Anticancer Drugs-Related Hypogonadism in Male Patients with Advanced Cancers on Active Treatment: A Systematic Review.

BACKGROUND: In male patients with cancer treated with antineoplastic drug, hypogonadism is a neglected cause of diminished quality of life. This condition may be cancer related as well as toxicity related. The role of antineoplastic drug in causing hypogonadism is poorly understood. The aim of this systematic review was to establish the prevalence, nature (primary/secondary), and impact of hypogonadism on quality of life in male patients with cancer on antineoplastic therapy. METHODS: The search strategy used PubMed, Embase, and Cochrane databases to select articles in English language that described hypogonadism in male patients with cancer. The search period was from January 1, 1945 to February 28, 2023. We included observational studies, case reports or case series and excluded studies concerning hematological malignancies, prostate cancer, female patients, and survivors. FINDINGS: Of 4488 records identified, 28 studies met inclusion criteria (17 observational studies, 11 case reports or case series). Anti-angiogenic drugs and crizotinib were found to have a role in the development of hypogonadism. Patients treated with immune checkpoint-inhibitors developed secondary hypogonadism due to immune-related hypophysitis or orchitis. As for active chemotherapy, platinum salts were often associated with hypogonadism, followed by antimetabolites and taxanes. Selected studies were heterogeneous for populations, interventions, and outcomes assessments. Thus, a generalization is difficult. Moreover, the role of concurrent etiologies cannot be excluded in most studies. CONCLUSION: Our research emphasizes the importance of evaluating the gonadal axis before treatment in patients considered at risk and testing it at regular intervals or in case of clinical suspicion.

Application and accuracy of the EAPC/IASP diagnostic algorithm for neuropathic cancer pain and quantitative sensory testing profile in patients with pain due to cancer.

Introduction: Better diagnosis and treatment of neuropathic cancer pain (NcP) remains an unmet clinical need. The EAPC/IASP algorithm was specifically designed for NcP diagnosis; yet, to date, there is no information on its application and accuracy. Objectives: Our aim was to determine the accuracy of the EAPC/IASP algorithm compared with the Neuropathic Special Interest Group grading system (gold standard) and to describe patients' sensory profile with quantitative sensory testing (QST). Methods: This is a cross-sectional observational study conducted in a palliative care and pain outpatient clinic. Patients with cancer pain intensity ≥3 (numerical rating scale 0-10) were eligible. The palliative care physician applied the EAPC/IASP algorithm as a grading system to diagnose probable or definite NcP, and an independent investigator applied the gold standard and performed the QST. Sensitivity and specificity of the EAPC/IASP algorithm were measured in comparison with the gold standard results. Kruskal-Wallis and unequal variance independent-samples t tests were used to compare the QST parameters in patients with and without NcP. Results: Ninety-eight patients were enrolled from August 2020 to March 2023. Sensitivity and specificity for the EAPC/IASP algorithm were 85% (95% CI 70.2-94.3) and 98.3% (95% CI 90.8-100), respectively. Patients with NcP in contrast to patients without NcP showed cold hypoesthesia (P = 0.0032), warm hypoesthesia (P = 0.0018), pressure hyperalgesia (P = 0.02), and the presence of allodynia (P = 0.0001). Conclusion: The results indicate a good performance of the EAPC/IASP algorithm in diagnosing NcP and the QST discriminated well between patients with and without NcP.

STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines.

INTRODUCTION: Thymic malignancies are rare tumors with few therapeutic options. The STYLE trial was aimed to evaluate activity and safety of sunitinib in advanced or recurrent type B3 thymoma (T) and thymic carcinoma (TC). METHODS: In this multicenter, Simon 2 stages, phase 2 trial, patients with pretreated T or TC were enrolled in two cohorts and assessed separately. Sunitinib was administered 50 mg daily for 4 weeks, followed by a 2-week rest period (schedule 4/2), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Progression-free survival, overall survival, disease control rate and safety were secondary endpoints. RESULTS: From March 2017 to January 2022, 12 patients with T and 32 patients with TC were enrolled. At stage 1, ORR was 0% (90% confidence interval [CI]: 0.0-22.1) in T and 16.7% (90% CI: 3.1-43.8) in TC, so the T cohort was closed. At stage 2, the primary endpoint was met for TC with ORR of 21.7% (90% CI: 9.0%-40.4%). In the intention-to-treat analysis, disease control rate was 91.7% (95% CI: 61.5%-99.8%) in Ts and 89.3% (95% CI: 71.8%-97.7%) in TCs. Median progression-free survival was 7.7 months (95% CI: 2.4-45.5) in Ts and 8.8 months (95% CI: 5.3-11.1) in TCs; median overall survival was 47.9 months (95% CI: 4.5-not reached) in Ts and 27.8 months (95% CI: 13.2-53.2) in TCs. Adverse events occurred in 91.7% Ts and 93.5% TCs. Grade 3 or greater treatment-related adverse events were reported in 25.0% Ts and 51.6% TCs. CONCLUSIONS: This trial confirms the activity of sunitinib in patients with TC, supporting its use as a second-line treatment, albeit with potential toxicity that requires dose adjustment.

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion.

INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.

Pralsetinib in RET fusion-positive non-small-cell lung cancer: A real-world data (RWD) analysis from the Italian expanded access program (EAP).

OBJECTIVES: The selective RET-inhibitor pralsetinib has shown therapeutic activity in early clinical trials in patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) gene fusions. To date, the real-world efficacy of pralsetinib in this population is unknown. MATERIALS AND METHODS: A retrospective efficacy and safety analysis was performed on data from patients with RET-fusion positive NSCLC enrolled in the pralsetinib Italian expanded access program between July 2019 and October 2021. RESULTS: Overall, 62 patients with RET-fusion positive NSCLC received pralsetinib at 20 Italian centers. Next-generation sequencing was used to detect RET alterations in 44 patients (73 %). The most frequent gene fusion partner was KIF5B (75 % of 45 evaluable). Median age was 62 years (range, 36-90), most patients were female (57 %) and never smokers (53 %). Brain metastases were known in 18 patients (29.5 %) at the time of pralsetinib treatment. 13 patients were treatment naïve (unfit for chemotherapy), 48 were pretreated (median number of previous lines: 1, range, 1-4). The objective response rate (ORR) was 66 % [95 % confidence interval (CI), 53-81] in the evaluable population (n = 59). The disease control rate (DCR) was 79 %. After a median follow-up of 10.1 months, the median progression free survival was 8.9 months (95 %CI, 4.7-NA). In patients with measurable brain metastases (n = 6) intracranial ORR was 83 %, intracranial DCR was 100 %. Overall, 83.6 % of patients experienced any-grade treatment-related adverse events (TRAEs), 39 % grade 3 or greater (G ≥ 3). The most common G ≥ 3 TRAEs were neutropenia (9.8 %), dry mouth/oral mucositis (8.2 %), and thrombocytopenia (6.6 %). Seven patients (12 %) discontinued pralsetinib due to TRAEs, twenty-six had at least one dose level modification due to TRAEs. Two treatment-related deaths were observed (1 sepsis, 1 typhlitis). CONCLUSIONS: In the real-world setting, pralsetinib confirmed durable systemic activity and intracranial response in RET-fusion positive NSCLC. Toxicity profile was consistent with previous reports.

Prognostic role of neutrophil-to-lymphocyte ratio and EPSILoN score in advanced non-small-cell lung cancer patients treated with first-line chemo-immunotherapy.

Background: Clinical and laboratory biomarkers in patients with advanced non-small-cell lung cancer (aNSCLC) receiving chemo-immunotherapy (CIT) are still poorly explored. Materials & methods: All consecutive aNSCLC patients who received at least one cycle of first-line CIT were enrolled. The impact of several clinical and laboratory biomarkers on outcomes was evaluated through Cox proportional hazard models. Results: Higher neutrophil-to-lymphocyte ratio was shown to be an independent prognostic biomarker of both worse progression-free survival and worse overall survival. The EPSILoN score was able to divide patients into three different prognostic groups, with a median overall survival of 73.2, 45.6 and 8.6 months for the favorable, intermediate and poor groups, respectively. Conclusion: The neutrophil-to-lymphocyte ratio and EPSILoN score were shown to have a prognostic value in aNSCLC patients treated with CIT.

Patients affected by inoperable lung cancer, due to great extension or to the presence of metastases, are currently treated with intravenous drugs that act on immune system activation alone or in combination with chemotherapy as first-line treatment. The characteristics of these patients (both their medical history and their blood exams) need to be studied to find out if some of them can help clinicians to predict if they will benefit from the combination of immunotherapy with chemotherapy. The authors collected the data of patients with advanced lung cancer treated in their hospital and found out that a value calculated from their blood exams, collected before the start of treatment and a combination of values named EPSILoN score (which considers patients' clinical condition, their history of tobacco smoking, the presence of metastases in the liver and two blood exam parameters, namely the neutrophil-to-lymphocyte ratio and LDH level) can predict how their disease will evolve during first-line treatment with chemotherapy in combination with immunotherapy.

Machine Learning Using Real-World and Translational Data to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy.

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO.

Monitoring patients with head and neck cancer for flu-like symptoms during the COVID-19 pandemic.

OBJECTIVE: To capture and monitor flu-like symptoms in relation to the clinical characteristics and the oncologic treatment of a large head and neck cancer (HNC) patient cohort during the Coronavirus disease 2019 (COVID-19) pandemic. METHODS: Patients were monitored through by 2 rounds of interviews. Clinical characteristics of patients with no symptoms (group 0) and of those reporting ⩾1 (group A), ⩾3 (group B), or ⩾5 symptoms (group C) were analyzed. Patients with ⩾1 symptom at both interviews were defined as group A2. RESULTS: Five hundred patients with HNC were analyzed. A higher frequency of patients with the following characteristics was observed in group A vs group 0: active treatment (40% vs 24%, p = 0.0002), gastrostomy (6% vs 2%, p = 0.027), recent active treatment (48% vs 29%, p < 0.0001), and higher number of concomitant medications (p = 0.01). A lower median age was observed in group B vs group no-B (patients with fewer than three symptoms) (59 vs 63.55 years, p = 0.016) and in group A2 vs group no-A2 (patients without at least one symptom at both interviews) (56 vs 63 years, p = 0.021); patients in group B received more recent active treatment than those in group no-B and in group A2 vs those in group no-A2 (p = 0.024 and 0.043, respectively); patients in group B had a lower body mass index than those in group no-B (22.4 vs 23.93 kg/m2, p = 0.0066). CONCLUSIONS: This work is based on patient-reported symptoms and signs independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. In the future, these results might serve as a a benchmark for clinicians triaging and managing patients with HNC during infectious outbreaks involving flu-like symptoms.

Immune-Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer With Uncommon Histology.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have significantly improved outcome of advanced non-small cell lung cancer (aNSCLC) patients. However, their efficacy remains uncertain in uncommon histologies (UH). MATERIALS AND METHODS: Data from ICI treated aNSCLC patients (April,2013-January,2021) in one Institution were retrospectively collected. Univariate and multivariate survival analyses were estimated by Kaplan-Meier and Cox proportional hazards regression model, respectively. Objective response rate (ORR) and disease control rate (DCR) were assessed. RESULTS: Of 375 patients, 79 (21.1%) had UH: 19 (24.1%) sarcomatoid carcinoma, 15 (19.0%) mucinous adenocarcinoma, 10 (12.6%) enteric adenocarcinoma, 8 (10.1%) adenocarcinoma not otherwise specified, 7 (8.9%) large-cell neuroendocrine carcinoma, 6 (7.6%) mixed histology non-adenosquamous, 5 (6.3%) adenosquamous carcinoma, 9 (11.4%) other UH. In UH group, programmed death-ligand 1 (PD-L1) <1%, 1-49%, ≥50% and unknown expression were reported in 27.8%, 22.8%, 31.7% and 17.7% patients respectively and ICI was the second/further-line in the majority of patients. After a median follow-up of 35.64 months (m), median progression-free survival (mPFS) was 2.5 m in UH [95% CI 2.2-2.9 m] versus (vs.) 2.7 m in CH [95% CI 2.3-3.2 m, P-value = .584]; median overall survival (mOS) was 8.8 m [95% CI 4.9-12.6 m] vs. 9.7 m [95% CI 8.0-11.3 m, P-value = .653]. At multivariate analyses only ECOG PS was a confirmed prognostic factor in UH. ORR and DCR were 25.3% and 40.5% in UH vs. 21.6% and 49.5% in CH [P-value = .493 and .155 respectively]. CONCLUSIONS: No significant differences were detected between UH and CH groups. Prospective trials are needed to understand ICIs role in UH population.

Fears, beliefs, and quality of life of patients with cancer vs the general population during the coronavirus disease 2019 (COVID-19) pandemic in Lombardy.

AIM: To understand how patients with cancer reacted to the coronavirus disease 2019 (COVID-19) pandemic and whether their quality of life (QoL) was affected. METHODS: In June 2020, 111 patients with cancer treated in the supportive care unit of a Comprehensive Cancer Center in Milan and 201 healthy controls from the general population were enrolled and assessed both quantitatively and qualitatively for fears and COVID-19-related beliefs as well as for QoL. RESULTS: Fear of COVID-19 was significantly lower among patients (41% vs 57.6%; p = 0.007), as was fear of cancer (61.5% vs 85.6%; p < 0.001) and other diseases. The perceived risk of getting COVID-19 was lower among patients (25.2% vs 52.7%; p < 0.001), as was the belief of having been exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (18.1% vs 40.8%; p < 0.001). The physical component of QoL was better among the population (54.5 vs 43.8; p < 0.001); the reverse was true for patients' psychological well-being (44.6 vs 39.6; p < 0.001). The qualitative data supported such results, showing a reduced psychological effect on the patients with cancer compared to the controls. Various reasons explain this result, including the awareness of being treated for cancer and nevertheless protected against getting infected in a cancer center of public health reorganized to continue treating patients by protecting them and personnel from the risk of infection. CONCLUSIONS: The experience of a cancer diagnosis, together with proper hospital reorganization, may act as protective factors from fears and psychological consequences of the COVID-19 outbreak.

Beyond First-Line Immunotherapy: Potential Therapeutic Strategies Based on Different Pattern Progressions: Oligo and Systemic Progression.

First-line immune-checkpoint inhibitor (ICI)-based therapy has deeply changed the treatment landscape and prognosis in advanced non-small cell lung cancer (aNSCLC) patients with no targetable alterations. Nonetheless, a percentage of patients progressed on ICI as monotherapy or combinations. Open questions remain on patients' selection, the identification of biomarkers of primary resistance to immunotherapy and the treatment strategies to overcome secondary resistance to first-line immunotherapy. Local ablative approaches are the main therapeutic strategies in oligoprogressive disease, and their role is emerging in patients treated with immunotherapy. Many therapeutic strategies can be adapted in aNSCLC patients with systemic progression to personalize the treatment approach according to re-characterization of the tumors, previous ICI response, and type of progression. This review's aim is to highlight and discuss the current and potential therapeutic approaches beyond first-line ICI-based therapy in aNSCLC patients based on the pattern of disease progression (oligoprogression versus systemic progression).

Immunotherapy in advanced Non-Small Cell Lung Cancer patients with poor performance status: The role of clinical-pathological variables and inflammatory biomarkers.

BACKGROUND: The introduction of immunotherapy has improved the prognosis of patients with Non-Small Cell Lung Cancer (NSCLC). However, data in poor ECOG Performance Status (PS) patients remain scant due to their exclusion from randomized trials. MATERIAL AND METHODS: We analyzed data of patients with advanced NSCLC treated with immunotherapy in two Italian Centers, to evaluate the impact of PS (0-1 vs 2) on disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Chi-square test was used to compare clinical-pathological variables, their impact on survival was evaluated through Cox proportional hazard models. RESULTS: Among 404 patients included, PS was 0 in 137 (33.9 %), 1 in 208 (51.5 %) and 2 in 59 (14.6 %) patients; 143 were female and 90 had squamous NSCLC. Clinical-pathological variables were uniformly distributed except for higher prevalence of liver metastases in patients with poor PS. We found that PS2 patients showed worse outcomes in terms of DCR (21.8 % vs 50.3 %, p = 0.001), PFS [2.0 (95 % CI 1.6-3.0) vs 3.0 (95 % CI 2.7-4.0) months, p < 0.0001] and OS [4.0 (95 % CI 2.8-5.7) vs 13.2 (95 % CI 11.0-15.8) months, p < 0.0001]. PS2 status, negative PDL1 expression and early corticosteroids exposure as well as higher Neutrophil to Lymphocyte Ratio and LDH at baseline were associated with worse outcomes at univariate and multivariable analysis. Subgroup analysis confirmed poor outcomes in PS2 patients with high LDH and concomitant corticosteroid therapies. The incidence of Grade 3/4 adverse events was 11.3 % in PS 0-1 and 10.2 % in PS 2 patients (p = 0.81). CONCLUSION: Our data confirm reduced efficacy of immunotherapy in patients with poor PS even though a good safety. Despite PS remains the most powerful independent prognostic factor for NSCLC, LDH levels and steroids exposure could support the decision making in PS2 patients.