Navigating the ICI Combination Treatment Journey: Patterns of Response and Progression to First-Line ICI-Based Combination Treatment in Metastatic Renal Cell Carcinoma.

The use of immune checkpoint inhibitors (ICIs) in combination with tyrosine kinase inhibitors or other ICIs has significantly improved the prognosis for patients with mccRCC. This marks a major milestone in the treatment of mccRCC. Nonetheless, most patients will discontinue first-line therapy. In this narrative review, we analyze the different patterns of treatment discontinuation in the four pivotal phase III trials that have shown an improvement in overall survival in mccRCC first-line therapy, starting from 1 January 2017 to 1 June 2023. We highlight the different discontinuation scenarios and their influences on subsequent treatment options, aiming to provide more data to clinicians to navigate a complex decision-making process through a narrative review approach. We have identified several causes for discontinuations for patients treated with ICI-based combinations, such as interruption for drug-related adverse events, ICI treatment completion, treatment discontinuation due to complete response or maximum clinical benefit, or due to progression (pseudoprogression, systemic progression, and oligoprogression); for each case, an extensive analysis of the trials and current medical review has been conducted.

Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis.

BACKGROUND: Radium 223 (Ra-223) was approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) patients with bone-only disease, following demonstration of significant improvement in overall survival (OS). To date, there are no validated prognostic factors useful in predicting outcome of mCRPC patients treated with Ra-223. Our retrospective study aims to evaluate the prognostic role of treatment discontinuation due to adverse events in mCRPC patients treated with Ra-223, and to identify which factors correlate with the toxicity onset. METHODS: We performed a retrospective analysis of all consecutive mCRPC patients treated with Ra-223 from September 2013 to December 2019 at our institute. Patients were divided in 2 groups according to the reason of Ra-223 therapy discontinuation: toxicity versus other causes. Outcome measures were progression-free survival (PFS) and OS. RESULTS: In the overall population (75 patients) median PFS and OS were 5.46 months and 11.15 months respectively. Patients who discontinued treatment due to toxicity had a lower median PFS (3.49 vs 5.89 months, HR: 1.88, 95% CI: 1.14-3.12, p = 0.014) and OS (8.59 vs 14.7 months HR: 3.33, 95% CI: 1.85-6.01, p < 0.001) than patients who discontinued therapy due to other causes. The risk of Ra-223 discontinuation due to toxicity correlates with the number of previous treatments (p = 0.002), previous chemotherapy treatment (p = 0.039), baseline LDH (p = 0.012), Hb (p = 0.021) and platelet-to-lymphocyte ratio (p = 0.024). CONCLUSIONS: Discontinuation due to toxicity is associated with worse outcomes in mCRPC patients treated with Ra-223. To reduce the risk of developing toxicities that may compromise treatment efficacy, Ra-223 should be used early in mCRPC patients.

Therapeutic sequencing in advanced renal cell carcinoma: How to choose considering clinical and biological factors.

In the last fifteen years a better understanding of the biological processes promoting tumour growth and progression led to an impressive revolution in metastatic renal cell carcinoma (mRCC) treatment landscape. Angiogenesis plays a critical role in the pathogenesis of RCC. These biological evidences led to targeted therapies interfering with vascular endothelial growth factor and mammalian target of rapamycin pathway. Another big step in the RCC therapeutic landscape was recently made because of the understanding of the interplay between angiogenesis and immune cells. Dual immune checkpoint inhibitors (ICIs) and ICIs plus tyrosine kinase inhibitors (TKI) combinations have been approved considering overall survival benefit compared to targeted therapies as first line treatment. We summarize the activity and the biological rationale of ICIs combinations as mRCC first line therapy. Additionally, we review the clinical and biological criteria useful to guide clinicians in the choice of treatment sequencing focusing on ICIs combinations resistance mechanisms.

Prognostic factors in metastatic castration resistant prostate cancer patients treated with radium-223: a retrospective study.

BACKGROUND: Our study aims to identify baseline prognostic factors in metastatic castration resistant prostate cancer (mCRPC) patients treated with radium-223. METHODS: Data about demographics, ECOG performance status, lymph node (LN) involvement, local treatment for prostate cancer, previous systemic treatments, cells blood count, PSA, ALP, albumin, LDH, bone protecting agents use (BPA), analgesic use and survival were collected. Univariable and multivariable analyses were performed. RESULTS: Seventy-five men received radium-223 between September 2013 and December 2019. Median age was 73 years. Thirty-four (45.3%) had ECOG PS 0, 41 (54.7%) PS 1-2. In univariable analysis, LN involvement (HR 1.68, 95% CI 1.01-2.80, P=0.047), absence of local treatment on primary tumor (HR 1.93, 95% CI 1.13-3.29, P=0.016), baseline strong opioidsuse (HR 1.82, 95% CI 1.08-3.06, P=0.024), high platelets to lymphocyte ratio (PLR) (HR 1.91, 95% CI 1.06-3.45, P=0.03), high baseline ALP (HR 1.81, 95% CI 1.10-2.99, P=0.019) and high baseline LDH (HR 3.86,95% CI 2.01-7.41, P<0.001) were significantly associated with worst OS. At multivariable analysis, LN involvement, strong opioids use, baseline ALP, LDH and PLR levels were significantly associated with outcome. CONCLUSIONS: In mCRPC patients treated with Radium-223, baseline ALP, LDH, strong opioid use, PLR, LN involvement and treatment on primary site are associated with different OS.

Are tyrosine kinase inhibitors an effective treatment in testicular metastases from kidney cancer? Case report.

Testicular metastases from renal cell carcinoma (RCC) are extremely rare. Tyrosine kinase inhibitors (TKI) are the cornerstone of systemic therapy for metastatic RCC. We report a case of testicular metastasis in a 72-year-old patient with RCC that developed 17 years after nephrectomy and response to TKI treatment, a retrospective literature search on testicular metastases from RCC, and the indirect evidence described in the literature on the efficacy of chemotherapy and target therapy on testicular lesions.

Renal cell carcinoma (RCC): fatter is better? A review on the role of obesity in RCC.

Obesity represents a well-known risk factor for renal cell carcinoma development. Several studies evaluated the relationship between obesity and outcome in patients with non-metastatic and metastatic renal cell carcinoma using different parameters such as BMI, visceral fat area and s.c. fat area. These studies suggest that obesity is associated with a better prognosis in renal cell carcinoma patients. This phenomenon is called obesity paradox and it was found in other diseases in which obesity represents an established risk factor such as heart failure, diabetes, atrial fibrillation, hypertension and coronary heart disease. The purpose of this review is to analyze the mechanisms by which obesity increases the risk of renal cell carcinoma development, to describe the evidence available to date about the link obesity-outcome and to evaluate the mechanisms to explain this apparently paradoxical relationship.

Prognostic role of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with metastatic castration resistant prostate cancer treated with abiraterone or enzalutamide.

BACKGROUND: Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are markers of systemic inflammation associated with poor outcome in several solid tumors. We retrospectively investigated the prognostic role of PLR and, secondly, NLR in mCRPC patients treated with abiraterone acetate (AA) or Enzalutamide (E), both in pre- and postdocetaxel setting. METHODS: Two hundred twenty-five mCRPC patients treated with AA or E with basal blood count were divided in three groups according to PLR (PLR1<128; PLR2 128-190; PLR>190) and in two groups according to NLR (<3 vs. ≥3). Outcome measures were progression-free survival (PFS) and overall-survival (OS). Univariate and multivariate analyses were performed. RESULTS: One hundred ten patients were in PLR1, 58 in PLR2 and 57 in PLR3. Median OS was 22.0, 20.6 and 21.2 months in PLR1, PLR2 and PLR3 (PLR2 vs. PLR1: HR 0.97, 95%CI 0.62-1.52, P=0.90; PLR3 vs. PLR1: HR 1.37, 95%CI 0.90-2.08, P=0.14). Median PFS was 9.2, 12.7 and 8.5 months in PLR1, PLR2 and PLR3 (PLR2 vs. PLR1: HR 0.87, 95%CI 0.59-1.27, P=0.47; PLR3 vs. PLR1: HR 1.15, 95%CI 0.80-1.66, P=0.45). 142 patients were in NLR<3 and 83 in NLR≥3. Median OS was 26.5 months in NLR<3 and 17.0 months in NLR≥3 (HR 1.75, 95%CI 1.22-2.51, P=0.02). Median PFS was 10.1 months in NLR<3 and 7.6 months in NLR≥3 (HR 1.37, 95%CI 1.00-1.88, P=0.05). CONCLUSIONS: In this retrospective analysis of mCRPC patients treated with AA or E we did not identify a prognostic role of baseline PLR, while we found a significant prognostic role of baseline NLR.

Prognostic role of the duration of response to androgen deprivation therapy in patients with metastatic castration resistant prostate cancer treated with enzalutamide or abiraterone acetate.

BACKGROUND: Our retrospective study aims to evaluate the prognostic role of duration of response to androgen deprivation therapy (ADT) in metastatic castration resistant prostate cancer (mCRPC) patients treated with enzalutamide (E) or abiraterone acetate (AA). MATERIALS AND METHODS: Data about ADT start and duration were available in 255 (82%) of 311 patients treated with AA or E. Patients were divided in three groups according to ADT response (group 1 [G1]: <12 months; group 2 [G2]: 12-36 months; group 3 [G3]: >36 months). Outcome measures were progression-free survival (PFS) and overall survival (OS). RESULTS: Patients with longer ADT response had better OS (median 17.3 months G1, 19.9 months G2, 31.6 months G3; HR G3 vs G1 0.41, 95% CI 0.25-0.64; p = 0.001) and better PFS (median 5.9 months G1, 8.8 months G2, 11.7 months G3; HR G3 vs G1 0.41, 95% CI 0.41-0.27; p < 0001). In docetaxel-naive patients, median OS was 18.8 in G1, 35.2 in G2, and not reached in G3 (HR G3 vs G1 0.33, 95% CI 0.14-0.78; p = 0.038), median PFS was 7 months G1, 9.3 months G2, and 20 months G3 (HR G3 vs G1 0.31, 95% CI 0.15-0.62; p = 0.003). In postdocetaxel patients, median OS was 13.1 months in G1, 17.2 months in G2, and 21.4 months in G3 (HR G3 vs G1 0.52, 95% CI 0.29-0.94; p = 0.082), while median PFS was 5.2 months in G1, 6.8 months in G2, and 8.3 months in G3 (HR G3 vs G1 0.54, 95% CI 0.32-0.91; p = 0.067). CONCLUSIONS: Duration of ADT response is an independent prognostic factor of outcome with AA or E.

48 h for femur fracture treatment: are we choosing the wrong quality index?

BACKGROUND: In the last 10 years, the rate of femur fractures treated within 48 h from trauma has been introduced as a performance index for hospital management in Italy. Literature showed a significant indirect correlation between early treatment and mortality/comorbidity. The aims of early treatment are pain management and reduction of time to ambulation. The purpose of this study is to evaluate whether early treatment has reduced time to ambulation in femur fracture. MATERIALS AND METHODS: All patients admitted to two level I trauma centers with proximal femoral fracture between 1/1/2017 and 31/12/2017 were included in this study. Exclusion criteria were patient age younger than 65 years, death before surgery, and nonsurgical treatment. The following data were collected: age, gender, date and time of admission to emergency department, height, weight, body mass index (BMI), type and side of fracture, American Society of Anesthesiologists (ASA) score, date and time of surgery, surgical time, length of hospitalization, death during hospitalization, time from surgery to physiotherapy start, and time from surgery to first walking day. RESULTS: The study sample resulted in 660 patients. Mean age was 82 years, 64 % were female, mean BMI was 24 kg/m2, mean ASA score was 2.7, and 42 % were medial fractures. Mean time from admission to surgery was 95 h; 49.8 % were treated within the first 48 h. Mean time from surgery to physiotherapy start was 2 days, 21 % were not able to walk during hospitalization, time from surgery to first walking day was 5 days, and mean hospitalization time was 15 days. Early surgery was significantly (p = 0.008) associated with the probability of ambulation recovery during hospitalization. No association (p = 0.513) was found between early surgery and time in bed without walking. CONCLUSIONS: Early surgery in femur fracture became a priority in the health system. However, according to our data, although 51 % of patients were treated within the first 48 h, time from surgery to physiotherapy start (2 days) was still too long. Furthermore, time from surgery to first walking day was 6 days, longer than in most published papers. These data suggest that the performance index (rate of femur fractures treated within 48 h) may be improved by changing it to rate of femur fractures surgically treated with return to walking in 96 h. LEVEL OF EVIDENCE: Level 4 (retrospective study).