Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer.

The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal. Therefore, recalling the need for a better articulation of the patient-centered strategies of surveillance for individuals with germline CDH1 and other similar alterations, to offer comprehensive approaches for prevention, early diagnosis, and treatment. Accordingly, this chapter aims to discuss the value and the role of integrated oncological care in the era of oncology sub-specializations. Additionally, it sheds light on how the harmonization across the health providers can enhance patient care in this setting.

Pattern of progression of intrahepatic cholangiocarcinoma: Implications for second-line clinical trials.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC-06 trial reported the superiority of FOLFOX vs clinical observation as a second-line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post-progression survival (PPS), similar to hepatocellular carcinoma. METHODS: Multicentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH). RESULTS: We included 206 patients from 5 centres. The median OS was 14.1 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509-0.961], performance status >2.445 [1.788-3.344], permanent first-line discontinuation 16.072 [5.102-50.633], registration of ascites 2.226 [1.448-3.420] or bilirubin >3 mg/dl 3.004 [1.935-4.664] during the follow-up, and disease progression 2.523 [1.261-5.050]. The appearance of NEH independently predicted OS 2.18 [1.55-3.06] in patients with radiological progression. Amongst 138 patients eligible for second-line treatment, PPS was 16.8 and 5.9 months in cases without and with NEH, respectively (P = .001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333-2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3 mg/dl and ascites. CONCLUSIONS: PPS of iCCA is influenced by progression pattern, with important implications for second-line trial design and analysis.

Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial.

BACKGROUND: A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs). PATIENTS & METHODS: Patients with histologic confirmation of TET diagnosis by central review who had received >1 systemic chemotherapy treatment were included. Patients received oral capecitabine (650 mg/mq twice daily on days 1-14) and intravenous gemcitabine (1000 mg/mq on days 1 and 8 every 3 weeks). RESULTS: Of the 30 patients included (18 men, 12 women; median age: 57 years, range: 48-61 years), the majority (73%) had thymoma, and the remaining thymic carcinoma. Eight patients developed grade 3-4 neutropenia. A total of 12 patients had a response. Median progression-free survival was 11 months (range: 6.5-16.5). CONCLUSION: Capecitabine and gemcitabine is highly active in TETs.

Carboplatin plus etoposide in heavily pretreated castration-resistant prostate cancer patients.

AIMS: Carboplatin plus etoposide has modest efficacy in docetaxel-pretreated castration-resistant prostate cancer patients. We hypothesized that carboplatin-etoposide could still exert some therapeutic activity after docetaxel, cabazitaxel and either abiraterone or enzalutamide. PATIENTS & METHODS: We enrolled 15 patients in the first step of a Phase II trial. The target sample size is 46 patients. The primary end point of the study was progression-free survival after 12 weeks. RESULTS: The median progression-free survival was 11 weeks (range: 8-18), while median overall survival was 18 weeks (range: 12-26). Of seven patients with measurable disease, two had a partial response, two showed stable disease and the remaining three had progressive disease as the best radiological response. Five patients were considered progression-free after 12 weeks, prompting continuation of the trial. CONCLUSION: Our preliminary findings support the hypothesis that carboplatin plus etoposide may yield some clinical benefit in a population of patients who failed all currently approved therapeutic options for prostate cancer.

Suboptimal outcomes of sorafenib as a second-line treatment after atezolizumab-bevacizumab for unresectable hepatocellular carcinoma.

BACKGROUND: Most patients receiving atezolizumab-bevacizumab (AB) for hepatocellular carcinoma will eventually experience disease progression. Randomized clinical trials (RCTs) are undergoing to identify second-line treatments. Where RCTs are unavailable or patients are non-eligible, sorafenib is often prescribed based on approval and reimbursement policies. However, evidence supporting this approach is minimal. OBJECTIVE: To assess the efficacy and safety of sorafenib in patients who permanently discontinued AB. METHODS: The ARTE database prospectively collects patients treated with AB in a real-life setting. We analysed the outcome of patients who received sorafenib as second-line treatment. RESULTS: Amongst 213 patients, 130 (61.0 %) permanently discontinued AB. Of them, 54 received second- line treatments, and sorafenib was prescribed in 40 patients. The disease control rate (DCR) was 10.0 %. The median progression-free (PFS) and overall survival were 3.3 (95 % confidence interval [CI] 2.7-3.9) and 6.9 months (95 % CI 2.7-11.1), respectively. CONCLUSIONS: In patients progressing under AB, the efficacy of sorafenib on different outcomes is limited.

Treatments, prognostic factors, and genetic heterogeneity in advanced cholangiocarcinoma: A multicenter real-world study.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA), a rare and aggressive hepatobiliary malignancy, presents significant clinical management challenges. Despite rising incidence and evolving treatment options, prognosis remains poor, motivating the exploration of real-world data for enhanced understanding and patient care. METHODS: This multicenter study analyzed data from 120 metastatic CCA patients at three institutions from 2016 to 2023. Kaplan-Meier curves assessed overall survival (OS), while univariate and multivariate analyses evaluated links between clinical variables (age, gender, tumor site, metastatic burden, ECOG performance status, response to first-line chemotherapy) and OS. Genetic profiling was conducted selectively. RESULTS: Enrolled patients had a median age of 68.5 years, with intrahepatic tumors predominant in 79 cases (65.8%). Among 85 patients treated with first-line chemotherapy, cisplatin and gemcitabine (41.1%) was the most common regimen. Notably, one-third received no systemic treatment. After a median 14-month follow-up, 81 CCA-related deaths occurred, with a median survival of 13.1 months. Two clinical variables independently predicted survival: response to first-line chemotherapy (disease control vs. no disease control; HR: 0.27; 95% CI: 0.14-0.50; p < 0.0001) and metastatic involvement (>1 site vs. 1 site; HR: 1.99; 95% CI: 1.04-3.80; p = 0.0366). The three most common genetic alterations involved the ARID1A, tp53, and CDKN2A genes. CONCLUSIONS: Advanced CCA displays aggressive clinical behavior, emphasizing the need for treatments beyond chemotherapy. Genetic diversity supports potential personalized therapies. Collaborative research and deeper CCA biology understanding are crucial to enhance patient outcomes in this challenging malignancy.

Peg-filgrastim and cabazitaxel in prostate cancer patients.

To determine the impact of prophylaxis with granulocyte-colony stimulating growth factor (G-CSF) on the risk of febrile neutropenia in a cohort of patients enrolled at the University Federico II of Naples and treated with cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC). We carried out a retrospective review of prospectively collected data of patients enrolled at our institution in a compassionate-use programme with cabazitaxel, aimed at providing early access to the drug before its commercial availability in mCRPC patients. Besides baseline clinical and demographic characteristics, data on treatment efficacy and toxicity, as well as those on the use of G-CSF per patient per cycle were extracted. Progression-free survival and overall survival were calculated using the Kaplan-Meier method. Fisher's exact test was used to explore a relationship between a single event of grade 3 or more neutropenia or febrile neutropenia and previous use of G-CSF. Univariate analysis was carried out to evaluate predictors of grade 3 or more neutropenia and/or febrile neutropenia. Of 34 patients enrolled at our institution from December 2010 to December 2011, 32 had received at least one dose of cabazitaxel and were included in the analysis. Patients received a median of 10 cabazitaxel cycles. Grade 3 or more neutropenia was common, occurring in 64.5% of patients. Three patients (9.3%) developed febrile neutropenia. Twenty-seven patients received prophylaxis with G-CSF during at least one cycle using peg-filgrastim. The risk of grade 3 or more neutropenia and/or febrile neutropenia per patient and per cycle was seven times lower when G-CSF was used. Baseline neutrophil count of less than 4570/mm was the strongest predictor of grade 3 or more neutropenia and/or febrile neutropenia. No toxic death was reported. Only one patient discontinued cabazitaxel because of an adverse event. Our analysis suggests that prophylaxis with peg-filgrastim may considerably reduce the incidence of grade 3 or more neutropenia and, possibly, of febrile neutropenia in mCRPC patients treated with cabazitaxel. Further analyses involving a larger population are warranted to confirm our results.

Potential value of Gleason score in predicting the benefit of cabazitaxel in metastatic castration-resistant prostate cancer.

AIM: This study aimed to identify predictive/prognostic factors in castration-resistant prostate cancer patients treated with cabazitaxel. PATIENTS & METHODS: Patients were enrolled from March 2011 to December 2011 in an international expanded access program. In January 2012, when cabazitaxel became commercially available, a prospective study was initiated at University Federico II of Naples and at Rionero in Vulture Hospital. RESULTS: Forty-seven patients were enrolled in this study. Patients received a median of nine cycles of cabazitaxel. Median progression-free survival was 7.0 months (95% CI: 5.7-8.0). Seventeen patients were still alive at the time of the analysis, with a median overall survival of 14 months (95% CI: 11-16). At multivariate analysis, a higher Gleason score (≥ 8) appeared to be associated with prolonged progression-free survival (hazard ratio: 0.36; 95% CI: 0.18-0.72); however, the higher Gleason score showed no statistical impact on overall survival. CONCLUSION: We hypothesize that the Gleason score has the potential to be incorporated in the clinical decision-making process for definition of treatment strategy in docetaxel-pretreated castration-resistant prostate cancer patients. We encourage further experimentation in this setting.

Non-hereditary early onset gastric cancer: An unmet medical need.

Gastric cancer (GC) is a lethal disease and the diagnosis in the young population is a major challenge from both individual and social point of views. Early-onset GC accounts for ∼5% of GC; among them, 3% are part of a hereditary syndrome and the majority are sporadic. However, even if the early-onset forms were less frequent in the past, the increasing number in the last decades has improved the interest and awareness of them in the society and in the scientific community. In particular, the different behaviour and characteristics of early-onset GC suggest that it is a completely different entity, which requires a tailored and personalized management. Here we provide an updated overview about non-hereditary early-onset GC, which is an unmet clinical need today, along with future perspectives in this field.

Role of Etiology in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Counterfactual Event-Based Mediation Analysis.

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Methods: Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan−Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Results: Median OS was 21 months (95% CI: 20−23) in the group with other etiologies and 15 months (14−16) in the group with viral etiology (p < 0.0001). The total effect of viral etiology was associated with OS (HR 2.76, 1.32−5.21), and it was mainly explained by the pure direct effect of viral etiology (HR 2.74, 1.15−4.45). By contrast, its total indirect effect was not associated with poorer survival (HR 1.05, 0.82−2.13). These results were confirmed when considering tobacco, alcohol consumption, or injection drug abuse as potential mediators. Median progression-free survival was 9 months (8−10) in patients with other etiologies and 6 months (5−7) in patients with viral etiology (p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process.