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Background: The BONSAI phase II trial recently demonstrated the activity of cabozantinib in metastatic collecting duct patients. The outcomes of patients in this setting treated with immunotherapy as second-line is unknown. The aim of the present report was to describe outcomes of patients enrolled in the BONSAI trial that received nivolumab as second-line treatment., Material and Methods: We describe the oncological outcomes in terms of overall response rate, progression-free survival, overall survival and safety. We excluded patients that did not receive any second-line treatment or were treated with agents other than nivolumab., Results: We identified five patients of whom one was excluded due to lack of data. Three patients obtained clinical benefit (one partial response, two stable disease); the second-line progression-free survival (nivolumab) ranged from 2.8 to 19.9 months to and second-line overall survival ranged from 5.1 to 26.5 months. No new safety signals were observed., Conclusions: Nivolumab may be considered as second-line therapy option after cabozantinib failure in selected metastatic collecting duct carcinoma patients.

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.

Background: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma., Methods: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves., Results: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population ( p = 0.013 and p < 0.0001, respectively), as well as at paired analysis ( p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months ( p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population ( p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively ( p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome., Conclusions: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.

Introduction: Therapeutic decision-making in metastatic castration-resistant prostate cancer (mCRPC) represents an open challenge. Radium-223 is approved for patients with symptomatic bone metastases, no visceral involvement, progressing after at least 2 lines of systemic therapy, or ineligible for any other systemic treatment., Methods: We performed a retrospective, observational study on patients with mCRPC treated with radium-223 at our institution outside of clinical trials, to assess the safety and activity in a real-world population. Data regarding baseline patient/disease characteristics and treatment outcomes (number of cycles, treatment-related adverse events [AEs], cause of discontinuation, and best response) were collected., Results: Overall, 41 patients were treated from September 2015 to September 2018. Median age was 73 years; baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0, 1, or 2 in 15%, 80%, and 5% of cases, respectively; and 3%, 41%, 44%, and 12% of patients had <6, 6-20, >20, and superscan bone lesions, respectively. A median number of 5 cycles (interquartile range 3-6) with median dose 19.52 MBq (interquartile range 12.87-24.83) was received. Treatment schedule was completed in 49% of cases; discontinuations due to AEs, disease-related death, or disease progression occurred in 24%, 33%, and 43% of patients, respectively. Any-grade AEs occurred in 73% and grade 3/4 treatment-related AEs occurred in 29% of patients, mainly anemia, decreased platelet count, and fatigue. No skeletal-related events or treatment-related deaths were recorded. After treatment, 66%, 2%, and 32% of patients had a stable, improved, or deteriorated ECOG PS versus baseline, respectively, and 24%, 61%, and 15% reported a stable, improved, or worsened pain symptom control. Post-treatment versus baseline alkaline phosphatase was reduced or stable in 46% and increased in 54% of patients, whereas prostate-specific antigen was decreased or stable in 83% and increased in 17% of patients., Conclusions: Our study provides clinically useful real-world data on radium-223, highlighting the importance of multidisciplinary patient management to guarantee the best continuum of care for patients with mCRPC.

Background: Stomatitis is highly prevalent in patients with cancer treated with the mammalian target of rapamycin inhibitor everolimus; it usually has an early onset and may compromise treatment dose intensity and patients' quality of life. Within the randomized controlled Stomatitis Prevention trial (STOP, ISRCTN14568888), we investigated the possibility of using a commercial natural multicomponent mouthwash (Orasol Plus ® ) to prevent the development of stomatitis of any grade in patients with advanced renal cell carcinoma (RCC) treated with everolimus., Methods: Overall, 62 patients were randomized to receive either Orasol Plus in addition to oral hygiene or oral hygiene alone (31 patients per treatment arm)., Results: In the whole study population, 28 episodes of stomatitis were observed (41.9%); in only 2 patients, stomatitis occurred more than once (2 episodes). As expected, the episodes of stomatitis occurred early in the course of treatment with everolimus. Treatment with Orasol Plus prevented the onset of everolimus-induced stomatitis: only 8 episodes of stomatitis were observed in the treated group with Orasol Plus in addition to oral hygiene vs 20 episodes in the group treated with oral hygiene only ( p = 0021). Also, a reduction in the average duration of mucositis in patients treated with Orasol Plus compared to patients treated with oral hygiene only was observed (8 days vs 11.2 days, p = 0.0416)., Conclusion: This study showed that the use of a natural multicomponent mouthwash coupled with regular oral hygiene was able to reduce the severity and duration of everolimus-induced stomatitis in patients with RCC., Trial Registration Number: ISRCTN14568888.

Purpose:: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients' response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery., Methods:: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation., Results:: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score., Conclusions:: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications.

Purpose:: Two randomized trials in the cytokine era showed that cytoreductive nephrectomy (CN) had a role in metastatic renal cell carcinoma (mRCC), increasing life expectancy. The survival benefit of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib, in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy. Therefore it is unknown if similar survival benefit with targeted agents could be achieved without CN. We hypothesize that in these patients CN could increase overall survival (OS) in comparison to targeted therapy without CN. We also will investigate mechanisms of primary and secondary resistance to TKIs in patients with mRCC and identify prognostic or predictive biomarkers., Methods:: This is a randomized, open-label, controlled, multicenter phase 3 study comparing sunitinib or pazopanib vs CN followed by sunitinib or pazopanib as first-line therapy for patients with mRCC who have not received surgery and prior systemic treatment for metastatic disease. We will identify 270 patients eligible for randomization. The planned treatment duration per patient will be until progressive disease is observed. Secondary endpoints are the evaluation of progression-free survival (PFS) and response rate and the assessment of the safety profile. Exploratory objectives include the evaluation of circulating tumor cells and circulating tumor DNA and correlation with response/resistance to treatment., Results:: The study is enrolling patients., Conclusions:: The use of CN in addition to targeted therapy in patients with renal cell carcinoma with synchronous metastases could lead to a significant improvement in OS and PFS.

Renal cell carcinoma (RCC) is the 10th most common cancer in Western countries. The prognosis of metastatic disease is unfavorable but may be different according to several risk factors, such as histology and clinical features (Karnofsky performance status, time from nephrectomy, hemoglobin level, neutrophils and thrombocytes count, lactate dehydrogenase and calcium serum value, sites and extension of the disease). In this review, we focused on some recent developments in the use of immunotherapy, surgery and cryotherapy in the treatment of advanced disease. While RCC is unresponsive to chemotherapy, recent advances have emerged with the development of targeted agents and innovative immunotherapy-based treatments. Surgical resection remains the standard of care for patients with small renal lesions but in patients with significant comorbidities ablative therapies such as cryoablation and radiofrequency ablation may lead to local cancer control and avoid surgical complications and morbidity. In the setting of metastatic RCC, radical nephrectomy, or cytoreductive nephrectomy, is considered a palliative surgery, usually part of a multimodality treatment approach that requires systemic treatments.

Aims and Background: The introduction of agents targeting vascular endothelial growth factor has radically changed the approach to metastatic renal cell carcinoma (mRCC): sunitinib and pazopanib are now the standard first-line therapy in mRCC. At sunitinib failure, second-line axitinib or everolimus or sorafenib should be considered to improve the clinical outcome. No data are available for a third-line tyrosine kinase inhibitor (TKI) after 2 previous lines of therapy with TKIs. At pazopanib failure, no prospective data are available., Study Design: The TOKIO study was designed to evaluate progression-free survival, safety, and efficacy of third-line therapy with TKI in 44 patients already treated with 2 previous lines of TKIs in 10 Italian centers, and relapsed from sunitinib-axitinib (group A) or pazopanib-sorafenib (group B). Standard treatment is sorafenib in group A and sunitinib in group B, administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety, and quality of life.

Hyponatremia is the most frequent electrolyte disorder in hospitalized patients but also a well known poor prognostic factor in cancer patients. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is often misdiagnosed by oncologist because of difficulties in the interpretation of laboratory tests. Etiology is heterogeneous but the predominant cause is represented by the unbalance between excessive presence of water and serum sodium deficiency. Ectopic production of arginine vasopressin (AVP) develops more frequently in small cell lung cancer but it is not so rare in other malignancies. Neurological impairment may range from subclinical to life-threating symptoms depending by the rate of serum sodium deficiency. Appropriate diagnosis is essential to set a proper therapy. When hyponatremia is caused by SIADH, hypertonic saline infusion is indicated for acute presentation whereas fluid restriction is preferred in case of chronic asymptomatic evolution. Other options include vaptans, vasopressin receptor antagonists, targeted specifically for the correction of euvolemic hyponatremia. The aim of this brief report is to provide concise and specific informations for the management of SIADH in oncology clinical practice.

The introduction of agents targeting vascular endothelial grow factors has radically changed the approach to metastatic renal cell carcinoma; however, cure is not within definitive reach. In many cases, the tumor will progress several months after the start of first-line therapy and new lines of therapy are required. Pazopanib and sorafenib are two frequently used targeted agents, and no sound data are currently available for patients who relapsed after pazopanib. In this paper we illustrate the SOAP study, which was designed to evaluate the safety and efficacy of sorafenib in terms of progression free-survival in 44 patients treated in 10 Italian centers who had relapsed after first-line pazopanib. Standard treatment with sorafenib will be administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety and quality of life. A subanalysis to evaluate toxicities as predictive factors has also been planned.

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.

The management of advanced genitourinary malignancies has undergone a major transformation with the advent of novel drugs and targeted therapies in recent years. Assessment of the treatment risks and benefits is required for each patient and therefore better knowledge of the different clinical and molecular aspects of these diseases is warranted. The results of further studies and biomarker validations are expected to provide more treatment options and improve outcomes in the future management of genitourinary malignancies.

The management of advanced genitourinary tumors is rapidly evolving thanks to the clinical availability of several targeted drugs with different mechanisms of action. Among clinicians, in-depth knowledge of all the aspects of the disease, together with the capacity to interpret and accurately correlate clinical data and imaging findings, are strongly needed. Moreover, the optimization of treatment sequences might lead to better disease control with respect to prognostic categories, radiological monitoring and newer biomarkers. Among the genitourinary tumors, only few data are available on bladder, testicular and penile cancers. Our report is supported by scientific and clinical experience in renal cell carcinoma and prostate cancer.

Background: Capecitabine in combination with oxaliplatin and irinotecan (COI regimen) is active and well tolerated in metastatic colorectal cancer. Since there is no internationally adopted standard regimen, we have conducted a pilot study of COI in untreated advanced gastric cancer., Methods: Patients received irinotecan, 180 mg/m2 infused over 90 min on day 1, followed by oxaliplatin, 85 mg/m2 in a 3-hr infusion on day 2, and capecitabine, 1000 mg/m2/day orally twice daily from days 2 to 6 of a biweekly schedule. Treatment was continued up to 8 cycles or until progression of disease occurred. Response (RECIST criteria) was assessed after the first three cycles and was to be confirmed at least 4 weeks following the first response., Results: A total of 12 patients (5 men and 7 women) with a median age of 54 years (range, 42-65) was prospectively enrolled. Most of the patients (83%) had metastatic disease. Three complete responses, four partial responses and two disease stabilizations occurred in the intention-to-treat cohort, with an overall response rate of 58% (95% confidence interval, 28-85%). Median time to progressive disease and overall survival were 6.4 and 12 months, respectively. A total of 68 cycles was administered, with a median of 6 cycles per patient (range, 1-8). Grade 3 neutropenia occurred in two patients. The most common non-hematologic grade 3 toxicities were nausea (3 patients) and diarrhea 12 patients)., Conclusions: These preliminary findings suggest that biweekly COI is a feasible and promising triplet for the first-line treatment of advanced gastric cancer. A large multi-institutional phase II study of the combination has already been planned in this setting.

We describe the case of a young man with refractory renal cell carcinoma who achieved an objective response in a metastatic lesion after biotherapy with the multikinase inhibitor sorafenib and also developed a severe skin reaction. The patient had been previously treated with various combinations of immunochemotherapy without any clinical benefit. We performed a brief review of the literature where similar cases were documented with the use of various anti-EGFR agents. The hypothesis of the correlation of skin toxicity with disease response is not new, but in the absence of any strong evidence remains controversial.

Neuroendocrine tumors of the larynx represent a rare group of neoplasms characterized by pathological and biological heterogeneity. The histological diagnosis is the most important step in the appropriate management of these tumors and the prognosis varies according to histological types. Here we report on a case of a laryngeal neuroendocrine tumor occurring in a 67-year-old man who underwent several locoregional and systemic treatments. Because of the very low incidence of neuroendocrine tumors in the larynx, a review of the literature has also been performed.