Advanced Gastric Cancer: Current Treatment Landscape and a Future Outlook for Sequential and Personalized Guide: Swiss Expert Statement Article.

BACKGROUND: Gastric cancer is a leading cause of cancer-related deaths worldwide. Several treatment possibilities have been investigated, but only a few show clinically meaningful results. SUMMARY: Systemic treatment options for advanced gastric cancer (aGC) have evolved over the recent years, implementing the growing molecular knowledge of this heterogeneous disease. Molecular profiling (at least for HER-2-expression, microsatellite instability status, Epstein-Barr virus expression, and programmed death ligand-1 expression/combined positive score [CPS]) is recommended for all therapy-fit patients prior to the start of a systemic treatment and is crucial for decisions on treatment strategy and drug selection. Various examples like the application of trastuzumab in the HER-2-positive subgroup underline the benefits of this approach starting from the first-line setting. A combination of platinum and fluoropyrimidine remains the first-line chemotherapy backbone in the treatment of advanced gastric cancer. Triplet combinations adding taxanes to the doublet regimen are reserved for certain scenarios. Unfortunately, almost all patients who receive first-line treatment (with or without anti-HER-2 blockade) progress and <70% are eligible for a second-line therapy. The addition of monoclonal antibodies has substantially improved outcomes in this setting. As such, ramucirumab has led to significant and clinically meaningful advancements in the second-line treatment. Furthermore, immuno-oncology with checkpoint inhibition and immune stimulation has evolved in the field of aGC. Recent first-line data show a significant survival benefit in aGC patients with a CPS ≥ 5 under immunochemotherapy. Nonetheless, the impact of immunotherapy combinations and immunochemotherapy remains an area of investigation. Key Message: In this review, we highlight recent improvements in the treatment landscape of advanced gastric cancer, the heterogeneity of this disease, and possible personalized targets.

Is a change in patient-reported dysphagia after induction chemotherapy in locally advanced esophageal cancer a predictive factor for pathological response to neoadjuvant chemoradiation?

GOALS OF WORK: In patients with locally advanced esophageal cancer, only those responding to the treatment ultimately benefit from preoperative chemoradiation. We investigated whether changes in subjective dysphagia or eating restrictions after two cycles of induction chemotherapy can predict histopathological tumor response observed after chemoradiation. In addition, we examined general long-term quality of life (QoL) and, in particular, eating restrictions after esophagectomy. MATERIALS AND METHODS: Patients with resectable, locally advanced squamous cell- or adenocarcinoma of the esophagus were treated with two cycles of chemotherapy followed by chemoradiation and surgery. They were asked to complete the EORTC oesophageal-specific QoL module (EORTC QLQ-OES24), and linear analogue self-assessment QoL indicators, before and during neoadjuvant therapy and quarterly until 1 year postoperatively. A median change of at least eight points was considered as clinically meaningful. MAIN RESULTS: Clinically meaningful improvements in the median scores for dysphagia and eating restrictions were found during induction chemotherapy. These improvements were not associated with a histopathological response observed after chemoradiation, but enhanced treatment compliance. Postoperatively, dysphagia scores remained low at 1 year, while eating restrictions persisted more frequently in patients with extended transthoracic resection compared to those with limited transhiatal resection. CONCLUSIONS: The improvement of dysphagia and eating restrictions after induction chemotherapy did not predict tumor response observed after chemoradiation. One year after esophagectomy, dysphagia was a minor problem, and global QoL was rather good. Eating restrictions persisted depending on the surgical technique used.

Prospective, observational practice survey of applied skin care and management of cetuximab-related skin reactions: PROSKIN study.

PURPOSE: The study aimed to investigate strategies to prevent and treat cetuximab-induced skin reactions and their perceived effectiveness in patients with metastatic colorectal cancer (mCRC) and recurrent/metastatic squamous cell cancer of the head and neck (SCCHN). METHODS: This open-label, prospective observational study was conducted in Switzerland. RESULTS: A total of 125 patients were included (n = 91 mCRC, n = 34 SCCHN; mean age 63.3 years; 73.6% males). The frequency of acneiform rash grade ≥ 2 increased from 12.6% at week 2 to 21.7% at week 16. The proportion of patients who reported no skin reaction decreased from 75.6% at week 2 to 43.3% at week 16. The most frequently used skin products at any time of observation were moisturizing (77.6%), lipid-regenerating (56.8%) or urea-containing products (52%), systemic antibiotics (49.6%), and vitamin K1 cream (43.2%). There was no clear effectiveness pattern for all product classes: in given patients, either the product showed no effect at all or a moderate/strong effect, consistently over time. CONCLUSIONS: A great variety of low-cost general skin care products were commonly used. According to physician's preference, systemic antibiotics and vitamin K1 cream are an appropriate approach to prevent or treat cetuximab-related skin toxicity.

Vascular endothelial growth factor A amplification in colorectal cancer is associated with reduced M1 and M2 macrophages and diminished PD-1-expressing lymphocytes.

VEGFA is an angiogenic factor secreted by tumors, in particular those with VEGFA amplification, as well as by macrophages and lymphocytes in the tumor microenvironment. Here we sought to define the presence of M1/M2 macrophages, PD-1-positive lymphocytes and PD-L1 tumoral and stromal expression in colorectal cancers harboring VEGFA amplification or chromosome 6 polysomy. 38 CRCs of which 13 harbored VEGFA amplification, 6 with Chr6 polysomy and 19 with neutral VEGFA copy number were assessed by immunohistochemistry for CD68 (marker for M1/M2 macrophages), CD163 (M2 macrophages), programmed death 1(PD-1)- tumor infiltrating and stromal lymphocytes as well as tumoral and stromal PD-1 ligand (PD-L1) expression. CRCs with VEGFA amplification or Chr6 polysomy were associated with decreased M1/M2 macrophages, reduced PD-1-expressing lymphocyte infiltration, as well as reduced stromal expression of PD-L1 at the tumor front. Compared to intermediate-grade CRCs, high-grade CRCs were associated with increased M1/M2 macrophages and increased tumoral expression of PD-L1. Our results suggest that VEGFA amplification or Chr6 polysomy is associated with an altered tumor immune microenvironment.

Cancer-Related Fatigue in Patients With and Survivors of Hodgkin Lymphoma: The Impact on Treatment Outcome and Social Reintegration.

Purpose Cancer-related fatigue occurs frequently in patients with Hodgkin lymphoma (HL) and has a major impact on their quality of life. We hypothesized that severe fatigue (sFA) might have an impact on patients' treatment outcome and social reintegration. Methods Of 5,306 patients enrolled in the German Hodgkin Study Group's fifth generation of clinical trials in HL (HD13, HD14, and HD15; nonqualified and older [> 60 years] patients excluded), 4,529 provided data on health-related quality of life. We describe sFA (defined as a score ≥ 50 on the 0 to 100 scale from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) before and up to 9 years after therapy and analyze its impact on treatment outcome and social reintegration. Results The proportion of patients reporting sFA was 37% at baseline and ranged from 20% to 24% during follow-up. Baseline sFA was associated with significantly impaired progression-free survival and a trend to impaired overall survival, which can be overcome in patients receiving highly effective HL therapies as applied in our fifth-generation trials. Our analysis revealed a significant negative association of sFA and employment in survivors: 5 years after therapy, 51% and 63% of female and male survivors, respectively, with sFA were working or in professional education, compared with 78% and 90% without sFA, respectively ( P < .001 adjusted for age, sex, stage, baseline employment status, and treatment outcome). sFA was also associated with financial problems and the number of visits to a general practitioner and medical specialists. Conclusion sFA is an important factor preventing survivors from social reintegration during follow-up. This observation underscores the need to address fatigue as a significant diagnosis when treating patients with and survivors of cancer.

Swiss primary care physicians' knowledge, attitudes and perception towards genetic testing for hereditary breast cancer.

PURPOSE: The Swiss Institute for Applied Cancer Research's (SIAK) Network for Cancer Predisposition Testing and Counseling was established in 1999. To define its role in the care of individuals with inherited cancer predisposition, attitudes, knowledge and perception of primary care physicians towards genetic counseling and testing for hereditary breast cancer were examined. METHODS: A questionnaire was sent to 1391 primary care physicians in private practice in the German-speaking Canton of Zürich. RESULTS: 628 (45%) questionnaires were returned: 319/778 (41%) general practitioners, 156/367 (43%) internists, 118/218 (54%) obstetrician-gynecologists and 22/28 (76%) oncologists answered. Socio-demographic characteristics were: 74% males and 26% females with a mean age of 51 and a mean number of 14 years in private practice. Fifty-two percent of responding physicians approved of genetic susceptibility testing and seventy-seven percent would recommend it to individuals at risk if asked for it. Of the responding physicians, 47% wanted to disclose test results and discuss its consequences and 79% wanted to provide long term care and support, whereas only 36% and 9%, respectively, assigned these tasks to specialized cancer genetics services. Eight knowledge questions had to be answered: 290 (46%) gave 0-2 correct answers, 284 (45%) gave 3-5 and 54 (9%) gave 6-8 correct answers. CONCLUSIONS: Our findings demonstrate that the majority of responding primary care physicians in the Canton of Zürich approve of genetic testing for hereditary breast cancer and want to play a central role in the management of these families, but lack the knowledge to do so efficiently. Our findings underline the importance of educational programs in cancer genetics.

Cetuximab in combination with chemoradiotherapy before surgery in patients with resectable, locally advanced esophageal carcinoma: a prospective, multicenter phase IB/II Trial (SAKK 75/06).

PURPOSE: This multicenter phase IB/II trial investigated cetuximab added to preoperative chemoradiotherapy for esophageal cancer. PATIENTS AND METHODS: Patients with resectable, locally advanced esophageal cancer received two 3-week cycles of induction chemoimmunotherapy (cisplatin 75 mg/m(2) day 1, docetaxel 75 mg/m(2) day 1, cetuximab 250 mg/m(2) days 1, 8,15 [400 mg/m(2) loading dose]) followed by chemoimmunoradiation therapy (CIRT) and surgery. CIRT consisted of 45 Gy radiotherapy (RT) plus concurrent cisplatin 25 mg/m(2) and cetuximab 250 mg/m(2) weekly for 5 weeks in cohort 1. If fewer than three of seven patients experienced limiting toxicity (LT), the next seven patients also received docetaxel (20 mg/m(2) weekly × 5). If fewer than three patients experienced LTs, 13 additional patients were treated at this dose. RESULTS: In total, 28 patients (median age, 64 years) with predominantly node-positive (82%) esophageal adenocarcinoma (15 patients) or squamous cell carcinoma (13 patients) were enrolled and 24 (86%) completed the entire trimodal therapy. During CIRT, no LT occurred, rash was not exacerbated within the RT field, and the main grade 3 toxicities were esophagitis (seven patients), anorexia (three), fatigue (three), and thrombosis (two). Surgery (R0 resection) was performed in 25 patients. Anastomotic leakage occurred in three patients: two recovered spontaneously and one successfully underwent re-operation. There were no deaths at 30 days and no treatment-related mortality after 12 months. Nineteen patients (68%) showed complete or near complete pathologic regression. CONCLUSION: Adding cetuximab to preoperative chemoradiotherapy is feasible without increasing postoperative mortality. Phase III investigation has begun based on the high histopathologic response and R0 resection rate.