ABSTRACT
Many systemic treatments used in genitourinary oncology negatively affect haematopoiesis, thus leading to neutropenia. Neutropenic patients are vulnerable to bacterial, and other infections. Often fever is the only symptom in these patients. Neutropenic fever is a major threat for these patients, as it may lead to life-threatening therapy complications that significantly impair the patient's quality of life, Moreover, it may also worsen the prognosis due to therapy delays or necessary dose modifications. Granulocyte colony stimulating factors (GCSF), which can improve neutrophil granulocyte formation, are used both for supportive treatment in febrile neutropenia and for its prophylaxis. The correct indication for such GCSF support depends on the general risk of febrile neutropenia of the therapy used, as well as on individual patient factors and the treatment intent (palliative vs. curative). Based on the current recommendations both of the German and international guidelines, this article aims to provide an up-to-date and practice-oriented overview of the use of GCSF in uro-oncology.
Subject(s)
Febrile Neutropenia , Granulocyte Colony-Stimulating Factor , Humans , Granulocyte Colony-Stimulating Factor/adverse effects , Quality of Life , Neutrophils , Fever/drug therapy , Fever/etiology , Fever/prevention & control , Febrile Neutropenia/complications , Febrile Neutropenia/drug therapyABSTRACT
Due to the approval of immuno-oncological therapies with immune checkpoint inhibitors, the treatment of metastatic urothelial carcinoma has become more complex in all lines of therapy. Thus, in first-line treatment, immunotherapy alone or immune maintenance therapy following platinum-based chemotherapy can be applied in addition to treatment with platinum-based combination therapies alone. In addition to the approval status and guideline recommendation, patient-specific factors such as comorbidities as well as patient preference must always be considered when choosing a therapy. In the following, we summarize the current data on treatment options in the first-line therapy of metastatic urothelial carcinoma and illustrate their practical application using a patient example.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Humans , Immune Checkpoint Inhibitors , Immunotherapy , Urinary Bladder Neoplasms/drug therapyABSTRACT
BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that CTLA4 promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate CTLA4 methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC. METHODS: CTLA4 methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, CTLA4 methylation as well as CD8+ T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post-tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation. RESULTS: CTLA4 promoter hypomethylation was significantly correlated with CTLA4 mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p<0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, CTLA4 promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of CTLA4 hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, CTLA4 promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003). CONCLUSIONS: Our study suggests CTLA4 methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.
