Analysis of Health-Related Quality of Life Reporting in Phase III RCTs of Advanced Genitourinary Tumors.

BACKGROUND: As recommended in the European Society for Medical Oncology (ESMO) guidelines, assessment of health-related quality of life (HRQoL) should be a relevant endpoint in randomized controlled trials (RCTs) testing new anticancer therapies. However, previous publications by our group and others revealed a frequent underestimation and underreporting of HRQoL results in publication of RCTs in oncology. Herein, we systematically reviewed HRQoL reporting in RCTs testing new treatments in advanced prostate, kidney and urothelial cancers and published between 2010 and 2022. METHODS: We searched PubMed RCTs testing novel therapies in genitourinary (GU) cancers and published in fifteen selected journals (Annals of Oncology, BMC Cancer, British Journal of Cancer, Cancer Discovery, Clinical Cancer Research, Clinical Genitourinary cancer, European Journal of Cancer, European Urology, European Urology Oncology, JAMA, JAMA Oncology, Journal of clinical Oncology, Lancet, Lancet Oncology and The New England Journal of Medicine). We excluded trials investigating exclusively best supportive care or behavioral intervention, as well as subgroup or post hoc analyses of previously published trials. For each RCT, we investigated whether HRQoL assessment was performed by protocol and if results were reported in the primary manuscript or in a secondary publication. RESULTS: We found 85 eligible trials published between 2010 and 2022. Only 1/85 RCTs (1.2%) included HRQoL among primary endpoints. Of note, 25/85 (29.4%) RCTs did not include HRQoL among study endpoints. HRQoL results were non-disclosed in 56/85 (65.9%) primary publications. Only 18/85 (21.2%) publications fulfilled at least one item of the CONSORT-PRO checklist. Furthermore, 14/46 (30.4%) RCTs in prostate cancer, 12/25 (48%) in kidney cancer and 3/14 (21.4%) in urothelial cancer reported HRQoL data in primary publications. Next, HRQoL data were disclosed in primary manuscripts of 12/32 (37.5%), 5/13 (38.5%), 5/16 (31.3%) and 5/15 (33.3%) trials evaluating target therapies, chemotherapy, immunotherapy and new hormonal agents, respectively. Next, we found that HRQoL data were reported in 16/42 (38%) and in 13/43 (30.2%) positive and negative trials, respectively. Finally, the rate of RCTs reporting HRQoL results in primary or secondary publications was 55.3% (n = 47/85). CONCLUSIONS: Our analysis revealed a relevant underreporting of HRQoL in RCTs in advanced GU cancers. These results highlight the need to dedicate more attention to HRQoL in RCTs to fully assess the value of new anticancer treatments.

Stereotactic body radiotherapy with CyberKnife® System for low- and intermediate-risk prostate cancer: clinical outcomes and toxicities of CyPro Trial.

Simple summary: Stereotactic body radiotherapy (SBRT) of 35-36.25 Gy in five fractions with the CyberKnife System yields excellent control with low toxicity in low-intermediate-risk prostate cancer patients. We found no differences in biochemical control and overall survival in relation to dose. There were no significant differences in toxicity or quality of life between the two groups. Aims: Stereotactic body radiotherapy (SBRT) is an emerging therapeutic approach for low- and intermediate-risk prostate cancer. We present retrospective data on biochemical control, toxicity, and quality of life of CyPro Trial. Materials and methods: A total of 122 patients with low- and intermediate-risk prostate cancer were treated with the CyberKnife System at a dose of 35 Gy or 36.25 Gy in five fractions. Biochemical failure (BF)/biochemical disease-free survival (bDFS) was defined using the Phoenix method (nadir + 2 ng/ml). Acute/late rectal and urinary toxicities were assessed by the Radiation Therapy Oncology Group (RTOG) toxicity scale. Quality of life (QoL) was assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and PR25. International Erectile Function Index-5 (IIEF5) and International Prostate Symptom Score (IPSS) questionnaires were administered at baseline, every 3 months after treatment during the first years, and then at 24 months and 36 months. Results: The 1-, 2-, and 5-year DFS rates were 92.9%, 92.9%, and 92.3%, respectively, while the 1-, 2-, and 5-year bDFS rates were 100%, 100%, and 95.7%, respectively. With regard to risk groups or doses, no statistically significant differences were found in terms of DFS or bDFS. Grade 2 urinary toxicity was acute in 10% and delayed in 2% of patients. No Grade 3 acute and late urinary toxicity was observed. Grade 2 rectal toxicity was acute in 8% and late in 1% of patients. No Grade 3-4 acute and late rectal toxicity was observed. Grade 2 acute toxicity appeared higher in the high-dose group (20% in the 36.25-Gy group versus 3% in the 35-Gy group) but was not statistically significant. Conclusion: Our study confirms that SBRT of 35-36.25 Gy in five fractions with the CyberKnife System produces excellent control with low toxicity in patients with low-intermediate-risk prostate cancer. We found no dose-related differences in biochemical control and overall survival. Further confirmation of these results is awaited through the prospective phase of this study, which is still ongoing.

Unilateral post-chemotherapy robot-assisted retroperitoneal lymph node dissection in Stage II non-seminomatous germ cell tumor: A tertiary care experience.

Objective: Post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) represents an integral component of the management of patients with non-seminomatous germ cell tumor (NSGCT). Modified templates have been proposed to minimize the surgical morbidity of the procedure. Moreover, the implementation of robotic surgery in this setting has been explored. We report our experience with unilateral post-chemotherapy robot-assisted retroperitoneal lymph node dissection (PC-rRPLND) for clinical Stages IIA and IIB NSGCTs. Methods: A retrospective single institution review was performed including 33 patients undergoing PC-rRPLND for Stages IIA and IIB NSGCTs between January 2015 and February 2019. Following orchiectomy, patients were scheduled for chemotherapy with three cycles of bleomycin-etoposide-cisplatin. Patients with a residual tumor of <5 cm and an ipsilateral metastatic disease on pre- and post-chemotherapy CT scans were eligible for a unilateral template in absence of rising tumor markers. Descriptive statistics were provided for demographics, clinical characteristics, intraoperative and postoperative parameters. Perioperative, oncological, and functional outcomes were recorded. Results: Overall, 7 (21.2%) patients exhibited necrosis or fibrosis; 14 (42.4%) had mature teratoma; and 12 (36.4%) had viable tumor at final histology. The median lymph node size at surgery was 25 (interquartile range [IQR] 21-36) mm. Median operative time was 180 (IQR 165-215) min and no major postoperative complications were observed. Anterograde ejaculation was preserved in 75.8% of patients. Median follow-up was 26 (IQR 19-30) months and a total of three recurrences were recorded. Conclusion: PC-rRPLND is a reliable and technically reproducible procedure with safe oncological outcomes and acceptable postoperative ejaculatory function in well selected patients with NSGCTs.

Feasibility of cabazitaxel in octogenarian prostate cancer patients.

Background: To evaluate the effectiveness and safety of cabazitaxel in castration-resistant prostate cancer patients aged ≥80 years, we performed a retrospective study on a sample of patients from 11 Italian cancer centers. Materials and methods: Fifty-seven patients aged ≥80 years were treated with cabazitaxel after previous failure with docetaxel; 39 completed a comprehensive geriatric assessment questionnaire (34 fit and 5 vulnerable) and 8 patients (14%) had an Eastern Cooperative Oncology Group performance status (PS) ≥2, while most had a PS of 0-1 (86%). Cabazitaxel was administered at a dose of 25 mg/m2 in 30 (52%) patients and 20 mg/m2 or adapted schedules in 27 (48%) patients. These schedules were adopted mainly in patients ≥85 years (75%), with a PS ≥2 (87.5%), and those classified as vulnerable (100%). Results: The duration of treatment was 4.8 months and was comparable in all subgroups; disease control rate was reported in 36 patients (63%); prostate-specific antigen response was recorded in 18 patients (31.5%). Median overall survival was 13.1 months regardless of age (<85/≥85 years), but overall survival was reduced in vulnerable (7.2 months) and PS ≥ 2 patients (6.8 months). The most frequently documented grade 3-4 toxicities were neutropenia (14%) and diarrhea (10.5%). Six patients (10.5%) dropped out due to severe toxicity. Conclusions: Octogenarian patients can be treated with cabazitaxel with reduced doses or alternative schedules that are associated with less toxicity and fewer treatment interruptions. Comprehensive geriatric assessment could facilitate more appropriate patient selection.

The role of immunotherapy treatment in non-clear cell renal cell carcinoma: An analysis of the literature.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group representing 15-30% of renal tumors. They are mostly excluded from immunotherapy trials due to their rarity and worse prognosis. This, alongside nccRCC misdiagnosis/misclassification, lack of immune-biomarker expression rate data, lack of homogeneous data reporting, the retrospective nature of many studies, small sample sizes, and the fact that high-grade evidence only stems from trials mostly addressing the clear cell subtype, result in poorly defined treatments. We thus reviewed available data from several clinical trials, retrospective studies, and meta-analyses on immunotherapy responses and their correlation with histological subtypes and prognostic biomarkers. The papillary and unclassified subtypes are the best candidate for immunotherapy, showing response rates up to ∼35%. Chromophobe cancers, on the other end, have mostly null response rates. Cancers with sarcomatoid features respond very well to immunotherapy, regardless of their histology. Available data for translocation, medullary, collecting duct, and other nccRCCs are inconclusive. Regarding PD-L1, its expression correlates with better responses, but its prognostic value remains to be determined due to small sample sizes hindering direct statistical comparisons. It is necessary to involve a larger number of nccRCC patients and centers in clinical trials and report tumor response rates and PD-(L)1 and other markers' expression rates divided by nccRCC subtypes and not just for the whole cohorts. This will allow us to collect more robust data to best identify patients who can benefit from immunotherapy and ultimately define the standard of treatment. AVAILABILITY OF DATA AND MATERIAL: N/A.

Clinical outcomes of volume of disease on patients receiving enzalutamide versus abiraterone acetate plus prednisone as first-line therapy for metastatic castration-resistant prostate cancer.

Background: Androgen receptor signaling inhibitors (ARSis) abiraterone acetate (AA) plus prednisone and enzalutamide (Enza), are currently the most administered first-line treatments for metastatic castration-resistant prostate cancer (mCRPC). AA and Enza have shown similar overall survival (OS) benefits and there is no consensus upon the best option for mCRPC first-line treatment. Volume of disease may represent a useful biomarker to predict response to therapy in such patients. Objectives: In this study, we seek to evaluate the impact of volume of disease on patients treated with first-line AA versus Enza for mCRPC. Design and methods: We retrospectively evaluated a cohort of consecutive patients with mCRPC categorized by volume of disease [high volume (HV) or low volume (LV) per E3805 criteria] at ARSi onset and treatment type (AA or Enza), assessing OS and radiographic progression-free survival (rPFS), from therapy start, as co-primary endpoints. Results: Of the 420 patients selected, 170 (40.5%) had LV and received AA (LV/AA), 76 (18.1%) LV and had Enza (LV/Enza), 124 (29.5%) HV and were given AA (HV/AA), and 50 (11.9%) HV and received Enza (HV/Enza). Among patients with LV, OS was significantly longer when treated with Enza [57.2 months; 95% confidence interval (CI): 52.1-62.2 months] versus AA (51.6 months; 95% CI, 42.6-60.6 months; p = 0.003). Consistently, those with LV receiving Enza showed increased rPFS (40.3 months; 95 CI, 25.0-55.7 months) than those having AA (22.0 months; 95% CI, 18.1-26.0 months; p = 0.004). No significant difference in OS or rPFS was observed in those with HV treated with AA versus Enza (p = 0.51 and p = 0.73, respectively). In multivariate analysis of patients with LV, treatment with Enza was independently associated with better prognosis than AA. Conclusion: Within the intrinsic limitations of a retrospective design and small population, our report suggests that volume of disease could be a useful predictive biomarker for patients starting first-line ARSi for mCRPC.

Clinical impact of volume of disease and time of metastatic disease presentation on patients receiving enzalutamide or abiraterone acetate plus prednisone as first-line therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer remains a challenging condition to treat. Among the available therapeutic options, the androgen receptor signaling inhibitors abiraterone acetate plus prednisone (AA) and enzalutamide (Enza), are currently the most used first-line therapies in clinical practice. However, validated clinical indicators of prognosis in this setting are still lacking. In this study, we aimed to evaluate a prognostic model based on the time of metastatic disease presentation (after prior local therapy [PLT] or de-novo [DN]) and disease burden (low volume [LV] or high-volume [HV]) at AA/Enza onset for mCRPC patients receiving either AA or Enza as first-line. METHODS: A cohort of consecutive patients who started AA or Enza as first-line treatment for mCRPC between January 1st, 2015, and April 1st, 2019 was identified from the clinical and electronic registries of the 9 American and European participating centers. Patients were classified into 4 cohorts by the time of metastatic disease presentation (PLT or DN) and volume of disease (LV or HV; per the E3805 trial, HV was defined as the presence of visceral metastases and/or at least 4 bone metastases of which at least 1 out the axial/pelvic skeleton) at AA/Enza onset. The endpoint was overall survival defined as the time from AA or Enza initiation, respectively, to death from any cause or censored at the last follow-up visit, whichever occurred first. RESULTS: Of the 417 eligible patients identified, 157 (37.6%) had LV/PLT, 87 (20.9%) LV/DN, 64 (15.3%) HV/PLT, and 109 (26.1%) HV/DN. LV cohorts showed improved median overall survival (59.0 months; 95% CI, 51.0-66.9 months) vs. HV cohorts (27.5 months; 95% CI, 22.8-32.2 months; P = 0.0001), regardless of the time of metastatic presentation. In multivariate analysis, HV cohorts were confirmed associated with worse prognosis compared to those with LV (HV/PLT, HR = 1.87; p = 0.029; HV/DN, HR = 2.19; P = 0.002). CONCLUSION: Our analysis suggests that the volume of disease could be a prognostic factor for patients starting AA or Enza as first-line treatment for metastatic castration-resistant prostate cancer, pending prospective clinical trial validation.

First-line treatment of metastatic castration-resistant prostate cancer: the real-world Italian cohort of the Prostate Cancer Registry.

BACKGROUND: With the availability of multiple treatment options for metastatic castration-resistant prostate cancer (mCRPC), new real-world data on disease management and drugs' performance are needed. METHODS: We described characteristics, management and clinical outcomes of patients receiving first-line mCRPC treatment within the Italian cohort of the real-world, prospective, international Prostate Cancer Registry. Patients were enrolled consecutively (2013-2016) in 32 Italian sites and followed for 3 years. RESULTS: 238 patients were included: 157 received first-line abiraterone acetate plus prednisone ("abiraterone" thereafter) and 70 first-line docetaxel; 11 patients receiving other treatments were not considered. Compared with docetaxel-treated patients, those receiving abiraterone were significantly older (age ⩾75: 63.7% vs 38.6%), less frequently had a Gleason score >8 (48.2% vs 67.6%, p<0.005) at initial diagnosis, and more frequently an ECOG score ⩾1 (52.7% vs 36.2%, p<0.05) and comorbidities (76.4% vs 57.1%, p<0.05) at baseline; they reported a lower analgesic use (15.3% vs 30%, p<0.005). In the abiraterone group (median follow-up 22.1 months), median time to progression (TTP) and progression-free survival (PFS) were, respectively, 14.4 months (95% confidence interval, CI, 10.6-18.0) and 13.0 months (95% CI, 9.1-16.8); median overall survival (OS) was not reached, and 3-year OS was 59.1%. In the docetaxel treatment group (median follow-up 25.3 months), median TTP, PFS and OS were, respectively, 8.2 months (95% CI, 6.1-10.3), 8.2 months (95% CI, 5.8-10.3) and 33.2 months (95% CI, 19.2-not estimable). CONCLUSION: This investigation provided valuable information on the overall mCRPC treatment pattern and the effectiveness of first-line abiraterone and docetaxel in a population representative of everyday practice.

Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer.

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called "kynurenine (Kyn) pathway", which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

Achieving Consensus for Management of Hormone-Sensitive, Low-Volume Metastatic Prostate Cancer in Italy.

Metastatic hormone-sensitive prostate cancer (mHSPC) is usually categorized as high- or low-volume disease. This is relevant because low- and high-volume metastatic disease are associated with different outcomes, and thus management of the two forms should differ. Although some definitions have been reported, the concept of oligometastatic disease is not so clearly defined, giving rise to further variability in the choice of treatment, mainly between systemic agents and radiotherapy, especially in the era of metastasis-directed therapy. With the aim of providing clinicians with guidance on best practice, a group of medical and radiation oncologists, experts in prostate cancer, used the round robin method to generate a series of consensus statements on management of low-volume mHSPC. Consensus was obtained on three major areas of controversy: (1) with regard to clinical definitions of mHSPC, it was held that oligometastatic and low-volume disease refer to different concepts and should not be used interchangeably; (2) regarding therapy of de novo low-volume metastatic disease, androgen deprivation therapy alone can be considered undertreatment, and all patients should be evaluated for systemic treatment combinations; local therapy should not be denied in patients with mHSPC, regardless of the intensity of systemic therapy, and metastasis-directed therapy can be proposed in selected cases; (3) with regard to treatment of metachronous metastatic disease, patients should be evaluated for systemic treatment combinations. Metastasis-directed therapy can be proposed to delay systemic treatment in selected cases, especially if prostate-specific membrane antigen positron emission tomography staging has been performed and when indolent disease occurs. It is hoped that clinicians treating patients with mHSPC in daily practice will find this expert opinion of value.

Reirradiation of Locally Recurrent Prostate Cancer with Cyberknife® System or Volumetric Modulated Arc Therapy (VMAT) and IGRT-Clarity®: Outcomes, Toxicities and Dosimetric Evaluation.

The management of prostate cancer recurrence following external beam radiotherapy is not defined yet. Stereotaxic body reirradiation therapy showed encouraging results for local and biochemical control. From April 2017 to December 2020, 29 patients with prostate cancer recurrence were collected, joining the retrospective studies CyPro (prot. 46/19 OSS) and CLARO (Prot. 19/20 OSS) trials. Patients received Cyberknife® treatment (17 pts) or alternatively VMAT (Volumetric Modulated Arc Technique) therapy by IGRT (Image-Guided Radiation Therapy)/Clarity® (12 pts). By comparing the reirradiation of two groups, urinary (GU), rectal (GI) toxicities, and biochemical control were investigated. Further, the two techniques were dosimetrically compared by rival plans. The VMAT-IGRT Clarity® treatments were replanned with an optimized template developed for prostate VMAT-SBRT in FFF mode keeping the same dose and fractionation scheduled for Cyberknife Group (30 Gy in 5 fx, at 80% isodose). In the CK group, 23% of patients experienced grade 2 acute GU, while 6% grade 2 acute GI. In the VMAT-Clarity® group, acute GU toxicity was recorded in 17%, while for 8% grade 2 late toxicity was recorded. The dosimetric analysis shows that the VMAT-FFF allows to deliver a biological equivalent dose to CK, with the advantage of reducing the likelihood of toxicities arising.

Management of Metastatic Disease in Campania (MAMETIC): An Observational Multicenter Retrospective and Prospective Trial on Palliative Radiotherapy in an Italian Region. Study Protocol.

Background: In the Italian Campania Region, 30.517 new cases of solid cancer have been diagnosed, in 2019. Of those, patients with metastatic disease are up to 20%. This class of patients is extremely diversified and copious, and the offer of radiotherapy may vary in different geographical areas within the same region. The aim of this observational multicenter retrospective and prospective trial is to evaluate the occurrence of metastatic metastatic cancer patients candidates for palliative radiotherapy in several areas of a great Italian region, the management of the disease through RT approaches, and its impact on cancer-related pain and overall HRQoL. Methods: This is a multicenter, retrospective and prospective observational investigation. The retrospective part of the study concerns all patients enrolled with a diagnosis of metastatic disease and treated in RT centers within the Campania Region between January 2019 and July 2020. The prospective phase is going to involve all the metastatic patients with an indication of palliative RT. Considering regional epidemiological data, we expect an enrollment of 12.500-21.000 patients in 5 years. Conclusion: The MAMETIC Trial in an observational study designed for investigating on the use of radiotherapy in patients with advanced disease within a regional area, and for evaluating the local response to the patient's request. It can be a unique opportunity, not only to highlight possible geographic differences but also to regularly collect and share data to standardize the therapeutic offer within the regional area. ClinicalTrials.gov ID NCT04595032, retrospectively registered.

The way to precision medicine in gynecologic cancers: The first case report of an exceptional response to alpelisib in a PIK3CA-mutated endometrial cancer.

Endometrial cancer (EC) is the most common gynecologic cancer in Europe and its prevalence is increasing. EC includes a biological and clinical heterogeneous group of tumors, usually classified as type I (endometrioid) or type II (non-endometrioid) based on the histopathological characteristics. In 2013, a new molecular classification was proposed by The Cancer Genome Atlas (TCGA) based on the comprehensive molecular profiling of EC. Several molecular somatic alterations have been described in development and progression of EC. Using these molecular features, EC was reclassified into four subgroups: POLE ultra-mutated, MSI hypermutated, copy-number low, and copy-number high that correlate with the prognosis. To this regard, it is widely reported that EC has more frequent mutations in the phosphatidylinositol 3-kinase (PI3K) pathway signaling than any other tumor. PIK3CA is the main significant mutated gene after PTEN alterations. Overall, over 90% of endometrioid tumors have activating PI3K molecular alterations that suggests its critical role in the EC pathogenesis. Thus, the dysregulation of PI3K pathway represents an attractive target in EC treatment. Herein, we report a radiological and clinically meaningful response to a selective PIK3 inhibitor in a patient with extensively pre-treated advanced endometrioid EC harboring a somatic activating PIK3CA hotspot mutation. These evidences provide the rational for translational strategies of the PI3K inhibition and could support the clinical usefulness of PIK3CA genotyping in advanced EC. To our knowledge, this is the first clinical case of PIK3CA-mutated EC successfully treated with alpelisib.

Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial.

BACKGROUND: Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration. RESULTS: The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1-20.6) in arm DE and 27.8% (95% CI 22.8-39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III-IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%). CONCLUSIONS: The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study's phase II design and the absence of an overall survival benefit. TRIAL REGISTRATION NUMBERS: EudraCT 2014-000175-43 - NCT02453009.

Oligometastatic prostate cancer treatment.

Oligometastatic prostate cancer is an intermediate state between localized disease and widespread metastasis. Its biological and clinical peculiarities are still to be elucidated. New imaging techniques contribute to the detection of patients with oligometastatic disease. PET/CT scanning with prostate-specific membrane antigen can improve the selection of men with true early, low-volume oligometastatic disease, who are candidates for metastasis-directed therapy. Clinical studies demonstrated that androgen deprivation therapy can be delayed in oligometastatic patients with a low tumor burden, although no survival benefit has been demonstrated at present. This article presents available evidence on the treatment strategies for oligometastatic prostate cancer.

Acute Toxicity in Hypofractionated/Stereotactic Prostate Radiotherapy of Elderly Patients: Use of the Image-guided Radio Therapy (IGRT) Clarity System.

BACKGROUND: The use of intra-fractional monitoring and correction of prostate position with the Image Guided Radio Therapy (IGRT) system can increase the spatial accuracy of dose delivery. Clarity is a system used for intrafraction prostate-motion management, it provides a real-time visualization of prostate with a transperineal ultrasound. The aim of this study was to evaluate the use of Clarity-IGRT on proper intrafraction alignment and monitoring, its impact on Planning Tumor Volume margin and on urinary and rectal toxicity in elderly patients not eligible for surgery. PATIENTS AND METHODS: Twenty-five elderly prostate cancer patients, median age=75 years (range=75-90 years) were treated with Volumetric Radiotherapy and Clarity-IGRT using 3 different schemes: A) 64.5/72 Gray (Gy) in 30 fractions on prostate and seminal vesicles (6 patients); B) 35 Gy in 5 fractions on prostate and seminal vesicles (12 patients); C): 35 Gy in 5 fractions on prostate (7 patients). Ultrasound identification of the overlapped structures to the detected ones during simulation has been used in each session. A specific software calculates direction and entity of necessary shift to obtain the perfect match. The average misalignment in the three-dimensional space has been determined and shown in a box-plot. RESULTS: All patients completed treatment with mild-moderate toxicity. During treatment, genitourinary toxicity was 32% Grade 1; 4% Grade 2, rectal was 4% Grade 1. At follow-up of 3 months, genitourinary toxicity was 20% Grade 1; 4% Grade 2, rectal toxicity was 4% Grade 2. At follow-up of 6 months, genitourinary toxicity was 4% Grade 1; 4% Grade 2. Rectal toxicity was 4% Grade 2. CONCLUSION: Radiotherapy with the Clarity System allows a reduction of PTV margins, the amount of fractions can be reduced increasing the total dose, not exacerbating urinary and rectal toxicity with greater patient's compliance.

From clinical trials to clinical use of checkpoint inhibitors for patients with metastatic urothelial cancer.

Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.

Correction to: Cabozantinib After a Previous Immune Checkpoint Inhibitor in Metastatic Renal Cell Carcinoma: A Retrospective Multi-Institutional Analysis.

While typesetting the article the Table 3 column/row entries are interchanged. Please find below the updated Table.

Correlation Between Immune-related Adverse Event (IRAE) Occurrence and Clinical Outcome in Patients With Metastatic Renal Cell Carcinoma (mRCC) Treated With Nivolumab: IRAENE Trial, an Italian Multi-institutional Retrospective Study.

BACKGROUND: Immunotherapy has brought clinical benefits to patients with metastatic renal cell cancer (mRCC). Most patients tolerate immunotherapy but serious immune-related adverse events (irAEs) have been reported. Some studies indicate a correlation between irAEs and clinical response in other cancer types (eg, lung cancer and melanoma). For patients with mRCC, the impact of irAE on clinical outcome is unknown. PATIENTS AND METHODS: A retrospective review of 167 patients with mRCC treated with nivolumab as standard of care between March 2017 and January 2018 in 16 Italian centers was performed. irAEs were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. RESULTS: Any grade and grade 3/4 irAEs occurred in 46% and 8.9% of patients, respectively. The median time to appearance of irAEs was 10 weeks; 38.8% of patients required steroid treatment. The most common irAEs were cutaneous (33.7%) and gastrointestinal (23.3%). The median overall survival and progression-free survival were 20.13 and 7.86 months, respectively. Patients with irAEs showed a greater overall survival (hazard ratio, 0.38; 95% confidence interval [CI], 0.23-0.63) and progression-free survival (hazard ratio, 0.44; 95% CI, 0.29-0.66) benefit as well as better overall response rate (27.3% vs. 13.7%; odds ratio, 2.36; 95% CI, 1.03-5.44) and disease control rate (68.8% vs. 48%; odds ratio, 2.4; 95% CI, 1.23-4.67) if compared with those without irAEs. No correlation was found between steroid use and clinical outcomes. CONCLUSIONS: Our analysis revealed that the appearance of irAEs was associated with better outcomes in patients treated with nivolumab. This data may be limited by sample size and the retrospective nature of the study.

Cabozantinib After a Previous Immune Checkpoint Inhibitor in Metastatic Renal Cell Carcinoma: A Retrospective Multi-Institutional Analysis.

BACKGROUND: Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy. OBJECTIVE: To describe the outcome of cabozantinib in patients previously treated with immunotherapy. PATIENTS AND METHODS: Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity. RESULTS: Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3-14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up. CONCLUSIONS: Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.