Short-Term Safety and Psychosocial Impact of the BNT162b2 mRNA COVID-19 Vaccine in Cancer Patients-An Italian Single-Center Experience.

Safety data regarding BNT162b2 in cancer patients (CPs) are scarce. Herein we report the side effects (SEs), the adverse events (AEs), and the patient-reported outcomes (PROs) following BNT162b2 administration in CPs treated at the San Luigi Gonzaga University Hospital. All CPs who agreed to participate in our vaccination campaign received BNT162b2 and were included in the descriptive analysis. An anonymous questionnaire investigating the occurrence of SEs/AEs and PROs was administered to the study population 21 days after the first dose. Pearson's chi-squared test was used to estimate the risk of experiencing SEs/AEs according to selected variables. A total of 997 patients were included in the study: 62.0% had stage IV cancer, and 68.8% were receiving an active treatment, of whom 15.9% were receiving immunotherapy. SEs/AEs were recorded in 37.1% of cases after the first dose and in 48.5% of cases after the second dose. The most common SEs were muscle pain/local rash (27.9% and 28%, after the first and second dose, respectively). Patients older than 70 years showed lower risk of SEs/AEs, while women showed a higher risk. Before receiving the vaccine, 18.2% of patients felt fearful and/or insecure about the vaccination. After the first dose, 57.5% of patients changed their feelings positively. Our data support the short-term safety of BNT162b2 in CPs, regardless of disease stage and concurrent treatments. Overall, the vaccination showed a positive impact on quality of life.

Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay.

Sequencing of cell-free DNA (cfDNA) in cancer patients' plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with <10% tumor fractions when compared against an independent assay. Finally, we applied PCF_SELECT to serial plasma samples intensively collected from three patients previously characterized as harboring alterations involving DNA repair genes and consequently offered PARP inhibition. We identified more extensive pan-genome allelic imbalance than previously recognized in prostate cancer. We confirmed high sensitivity detection of BRCA2 allelic imbalance with decreasing tumor fractions resultant from treatment and identified complex ATM genomic states that may be incongruent with protein losses. Overall, we present a framework for sensitive detection of allele-specific copy number changes in cfDNA.

Immune-checkpoint inhibition in stage III unresectable NSCLC: Challenges and opportunities in the post-PACIFIC era.

The PACIFIC trial marked a new era in the treatment of stage III unresectable NSCLC, establishing durvalumab consolidation as new standard of care worldwide, with about 14 % increase of long-term survival and half of the patients alive at 4 years. A series of intensified immune-checkpoint inhibition regimens are currently under investigation in clinical trials in order to optimize the therapeutic benefit obtained in this population, while the identification of personalized approaches as well as the development of effective treatments in the post-durvalumab progression setting represent an actual and controversial topic for clinical lung cancer research. This review describes the current real-word treatment scenario for stage III unresectable NSCLC in Italy, and provides an updated overview of the upcoming therapeutic strategies under clinical investigation, discussing the most relevant challenges and opportunities featuring the post-PACIFIC era.

Italian survey on the clinical management of non-small cell lung cancer patients during the COVID-19 pandemic: A lesson for the second wave.

This study investigated the clinical management of non small cell lung cancer (NSCLC) patients during the first wave of coronavirus disease 2019 (COVID-19) outbreak in Italy. A 29-questions survey was sent to 95 Italian thoracic oncologists, with 77 % of them declaring significant changes in the outpatients management and treatment. The results of this survey pointed out a significant delay of lung cancer diagnosis along with a relevant reduction of patients' accrual within clinical trials. Telemedicine emerged as a valid support for patient-healthcare interactions. Therapeutic indications followed the guidelines for adjuvant chemotherapy and concurrent chemo-radiation. Clinical indications to first-line therapies were largely confirmed, while major changes regarded the selection of second line treatment options as well as the management of elderly population. This work may represent a valid source of information to improve the clinical management of NSCLC patients during second wave of COVID-19 pandemic.

Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: A case-control matched analysis from a large multicenter study.

BACKGROUND: Improved outcome in tobacco smoking patients with non-small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first-line immunotherapy in patients with high PD-L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. METHODS: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first-line pembrolizumab and platinum-based chemotherapy. RESULTS: A total of 962 NSCLC patients with PD-L1 expression ≥50% who received first-line pembrolizumab and 462 NSCLC patients who received first-line platinum-based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15-1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02-1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52-1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45-1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case-control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression-free survival (PFS) (HR = 1.68 [95% CI: 1.17-2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84-2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49-0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45-0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. CONCLUSIONS: Among metastatic NSCLC patients with PD-L1 expression ≥50% receiving first-line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first-line chemotherapy.

Is there any place for immune-checkpoint inhibitors in the treatment algorithm of fusion-driven non-small cell lung cancer?-a literature review.

The advent of immune-checkpoint inhibitors (ICIs) targeting the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis, produced a paradigm change of the treatment algorithm for metastatic, non-oncogene addicted, non-small cell lung cancer (NSCLC). However, the majority of patients with oncogene-addicted disease have been excluded from the "immunotherapy revolution", thus the clinical efficacy of these agents in this subset of patients remains largely unknown. Although pre-clinical evidence provided a good rationale to pursue the investigation of ICI treatment in specific subgroups of oncogene-addicted NSCLC, current available evidence suggested that tumors harboring molecular alterations likely do not represent the best candidate to single agent ICI therapy. Furthermore, the prospect of further improving overall survival (OS) with the combination of tyrosine kinase inhibitors (TKIs) and ICIs led to unexpected poor results and safety issues in recent phase I trials exploring different therapeutic associations. Conversely, the combination of immunotherapy and chemotherapy is emerging as a potential effective strategy in specific subsets of NSCLC patients harboring oncogenic drivers. In this review we particularly focus on the subgroup of patients whose disease harbor oncogenic rearrangements, summarizing current evidence from preclinical and clinical studies and discussing their practical implications, in order to define the potential role of ICIs in the clinical management of fusion-driven NSCLC.

Bipolar androgen therapy in prostate cancer: Current evidences and future perspectives.

Testosterone suppression by androgen deprivation therapy is the cornerstone of prostate cancer treatment. New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease. However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments. In this contest, new strategies that could be able to delay or even revert resistance are needed. The bipolar androgen therapy is an under-investigation treatment that consists in periodical oscillation between castration levels and supraphysiological levels of testosterone in order to prevent the adaptation of prostate cancer cells to a low-androgen environment. This review aims to underline the biological rationale of bipolar androgen therapy and gather evidences from the most recent clinical trials.

SARS-CoV-2 Infection in Cancer Patients: A Picture of an Italian Onco-Covid Unit.

Background: The world, and Italy on the front lines, has experienced a major medical emergency due to the novel coronavirus outbreak. Cancer patients are one of the potentially most vulnerable cohorts of people, but data about their management are still few. Patients and Methods: In this monocentric retrospective study we included all SARS-CoV-2 oncological patients accepted, between March 27th and April 19th 2020, at the Onco-COVID Unit at San Luigi Gonzaga Hospital, one of the few Italian oncological-COVID wards. Data were obtained from medical records. Results: Eighteen cancer patients with COVID-19 were included. The mean (±SD) age of patients was 67 ± 14 years, 89% were men. Seven (39%) developed infection in communities and 11 (61%) during hospitalization. Lung cancer was the most frequent type of cancer (10, 56%). Seven patients (39%) were symptomatic for COVID-19 at the time of diagnosis and symptoms began 2 (±2) days before. The most common were shortness of breath and diarrhea. Fever was present in 5 patients (28%). Among the 11 asymptomatic patients, 8 (73%) became symptomatic during the hospitalization (mean time of symptoms onset 4 days ±4). Six patients (33%) were on active anti-tumor treatment: 2 (33%) received anti-tumor therapy within 2 weeks before the infection diagnosis and 2 (33%) continued oncological treatment after SARS-CoV-2 positivity. Eight (44%) patients died within a mean of 12 days (±8) from the infection diagnosis. Conclusions: Our series confirms the high mortality among cancer patients with COVID-19. The presence of asymptomatic cases evidences that typical symptoms and fever are not the only parameters to suspect the infection. The Onco-Covid unit suggests the importance of a tailored and holistic approach, even in this difficult situation.

Quality of life assessment and reporting in colorectal cancer: A systematic review of phase III trials published between 2012 and 2018.

BACKGROUND: In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials. METHODS: We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals. RESULTS: Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints. CONCLUSIONS: QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.

Quality of life analysis in lung cancer: A systematic review of phase III trials published between 2012 and 2018.

OBJECTIVES: We previously reported that quality of life (QoL) is not included among trial endpoints and QoL results are underreported in a significant proportion of phase III oncology trials. Here we describe QoL adoption, reporting and methodology of QoL analysis in lung cancer trials. MATERIALS AND METHODS: We selected all primary publications of lung cancer phase III trials assessing anticancer drugs published between 2012 and 2018 by 11 major journals. RESULTS: 122 publications were included. In 39 (32.0%) publications, QoL was not listed among endpoints: in 10/17 (58.8%) early stage/locally advanced NSCLC, in 15/54 (27.8%) first-line of advanced NSCLC; in 10/41 (24.4%) second and further lines of advanced NSCLC, in 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. Out of 83 trials including QoL among endpoints, QoL results were absent in 36 primary publications (43.4%). Proportion of trials without QoL results in primary publication increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p = 0.005). Overall, QoL data were not available in 75/122 (61.5%) primary publications, due to the absent endpoint or unpublished results. QoL data were lacking in 48/68 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement comparing 2012-2015 vs. 2016-2018. CONCLUSION: QoL is not assessed or published in many phase III lung cancer trials, a setting where QoL value should be highly considered, due to high symptom burden and generally limited life expectancy. Timely inclusion of results in primary publications is worsening in recent years.

Quality-of-Life Assessment and Reporting in Prostate Cancer: Systematic Review of Phase 3 Trials Testing Anticancer Drugs Published Between 2012 and 2018.

Quality of life (QoL) is not included among the end points in many studies, and QoL results are underreported in many phase 3 oncology trials. We performed a systematic review to describe QoL prevalence and heterogeneity in QoL reporting in recently published prostate cancer phase 3 trials. A PubMed search was performed to identify primary publications of randomized phase 3 trials testing anticancer drugs in prostate cancer, issued between 2012 and 2018. We analyzed QoL inclusion among end points, presence of QoL results, and methodology of QoL analysis. Seventy-two publications were identified (15 early-stage, 20 advanced hormone-sensitive, and 37 castration-resistant prostate cancer [CRPC]). QoL was not listed among study end points in 23 studies (31.9%) (40.0% early stage, 40.0% advanced hormone sensitive, and 24.3% CRPC). QoL results were absent in 15 (30.6%) of 49 primary publications of trials that included QoL among end points. Overall, as a result of absent end point or unpublished results, QoL data were lacking in 38 (52.8%) primary publications (53.3% early stage, 55.0% in advanced hormone sensitive, and 51.4% in CRPC). The most commonly used QoL tools were Functional Assessment of Cancer Therapy-Prostate (FACT-P) (21, 53.8%) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (14, 35.9%); most common methods of analysis were mean changes or mean scores (28, 71.8%), time to deterioration (14, 35.9%), and proportion of patients with response (10, 25.6%). In conclusion, QoL data are lacking in a not negligible proportion of recently published phase 3 trials in prostate cancer, although the presence of QoL results is better in positive trials, especially in CRPC. The methodology of QoL analysis is heterogeneous for type of instruments, analysis, and presentation of results.

Role of radiotherapy in improving activity of immune-modulating drugs in advanced renal cancer: Biological rationale and clinical evidences.

In the last few years, immune checkpoint inhibitors have been extensively investigated in renal cell carcinoma and led to remarkable results. Radiation therapy may increase the activity of immune modulating agents through different mechanisms, priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. Preclinical studies reported increased loco-regional control when radiation is combined with immune-checkpoint blockade. Moreover, increased systemic disease control has been demonstrated when local radiation is combined with both anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors. Actually, several trials are ongoing testing the activity of radiation therapy in combination with different immune-modulating agents for the treatment of metastatic renal cell carcinoma. The aim of this paper is to focus on the biological rationale of adding radiation therapy to immune-modulating agents in renal cell carcinoma and to review the currently available clinical evidence about the combination of radiotherapy and immunotherapy.

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer.

Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4-6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castration-resistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on new-generation hormonal therapies. Several in vitro studies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined.

Hormonal treatment and quality of life of prostate cancer patients: new evidence.

Androgen deprivation therapy (ADT) is the mainstay of treatment of patients with relapsed or metastatic hormone-sensitive prostatic carcinoma. The dramatic reduction of serum testosterone levels induced by ADT produces multiple side effects as vasomotor flushing, sexual dysfunction, fatigue, impairment of cognitive function, reduced quality of sleep, gynecomastia and anemia, that are able to decrease health-related quality of life (QoL). In addition, hormonal therapy can interfere with bone metabolism and induce metabolic and cardiovascular complications. Recently, new-generation hormonal therapies, such as abiraterone and enzalutamide, have been tested and approved in castration resistant prostatic cancer patients and current studies are moving forward to the earlier use of these two drugs. In this evolving scenario, the management of hormonal therapy toxicity, given the long duration of treatment and the potentially high impact of side effects on patients' functional status and quality of life, is a critical challenge for clinicians. A correct information of patients before the initiation of treatment, together with the adoption of preventive measures, could help to ameliorate their quality of life. The aim of this review is to describe the impact on quality of life of endocrine treatment side effects and analyze possible interventions to alleviate them.

Chemotherapy-Induced Neutropenia and Outcome in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With First-Line Docetaxel.

BACKGROUND: Neutropenia is a common side effect associated with docetaxel use. We retrospectively investigated the association between chemotherapy-induced neutropenia and survival in metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line docetaxel. PATIENTS AND METHODS: Metastatic castration-resistant prostate cancer patients treated with first-line docetaxel, with known neutrophils value 10 days after first administration, were included in this retrospective analysis. Neutropenia was categorized in Grade 0 to 1 (G0-1), Grade 2 to 3 (G2-3), and Grade 4 (G4). Outcome measures were progression-free survival (PFS) and overall survival (OS). RESULTS: Eighty patients were analyzed. Median PFS was 5.4 months in patients with G0-1 neutropenia, 6.9 months with G2-3 neutropenia (hazard ratio [HR] vs. G0-1, 0.69; 95% confidence interval [CI], 0.35-1.35; P = .27) and 9.5 months with G4 neutropenia (HR vs. G0-1, 0.30; 95% CI, 0.16-0.57; P < .0001). Median OS was 11.6 months in patients with G0-1 neutropenia, 25.5 months in patients with G2-3 neutropenia (HR vs. G0-1, 0.36; 95% CI, 0.16-0.80; P = .012) and 39.3 months in patients with G4 neutropenia (HR vs. G0-1, 0.19; 95% CI, 0.09-0.41; P < .0001). In multivariate analysis, the occurrence of severe neutropenia showed a statistically significant association with OS (HR G4 vs. G0-1, 0.14; 95% CI, 0.03-0.67; P = .013; HR G2-3 vs. G0-1, 0.42; 95% CI, 0.11-1.57; P = .20) and PFS (HR G4 vs. G0-1, 0.28; 95% CI, 0.09-0.86; P = .03; HR G2-3 vs. G0-1, 1.07; 95% CI, 0.38-2.96; P = .90). CONCLUSION: Docetaxel-induced neutropenia is associated with better survival of mCRPC.

Immunotherapy for Patients with Advanced Urothelial Cancer: Current Evidence and Future Perspectives.

In recent years, immunotherapy has produced encouraging results in a rapidly increasing number of solid tumors. The responsiveness of bladder cancer to immunotherapy was first established in nonmuscle invasive disease in 1976 with intravesical instillations of bacillus Calmette-Guérin (BCG). Very recently immune checkpoint inhibitors demonstrated good activity and significant efficacy in metastatic disease. In particular the best results were obtained with programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors, but many other immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, are currently under investigation in several trials. Simultaneously other therapeutic strategies which recruit an adaptive immune response against tumoral antigens or employ externally manipulated tumor infiltrating lymphocytes might change the natural history of bladder cancer in the near future. This review describes the rationale for the use of immunotherapy in bladder cancer and discusses recent and ongoing clinical trials with checkpoint inhibitors and other novel immunotherapy agents.