Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis.

The peritoneum is a common site of metastasis in advanced gastric cancer (GC). Diagnostic laparoscopy is now routinely performed as part of disease staging, leading to an earlier diagnosis of synchronous peritoneal metastasis (PM). The biology of GCPM is unique and aggressive, leading to a dismal prognosis. These tumors tend to be resistant to traditional systemic therapy, and yet, this remains the current standard-of-care recommended by most international clinical guidelines. As this is an area of unmet clinical need, several translational studies and clinical trials have focused on addressing this specific disease state. Advances in genomic sequencing and molecular profiling have revealed several promising therapeutic targets and elucidated novel biology, particularly on the role of the surrounding tumor microenvironment in GCPM. Peritoneal-specific clinical trials are being designed with a combination of locoregional therapeutic strategies with systemic therapy. In this review, we summarize the new knowledge of cancer biology, advances in surgical techniques, and emergence of novel therapies as an integrated strategy emerges to address GCPM as a distinct clinical entity.

Resistance to systemic immune checkpoint inhibition in the peritoneal niche.

Immune checkpoint inhibition (ICI) is an established therapeutic option for patients with deficient mismatch repair or high levels of microsatellite instability tumors. Yet, response to ICI among this group is varied, with nearly one-third of patients exhibiting primary resistance. Initial efforts in studying mechanisms of resistance to ICI have focused on intrinsic tumor factors. Host factors such as metastatic niches have unique biological properties that may mediate resistance to ICI but have been less studied date. Patients with metastatic d-MMR/MSI-H gastrointestinal cancers and peritoneal metastases (PM) who had concurrent ascites have been recently shown to have worse outcomes with ICI therapy compared with patients with PM without ascites and patients with non-PM metastases. The juxtaposition of tumors with an intrinsic sensitivity to ICI failing to respond by virtue of the presence of ascites within the peritoneum, brings to the forefront the critical role of the metastatic niche. In this commentary, we discuss mechanisms for ICI resistance that may arise from the immunoprivileged state of the peritoneal cavity, paracrine factors within malignant ascites or tumor-peritoneum interactions. An improved understanding of the peritoneal microenvironment and the use of peritoneal-directed therapies may ameliorate the modest benefit of ICIs in this unique clinical entity.

Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: Experience from a single Asian centre.

BACKGROUND: The importance of immune-checkpoint inhibitors (ICI) can no longer be understated since its move to front-line treatment in non-small cell lung cancer (NSCLC) in recent years. However, the safety and efficacy of ICI in special populations such as those with infections like tuberculosis (TB) and hepatitis B (HBV) remain unknown as they are routinely excluded from clinical trials. METHODS: Records of patients with advanced NSCLC who were treated with ICI from January 2014 to June 2019 at a single Asian centre were reviewed. Those with a history of HBV and/or TB were selected. In this group, safety and treatment outcomes including overall survival (OS), progression-free survival (PFS) and response rate were reported and compared against control. RESULTS: 191 patients received ICI, 47 (24.6%) had a history of TB/HBV. The median PFS in those with a history of TB/HBV was 5.7 months (95% CI 3.9-7.6), compared to 3.1 months (95% CI 2.4-3.8) in control (HR 0.61, 95% CI 0.39-0.93, p = 0.021). Median OS was 15.6 months (95% CI 10.2-21.0) compared to 11.1 months (95% CI 7.6-14.7 months) in the control group (HR 0.58, 95% CI 0.34-0.99, p = 0.046). Adverse events of any grade (G) were similar in both groups; slightly more patients with TB/HBV experienced G3 or higher adverse events. Four patients developed TB after initiation of ICI, none with previously documented TB experienced reactivation. Of the 42 patients with a history of HBV, eight had inactive chronic HBV and six had detectable viral load. None of the 34 patients who were previously exposed to HBV had reactivation. CONCLUSION: The use of ICI appears to be safe and efficacious in patients with TB/HBV infection. Prospective studies are required to identify those at risk in order to optimise care to these groups of patients.

Modern-day palliative chemotherapy for metastatic colorectal cancer: does colonic resection affect survival?

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) with surgically incurable metastases would be recommended for palliative chemotherapy (PC). The role of surgical intervention is debatable with no conclusive evidence for routine primary tumour resection (PTR) or stoma creation. We aimed to study if surgical intervention conferred a survival benefit in patients with mCRC who received upfront systemic therapy. METHODS: A retrospective review of a prospectively collected database in a single centre was performed. Patients diagnosed with mCRC from January 2004 to December 2014 were included. We excluded patients who had an upfront surgical intervention, had no treatment with systemic therapy or had attained curative resection. The decision for surgery was based on the outcome of a multidisciplinary tumour board. Demographic, clinicopathological, treatment and follow-up data were collected. Univariate and multivariate analyses were performed. RESULTS: Out of 408 patients with mCRC with incurable metastases, we analysed 124 patients who had upfront PC. Twenty-nine had PC + PTR (group A), 10 had PC + stoma (group B) and 85 had PC only (group C). Undergoing PTR led to significant improvement in overall survival (OS; 30.8 versus 13.4 versus 11.0 months, P < 0.001). With multivariate analysis, undergoing PTR and receiving biologics were independent good prognostic variables. Surgical resection was safe with minimal complications. CONCLUSIONS: PTR was found to increase OS while stoma creation had no impact on OS. The benefits and safety of undergoing PTR may be a result of selection bias. Further prospective studies are required to confirm the observations of this study.