Benzodiazepines (BZD) are commonly prescribed to cancer patients to treat anxiety, insomnia, and chemotherapy-induced nausea. This is the first study to identify an association between BZDs and survival outcomes in early- and late-stage disease across multiple cancer types. In pancreatic cancer patients receiving chemotherapy, lorazepam (LOR) was associated with worsened progression-free survival outcomes. Furthermore, the experiments in pancreatic ductal adenocarcinoma (PDAC) murine tumours showed that LOR stimulates fibrosis and inflammatory signalling, and promotes desmoplasia and ischemic necrosis.
Cancer is a devastating diagnosis associated with emotional distress, anxiety, and depression. Harsh surgical, radiologic, and chemotherapeutic interventions can induce numerous side effects, including nausea, anxiety, fatigue, and insomnia. To combat these cancer-associated effects, patients are frequently prescribed an array of palliative care drugs such as aspirin, cannabinoids, antihistamines, selective serotonin reuptake inhibitors, opioids, and benzodiazepines (BZD). There is a growing appreciation that many commonly prescribed drugs can positively or negatively impact cancer risk, tumour progression, and chemotherapeutic efficacy. This research investigates the association between BZDs and cancer patient survival outcomes, with a special focus on pancreatic ductal adenocarcinoma (PDAC), encompassing analyses of the pancreatic cancer tumour microenvironment and cancer-associated fibroblast (CAF) signalling.
This study used Multivariate Cox regression modelling to retrospectively examine survival outcomes in Roswell Park cancer patients with BZD prescription records (2000-2022). Various techniques, including IHC, H&E staining, Masson’s trichrome staining, RNAscope, RNA sequencing, ELISA, and qPCR, were used to assess the influence of lorazepam (LOR) on murine PDAC tumours and the effect of BZDs on IL6 expression and secretion by human-immortalised pancreatic CAFs. Additionally, PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signalling.
In pancreatic cancer patients receiving chemotherapy, LOR was associated with significantly worse PFS (HR: 3.83) compared to patients not prescribed LOR. In contrast, alprazolam (ALP) was associated with significantly improved PFS (HR: 0.38). Based on these differential effects on pancreatic cancer patient survival, researchers investigated how these BZDs impact the growth and histology of murine PDAC. The experiments in PDAC murine tumours showed that LOR promotes desmoplasia (i.e., fibrosis and extracellular matrix protein deposition), inflammatory signalling, and ischemic necrosis. Notably, GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 expression in human CAFs in a pH and GPR68-independent manner.
Building upon these findings, OS differences were compared between the Roswell Park patients prescribed LOR or ALP relative to patients with no record of BZDs who were treated for several types of tumours. LOR was associated with significantly worse OS and PFS in prostate (HR OS: 2.160, PFS: 1.899), ovarian (HR OS: 1.521, PFS: 1.464), invasive nevi/melanoma (HR OS: 1.978, PFS: 2.195), head and neck (HR OS: 1.629, PFS: 1.635), colon (HR OS: 1.620, PFS: 1.782), uterine (HR OS: 1.376), and breast (HR OS: 1.248, PFS: 1.345) cancers, compared with patients without a BZD prescription. In contrast, ALP showed minor effects on survival outcomes, except in hormonal cancers, where it was associated with worse OS and PFS in breast cancer (HR OS: 1.867, PFS: 1.850) and worse OS in prostate (HR OS: 1.464) and uterine cancers (HR PFS: 1.668). Intriguingly, LOR was associated with significantly improved OS in patients with brain cancer (HR:0.779).
This is the first study to identify an association between BZDs and survival outcomes in early- and late-stage disease across multiple cancer types. In pancreatic cancer patients receiving chemotherapy, LOR correlates with worse PFS outcomes, while ALP is associated with improved PFS. Mechanistically, LOR stimulates fibrosis, inflammatory signalling, desmoplasia and ischemic necrosis in murine PDAC tumours. These findings underscore the need for prospective clinical trials to assess the impact of different BZDs on survival across different cancer types.
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