Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study).

Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.

Neutrophil-to-Eosinophil Ratio Predicts the Efficacy of Avelumab in Patients With Advanced Urothelial Carcinoma Enrolled in the MALVA Study (Meet-URO 25).

BACKGROUND: Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb ([MALVA] in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25). PATIENTS AND METHODS: Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported. RESULTS: At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (

Assessing the effectiveness and safety of lenvatinib and everolimus in advanced renal cell carcinoma: insights from the RELIEVE study's analysis of heavily pretreated patients.

Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging. Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination. Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy. Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters. Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases (p = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 (p = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant (p = 0.03) while a shorter PFS was associated with lung (p = 0.048) and brain metastases (p = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3. Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.

Clinical Outcomes and Prognostic Factors in Patients With Penile Carcinoma: A Sub-Analysis From Meet-URO 23 (I-RARE) Registry Study.

INTRODUCTION: Penile squamous cell carcinoma (PSCC) is a rare tumor with an aggressive behavior. The Meet-URO 23/I-RARE registry includes rare genitourinary malignancies. We extracted patients with PSCC to conduct a retrospective study aimed at assessing clinical outcomes and prognostic factors. PATIENTS AND METHODS: Primary endpoints were overall survival and progression-free survival. Prognostic factors for OS and PFS were analyzed using univariate and multivariate analysis. From the Meet-URO 23/I-RARE database, we extracted 128 patients with diagnosis of PSCC. About 48% of patients underwent first-line of therapy. RESULTS: In the overall population, median OS from diagnosis was 34.6 months. Significant differences in median OS were observed according to ECOG PS at diagnosis (57.3 months vs. 8.3 months; P < .001), and median age (≤77y 88.8 months vs. >77y 26 months; P = .013). At multivariate analysis, ECOG PS 2-4 at diagnosis (HR 3.04) and lymph node metastases (HR 2.49) were independently associated with a higher risk of death. Among patients undergoing first-line therapy (n = 61), median OS was 12.3 months, and a statistically significant difference was found according to type of response to first-line (DCR 24.4 months vs. PD 7.1 months; P < .001). Multivariate analysis showed that only age >77 years was associated with a worse OS (HR 2.16). A statistically significant difference in PFS was found according to platinum plus 5-fluorouracil versus platinum plus taxane (4.9 vs. 3.4 months; P = .036) and regimens with 2 versus 3 drugs (3.4 vs. 8.6 months; P = .019). At the multivariate analysis only regimens with platinum plus taxane were associated with worse PFS (HR 2.83). CONCLUSION: In our registry study, PSCC is confirmed to be an aggressive disease. Poor ECOG PS, presence of lymph node metastases, and higher age at diagnosis appear to be associated with worse survival outcomes.

Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study).

Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.

[Box: see text].

Avelumab Plus Intermittent Axitinib in Previously Untreated Patients with Metastatic Renal Cell Carcinoma. The Tide-A Phase 2 Study.

BACKGROUND: Combinations of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitor (ICI) against PD1/PD-L1 are the standard first-line therapy for patients with metastatic renal cell carcinoma (mRCC), irrespective of the prognostic class. OBJECTIVE: To investigate the feasibility and safety of withdrawing VEGFR-TKI but continuing anti-PD1/PD-L1 in patients who achieve a response to their combination. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with treatment-naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases. INTERVENTION: Enrolled patients received axitinib + avelumab; after 36 wk of therapy those who achieved a tumour response interrupted axitinib and continued avelumab maintenance until disease progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of patients without progression 8 wk after the axitinib interruption. The secondary endpoints were the median value for progression-free (mPFS) and overall (mOS) survival and the safety in the overall population. RESULTS AND LIMITATIONS: Seventy-nine patients were enrolled and 75 were evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after 8 wk and thus achieving the primary endpoint. The mPFS of the overall population was 24 mo, while the mOS was not reached. The objective response rate was 76% (12% complete response and 64% partial response), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of adverse events of any grade was 59% for grade 3 and 3% for grade 4. This study was limited by the lack of a comparative arm. CONCLUSIONS: The TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of a response to the VEGFR-TKI + ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance leads to decreased side effects and should be investigated further as a new strategy to delay tumour progression. PATIENT SUMMARY: We evaluated whether certain patients with advanced kidney cancer treated with the fist-line combination of axitinib plus avelumab can interrupt the axitinib in case of a tumour response after 36 wk of therapy. We found that axitinib interruption improved the safety of the combination, while the maintenance with avelumab might delay tumour progression.

Instrumental activities of daily living in older patients with metastatic prostate cancer: results from the meet-URO network ADHERE prospective study.

Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients' IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5-ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28-37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs.

Time to strategy failure and treatment beyond progression in pretreated metastatic renal cell carcinoma patients receiving nivolumab: post-hoc analysis of the Meet-URO 15 study.

Background: Immunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy. Methods: The Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This post-hoc analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS. Results: Overall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 - 10.1), while mPFS was 7.0 months (95% CI: 5.7 - 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months; p < 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%; p = 0.075) and disease control rate (61.3% vs 55.5%; p = 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59). Conclusion: We found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.

External validation of a red cell-based blood prognostic score in patients with metastatic renal cell carcinoma treated with first-line immunotherapy combinations.

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling.

Impact of Metastatic Site in Favorable-Risk Renal Cell Carcinoma Receiving Sunitinib or Pazopanib.

BACKGROUND: Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice. MATERIAL AND METHODS: Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups. RESULTS: A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis. CONCLUSION: In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites.

Corrigendum: Impressive reduction of brain metastasis radionecrosis after cabozantinib therapy in metastatic renal carcinoma: a case report and review of the literature.

[This corrects the article DOI: 10.3389/fonc.2023.1136300.].

Advanced Non-Clear Cell Renal Cell Carcinoma Treatments and Survival: A Real-World Single-Centre Experience.

BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of cancer. Treatment recommendations are extrapolated from ccRCC and lack solid evidence. Here, we review advanced nccRCC patients treated at our institute. PATIENTS AND METHODS: We collected retrospective data on all advanced nccRCC pts treated at the Istituto Oncologico Veneto from January 2008. We compared overall response rate (ORR), progression free survival (PFS) and overall survival (OS) according to histological subtypes and type of systemic treatments. Kaplan-Meier method, log-rank test and Cox regression were used to estimate and compare PFS and OS. RESULTS: Of 1370 RCC patients, 289 had a diagnosis of nccRCC and 121 were eligible for the analysis. Fifty-three pts showed papillary histology (pRCC), 15 chromophobe; 37 unclassified RCC (NOS-RCC), 16 other histologies. Pts with chromophobe and other hystologies showed poorer survival rates compared to pRCC and NOS-RCC (mOS 10.7 vs. 20.7 vs. 30.7, p = 0.34). Pts treated with combination regimens achieved a better OS (30.7 vs. 13.7, p = 0.10), PFS (12.7 vs. 6.4, p = 0.10) and ORR (42.4% vs. 13.9%, p = 0.002) than those treated with monotherapy. IMDC and Meet-URO score retained their prognostic value. CONCLUSION: Our retrospective real-life cohort of advanced nccRCC patients shows that immunotherapy-based combinations could improve ORR, PFS and OS compared to TKI monotherapy. Prospective trials for nccRCC patients utilizing novel therapies are ongoing and their results eagerly awaited.

Prognostic role of systemic inflammation indexes in metastatic urothelial carcinoma treated with immunotherapy.

Aims: Inflammation indexes had been associated with overall survival (OS) and immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). Materials & methods: in 72 patients treated with ICIs for metastatic urothelial carcinoma (mUC) we evaluate differences in OS, response rate and toxicities, according to baseline inflammation indexes values. Results: neutrophil-to-lymphocite ratio (NLR) <3 was associated to longer progression-free survival (PFS; 4.9 vs 3.1 months) and OS (15.7 vs 7.6 months); monocyte-to-lymphocite ratio (MLR) <0.4 was associated to longer PFS (4.6 vs 2.8 months). Overall response rate (ORR), disease control rate (DCR) were higher in these patients. Patients with an irAE had longer PFS and OS. Conclusion: baseline inflammatory indexes are prognostic for mUC patients treated with ICIs.

Between 2019 and 2021, 72 patients received immunotherapy for a metastatic urothelial carcinoma at our institution. We detected markers of inflammation from a common blood test (neutrophils, lymphocytes, platelets and monocytes). We analyzed the role of these markers in our patients. Patients with a lower ratio of these biomarkers at baseline had a significantly longer time to disease progression. They also has a longer survival and higher chance of disease reduction. Moreover, patients with a specific ratio (NLR) increasing more than 0.5, after the first cycle of therapy, had a worse prognosis. It is necessary to evaluate the role of these markers in a trial with new patients enrolled in a prospective way. In fact, the role of these marker in predicting survival and adverse events could be very important for patients' management.

Role of enhancement modifications in evaluating tumor response to immunotherapy in metastatic renal cell carcinoma.

INTRODUCTION: Evaluation of tumor response according only to dimensional criteria may underestimate treatment benefit in patients treated for metastatic renal cell carcinoma (RCC). In this study we evaluated the role of lesion enhancement modifications and Choi criteria in patients affected by renal cell carcinoma treated with immunotherapy. METHODS: We collected data of 60 consecutive patients (with a total of 154 measurable lesions) treated with immunotherapy (nivolumab or ipilimumab plus nivolumab) at a single Institution. We evaluated tumour response using both RECIST1.1 criteria and Choi criteria at the first radiological assessment; we subsequently associated response with progression free survival and overall survival. RESULTS: Choi criteria found a higher rate of objective response compared to RECIST criteria (38.3% vs 18.3%). An objective response according to both criteria was associated with longer progression free survival and overall survival. Response rate for Choi did not vary according to lesion site. CONCLUSION: Choi criteria seemed to be able to predict clinical benefit in a higher proportion of patients with renal cell carcinoma treated with immunotherapy than RECIST criteria. Partial response according to RECIST was confirmed as a predictor of longer progression-free survival and overall survival.

The role of the caregiver in older patients with advanced prostate cancer: results from the ADHERE Prospective Study of the Meet-URO network.

PURPOSE: To assess caregivers' characteristics and influence of the presence or absence of the caregiver on clinical outcomes of older (≥70 years) metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone (ABI) or enzalutamide (ENZ). METHODS: Patients from the Meet-URO 5 ADHERE study were assessed with a 5-item caregiver evaluation questionnaire focusing on the presence, age, degree of kinship, working status and qualification of the caregiver. We investigated the association between the presence of a caregiver and the clinical characteristics and outcomes of enrolled patients. RESULTS: No differences were found in the main clinical characteristics between patients with or without a caregiver, except for a lower median G8 score (p = 0.0453) in the caregiver group. A longer radiographic PFS (rPFS) was observed in the group without a caregiver, with a trend towards more prolonged overall survival (OS) in the same group. CONCLUSION: Our work suggests a detrimental effect of caregivers in managing older mCRPC patients treated with ABI or ENZ, especially those identified as frail by the geriatric G8 screening score. Further work is needed to identify and address patients' vulnerability areas, which could have a detrimental effect on prognosis.

The prognostic Value of Thyroid Hormone Levels in Immunotherapy-Treated Patients With Metastatic Urothelial Carcinoma.

INTRODUCTION: A low fT3/fT4 ratio has been associated with a poorer prognosis in patients treated for different solid malignancies. However, the prognostic role of baseline thyroid function in patients with metastatic urothelial carcinoma (mUC) has not yet been established. PATIENTS AND METHODS: We analyzed 72 consecutive immunotherapy-treated patients with mUC from a single institution. We recorded clinical data, baseline blood test results, and oncological outcomes. We stratified patients into three groups according to the fT3/fT4 ratio value and analyzed differences in progression-free survival (PFS), overall survival (OS), and radiological response in the three groups. We also conducted univariate and multivariate analyses to identify prognostic factors for PFS and OS. RESULTS: The median PFS in the low, intermediate, and high fT3/fT4 ratio groups was 2.2, 4.1, and 8.2 months, respectively (P < 0.01). The median OS in the low, intermediate, and high fT3/fT4 groups was 3.6, 10.3, and 19.1 months, respectively (P < .01). The low fT3/fT4 ratio maintained its prognostic role independently of other prognostic factors. Patients with a high fT3/fT4 ratio had an increased radiological response. CONCLUSION: Thyroid hormone impairment, as measured by the fT3/fT4 ratio, is a strong prognostic factor in patients treated with immunotherapy for urothelial carcinoma.

Liver Metastases of Unknown Primary Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors Plus Tyrosine Kinase Inhibitors: A Case Report and Literature Review.

BACKGROUND/AIM: Renal cell carcinoma (RCC) constitutes approximately 3% of all cancers. More than 60% of RCCs are detected incidentally; one-third of patients present with regional or distant metastases, and another 20-40% of patients develop metastases after radical nephrectomy. RCC can metastasize to any organ. In contrast, metastatic RCC (mRCC) without evidence of a primary tumor is extremely rare, with only a few reported cases. CASE REPORT: We present a case of mRCC that initially presented with multiple liver and lymph node metastases but no primary renal lesion. An impressive response to treatment was achieved with a combination of immune checkpoint inhibitors and tyrosine kinase inhibitors. A clinical, radiological, and pathological diagnostic strategy, particularly in the context of a multidisciplinary team, are crucial for reaching a definitive diagnosis. This approach allows to select the appropriate treatment, making a huge difference for a mRCC due to its resistance to standard chemotherapy. CONCLUSION: There are currently no guidelines available for mRCC without primary tumor. Nevertheless, a combination of TKI and immunotherapy could be the optimal first-line treatment if systemic therapy is required.

Estimated Direct Costs of Renal Cancer by Stage of Disease at Diagnosis and Phase of Its Management: A Whole-Disease Model.

BACKGROUND: Renal cell carcinoma (RCC) is the seventh most common neoplasm in high-income countries. New clinical pathways have been developed to deal with this tumor, which includes costly drugs that pose an economic threat to the sustainability of healthcare services. This study provides an estimate of the direct costs of care for patients with RCC by stage of disease (early vs. advanced) at diagnosis, and disease management phase along the pathway recommended by local and international guidelines. MATERIALS AND METHODS: Considering the clinical pathway for RCC adopted in the Veneto region (north-east Italy) and the latest guidelines, we developed a very detailed "whole-disease" model that covers the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of RCC. Based on the cost of each procedure according to the Veneto Regional Authority's official reimbursement tariffs, we estimated the total and average per-patient costs by stage of disease (early or advanced) and phase of its management. RESULTS: In the first year after diagnosis, the mean expected cost of a patient with RCC is €12,991 if it is localized or locally-advanced and reaches €40,586 if it is advanced. For early disease, the main cost is incurred by surgery, whereas medical therapy (first and second line) and supportive care become increasingly important for metastatic disease. CONCLUSION: It is crucially important to examine the direct costs of care for RCC, and to predict the burden on healthcare services of new oncological therapies and treatments, as the findings could be useful for policy-makers planning the allocation of resources.

Impressive reduction of brain metastasis radionecrosis after cabozantinib therapy in metastatic renal carcinoma: A case report and review of the literature.

Introduction: Radionecrosis is a consequence of SRS (stereotactic radiosurgery) for brain metastases in 34% of cases, and if symptomatic (8%-16%), it requires therapy with corticosteroids and bevacizumab and, less frequently, surgery. Oncological indications are increasing and appropriate stereotactic adapted LINACs (linear accelerators) are becoming more widely available worldwide. Efforts are being made to treat brain radionecrosis in order to relieve symptoms and spare the use of active therapies. Case presentation: Herein, we describe a 65-year-old female patient presenting with brain radionecrosis 6 months after stereotactic radiotherapy for two brain metastatic lesions. Being symptomatic with headache and slow cognitive-motor function, the patient received corticosteroids. Because of later lung progression, the patient took cabozantinib. An impressive reduction of the two brain radionecrosis areas was seen at the brain MRI 2 months after the initiation of the angiogenic drug. Discussion: The high incidence of radionecrosis (2/2 treated lesions) can be interpreted by the combination of SRS and previous ipilimumab that is associated with increased risk of radionecrosis. The molecular mechanisms of brain radionecrosis, and its exact duration in time, are poorly understood. We hypothesize that the antiangiogenic effect of cabozantinib may have had a strong effect in reducing brain radionecrosis areas. Conclusion: In this clinical case, cabozantinib is associated with a fast and significant volume reduction of brain radionecrosis appearing after SRS and concomitant immunotherapy. This drug seems to show, like bevacizumab, clinical implications not only for its efficacy in systemic disease control but also in reducing brain radionecrosis. More research is needed to evaluate all molecular mechanisms of brain radionecrosis and their interaction with systemic therapies like third-generation TKIs.

A multicenter phase 2 single arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pre-treated with one immune-checkpoint inhibitor: The BREAKPOINT trial (Meet-Uro trial 03).

BACKGROUND: First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear. METHODS: This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. RESULTS: 31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension. CONCLUSIONS: The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable. TRIAL REGISTRATION NUMBER: NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681.