The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.

Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.

Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were ß-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma.

BACKGROUND: To examine the association between hypertension (HTN), angiotensin system inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU). METHODS: We retrospectively reviewed all patients with mRCC who received SU as first-line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre-existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HRs) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, International mRCC Database Consortium risk group and histology. RESULTS: Among 213 patients with a 3.6-year median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the two exposures (P < 0.0001). Hypertensive patients have longer OS (median: 41.6 versus 16.4 months, P < 0.0001) and longer PFS (median: 12.9 versus 5.6 months, P < 0.0001) than non-hypertensive patients (n = 79). ASI users (n = 105) had more HTN_PRE compared with those (n = 108) who did not (65% versus 19%, P < 0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (P = 0.05) and marginally with PFS (P = 0.06) while ASI intake was significantly associated with better OS [HR = 0.40; 95% CI (0.24-0.66), P < 0.001] and PFS [HR = 0.55 (0.35-0.86), P = 0.009]. The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment. CONCLUSION: Concomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients.

Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis.

BACKGROUND: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 → 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS: In group 4/2 → 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 → 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.

VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide.

BACKGROUND: No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone. METHODS: Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (-2578A/C, -634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy-Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan-Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant. RESULTS: Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the -2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the -634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the -634CC genotype had a median PFS of 2.2 months whereas patients with the genotype -634CG/GG had a median PFS of 6.25 months (P=0.0042). CONCLUSION: The -634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule.

Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study.

BACKGROUND: Cabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown. PATIENTS AND METHODS: We carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (Cmeas) to determine the area under the curve (AUC), apparent clearance (Cl/F) and residual blood concentration (Ctrough). Best overall response according to RECIST 1.1 and relevant toxicity (adverse event grade 3-4 or grade 2 requiring dose reduction or discontinuation) were assessed according to Cmeas, Ctrough, AUC and Cl/F. RESULTS: We enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median Ctrough (406 versus 634 ng/ml, P = 0.001), Cl/F (2 versus 2.9 l/h, P = 0.002) and AUC (16 versus 20 µg h/ml, P = 0.037) compared with patients who had disease control as best response. Patients with relevant toxicity had a significantly higher Cmeas (732 versus 531 ng/ml, P = 0.006), Ctrough (693 versus 521 ng/ml, P = 0.005) and AUC (21 versus 16 µg h/ml, P = 0.046) compared with patients who did not experience any grade relevant toxicity. Receiver operating characteristic curves obtained from our study defined a threshold for drug efficacy of 536.8 ng/ml and of 617.7 ng/ml for toxicity. CONCLUSION: We first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.

Prognosis of renal cell carcinoma with bone metastases: Experience from a large cancer centre.

BACKGROUND: Bone metastases (BMs) are associated with significant morbidity and shorter survival in renal cell carcinoma (RCC). Our purpose was to identify prognostic factors for overall survival (OS) in RCC patients with BMs. METHODS: Data from patients with BMs from RCC treated at Gustave Roussy between April 1992 and March 2016 were retrospectively collected. Age, sex, Eastern Cooperative Oncology Group-Performance Status, Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups, histology, number and site of bone lesions, concomitant metastases (presence and sites), therapy for BMs (radical resection or palliative surgery, radiotherapy and other local and systemic treatments) and time from diagnosis to BMs were analysed. Synchronous solitary bone metastasis (SSBM) was defined as a single BM without concomitant visceral lesions at the initial diagnosis of RCC. OS was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan-Maier method and modelled with Cox regression analysis. RESULTS: From 1750 patients with diagnosis of RCC followed at Gustave Roussy Cancer Campus, 300 patients with BMs were identified. Median time from diagnosis to BMs was 32.4 months (range 0-324 months). In 64 patients (21%), bone was the only metastatic site, and 22 patients (7%) had an SSBM and 236 patients (79%) had concomitant metastases in other sites. Median OS was 23.2 months (95% confidence interval 19.9-26.2). SSBM patients had better OS than those with concomitant metastases (40 vs 20 months; P < 0.001). At multivariate analysis, concomitant metastases remained predictor of poor prognosis, while MSKCC risk group, radical resection and SSBM were predictors of better OS. CONCLUSIONS: This study suggests that MSKCC score, numbers of BMs and radical resection are important prognostic factors for RCC patients with BMs. Additionally, in the presence of solitary BM without concomitant metastases at the initial diagnosis of RCC, bone surgery should be considered to achieve local tumour control and likely increase OS.

Screening for consumptive coagulopathy in preeclampsia.

OBJECTIVE: To identify a practical and cost-effective profile of tests to screen for consumptive coagulopathy in preeclampsia (PE). METHODS: Retrospective analysis of the results of measurements of platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen and D-dimers in 100 patients presenting with PE uncomplicated by other disease or antepartum hemorrhage. Twenty-four patients had pregnancy-induced hypertension only, and 76 hypertension with proteinuria. RESULTS: The incidence of abnormal tests on presentation was raised D-dimers 34%, thrombocytopenia 14%, prolonged APTT 12%, prolonged PT 3%, and low fibrinogen 2%. Prolonged APTT without thrombocytopenia occurred in 8% of patients. In 19 patients with elevation of D-dimers alone, only one showed evidence of consumption of coagulation factors on subsequent testing. CONCLUSIONS: A combination of platelet count and APTT is probably a practical and cost-effective combination to screen for consumptive coagulopathy in PE.

Two cases of the diagnosis of optic neuritis leading to the diagnosis of multiple sclerosis.

More than one of three persons with multiple sclerosis will eventually get optic neuritis during the course of their disease. In each case below, a patient presented to an optometrist with optic neuritis, the discovery of which aided in the subsequent diagnosis of multiple sclerosis. These patients exhibited most of the typical signs of optic neuritis; reduced visual acuity, Marcus Gunn pupil, central scotomata, reduced color vision, abnormal funduscopic appearance, and pain on eye movement.