Gender differences in tumor characteristics, treatment allocation and survival in stage I-III pancreatic cancer: a nationwide study.

INTRODUCTION: Sex and gender are modulators of health and disease and may have impact on treatment allocation and survival in patients with cancer. In this study, we analyzed the impact of sex and gender on treatment allocation and overall survival in patients with stage I-III pancreatic cancer. METHODS: Patients with stage I-III pancreatic cancer diagnosed between 2015 and 2020 were selected from the nationwide Netherlands Cancer Registry. Associations between sex and gender and the probability of receiving surgical and/or systemic treatment were examined with multivariable logistic regression analyses. Overall survival was assessed with log rank test and multivariable Cox proportional hazard analysis. RESULTS: Among 6855 patients, 51.2 % were female. Multivariable logistic regression analyses with adjustment for known confounders (age, performance status, comorbidities, tumor location, tumor stage and previous malignancies) showed that females less often received systemic chemotherapy compared to males (OR 0.799, 95 %CI 0.703-0.909, p < .001). No difference was found in the probability for undergoing surgical resection. Furthermore, females had worse overall survival compared to males (median OS 8.5 and 9.2 months respectively, 95 %CI 8.669-9.731). CONCLUSION: This nationwide study found that female patients with stage I-III pancreatic cancer significantly less often received systemic treatment and had worse overall survival as compared to males. Disparities in pancreatic cancer care can be decreased by recognizing and resolving potential obstacles or biases in treatment decision-making.

ESMO Congress 2021: highlights from the EORTC gastrointestinal tract cancer group's perspective.

There has been no major change of practice in gastrointestinal oncology at the European Society for Medical Oncology (ESMO) symposium 2021, but confirmation that immunotherapy in combination with chemotherapy has become standard of care in several indications. The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Track Cancer Group has selected important phase II and III trials presented during the symposium across all gastrointestinal cancers as well as early reports on new drugs or new combinations that may change practice in the future.

Gender medicine and oncology: report and consensus of an ESMO workshop.

BACKGROUND: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. DESIGN: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. RESULTS: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. CONCLUSION: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.

Kinetics of Rituximab Excretion into Urine and Peritoneal Fluid in Two Patients with Nephrotic Syndrome.

Clinical observations suggest that treatment of Rituximab might be less effective in patients with nephrotic range proteinuria when compared to nonnephrotic patients. It is conceivable that the reason for this is that significant amounts of Rituximab might be lost in the urine in a nephrotic patient and that these patients require a repeated or higher dosage. However, this has not been systematically studied. In this case report we describe two different patients with nephrotic range proteinuria receiving Rituximab. The first patient received Rituximab for therapy resistant cryoglobulinemic membranoproliferative glomerulonephritis and the other for second line treatment of Felty's syndrome. We employed flow cytometry to determine the amount of Rituximab excretion in both urine and peritoneal fluid specimens in these patients following administration of Rituximab. We found that a significant amount of Rituximab is lost from the circulation by excretion into the urine. Furthermore we saw a close correlation of the excretion of Rituximab to the excretion of IgG molecules suggesting selectivity of proteinuria as the determining factor of Rituximab excretion. Further larger scale clinical studies could have the potential to evaluate an optimal cut-off value of IgG urinary loss before a possible administration of Rituximab therefore contributing to a more individualized treatment approach in patients with nonselective and nephrotic range proteinuria.

Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29).

BACKGROUND: Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. PATIENTS AND METHODS: Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. RESULTS: A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. CONCLUSIONS: No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. CLINICALTRIALSGOV: NCT01005199.

[News and perspectives in the treatment of advanced gastric and colorectal cancers]. / Nouveautés et perspectives dans la prise en charge des cancers colorectaux et gastriques avancés.

Colorectal and gastric cancers are the fourth and third leading causes of cancer death world-wide. Unfortunately, gastric cancer is usually diagnosed at an advanced stage after becoming metastatic in distant sites, so that palliative therapy is the mainstay of treatment. Major progress in the understanding of the biology, the development of valid biomarkers and molecular targeted drugs have improved the treatment options and prognosis of both cancers significantly in the last years. Here, we review the current standards of care for patients with advanced and metastatic colorectal and gastric cancer and outline the perspectives for the future.

[Interventional radiology procedures for malignancies of the liver: ablation procedures]. / Traitement des tumeurs malignes du foie par radiologie interventionnelle: techniques ablatives.

Percutaneous ablative procedures allow curative treatment of stage BCLC 0 or BCLC A hepatocellular carcinoma, as well as liver metastases of colorectal cancer. Several methods exist including radiofrequency ablation, the most commonly used. These techniques can be used in combination with surgical excision or alone if surgery is contraindicated. They are associated with significantly reduced mortality as compared to surgery.

[Interventional radiology procedures for malignancies of the liver treatment: Intraarterial procedures]. / Traitement des tumeurs maligne du foie par radiologie interventionnelle: techniques intra-artérielles.

Intraarterial procedures such as chemoembolization and radioembolization aim for the palliative treatment of advanced hepatocellular carcinoma (stage BCLC B and C with tumoral portal thrombosis). The combination of hepatic intraarterial chemotherapy and systemic chemotherapy can increase the probability of curing colorectal cancer with hepatic metastases not immediately accessible to surgical treatment or percutaneous ablation.

Esophagogastric cancer: integration of targeted therapies into systemic chemotherapy.

Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER-2 status in the tumor. Trastuzumab in combination with cisplatin/5-fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer.

[Anti-angiogenic therapies for metastatic colorectal, breast and lung cancer: benefits and risks]. / Traitements antiangiogéniques des cancers métastatiques du côlon et du rectum, du sein et du poumon: bénéfices et risques.

Anti-angiogenic therapies have recently enriched the therapeutic armentarium against the most common cancers. Among these, bevacizumab, a monoclonal antibody against vascular endothelial growth factor, is currently used most frequently. While the addition of bevacizumab to chemotherapy improves overall survival in first and second line treatment of metastatic colorectal cancer, its effect in metastatic breast cancer is limited to improvements in tumor response and progression-free-survival. In non-small-cell lung cancer, the positive results of a first American phase III study have not been confirmed by a second European study and are subject to controversies. A summary of the data concerning anti-angiogenic therapies in these three cancers is presented including safety information.

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials.

BACKGROUND: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. METHODS: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m(-2) over 30 min), oxaliplatin (65 mg m(-2)) and 5-FU (1500 mg m(-2) over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. RESULTS: Response rates were 19% (95% CI: 6-32%) and 23% (95% CI: 9-37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6-12.4) and 9.9 months (95% CI: 7.5-12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. CONCLUSION: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

[Immune reconstitution inflammatory syndrome (IRIS)]. / Das entzündliche Immunrekonstitutionssyndrom.

Overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens has been termed immune reconstitution inflammatory syndrome (IRIS). IRIS has mainly been described in patients with human immunodeficiency virus (HIV). However, IRIS is not restricted to HIV-patients and may occur in other infections and immunodeficiencies. In our clinic, we experienced a Whipple's disease patient with IRIS. IRIS occurs mainly after initiation of the highly active anti-retroviral therapy (HAART). Soon after HAART initiation, a marked inflammatory reaction can occur, triggered by restoration of pathogen-specific immunity. IRIS may be targeted by various infective antigens, dead or dying infective antigens, host antigens, tumor antigens and other antigens, giving rise to a heterogenous range of clinical manifestations. Treatment should be optimized for the associated condition and initiated immediately. Glucocorticoids should be used in patients who are severely affected by IRIS.

Gemcitabine, oxaliplatin and weekly high-dose 5-FU as 24-h infusion in chemonaive patients with advanced or metastatic pancreatic adenocarcinoma: a multicenter phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: Combinations of gemcitabine-oxaliplatin, gemcitabine-5-fluorouracil (5-FU) and 5-FU-oxaliplatin have synergistic activity and nonoverlapping adverse effect profiles. This trial assessed efficacy and safety of the triple combination gemcitabine-oxaliplatin and infusional 5-FU in patients with locally advanced (n=11) or metastatic (n=32) pancreatic adenocarcinoma. PATIENTS AND METHODS: A total of 43 eligible patients were treated with intravenous infusions of gemcitabine (900 mg/m2 over 30 min), followed by oxaliplatin (65 mg/m2 over 2 h) and 5-FU (1500 mg/m2 over 24 h) on days 1 and 8 of a 21-day cycle. RESULTS: Among all 43 patients, the tumor response rate was 19% [95% confidence interval 7% to 30%]. Nine patients were nonassessable for response because they did not complete the first two cycles of chemotherapy due to rapid disease progression, early death or treatment refusal. One patient was lost to follow-up. Median time to progression and overall survival were 5.7 and 7.5 months. Principal grade III/IV toxic effects were leucopenia in 11 (2%), thrombocytopenia in 13 (2%), nausea in 13 (0%), anorexia 16 (7%) and sensory neuropathy in 18 (0%) of patients. Unexpected cardiotoxicity was observed in this trial. CONCLUSION: Response rates and survival of the three-drug combination compare favorably with single-agent gemcitabine, but do not exceed results for doublets.

[Giant cell arteritis (temporal arteritis). Pathophysiology, immunology]. / Riesenzellarteriitis (Arteriitis temporalis, Arteriitis cranialis). Pathophysiologie, Immunologie.

The diagnosis of giant cell arteritis is established by temporal artery biopsy. The findings are those of a panarteritis with mononuclear infiltrates penetrating all layers of the arterial wall. Typically, activated T cells and macrophages are arranged in granulomas. Multinucleated giant cells, when present, are usually close to the fragmented internal elastic lamina. Often, the intimal layer is hyperplastic, leading to concentric occlusion of the lumen. The CD4(+) T cells are the main players in the disease process. T-cell activation in the arterial wall requires the presence of specialized antigen-presenting cells, the dendritic cells. The activation of monocytes and macrophages is responsible for the systemic inflammatory syndrome in giant cell arteritis and polymyalgia rheumatica. The blood vessel wall determines the site specificity of giant cell arteritis and provides the ground for the cell to cell interaction.

Chemotherapy for advanced gastric cancer.

BACKGROUND: Gastric cancer currently ranks second in global cancer mortality. Most patients are either diagnosed at an advanced stage, or develop a relapse after apparently curative operation. Apart from supportive measures, systemic chemotherapy is the only treatment option available in this situation. OBJECTIVES: To assess the effect of chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapy regimens in advanced gastric cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004), MEDLINE and EMBASE up to February 2004 and reference lists of articles. We also contacted pharmaceutical companies as well as national and international experts. SELECTION CRITERIA: Randomised controlled trials on systemic intravenous chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapies in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: Chemotherapy versus best supportive care consistently demonstrated a significant benefit in terms of overall survival in favour of the group receiving chemotherapy (Hazard Ratios (HR) 0.39; 95% confidence intervals (CI) 0.28 to 0.52). Combination versus single-agent chemotherapy provides evidence for a survival benefit in favour of combination chemotherapy (HR 0.85; 95% CI 0.76 to 0.96). Numbers included in these comparisons were 184 and 1338 participants respectively. This benefit is achieved at the price of increased toxicity in the combination chemotherapy arms. When comparing 5-FU/cisplatin-containing combination therapy regimens with anthracyclines versus those without anthracyclines (HR 0.77; 95% CI 0.62 to 0.95 based on 501 participants) and 5-FU/anthracycline-containing combinations with cisplatin versus those without cisplatin (HR 0.83; 95% CI 0.76 to 0.91 based on 1147 participants), there was a significant survival benefit for regimens including 5-FU, anthracyclines and cisplatin. AUTHORS' CONCLUSIONS: Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU, but the effect size is much smaller. Among the combination chemotherapy regimens studied, best survival results are achieved with regimens containing 5-FU, anthracyclines and cisplatin. In this category, ECF (epirubicin, cisplatin and continuous infusion 5-FU) is tolerated best.