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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 Background Surrogates are frequently used in cancer medicine as the end-point of clinical trials and as the basis of United States Food and Drug Administration approvals, but they do not always represent outcomes that are important for patients. We aim to build upon previous umbrella reviews of surrogate validation studies by identifying and examining all meta-analyses of randomised controlled trials that evaluate the strength of correlation between overall survival (OS) and surrogate markers. Methods Google Scholar and PubMed were searched by two independent reviewers for all eligible meta-analyses of randomised controlled trials examining the correlation between a surrogate end-point and OS in medical oncology. Included studies were trial-level (level-1) meta-analyses of randomised controlled trials in cancer. Data abstracted include date of publication, tumour type, setting, trial set, number of studies included in the analysis, dates of included publications, correlation coefficients and method to determine the correlation coefficient. Results Seventy-eight articles met the inclusion criteria and reported correlations in 89 settings. Eleven (12%) of these validation studies found only high correlation(s), while nine (10%) settings showed a moderate-only correlation. Thirty-four (38%) reported only low correlation(s). Thirty-five (39%) reported correlations of different strengths, depending on surrogate marker used and test of correlation. Conclusions In this large, umbrella analysis of surrogate validation studies, we found most surrogates in oncology had low or modest correlation with OS, which suggests that caution should be used when making conclusions based on surrogate markers. Highlights • Almost half (n = 37) of included studies were published after the previous umbrella review in 2015. • Of the 193 individual trial-level correlations, 34 were high correlation, 55 were moderate, and 104 had low correlation. • The percent of studies published with high correlation only was no higher after 2015 (11%) than all studies combined (12%). [ABSTRACT FROM AUTHOR]

Abstract Background We aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST) criteria–based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could be valid surrogate end-points for overall survival (OS) in anti–programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) trials. Methods We systematically reviewed phase 2 and phase 3 trials of anti–PD-1/PD-L1 drug trials of advanced or recurrent solid tumours that reported OS and at least one of the RECIST criteria–based end-points. We used Spearman rank correlation to evaluate the strength of the association between these end-points and OS and a linear regression model, weighted by the sample size, to assess the association between the treatment effect on these end-points and OS. We also performed sensitivity analyses and a leave-one-out cross-validation approach to evaluate the robustness of our findings. Results Forty-three qualifying trails comprising 15,088 patients were eligible. PFS showed good correlation with OS (squared Spearman rank correlation coefficient [ r s 2 ] = 0.54; P < 0.001), while ORR and DCR illustrated moderate association with OS (r s 2 = 0.29 and 0.28, respectively; both P < 0.001). The correlation was moderate between the treatment effects on PFS and OS (coefficient of determination [ R 2 ] = 0.37, P < 0.001) and poor among ORR, DCR and OS (R 2 = 0.10 and 0.08, respectively); these were confirmed by sensitivity analyses (all R 2 < 0.75) and the leave-one-out cross-validation approach. Conclusions No RECIST criteria–based end-points could be a valid surrogate for OS. At present, we proposed to set OS as the primary end-point in anti–PD-1/PD-L1 drug trials of advanced or recurrent solid tumours. Highlights • None of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria–based end-points could be a valid surrogate for overall survival (OS). • Optimisation of the RECIST criteria in immunotherapy trials is still urgently needed. • OS should still be set as the primary end-point in anti–programmed death-1/programmed death ligand 1 drug trials. [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]

Background Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before. Aim To study the outcome of AYA patients in phase I clinical trials. Methods Clinical trial data of AYAs (defined as aged 15–39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed. Results From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3–9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations. Conclusion We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options. [ABSTRACT FROM AUTHOR]

Background Long-term responders have been observed with anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD(L)1). Optimal duration of therapy in responding and stable disease (SD) patients is unclear with various attitudes encompassing treatment until progression disease, stopping therapy after a defined timeframe. Patients and methods We report the experience of 13 patients who discontinued immune checkpoint inhibitor in phase I trials as per protocol while experiencing a tumour-controlled disease. According to protocols, patients could restart the same immunotherapy if radiological or clinical progression occurred. Results Patients were treated for colorectal microsatellite instability–high genotype (n = 5), urothelial carcinoma (n = 3), melanoma (n = 2), non–small-cell lung cancer (n = 2) and triple-negative breast cancer (n = 1) for a median time of 12 months (range 10.6–12). Patients achieved 1 (8%) complete response, 10 (77%) partial response (PR) and 2 (15%) SD. The median progression-free survival 1 (PFS1) defined as the time from the first infusion until progression was 24.4 months (range 15.8–49). The median time free-treatment after discontinuation was 12.6 months (range 4–39.7). Eight patients experienced disease progression and were retreated. Best responses observed after rechallenging were 2 PR (25%) and 6 SD (75%). Median PFS2 defined from the first day of retreatment until disease progression or the last news was 12.9 months (range 5–35.4). No grade 3/4 events occurred during the study period. Conclusion Our data suggest that anti–PD(L)1 therapy should be resumed if progression occurs after a planned anti–PD(L)1 interruption. Further prospective studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background The development of immune checkpoint blocker development brings new hope in older patients (OPs) because of clinical efficacy and low toxicity. Clinical indications are rising steadily, but very few data are available in the geriatric population where comorbidities, reduced functional reserve and immunosenescence may affect efficacy and tolerance. Methods All cases of patients enrolled in immunotherapy phase I trials between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy were retrospectively reviewed. Case–control analysis was performed in OPs (patients ≥ 70 years) matched to younger patients (YPs) (patients < 70 years) by trial and treatment dose. We compared cumulative incidence, grade and type of immune-related adverse events (IrAEs) and survival outcomes. Results Among the 46 OPs and the 174 YPs enrolled in 14 phase I/II trials, 10 (22%) and 23 (13%) patients experienced grade III–IV IrAEs. Cumulative incidence of grade I–II IrAEs was significantly higher in OPs than YPs (p < 0.05). No significant difference was observed between the two groups for grade III–IV IrAEs (p = 0.50). Older age was not associated with lower dose intensity of treatment (p = 0.14). No significant difference was observed between OPs and YPs in median progression-free survival (hazards ratio 1.41, 95% confidence interval [CI] [0.94–2.11] p = 0.09) or median overall survival (HR 0.92, 95% CI [0.61–1.39] p = 0.77). Conclusion Immune checkpoint blockade appears to be an acceptable treatment option for OPs in the setting of phase I trials. [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]

Aim The aim of this study is to firmly delineate temporal and age trends regarding sex discrepancies in cancer risk and survival as well as quantifying the potential gain achieved by eliminating this inequality. Methods We performed a population-based cohort study using data on all adult incident cancer cases (n = 872,397) recorded in the Swedish Cancer Register in 1970–2014. To assess the associations between sex and cancer risk and sex and survival, male-to-female incidence rate ratios (IRRs) and excess mortality ratios (EMRs) adjusted for age and year of diagnosis were estimated using Poisson regression. Results Men were at increased risk for 34 of 39 and had poorer prognosis for 27 of 39 cancers. Women were at increased risk for 5 of 39 and had significantly poorer survival for 2 of 39 cancers. IRRs among male predominant sites ranged from 1.05; 95% confidence interval (CI), 1.03–-1.1 (lung adenocarcinoma) to 8.0; 95% CI, 7.5–8.5 (larynx). EMRs among sites with male survival disadvantage ranged from 1.1; 95% CI, 1.03–1.1 (colon) to 2.1; 95% CI, 1.5–-2.8 (well-differentiated thyroid). Conclusion Male sex is associated with increased risk and poorer survival for most cancer sites. Identifying and eliminating factors driving the observed sex differences may reduce the global cancer burden. [ABSTRACT FROM AUTHOR]

Introduction A number of phase I immunotherapy trials for cancer patients incorporate the absolute lymphocyte count (ALC) as an inclusion criteria. This study aims to assess whether ALC is associated with a lack of response to anti-PD-1/PD-L1 in early clinical trials. Methods All consecutive patients treated with anti-PD-1/PD-L1 monotherapy in phase I trials in our institution between December 2011 and January 2014 were reviewed. Baseline ALC, neutrophil-to-lymphocyte ratio (NLR), Royal-Marsden Hospital (RMH) prognostic score, objective response rate (ORR) and disease control rate (DCR = SD + PR + CR, stable disease (SD), partial response (PR), complete response (CR)) defined by Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 were retrieved. Results Out of a total of 167 patients, 48 (28.7%) and 8 patients (4.8%) had baseline ALCs of <1 G/l and <0.5 G/l, respectively. The RECIST change (%) was not correlated with ALC (G/l) (Spearman's rho = −0.06, P = 0.43). We did not observe any difference in terms of ORR (8.3% versus 15.1%, P = 0.32) or of DCR (58.3% versus 61.3%, P = 0.73) between patients with ALC <1 G/l versus >1 G/l. When using 0.5 G/l as ALC threshold, we did not find any difference either in ORR or in DCR. In a multivariate Cox regression analysis, baseline ALC was not associated with overall survival, whereas the RMH and the number of previous lines of treatment remained independent prognostic factors. Conclusions Baseline ALC was not associated with response to anti-PD-1/PD-L1 in cancer patients enrolled in phase I trials. Patients should not be excluded from early phase clinical trials testing immune checkpoints blockers because of ALC. [ABSTRACT FROM AUTHOR]

Introduction Life expectancy evaluation is crucial when selecting patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on three objective variables (number of metastatic sites, lactate dehydrogenase (LDH) and serum albumin) was validated in patients treated with cytotoxics and targeted therapies. We aimed to determine if those factors were applicable to immune-checkpoint therapies (ICTs) in phase I trials and to evaluate new variables that may preclude a better prognosis in patients receiving ICT. Patients and methods We conducted a retrospective analysis of survival risk factors in a discovery cohort of 155 patients enrolled into ICT phase I trials at our institution. We computed univariate analysis and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in phase I ICT trials was used to prospectively validate this score. Results A total of 155 patients (M/F: 83/72; median age 59) receiving an experimental ICT between March 2012 and January 2016 were included in the discovery cohort. An MVA assessing the RMH score variables showed that low albumin (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.05–2.86) and LDH > upper limit normal (ULN) (HR 1.88, 95% CI 1.12–3.15) were independent negative prognostic factors for OS. Interestingly, neutrophil-to-lymphocyte ratio (NLR) > 6 (HR 1.75, 95% CI 1.04–2.95) was associated with a decrease in OS. The number of metastases was not associated with a poorer outcome for this ICT cohort (HR 0.83, 95% CI 0.51–1.35). A risk score based on the results of the MVA (NLR > 6 = 1; LDH > ULN = 1; albumin < 35 g/l = 1) showed that patients presenting a high score (>1) had a significantly shorter OS (20.4 weeks; 95% CI 5.7–35.2) compared to those with a low score (0 or 1) (68.9 weeks; 95% CI 50–83.7) (HR 2.9, 95% CI 1.87–4.64). In the validation cohort of 113 patients, again the patients presenting a high score showed an inferior OS (HR 6.3, 95% CI 2.7–14.8). Conclusion In ICT phase I trials, traditional prognostic variables included in the RMH score may be suboptimal to determine patient's prognosis. In this context, the NLR is a significant prognostic variable. The Gustave Roussy Immune Score, based on albumin, LDH and NLR, allows a better selection of patients for ICT phase I trials. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase (IDO, also referred to as IDO1) has been demonstrated to be a normal endogenous mechanism of acquired peripheral immune tolerance in vivo . In the field of oncology, IDO expression and/or activity has been observed in several cancer types and has usually been associated with negative prognostic factors and worse outcome measures. This manuscript reviews current available data on the role of IDO in cancer and the current results obtained with IDO inhibition, both in animal models and in phase 1 and 2 clinical trials in humans. Preliminary results with IDO inhibitors, usually combined with other anti-cancer drugs, seem encouraging. Further studies are needed to clarify the conditions in which IDO inhibitors can be of value as an anti-cancer strategy. In addition, further research should address whether the expression of IDO in tissue or blood can be a marker to select patients who can benefit most from IDO inhibition. [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]

Population-based cancer research is paramount for controlling cancer. Cancer research is increasingly dependent on access to biospecimens from subjects that have been followed-up for future health outcomes. This is achieved using longitudinal follow-up of cohorts and biobanks using cancer registry linkages. All over the world, more and more large population-based cohorts and advanced biobanking facilities are established. International standardisation and networking in the linkage of cohorts and biobanks to cancer registries is required in order to enable international cancer research and comparability of research results. An international operating procedure and standard minimum dataset for linkages of biobanks, cohorts and cancer registries is proposed. An internationally comparable provision of well characterised study bases for molecular cancer research will be an essential prerequisite for the success of translational medicine. [ABSTRACT FROM AUTHOR]

SMIP-016, a new anti-tumour agent, is a mouse/human chimeric fusion protein built on the ADAPTIR™ (modular protein therapeutic) platform targeting human CD37. In this study, for the first time, we examined pro-apoptotic activity of SMIP-016 in combination with monoclonal anti-CD20 antibody, ofatumumab (HuMax-CD20) in de novo chronic lymphocytic leukaemia (CLL) cells and in different B-cell neoplasm-derived lines. In CLL cells SMIP-016 exerted significant cytotoxicity (versus control – p = 0.01). In the in vitro models, SMIP-016 was also distinctly active against Raji line (Burkitt lymphoma; BL) (versus control – p = 0.007), Riva-1 line (diffuse large B-cell lymphoma; DLBCL) (versus control – p = 0.002) and RPMI 8226 line (multiple myeloma cells; MM) (versus control – p = 0.03). In studies combining SMIP-016 and ofatumumab, the cytotoxicity against CLL cells was significantly higher than the agents used alone ( p < 0.03). Remarkably enhanced cytotoxic activity of SMIP-016 and ofatumumab in combination was also observed in Raji and Riva-1 cell lines ( p < 0.01 and p < 0.003, respectively). Importantly, both agents induced cytotoxicity at very low concentrations which suggests that potential side-effects may be decreased in clinical practice. The mechanism responsible for cytotoxicity of SMIP-016 in all the examined models was connected with caspase-dependent apoptosis. In majority of cell types SMIP-016 induced overexpression of Bax protein, as well as downregulation of Bcl-2, cIAP1 ( p < 0.03) and Smac/DIABLO ( p < 0.003) apoptosis-regulating proteins. In conclusion, our study demonstrated high pro-apoptotic activity of SMIP-016, especially in combination with ofatumumab, against ex vivo CLL cells, and BL or DLBCL in vitro cell lines. Thus, further preclinical studies in in vivo models are warranted, as this combination may be a promising therapeutic concept for treatment of those malignancies. [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: Trabectedin (Ecteinascidin-743 or ET-743) is a novel antitumour agent of marine origin with potent antitumour activity both in vitro and in vivo. It interacts with the minor groove of DNA, interfering with transcriptional activity and DNA repair pathways. Here, we report a novel mechanism by which trabectedin exerts its cytotoxic effects on carcinoma cells. It is based on its ability to impair the function of the High-Mobility Group A (HMGA) proteins. These proteins have a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. They bind the minor groove of DNA, alter chromatin structure and, thus, regulate the transcription of several genes by enhancing or suppressing the activity of transcription factors. We first report that trabectedin has a higher cytotoxic effect on thyroid and colon carcinoma cells expressing abundant levels of HMGAs in comparison with cells not expressing them. Then, we have shown that trabectedin treatment displaces HMGA proteins from the HMGA-responsive promoters, including ATM promoter, impairing their transcriptional activity. Finally, we report a synergism between Ionising Radiations and trabectedin treatment restricted to the HMGA-overexpressing cancer cells. This result might have important clinical implications since it would suggest the use of trabectedin for the treatment of neoplasias expressing abundant HMGA levels that are frequently associated to chemoresistance and poor prognosis. [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]

Abstract: Introduction: Components of the systemic inflammatory response, combined to form inflammation-based prognostic scores (modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI), Prognostic Nutritional Index (PNI)) have been associated with cancer specific survival. The aim of the present study was to compare the prognostic value of these scores. Methods: Patients (n =27,031) who had an incidental blood sample taken between 2000 and 2007 for C-reactive protein, albumin, white cell, neutrophil, lymphocyte and platelet counts, as well as a diagnosis of cancer (Scottish Cancer Registry) were identified. Of this group 8759 patients who had been sampled within two years following their cancer diagnosis were studied. Results: On follow up, there were 5163 deaths of which 4417 (86%) were cancer deaths. The median time from blood sampling to diagnosis was 1.7months. An elevated mGPS, NLR, PLR, PI and PNI were predictive of a reduced cancer specific survival independent of age, sex and deprivation and tumour site (all p <0.001). The area under the receiver operator curves was greatest for mGPS and PI. Specifically, in colorectal cancer, an elevated mGPS and PI were predictive of a reduced cancer specific survival independent of age, sex, deprivation and tumour stage (both p <0.001). Conclusion: The results of the present study show that systemic inflammation-based scores, in particular the mGPS and PI, have prognostic value in cancer independent of tumour site. Based on the present results and the existing validation literature, the mGPS should be included in the routine assessment of all patients with cancer. [Copyright &y& Elsevier]

Abstract: Aim: To ensure safety and optimise efficacy, careful patient selection for participation in oncologic phase I trials is warranted. Therefore, we did a validation study on existing phase I prognostic scores, and subsequently aimed to make an even more simple prognostic score. Patients and methods: We retrospectively analysed characteristics and clinical outcome of 122 patients who participated in eight different phase I studies in our centre. A literature search was performed for existing prognostic scores which were validated in our dataset. Additionally, a simple prognostic score able to predict overall survival (OS), progression free survival (PFS), 90-d mortality and duration of participation was developed. Results: In our population the median OS was 31 (range 4–241) weeks, median PFS was 10 (range 3–119) weeks. Thirteen patients (11%) died within 90-d and median participation duration was 11 (range 1–119) weeks. Two out of five existing prognostic scores could be validated in this dataset for OS. Based on multivariate analyses a new, objective and simple score, consisting of LDH, sodium and haemoglobin, was tested. High score (2–3 points) compared to low score (0–1) significantly predicted OS (HR 1.878, p =0.003), PFS (HR 1.156, p =0.038), participation duration (HR 1.858, p =0.004) and 90-d mortality (OR 4.200, p =0.022). Conclusion: We propose a new prognostic model, using LDH, sodium and haemoglobin, helpful to predict OS, PFS, participation duration and 90-d mortality. Larger multicentre studies are needed to validate this score. [Copyright &y& Elsevier]

Current staging classifications in colorectal cancer are not able to accurately predict patient outcome, and the need for novel prognostic markers is evident. S100A4 is a Ca2+-binding protein which promotes metastasis in several tumour types, and the aim of the present study was to investigate the prognostic impact of S100A4 expression in colorectal cancer. Two hundred and forty two patients with curatively resected adenocarcinoma of the colon or rectum were prospectively included in the study at the time of surgery. S100A4 expression was analysed by immunohistochemistry, and associations with clinicopathological variables and patient outcome were investigated. Nuclear expression of S100A4 was observed in 29% and cytoplasmic expression was observed in 64% of the tumours. In univariate analysis, nuclear S100A4 was a negative predictor of metastasis-free (P =0.006) and overall survival (P =0.01), whereas cytoplasmic S100A4 was not associated with patient outcome. In multivariate analysis, nuclear localisation was inversely associated with metastasis-free (P =0.03) and overall survival (P =0.02). Interestingly, the prognostic impact was largely confined to TNM stage II, and stage II patients with tumours expressing nuclear S100A4 had a similar prognosis as stage III patients. In conclusion, nuclear expression of S100A4 is a novel prognostic marker in colorectal cancer, and the prognostic value in TNM stage II suggests that nuclear S100A4 could be used in the stratification of stage II patients for adjuvant treatment. [Copyright &y& Elsevier]

Abstract: Background: Sexual dysfunction might be symptomatic of cancer spreading beyond the prostate by local invasion, a mechanism of tumour progression associated with prognosis. Conversely, among men with raised prostate-specific antigen (PSA) levels, a negative association might be expected if sexual dysfunction was symptomatic of benign, rather than malignant, prostatic disease. Patients and methods: Cases and controls were selected from among men recruited to the UK population-based ProtecT (Prostate testing for cancer and Treatment) study. Men aged 50–69years were invited for PSA testing and those with a PSA level ⩾3.0ng/ml were invited for biopsy. We investigated whether symptoms of sexual dysfunction, determined by self-completed questionnaire prior to biopsy, were associated with prostate cancer. Results: Of the 8924 men who had a PSA level ⩾3.0ng/ml (11% of the men who had a PSA test), 6585 underwent biopsy of whom 2813 and 421, respectively, were subsequently diagnosed with localised and advanced prostate cancer and 3351 had a negative biopsy result. No individual symptom of sexual dysfunction was associated with risk of prostate cancer. The symptom score was associated with advanced (odds ratio (OR) per one unit increase in score=1.06; 1.00–1.12; P =0.07) but not with localised (OR=1.00; 0.97–1.02; P =0.9) prostate cancer (P =0.05 for heterogeneity). Conclusions: Our study provides weak evidence that sexual dysfunction may be associated with PSA-detected advanced, but not localised, prostate cancer among men with raised PSA levels. [Copyright &y& Elsevier]