Presurgical Therapy Research Articles

"A Retrospective Evaluation of the Impact of Prenatal Diagnosis of Facial Clefts. Does Prenatal Diagnosis Matter?"

With the advent of improved prenatal detection, some patients with facial clefting are diagnosed prenatally while others are diagnosed postnatally. There is limited data regarding the utility of prenatal diagnosis and how this affects care of patients with facial clefts. A retrospective chart review was performed. Children with incomplete demographic data and those with syndromic conditions were excluded. The data were analyzed via Fisher's exact tests and Kruskal-Wallis tests (p < 0.05). 106 patients met inclusion criteria. Facial clefting was diagnosed prenatally at different frequencies depending on type of facial cleft- patients with cleft palate alone were less likely to be identified prenatally (p < 0.0001). Patients diagnosed prenatally were seen by craniofacial specialists at an earlier age compared to those diagnosed after birth (0.27 months vs 0.7 months, p < 0.001). Similarly, those with prenatal diagnosis underwent surgery at a younger age compared to those who were diagnosed postnatally (median: 3.6 months vs 10.67 months, p < 0.001) and experienced shorter lag time (median: 3.4 months vs 8.4 months, p = 0.027) from consultation to surgery. Importantly, prenatal diagnosis resulted in pre-surgical therapy more often than in children diagnosed postnatally (86% vs 22.2%, p < 0.001). Our data suggests that patients with prenatal diagnosis of facial clefts were more likely to undergo pre-surgical therapy, presented to a craniofacial specialist at an earlier age, underwent surgery at an earlier age, and experienced less lag time between initial visit and surgery. More study is warranted to improve protocols for prenatal diagnoses to improve surgical outcomes.

Evaluation of Applicability of Tumor Budding and Poorly Differentiated Clusters as Additional Prognostic Markers in Colorectal Cancers

Purpose Very few studies have assessed tumor budding (TB) and poorly differentiated cell clusters (PDCs) simultaneously in colorectal cancers (CRCs). The goal of this study was to establish a correlation between these two pertinent histological features and to reinforce the importance of their incorporation in routine histopathological reporting of CRC cases as a means to predict clinical outcome. Methods Resection specimens of colorectal carcinoma were included in the study. Patients who received presurgical therapy, or refused consent were excluded. PDC and TB were evaluated in routine hematoxylin and eosin-stained histopathological sections taken from the advancing edge of the tumor. TB and PDC were reported by selecting a “hotspot” chosen after review of all available slides with invasive tumor. It was then followed by their correlation with other known prognostic factors. Results Spearman's rho calculator for strength of association between TB and PDC as well as association of TB and PDC individually with known prognostic factors revealed statistical significance. Correlation of TB and PDC with histologic grade, primary tumor (pT), and regional lymph node (pN) stage was done based on one-way analysis of variance calculator, which yielded statistically significant results. Conclusion Evaluation of these two histological parameters in the same hotspot field at the tumor invasive front plays a fundamental role in the definition of cancer aggressiveness and prediction of tumor behavior.

The efficacy and safety of presurgical therapy with tislelizumab and axitinib for renal cell carcinoma with inferior vena cava tumor thrombus.

The efficacy and safety of presurgical therapy with tislelizumab and axitinib for renal cell carcinoma with inferior vena cava tumor thrombus.

Comparative analysis of outcomes of neoadjuvant and adjuvant systemic therapy in non-metastatic renal cell carcinoma: A propensity score-matched analysis from the INMARC registry.

414 Background: Receipt of adjuvant therapy has become a standard of care for management of high risk localized renal cell carcinoma (RCC), with emerging literature demonstrating longer disease-free survival. Neoadjuvant approaches have been utilized investigationally to facilitate complete surgical resections in high risk and complex renal masses. We sought to evaluate outcomes of patients treated with neoadjuvant or adjuvant therapy in non-metastatic RCC utilizing a propensity score model. Methods: We queried the INMARC database for patients with localized surgically treated RCC who underwent systemic neoadjuvant or adjuvant therapy. Neoadjuvant therapy was defined as presurgical therapy given in the setting of localized disease and adjuvant therapy as systemic therapy given postoperatively in the absence of documented metastases. Patients with metastases at time of diagnosis were excluded from the analysis. A propensity score match (PSM) model in a 1:3 ratio was conducted within a caliper width of 0.1 including: age, sex, hypertension, Charlson Comorbidity Index, tumor size, tumor necrosis, stage, surgical margin, tumor grade and type of surgery [radical vs. partial nephrectomy]. Primary outcome was all-cause mortality (ACM), and secondary outcome was cancer-specific mortality (CSM). Multivariable analysis (MVA) via Cox regression was fitted for the outcomes of interest. Kaplan-Meier analysis (KMA) for overall (OS), cancer specific survival (CSS) was conducted for 5-year survival assessment. Results: After PSM 293 patients were analyzed [adjuvant n=203, (69.2%), 109 targeted therapy (TT) vs. 94 immunotherapy; neoadjuvant n=90, (30.7%), 59 TT vs. 31 immunotherapy]; median follow up was 50 (IQR 20-76) months from surgery . MVA revealed adjuvant vs. neoadjuvant (HR 1.98, p=0.007) and positive margin (HR 2.01, p=0.046) to be associated with increased risk of ACM; immunotherapy vs. TT (HR 0.47, p=0.001) was associated with a decreased risk. MVA for CSM revealed that adjuvant vs. neoadjuvant (HR 2.18, p=0.016) and positive margin (HR 2.41, p=0.028) were associated with increased risk of CSM, while immunotherapy vs. TT (HR 0.35, p&lt;0.001) was associated with decreased risk. KMA comparing neoadjuvant vs. adjuvant 5-year OS was 80.4% vs. 64.8% (p=0.04), while CSS was 88.1% vs. 76.2% (p=0.03). Conclusions: In a comparison of patients with localized RCC who underwent adjuvant or neoadjuvant systemic therapy, receipt of neoadjuvant therapy was associated with superior survival outcomes. These findings are hypothesis generating and call for consideration for a clinical trial to compare outcomes of adjuvant vs. neoadjuvant therapy in high-risk localized RCC.

Contemporary Patients Have Better Perioperative Outcomes Following Cytoreductive Nephrectomy: A Multi-institutional Analysis of 1272 Consecutive Patients

To evaluate factors associated with perioperative outcomes in a multi-institutional cohort of patients treated with cytoreductive nephrectomy (CN). Data wereanalyzed for metastatic renal cell carcinoma patients treated with CN at 6 tertiary academic centers from 2005 to 2019. Outcomes included: Clavien-Dindo complications, mortality, length of hospitalization, 30-day readmission rate, and time to systemic therapy. Univariate and multivariable models evaluated associations between outcomes and prognostic variables including the year of surgery. A total of 1272 consecutive patients were treated with CN. Patients treated in 2015-2019 vs 2005-2009 had better performance status (P<.001),higher pathologic N stage (P=.04), more frequent lymph node dissections (P<.001), and less frequent presurgical therapy (P=.02). Patients treated in 2015-2019 vs 2005-2009 had lower overall and major complications from surgery, 22% vs 39%, P<.001% and 10% vs 16%, P=.03. Mortality at 90days was higher for patients treated 2005-2009 vs 2015-2019; 10% vs 5%, P=.02. After multivariable analysis, surgical time period was an independent predictor of major complications and 90-day mortality following cytoreductive surgery. Postoperative major complications and mortality rates following CN are significantly lower in patients treated within the most recent time period.

Efficacy of Surgery on the Primary Tumour in Patients with Metastatic Bladder Cancer: A Comprehensive Review.

The benefit of surgery of the primary tumor in metastatic bladder cancer is unknown. Perform a comprehensive contemporary literature review on the benefit of surgery of the primary tumor in metastatic bladder cancer. Ovid MEDLINE, Ovid EMBASE, and Cochrane Library from January 1, 1990 to April 20, 2020 were queried for relevant articles published in English. Each article was evaluated by at least two content experts prior to inclusion which were blinded to the other's evaluation. A third content expert was used when there was not a unanimous decision. Additional articles were added at the discretion of the authors. Long-term survival is possible in patients with initially unresectable and/or limited metastatic disease. Multi-modal therapy with chemotherapy and surgery have the most favorable outcomes when compared to single treatment modalities in selected populations. Patients who demonstrate a robust response to pre-surgical therapy are likely to benefit the most from consolidative surgery. Patients with distant metastatic disease may benefit from consolidative surgery; however, this benefit may only be seen in those with metastatic disease limited to one site. Surgery of the primary tumor in metastatic bladder cancer either in the setting of surgery alone, consolidative therapy or coupled with adjuvant therapy may be beneficial in well selected patients and should generally be limited to those who have a response to primary chemotherapy. Randomized clinical control trials are needed to further our understanding of the role of surgery in metastatic bladder cancer.

Impact of neoadjuvant immune checkpoint inhibitor therapy on primary tumor size and complexity: Correlation with surgical quality and short term oncological outcomes.

390 Background:The concept of primary systemic therapy has gained increasing traction in the management of metastatic and locally advanced Renal Cell Carcinoma (RCC). Most series have evaluated the use of tyrosine-kinase inhibitors, however, with the emergence of immune checkpoint inhibitor therapy as first line agents in advanced RCC, further assessment of efficacy is warranted. We examined the effects of immunotherapy (IO) combinations on the primary tumor and consequent surgical quality and short-term oncological outcomes. Methods: We conducted a multi-center, retrospective analysis of patients with advanced/metastatic RCC having received IO followed by Radical (RN) or partial nephrectomy (PN). Primary outcome was achievement of Bifecta (composite outcome of complete resection and no 30-day post-operative complications). Predictors for achievement of Bifecta were assessed with logistic regression multivariable analysis. Secondary outcomes were change in maximal tumor dimension, RENAL nephrometry score and disease progression. Kaplan-Meier analysis was used to assess progression-free survival (PFS) for Bifecta and non-Bifecta patients. Results: We identified 52 patients with advanced RCC across 9 institutions who were eligible. The median age was 63 years and 60.4% were males. Median tumor size at diagnosis was 9.3 cm. 19.6% had T4 disease and 75% had AJCC Stage IV disease. IO treatment resulted in significant reductions in median tumor size (-25.4%; 9.7 cm vs. 7.3cm p = 0.0129) and RENAL nephrometry score (9 to 8, p = 0.032). 43 (83%) of patients underwent RN and (9) 17% had PN. Median tumor size was smaller for PN (8 vs. 4.1 cm, p &lt; 0.001), and 30 day complication rates were higher (p = 0.024). Bifecta was achieved in 39 patients [33/42 (78.6%) RN and 6/9 (67%) PN, p = 0.264). Predictors for achievement of Bifecta were younger age (OR 1.06, p = 0.01), increasing reduction in tumor size (OR 1.187, p &lt; 0.001), and shorter time between therapy and surgery (OR 1.07, p &lt; 0.001). Kaplan-Meier analysis demonstrated longer median time to progression in the Bifecta-positive group compared to patients who failed to achieve Bifecta (75 vs. 30 months, p = 0.04). Conclusions: Pre-surgical therapy resulted in tumor size and complexity reduction. Tumor size reduction was predictive for achievement of Bifecta, which was associated with improved short term oncological outcomes. To our knowledge, this is the first series evaluating the effect of neoadjuvant systemic therapy on the primary tumor prior to surgical intervention.

Abstract PL1: Genomic Profiling in Early Stage ER Positive Breast Cancers/Precision Medicine

Abstract Genomic profiling has become mainstream for the management of early ER+ breast cancer and has become a favoured approach for research into pathways that govern prognosis and response and resistance to medical therapies.Management: Several commercial tests are available for the assessment of residual risk of recurrence of patients receiving hormonal therapies. We have compared several of these in postmenopausal patients treated with anastrozole or tamoxifen in the ATAC trial, including OncotypeDX (ODX), Prosigna (PAM50) and EndoPredict (EP). While PAM50 and EP provide estimates of risk that by design integrate tumour size and nodal status, estimates from ODX are also improved substantially by integration with clinicopathologic factors. The 3 tests include genes related to proliferation and to dependence on estrogen signalling with the ODX being dominated by the latter and PAM50 by the former. This may explain the better performance of the PAM50 than ODX at cessation of endocrine treatment after 5 years when the outcome for patients with high ER appears to worsen. While the tests have largely been validated in postmenopausal cases they are used in premenopausal cases as well. We found that while individual gene modules varied in expression across the menstrual cycle there was little systemic variability in the overall estimates of risk. Our recent work has indicated that mutations in TP53 add significant prognostic information to that from the commercial profiling tests.Research: We have conducted genomic analyses during presurgical therapy of ER+ breast cancer to determine the key pathways of endocrine resistance using change in Ki67 as the end-point of response. Very few tumours with low levels of ER by IHC (&amp;lt;10% positive cells) or rtPCR showed a Ki67 response. A group of the most widely studied genes in breast cancer including FOS and JUN show very marked increases in expression during surgical procedures and can lead to erroneous interpretation in the absence of controls. Considering intrinsic subtypes, tumours categorised as basal-like or HER2-enriched have little chance of Ki67 response; luminal B tumours showed a slightly lower chance of response. GSEA revealed that several hallmarks reflecting immune signalling were those most strongly associated poor Ki67 response with the interferon gamma and alpha and IL6-JAK-STAT3 signalling hallmarks being particularly involved. TME deconvolution indicated a broad involvement of many immune cell types. Other hallmarks of resistance included E2F target genes and hypoxia. Mutation of TP53 was strongly associated with Ki67 poor response. RNAseq profiling of patients treated with palbociclb as well as letrozole revealed high CCNE1 expression as associated with endocrine resistance. Citation Format: M Dowsett. Genomic Profiling in Early Stage ER Positive Breast Cancers/Precision Medicine [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PL1.

Giant Renal Cell Carcinoma Surgical Challenges and Life Expectancy: A Real-World Analysis of Serial Cases

Giant renal cell carcinoma is a rare case. We reported six cases of giant renal cell carcinoma, which required surgical resection of the tumor, including a 9.900 cm3 of encapsulated neoplasm removal. To our knowledge, this is the largest giant clear cell RCC ever reported in Asia. Cytoreductive nephrectomy without targeted therapy was performed in all cases. The most common type in all cases was clear cell carcinoma. From six cases, four patients died during follow-up of more than 6 months. The number of cases that died in our case was related to poor preoperative status performance, while one of the patients had a histopathological sarcomatoid cell result with a poor prognosis. We should consider performing cytoreductive nephrectomy in younger patients, clear-cell histology, good performance status, limited metastatic burden, 3 or less International Metastatic RCC Database Consortium (IMDC) risk factors, responding to presurgical therapy, preferably in high-volume centers. Cytoreductive nephrectomy is not for every patient, and it’s associated with longer survival in well-selected patients.

Ki-67 and mitotic index in triple-positive breast cancer.

e12551 Background: A grade in breast cancer is the strongest prognostic factor. In the new edition of the AJCC 8th, the tumor grade is one of the criteria that determines patients with breast cancer in the prognostic groups. According to the Nottingham system the mitotic count (MC) mostly determines the grade. Interobserver reproducibility for MC is not as good as for IHC marker phh3. The group of triple-positive breast cancer (TPBC) is characterized by the presence of a crosstalk mechanism between the signaling pathways of ER and HER2, which leads to the development of resistance to therapy. However, according to the 8th AJCC, patients with ER+/HER2+ belong to a more favorable prognostic group. Methods: We selected 284 patients with early BC who received treatment at our centre from 2012 to 2020 and didn’t receive presurgical therapy. The patients were divided according to the surrogate subtype into triple-positive (n = 90) and other subtypes (n = 194). The Ki-67, the number of nuclei of tumor cells stained with anti-phh3 antibody, the cell density of the tumor per 1 mm2 and the number of phh3 + per 1000 tumor cells were assessed. Results: Visually accessed number of mitoses was grade 3 in 30% of tumors in the TPBC group and 29% in the second group. There was no statistically significant difference in the Ki-67 index of proliferative activity in the two studied groups. In the TPBC group the median Ki-67 was 16.8%, in the second group - 18.3% (p = 0.376516), while the groups differed significantly in terms of the phh3 index (the median in the TPBC was 23.7/mm2, the median in the second group - 16.06/mm2, p = 0.024703). The groups also significantly differed in the number of nuclei of tumor cells that directly entered the mitotic phase (5.1/1000 nuclei in the TPBC group versus 3.2/1000 nuclei in the second group, p = 0.003901). Conclusions: Despite similar indices of proliferative activity in the TPBC and non-TPBC groups, mitotic activity and the number of directly dividing tumor cells in the TPBC group are significantly higher than in the rest of the BC population. Considering the criteria for assessing phh3 (MC 1 &lt; 4/mm2, MC 2 2 4 to 7/mm2, MC 3 &gt; 7/mm2), most TPBCs will have a histological malignancy grade of 3, which according to AJCC 8th places them in the group of poor outcome. We suggest that these differences may be due to the crosstalk mechanism. The second conclusion of our study is the fact that Ki-67 is a poor predictor of the MC.

For women with endometriosis, what are the effects of presurgical and postsurgical medical therapy?

For women with endometriosis, what are the effects of presurgical and postsurgical medical therapy?

Efficacy and predictors of short-term first-generation somatostatin analog presurgical treatment in acromegaly: A hospital-based study of 237 cases

ObjectiveTo investigate the effectiveness and predictors of short-term somatostatin analog (SSA) presurgical therapy in a large cohort and to assess the correlation between clinical and pathological variables. Design237 newly diagnosed patients with acromegaly received presurgical SSA treatment for three months were recruited. Clinical characteristics were collected, and response to SSA in hormone and tumor size was evaluated. The correlation between clinical information and pathological variables were analyzed. ResultsAfter 3 months presurgical SSA therapy, 51 (21.5%) patients were biochemically responsive with ≥50% decrease in IGF-1 while 126 (53.2%) patients showed at least 20% tumor size decrease. Biochemical responders were associated with a smaller maximum tumor diameter (MTD) and an older age (OR, 0.448; P = 0.003; OR, 1.050; P = 0.001). Tumor size responders were associated with a smaller MTD (OR, 0.435; P < 0.001). A combination of MTD < 2 cm and age ≥49 years predicted biochemical responders (PPV, 54.5%; NPV, 86.0%; P < 0.001), while MTD ≤2.2 cm (PPV, 67.1%; NPV, 67.0%; P < 0.001) predicted tumor size responders. Compared to patients with MTD < 2 cm, patients with MTD ≥ 2 cm showed higher percentage of sparsely granulated (SG) adenoma (62.1% vs. 31.3%, P = 0.005). In addition, the percentage of SG adenoma tended to be higher in patients < 49 years than ≥49 years (48.1% and 31.0% P = 0.089). ConclusionsThe baseline MTD and age correlate with granulation patterns and may be used as easily acquired predictors of presurgical SSA treatment in acromegaly. Patients over their 50s with a tumor less than 2 cm in diameter are more likely to have a response to the short-term presurgical SSA therapy.

Presurgical Nasoalveolar Molding Therapy in Bilateral Cleft Lip and Palate – A Case Report

Presurgical Nasoalveolar Molding Therapy in Bilateral Cleft Lip and Palate – A Case Report

Abstract 3450: Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors

Abstract Peripheral sympathetic nervous system tumors are the most common extra-cranial pediatric tumors in children and include neuroblastoma, ganglioneuroblastoma (intermixed and nodular) and ganglioneuroma. The etiology and molecular pathogenesis of ganglioneuromas remains largely unknown. Surgery is the only effective therapy for ganglioneuroma, which can be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is need for well tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma, and therefore limit surgical morbidity. Here we found high levels of phosphorylated AKT expressed in 10 of 11 patients with ganglioneuroma, but only in 1 of 15 who had poorly differentiated neuroblastoma (p&amp;lt;0.0001, Fisher's exact test). Consistent with these results, zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Histopathological analysis and whole-transcriptome sequencing revealed that zebrafish ganglioneuroma highly resembles human ganglioneuroma. Inhibition of the downstream AKT target, mTOR, using sirolimus in zebrafish with ganglioneuroma effectively reduced the tumor burden, providing preclinical evidence for efficacy with this well tolerated drug. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of sirolimus as a means to shrink large ganglioneuromas prior to resection in order to reduce surgical morbidity. Citation Format: Ting Tao, Hui Shi, Adam D. Durbin, Meng Wang, Antonio R. Perez-Atayde, Wendy B. London, Alejandro Gutierrez, Bernardo Lemos, A. Thomas Look. Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3450.

Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors.

Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT-mTOR-S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity.

Surgical Pathology Findings in Patients Who Have Undergone Radical Cystectomy/Cystoprostatectomy With Extended Versus Standard Lymph Node Dissection for Urothelial Carcinoma of the Bladder: A Contemporary Analysis

Radical cystectomy/cystoprostatectomy with pelvic lymph node dissection (with or without neoadjuvant chemotherapy) is the gold standard in the management of patients with urothelial carcinoma (UCa) with muscularis propria (detrusor muscle) invasion. However, it remains controversial how extensive the lymph node dissection should be. In this article, we analyzed the clinicopathologic findings in patients who had radical cystectomy/cystoprostatectomy with extended versus standard lymph node dissection. A search was made through our Urologic Pathology files for radical cystectomy/cystoprostatectomy cases with extended and standard lymph node dissection for UCa. A total of 264 cases were included in the study (218 cystoprostatectomy and 46 cystectomy specimens). Mean patients age was 68 years (range = 32-92 years). Patients in all stage categories had more extended lymph node dissection performed compared with standard lymph node dissection: pT0 (20 vs 7), pTis (40 vs 12), pTa (8 vs 4), pT1 (27 vs 5), pT2 (39 vs 8), pT3 (51 vs 17), and pT4 (18 vs 8). In cases with neoadjuvant therapy there was a 19% lymph node positivity rate compared with a 24% positivity rate in those with no presurgical therapy. The only cases categorized as pT2 and below with positive lymph node metastasis were those that had extended lymph node dissection performed. Positive lymph nodes were more frequently detected in cases that had extended lymph node dissection. More than 35% of the positive lymph nodes were in nonregional distribution. Extended lymph node dissection should be considered in patients with UCa even in the low stage or post-neoadjuvant chemotherapy setting.

Randomized phase II trial of presurgical androgen deprivation therapy (ADT) with or without axitinib in prostate cancer (PCa) presenting with lymph node (LN) metastasis.

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]

Hypoxia signaling and immune infiltration in a presurgical trial of sunitinib in patients with clear cell renal cell carcinoma (RCC).

e16115 Background: Presurgical clinical trial design allow for pharmacodynamically relevant tissue collection that can inform regarding drivers of tumor biology. An unmet need is the ability to identify tumors that may respond to immunotherapy and the underlying mechanism of immune infiltration. Methods: This single arm phase II study was designed to test efficacy and safety of presurgical sunitinib treatment in metastatic RCC, and to identify drivers of tumor biology. Patients (pts) with metastatic RCC and a resectable primary received sunitinib 50mg PO daily for four weeks, and underwent restaging. If deemed a candidate, pts underwent cytoreductive nephrectomy (CN) during their second cycle of sunitinib, with last dose administered the day before surgery. Pts were restaged postoperatively and continued on sunitinib if no progressive disease was seen. Genomic and histological characteristics of RCC were evaluated for correlations between response and biological features. Results: Between June 2008 and October 2011, 50 pts were enrolled. 41 underwent CN. Seven pts showed refractory disease and were not considered surgical candidates. No sunitinib related perioperative toxicities were observed. Six pts progressed on first postoperative imaging studies, with three patients developing new brain metastases. Median progression free survival (PFS) was 8.6 months, and overall survival was 38 months. Objective response rate was 30 percent with 2 pts demonstrating a complete response. Analysis on 39 pts showed HIF1a staining was significantly associated with PFS (p = 0.023*, univariate Cox model), with a hazard ratio (HR) of 1.028 (95% CI, 1.004-1.053). This association remained significant in a multivariate Cox model adjusting for age and gender (p = 0.019*). In addition, HIF1a correlated with multiple immune markers (CD8, CD45RO, PD1, Treg, CD68, and LAG3). Analysis of genomic correlates is ongoing. Conclusions: Presurgical sunitinib therapy in RCC is safe and efficacious. HIF1a staining is associated with shorter PFS, and with increased immune infiltration. Tissue HIF1a should be explored as a marker, and studied mechanistically as a driver of the immune microenvironment in RCC. Clinical trial information: NCT00715442.

Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives.

Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma have continued to evolve in two directions: (i) as adjuvant therapy (to reduce the risk of recurrence or progression in high-risk localized groups); or (ii) as neoadjuvant therapy 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. In the realm of adjuvant therapy, the results of adjuvant therapy phaseIII randomized clinical trials have been mixed and contradictory; nevertheless, the findings of the landmark Sunitinib Treatment of Renal Adjuvant Cancer study have led to approval of sunitinib as an adjuvant agent in the USA. In the realm of neoadjuvant therapy, presurgical tumor reduction has been shown in a number of phaseII studies utilizing targeted molecular agents and in a recently published small randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. 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 adjuvant and neoadjuvant strategies. The present article reviews the current status and future prospects of adjuvant and neoadjuvant therapy in localized and locally advanced renal cell carcinoma.

Position of cytoreductive nephrectomy in the setting of metastatic renal cell carcinoma patients: does the CARMENA trial lead to a paradigm shift?

Introduction > The role of cytoreductive nephrectomy (CN) in combination with targeted therapy has been debated after the results of the CARMENA trial. We decided to reassess the available evidence on the setting of CN in metastatic renal cell carcinoma (mRCC) patients. Methods > Critical review of the literature focusing on CN in mRCC patients. Results > Previous trials demonstrated a survival benefit of CN during the cytokine-era. In the targeted therapies-era, retrospective studies has confirmed the survival benefit of CN but presented inherent selection biases. Recently, the CARMENA trial showed that sunitinib alone was not inferior to CN plus sunitinib, and could be followed by subsequent CN in good-responders patients. CN is found to be a morbid surgery (perioperative mortality rate of 0-13% and major postoperative complications rate of 3-36%) and should be avoided in patients with primary refractory disease, using targeted therapy as a selection tool. Some parameters have been associated with shorter overall survival, leading to propose up-front CN only to patients with good performance status, a high-volume renal tumor and a low metastatic burden. Conclusions > While previous studies demonstrated a survival benefit of CN, the CARMENA trial showed that immediate CN was not necessary in some patients with mRCC, leading to a paradigm shift. Targeted therapy should be proposed as first line treatment, and the response to pre-surgical therapy could be used as a selection tool for subsequent decision of CN in good-responders patients.