Chemotherapy following immune checkpoint inhibitors in patients with locally advanced or metastatic urothelial carcinoma.

BACKGROUND: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). METHODS: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities. RESULTS: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (< or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients. CONCLUSION: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data.

First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma: What Are the Most Appropriate Combination Therapies?

The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium growth factor (VEGF) over sunitinib monotherapy. The question is therefore what is the best combination for a given patient? A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. However, several issues remain unresolved and require further investigation, such as the PD-L1 status, the relevance of possible options based on the patient's profile, and consideration of second-line and subsequent treatments.

Effect of genetic polymorphisms in CYP3A4, CYP3A5, and m-TOR on everolimus blood exposure and clinical outcomes in cancer patients.

Genetic variations in CYP3A4, CYP3A5, and m-TOR could contribute to interpatient variability regarding m-TOR inhibitors pharmacokinetics or cellular effects. The purpose of this study was to evaluate the influence of selected candidate variations in these genes on everolimus pharmacokinetics, efficacy, and toxicity in cancer patients. Thirty-four patients receiving everolimus for breast (n = 22) or renal (n = 10) cancers, or neuroendocrine tumors of pancreatic origin (n = 2) were included in the study. Six variants in genes related to everolimus pharmacokinetics (CYP3A4*22 and CYP3A5*3) or pharmacodynamics (m-TOR rs2295079, rs2295080, rs2024627 and rs1057079) were genotyped. Associations with trough concentrations (C0), dose reductions, or treatment interruptions due to toxicity and progression-free survival were investigated using generalized estimating equations and Cox models. CYP3A5 nonexpressers had significantly higher C0 as compared with expressers (ßGG vs AG = + 6.32 ± 2.22 ng/mL, p = 0.004). m-TOR rs2024627 was significantly associated with an increased risk of cancer progression studied alone or as part of an haplotype (T vs C: HR = 2.60, 95% CI [1.16-5.80], p = 0.020; CTCG vs other haplotypes HR = 2.29, 95% CI [1.06-4.95], p = 0.035, respectively). This study showed that CYP3A5 expression impacts everolimus pharmacokinetics in cancer patients and identified a genetic variation in m-TOR associated with the risk of cancer progression.

Therapeutic Drug Monitoring of Everolimus in Oncology: Evidences and Perspectives.

Everolimus is a mammalian target of rapamycin (m-TOR) inhibitor that has been approved for the treatment of hormone receptor-positive advanced breast cancer, metastatic renal cancer, and neuroendocrine tumors. Although therapeutic drug monitoring (TDM) of everolimus is well established in the transplantation field, it is not currently performed in oncology. The last consensus conference about the TDM of everolimus states that for the use of everolimus in oncology, "further studies are required to determine the clinical utility of TDM for everolimus in oncology settings." In this review, the authors will discuss the current evidences and perspectives, based on observational studies available, in favor of the TDM of everolimus in oncology focusing on (1) the management of everolimus in routine practice, (2) the prerequisites for TDM of everolimus in oncology, (3) the pharmacodynamics (including a description of the biomarker of resistance and mutations in m-TOR), and (4) a general outlook.

Vaginal metastasis of renal clear-cell cancer.

BACKGROUND: Vaginal metastases originating from renal cancer remain a rare event, with less than 100 cases reported in the literature. The spreading mechanism is still under scrutiny. The tumoral bleeding often is a symptom revealing vaginal metastases. CASE: The present work reports patient case having vaginal metastasis of renal clear-cell cancer. The vaginal metastasis was treated by a 3-D conformational radiotherapy. Our experience is discussed with respect to an updated literature review concerning the medical management of vaginal metastasis related to kidney cancer. CONCLUSION: In our case, a 15 Gy hypofractionatedradiotherapy is efficient to control bleeding on the vaginal metastases of the kidney cancer. To add up a 15 Gy hypofractionated-radiotherapy in 5 fractions is an option if bleeding is still present. The tolerance of the treatment is excellent and no side effects have been described.

Résistance aux inhibiteurs des tyrosines kinases dans le cancer du rein.

FOCUS ON RESISTANCE TO TYROSINE KINASE INHIBITORS IN RENAL CANCER: The last decade has seen significant advances in understanding the biology and genetics of kidney cancer, some of which have radically changed treatment standards, including the emergence of targeted therapies. TKIs have significantly improved outcome in patients with metastatic disease. Nevertheless, a subset of patients (approximately 25 %) does not show any clinical benefit from targeted therapies. In many cases, patients initially respond to therapy but resistance to targeted agents has been shown to develop after a median of 6-12 months of treatment. Two general models of tumor resistance to anti-angiogenic agents targeting the VEGF pathway have been proposed: an adaptive (evasive) resistance, which occurs after a prolonged application of a drug (providing a period of tumor control), or intrinsic one (preexisting) non-responsiveness despite the presence of an active agent, showing no therapeutic benefit. Intrinsic resistance is related to tumor redundancy of pro-angiogenic pathways. Acquired resistance is associated with activation of alternative pathways either by upregulation of the VEGF pathway or by recruitment of alternative angiogenic factors responsible for tumor revascularization. Because different combinations and sequences of TKI are tested in clinical trials and immunotherapy (alone or in combination) radically alters patient management in its metastatic disease, the current effort aims at identifying resistance processes, evaluating their importance and proposing rational therapeutic approaches in order to obtain an additional clinical benefit. Our article summarizes the different mechanisms of resistance described in the literature.

Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study.

BACKGROUND: Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC. METHODS: Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6-9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors. RESULTS: No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29-8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10-3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70-10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48-4.23], p = 0.0006 and OR = 2.99[1.63-5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63-6.96], p = 0.0010). CONCLUSIONS: Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup. TRIAL REGISTRATION: Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008-0144.

[Crossed perceptions about malnutrition in patients and their doctors in oncology]. / Représentations croisées sur l'alimentation et la dénutrition chez les patients atteints de cancer : résultats de l'étude NutriCancer2012.

Malnutrition is common in oncology. However, it is often detected too late and nutritional support is sub-optimal. The patient's opinion, although often sought in therapeutic decisions in oncology, does not appear to be frequently taken into account in dietetic management. In NutriCancer2012 study, we interviewed patients, relatives and doctors about their perceptions of the impact of malnutrition and its quality of care. Of the 2209 patients questioned, majority said they were concerned about nutrition with 75% considering it essential to take appropriate nutritional care but only 19% self-reported link between malnutrition and fatigue. Physicians underestimated impact of malnutrition on patient's "quality of life". Doctors referred to the lack of human resources and knowledge in nutrition, and more than 80% wished the creation of nutrition teams. Sensitization of the general public and patients (and relatives) as soon as the cancer diagnosis could lead to better malnutrition's screening. Better nutrition training for physicians and creation of nutrition team could optimize management and improve efficacy during cancer treatments.

Towards therapeutic drug monitoring of everolimus in cancer? Results of an exploratory study of exposure-effect relationship.

INTRODUCTION: Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C0) target has been yet defined. The aim of this study was to determine everolimus C0 target for toxicity and efficacy. MATERIALS AND METHODS: Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was defined by termination, temporary interruption and/or dose reduction of everolimus while efficacy was defined as progression-free survival. C0 values were dichotomized by ROC curve analysis and the association between exposure and outcome was determined using Cox models for repeated events (toxicity) or Cox model censured at the first event (progression free survival). RESULTS: Among the 42 patients (77.8%) with breast cancer, 10 (18.5%) kidney cancer and 2 (3.7%) neuroendocrine cancer, adverse events were reported in 75.9% of the patients (everolimus termination in 25.9% patients). C0 everolimus higher than 26.3ng/mL (Sen=0.38,Spe=0.88) were associated with a 4-fold increased risk of toxicity (HR=4.12, IC95%=[1.48-11.5], p=0.0067) whereas C0 lower than 11.9ng/mL were associated with a 3-fold increased risk of progression (HR=3.2, IC95%=[1.33-7.81],p=0.001). DISCUSSION: Further studies are required to evaluate the everolimus C0 threshold proposed for toxicity (26.3ng/mL) and for progression (11.9ng/mL) especially with a large number of patients and more homogeneous types of cancer. However, these results are in favour of TDM for everolimus in oncology.

Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma-Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study.

AIM: To assess the efficacy and tolerability of sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: This observational study comprised 61 mRCC patients at 19 centres in France who received sunitinib rechallenge between January 2006 and May 2013. Patients received first-line sunitinib, ≥1 different targeted therapies, and then sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in sunitinib rechallenge. RESULTS: Analyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90-100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The sunitinib rechallenge safety profile was as expected, with no new adverse events reported. CONCLUSIONS: Sunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line sunitinib may not be associated with complete or irreversible resistance to therapy.

Radiodermatitis prevention with sucralfate in breast cancer: fundamental and clinical studies.

BACKGROUND: Acute radiodermatitis induced by radiotherapy may affect the quality of life and in some cases requires withholding treatment. The present study concerns the protective effect of a 1% sucralfate lotion. We propose joint fundamental and clinical points of view. METHODS: The free radical scavenging capacity of sucralfate was measured with electron spin resonance and was supported by theoretical calculations. The clinical effects of sucralfate lotion were evaluated on 21 women treated for breast cancer. Breast skin response was evaluated at 0, 10, 20, 30, 40, and 50 Gy, according to (1) the radiation therapy oncology group (RTOG) acute toxicity scale and (2) spectrophotometry data obtained with X-Rite SP60. RESULTS AND CONCLUSIONS: Sucralfate appeared as a relatively poor free radical scavenger (compared to reference compounds such as vitamin E). The sucralfate-containing lotion used in the present study did not provide systematic radiodermatitis prevention. Spectrophotometric evaluation of the skin response to irradiation appeared to be a very effective and more sensitive technique than the RTOG scale. Its use should be recommended to study cutaneous radioprotective action.