Abstract
Background: Brain metastases frequently occur in patients with late-stage cancers. Treatment with high-dose glucocorticoids (GCs) is usually started to prevent or reduce tumor-related edema ...and its deadly complications. However, treatment with high-dose GCs is associated with serious side effects, including diabetes and immunosuppression, which could promote tumor growth or reduce the effectiveness of antitumor therapies. Based on its potential antitumor properties and on its ability to prevent GC-induced diabetes, the antidiabetic compound Metformin could reduce short-term mortality in patients with brain metastases taking high-dose GCs. Methods: The OPTIMAL study is a monocentric, open label, randomized Phase II trial in patients with brain metastases from melanoma, lung or breast cancer, who require treatment with high-dose dexamethasone, as defined as a minimum of 8 mg daily based on the clinician judgment, for at least three consecutive weeks. At enrollment, patients are randomized in a 1:1 ratio to receive high-dose dexamethasone +/- metformin 2550 mg/day for 30 days. At randomization, patients are stratified according to: tumor origin, dose of dexamethasone (8-12 vs. > 12 mg/day) and baseline fasting glycemia (< 100 vs. 100-125 mg/dl). Patients may receive concomitant radiotherapy based on the judgment of the physician. The primary study endpoint is the rate of precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl. Discussion: The OPTIMAL study aims to evaluate the efficacy of upfront use of metformin in preventing the onset of GCs-induced diabetes and other metabolic perturbations in patients with brain metastases from melanoma, lung or breast cancer. Other clinical objectives consist in investigating the impact of metformin on precocious mortality, deterioration of ECOG PS and local (brain) disease control rate at one month after dexamethasone initiation. The effect of dexamethasone +/- metformin on other metabolites or growth factors, including amino acids, fatty acids, ketone bodies, IGF-1, as well as on the number, activation status and metabolism of peripheral blood immune cell populations will be evaluated as well. Trial registration: The OPTIMAL trial is registered at ClinicalTrials.gov (NCT04001725, June 28, 2019) and EudraCT (2019-000105-73, January 8, 2019).
Citation Format: Claudio Vernieri, Federico Nichetti, Francesca Ligorio, Emma Zattarin, Teresa Beninato, Riccardo Lobefaro, Giulia Bianchi, Giuseppe Capri, Marina Garassino, Giuseppe Lo Russo, Michele Del Vecchio, Paola Corsetto, Licia Rivoltini, Chiara Castelli, Filippo de Braud. Efficacy of metfOrmin in PrevenTIng glucocorticoid-induced diabetes in Melanoma, breAst or Lung Cancer patients with brain metastases: The phase II OPTIMAL study abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT198.
Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to ...explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib.
mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared.
Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017).
Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.
Background
Pediatric oncohematologic patients are a high‐risk population for clinical deterioration that might require pediatric intensive care unit (PICU) admission. Several studies have described ...outcomes and mortality predictors for patients post hematopoietic stem cell transplantation (HSCT), but fewer data exist regarding the category of non‐HSCT patients.
Procedure
All oncohematologic non‐HSCT patients ≤18 years requiring PICU admission from 1998 to 2015 in our tertiary‐care academic hospital were retrospectively evaluated by means of the pediatric hematology‐oncology unit database and the Italian PICUs data network database. We assessed the relation between demographic and clinical characteristics and 90‐day mortality after PICU admission.
Results
Of 3750 hospitalized oncohematologic patients, 3238 were non‐HSCT and 63 (2%) of them were admitted to the PICU. Patients were mainly affected by hematological malignancies (70%) and mostly were in the induction‐therapy phase. The main reasons for admission were respiratory failure (40%), sepsis (25%), and seizures (16%). The median PICU stay was 5 days (range 1‐107). The mortality rate at PICU discharge was 30%, and at 90 days it was 35%. Fifty‐five percent of deaths happened in the first 2 days of the PICU stay. Cardiac arrest (P = .007), presence of disseminated intravascular coagulation (DIC, P = .007), and acute kidney injury (AKI) at PICU admission (P < .001) and during PICU stay (P = .021) were significant predictors of mortality in the multivariate analysis. Respiratory failure and mechanical ventilation were not associated with mortality.
Conclusions
A relatively small percentage of non‐HSCT patients required PICU admission, but the mortality rate was still high. Hemodynamic instability, DIC, and AKI, but not respiratory failure, were significant predictors of mortality.
Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting ...remains unclear.
We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates.
Of 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009).
CG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile.
Single-agent chemotherapy, alone or with immunotherapy, represents the first-line standard-of-care treatment for advanced TNBC patients. This study conducted in 88 TNBC patients supports the use of carboplatin-based doublets as first-line regimens and provides evidence of better survival outcomes with carboplatin-gemcitabine among patients previously treated with taxanes in the (neo)adjuvant setting. Future studies are needed to investigate chemo-immunotherapy combinations containing carboplatin-based doublets.
In prostate cancer , there has recently been an emerging interest in mutations in genes belonging to the homologous recombination repair (HRR) pathway and in the inhibition of poly (ADP-ribose) ...polymerase (PARP) proteins.
Mutations in the HRR genes, including BRCA1, BRCA2, and Ataxia-Telangiesctasia mutated (ATM), have been reported in prostate cancer, with different incidence in the localized and advanced settings. The PARP enzyme complex is involved in repair of DNA damage and its inhibition causes the accumulation of DNA mutations in HRR deficient cells. Several PARP inhibitors (PARPi) are under development, such as olaparib, talazoparib, niraparib, rucaparib, and veliparib. In metastatic castration resistant prostate cancer (mCRPC), olaparib has been the most studied and its clinical efficacy has been validated in a phase III clinical trial. Rucaparib and niraparib have also shown promising results in the preliminary analyzes of two phase II trials, while talazoparib is currently under development.
PARPi have become part of the treatment of mCRPC. Early results of combination therapy with PARPi and new hormonal therapy are promising and are supported by a strong biological rationale. Current results need to be validated in randomized phase III-controlled trials in order to translate the use of PARPi into real world practice.
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Background: The multikinase inhibitor cabozantinib (Cabo) is an effective treatment option for metastatic renal cell carcinoma (mRCC). However, data on the optimal sequencing of ...Cabo and other available therapies are lacking. In particular, the strategy of continuing Cabo administration after disease progression (PD) has never been investigated yet. In light of its ability of inhibiting MET and AXL, which are implied in VEGFR acquired resistance, the hypothesis of a prolonged efficacy in slowing tumor growth, despite first radiological PD, is worth to be investigated. Methods: We conducted a retrospective multicenter study of mRCC patients (pts) treated with oral Cabo as second or subsequent line between 2014 and 2020 in 11 Italian Oncology units. Our study population included pts treated beyond RECIST first PD due to the clinical benefit and tolerance to therapy demonstrated. As a control group we analyzed pts treated with other therapies (thyrosin-kinase inhibitors (TKIs), everolimus, nivolumab or other) after first radiological PD with Cabo. Our aim was to evaluate the post-progression outcome according the two treatment strategies: Cabo beyond PD or other subsequent therapy. Results: 89 pts were included in the analysis: 45 pts received Cabo beyond PD and 44 another therapy: 22 pts nivolumab, 7 everolimus, 6 sorafenib and the others lenvatinib plus everolimus, sunitinib, HD-IL2, pazopanib or axitinib. The median age of all pts was 61.6 years (22.7-83.2) and 77.5% were male. 40.4% and 31.5% of pts had received one or two prior treatment lines, respectively; the remaining 28.1% received Cabo > 3 line. At Cabo start, 83.9% were intermediate-poor risk according IMDC score (77.8% in CABO beyond PD and 90.5% in the control group) and the most common metastatic sites were lung (76.4%), lymph nodes (69.7%), bone (56.2%), liver (30.3%) and brain (14.8%). The objective response rate to Cabo before PD was significantly higher in pts continuing Cabo beyond PD than in those who were treated with other after first radiological PD (46.7% vs 25%, p = 0.03) and a longer but not statistically significant PFS was observed (median 8.1 vs 5.9 months, p = 0.377). Moreover, the median number of prior therapy lines was significantly higher for pts who were treated with Cabo beyond PD than other (2 vs 1, p = 0.016). Median duration of treatment with Cabo beyond PD was 6.4 months. In addition, continuing Cabo beyond PD was associated with a significantly better post-progression overall survival (OS) than switching to other therapy at PD (median OS 16.9 vs 13.2 months, Hazard Ratio 0.66, 95%CI 0.48 – 0.92, p = 0.011). Conclusions: This study showed a longer post-progression OS in pts continuing Cabo beyond PD than in those who switched to another therapy. With the limitations of a retrospective analysis, this is the first evidence suggesting that maintaining Cabo beyond PD is an effective strategy in pts with mRCC.
•Efficacy of Immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer with uncommon histology is an unmet need.•Our findings highlight no progression-free survival and overall survival ...difference compared to common histotypes•Further prospective trials are needed to clarify ICIs role in uncommon histotypes.•Combination of ICIs and chemotherapy should be explored in uncommon histologies with a more aggressive behavior.
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).
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.
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.
No significant differences were detected between UH and CH groups. Prospective trials are needed to understand ICIs role in UH population.
ICIs role aNSCLC with UH is still unclear. In this retrospective study conducted in 375 pts – with 79 pts having a UH – no significant difference was found between the UH and CH group treated with ICIs. Given the retrospective nature of this study, further prospective trials are needed to clarify ICIs role in UH patients.
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.
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e15543
Background: Outcomes of patients affected by advanced neuroendocrine carcinomas (NEC) with Ki-67 labeling index > 55% are heterogeneous regardless of the primary tumor site. We ...explored baseline inflammatory indexes and serum albumin levels to identify markers of response to standard first line chemotherapy. Methods: We retrospectively identified patients with advanced NEC treated with cisplatin (CP) or carboplatin (CB) and etoposide between 2015 and 2019 at the National Cancer Institute of Milan. Linear and Cox regressions were used to investigate, respectively, numeric and time-to-event outcomes. Maximization of log-rank statistics was used for optimal cutoffs finding. An artificial intelligence algorithm, random forest, was used to rank the impact of different clinical features on OS and PFS. Results: A total of 81 consecutive patients with different primary tumors (53 small cell lung carcinoma, 12 large cell neuroendocrine carcinoma, 10 gastrointestinal neuroendocrine carcinoma and 6 Merkel cell carcinoma) either treated with CP (n = 39) or CB (n = 42) were analyzed. Overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were, respectively, 50.6%, 5.5 months (m) and 9.1m. Considered together, high serum albumin (SA > 3.5 g/dl) and low neutrophile-to-lymphocyte ratio (NLR < 3.59) identified a group of patients (n = 42) with longer median PFS and OS compared to the rest of the cohort (8.3m vs 1.5m, HR 3.58, CI 2.14-6.02, p < 0.001 for PFS and 12.6m vs 4.4m, HR 3.11, CI 1.88-5.18, p < 0.001 for OS); within this group a higher ORR (74% vs 36%, OR 5.01, CI 1.83-14.64, p = 0.002) was observed. Two multivariate models showed statistically significant associations of SA and NLR with PFS ( p = 0.017 and p = 0.005) and OS ( p = 0.016 and p = 0.036), independent of baseline ECOG performance status, age, sex, body mass index, smoking status, stage, hepatic tumor burden, primary site, histology, lactate dehydrogenase (LDH) serum levels, type of platinating agent and number of cycles. Two random forest models ranked SA, NLR and LDH as the most important factors for PFS and OS prediction. Conclusions: In the setting of advanced NEC with Ki-67 > 55% the combined use of SA and NLR identified two groups of patients with remarkably different outcomes, suggesting that these serum markers at baseline may have prognostic implications and be predictive of response to platinating agents. Prospective studies should validate these preliminary findings.
Cabozantinib improves survival in metastatic renal cell carcinoma (mRCC) after prior antiangiogenics. The best treatment at disease progression (PD) is unknown. Being also a AXL/MET inhibitor, ...involved in acquired resistance, we hypothesized a prolonged tumor growth control in patients continuing cabozantinib despite PD.
This retrospective multicenter study enrolled patients receiving cabozantinib after the first line between 2014 and 2020. We compared patients maintaining cabozantinib after first PD due to clinical benefit and good tolerability with those who changed therapy. The postprogression survival (PPS) of both was our primary endpoint.
We analyzed 89 patients: 45 received cabozantinib beyond PD and 44 switched therapy. 40.4%, 31.5%, and 28.1% of patients received 1, 2, or >2 prior treatment, respectively. 84.3% were intermediate-poor International Metastatic Renal Cell Carcinoma Database risk. Patients continuing cabozantinib showed a higher response rate to cabozantinib before PD (46.7% vs 25%, p = 0.03) and were more heavily pretreated. Continuing cabozantinib showed a significantly longer PPS compared with switching therapy (median PPS 16.9 vs 13.2 months, HR 0.66, 95%CI 0.48-0.92, p = 0.011).
We observed longer PPS in patients continuing cabozantinib beyond PD, suggesting that this could be an effective option.
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