Time from nephrectomy as a prognostic factor in metastatic renal cell carcinoma patients receiving targeted therapies: overall results from a large cohort of patients.

OBJECTIVE: To investigate whether time from nephrectomy (Nx) to the diagnosis of metastatic disease may be an independent prognostic factor in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies (TTs). SUBJECTS AND METHODS: All patients who underwent Nx and at least 1 TT were considered. The patients were divided into two groups based on time from Nx [>1 year (Nx >1) and <1 year (Nx <1)] and a third group for cytoreductive Nx (cNx). Median overall survival (OS) represented the primary outcome. RESULTS: A total of 297 patients met the inclusion criteria. The time from Nx was >1 year in 47%, <1 year in 26% and concomitant with the diagnosis of metastatic disease in 27% of the cases (i.e. cNx). The median OS was 40.6 months (95% CI 30.5-50.7) for the Nx >1 group, 24.3 months (95% CI 17.7-31) for the Nx <1 group and 16.2 months (95% CI 11.2-21.3) for the cNx group (p < 0.05 for all comparisons). On multivariate analysis, time from Nx resulted to be an independent prognostic factor (Nx <1 vs. cNx: HR = 0.62, 95% CI 0.42-0.90, p = 0.13; Nx >1 vs. cNx: HR = 0.43, 95% CI 0.31-0.61, p < 0.001). CONCLUSION: We report that time from Nx is an independent prognostic factor for OS in patients affected by mRCC treated with TTs.

Targeted therapies in advanced renal cell carcinoma: the role of metastatic sites as a prognostic factor.

AIM: This retrospective study evaluates whether metastatic sites were associated with progression-free survival (PFS) and overall survival (OS) in patients with renal cell carcinoma treated with targeted therapies. PATIENTS & METHODS: In total, 358 patients were analyzed. RESULTS & CONCLUSION: After a median follow-up of 56.1 months, median PFS was 11 months and median OS was 24.2 months. Metastatic sites were associated with PFS: lymph nodes (HR: 1.43; 95% CI: 1.12-1.83; p = 0.004), liver (HR: 1.41; 95% CI: 1.05-1.90; p = 0.021), bone (HR: 1.26; 95% CI: 0.96-1.65; p = 0.091), brain (HR: 0.81; 95% CI: 0.46-1.43; p = 0.474) and other sites (HR: 1.07; 95% CI: 0.83-1.38; p = 0.589). Metastatic sites were associated with OS: lymph nodes (HR: 1.73; 95% CI: 1.31-2.29; p < 0.001), liver (HR: 1.71; 95% CI: 1.23-2.37; p = 0.002), bone (HR: 1.48; 95% CI: 1.10-1.98; p = 0.009), brain (HR: 1.21; 95% CI: 0.64-2.28; p = 0.568) and other sites (HR: 1.09; 95% CI: 0.81-1.47; p = 0.568). Patients with >2 metastatic sites had shorter PFS and OS. Every association was lost when introducing the Motzer score in regression models.

Safety profile and treatment response of everolimus in different solid tumors: an observational study.

AIM: Only few efforts have been taken to investigate the potential existence of disease-specific differences in the safety profile of everolimus. We analyze here the correlation between different patient and tumor characteristics on the safety profile of this molecule. Information on treatment response is also provided. METHODS: Consecutive patients with metastatic renal cell carcinoma (mRCC), pancreatic neuroendocrine tumors (pNET) or biliary tract cancer were included in this retrospective study. All patients received everolimus 10 mg/day or 5 mg/day. Clinical assessments were performed every 3 weeks. RESULTS: In total, 98 patients were enrolled: 51 with mRCC, 25 with pNET and 22 with biliary tract cancer. The incidence of toxicities (any grade) was 76% with mRCC, 64% with pNET and 95% with biliary tract cancer. Patients with biliary tract cancer also presented a higher frequency of severe toxicities: 64 versus 18% with mRCC and 32% with pNET. Multivariate analysis disclosed that biliary tract cancer (odds ratio [OR]: 23.8; 95% CI: 6.0-117.8; p < 0.0001) is a predictive factor for the development of toxicities during everolimus treatment. No correlations between liver metastasis and toxicities were identified. Disease control rate (DCR) was 45% in mRCC patients, 96% in pNET and 50% for biliary tract cancer patients. pNET tumors were associated with a higher DCR than the mRCC and biliary tract cancer (OR vs mRCC: 66.7; 95% CI: 6.2-276.5; p = 0.004; OR vs biliary tract cancer: 2.6; 95% CI: 0.5-14.2; p = 0.025). CONCLUSION: This study suggests that the safety profile of everolimus is acceptable in patients with either mRCC or pNET. In addition, the onset of toxicities is associated with an improved DCR. In patients with biliary tract cancer, everolimus is safe but associated with a higher incidence of adverse events.

Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial.

PURPOSE: For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life. Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC. METHODS: In this global phase III trial, patients were randomly assigned 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary end point was radiological progression-free survival (rPFS). RESULTS: From March 2021 to August 2022, 669 patients were randomly assigned (darolutamide n = 446; placebo n = 223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46% versus placebo plus ADT (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.71]; P < .0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR, 0.81 [95% CI, 0.59 to 1.12]), and clinical benefits were seen across all other secondary end points, including delayed time to metastatic castration-resistant prostate cancer (HR, 0.40 [95% CI, 0.32 to 0.51]) and time to pain progression (HR, 0.72 [95% CI, 0.54 to 0.96]). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment because of adverse events. CONCLUSION: These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase III darolutamide trials.

Patient approach in advanced/metastatic renal cell carcinoma: focus on the elderly population and treatment-related toxicity.

Recent therapeutic advances have changed the treatment landscape of metastatic renal cell carcinoma. Unfortunately, the seven agents now available are not based on biomarkers that would indicate which one could provide the best benefit for every patient. We have reviewed the avaliable information concerning the impact of each treatment on comorbidities or status that are frequently seen before commencing treatment for the advanced disease: elderly and patients with cardiovascular complications, metabolic and endocrinology disorders, and infections, as well as impaired organ function (kidney, liver and heart). Additional new drugs will be launched, but no predictive biomarkers are available. Head-to-head studies to evaluate the safety of the different drugs are rare. In this quite complex scenario, we believe that a decision-making approach focused on the patient may represent a suitable strategy.

Lecture: management of chemotherapy-induced febrile neutropenia; guidelines and colony stimulating factors.

Chemotherapy-induced febrile neutropenia (FN) is a major risk factor for severe infections potentially fatal, and also a dose-limiting toxicity, so causing dose reductions and/or delays in scheduled chemotherapy. This lecture provides recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. If expected risk of FN is equal or superior to 20%, a primary prophylaxis of FN with G-CSF is recommended. Primary prophylaxis can be considered in case of intermediate 10-20% risk of FN, in presence of factors that increase the frequency/risk of FN, such as age >65, advanced disease, prior episode of FN, poor performance status, radiotherapy to a wide body area (>20%). In case of low risk of FN (<10%), primary prophylaxis is not recommended. We also described the differences in potency and efficacy between two G-CSF, lenograstim (glycosylated) and filgrastim (non-glycosylated), which should be considered when deciding the G-CSF for each patient, particularly in high risk settings for FN.

Everolimus and temsirolimus are not the same second-line in metastatic renal cell carcinoma. A systematic review and meta-analysis of literature data.

BACKGROUND: Two mTOR inhibitors, TEM and EVE, proved to be active in mRCC but have never been compared in a prospective trial. We aimed to compare their effectiveness in mRCC patients previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor, and performed a systematic review and meta-analysis of available evidence. MATERIALS AND METHODS: The MEDLINE/PubMed database was reviewed for studies that compared EVE with TEM from January 2006 to May 2014. Summary hazard ratio (HR) for overall survival (OS) and time to treatment failure (TTF) were calculated using random and fixed effects models depending on the heterogeneity of included studies. Statistical heterogeneity was assessed using the χ(2) test, and inconsistency was quantified with the I(2) statistic. Publication bias was evaluated using the Begg and Egger test. RESULTS: Four studies were included in the meta-analysis; data of 937 patients were available: 545 received EVE and 392 TEM. Among the included patients, 863 [92%] were treated with sunitinib and 74 [8%] with pazopanib or sorafenib as first-line therapy. In the overall population, treatment with EVE decreased the risk of death by 26% over TEM (HR, 0.74; 95% confidence interval [CI], 0.59-0.93; P = .008). The TTF was evaluable in 692 patients; in this group, treatment with EVE decreased the risk of treatment failure by 30% (HR, 0.70; 95% CI, 0.56-0.88; P = .002). No significant heterogeneity or publication bias was found for OS and TTF. CONCLUSION: In this analysis, we compared EVE with TEM as second-line therapy in mRCC, and report a significant difference between mTOR inhibitors, even if these results need to be confirmed in a prospective trial.

Safety of Abiraterone Acetate in Castration-resistant Prostate Cancer Patients With Concomitant Cardiovascular Risk Factors.

OBJECTIVES: The aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset. PATIENTS AND METHODS: A retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. RESULTS: A total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel-based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%). CONCLUSIONS: AA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases.

Everolimus in advanced solid tumors: when to start, early or late?

Everolimus is an oral derivative of rapamycin which acts as a signal transduction inhibitor. It targets the mammalian target of rapamycin (mTOR), a key serine/threonine kinase regulating cell growth and angiogenesis. Everolimus has been approved for the treatment of pancreatic neuroendocrine tumors (pNETs), metastatic renal cell carcinoma (mRCC), and breast carcinoma. The activity of everolimus was demonstrated in three phase III randomized placebo-controlled trials, RADIANT-3, RECORD 1 and BOLERO 2, in patients with pNETs, mRCC and breast carcinoma, respectively. All three trials reported a statistically significant increase in median progression-free survival, the primary endpoint of the studies, in favor of everolimus. The absence of an overall survival benefit could be related to the cross-over design and subsequent therapies. The focus of our paper is on the best timing to start treatment with everolimus, while additional questions concern the opportuneness of intermittent use of everolimus specifically in long-responding patients. Lastly, we suggest this treatment could be optimized on the basis of patient and disease characteristics.

Response to targeted therapy in urachal adenocarcinoma.

We report the case of a young woman diagnosed with metastatic urachal carcinoma. A multimodal approach was used for the management of this patient. Due to disease progression despite surgery and two different chemotherapy regimens (neoadjuvant capecitabine + irinotecan + oxaliplatin and docetaxel + cisplatin after surgery), treatment with sunitinib was eventually started. Treatment with sunitinib resulted in stable disease and improvement of symptoms. Sunitinib was discontinued due to the occurrence of metrorrhagia, and restarted one week later. Disease eventually progressed and the patient died 18 months after the onset of symptoms. This is the first report on the use of sunitinib for the management of urachal carcinoma and provides initial evidence supporting the use of targeted therapy in this setting.

Rationale and protocol of RESORT, a randomized, open-label, multicenter phase II study to evaluate the efficacy of sorafenib in patients with advanced renal cell carcinoma after radical resection of the metastases.

The introduction of targeted agents did not totally resolve the approach to the treatment of metastatic renal cell carcinoma (mRCC) because complete response is rarely achieved. Recent findings seem to indicate that metastasectomy may improve survival. The RESORT study was designed to evaluate the additional clinical benefit of metastasectomy followed by sorafenib in a population of mRCC patients. With the aim of evaluating time to recurrence, 132 patients with mRCC who underwent radical resection of metastases at the time of recurrence after nephrectomy will be randomized to receive either sorafenib or best supportive care. Targeted treatment will be administered for up to 52 weeks or discontinued in the case of disease recurrence or unacceptable toxicity. Patients will be followed for a period of 36 months.

Sequential Tyrosine Kinase Inhibitors (TKIs) in metastatic renal cell carcinoma: results from a large cohort of patients.

BACKGROUND: Only scanty data are available to evaluate the impact of sequential TKIs on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). This retrospective study investigated the efficacy of the sequence sorafenib-sunitinib (SO-SU) and vice versa (SU-SO) in a real-life scenario. PATIENTS AND METHODS: Median progression free-survival (PFS) and OS were evaluated. The correlation between PFS and OS was also assessed. RESULTS: In total, 104 patients received SO-SU and 21 (16.8%) SO-SU. No differences in PFS or OS were observed (PFS for SO-SU=26.1 months, and for SU-SO=20.0 months; OS=35.3 and 27.0 months, respectively). For both sequences, only a weakly-positive correlation between PFS and OS was observed. CONCLUSION: Our data support the use of the sequence of the two TKIs in a real-life setting. No strong evidence of a correlation between PFS and OS was observed.

Targeted treatments in advanced renal cell carcinoma: focus on axitinib.

Antiangiogenesis options have evolved rapidly in the last few years, with an increasing number of agents currently approved by the US Food and Drug Administration and European Medicines Agency. Angiogenesis inhibitors have been shown to be very effective for the treatment of metastatic renal cancer cell. Axitinib is a third-generation inhibitor of vascular endothelial growth factor receptor and is currently being developed for the treatment of various malignancies. The pharmacokinetic properties of axitinib may have a selective therapeutic effect, with minimal adverse reactions and enhanced safety. In a large Phase III study of previously treated patients with metastatic renal cell carcinoma, axitinib achieved a longer progression-free survival than sorafenib with an acceptable safety profile and good quality of life. This review focuses on the pharmacology, pharmacokinetics, and clinical activity of axitinib in the current treatment of renal cell carcinoma. The role of axitinib in the adjuvant and/or neoadjuvant setting needs to be evaluated in further clinical trials.

Treatment of collecting duct carcinoma: current status and future perspectives.

BACKGROUND: Chemotherapy for collecting duct carcinoma (CDC) has demonstrated only limited efficacy in the advanced setting. The present study evaluated the activity of targeted therapies in metastatic CDC. PATIENTS AND METHODS: We evaluated a cohort of 384 consecutive patients with metastatic renal cell carcinoma (mRCC). The characteristics of patients with CDC were compared against those of the remaining cohort. All patients with CDC were treated with targeted therapies. RESULTS: Thirteen patients with advanced CDC were referred to our Center (incidence: 3.4% of all mRCC). Median age was 57 and 62 years in the CDC and non-CDC groups, respectively. The overall disease control in the CDC population was 23%, and median overall survival was 4 (95% confidence interval(CI)=2.4-5.6) months. Three patients obtained a satisfying response (disease control lasting 6-33 months). CONCLUSION: CDC has a poor prognosis compared to non-CDC renal cell carcinoma. Treatment for CDC represents a future challenge and targeted therapies may play a role in selected cases.

Experience with sorafenib in the treatment of advanced renal cell carcinoma.

The molecular-targeted agent sorafenib is the first anticancer agent able to slow the progression of advanced/metastatic renal cell carcinoma, a tumor that was formerly refractory to conventional therapy. Experience from everyday clinical practice and investigations exploring the suitability of this agent for patients with harmful pathological conditions has extended the use of sorafenib to other settings of renal cell carcinoma and to particular risk populations. The aim of this review is to provide evidence on the most effective and safe use of sorafenib. The review pays particular attention to patients who have several comorbidities, such as impaired renal and cardiac function, and older patients whose frailty due to impaired organ function necessitates the most careful administration of targeted antineoplastic agents.

Palonosetron: an evidence-based choice in prevention of nausea and vomiting induced by moderately emetogenic chemotherapy.

AIMS AND BACKGROUND: In 2003, the second-generation, 5-HT(3) receptor antagonist (5-HT(3) RA) palonosetron was approved by the FDA for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy. We reviewed the current knowledge on the role of palonosetron against acute and delayed emesis in patients with solid tumors undergoing single-day moderately emetogenic chemotherapy regimens. METHODS: A literature review in PubMed was performed to update currently available preclinical and clinical evidence on palonosetron, prioritizing randomized clinical trials. RESULTS: The distinct pharmacology of palonosetron provides a rationale behind the improved efficacy observed with the drug in prevention of delayed symptoms. This may be explained by allosteric binding properties and by palonosetron-triggered receptor internalization, which result in prolonged inhibition of the 5-HT(3) receptor function. Very recent pharmacology experiments have also suggested that palonosetron would be able to differentially inhibit 5-HT(3)/neurokinin 1 (NK-1) receptor signaling cross-talk. In two recent meta-analyses, palonosetron was shown to be more effective than other available 5-HT(3) RAs in preventing acute and delayed nausea and vomiting for both HEC and MEC. Recent findings also suggest that a single-day regimen of palonosetron plus dexamethasone (both drugs administered intravenously) may provide a reasonable therapeutic alternative to reduce the total dexamethasone dose administered in patients undergoing moderately emetogenic chemotherapy. CONCLUSIONS: On the basis of accumulating data, the evidence-based international guidelines devised from the major organizations have been recently updated to recommend the use of palonosetron plus 3-day dexamethasone for the optimal prevention of nausea and vomiting due to moderately emetogenic chemotherapy. There is still a need to investigate the efficacy of palonosetron in combination with an NK-1 receptor antagonist and dexamethasone in well-designed randomized trials.