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Suppl. tab. S1 | Multivariable Cox regression of baseline factors associated with overall survival in all first-line checkpoint inhibitor treated patients Suppl. tab. S2 | Multivariable Cox regression of baseline factors associated with overall survival in first-line checkpoint inhibitor treated patients experiencing severe immune related adverse events managed with immunosuppression

Purpose:Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown.Experimental Design:Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients.Results:A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity [hazard ratio (HRadj) = 0.77; 95% confidence interval (CI), 0.63–0.93]. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF ± steroids for steroid-refractory toxicity compared with patients who were managed with steroids only (HRadj = 1.61; 95% CI, 1.03–2.51), with a median OS of 17 and 27 months, respectively.Conclusions:Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy.See related commentary by Weber and Postow, p. 2085

Contains fulltext : 287666.pdf (Publisher’s version ) (Open Access) There is no consensus on the optimal treatment duration of anti-PD-1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti-PD-1 discontinuation, the association of treatment duration with progression and anti-PD-1 re-treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first-line anti-PD-1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti-PD-1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti-PD-1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24-month progression-free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti-PD-1 discontinuation was not due to adverse events. Having a PR at anti-PD-1 discontinuation and longer time to first response were associated with progression [hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11-2.97) and HR = 1.10 (95% CI = 1.02-1.19; per month increase)]. In 17 of the 27 anti-PD-1 re-treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti-PD-1 discontinuation.

Contains fulltext : 229623.pdf (Publisher’s version ) (Open Access) BACKGROUND: Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now. METHODS: Risk ratios of severe (grade ≥3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry. RESULTS: 111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RR(adj)) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RR(adj) 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs. CONCLUSION: In patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found.

Whole genome sequencing (WGS) using fresh frozen tissue and matched blood samples from cancer patients is becoming in reach as the most complete genetic tumor test. With a trend towards the availability of small biopsies and the need to screen an increasing number of (complex) biomarkers, the use of a single all-inclusive test is preferred over multiple consecutive assays. To meet high-quality diagnostics standards, we optimized and clinically validated WGS sample and data processing procedures resulting in a technical success rate of 95.6% for fresh-frozen samples with sufficient (≥20%) tumor content.Independent validation of identified biomarkers against commonly used diagnostic assays showed a high sensitivity (recall) (98.5%) and precision (positive predictive value) (97.8%) for detection of somatic SNV and indels (across 22 genes), and high concordance for detection of gene amplification (97.0%, EGRF and MET) as well as somatic complete loss (100%, CDKN2A/p16). Gene fusion analysis showed a concordance of 91.3% between DNA-based WGS and an orthogonal RNA-based gene fusion assay. Microsatellite (in)stability assessment showed a sensitivity of 100% with a precision of 94%, and virus detection (HPV) an accuracy of 100% compared to standard testing.In conclusion, whole genome sequencing has a >95% sensitivity and precision compared to routinely used DNA techniques in diagnostics and all relevant mutation types can be detected reliably in a single assay.

Contains fulltext : 215533.pdf (Publisher’s version ) (Open Access) The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (>/=2x upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4-5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH.

3013 Background: In the next few years numerous drugs will be approved for defined genomic targets, most of these in a tumor agnostic manner. Identifying patients who can benefit from this is critical for the future success of precision medicine, ideally using a single comprehensive test to detect all possible biomarkers. The WIDE study (WGS Implementation in standard cancer Diagnostics for Every cancer patient) aimed to evaluate the feasibility, clinical validity (primary endpoints) and added value (secondary endpoint) of clinical grade Whole Genome Sequencing (cWGS) in routine clinical practice. Methods: cWGS was prospectively performed on 1,200 consecutive patients with (suspected) metastatic cancer. Tumor material was obtained during routine clinical procedures for both Standard-Of-Care (SOC) and cWGS. Next to securing a high quality specimen for SOC diagnostics, multiple frozen sections per patient were evaluated to identify the sample most suitable for WGS. cWGS was conducted independently of, but in parallel with SOC diagnostics, which included SOC molecular diagnostics (Moldx) for 48% of patients. cWGS and MolDx results were compared and discussed in a dedicated tumor board. Additional tests for resolving discordances were applied when needed. Results: cWGS was successfully performed in 69% (841/1217) of samples with a technical success rate of 97% (841/871). An insufficient amount of tumor cells ( < 20%) was the main reason for not completing cWGS (25%, 310/1217). cWGS turn-around-time (TAT), due to continuous improvements to the clinical procedure and cWGS pipeline over the course of the study, decreased to 10 working days. A total of 856 genomic biomarkers identified by SOC MolDx could be compared to cWGS results. Initial analyses of discordances revealed an error rate of 2.1% (18/856) for cWGS compared to a 1.0% (8/856) error rate for SOC Moldx. After optimizing cWGS and SOC pipelines based on these findings, error rates dropped to 0.6% (5/856) and 0.7% (6/856) for cWGS and SOC MolDx, respectively. Overall, cWGS identified clinically actionable (routine practice and experimental) biomarkers in 71% of all patients tested. Compared to SOC MolDx, cWGS identified one or more additional clinically actionable biomarkers in 54% (446/832) of patients. Interestingly, in patients who were not tested by SOC MolDx, actionable variants were identified by cWGS in 54% (153/282). Conclusions: The WIDE study has shown that cWGS is feasible in routine clinical practice in a comprehensive cancer center setting, using tumor material obtained during routine procedures. Furthermore, cWGS showed added value by identifying one or more additional clinically actionable biomarkers in 54% of patients including patients who had not received SOC Moldx. These outcomes have led to the successful adoption of cWGS at the Netherlands Cancer Institute as part of routine care, which will further facilitate precision medicine for cancer patients.

Contains fulltext : 174807.pdf (Publisher’s version ) (Closed access) BACKGROUND: In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration. METHODS: The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma. This includes tumour and patient characteristics, treatment patterns, clinical outcomes, quality of life, healthcare utilisation, informal care and productivity losses. These data are used for clinical auditing, increasing the transparency of melanoma care, providing insights into real-world cost-effectiveness and creating a platform for research. RESULTS: Within 1 year, all melanoma centres were participating in the DMTR. The quality performance indicators demonstrated that the BRAF inhibitors and ipilimumab have been safely introduced in the Netherlands with toxicity rates that were consistent with the phase III trials conducted. The median overall survival of patients treated with systemic therapy was 10.1 months (95% confidence interval [CI] 9.1-11.1) in the first registration year and 12.7 months (95% CI 11.6-13.7) in the second year. CONCLUSION: The DMTR is the first comprehensive multipurpose nationwide registry and its collaboration with all stakeholders involved in melanoma care reflects an integrative view of cancer management. In future, the DMTR will provide insights into challenging questions regarding the definition of possible subsets of patients who benefit most from the new drugs.

The aim of this population-based study was to identify the factors associated with clinical outcomes in vemurafenib-treated patients and to evaluate outcomes across subgroups of patients with different risk profiles. Data were retrieved from the Dutch Melanoma Treatment Registry. Time to next treatment (TTNT) and overall survival (OS) of all metastatic melanoma patients who received vemurafenib between 2012 and 2015 were assessed using Kaplan-Meier estimates. A risk score was developed on the basis of all prognostic factors associated with TTNT and OS derived from multivariable Cox regression analyses. Patients were stratified according to the presence of prognostic risk factors by counting the number of factors, ranging from 0 to 6. A total of 626 patients received vemurafenib with a median follow-up of 35.8 months. The median TTNT and OS were 4.7 months [95% confidence intervals (CI): 4.4-5.1] and 7.3 months (95% CI: 6.6-8.0). The strongest prognostic factors were serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance score, number of organ sites involved and brain metastases. Patients with a favourable risk profile (no risk factors) had a median TTNT and OS of 7.1 (95% CI: 5.8-8.5) and 15.4 months (95% CI: 10.0-20.9). The median OS more than halved for patients with greater than or equal to 2 risk factors compared with patients with no risk factors. The clinical outcomes of vemurafenib in metastatic melanoma patients with a favourable risk profile are comparable with the results of the trials. Combining prognostic factors into a risk score could be valuable to stratify patients into favourable and poor-prognosis groups. Copyright (c) 2018 Wolters Kluwer Health, Inc. All rights reserved.

// Eveline M. Dijkgraaf 1 , Saskia J.A.M. Santegoets 1 , An K.L. Reyners 2 , Renske Goedemans 1 , Hans W. Nijman 3 , Mariette I.E. van Poelgeest 4 , Arien R. van Erkel 5 , Vincent T.H.B.M. Smit 6 , Toos A.H.H. Daemen 7 , Jacobus J.M. van der Hoeven 1 , Cornelis J.M. Melief 8 , Marij J.P. Welters 1 , Judith R. Kroep 1, * , Sjoerd H. van der Burg 1, * 1 Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands 2 Department of Clinical Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands 3 Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands 4 Department of Gynecology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands 5 Department of Radiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands 6 Department of Pathology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands 7 Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands 8 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands * These authors have contributed equally to this work Correspondence to: Sjoerd H. van der Burg, e-mail: shvdburg@lumc.nl Judith R. Kroep, e-mail: j.r.kroep@lumc.nl Keywords: ovarian cancer, p53, immunotherapy, chemoresistance, tumor immunity Received: May 27, 2015 Accepted: August 03, 2015 Published: August 14, 2015 ABSTRACT Purpose : Preclinical tumor models show that chemotherapy has immune modulatory properties which can be exploited in the context of immunotherapy. The purpose of this study was to determine the feasibility and immunogenicity of combinations of such an immunomodulatory chemotherapeutic agent with immunotherapy, p53 synthetic long peptide (SLP) vaccine and Pegintron (IFN-α) in patients with platinum-resistant p53-positive epithelial ovarian cancer (EOC). Experimental design : This is a phase 1/2 trial in which patients sequential 6 cycles of gemcitabine (1000 mg/kg 2 iv; n = 3), gemcitabine with Pegintron before and after the first gemcitabine cycle (Pegintron 1 μg/kg sc; n = 6), and gemcitabine and Pegintron combined with p53 SLP vaccine (0.3 mg/peptide, 9 peptides; n = 6). At baseline, 22 days after the 2 nd and 6 th cycle, blood was collected for immunomonitoring. Toxicity, CA-125, and radiologic response were evaluated after 3 and 6 cycles of chemotherapy. Results : None of the patients enrolled experienced dose-limiting toxicity. Predominant grade 3/4 toxicities were nausea/vomiting and dyspnea. Grade 1/2 toxicities consisted of fatigue (78%) and Pegintron-related flu-like symptoms (72%). Gemcitabine reduced myeloid-derived suppressor cells ( p = 0.0005) and increased immune-supportive M1 macrophages ( p = 0.04). Combination of gemcitabine and Pegintron stimulated higher frequencies of circulating proliferating CD4+ and CD8+ T-cells but not regulatory T-cells. All vaccinated patients showed strong vaccine-induced p53-specific T-cell responses. Conclusion : Combination of gemcitabine, the immune modulator Pegintron and therapeutic peptide vaccination is a viable approach in the development of combined chemo-immunotherapeutic regimens to treat cancer.

Objective: The purpose of the study was to compare early changes in blood flow (BF) and glucose metabolism (MRglu) in metastatic breast cancer lesions of patients treated with chemotherapy. Methods: Eleven women with stage IV cancer and lesions in breast, lymph nodes, liver, and bone were scanned before treatment and after the first course of chemotherapy. BF, distribution volume of water (V-d), MRglu/BF ratio, MRglu and its corresponding rate constants K-1 and k(3) were compared per tumor lesion before and during therapy. Results: At baseline, mean BF and MRglu varied among different tumor lesions, but mean V-d was comparable in all lesions. After one course of chemotherapy, mean MRglu decreased in all lesions. Mean BF decreased in breast and node lesions and increased in bone lesions. V-d decreased in breast and nodes, but did not change in bone lesions. The MRglu/BF ratio decreased in breast and bone lesions and increased in node lesions. In patients with multiple tumor lesions BF and MRglu response could be very heterogeneous, even within similar types of metastases. BF and MRglu increased in lesions of patients who experienced early disease progression or showed no response during clinical follow-up. Conclusion: BF and MRglu changes separately give unique information on different aspects of tumor response to chemotherapy. Changes in BF and MRglu parameters can be remarkably heterogeneous in patients with multiple lesions.

Results of standard multimodality treatment for locally advanced breast cancer (LABC) are still disappointing, due to a persistent high risk of relapse and death with longer-term follow-up. Increasing knowledge of tumour immunology provides the basis for new strategies in clinical trial design. Chemotherapy reduces tumor mass and tumor-derived immunosuppressive factors and, at the same time, causes release of tumor antigens; thereby favouring immune activation. An intermediate high-dose chemotherapy schedule with doxorubicin and cyclophosphamide, in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) has been developed. Long-term neoadjuvant application of this regimen may overcome the dysfunction of the immune system and help to eradicate the tumor. Furthermore, tumor-derived antiangiogenic factors might inhibit outgrowth of micrometastases. This review aims to discuss current experience with LABC treatment, taking into account therapeutic alternatives and biological concepts tested in an international phase III trial; the Spinoza Trial.

Summary. A prospective study was performed, comparing gallium scintigraphy (67Ga) and positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (18FDG), to monitor the response of aggressive non-Hodgkin's lymphoma during treatment. 67Ga and 18FDG scans were performed in 26 patients after two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy. The scans were reviewed independently by four experienced nuclear physicians, who were blinded for the alternative scan technique and follow-up. Eleven out of 26 patients remained free from progression with a mean follow up of 25 ± 5 months, whereas 14 patients relapsed, and one died of lung cancer. Interobserver variation was significantly greater for 67Ga than for 18FDG PET. Some 64% of patients who had a negative early restaging 18FDG PET remained free from progression versus 50% of patients with negative 67Ga scans. Only 25% of patients with a positive PET remained disease free versus 42% of 67Ga-positive patients. Time to progression was associated with 18FDG PET results, but not with those by 67Ga. 18FDG PET had better test characteristics than 67Ga for the evaluation of early response in aggressive non-Hodgkin's lymphoma patients.

Background It is a challenge for oncologists to distinguish patients with breast cancer who can forego adjuvant systemic treatment without negatively affecting survival from those who cannot. Risk prediction models (RPMs) have been developed for this purpose. Oncologists seem to have embraced RPMs (particularly Adjuvant!) in clinical practice and often use them to communicate prognosis to patients. We performed a systematic review of published RPMs and provide an overview of the prognosticators incorporated and reported clinical validity. Subsequently, we selected the RPMs that are currently used in the clinic for a more in-depth assessment of clinical validity. Finally, we assessed lay comprehensibility of the reports generated by RPMs. Methods Pubmed, EMBASE, and Web of Science were searched. Two reviewers independently selected relevant articles and extracted data. Agreement on article selection and data extraction was achieved in consensus meetings. Results We identified RPMs based on clinical prognosticators (N = 6) and biomolecular features (N = 14). Generally predictions from RPMs seem to be accurate, except for patients ≤ 50 years or ≥ 75 years at diagnosis, in addition to Asian populations. RPM reports contain much medical jargon or technical details, which are seldom explained in lay terms. Conclusion The accuracy of RPMs' prognostic estimates is suboptimal in some patient subgroups. This urgently needs to be addressed. In their current format, RPM reports are not conducive to patient comprehension. Communicating survival probabilities using RPM might seem straightforward, but it is fraught with difficulties. If not done properly, it can backfire and confuse patients. Evidence to guide best communication practice is needed.

Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron (Fe(3+)). Because Fe(3+) is needed for ribonucleotide reductase activity--and thus DNA synthesis--gallium can inhibit DNA production and cell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, in vitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activity against HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials, to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominately to serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patient with advanced HCC (20 × 10 cm primary tumor, ascites around liver and spleen, resistant to Nexavar(®) (sorafenib)), whose cancer was highly gallium-avid in a (67)Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patient had a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation-related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor.

Purpose Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter 11C. Non-invasive measurements of [11C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [11C]docetaxel in humans. Methods Biodistribution of [11C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [11C]docetaxel uptake) or CT (low [11C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software. Results Gall bladder and liver demonstrated high [11C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 ± 9%. [11C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [11C]docetaxel uptake in tumours was moderate and highly variable between tumours. Conclusion The effective dose of [11C]docetaxel was 4.7 µSv/MBq. As uptake in normal lung is low, [11C]docetaxel may be a promising tracer for tumours in the thoracic region.

The use of calcium antagonists as multidrug resistance reversing agents is limited by acute cardiac toxicity which, for verapamil, becomes prohibitive when concentrations in plasma approach those required in vitro for its action. A new calcium antagonist, bepridil, is as active as verapamil in reversing drug resistance in vitro . In addition, bepridil has some more favourable pharmacological properties compared with verapamil and other calcium antagonists. 14 patients with progressive advanced cancer, resistant to doxorubicin or epirubicin, were treated with the same anthracycline in combination with bepridil. Bepridil was administered in a continuous 36 h infusion at 22 mg/kg/36 h, with a dose scheme which should result in a steady state plasma concentration of approximately 5 μmol/l, able to reverse anthracycline resistance in vitro . Pharmacokinetic studies demonstrated a median bepridil plasma concentration of 5.3 μmol/l (range 2.6–19.3 μmol/l, at the time of administration of the anthracycline. No acute cardiac toxicity was observed and apparently bepridil did not induce an increase or change in anthracycline toxicity. However, 2 patients developed overt chronic heart failure after treatment discontinuation, which caused 1 patient's death, and a significant reduction in left ventricular ejection fraction was seen in 4 patients. This chronic cardiac toxicity could be related to the total anthracycline dose received. 5 patients attained short lasting minor responses, 3 had stable disease and 6 progressed. Immunohistochemical studies in 7 tumours failed to reveal P-glycoprotein expression. Further trials with escalating doses of bepridil in combination with multiple drug resistance related anticancer agents are warranted.

Purpose Patients with adenocarcinoma of unknown primary origin (ACUP) constitute approximately 4% of all malignancies. For effective treatment of these patients, it is considered optimal to identify the primary tumor origins. Currently, the success rate of the diagnostic work-up is only 20% to 30%. Our goal was to evaluate the contribution of gene expression profiling for routine clinical practice in patients with ACUP. Patients and Methods Formalin-fixed, paraffin-embedded (FFPE) samples were obtained from 84 patients with a known primary adenocarcinoma and from 38 patients with ACUP. An extensive immunohistochemical panel classified 16 of the patients with ACUP, whereas 22 patients remained unclassified for their histogenetic origin. Information about staging procedures and clinical follow-up were available in all patient cases. The expression data were analyzed in relation to clinicopathologic variables and immunohistochemical results. Results The gene expression–based assay classified the primary site correctly in 70 (83%) of 84 patient cases of primary and metastatic tumors of known origin, with good sensitivity for the majority of the tumor classes and relatively poor sensitivity for primary lung adenocarcinoma. Gene expression profiling identified 15 (94%) of 16 patients with initial ACUP who were classified by immunohistochemistry, and it made a valuable contribution to a potential site of origin in 14 of the 22 patients with ACUP. Conclusion The gene expression platform can classify correctly from FFPE samples the majority of tumors classes both in patients with known primary and in patients with ACUP. Therefore, gene expression profiling represents an additional analytic approach to assist with the histogenetic diagnosis of patients with ACUP.

Item does not contain fulltext BACKGROUND: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8.5 months in the observation group and 11.7 months in the maintenance group (HR 0.67, 95% CI 0.56-0.81, p

Objectives: To prospectively investigate determinants of the accuracy of staging axillary lymph nodes in breast cancer using [F-18]fluorodeoxyglucose positron emission tomography (FDG PET). Methods: Patients with primary operable breast cancer underwent FDG PET of the chest followed by sentinel node biopsy (SNB, n = 47) and/or complete axillary lymph node dissection (ALND, n = 23). PET scans were independently interpreted by three observers in a blinded fashion with respect to the FDG avidity of the primary tumor and the axillary status. The results were compared to histopathological analyses of the axillary lymph nodes. Clinicians were blinded to the PET results. Results: Axillary lymph node specimens and FDG PET scans were evaluated in 70 patients (59% cT1). Overall, 32 (46%) had lymph node metastases as established bv SNB (18/47) or ALND (14/23), 20 of which were confined to a single node. The overall sensitivity of FDG PET was 25%, with a specificity of 97%. PET results were false-negative in all 18 positive SNBs and true-positive in 8/14 in the ALND group. The performance of FDG PET depended on the axillary tumor load and the FDG avidity of the primary tumor. Intense uptake in the primary tumor was found in only 57% of the patients, and this was independent of the size. There was excellent interobserver agreement of visual assessment of FDG uptake in primary tumor and axillary lymph nodes. Conclusions: The sensitivity of FDG PET to detect occult axillary metastases in operable breast cancer was low, and it was a function of axillary tumor load and FDG avidity of the primary tumor. Even though the clinical relevance of occult disease detected by SNB needs to be confirmed, it is suggested that FDG PET in these patients should be focused on exploiting its nearly perfect specificity and the potential prognostic relevance of variable FDG uptake.

TPS10632 Background: An 18-gene expression profile, ColoPrint, has been developed for identifying colon cancer patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature was validated in public datasets and independent patient cohorts (stage II and III patients). Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) (median follow-up 70 months). ColoPrint classifies 65% of stage II patients as Low Risk. The 3-year RFS was 91% for Low Risk and 74% for High Risk patients with a HR of 2.9 (p=0.001). ColoPrint was the only significant prognostic marker in the subgroup of patients with T3-MSS phenotype (Tabernero, ASCO GI 2012). Methods: A blinded prospective trial, PARSC (Prospective study for the Assessment of Recurrence risk in Stage II colon cancer patients) using ColoPrint has been initiated. Objectives are: (1)To validate the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage II colon cancer. (2) To compare the risk assessment in stage II patients using the ColoPrint profile vs a clinical risk assessment based on Investigator’s assessment of risk and ASCO high-risk recommendations. (3) To investigate therapy as a potential confounding factor for ColoPrint results. (4) To assess the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage III colon cancer. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II and III, no prior neo-adjuvant therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician adhering to National Comprehensive Cancer Network (NCCN)-approved regimens or a recognized alternative (blinded for ColoPrint result). The trial started in Sept. 2008 with currently 32 participating sites in 11 countries. Thus far, 340 eligible stage II and 280 stage III patients have been enrolled. The aim is to enroll 575 stage II patients. Clinical trial registry number: NCT00903565.