'control' and simulated 'more effective' drug. We propose and test an alternative benefit metric: the model-projected time that tumour size reaches 120% of baseline (TTB120). Results Depending on indication, 3–27% of patients are estimated to have a paradoxically inverse relationship between k and TTP20. Simulated head-to-head studies show that TTP20-based PFS can favour the less effective drug. In contrast, TTB120 always favours the more effective drug. Conclusion We demonstrate the paradoxical behaviour of RECIST TTP20 – as an exemplar of percent-change-from-nadir based cancer progression criterion – both in theory and in observed patient data at the individual and trial level. We propose an alternative tumour size–based criterion (TTB120) that is directionally consistent with tumour shrinkage rate. Highlights • A Response Evaluation Criteria in Solid Tumors (RECIST) time to progression (TTP) criterion is tumour size exceeding 120% of its minimum. • A simple mathematical model well describes tumour response and relapse in treated patients. • Increasing tumour shrinkage rate in this model often leads to paradoxically shorter TTP. • This effect is large and frequent enough to invert population-level TTP-based outcomes. • We propose an alternative time to event metric that is consistent with shrinkage rate. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract Background Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti–PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti–PD-1 treatment efficacy. Patients and methods We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS. Results We identified 106 patients. Primary diagnoses were lung cancer (n = 77), melanoma (n = 8), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5–31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.2, P = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences. Conclusion In advanced cancer treated with single-agent anti–PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti–PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy. Highlights • In advanced cancer treated with anti–PD-1 antibodies nivolumab or pembrolizumab, incidence of irAEs was associated with a marked efficacy. • Response rate increased significantly from 16.6% to 82.5% when an irAE was present. • The follow-up showed an increase of PFS from 3 to 10 months when an irAE was present. • The follow-up showed an increase of OS from 22 to 32 months when an irAE was present. [ABSTRACT FROM AUTHOR]

Abstract Introduction There have been no reports about predicting survival of patients with advanced cancer constructed entirely with objective variables. We aimed to develop a prognostic model based on laboratory findings and vital signs using a fractional polynomial (FP) model. Methods A multicentre prospective cohort study was conducted at 58 specialist palliative care services in Japan from September 2012 to April 2014. Eligible patients were older than 20 years and had advanced cancer. We developed models for predicting 7-day, 14-day, 30-day, 56-day and 90-day survival by using the FP modelling method. Results Data from 1039 patients were analysed to develop each prognostic model (Objective Prognostic Index for advanced cancer [OPI-AC]). All models included the heart rate, urea and albumin, while some models included the respiratory rate, creatinine, C-reactive protein, lymphocyte count, neutrophil count, total bilirubin, lactate dehydrogenase and platelet/lymphocyte ratio. The area under the curve was 0.77, 0.81, 0.90, 0.90 and 0.92 for the 7-day, 14-day, 30-day, 56-day and 90-day model, respectively. The accuracy of the OPI-AC predicting 30-day, 56-day and 90-day survival was significantly higher than that of the Palliative Prognostic Score or the Prognosis in Palliative Care Study model, which are based on a combination of symptoms and physician estimation. Conclusion We developed highly accurate prognostic indexes for predicting the survival of patients with advanced cancer from objective variables alone, which may be useful for end-of-life management. The FP modelling method could be promising for developing other prognostic models in future research. Highlights • We developed a prognostic index that required only laboratory data and vital signs. • Survival of advanced cancer patients can be predicted without a physician's assessments. • Our prognostic index was more accurate than existing predictive tools. • Our prognostic index could minimize attrition rates of clinical trials. • Fractional polynomials model is a promising way to develop prognostic indexes. [ABSTRACT FROM AUTHOR]

Objective Patients with autoimmune or inflammatory disease (AID) are susceptible to immune-related adverse events (irAEs) when treated with immune check-point inhibitors (ICIs). We decided to analyse the safety and effectiveness of anti-PD-1 antibodies in AID patients and look for an association between the presence of pre-existing AID and the clinical outcome. Methods In a prospective study of the REISAMIC registry of grade ≥2 irAEs occurring in ICI-treated patients, we studied the associations between pre-existing AID on one hand and irAE-free survival, overall survival and best objective response rate on the other. Results We identified 45 patients with 53 AIDs in REISAMIC. The cancer diagnoses included melanoma (n = 36), non–small-cell lung cancer (n = 6) and others (n = 3). The most frequent pre-existing AIDs were vitiligo (n = 17), psoriasis (n = 12), thyroiditis (n = 7), Sjögren syndrome (n = 4) and rheumatoid arthritis (n = 2). Twenty patients (44.4%) presented with at least one irAE: eleven of these were associated with a pre-existing AID (‘AID flare’). Treatment with anti-PD-1 antibodies was maintained in 15 of the 20 patients with an irAE. The IrAE-free survival time was significantly shorter in AID patients (median: 5.4 months) than in AID-free patients (median: 13 months, p = 2.1 × 10 −4 ). The AID and AID-free groups did not differ significantly with regard to the overall survival time and objective response rate (p = 0.38 and 0.098, respectively). Conclusion In patients treated with anti-PD-1 antibody, pre-existing AID was associated with a significantly increased risk of irAEs. Our results indicate that cancer treatments with anti-PD-1 antibodies are just as effective in AID patients as they are in AID-free patients. [ABSTRACT FROM AUTHOR]

Background Cancer registries (CRs) are fundamental for estimating cancer burden, evaluating screening and monitoring health service performance. Stage at diagnosis—an essential information item collected by CRs—has been made available, for the first time, by CRs participating in EUROCARE-5. We analysed the quality of this information and estimated stage-specific survival across Europe for CRs with good data quality. Data and methods Sixty-two CRs sent stage (as TNM, condensed TNM or extent of disease) for 15 cancers diagnosed in 2000–2007. We assessed the quality, partly by comparing stage according to the three systems. We also developed procedures to reconstruct stage (categories: local, regional, metastatic and unknown) using information from all three systems, thus minimising the amount of missing information. Results Moderate-to-excellent stage concordance was found for practically all 24 CRs, for which it was possible to compare at least two staging systems. However, since stage was often incorrectly assigned, and information on the presence/absence of metastases was often lacking, data on only 7/15 cancers from 34/62 CRs (15 countries) were of sufficient quality for further analysis. Cases diagnosed ≥70 years had more advanced (or lacking) stage– and worse stage-specific survival than those <70 years. Conclusions Many European CRs collect and record reasonably accurate stage information. Others have difficulties. Both the completeness of primary data and the accuracy of stage coding need to be improved in order for CRs to fulfil their expanding roles in cancer control. We propose our stage reconstruction/checking procedures as a means of fully exploiting the stage information provided by EUROCARE CRs. More advanced (or lacking) stage at diagnosis plus poorer stage-specific survival in the elderly are worrying. [ABSTRACT FROM AUTHOR]

Introduction Performance status (PS) is an established prognostic factor in patients with advanced cancer and is usually scored by the treating physician. The EORTC QLQ-C30 questionnaire as reported by cancer patients is a validated tool to assess quality of life (QoL). Subjectivity plays a role in both assessments, and data on a direct comparison are scarce. Methods We compared the prognostic value for overall survival (OS) of the WHO PS to the baseline physical function scale of the EORTC QLQ-C30 (QLQ-C30 PF) in a prospective randomised phase 3 trial in advanced colorectal cancer (ACC), the CAIRO study. Patients were divided into two groups based on the baseline QLQ-C30 PF. QLQ-C30 PF was considered ‘good’ if the score was more than 66.7% and ‘poor’ if 66.7% or less. Results were validated in a subsequent phase 3 study in ACC, the CAIRO2 study. Results The median OS for patients with a ‘good’ QLQ-C30 PF and a ‘poor’ PF in patients with WHO PS 0 was 20.3 months (n = 300) and 10.4 months (n = 44), in patients with WHO PS 1 16.8 months (n = 125) and 10.1 months (n = 63), and in patients with WHO PS 2 16.2 months (n = 11) and 9.9 months (n = 12), respectively. In a Cox regression model which included other prognostic factors, ‘good’ versus ‘poor’ QLQ-C30 PF was significantly prognostic for OS (0.57 95% confidence interval: 0.46–0.72), but not WHO PS. These results were confirmed in the CAIRO2 study. Conclusions We demonstrate in ACC patients that PF, as assessed by patients using the EORTC QLQ-C30, is superior in terms of prognostic value to WHO PS as scored by physicians. Our data support to include the results of baseline EORTC QLQ-C30 PF instead of WHO PS as a stratification parameter in oncology trials. [ABSTRACT FROM AUTHOR]

Background Clinician prediction of survival (CPS) has low accuracy in the advanced cancer setting, raising the need for prediction models such as the palliative prognostic (PaP) score that includes a transformed CPS (PaP-CPS) and five clinical/laboratory variables (PaP-without CPS). However, it is unclear if the PaP score is more accurate than PaP-CPS, and whether PaP-CPS helps to improve the accuracy of PaP score. We compared the accuracy among PaP-CPS, PaP-without CPS and PaP-total score in patients with advanced cancer. Patients and methods In this prospective study, PaP score was documented in hospitalised patients seen by palliative care. We compared the discrimination of PaP-CPS versus PaP-total and PaP-without CPS versus PaP-total using four indices: concordance statistics, area under the receiver-operating characteristics curve (AUC), net reclassification index and integrated discrimination improvement for 30-day survival and 100-day survival. Results A total of 216 patients were enrolled with a median survival of 109 d (95% confidence interval [CI] 71–133 d). The AUC for 30-day survival was 0.57 (95% CI 0.47–0.67) for PaP-CPS, 0.78 (95% CI 0.7–0.87) for PaP-without CPS, and 0.73 (95% CI 0.64–0.82) for PaP-total score. PaP-total was significantly more accurate than PaP-CPS according to all four indices for both 30-day and 100-day survival (P < 0.001). PaP-without CPS was significantly more accurate than PaP-total for 30-day survival (P < 0.05). Conclusion We found that PaP score was more accurate than CPS, and the addition of CPS to the prognostic model reduced its accuracy. This study highlights the limitations of clinical gestalt and the need to use objective prognostic factors and models for survival prediction. [ABSTRACT FROM AUTHOR]

Background Body composition plays an important role in predicting treatment outcomes in adults with cancer. Using existing computed tomographic (CT) cross-sectional imaging and readily available software, the assessment of skeletal muscle mass to evaluate sarcopenia has become simplified. We performed a systematic review and meta-analysis to quantify the prognostic value of skeletal muscle index (SMI) obtained from cross-sectional CT imaging on clinical outcomes in non-haematologic solid tumours. Methods We searched PubMed and the American Society Clinical Oncology online database of meeting abstracts up to October 2015 for relevant studies. We included studies assessing the prognostic impact of pre-treatment SMI on clinical outcomes in patients with non-haematologic solid tumours. The primary outcome was overall survival (OS) and the secondary outcomes included cancer-specific survival (CSS), disease-free survival (DFS), and progression-free survival (PFS). The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated. Results A total of 7843 patients from 38 studies were included. SMI lower than the cut-off was associated with poor OS (HR = 1.44, 95% CI = 1.32–1.56, p < 0.001). The effect of SMI on OS was observed among various tumour types and across disease stages. Worse CSS was also associated with low SMI (HR = 1.93, 95% CI = 1.38–2.70, p < 0.001) as well as DFS (HR = 1.16, 95% CI = 1.00–1.30, p = 0.014), but not PFS (HR = 1.54, 95% CI = 0.90–2.64, p = 0.117). Conclusions This meta-analysis demonstrates that low SMI at cancer diagnosis is associated with worse survival in patients with solid tumours. Further research into understanding and mitigating the negative effects of sarcopenia in adults with cancer is needed. [ABSTRACT FROM AUTHOR]

Background Central nervous system (CNS) metastases represent a devastating complication for advanced breast cancer patients. This observational study examines the influence of patient, tumour and treatment characteristics on overall survival after synchronous or metachronous CNS metastases. Methods Information on 992 breast cancer patients with CNS metastases (whose primary tumour was diagnosed between 2004 and 2010) was retrieved from the Netherlands Cancer Registry (NCR). Overall survival was calculated from the date of CNS metastatic diagnosis, and the impact of prognostic factors on survival was assessed using univariate and multivariate extended Cox-regression models. Results We identified 165 patients with synchronous and 827 patients with metachronous CNS metastases. The majority of patients (88%) presented with brain metastases only, 12% had leptomeningeal metastases. Overall median survival was 5.0 months. Non-triple-negative breast cancer and systemic therapy were associated with improved survival in both groups. In patients with synchronous CNS metastases, surgery for the primary tumour and the metastases also improved survival. In patients with metachronous metastases, younger age (<50 years), lower initial tumour stage (I), ductal carcinoma, a prolonged time interval until diagnosis of CNS metastasis (>1 year), and absence of extracranial metastases were associated with improved survival. Metastasectomy and radiation therapy did not provide benefit beyond the first six months. Conclusions No difference in survival was established between synchronous and metachronous CNS metastases. Triple-negative disease is prognostically unfavourable in both groups, while those receiving treatment have a better outcome. Metastasectomy and radiotherapy improve survival within the first six months, and additional benefit may be derived from systemic therapy. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Progressive disease (PD) per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 is defined as growth of measurable target lesions, presence of new lesions or unequivocal progression of non-target disease. In this manuscript we explored whether a more refined categorisation of tumour response and/or these components of progression, varying over time, can improve prediction of overall survival (OS) in the RECIST database. Methods: Data were randomly selected from 13 randomised clinical trials (3758 patients with breast, lung or colorectal cancer). A maximum of five target lesions contributed to the sum of longest diameters. At each measurement time we determined: best target response as best % improvement from baseline; tumour growth of target lesions as worst % change and worst rate of increase (mm/week) from nadir; presence of new lesions and occurrence of non-target PD. OS was analysed by tumour type using Cox regression, adjusting for baseline sum and including these parameters as time-dependent covariates. Results: 36% of patients had new lesions, 28% non-target PD and 49% experienced target lesion growth (median strongest growth 1.5mm/week). Regardless of tumour type, presence of new lesions (hazard ratio (HR) ranging 1.5–2.3) and non-target PD (HR 1.5–2.0) were strongly associated with worse OS. The explanatory value of tumour growth for OS was low compared to the other components. Conclusion: Modelling target lesion tumour growth did not show a marked improvement in OS prediction over and above the other components. These analyses enable a better understanding of the role of each component in PD evaluation. Work is ongoing to incorporate this information into an updated version of RECIST with enhanced prediction of subsequent survival. [Copyright &y& Elsevier]

Abstract: Introduction: Mucinous adenocarcinomas represent a potentially poor prognostic subgroup identifiable by imaging. We compared outcomes between magnetic resonance imaging (MRI) detected rectal mucinous carcinoma and adenocarcinomas. The diagnostic performance of MRI compared with initial biopsy in detecting mucinous adenocarcinoma was also assessed. Methods: The proportion of patients downstaged in the mrMucinous and adenocarcinoma groups was compared. Cox proportional hazard models were used to test independence of mucinous status and baseline MRI and clinical variables on survival. Differences in survival for mucinous versus non-mucinous tumours were tested for significance using the Mantel-Cox log rank test. Results: 60/330 (18%) patients were correctly diagnosed with mucinous rectal cancer based on pre treatment MRI compared with 15/330 (5%) on initial biopsy (diagnostic odds ratio=4.67, p <0.05). All 60 (100%) patients undergoing surgery for mrMucinous tumours were confirmed as such on final histopathology. Significantly fewer mrMucinous tumours showed ypT downstaging when compared with non-mucinous tumours (14/60 (23%) versus 111/270 (40%), p =0.01). Three-year survival outcomes for patients for MRI detected mucinous tumours were significantly worse: disease free survival (DFS) was 48% versus 71%, p =0.006 and OS was 69% versus 79% p =0.04. MRI Mucin was an independent variable for poor DFS (hazard ratios (HR)) 0.58 95% Confidence interval (CI) 0.38–0.89). Conclusions: MRI diagnosis of mucinous adenocarcinoma is diagnostically superior to preoperative biopsy and occurs in up to 20% of rectal cancer patients. It is an independent imaging biomarker for response to preoperative chemoradiotherapy (CRT) and prognosis. MRI documentation of mucinous status will enable future pursuit of treatment strategies in this poor prognostic subgroup. [Copyright &y& Elsevier]

Abstract: Background: Vasculogenic mimicry (VM) has been reported in various malignant tumours and is known to play an important role in cancer progression and metastasis. However, the impact of VM on the overall survival of human cancer patients remains controversial. The goal of this study was to evaluate whether VM is associated with 5-year survival of human cancer patients. Methods: Twenty-two eligible clinical studies with data on both tumour cell-dominant VM and the 5-year survival of 3062 patients involved in 15 types of cancers were pooled in the meta-analysis. Results: The 5-year overall survival of VM-positive and -negative cancer patients was 31% and 56%, respectively. The relative risk (RR) of the 5-year survival of VM-positive patients was significantly higher than that of VM-negative cases (RR=1.531; 95% confidence interval (CI): 1.357–1.726; P <0.001). Notably, metastatic melanoma patients demonstrated a higher VM rate (45.3%) than patients with primary melanoma (23.1%) and showed worse 5-year survival, suggesting that VM contributes to tumour metastasis and poor prognosis in cancer patients. Subgroup analysis indicated that a poor 5-year survival was significantly associated with eight types of VM-positive malignant tumours, such as lung, colon, liver cancers, sarcomas and melanoma; but was not associated with the seven other types of cancers, such as prostate cancer. Heterogeneity and publication biases were found among the 22 studies, mainly due to the divergent characteristics of cancers and extremely low survival rate in six types of malignant tumours. Conclusion: VM-positive cancer patients show a poor 5-year overall survival compared with VM-negative malignant tumour cases, particularly in metastatic cancer. [Copyright &y& Elsevier]

Abstract: Background: Previous studies have reported a poor outcome for synovial sarcoma patients whose tumours relapse. Methods: This study analysed 44 relapsing cases in a series of 118 consecutive patients <21yr of age with non-metastatic synovial sarcoma prospectively enrolled in Italian paediatric protocols between 1979 and 2006. In an effort to identify a possible risk-adapted stratification enabling a better planning of second-line treatment, the relapsing patients’ outcome was analysed vis-à-vis their clinical picture at onset, first-line treatments, clinical findings at the time of first relapse and second-line treatment modalities. Results: The first event was a local recurrence in only 15 cases, and metastatic in 29 (associated with local relapse too in 7 cases). The time to relapse ranged from 4 to 108months (median 20months). Overall survival was 29.7% and 21.0% five and ten years after relapsing, respectively. The variables influencing survival were the timing and type of relapse (combined) and the chances of a secondary remission, which correlated strongly with the feasibility of complete surgery. Conclusions: Our study confirmed a largely unsatisfactory prognosis after recurrences in children and adolescents with synovial sarcoma: the chances of survival can be estimated on the basis of several variables for the purposes of planning risk-adapted salvage protocols. An aggressive surgical approach should be recommended. New effective systemic agents are warranted, and experimental therapies can be offered to patients with little chance of salvage. [Copyright &y& Elsevier]

Abstract: We hypothesised that host-related markers, possibly reflecting tumour aggressiveness, such as circulating endothelial cells (CEC) and circulating VEGFR2+ bone marrow-derived (BMD) progenitor cells, could have prognostic value in patients with advanced cancer enrolled in early anticancer drug development trials. Baseline CECs (CD45–CD31+CD146+7AAD– cells) and circulating VEGFR2+-BMD progenitor cells (defined as CD45dimCD34+VEGFR2+7AAD– cells) were measured by flow-cytometry in 71 and 58 patients included in phase 1 trials testing novel anti-vascular or anti-angiogenic agents. Correlations between levels of CECs, circulating VEGFR2+-BMD progenitor cells, clinical and biological prognostic factors (i.e. the Royal Marsden Hospital (RMH) score), and overall survival (OS) were studied. The median value of CECs was 12 CEC/ml (range 0–154/ml). The median level of VEGFR2+-BMD progenitor cells was 1.3% (range 0–32.5%) of circulating BMD-CD34+ progenitors. While OS was not correlated with CEC levels, it was significantly worse in patients with high VEGFR2+-BMD progenitor levels (>1%) (median OS 9.0 versus 17.0months), and with a RMH prognostic score >0 (median OS 9.0 versus 24.2months). The prognostic value of VEGFR2+-BMD progenitor levels remained significant (hazard ratio (HR)=2.3, 95% confidence interval (CI), 1.1–4.6, p =0.02) after multivariate analysis. A composite VEGFR2+-BMD progenitor level/RHM score ⩾2 was significantly associated with an increased risk of death compared to scores of 0 or 1 (median OS 9.0 versus 18.4months, HR=2.6 (95%CI, 1.2–5.8, p =0.02)). High circulating VEGFR2+-BMD progenitor levels are associated with poor prognostics and when combined to classical clinical and biological parameters could provide a new tool for patient selection in early anticancer drug trials. [Copyright &y& Elsevier]