Metastasis-directed therapy in testicular cancer.

PURPOSE OF REVIEW: This review highlights the importance of addressing testicular cancer metastasizing beyond the retroperitoneum, focusing on multidisciplinary approaches and advances in treatment. RECENT FINDINGS: Recent literature emphasizes on the evolving landscape of metastasis-directed therapy, including surgical interventions, chemotherapy regimens, and radiation therapy. The effectiveness of these treatments varies depending on the site of metastasis, with various approaches improving survival rates and quality of life for patients. We divide our review in an organ-specific manner and focus on chemotherapeutic, surgical, and radiation therapy approaches pertaining to each site of metastasis. SUMMARY: Our review suggests the pressing need for continued research to refine and personalize treatment strategies. These efforts are important for enhancing clinical practice, ultimately leading to better outcomes for patients with metastatic testicular cancer.

Evaluation and Management of Testicular Cancer After Late Relapse.

A 41-year-old man presented to his primary care physician with a 1-month history of left neck adenopathy in the context of a history of nonseminomatous germ cell tumors (NSGCTs). In 2011, the patient was treated for stage IB (T2N0M0S0) right-sided NSGCTs of the testis, which were 95% embryonal and 5% yolk sac tumors. He underwent a right radical orchiectomy and was followed until 2022 without recurrence. In the work-up for his adenopathy, laboratory results for human chorionic gonadotropin, lactate dehydrogenase, and α-fetoprotein were normal. CT scans confirmed clustered enlarged lymph nodes in the left lower spinal accessory posterior triangle, enlarged left lower neck lymph nodes, and several foci of enlarged left retroperitoneal periaortic lymph nodes. Fine needle aspiration of a left neck lymph node identified malignant tumor cells. A left neck dissection showed embryonal carcinoma in 12 of 28 nodes. Immunostaining showed the tumor cells were positive for SALL4 and CD30 but negative for CD117. This patient likely had a contralateral late relapse of his original right NSGCT after 11 years of remission. The patient's original cancer was on the right side, with recurrence surrounding the aorta on the contralateral side, representing an atypical pattern of spread.

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Change in platelet count as a prognostic indicator for response to primary tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma.

OBJECTIVE: To evaluate change in platelet count as an indicator of response to primary tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: We conducted a multicentre retrospective analysis of patients with mRCC undergoing primary TKI therapy from May 2005 to August 2014. Change in platelet count was defined as post-treatment platelet count after the first cycle of treatment minus the pretreatment platelet count. Response Evaluation Criteria in Solid Tumours were used to define partial response (PR), stable disease (SD) and progressive disease (PD). Analysis was conducted between subgroups with stable/increased (+ΔPlt) and decreased (-ΔPlt) counts. The primary outcome was overall survival (OS), determined using Kaplan-Meier analysis. Multivariable analysis was conducted for risk factors associated with PD. RESULTS: A total of 115 patients with mRCC were analysed, of whom 19 (16.6%) had a +ΔPlt and 96 (83%) a -ΔPlt. More patients with a +ΔPlt had a Karnofsky score <80 (42.1 vs 14.6%; P = 0.005) and >2 metastatic sites (78.9 vs 51%; P = 0.041). More patients with +ΔPlt than with -ΔPlt had PD (89.4 vs 19.1%; P < 0.001) and more of those with -ΔPlt than with +ΔPlt had SD/PR (80.9 vs 10.6%; P < 0.001). Multivariable analysis showed that +ΔPlt (odds ratio [OR] 5.36, P < 0.001), Karnofsky score < 80 (OR 2.96, P = 0.002) and >2 metastatic sites at presentation (OR 1.87, P = 0.013) were risk factors for PD. Kaplan-Meier analysis showed a lower 5-year OS in patients with +ΔPlt than in those with -ΔPlt (23 vs 53%; P < 0.0001). +ΔPlt had a sensitivity of 48.6%, a specificity of 97.4%, a positive predictive value of 89.5% and a negative predictive value of 80.9% for PD. CONCLUSIONS: Patients with a -ΔPlt were more likely to respond to TKI therapy and had longer OS. +ΔPlt above baseline had a high specificity for PD after primary TKI. Further investigation is required to determine the utility of ΔPlt.

Does timing of targeted therapy for metastatic renal cell carcinoma impact treatment toxicity and surgical complications? A comparison of primary and adjuvant approaches.

INTRODUCTION: To compare surgical complications and tyrosine kinase inhibitor (TKI)-toxicities in patients who underwent primary cytoreductive nephrectomy (CN) followed by adjuvant TKI therapy versus those who underwent neoadjuvant TKI therapy prior to planned CN for metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Two-center retrospective analysis. Sixty-one mRCC patients underwent TKI therapy with sunitinib between July 2007 to January 2014. Patients were divided into three groups: primary CN followed by adjuvant TKI (n = 27, Group 1), neoadjuvant TKI prior to CN (n = 21, Group 2), and primary TKI alone (no surgery, n = 13, Group 3). Primary outcome was frequency and severity of surgical complications (Clavien). Secondary outcome was frequency and severity of TKI-related toxicities (NIH Common Toxicity Criteria). Multivariable analysis was carried out for factors associated with complications. RESULTS: There were no significant differences in demographics, ECOG status, and median number TKI cycles (p = 0.337). Mean tumor size (cm) was larger in Group 3 (12.8) than Group 2 (8.9) and Group 1 (9.3), p = 0.014. TKI-related toxicities occurred in 100%, 90.5%, and 88.9% in Group 3, Group 2, and Group 1 (p = 0.469). There was no difference in incidence of high grade (p = 0.967) and low grade (p = 0.380) TKI-toxicities. Overall surgical complication rate was similar between Group 2 (47.6%) and Group 1 (33.3%), p = 0.380. Group 2 had more high grade surgical complications (28.6%) than Group 1 (0%), p = 0.004. Multivariable analysis demonstrated increasing age was independently associated with development of surgical complications (HR 1.059, p = 0.040). CONCLUSION: Patients receiving neoadjuvant TKI therapy prior to CN experienced more high grade surgical complications than patients who underwent primary CN. Potential for increased high grade surgical complications requires further investigation and may impact pretreatment counseling.

Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art.

Renal cell carcinoma (RCC) is among the most prevalent malignancies in the USA. Most RCCs are sporadic, but hereditary syndromes associated with RCC account for 2-3 % of cases and include von Hippel-Lindau, hereditary leiomyomatosis, Birt-Hogg-Dube, tuberous sclerosis, hereditary papillary RCC, and familial renal carcinoma. In the past decade, our understanding of the genetic mutations associated with sporadic forms of RCC has increased considerably, with the most common mutations in clear cell RCC seen in the VHL, PBRM1, BAP1, and SETD2 genes. Among these, BAP1 mutations are associated with aggressive disease and decreased survival. Several targeted therapies for advanced RCC have been approved and include sunitinib, sorafenib, pazopanib, axitinib (tyrosine kinase inhibitors (TKIs) with anti-vascular endothelial growth factor (VEGFR) activity), everolimus, and temsirolimus (TKIs that inhibit mTORC1, the downstream part of the PI3K/AKT/mTOR pathway). High-dose interleukin 2 (IL-2) immunotherapy and the combination of bevacizumab plus interferon-α are also approved treatments. At present, there are no predictive genetic markers to direct therapy for RCC, perhaps because the vast majority of trials have been evaluated in unselected patient populations, with advanced metastatic disease. This review will focus on our current understanding of the molecular genetics of RCC, and how this may inform therapeutics.

What is the incidence of kidney stones after chemotherapy in patients with lymphoproliferative or myeloproliferative disorders?

INTRODUCTION: This study describes the incidence and risk factors of de novo nephrolithiasis among patients with lymphoproliferative or myeloproliferative diseases who have undergone chemotherapy. MATERIALS AND METHODS: From 2001 to 2011, patients with lymphoproliferative or myeloproliferative disorders treated with chemotherapy were retrospectively identified. The incidence of image proven nephrolithiasis after chemotherapy was determined. Demographic and clinical variables were recorded. Patients with a history of nephrolithiasis prior to chemotherapy were excluded. The primary outcome was incidence of nephrolithiasis, and secondary outcomes were risk factors predictive of de novo stone. Comparative statistics were used to compare demographic and disease specific variables for patients who developed de novo stones versus those who did not. RESULTS: A total of 1,316 patients were identified and the incidence of de novo nephrolithiasis was 5.5% (72/1316; symptomatic stones 1.8% 24/1316). Among patients with nephrolithiasis, 72.2% had lymphoproliferative disorders, 27.8% had myeloproliferative disorders, and 25% utilized allopurinol. The median urinary pH was 5.5, and the mean serum uric acid, calcium, potassium and phosphorus levels were 7.5, 9.6, 4.3, and 3.8 mg/dL, respectively. In univariate analysis, mean uric acid (p=0.013), calcium (p<0.001)), and potassium (p=0.039) levels were higher in stone formers. Diabetes mellitus (p<0.001), hypertension (p=0.003), and hyperlipidemia (p<0.001) were more common in stone formers. In multivariate analysis, diabetes mellitus, hyperuricemia, and hypercalcemia predicted stone. CONCLUSIONS: We report the incidence of de novo nephrolithiasis in patients who have undergone chemotherapy. Diabetes mellitus, hyperuricemia, and hypercalcemia are patient-specific risk factors that increase the odds of developing an upper tract stone following chemotherapy.

Virtual Follow-Up in Patients Initiating Antineoplastic Treatment in the Ambulatory Setting.

PURPOSE: Initiating antineoplastic therapy can be distressful and affect patient retention of treatment-related side effects and safety protocols. Return visits can range from 8 to 28 days after treatment, during which patients may develop treatment-related questions and toxicities. This study's objective is to evaluate how implementing a follow-up phone call 24-48 hours after initial antineoplastic infusion, compared with standard pretreatment education, affects patient satisfaction and education retention. METHODS: We conducted a single-center pilot study where patients who were literate, English-speaking, with genitourinary malignancies, initiating intravenous chemotherapy or immunotherapy were eligible. The primary end point was patient knowledge retention. Secondary end points included patient satisfaction. The Leuven's Questionnaire Patient Knowledge Tool, a validated, standardized tool, was used to evaluate patient knowledge retention, with a higher score indicating more retention. Telephone follow-up was initiated 24-48 hours after initial infusion, where Leuven's Questionnaire was used to assess patient knowledge. A nurse then reinforced treatment-related education, reviewed notification parameters, and coordinated appropriate follow-up. One week later, participants were sent a follow-up Leuven's Questionnaire and standardized patient satisfaction assessment. RESULTS: Thirty-one patients with renal cell carcinoma, prostate, bladder, germ cell/testicular, or adrenal cancers were included in the study. Mean preintervention Leuven's Questionnaire score was 5.3 and mean postintervention score was 8.1 on a 1-10 scale (P < .0001). Ninety-seven percent of patients reported improved satisfaction postintervention. CONCLUSION: Proactive telephonic follow-up for oncology patients improves education retention, patient satisfaction, and has potential to improve patient safety and quality of care.

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.

Are repeat prostate biopsies safe? A cohort analysis from the SEARCH database.

PURPOSE: Patients question whether multiple biopsy sessions cause worse prostate cancer outcomes. Therefore, we investigated whether there is an association between the number of prior biopsy sessions and biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: Men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database who underwent radical prostatectomy between 1988 and 2010 after a known number of prior biopsies were included in the analysis. Number of biopsy sessions (range 1 to 8) was examined as a continuous and categorical (1, 2 and 3 to 8) variable. Biochemical recurrence was defined as a prostate specific antigen greater than 0.2 ng/ml, 2 values at 0.2 ng/ml or secondary treatment for an increased prostate specific antigen. The association between number of prior biopsy sessions and biochemical recurrence was analyzed using the Cox proportional hazards model. Kaplan-Meier estimates of freedom from biochemical recurrence were compared among the groups. RESULTS: Of the 2,739 men in the SEARCH database who met the inclusion criteria 2,251 (82%) had only 1 biopsy, 365(13%) had 2 biopsies and 123 (5%) had 3 or more biopsies. More biopsy sessions were associated with higher prostate specific antigen (p<0.001), greater prostate weight (p<0.001), lower biopsy Gleason sum (p=0.01) and more organ confined (pT2) disease (p=0.017). The Cox proportional hazards model demonstrated no association between number of biopsy sessions as a continuous or categorical variable and biochemical recurrence. Kaplan-Meier estimates of freedom from biochemical recurrence were similar across biopsy groups (log rank p=0.211). CONCLUSIONS: Multiple biopsy sessions are not associated with an increased risk of biochemical recurrence in men undergoing radical prostatectomy. Multiple biopsy sessions appear to select for a low risk cohort.

The Prognostic Significance of Homologous Recombination Repair Pathway Alterations in Metastatic Hormone Sensitive Prostate Cancer.

INTRODUCTION: The homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations. METHODS: We conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival. RESULTS: 151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations. CONCLUSION: HRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients.

Germline alterations among Hispanic men with prostate cancer.

BACKGROUND: Little is known about the true rate of pathogenic (P)/likely pathogenic (LP) germline alterations in Hispanic men with prostate cancer as most studies analyzing the prevalence of P/LP germline alterations were performed in a largely non-Hispanic white population (NHW). METHODS: We performed a retrospective analysis of two separate cohorts of men with prostate cancer: (1) a multicenter cohort of 17,256 men who underwent germline testing in a CLIA-certified laboratory and (2) a single-center cohort of all men eligible for germline testing between 2018 and 2020. The proportions of P/LP alterations and variants of uncertain significance (VUS) were computed. Fisher's exact test was used to compare germline alteration rates for significance. A multivariate logistic regression was performed adjusting for demographic and clinical factors to examine factors associated with germline testing. RESULTS: In the multicenter cohort, the rate of P/LP germline alterations among self-reported Hispanic men was 7.1%, which was lower than self-reported NHW men (9.7% vs. 7.1%, p = 0.058), but was not statistically significant. The VUS rate was significantly higher among the Hispanic cohort (21.5% vs. 16.6%, p = 0.005). In the single-center cohort, 136 Hispanic patients were eligible for testing of which 34 underwent germline testing (26.1%, N = 34/136). Of all prostate cancer patients in the single-center cohort undergoing germline testing (n = 173), the rate of P/LP alterations in Hispanic patients was not significantly different compared to NHW patients (14.7% vs. 12.2%, p = 0.77). The rate of VUS in Hispanic patients was significantly higher than that of NHW patients (20.6% vs. 7.2%, p = 0.047). CONCLUSION: The P/LP germline alteration rate in our cohorts was similar between Hispanic and NHW men. The rate of VUS was significantly higher in Hispanic men, a consequence of undertesting in minority populations. These data support that Hispanic men with prostate cancer should be screened for germline testing similar to NHW men.

Update on chemotherapy in the treatment of urothelial carcinoma.

Urothelial carcinoma is the fifth most common malignancy diagnosed each year in the United States. Neoadjuvant and adjuvant chemotherapy are given to decrease the risk of recurrent or metastatic disease with the more robust clinical data supporting the former. Bladder preservation utilizes a trimodality approach with maximal transurethral resection followed by concurrent chemotherapy and radiation and is appropriate for select patients. Gemcitabine and cisplatin is the current standard of care for first-line treatment in fit patients with metastatic disease. Optimal second-line therapy remains undefined, and targeted agents are under investigation. Clinical trial participation should be encouraged in patients with urothelial carcinoma of the bladder to help improve treatment regimens and outcomes. Synopsis. Chemotherapy is commonly used in the treatment of urothelial carcinoma of the bladder. This paper will review the role of chemotherapy in the neoadjuvant, adjuvant, bladder sparing, and metastatic settings.

Analysis of the Prognostic Significance of Circulating Tumor DNA in Metastatic Castrate Resistant Prostate Cancer.

BACKGROUND: There has been considerable interest in ctDNA next generation sequencing platforms to assess genomic alterations in mCRPC given its accessibility and identification of temporal genomic data. PATIENTSAND METHODS: In this retrospective analysis, we analyzed 63 patients who underwent ctDNA genomic profiling during their mCRPC disease course using a CLIA-certified commercial assay. The primary objective was to assess the feasibility of commercial ctDNA analysis in a real world mCRPC cohort. Key secondary objectives included assessment of the landscape of pathogenic ctDNA alterations and the prognostic significance of ctDNA detection on overall survival (OS). RESULTS: Among the cohort, at the time of ctDNA collection, median age was 70 years, and 47.6% (N = 30/63) had bone-only metastases. ctDNA was detected in the majority of patients with at least 1 pathogenic alteration detected in 90.5% (N = 57/63) of individuals. The most common alterations detected were in AR, TP53, and PIK3CA. Actionable alterations with FDA-approved therapies were found in 15.8% (N = 10) of the cohort. The presence of ≤ 1 versus > 1 alteration on ctDNA analysis was strongly associated with inferior OS with a median OS of 26.1 versus 8.8 months, respectively (HR = 7.0, 95% CI, 2.2-23.1, P < .001). In multivariate analysis, the number of detected alterations remained a significant predictor for OS. Lastly, there was weak correlation between Prostate-Specific Antigen (PSA), and ctDNA characteristics. CONCLUSION: ctDNA is a viable next generation sequencing (NGS) platform in mCRPC and can be utilized to identify actionable alterations. The presence and extent of ctDNA alterations appear to be prognostic of OS in mCRPC.

IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP). METHODS: Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3H-thymidine incorporation, and ELISA. RESULTS: Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3-2.6-fold increases in CD4+T, CD8+T, and CD56bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group. CONCLUSIONS: Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.

Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery.

OBJECTIVE: To investigate efficacy of neoadjuvant tyrosine kinase-inhibitor therapy (TKI) before imperative nephron-sparing surgery (NSS), as NSS in patients with large locally advanced or centrally located tumours can be challenging, and TKI therapy might result in a reduction of primary tumour burden and increase the feasibility of NSS. PATIENTS AND METHODS: This was a multicentre retrospective review and prospective pilot study of patients undergoing neoadjuvant sunitinib before planned NSS from February 2006 to February 2009. All patients underwent confirmatory biopsy for clear cell renal cell carcinoma. Patients received two 28-day cycles of sunitinib before NSS. Demographics/tumour characteristics, tumour response (by the Response Evaluation Criteria In Solid Tumors), outcomes and complications were analysed. RESULTS: Twelve patients (seven men and five women; mean age 60.1 years, tumours on 14 renal units) were given TKI before NSS for imperative indications. The mean pretreatment tumour diameter was 7.1 cm; all patients had a decrease in size of the primary tumour after TKI, with a mean reduction in maximum diameter of 1.5 cm (21.1%). Four of 14 and 10 of 14 primary tumours had a partial response and stable disease after TKI. NSS was achievable in all 14 kidneys. Four patients had a concurrent metastasectomy. The mean warm ischaemia time was 22.5 min; postoperative dialysis was not required in any patients. Final pathology revealed negative tumour margins in all 14 tumours. The mean creatinine and estimated glomerular filtration rate (before/after NSS) were 1.34/1.40 mg/dL (P = 0.431) and 57.7/53.4 mL/min/1.73 m(2) (P = 0.475), respectively. At a mean follow-up of 23.9 months, 10 of the 12 patients were alive, one died from metastatic RCC and none required dialysis. Three of the 14 renal units developed delayed urinary leaks, all in patients who also received postoperative sunitinib. All leaks resolved with conservative measures. CONCLUSIONS: Neoadjuvant TKI followed by NSS is safe and feasible, with all patients achieving a reduction in maximum tumour diameter, and with NSS being achievable with negative margins and with no requirement for postoperative dialysis. Further investigation is required.

Neoadjuvant Sunitinib Decreases Inferior Vena Caval Thrombus Size and Is Associated With Improved Oncologic Outcomes: A Multicenter Comparative Analysis.

BACKGROUND: We analyzed outcomes of neoadjuvant sunitinib in patients with renal-cell carcinoma (RCC) and inferior vena caval (IVC) tumor and compared outcomes to patients who did not undergo neoadjuvant therapy before surgery. PATIENTS AND METHODS: We performed a multicenter retrospective comparison of RCC patients with IVC tumor who underwent neoadjuvant sunitinib before surgery versus those who did not. Response to sunitinib was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Primary outcome was cancer-specific survival. Secondary outcomes included overall survival. Multivariate analysis was performed to identify risk factors associated with primary and secondary outcomes. Kaplan-Meier analysis compared survival in neoadjuvant and primary surgery groups. RESULTS: Data of 53 patients were analyzed (19 neoadjuvant sunitinib, 34 primary surgery; median follow-up, 58 months). Eighteen (9 in each group, P = .143) had metastatic RCC. There was no difference in IVC tumor level between the 2 groups (P = .76). After neoadjuvant sunitinib, median primary tumor decreased size from 8.1 to 6.8 cm, and IVC tumor decreased by 1.3 cm. IVC tumor level decreased in 8 (42.1%) of 19 and was stable in 10 (52.6%) of 19; 5 (26.3%) of 19 experienced partial response. Similar proportions of patients underwent robot-assisted or minimally invasive approaches (P = .351), and no differences were noted in complications (P = .194). Multivariate analysis showed neoadjuvant sunitinib was associated with improved cancer-specific survival (odds ratio = 3.28; P = .021). Kaplan-Meier analysis demonstrated significantly longer median cancer-specific survival (72 vs. 38 months, P = .023) for neoadjuvant sunitinib. CONCLUSION: Neoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size as well as improved survival. Further investigation is needed to determine the utility of neoadjuvant sunitinib in RCC with IVC tumor.

A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and Caucasian cancer patients: CALGB 9871.

PURPOSE: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients. EXPERIMENTAL DESIGN: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m(2) as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done. RESULTS: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied. CONCLUSIONS: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.

Neoadjuvant therapy for localized and locally advanced renal cell carcinoma.

Neoadjuvant Targeted Molecular Therapy in the setting of localized and locally advanced renal cell carcinoma has emerged as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. Presurgical tumor reduction has been demonstrated in a number of studies including a recently published randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Nonetheless, most reports are small phase II clinical trials or retrospective reports. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for neoadjuvant strategies. This article reviews the current status and future prospects of neoadjuvant therapy in nonmetastatic renal cell carcinoma.

Renal Functional Outcome of Partial Nephrectomy for Complex R.E.N.A.L. Score Tumors With or Without Neoadjuvant Sunitinib: A Multicenter Analysis.

BACKGROUND: Sunitinib might optimize the feasibility of partial nephrectomy (PN) for complex renal tumors with imperative indications. We compared the renal functional outcomes of patients with complex renal masses who had undergone sunitinib before PN with those of patients who had not required neoadjuvant sunitinib before PN. PATIENTS AND METHODS: We performed a multicenter retrospective analysis of patients with renal cell carcinoma who had undergone PN for a complex renal mass (R.E.N.A.L. nephrometry score, 10-12) and imperative indications from January 2012 to July 2014. Neoadjuvant sunitinib was used in cases for which PN was not considered feasible. The cohort was divided into those patients who had undergone PN without neoadjuvant sunitinib and those who had undergone PN after sunitinib (no-neoadjuvant vs. neoadjuvant). The change in tumor size and R.E.N.A.L. score were assessed. The primary outcome was the change in the estimated glomerular filtration rate (ΔeGFR) from preoperatively to the last postoperative follow-up visit. RESULTS: The data from 125 consecutive patients were analyzed (47 neoadjuvant and 78 no-neoadjuvant; median follow-up, 21 months). The neoadjuvant plus PN patients had had a greater median tumor size preoperatively (7.2 vs. 6 cm; P = .045). Sunitinib caused a significant decrease in the median tumor size (from 7.2 to 5.8 cm [19.4%]; P = .012) and R.E.N.A.L. score (from 11 to 9; P = .001). No significant differences were found between the neoadjuvant and no-neoadjuvant groups in the ischemia time (P = .413) or incidence of complications (P = .728). The median ΔeGFR was similar (neoadjuvant, 6.4; no-neoadjuvant, 6.1; P = .534). Linear regression analysis for factors associated with an increasing ΔeGFR demonstrated increasing age (estimate, -0.074; P = .009) increasing body mass index (estimate, -0.087; P = .043), and decreasing baseline eGFR (estimate, -0.104; P = .02) as significant factors. CONCLUSION: The use of neoadjuvant sunitinib might facilitate complex PN and result in renal functional outcomes similar to those of patients with a complex renal mass who had not required neoadjuvant sunitinib.