Clinical Potential of Circulating Cell-Free DNA (cfDNA) for Longitudinally Monitoring Clinical Outcomes in the First-Line Setting of Non-Small-Cell Lung Cancer (NSCLC): A Real-World Prospective Study.

BACKGROUND: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. METHODS: From February 2020 to May 2022, treatment-naïve patients with advanced NSCLC were consecutively enrolled at the Medical Oncology Unit of the Paolo Giaccone University Hospital, Palermo (Italy). We quantified cfDNA in terms of ng/µL using a QubitTM dsDNA HS Assay Kit. The agreement between the cfDNA and radiologic response was evaluated from baseline (T0) to the radiologic evaluation (T1). RESULTS: A total of 315 liquid biopsy samples were collected from 63 patients at baseline, with a total of 235 paired plasma samples from 47 patients at disease re-evaluation. A fair concordance was observed between early and durable radiographic and cfDNA response (Cohen's kappa coefficient = 0.001); 11 and 18 patients receiving TKI (Pearson's chi-squared test = 4.278; Cohen's kappa coefficient = 0.039) and IO treatments (Pearson's chi-squared test = 7.481; Cohen's kappa coefficient = 0.006) showed a significant and durable association between cfDNA dynamics and the first radiologic evaluation, whereas among the 18 patients undergoing CT, no significant correlation was observed (Pearson's chi-squared test = 0.720; Cohen's kappa coefficient = 0.396). The ECOG-PS 2 patients presented with the mean baseline cfDNA levels 2.6-fold higher than those with ECOG-PS 0-1 (1.71 vs. 0.65 ng/µL; p = 0.105). CONCLUSIONS: Our real-world study demonstrates that quantitative changes in cfDNA values correlated with responses to therapy and relapse of disease in treatment-naïve patients with advanced NSCLC undergoing TKI- and IO-based treatments.

The diagnostic accuracy of PIK3CA mutations by circulating tumor DNA in breast cancer: an individual patient data meta-analysis.

Background: The circulating tumor DNA (ctDNA) diagnostic accuracy for detecting phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations in breast cancer (BC) is under discussion. We aimed to compare plasma and tissue PIK3CA alterations, encompassing factors that could affect the results. Methods: Two reviewers selected studies from different databases until December 2020. We considered BC patients with matched tumor tissue and plasma ctDNA. We performed meta-regression and subgroup analyses to explore sources of heterogeneity concerning tumor burden, diagnostic technique, sample size, sampling time, biological subtype, and hotspot mutation. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the related area under the curve (AUC) were elaborated for the overall population and each subgroup. Results: The pooled analysis was carried out on 25 cohorts for a total of 1966 patients. The overall ctDNA sensitivity and specificity were 0.73 (95% CI: 0.70-0.77) and 0.87 (95% CI: 0.85-0.89). The AUC was 0.93. Pooled concordance, negative predictive value and positive predictive value values were 0.87 (95% CI: 0.82-0.92), 0.86 (95% CI: 0.81-0.90), and 0.89 (95% CI: 0.81-0.95) with pooled PLR, NLR, and DOR of 7.94 (95% CI: 4.90-12.86), 0.33 (95% CI: 0.25-0.45), and 33.41 (95% CI: 17.23-64.79), respectively. The pooled results consistently favored next-generation sequencing (NGS)- over polymerase chain reaction-based methodologies. The best ctDNA performance in terms of sensitivity, specificity, and AUC (0.85, 0.99, and 0.94, respectively) was observed in the low-time sampling subgroup (⩽18 days between tissue and plasma collection). Meta-regression and subgroup analyses highlighted sampling time as a possible major cause of heterogeneity. Conclusions: These findings reliably estimate the high ctDNA accuracy for the detection of PIK3CA mutations. A ctDNA-first approach for the assessment of PIK3CA mutational status by NGS may accurately replace tissue tumor sampling, representing the preferable strategy at diagnosis of metastatic BC in patients who present with visceral involvement and at least two metastatic lesions, primarily given low clinical compliance or inaccessible metastatic sites.

Opioids in advanced cancer: use, storage and disposal in the home.

OBJECTIVES: To determine the patterns of storing, using and disposing of opioids among patients with advanced cancer followed at home. METHODS: Patients who were prescribed opioids were selected. Prescribed opioids and their doses used for background pain and breakthrough pain were collected, as well as CAGE (cut down, annoyed, guilty and eye opener) for alcohol and drugs, smoking and history of illicit substance use. Questions regarding the opioid use, storage and disposal were posed. RESULTS: 100 patients were surveyed. Fifty-one patients had unused opioids at home, 25 patients did not throw away the drugs, 40 patients saved opioids for future use and 35 patients were unaware of proper opioid disposal methods. A total of 28 patients reported unsafe use by sharing or losing their opioids; 12 patients were unaware that their opioid could be fatal when taken by others. Most patients acknowledged that pain medications could be dangerous when taken by others. Patients with a partner and who were married were more likely to keep their opioids locked (p=0.028 and p=0.025, respectively). CONCLUSION: A large number of patients with advanced cancer followed at home do not store, use and dispose of opioids safely. Patient education programmes should be incorporated to decrease the availability of opioids at home for abuse, diversion, and accidental poisoning.

Is there any room for PD-1 inhibitors in combination with platinum-based chemotherapy as frontline treatment of extensive-stage small cell lung cancer? A systematic review and meta-analysis with indirect comparisons among subgroups and landmark survival analyses.

BACKGROUND: The addition of PD-L1 inhibitors to platinum-based chemotherapy (CT) has newly received United States Food and Drug Administration (FDA) approval in extensive stage-small cell lung cancer (ES-SCLC). PD-1 agents similarly improved survival rates, even if not yet supported by international regulatory agencies. The current work aims to assess different efficacy and safety profiles among chemoimmunotherapy plus immuno-oncology (CT+IO) approaches according to different immune checkpoint inhibitor (ICI) subtypes. MATERIAL & METHODS: We included in our meta-analysis six first-line randomised controlled trials (RCTs) comparing the association of single-agent ICI with CT versus CT alone in ES-SCLC. Pooled hazard ratios (HRs) and risk ratios (RRs) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), 12-month duration of response rate (DORR), disease control rate (DCR), treatment-related adverse events (TRAEs) and discontinuation rates (DRs) were obtained. Moreover, we performed indirect comparisons according to ICI subtypes, also among subgroups and landmark survival analyses. RESULTS: Although no ORR benefit was observed, our results showed how CT+IO significantly improved DORR, resulting in improved PFS and OS with no differences in TRAEs; however, CT+IO led to a significant increase in DR. Interestingly, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, the use of cisplatin, and the absence of brain metastases seem to be associated with a survival gain using CT+IO in ES-SCLC. Indirect comparisons suggested a slight advantage in favour of programmed cell death-1 (PD-1) and programmed death ligand 1 (PD-L1) over anti-CTLA-4 agents in terms of efficacy with no additional safety concerns. No further differences were observed between PD-1 and PD-L1 inhibitors among subgroups and landmark survival analyses with benefit trends towards anti-PD-1 in terms of DORR and DR. CONCLUSION: While confirming a survival advantage of CT+IO in selected patients, these results suggested the association of PD-1 inhibitors with CT as a viable option for novel therapeutic approaches in the frontline management of ES-SCLC. Further trials evaluating anti-CTLA-4 agents should be carefully studied in biomarker-selected patients.

How do skeletal morbidity rate and special toxicities affect 12-week versus 4-week schedule zoledronic acid efficacy? A systematic review and a meta-analysis of randomized trials.

BACKGROUND: Zoledronic Acid is a bisphosphonate used in a 4-week schedule for the treatment of bone metastases. Some randomized trials supported its role also when administered every 12 weeks. METHODS: we performed a systematic review and a meta-analysis in order to evaluate the two different schedules in terms of skeletal morbidity rate (SMR), skeletal related events (SRE) and adverse events (AEs). RESULTS: our results showed a clinical difference favouring the 12-week schedule in terms of AEs (RR 1.17, 95% CI 1.06-1.29). No signifcant differences were found for SMR (RR 0.97, 95% CI 0.84-1.13) and SRE (RR 1.02, 95% CI 0.89-1.16). CONCLUSIONS: Our findings support in clinical practice the 12-week schedule an alternative to the standard 4-week schedule in advanced breast and prostate cancer, in particular when the clinical comorbidities of the patients suggest a higher risk of renal failure or hypocalcaemia.

Denosumab for bone health in prostate and breast cancer patients receiving endocrine therapy? A systematic review and a meta-analysis of randomized trials.

Hormonal therapies for receptor positive-breast and prostate cancer patients have shown clinical efficacy but also several side effects including osteoporosis, loss of bone mass and increased fracture risk. Denosumab represents an anti RANKL (receptor activator of nuclear factor-kB ligand) monoclonal anti-body acting as inhibitor of osteoclasts formation, function, and survival, then increasing bone mass. Herein, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the role of Denosumab in saving bone health in prostate and breast cancer patients receiving respectively androgen deprivation therapy and adjuvant endocrine therapy. Moreover, selected patients have to be treated with Denosumab at the dose of 60 mg every six month or placebo. Outcomes studied included the bone mass density (BMD) increase at 24 and 36 months, BMD loss, reduction of fractures risk (in particular vertebral) at 24 and 36 months and safety (overall, serious adverse events - SAEs and discontinuation rate). Our results showed a reduction of the BMD loss up to 36 months both at the lumbar and femoral level and a BMD increase both at 24 and 36 months. It was also found a reduction in the number of new vertebral and femoral fractures at 24 and 36 months. Finally, our pooled analysis showed that Denosumab did not affect both the SAEs and therapy discontinuation risk. In conclusion, Denosumab administration can be considered effective and safe in the prevention and management of the above mentioned adverse events related to hormonal therapies designed for breast and prostate tumors.

How to Deal with Second Line Dilemma in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis.

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy with chemotherapy (CT) as second line treatment for metastatic colorectal cancer (mCRC). The right sequence of the treatments in all RAS (KRAS/NRAS) wild type (wt) patients has not precisely defined. We evaluated the impact of aforementioned targeted therapies in second line setting, analyzing efficacy and safety data from phase III clinical trials. We performed both direct and indirect comparisons between anti-EGFR and anti-VEGF. Outcomes included disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and G3-G5 toxicities. Our results showed significantly improved OS (HR 0.83, 95% CI 0.72-0.94) and DCR (HR 1.27, 95% CI 1.04-1.54) favouring anti-VEGF combinations in overall population; no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70-1.09). Anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31-0.96), showing a trend also in all RAS wt patients (RR 0.63, 95% CI 0.48-0.83). No significant difference in PFS and DCR all RAS was registered. Our results provided for the first time a strong rationale to manage both targeted agents in second line setting.

Immuno-targeted combinations in oncogene-addicted non-small cell lung cancer.

The identification of tumor "oncogenic drivers" and the subsequent development of targeted therapy represented a milestone in the treatment of lung cancer over the last years. Tumor genotyping has been incorporated into therapeutic decision making of advanced non-small cell lung cancer (NSCLC) since has become clear that individuals with actionable molecular alterations receiving a matched targeted agent certainly live longer and better. The recent understanding of biological mechanisms underlying cancer immune evasion has allowed the development of a new class of immunomodulatory agents which are able to reactivate host immune-response, offering the potential for long-term disease control and survival in a significant subgroup of lung cancer patients. The complementary therapeutic effects of these two different approaches suggested intriguing potential for therapeutic synergy with combination strategies. Indeed, immunotherapy could consolidate the dramatic but transient tumor responses achieved with targeted therapy into long-term survival benefit, due to the induction of specific anti-tumor memory. However, the great emphasis and expectations linked to immune-targeted combinations have been mostly disappointed by the initial controversial results of early-phase trials, raising relevant concerns about the use of these combinations for lung cancer treatment. This review briefly summarizes the basis of immunogenicity and immune escape in oncogene addicted NSCLC, providing an updated overview of clinical trials, with the final aim of defining the current unmet needs of immuno-targeted combinations in clinical practice.

Laparoscopic Approach for Thermoablation Microwave in the Treatment of Hepatocellular Carcinoma: A Single Center Experience.

BACKGROUND: The surgical therapy of choice for hepatocellular carcinoma (HCC) is liver transplantation (LT) or hepatic resection, although only a small percentage of patients can undergo these procedures. Microwave thermal ablation (MWTA) can be an effective alternative treatment for HCC that complicates a cirrhotic liver disease, either as a final procedure or for downstaging patients on the waiting list for LT, or in combination with resective surgery to achieve oncological radicality. OBJECTIVE: The purpose of this retrospective study was to evaluate experience with the laparoscopic approach of MWTA at our center. MATERIALS AND METHODS: In a cohort of 35 consecutive patients undergoing MWTA with laparoscopic approach between January, 2013 and May, 2016, we reviewed the demographic data, the Barcelona clinic liver cancer stage, the severity of cirrhotic liver disease, the size of the ablated lesion, the duration of the procedure, and complications occurring within 90 days of surgery. RESULTS: MWTA was performed by applying one to three hepatic parenchymal insertions (mean 1.8) per patient. The mean duration of surgery was 163 ± 18 minutes. There was no blood loss in any of the procedures. Complete necrosis on CT scan was achieved in 26/35 patients (75%). The mean hospital stay was 4.6 (range 2-7) days; major complications were postablation syndrome in 2/35 (5.7%), peritoneal fluid in 4/35 (11.4%), and transient jaundice in 1/35 (2.8%) patients. There was no mortality. CONCLUSIONS: Laparoscopic MTWA is a safe and effective treatment for unresectable HCC and when a percutaneous procedure is not feasible.