Introduction Cisplatin, a platinum-based antineoplastic agent, is the cornerstone for the treatment of many malignancies. Nephrotoxicity is the primary dose-limiting toxicity, and various hydration regimens and supplementation strategies are used to prevent cisplatin-induced kidney injury. However, evidence-based recommendations on specific hydration regimens are limited. A systematic review was performed to evaluate clinical studies that have examined hydration and supplementation strategies to prevent cisplatin-induced nephrotoxicity. Materials and methods PubMed and Excerpta Medica databases were searched from 1966 through October 2015 for clinical trials and other studies focused on hydration regimens to prevent nephrotoxicity in cancer patients treated with cisplatin. The University of Oxford Centre for Evidence-Based Medicine criteria were used to grade level of evidence. Results Among the 1,407 identified studies, 24 were included in this systematic review. All studies differed on type, volume, and duration of hydration. Among the 24 studies, 5 evaluated short-duration hydration, 4 evaluated low-volume hydration, 4 investigated magnesium supplementation, and 7 reviewed forced diuresis with hydration. Short-duration and lower-volume hydration regimens are effective in preventing cisplatin-induced nephrotoxicity. Magnesium supplementation may have a role as a nephroprotectant, and forced diuresis may be appropriate in some patients receiving cisplatin. Conclusion Hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity. Specifically, short-duration, low-volume, outpatient hydration with magnesium supplementation and mannitol forced diuresis (in select patients) represent best practice principles for the safe use of cisplatin. The Oncologist 2017;22:609-619 IMPLICATIONS FOR PRACTICE: The findings contained within this systematic review show that (a) hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity, (b) short-duration, low-volume, outpatient hydration regimens appear to be safe and feasible, even in patients receiving intermediate- to high-dose cisplatin, (c) magnesium supplementation (8-16 milliequivalents) may limit cisplatin-induced nephrotoxicity, and (d) mannitol may be considered for high-dose cisplatin and/or patients with preexisting hypertension. These findings have broad implications for clinical practice and represent best practice principles for the prevention of cisplatin-induced nephrotoxicity.

A Systematic Review of Strategies to Prevent Cisplatin‐Induced Nephrotoxicity

Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword.

Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN

https://www.jto.org/article/S1556-0864(15)32858-6/pdf

Sarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1)

Sirolimus (Rapamune), a mammalian target of Rapamycin (mTOR) inhibitor, which has been used extensively in children following solid organ transplantation, has been demonstrated to have anti-angiogenic activity in pre-clinical models. Limited experience suggests that it may have application to the treatment of vascular lesions. We describe our experience with a 1-year-old female with a kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon who had rapid and dramatic response to sirolimus (0.1 mg/kg/day). This case provides further rationale for clinical trials of sirolimus in the treatment of vascular lesions.

Treatment of childhood kaposiform hemangioendothelioma with sirolimus.

Pulmonary Epithelioid Haemangioendothelioma and Bevacizumab

Toll-like receptors (TLRs) play a crucial role in the innate and adaptive immune responses against microbial infection, tissue injury and cancer. Ligands of TLR9 have been developed as therapy in non-small-cell lung carcinoma (NSCLC). However, phase III clinical trials in metastatic NSCLC were negative. Our objective was to determine whether TLR9 affects tumor growth. We generated a mouse model of lung adenocarcinoma (ADC) mutated for K-ras (K-ras(LA1) ), with and without TLR9 inactivation (K-ras(LA1) TLR9(-/-) and K-ras(LA1) TLR9(+/+) , respectively). TLR9 was functionally expressed only in mononuclear cells of K-ras(LA1) TLR9(+/+) mice. These mice had significantly worse survival and a higher tumor burden than K-ras(LA1) TLR9(-/-) mice. Lung tumors were analyzed for 24 cytokines/growth factors using Bio-Plex multiplex bead-based assays. Factor VIII was assessed by immunochemistry. Tumors from K-ras(LA1) TLR9(+/+) mice were characterized by an angiogenic phenotype with higher concentrations of vascular endothelial growth factor (VEGF) and higher microvessel density than from K-ras(LA1) TLR9(-/-) mice. LKR13 cells, an ADC cell line derived from K-ras(LA1) mice, were subcutaneously injected into TLR9(-/-) and TLR9(+/+) mice. Syngeneic tumors regressed in TLR9(-/-) but not in TLR9(+/+) mice. Peripheral blood mononuclear cells from TLR9(-/-) mice released less VEGF than those from TLR9(+/+) mice. In 61 patients with early-stage NSCLC, TLR9 was expressed in mononuclear cells that infiltrated tumors, as assessed by immunochemistry, and contributed to worse survival. Our results suggest that TLR9 expression in mononuclear cells was associated with an angiogenic phenotype and promoted lung cancer progression. These findings may aid clinical development of TLR9 ligands to treat cancers.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.28413

Expression of TLR9 in tumor-infiltrating mononuclear cells enhances angiogenesis and is associated with a worse survival in lung cancer

https://www.jto.org/article/S1556-0864(15)33276-7/pdf

Secondary Resistance to Erlotinib: Acquired T790M Mutation and Small-Cell Lung Cancer Transformation in the Same Patient

Background Cisplatin is a pivotal drug in combined chemotherapy for non-small cell and small-cell lung cancers (NSCLC or SCLC), but its renal toxicity limits its use. Current guidelines recommend 24 h hydration: thus hospitalization is required. The aim of this retrospective study was to confirm the safety of short hydration before giving an intermediate-to-high dose of cisplatin in an outpatient clinic. Patients and methods Patients eligible had NSCLC or SCLC and were being treated with a chemotherapy regimen that included cisplatin ≥ 75 mg/m 2 . They were given the same short hydration protocol for 1 day. Nephrotoxicity was defined as ≥ grade 1 according to NCIC common toxicity criteria. Predictive factors for nephrotoxicity were analyzed. Results Three hundred and fifty-seven consecutive patients (median age 58 years, range: 25-81) were reviewed. Twenty-one patients (6%) had ≥ grade 1 nephrotoxicity and all except one had grade 1 toxicity according to NCIC criteria for common toxicity (SC  P  = 0.002), initial serum creatinine ≥ 100 μmol/L (OR = 8.3 CI 95% [2.55-27.4] P  = 0.0005), and dose cycle of cisplatin ≥ 100 mg/m 2 (OR = 10.8 CI 95% [3.6-32.5] P Conclusion Rapid outpatient administration of a single dose of cisplatin at ≥ 75 mg/m 2 is feasible without a high risk of nephrotoxicity.

Routine administration of a single dose of cisplatin ≥ 75 mg/m2 after short hydration in an outpatient lung-cancer clinic.

Resume Au cours de l’infection au virus de l’immunodeficience humaine (VIH), le sida etait responsable de la majorite des deces avant 1996 mais, depuis l’introduction des therapeutiques antiretrovirales, les causes de mortalite ont beaucoup evolue. En 2010, 75 % des deces sont secondaires a des maladies non-classant sida et les cancers constituent la plus grande proportion de cas. Le cancer du poumon est le plus frequent, en termes d’incidence mais egalement de mortalite. Il presente certaines particularites par rapport a la population generale : il existe un exces de risque, en raison d’une plus grande exposition au tabagisme mais aussi probablement en raison de l’immunodepression. L’âge de survenue est plus jeune, et le pronostic est plus mauvais que dans la population generale. La difficulte de prise en charge est liee d’une part a l’agressivite particuliere de la tumeur et d’autre part aux comorbidites de ces patients et aux interactions potentielles entre les anticancereux et les therapies antiretrovirales. Un essai therapeutique de phase II (IFCT-CHIVA 1001) est en cours au niveau national.

Laure Belmont

Papers

Pulmonary Epithelioid Haemangioendothelioma and Bevacizumab

Expression of TLR9 in tumor-infiltrating mononuclear cells enhances angiogenesis and is associated with a worse survival in lung cancer

Secondary Resistance to Erlotinib: Acquired T790M Mutation and Small-Cell Lung Cancer Transformation in the Same Patient

Routine administration of a single dose of cisplatin ≥ 75 mg/m2 after short hydration in an outpatient lung-cancer clinic.

Cancer du poumon et infection par le Virus de l’Immunodéficience Humaine