What have we learnt from the past - would treatment decisions for GEP-NET patients differ between 2012 to 2016 by the new recommendations in 2022?

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors with a broad range of local and systemic treatment options. Still a lack of data regarding treatment sequences exists. The aim of this study was to analyse outcomes in GEP-NETs depending on stage and treatment steps and compare our treatment decisions to the latest treatment recommendations of European Society of Medical Oncology (ESMO) 2020 for GEP-NETs. METHODS: Patients were included in this retrospective single-center analysis from 2012-2016. All patients suffering from a GEP-NET, who were screened, treated or evaluated at ENETS Center in Zurich, Switzerland were included in analysis. Patients with any other diagnosis of NET were not included. We used Kaplan Meier estimator as well as Cox regression to compare survival rates between different sites of localization, grades or stages and treatment sequences. RESULTS: Overall, we identified 256 GEP-NETs, most in advanced stage (62%) and located in small intestine tract or pancreatic gland. Survival depended on stage, grade, primary site and duration of response for the early systemic treatment. On average patients underwent 2.6 different treatment modalities, mostly depending on stage and higher tumor grade. Surgery was performed early but also in advanced stages, usually followed by Somatostatine-Agonist modalities. In distant disease (Stage IV), we investigated a positive effect of PFS after treatment with Somatostatine Analogues (SSA) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21 - 0.97; p = 0.04) and systemic treatment (HR, 0.51; 95% CI, 0.26 - 0.99; p = 0.047) if patients underwent prior surgery or endoscopic resection. Kaplan Meier distributions predict shorter OS in distant disease (Stage IV), (Figure. 1; HR, 2.06; 95% CI, 1.46 - 2.89; log-rank test, p < 0.001). CONCLUSION: This retrospective analysis presents a great overview of all patients', disease and treatment characteristics of GEP-NETs at ENETS Center in Zurich, Switzerland. We illustrated survival (PFS) depending on implemented therapies. According to these findings, we formed a suggested treatment algorithm for advanced GEP-NETs, which does not differ from the latest treatment recommendation by ESMO guidelines for GEP-NETs. The results of this project may define GEP-NET patients' selection for upcoming clinical prospective studies.

Outcome of carcinoid heart syndrome in patients enrolled in the SwissNet cohort.

BACKGROUND: Carcinoid heart disease is a rare disease which develops in patients with functional neuroendocrine tumors in an advanced tumor state. Patients diagnosed with carcinoid heart disease have a poor longtime prognosis with respect to morbidity and mortality and long-term data on patient outcomes are lacking. METHODS AND RESULTS: In this retrospective study, we analyzed outcomes of 23 patients with carcinoid heart disease enrolled into the SwissNet database. We observed that early diagnosis with echocardiographic surveillance of carcinoid heart disease during the course of the neuroendocrine tumor disease was beneficial to overall survival of patients. CONCLUSION: Through nationwide patient enrollment, the SwissNet registry is a powerful data tool to identify, follow-up and evaluate long-term patient outcomes in patients with rare neuroendocrine tumor driven pathologies including carcinoid heart syndrome with observational methods enabling better therapy optimization to improve patient`s long-term perspectives and survival. In line with the current ESMO recommendations, our data proposes that heart echocardiography should be included as part of the general physical assessment in patients with newly diagnosed NET.

Lifestyle factors associated with inflammatory bowel disease: data from the Swiss IBD cohort study.

BACKGROUND: Various environmental risk factors have been associated with the pathogenesis of inflammatory bowel disease. In this study we aimed to identify lifestyle factors that affect the onset of Crohn's disease and ulcerative colitis. METHODS: 2294 patients from the Swiss IBD Cohort Study received a questionnaire regarding physical activity, nutritional habits and status of weight. In addition, a control group was formed comprising patients' childhood friends, who grew up in a similar environment. RESULTS: Overall, 1111 questionnaires were returned (response rate: 48.4%). Significantly more patients with inflammatory bowel disease reported no regular practice of sport during childhood and beginning of adulthood compared to the control group (p = 0.0001). No association between intake of refined sugar and onset of inflammatory bowel disease was observed. More patients with Crohn's disease compared to ulcerative colitis and controls suffered from overweight during childhood (12.8% vs. 7.7% and 9.7%, respectively; p = 0.027). CONCLUSIONS: Our study underlines the relevance of environmental factors in the development of inflammatory bowel disease. Our results imply a protective effect of physical activity regarding the onset of inflammatory bowel disease.

Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association.

In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome-ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

BACKGROUND & AIMS: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.

A higher ctDNA fraction decreases survival in regorafenib-treated metastatic colorectal cancer patients. Results from the regorafenib's liquid biopsy translational biomarker phase II pilot study.

The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of our study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next-generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and Eastern Cooperative Oncology Group. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 of 14 KRAS-positive tumors; in three patients without KRAS mutation in the respective tumors, acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (P = .022; hazard ratio 3.110 (95% confidence interval: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations in advanced cancer patients.

Combination of HAI-FUDR and Systemic Gemcitabine and Cisplatin in Unresectable Cholangiocarcinoma: A Dose Finding Single Center Study.

BACKGROUND: Unresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma. METHODS: Twelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m2 gemcitabine and predefined doses of cisplatin 25 mg/m2 on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1-14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported. RESULTS: The determined MTD for gemcitabine was 800 mg/m2. Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1-49), and median progression-free survival 10.1 months (range 2-40). CONCLUSIONS: Intravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.

Abdominal pain in patients with inflammatory bowel disease: association with single-nucleotide polymorphisms prevalent in irritable bowel syndrome and clinical management.

BACKGROUND: Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear. METHODS: Data of 857 UC and 1206 CD patients from the Swiss IBD Cohort Study were analysed. We tested the association of the maximum of the abdominal pain item of disease activity indices in UC and CD over the study period with 16 IBS-associated SNPs, using multivariate ANOVA models. RESULTS: In UC patients, the SNPs rs1042713 (located on the ADRB2 gene) and rs4663866 (close to the HES6 gene) were associated with higher abdominal pain levels (P = 0.044; P = 0.037, respectively). Abdominal pain was not associated with any markers of patient management in a model adjusted for confounders. In CD patients, higher levels of abdominal pain correlated with the number of physician contacts (P < 10-15), examinations (P < 10-12), medical therapies (P = 0.023) and weeks of hospitalisation (P = 0.0013) in a multivariate model. CONCLUSIONS: We detected an association between maximal abdominal pain in UC patients and two IBS-associated SNPs. Abdominal pain levels had a pronounced impact on diagnostic and therapeutic procedures in CD but not in UC patients.

Population-based SEER analysis of survival in colorectal cancer patients with or without resection of lung and liver metastases.

BACKGROUND: Approximately one third of all patients with CRC present with, or subsequently develop, colorectal liver metastases (CRLM). The objective of this population-based analysis was to assess the impact of resection of liver only, lung only and liver and lung metastases on survival in patients with metastatic colorectal cancer (mCRC) and resected primary tumor. METHODS: Ten thousand three hundred twenty-five patients diagnosed with mCRC between 2010 and 2015 with resected primary were identified in the Surveillance, Epidemiology and End Results (SEER) database. Overall, (OS) and cancer-specific survival (CSS) were analyzed by Cox regression with multivariable, inverse propensity weight, near far matching and propensity score adjustment. RESULTS: The majority (79.4%) of patients had only liver metastases, 7.8% only lung metastases and 12.8% metastases of lung and liver. 3-year OS was 44.5 and 27.5% for patients with and without metastasectomy (HR = 0.62, 95% CI: 0.58-0.65, P < 0.001). Metastasectomy uniformly improved CSS in patients with liver metastases (HR = 0.72, 95% CI: 0.67-0.77, P < 0.001) but not in patients with lung metastases (HR = 0.84, 95% CI: 0.62-1.12, P = 0.232) and combined liver and lung metastases (HR = 0.89, 95% CI: 0.75-1.06, P = 0.196) in multivariable analysis. Adjustment by inverse propensity weight, near far matching and propensity score and analysis of OS yielded similar results. CONCLUSIONS: This is the first SEER analysis assessing the impact of metastasectomy in mCRC patients with removed primary tumor on survival. The analysis provides compelling evidence of a statistically significant and clinically relevant increase in OS and CSS for liver resection but not for metastasectomy of lung or both sites.

The tumour microenvironment and immune milieu of cholangiocarcinoma.

Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.

Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of Colorectal Origin.

BACKGROUND: Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear. METHODS: Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction. RESULTS: Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination [development area under the curve (AUC) = 0.72, validation AUC = 0.70], calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes. CONCLUSION: RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.

Adjuvant treatment of resectable biliary tract cancer with cisplatin plus gemcitabine: A prospective single center phase II study.

BACKGROUND: Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC. METHODS: Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed. RESULTS: Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3-100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50-100) for cisplatin and 100% (IQR 75-100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0-33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8-62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts. CONCLUSION: Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients. TRIAL REGISTRATION: The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

Concurrent chemoradiotherapy vs. radiotherapy alone in locally advanced cervix cancer: A systematic review and meta-analysis.

The efficacy of concurrent chemoradiotherapy (CTRT) in locally advanced cervix cancer (LACC, stages IIB-IVA) is contentious. This is due to the variable extent of therapeutic benefit reported in different randomized clinical trials and meta-analyses that usually include all stages of cervix cancer. A systematic review and meta-analysis was therefore conducted to evaluate the efficacy of concurrent CTRT over radiotherapy (RT) alone, predominantly in LACC for the key endpoints; complete response (CR), long-term loco-regional control (LRC), overall survival (OS), grade III/IV acute and late toxicities. Six databases namely - PubMed, EMBASE, SCOPUS, Web of Science, Google Scholar and Cochrane library were explored and supplemented by hand-searching. Only prospective randomized trials conducted in LACC between concurrent CTRT and RT alone with no surgical interventions were included. Fourteen English language articles from 1788 citations were shortlisted for the final analysis. Of the 2445 patients evaluated (CTRT: n=1217; RT: n=1228), 95.7% had LACC and 96% had a squamous cell histology. Eight studies used cisplatin alone, 4 had cisplatin-based combination chemotherapy (CT) while 2 used mitomycin-C, either alone or in combination. CTRT improved the CR (+10.2%, p=0.027), LRC (+8.4%, p<0.001) and OS (+7.5%, p<0.001) over RT alone. However a 10.4% higher incidence of grade III/IV acute toxicities (p<0.001) was also evident with CTRT. Late toxicities in both groups were equivalent. Subgroup analysis and meta-regression did not reveal any significant advantage in outcomes between the 3 CTRT regimens. Thus, although concurrent CTRT provides conclusive therapeutic benefit over RT alone in LACC, the choice of CT agents should be based on their cost-effectiveness and the anticipated expenses for the management of any associated acute toxicities. This assumes importance particularly in resource-constrained low-middle-income countries with the highest burden of LACC, where majority of the patients meet the treatment costs as out-of-pocket expenses.

Impact of sex on treatment decisions and outcome in patients with neuroendocrine neoplasms.

Sex differences affect the management of several diseases in both male and female patients. However, the influence of sex on neuroendocrine neoplasms (NENs) has been scarcely investigated. Thus, this study aimed to compare tumor characteristics, treatment decisions, and overall survival in patients with NENs, stratified by sex. The retrospective analysis of the SwissNET cohort covered NENs of gastroenteropancreatic, pulmonary, or unknown origin from July 2014 to September 2022. The analysis included 1985 patients (46% female and 54% male). No significant difference in tumor grading was found between male and female patients. However, male patients presented with higher staging at time of diagnosis and with more lymph node and bone metastases. Surgery was performed more often in female compared to male patients (73.4% vs 68.7%, P = 0.023). Male patients received peptide receptor nuclide therapy (PRRT) earlier than female patients (7.8 months vs 13.1 months from time of diagnosis, P = 0.003). The median overall survival was significantly shorter for male compared to female patients (male: 18 years, female: not reached, P < 0.001, hazard ratio (HR) 1.55 (1.19-2.01), P = 0.001). Multivariable analyses revealed advanced age (HR 1.02 (1.01-1.04)), cancer of unknown origin (HR 2.01 (1.09-3.70)), higher grading (G3: HR 6.74 (4.22-10.76)), having metastases at the time of diagnosis (HR 2.11 (1.47-3.02)), and surgical treatment (HR 0.67 (0.48-0.93)) as independent predictors for overall survival. In conclusion, male sex was associated with worse outcome in NEN patients, likely due to more advanced tumor stage at the time of diagnosis. Further investigations are required to understand the underlying mechanisms of these sex differences.

Olaparib not cost-effective as maintenance therapy for platinum-sensitive, BRCA1/2 germline-mutated metastatic pancreatic cancer.

OBJECTIVE: To assess the cost-effectiveness and budget impact of olaparib as a maintenance therapy in platinum-responsive, metastatic pancreatic cancer patients harboring a germline BRCA1/2 mutation, using the Swiss context as a model. METHODS: Based on data from the POLO trial, published literature and local cost data, we developed a partitioned survival model of olaparib maintenance including full costs for BRCA1/2 germline testing compared to FOLFIRI maintenance chemotherapy and watch-and-wait. We calculated the incremental cost-effectiveness ratio (ICER) for the base case and several scenario analyses and estimated 5-year budget impact. RESULTS: Comparing olaparib with watch-and wait and maintenance chemotherapy resulted in incremental cost-effectiveness ratios of CHF 2,711,716 and CHF 2,217,083 per QALY gained, respectively. The 5-year costs for the olaparib strategy in Switzerland would be CHF 22.4 million, of which CHF 11.4 million would be accounted for by germline BRCA1/2 screening of the potentially eligible population. This would amount to a budget impact of CHF 15.4 million (USD 16.9 million) versus watch-and-wait. CONCLUSIONS: Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

Outcome analysis in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with Lu-177-DOTATATE.

Background: Patients with neuroendocrine tumors (NET) of the gastroenteropancreatic tract (GEP-NET) were effectively treated with peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTATATE in the NETTER-1 trial. The aim of this study was to assess the outcome of metastatic GEP-NET patients within a European Neuroendocrine Tumor Society (ENETS) certified center of excellence after this treatment. Methods: A total of 41 GEP-NET patients who received PRRT with Lu-177-DOTATATE between 2012 and 2017 at a single center were included in this analysis. Data on pre- and post-PRRT treatments [selective internal radiation therapy (SIRT), somatostatin analogue therapy (SSA), blood parameters, patient symptomatic burden and overall survival] was extracted from patient records. Results: Overall, PRRT was well tolerated and did not increase patient symptomatic burden. Blood parameters were not significantly affected by PRRT (means before and after therapy: hemoglobin: 125.4 vs. 122.3 mg/L, P=0.201; creatinine: 73.8 vs. 77.7 µmol/L, P=0.146), while leukocytes (6.6 vs. 5.6 G/L, P<0.01) and platelets (269.9 vs. 216.7 G/L, P<0.001) were significantly decreased yet without clinical significance in our study. Seven of 9 patients with SIRT treatment prior to PRRT were deceased (mortality odds ratio =4.083). The mortality odds ratio of patients with a pancreatic tumor and SIRT was 1.33 compared to patients with a different tumor origin. 6 of 15 patients (40%) with post-PRRT SSA were deceased (mortality odds ratio =0.429 without SSA after PRRT). Conclusions: Patients with advanced GEP-NET might benefit from PRRT with Lu-177-DOTATATE as it can provide a valuable treatment modality in advanced disease stages. Safety profiles of PRRT were manageable without increasing the symptomatic burden. SIRT before PRRT or lack of SSA after PRRT seem to impair the response and reduce survival.

Acupuncture for the prevention of chemotherapy-induced nausea and vomiting in cancer patients: A systematic review and meta-analysis.

PURPOSE: To assess the effectiveness and safety of acupuncture for the prevention of chemotherapy-induced nausea and vomiting (CINV), with a specific intention on exploring sources of between-study variation in treatment effects. METHODS: MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL, Chinese Biomedical Literature Database, VIP Chinese Science and Technology Periodicals Database, China National Knowledge Infrastructure, and Wanfang were searched to identify randomized controlled trials (RCTs) that compared acupuncture to sham acupuncture or usual care (UC). The main outcome is complete control (no vomiting episodes and/or no more than mild nausea) of CINV. GRADE approach was used to rate the certainty of evidence. RESULTS: Thirty-eight RCTs with a total of 2503 patients were evaluated. Acupuncture in addition to UC may increase the complete control of acute vomiting (RR, 1.13; 95% CI, 1.02 to 1.25; 10 studies) and delayed vomiting (RR, 1.47; 95% CI, 1.07 to 2.00; 10 studies) when compared with UC only. No effects were found for all other review outcomes. The certainty of evidence was generally low or very low. None of the predefined moderators changed the overall findings, but in an exploratory moderator analysis we found that an adequate reporting of planned rescue antiemetics might decrease the effect size of complete control of acute vomiting (p = 0.035). CONCLUSION: Acupuncture in addition to usual care may increase the complete control of chemotherapy-induced acute vomiting and delayed vomiting but the certainty of evidence was very low. Well-designed RCTs with larger sample sizes, standardized treatment regimens, and core outcome measures are needed.

Improvement of Lung NET Management through Standardized Care-A Swiss Nationwide Observational Study.

Typical (TC) and atypical carcinoids (AC) are the most common neuroendocrine tumors (NETs) of the lung. Because these tumors are rare, their management varies widely among Swiss centers. Our aim was to compare the management of Swiss patients before and after the publication of the expert consensus of the European Neuroendocrine Tumor Society (ENETS) in 2015. We used data from the Swiss NET registry from 2009 to 2021 with patients with TC and AC. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Overall, 238 patients were included, 76% (180) thereof with TC and 24% (58) with AC, including 155 patients before and 83 patients after 2016. An increase in the use of functional imaging was observed, 16% (25) before and 35% (29) after 2016, p < 0.001. The presence of SST2A-receptors was determined more often: 32% (49 times) before 2016 and 47% (39 times) after, p = 0.019. Concerning therapy, higher removal of lymph nodes after 2016 was observed, 54% (83) before versus 78% (65) after, p < 0.001. Median overall survival for patients with AC was significantly shorter, with 89 months compared to 157 months for patients with TC, p < 0.001. While the implementation of a more standardized approach was observed over the years, there is still room for amelioration in the management of TC and AC in Switzerland.

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma.

Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. Impact and implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy.

Orchestrating Treatment Modalities in Metastatic Pancreatic Neuroendocrine Tumors-Need for a Conductor.

Pancreatic neuroendocrine tumors (pNETs) are a vast growing disease. Over 50% of these tumors are recognized at advanced stages with lymph node, liver, or distant metastasis. An ongoing controversy is the role of surgery in the metastatic setting as dedicated systemic treatments have emerged recently and shown benefits in randomized trials. Today, liver surgery is an option for advanced pNETs if the tumor has a favorable prognosis, reflected by a low to moderate proliferation index (G1 and G2). Surgery in this well-selected population may prolong progression-free and overall survival. Optimal selection of a treatment plan for an individual patient should be considered in a multidisciplinary tumor board. However, while current guidelines offer a variety of modalities, there is so far only a limited focus on the right timing. Available data is based on small case series or retrospective analyses. The focus of this review is to highlight the right time-point for surgery in the setting of the multimodal treatment of an advanced pancreatic neuroendocrine tumor.