From bench to bedside

The adaptive immune system has been the main focus of immunological strategies in oncology with only more recent approaches targeting innate immunity. Endosomal toll-like receptors (TLR-7, TLR-9) activate innate immune responses by signaling damage-associated molecular patterns (DAMP) from decaying tumor cells. This has led to the development of DNA-based TLR-9 agonists, which induce antitumor activity through innate and subsequent adaptive immune responses. Early clinical trials with CpG-ODN as TLR-9 agonists were associated with unfavorable tolerability and narrow clinical efficacy, leading to failure in pivotal trials. dSLIM®, the active ingredient of MGN1703, is a DNA-based, radically different molecular alternative to CpG-ODN, which results in genuine antitumor immunomodulation. Preclinical and clinical studies of MGN1703 have confirmed that this TLR-9 agonist has therapeutic potential in a variety of solid tumors, while long-term treatment with high doses was very well tolerated. A pivotal trial of first-line maintenance treatment with MGN1703 in patients with metastatic colorectal cancer is underway

Adjuvante Therapie des Kolonkarzinoms

Adjuvant Therapy in Colon Cancer The goal of improving adjuvant treatment can be reached in two ways: firstly, by developing more effective drugs and protocols and, secondly, by selecting suitable patients on the basis of clinical and molecular factors. In UICC (Union internationale contre le cancer) stage II, microsatellite instability (MSI) is a strong prognostic factor. Whether it can also be used as a predictive marker is currently a matter of controversy because the available data are contradictory. The question whether or not the MSI status should be checked before treatment decisions are made in stage II patients can therefore not be clearly answered at present. For adjuvant treatment in stage III, with capecitabine/oxaliplatin (XELOX) there is now a new protocol available that is based on the orally administered prodrug capecitabine. With regard to the question of how much older patients in this stage may also benefit from a combination chemotherapy, new - and contradictory - data have emerged recently: firstly, preliminary results of two new studies have given rise to safety concerns and, secondly, an analysis by the `ACCENT Collaborative Group' indicated lower efficacy of the `newer' adjuvant protocols in older people. These findings, however, have now been called into question as a result of a new subgroup analysis from the XELOXA study. The expert group therefore recommended that the decision whether to treat patients older than 70 years with an ( oral) fluoropyrimidine alone or in combination with oxaliplatin should be based on clinical parameters such as biological age and comorbidities

Spezielle Therapiesituationen beim metastasierten kolorektalen Karzinom

Specific Treatment Situations in Metastatic Colorectal Cancer As far as the management of primary resectable liver metastases is concerned, three approaches are currently competing with each other: surgery alone, surgery with pre- and postoperative chemotherapy, and surgery with postoperative chemotherapy alone. The core of the argument for pre- and postoperative chemotherapy in these patients is the European Organisation for Research and Treatment of Cancer (EORTC) 40983 study, which concluded that, in comparison with surgery alone, perioperative chemotherapy improved the 3-year progression-free survival (PFS) by 7 months. In contrast to this, there are two smaller studies - at a somewhat lower strength of evidence - indicating that adjuvant chemotherapy extends PFS by 9.1 months compared with surgery alone. In Germany, the adjuvant approach continues to be favored in many places; this can also be seen in the formulation of the S3 guideline. In patients with unresectable liver metastases - with the associated difficulty of classification due to the lack of clear and definitive criteria preoperative systemic therapy to induce `conversion' is indicated, in order to allow secondary resection. In KRAS wild-type tumors, high response rates ( in terms of a reduction in size of the metastases, such as according to RECIST ( Response Evaluation Criteria in Solid Tumors)) and a high conversion rate are achieved using a cetuximab/chemotherapy combination. Triple chemotherapy combinations with 5-fluorouracil (5-FU), oxaliplatin and irinotecan also produce high response rates. Bevacizumab/chemotherapy combinations have led to a high number of complete and partial pathohistological remissions in phase II studies; these seem to correlate with long survival times. In the absence of long-term survival data, it therefore seems to remain unclear as to what is the best parameter to use in order to assess the success of preoperative treatment. Lung metastases, too, or local peritoneal carcinomatosis can nowadays be operated on in selected patients with a good prospect of long-term remission or even cure. The surgery should, however, generally only be carried out in experienced centers, especially in the case of peritoneal carcinomatosis. For synchronous metastasization, the appropriate management depends on the size and extent of liver metastases and of the primary tumor. Small, peripherally lying and safely resectable liver metastases can be removed before or at the same time as the primary tumor, especially if a hemicolectomy is being carried out. If the metastases are unresectable and there is no bleeding or stenosis, the primary tumor can also be left in situ and systemic chemotherapy can be carried out first. However, it should be borne in mind that, according to current data, palliative resection of the primary tumor combined with systemic therapy leads to longer overall survival than does chemotherapy alone. Whether resection or chemotherapy should be done first therefore depends on the patient's clinical situation

Severe thrombocytosis and anemia associated with celiac disease in a young female patient: a case report

<p>Abstract</p> <p>Introduction</p> <p>Platelet counts exceeding 1.000 × 10³/μl are usually considered secondary to another cause, particularly to chronic myeloproliferative disease (CMPD). Reactive thrombocytosis due to iron deficiency rarely exceeds platelet counts of 700 × 10³/μl.</p> <p>Case presentation</p> <p>Here we report the case of a young woman presenting with clinical signs of severe anemia. Laboratory findings confirmed an iron-deficiency anemia associated with severe thrombocytosis of 1703 × 10³/μl. Macroscopic gastrointestinal and genitourinary tract bleeding was excluded. The excessive elevation of platelets, slightly elevated lactate dehydrogenase and slightly elevated leukocytes along with the absence of other inflammation parameters raised the suspicion of an underlying hematological disease. However, bone marrow evaluation could not prove the suspected diagnosis of a CMPD, especially essential thrombocythemia (ET). In the further clinical course the platelet count returned to normal after raising the hemoglobin to a level close to normal range with erythrocyte transfusion, and normalization of serum iron and decline of erythropoietin. Finally, following small bowel biopsy, despite the absence of typical clinical signs, celiac disease was diagnosed. After discharge from hospital the patient was commenced on a gluten-free diet and her hemoglobin almost completely normalized in the further follow-up period.</p> <p>Conclusion</p> <p>This case illustrates the rare constellation of an extreme thrombocytosis most likely secondary to iron deficiency due to celiac disease. This represents, to the best of the authors' knowledge, the highest reported platelet count coincident with iron deficiency. A potential mechanism for the association of iron-deficiency anemia and thrombocytosis is discussed. Even in the presence of 'atypically' high platelets one should consider the possibility of reactive thrombocytosis. Extreme thrombocytosis could emerge in the case of iron deficiency secondary to celiac disease.</p

a randomized, placebo-controlled phase II AIO trial with serum biomarker program

Background As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. Methods This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. Results Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed. Conclusions Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti- angiogenic RTK inhibitors are warranted. Trial registration This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland- Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer A Secondary Analysis of the AVANT Trial

IMPORTANCE: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. OBJECTIVE: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. INTERVENTION: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. MAIN OUTCOMES AND MEASURES The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. RESULTS The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. CONCLUSIONS AND RELEVANCE: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited

Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database

Purpose: Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods: Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results: Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion: A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis Show less Jun Yin*, Shaheenah Dawood*, Romain Cohen, Jeff Meyers, John Zalcberg, Takayuki Yoshino, Matthew Seymour, Tim Maughan, Leonard Saltz, Eric Van Cutsem, Alan Venook, Hans-Joachim Schmoll, Richard Goldberg, Paulo Hoff, J. Randolph Hecht, Herbert Hurwitz, Cornelis Punt, Eduard Diaz Rubio, Miriam Koopman, Chiara Cremolini, Volker Heinemann, Christophe Tournigard, Carsten Bokemeyer, Charles Fuchs, Niall Tebbutt, John Souglakos, Jean-Yves Doulliard, Fairooz Kabbinavar, Benoist Chibaudel, Aimery de Gramont, Qian Shi, Axel Grothey, Richard AdamsFirst Published June 30, 2021 Research Article https://doi.org/10.1177/17588359211020547 Article information Article has an altmetric score of 7 Open AccessCreative Commons Attribution, Non Commercial 4.0 License Article Information Volume: 13 Article first published online: June 30, 2021; Issue published: January 1, 2021 Received: December 29, 2020; Accepted: May 05, 2021 Jun Yin* Department of Health Sciences Research, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA Shaheenah Dawood* Mediclinic City Hospital: North Wing, Dubai Health Care City, Dubai UAE Romain Cohen Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA Jeff Meyers Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA John Zalcberg School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia Takayuki Yoshino Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan Matthew Seymour NIHR Clinical Research Network, Leeds, UK Tim Maughan CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, UK Leonard Saltz Memory Sloan Kettering Cancer Center, New York, NY, USA Eric Van Cutsem Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium Alan Venook Department of Medicine, The University of California San Francisco, San Francisco, CA, USA Hans-Joachim Schmoll Klinik fur Innere Med IV, University Clinic Halle, Saale, Germany Richard Goldberg Department of Oncology, West Virginia University, Morgantown, WV, USA Paulo Hoff Centro de Oncologia de Brasilia do Sirio Libanes: Unidade Lago Sul, Siro Libanes, Brazil J. Randolph Hecht Ronald Reagan UCLA Medical Center, UCLS Medical Center, Santa Monica, CA, USA Herbert Hurwitz Duke Cancer Institute, Duke University, Durham, NC, USA Cornelis Punt Department of Medical Oncology, University of Amsterdam, Amsterdam, The Netherlands Eduard Diaz Rubio Department Oncology, Hospital Clínico San Carlos, Madrid, Spain Miriam Koopman Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands Chiara Cremolini Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy Volker Heinemann Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany Christophe Tournigard Hopital Henri Mondor, Creteil, France Carsten Bokemeyer Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Charles Fuchs Director of Yale Cancer Center, Boston, MA, USA Niall Tebbutt Sydney Medical School, University of Sydney, Sydney, Australia John Souglakos University of Crete, Heraklion, Greece Jean-Yves Doulliard University of Nantes Medical School, Nantes, France Fairooz Kabbinavar UCLA Medical Center, Santa Monica, CA, USA Benoist Chibaudel Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France Aimery de Gramont Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France Qian Shi Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA Axel Grothey West Cancer Center, Germantown, TN, USA Richard Adams Cardiff University and Velindre Cancer Center, Cardiff, UK Corresponding Author: [email protected] *Co-first authors. https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). Abstract Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland (p = 0.0034 and p < 0.001, respectively), with median difference of 3–4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients (p < 0.001). Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies

Metastatic colorectal cancer outcomes by age among ARCAD first- and second-line Clinical trials

Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy

Evaluation of intratumoral response heterogeneity in metastatic colorectal cancer and Its impact on patient overall survival: findings from 10,551 patients in the ARCAD database

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes