Publications by authors named "Pooja Ghatalia"

45 Publications

The Role of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma: A Real-World Multi-Institutional Analysis.

J Urol 2022 07 25;208(1):71-79. Epub 2022 Feb 25.

Department of Urology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) was challenged by the results of the CARMENA trial. Here we evaluate the role of CN in mRCC patients, including those receiving modern therapies.

Materials And Methods: We included patients with synchronous mRCC between 2011-2020 from the de-identified nationwide Flatiron Health database. We evaluated 3 groups: systemic therapy alone, CN followed by systemic therapy (up-front CN [uCN]) and systemic therapy followed by CN (deferred CN [dCN]). The primary outcome was median overall survival (mOS) in patients receiving systemic therapy alone vs uCN. Secondary outcome was overall survival in patients receiving uCN vs dCN. First-treatment, landmark and time-varying covariate analyses were conducted to overcome immortal time bias. Weighted Kaplan-Meier curves, log-rank tests and Cox proportional hazards regressions were used to assess the effect of therapy on survival.

Results: Of 1,910 patients with mRCC, 972 (57%) received systemic therapy, 605 (32%) received uCN, 142 (8%) dCN and 191 (10%) CN alone; 433 (23%) patients received immunotherapy-based therapy. The adjusted mOS was significantly improved in first-treatment, landmark and time-varying covariate analysis (mOS 26.6 vs 14.6 months, 36.3 vs 21.1 months and 26.1 vs 12.2 months, respectively) in patients undergoing CN. Among patients receiving CN and systemic therapy, the timing of systemic therapy relative to CN was not significantly related to overall survival (HR=1.0, 95% CI 0.76-1.32, p=0.99).

Conclusions: Our findings support an oncologic role for CN in select mRCC patients. In patients receiving both CN and systemic therapy, the survival benefit compared to systemic alone was similar for up-front and deferred CN.
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http://dx.doi.org/10.1097/JU.0000000000002495DOI Listing
July 2022

A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1).

Prostate Cancer Prostatic Dis 2022 Jan 25. Epub 2022 Jan 25.

Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Background: Metformin may have anticancer effects that are independent of its hypoglycemic effects. Retrospective studies have shown that metformin use is associated with decreased incidence of prostate cancer and prostate cancer-specific mortality. Preclinical studies suggesting additive anticancer effects of combining metformin and bicalutamide prompted this clinical trial (NCT02614859).

Methods: This open-label, randomized, phase 2 trial enrolled non-diabetic patients with biochemically recurrent prostate cancer, a PSADT of 3-9 months, BMI > 25 and normal testosterone. Patients were randomized 1:2 to observation for an initial 8 weeks (Arm A) or metformin 1000 mg twice daily (Arm B). Bicalutamide 50 mg/day was added after 8 weeks to both arms. The primary objective was to evaluate the number of patients with undetectable PSA ( < 0.2 ng/mL) at the end of 32 weeks. Immune correlatives were assessed as exploratory endpoints.

Results: A total of 29 patients were enrolled from March 2015 to January 2020. No difference was seen between the 2 arms in the proportion of patients with undetectable PSA. Modest PSA decrease ranging from 4% to 24% were seen in 40.0% (95% CI: 19.1-64.0%) of patients with metformin monotherapy, compared to 11.1% (95% CI: 0.3-48.3%) in the observation arm. Metformin monotherapy reduced PD-1 NK cells, and increased NKG2D NK cells. The combination of metformin and bicalutamide led to greater reductions in PD-1 expressing NK, CD4 T, and CD8 T-cell subsets compared to bicalutamide alone. The trial was stopped early due to predicted inability to achieve its primary endpoint.

Conclusions: Although metformin plus bicalutamide was well tolerated, there was no improvement in rates of achieving undetectable PSA at 32 weeks. Metformin monotherapy induced modest PSA declines in 40% of patients after 8 weeks. Metformin, given alone and in combination with bicalutamide, displayed immune modifying effects, primarily within NK and T cells subsets.

Trial Registration: Trial Registration Number: NCT02614859.
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http://dx.doi.org/10.1038/s41391-022-00492-yDOI Listing
January 2022

Combination Strategies for Immune Checkpoint Inhibitors in PBRM1-mutant Renal Cell Carcinoma: To PARP or Not To PARP?

Eur Urol 2022 02 6;81(2):149-150. Epub 2021 Nov 6.

Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA; Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2021.10.028DOI Listing
February 2022

Role of immunotherapy in localized muscle invasive urothelial cancer.

Ther Adv Med Oncol 2021 22;13:17588359211045858. Epub 2021 Sep 22.

Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

The standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy or trimodality therapy with chemoradiation in select patients. Pathologic complete response (pCR) to neoadjuvant chemotherapy is a reliable predictor of overall and disease-specific survival in MIBC. A pCR rate of 35-40% is attained with neoadjuvant cisplatin-based chemotherapy. With the approval of immune checkpoint inhibitors (ICIs) for the treatment of metastatic urothelial cancer, these agents are now being studied in the neoadjuvant setting for MIBC. We describe the results from clinical trials using single agent ICI, ICI/ICI and ICI/chemotherapy combination therapies in the neoadjuvant setting for MIBC. These single-arm clinical trials have demonstrated safety and pCR comparable to cisplatin-based chemotherapy. Neoadjuvant ICI is a promising approach for cisplatin-ineligible patients, and the role of adding ICIs to cisplatin-based chemotherapy is also being investigated in randomized phase III clinical trials. Ongoing biomarker research to suggest a response to neoadjuvant ICIs will also guide appropriate treatment selection. We also describe the studies using ICIs for adjuvant therapy and in combination with chemoradiation.
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http://dx.doi.org/10.1177/17588359211045858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461126PMC
September 2021

Safety of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer and malignant ureteric obstruction.

BJU Int 2022 03 26;129(3):364-372. Epub 2021 Apr 26.

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Objectives: To determine whether patients with carcinoma invading bladder muscle (MIBC) and ureteric obstruction can safely receive cisplatin-based neoadjuvant chemotherapy (C-NAC), and to determine whether such patients require relief of obstruction with a ureteric stent or percutaneous nephrostomy prior to beginning C-NAC.

Patients And Methods: We performed a single-institution retrospective analysis of MIBC patients receiving C-NAC and falling into three groups: no ureteric obstruction (NO); relieved ureteric obstruction (RO); and unrelieved ureteric obstruction (URO). To address whether patients with obstruction can safely receive C-NAC, we compared patients with NO to those with RO, with the primary outcome of premature chemotherapy discontinuation. To investigate whether patients with obstruction should have the obstruction relieved prior to NAC, we compared RO to URO patients using a primary composite outcome of grade ≥ 3 adverse events, premature chemotherapy discontinuation, dose reduction, or dose interruption. The primary outcomes were compared using multivariable logistic regression. Sensitivity analyses were performed for the RO vs URO comparison, in which patients with only mild degrees of obstruction were excluded from the URO group.

Results: A total of 193 patients with NO, 49 with RO, and 35 with URO were analysed. There were no statistically significant differences between those with NO and those with RO in chemotherapy discontinuation (15% vs 22%; P = 0.3) or any secondary outcome. There was no statistically significant difference between those with RO and URO in the primary composite outcome (51% vs 53%; P = 1) or any secondary outcome.

Conclusion: Patients with ureteric obstruction can safely receive C-NAC. Relief of obstruction was not associated with increased safety of C-NAC delivery.
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http://dx.doi.org/10.1111/bju.15410DOI Listing
March 2022

Cystoscopy and Systematic Bladder Tissue Sampling in Predicting pT0 Bladder Cancer: A Prospective Trial.

J Urol 2021 06 4;205(6):1605-1611. Epub 2021 Feb 4.

Division of Urological Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: Concern for discordance between clinical staging and final pathology drives current management of patients deemed appropriate candidates for radical cystectomy. Therefore, we set out to prospectively investigate reliability and shortcomings of cystoscopic evaluation in radical cystectomy candidates.

Materials And Methods: Patients undergoing radical cystectomy for urothelial carcinoma were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation in predicting pT0 urothelial carcinoma (NCT02968732). Systematic Endoscopic Evaluation consisted of cystoscopy and tissue sampling at the time of radical cystectomy. Systematic Endoscopic Evaluation results were compared to radical cystectomy pathology. The primary end point was the negative predictive value of Systematic Endoscopic Evaluation findings in predicting radical cystectomy pathology.

Results: A total of 61 patients underwent Systematic Endoscopic Evaluation and radical cystectomy. Indications included muscle invasive bladder cancer in 42 (68.9%) and high risk nonmuscle invasive bladder cancer in 19 (31.1%). In all, 38 (62.3%, 90.5% of patients with muscle invasive bladder cancer) received neoadjuvant chemotherapy. On Systematic Endoscopic Evaluation, 31 (50.8%) patients demonstrated no visual nor biopsy-based evidence of disease (seeT0), yet 16/31 (51.6%) harbored residual disease (>pT0), including 8 (8/31, 25.8%) with residual ≥pT2 disease upon radical cystectomy. The negative predictive value of Systematic Endoscopic Evaluation predicting a pT0 bladder was 48.4% (CI 30.2-66.9), which was below our prespecified hypothesis. Therefore, the trial was stopped for futility.

Conclusions: Approximately 1 of 4 patients with seeT0 at the time of radical cystectomy harbored residual muscle invasive bladder cancer. These prospective data definitively confirm major limitations of endoscopic assessment for pT0 bladder cancer. Future work should focus on novel imaging and biomarker strategies to optimize evaluations before radical cystectomy for improved decision making regarding bladder preservation.
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http://dx.doi.org/10.1097/JU.0000000000001602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006869PMC
June 2021

Systemic therapy in bladder preservation.

Urol Oncol 2020 Nov 19. Epub 2020 Nov 19.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address:

Bladder cancer is an aggressive and lethal disease. Even when presenting as localized muscle-invasive disease, the 5-year survival rate is about 70%, and the recurrence rate after radical cystectomy is approximately 50%. Neoadjuvant chemotherapy (NAC) has the potential to downstage the primary tumor and treat micrometastases, leading to a decrease in recurrence rates and an increase in cure rates. There is level 1 evidence in favor of neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy. However, data from clinical trials evaluating NAC for patients undergoing bladder-sparing treatments are less robust, so this strategy remains controversial. The response to NAC is prognostic and patients with favorable pathological response have better overall survival. Strategies to select patients based on molecular biomarkers have the potential to guide treatment decisions and even de-intensify treatment, avoiding local treatment for those with complete responses to systemic therapy. This review outlines the current literature on the use of NAC in the context of bladder preservation for muscle-invasive bladder cancer, highlights neoadjuvant studies in patients ineligible for cisplatin-based NAC, and discusses novel bladder-preservation strategies, including multimodality combinations and biomarker-driven studies of definitive chemotherapy.
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http://dx.doi.org/10.1016/j.urolonc.2020.10.006DOI Listing
November 2020

Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients.

Oncoimmunology 2020 06 10;9(1):1773200. Epub 2020 Jun 10.

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, US.

Background: Biomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice.

Methods: Tumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome.

Results: For 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant ( = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved ( = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%).

Conclusions: Cell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings.
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http://dx.doi.org/10.1080/2162402X.2020.1773200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458647PMC
June 2020

Integration of Immunotherapy Into the Treatment of Advanced Urothelial Carcinoma.

J Natl Compr Canc Netw 2020 03;18(3):355-361

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Five new PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma (UC): pembrolizumab, atezolizumab, durvalumab, nivolumab, and avelumab. Although cisplatin-based chemotherapy remains the recommended frontline option for cisplatin-eligible patients with metastatic UC, immunotherapy is now an available option in the second-line setting as well as the frontline setting for selected cisplatin-ineligible patients who are either unable to tolerate chemotherapy or PD-L1-positive. This review describes the updated clinical efficacy of these checkpoint inhibitors in the treatment of advanced UC and suggests how they can be sequenced in the context of available chemotherapeutic options.
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http://dx.doi.org/10.6004/jnccn.2020.7539DOI Listing
March 2020

PGC1α suppresses kidney cancer progression by inhibiting collagen-induced SNAIL expression.

Matrix Biol 2020 07 23;89:43-58. Epub 2020 Jan 23.

Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35233, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA. Electronic address:

The transcriptional events that promote invasive and metastatic phenotypes in renal cell carcinoma (RCC) remain poorly understood. Here we report that the decreased expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) and the increased expression of several genes encoding collagen family members are associated with RCC tumor progression. PGC1α restoration attenuates invasive phenotypes and suppresses tumor progression in vivo. In contrast, collagens produced by RCC cells promote invasive and migratory phenotypes. PGC1α restoration suppresses the expression of collagens and tumor phenotypes via the induction of miR-29a. Furthermore, decreased collagens via the PGC1α/miR-29a axis suppresses collagen-mediated activation of discoidin domain receptor 1 (DDR1)/ERK signaling. In turn, the suppression of collagen/DDR1 signaling by PGC1α leads to decreased levels of the known EMT regulators SNAIL1 and 2. Collectively, our results demonstrate a novel role for PGC1α in the regulation of proinvasive SNAIL proteins.
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http://dx.doi.org/10.1016/j.matbio.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712461PMC
July 2020

Biomarkers for neoadjuvant checkpoint blockade response in urothelial cancer.

Nat Med 2019 11;25(11):1650-1651

Fox Chase Cancer Center, Philadelphia, PA, USA.

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http://dx.doi.org/10.1038/s41591-019-0645-6DOI Listing
November 2019

Correction to: Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma.

J Immunother Cancer 2019 Oct 22;7(1):273. Epub 2019 Oct 22.

Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA.

Following publication of the original article [1], the author reported that the current funding section "Kidney Cancer Association Young Investigator Grant provided funding for this project" should be replaced with "Kidney Cancer Association Young Investigator Grant and Bucks County Board provided funding for this project."
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http://dx.doi.org/10.1186/s40425-019-0735-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806554PMC
October 2019

Dual Checkpoint Inhibition with Ipilimumab plus Nivolumab After Progression on Sequential PD-1/PDL-1 Inhibitors Pembrolizumab and Atezolizumab in a Patient with Lynch Syndrome, Metastatic Colon, and Localized Urothelial Cancer.

Oncologist 2019 11 23;24(11):1416-1419. Epub 2019 Aug 23.

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

Immune checkpoint blockade (ICB) is an approved therapy for advanced metastatic mismatch repair (MMR)-deficient cancer regardless of tissue of origin. Although therapy is effective initially, recurrence rates are significant, and long-term outcomes remain poor for most patients. It is not currently recommended to give sequential ICB for advanced MMR-deficient colorectal cancer (CRC) or for patients with metastatic cancer from Lynch syndrome. The need for subsequent therapy options in advanced MMR-deficient cancer beyond the first ICB regimen arises in clinical practice, and there are often no effective standard chemotherapies or other targeted therapies. We report the case of a Lynch syndrome patient with metastatic CRC and urothelial cancer who was treated sequentially with pembrolizumab (targeting PD1), atezolizumab (targeting PD-L1), brief rechallenge with pembrolizumab, and finally the combination of ipilimumab (targeting CTLA-4) and nivolumab (targeting PD1). Over a 28-month period the patient experienced prolonged disease control with each different regimen the first time it was given, including metabolic response by positron emission tomography and computed tomography scanning and tumor marker reductions. The case suggests that some patients with advanced MMR-deficient CRC may experience meaningful clinical benefit from multiple sequential ICB regimens, a strategy that can be further tested in clinical trials. KEY POINTS: The case exemplifies clinical benefit from sequential immune checkpoint blockade in a patient with Lynch syndrome with advanced metastatic colorectal cancer and urothelial cancer.Metabolic response, with decreased fluorodeoxyglucose avidity on positron emission tomography and computed tomography, and reductions in tumor markers, such as carcinoembryonic antigen, were helpful in this case to monitor disease status over a 28-month period of therapy.The concept of sequential immune checkpoint blockade in patients with advanced mismatch repair-deficient cancer merits further study to determine which patients are most likely to benefit.
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http://dx.doi.org/10.1634/theoncologist.2018-0686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853126PMC
November 2019

Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma.

J Immunother Cancer 2019 05 28;7(1):139. Epub 2019 May 28.

Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA.

Background: The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurrence following surgery in localized ccRCC.

Methods: We morphologically identified and scored tumor infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) stained slides of patients with localized ccRCC (stage ≥T1b excluding stage IV). The University of Alabama at Birmingham (UAB) dataset (n = 159) was used to discover and the Fox Chase Cancer Center (FCCC) dataset (n = 198) was used to validate the results of morphologic immune cell analysis. We then performed gene expression analysis using the Immune Profile panel by NanoString in the UAB cohort and identified immune cells and pathways associated with recurrence, followed by validation in the Cancer Genome Atlas (TCGA) ccRCC dataset. Infiltrating immune cell types were identified by gene expression deconvolution.

Results: The presence of TILs identified by morphology correlated with higher T cell, Th1, CD8+ T and Treg gene signatures. Recurrence was associated with lower T cells and higher neutrophils. Higher Teffector (Teff)/Treg ratio correlated with lower rate of recurrence and was validated in the TCGA dataset. Genes associated with adaptive immune response were downregulated in tumors that recurred. Unsupervised hierarchical clustering identified a subset of patients with over-expression of adaptive response genes including CD8, CD3, GZMA/B, PRF1, IDO1, CTLA4, PDL1, ICOS and TIGIT. These patients had higher morphologic lymphocyte infiltration and T cell gene expression. Higher levels of TILs identified by morphology correlated with higher rates of recurrence in our discovery dataset but not in our validation set.

Conclusions: Recurrence of ccRCC following surgery was associated with lower T cell infiltrate, lower adaptive immune response and higher neutrophil gene expression. Presence of higher Teff/Treg ratio correlated with lower recurrence.
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http://dx.doi.org/10.1186/s40425-019-0621-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540413PMC
May 2019

First-line Immunotherapy in Metastatic Urothelial Carcinoma.

Eur Urol Focus 2020 01 15;6(1):45-47. Epub 2019 May 15.

Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address:

Update on first-line immunotherapy in metastatic urothelial carcinoma.
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http://dx.doi.org/10.1016/j.euf.2019.04.015DOI Listing
January 2020

Update on perioperative systemic therapy for urothelial carcinoma.

Clin Adv Hematol Oncol 2019 Mar;17(3):176-183

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Level 1 evidence supports cisplatin-based neoadjuvant chemotherapy (NAC) in muscle-invasive urothelial bladder cancer (MIUBC). Recent data from small prospective trials with neoadjuvant immune checkpoint inhibitors are encouraging, but long-term follow-up is required. Randomized trials have failed to accrue a sufficient number of patients and have not demonstrated a survival benefit with adjuvant chemotherapy in MIUBC, but for those with high-risk features at surgery, adjuvant cisplatin-based therapy is appropriate. In upper tract urothelial carcinoma, several retrospective trials and one recent phase 2 prospective trial support the use of NAC, and a randomized trial with adjuvant chemotherapy demonstrated improved disease- and metastasis-free survival and a trend toward improved overall survival.
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March 2019

Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients.

J Immunother Cancer 2019 02 1;7(1):27. Epub 2019 Feb 1.

Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

Background: Resistance to immune checkpoint inhibitors (ICIs) has been linked to local immunosuppression independent of major ICI targets (e.g., PD-1). Clinical experience with response prediction based on PD-L1 expression suggests that other factors influence sensitivity to ICIs in non-small cell lung cancer (NSCLC) patients.

Methods: Tumor specimens from 120 NSCLC patients from 10 institutions were evaluated for PD-L1 expression by immunohistochemistry, and global proliferative profile by targeted RNA-seq.

Results: Cell proliferation, derived from the mean expression of 10 proliferation-associated genes (namely BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, and TOP2A), was identified as a marker of response to ICIs in NSCLC. Poorly, moderately, and highly proliferative tumors were somewhat equally represented in NSCLC, with tumors with the highest PD-L1 expression being more frequently moderately proliferative as compared to lesser levels of PD-L1 expression. Proliferation status had an impact on survival in patients with both PD-L1 positive and negative tumors. There was a significant survival advantage for moderately proliferative tumors compared to their combined highly/poorly counterparts (p = 0.021). Moderately proliferative PD-L1 positive tumors had a median survival of 14.6 months that was almost twice that of PD-L1 negative highly/poorly proliferative at 7.6 months (p = 0.028). Median survival in moderately proliferative PD-L1 negative tumors at 12.6 months was comparable to that of highly/poorly proliferative PD-L1 positive tumors at 11.5 months, but in both instances less than that of moderately proliferative PD-L1 positive tumors. Similar to survival, proliferation status has impact on disease control (DC) in patients with both PD-L1 positive and negative tumors. Patients with moderately versus those with poorly or highly proliferative tumors have a superior DC rate when combined with any classification schema used to score PD-L1 as a positive result (i.e., TPS ≥ 50% or ≥ 1%), and best displayed by a DC rate for moderately proliferative tumors of no less than 40% for any classification of PD-L1 as a negative result. While there is an over representation of moderately proliferative tumors as PD-L1 expression increases this does not account for the improved survival or higher disease control rates seen in PD-L1 negative tumors.

Conclusions: Cell proliferation is potentially a new biomarker of response to ICIs in NSCLC and is applicable to PD-L1 negative tumors.
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http://dx.doi.org/10.1186/s40425-019-0506-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359802PMC
February 2019

Clinical Utilization Pattern of Liquid Biopsies (LB) to Detect Actionable Driver Mutations, Guide Treatment Decisions and Monitor Disease Burden During Treatment of 33 Metastatic Colorectal Cancer (mCRC) Patients (pts) at a Fox Chase Cancer Center GI Oncology Subspecialty Clinic.

Front Oncol 2018 17;8:652. Epub 2019 Jan 17.

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States.

Liquid biopsy (LB) captures dynamic genomic alterations (alts) across metastatic colorectal cancer (mCRC) therapy and may complement tissue biopsy (TB). We sought to describe the utility of LB and better understand mCRC biology during therapy. Thirty-three patients (pts) with mCRC underwent LB. We used permutation-based -tests to assess associations between alts, and clinical variables and used Kendall's tau to measure correlations. Of 33 pts, 15 were women; 22 had colon, and the rest rectal cancer. Pts received a median of two lines of therapy before LB. Nineteen pts had limited testing on TB (), 11 extended NGS, and 3 no TB. Maxpct and alts correlated with CEA ( < 0.001, respectively). In 3/5 pts with serial LB, CEA correlated with maxpct trend, and CT tumor burden. In 6 pts, mutant was seen in LB and not TB; 5/6 had received anti-EGFR therapy prior to LB, suggesting alts developed post-therapy. In two pts -mutated by TB, no alts were detected on LB; these pts had low disease burden on CT at time of LB that also did not reveal or alts. In six patients who were KRAS wt based on TB, post anti-EGFR LB revealed subclonal KRAS mutations, likely a treatment effect. The median number of alts was higher post anti-EGFR LB ( = 12) vs. anti-EGFR naïve LB ( = 22) (9.5 vs. 5.5, = 0.059) but not statistically significant. More alts were also noted in post anti-EGFR therapy LB vs. wt anti-EGFR-naïve LB ( = 6) (9.5 vs. 5) among patients with wild-type tumors, although the difference was not significant ( = 0.182). LB across mCRC therapy detects driver mutations, monitors disease burden, and identifies sub-clonal alts that reflect drug resistance, tumor evolution, and heterogeneity. Interpretation of LB results is impacted by clinical context.
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http://dx.doi.org/10.3389/fonc.2018.00652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344461PMC
January 2019

Interaction of germline variants in a family with a history of early-onset clear cell renal cell carcinoma.

Mol Genet Genomic Med 2019 03 24;7(3):e556. Epub 2019 Jan 24.

Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Background: Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival.

Methods: We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by whole-exome sequencing (WES), coupled with WES analysis of germline DNA from additional affected and unaffected family members.

Results: This work identified multiple predicted protein-damaging variants relevant to the pattern of inherited cancer risk. Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA, a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient's tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2, TRAP1, PARP1, and EGF, each potentially relevant to cancer risk alone or in conjunction with the SDHA variant. In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband.

Conclusion: Together, these data suggest the possibility of risk associated with interaction of two or more variants.
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http://dx.doi.org/10.1002/mgg3.556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418363PMC
March 2019

Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors.

J Immunother Cancer 2019 01 24;7(1):18. Epub 2019 Jan 24.

Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA.

Background: PD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures.

Methods: A total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels.

Results: Assessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for "RNA-seq low vs high" in melanoma.

Conclusions: Measurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies.
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http://dx.doi.org/10.1186/s40425-018-0489-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346512PMC
January 2019

Evolving landscape of the treatment of metastatic clear cell renal cell carcinoma.

Clin Adv Hematol Oncol 2018 Oct;16(10):677-686

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

The management of advanced clear cell renal cell carcinoma (RCC) has evolved over the past decade with the introduction of targeted therapies and immune checkpoint inhibitors. Recently, studies of dual checkpoint inhibition and of vascular endothelial growth factor (VEGF) inhibition combined with checkpoint inhibition have shown promising results, adding newer options to the treatment armamentarium for advanced RCC. Specifically, therapies combining checkpoint inhibitors of different classes and combining VEGF inhibitors with checkpoint inhibitors have gained much interest, and results from studies of several other combinations are awaited. These and previously approved treatments offer multiple options to patients with advanced RCC. In this review, we discuss the efficacy and safety results from the pivotal trials of these therapies, how the trial data can guide selection of the most appropriate therapy, and how to consider sequencing therapies in the care of patients with advanced RCC.
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October 2018

The Evolution of Clinical Trials in Renal Cell Carcinoma: A Status Report for 2013-2016 from the ClinicalTrials.gov Website.

Kidney Cancer 2017 Nov 27;1(2):151-159. Epub 2017 Nov 27.

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: We previously published an analysis of clinical trials in renal cell carcinoma (RCC) using the publicly available ClinicalTrials.gov registry. Here we present a 3-year update to understand clinical research current trends in RCC compared to 2013.

Methods: The Website's advanced search function was used to search for RCC trials. The characteristics of the trial were extracted, summarized and compared to 2013 data using Fisher's exact tests.

Results: We locked our search on May 26, 2016 with 165 trials eligible, compared with 169 trials on Sep 25, 2013. There were more phase I and I/II trials in 2016 compared to 2013 (40.8% vs 24.9%,  = 0.05). More clinical trials in 2016 compared to 2013 used immunotherapy (IT) alone or in combination with other drugs (24.2% vs 10.7%,  = 0.001), and the use of targeted therapy alone (TT) declined (32.9% vs 47.9%,  = 0.005). TT+IT combination trials more than doubled (6.7% vs 2.3%,  = 0.07). The number of trials with treatment in (neo)adjuvant settings in 2016 and 2013 were similar (9.7% vs 10.6%,  = 0.77), respectively. Compared to 2013, the number of trials with non-clear cell histology remained low ( = 10). Many more trials were sponsored by the pharmaceutical industry in 2016 vs 2013 (41.5% vs 16.0%,  = <0.001).

Conclusion: IT-based and industry sponsored clinical trials significantly increased from 2013 to 2016 with a concomitant drop in TT only trials. The increase in industry-sponsored studies may reflect the rapid uptake of expensive IT drugs. There continues to be a paucity of (neo)adjuvant studies and for non-clear cell histologies.
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http://dx.doi.org/10.3233/KCA-170015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179107PMC
November 2017

Systematic Review: ClearCode 34 - A Validated Prognostic Signature in Clear Cell Renal Cell Carcinoma (ccRCC).

Kidney Cancer 2018 30;2(1):23-29. Epub 2018 Mar 30.

Department of Medicine, Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN.

The standard of care of patients with localized clear cell RCC (ccRCC) is observation after nephrectomy. However, a third of these patients have local or distant recurrence. Along with basic clinical and pathologic variables like stage, necrosis and grade, robust molecular based prognostic markers are needed that could help better predict groups of patients who will most benefit from such adjuvant treatment approaches. ccA/ccB classification was developed to classify ccRCC patients into high and low risk based on gene expression patterns. ClearCode 34 is a genetic signature that was developed from the ccA/ccB classification to predict recurrence in localized ccRCC patients. This signature has been validated in several patient cohorts and is ready for future testing in a variety of clinical scenarios. This review will evaluate the molecular signature ClearCode34, discuss its role in predicting recurrence and consider the rational application of this example of a molecular biomarker in the management of ccRCC.
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http://dx.doi.org/10.3233/KCA-170021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176730PMC
March 2018

Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis.

Mol Cancer Res 2019 01 21;17(1):84-96. Epub 2018 Aug 21.

Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.

The Cancer Genome Atlas (TCGA) and other large-scale genomic data pipelines have been integral to the current understanding of the molecular events underlying renal cell carcinoma (RCC). These data networks have focused mostly on primary RCC, which often demonstrates indolent behavior. However, metastatic disease is the major cause of mortality associated with RCC and data sets examining metastatic tumors are sparse. Therefore, a more comprehensive analysis of gene expression and DNA methylome profiling of metastatic RCC in addition to primary RCC and normal kidney was performed. Integrative analysis of the methylome and transcriptome identified over 30 RCC-specific genes whose mRNA expression inversely correlated with promoter methylation, including several known targets of hypoxia inducible factors. Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation including hexokinase 2, aldolase C, stearoyl-CoA desaturase, and estrogen-related receptor-γ (ESRRG), which has a known role in the regulation of nuclear-encoded mitochondrial metabolism genes. Several gene expression changes could portend prognosis in the TCGA cohort. Mechanistically, ESRRG loss occurs via DNA methylation and histone repressive silencing mediated by the polycomb repressor complex 2. Restoration of ESRRG in RCC lines suppresses migratory and invasive phenotypes independently of its canonical role in mitochondrial metabolism. IMPLICATIONS: Collectively, these data provide significant insight into the biology of aggressive RCC and demonstrate a novel role for DNA methylation in the promotion of HIF signaling and invasive phenotypes in renal cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222224PMC
January 2019

Approved checkpoint inhibitors in bladder cancer: which drug should be used when?

Ther Adv Med Oncol 2018 30;10:1758835918788310. Epub 2018 Jul 30.

Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

The treatment of advanced metastatic urothelial carcinoma has recently evolved with the approval of five checkpoint inhibitors. In the second-line setting, in patients who have progressed on cisplatin-based chemotherapy, pembrolizumab, atezolizumab, durvalumab, nivolumab and avelumab are United States Food and Drug Administration (FDA) approved. In cisplatin-ineligible patients, atezolizumab and pembrolizumab are the FDA-approved checkpoint inhibitors. Here we describe the updated clinical efficacy of these checkpoint inhibitors in the treatment of advanced urothelial carcinoma and then suggest how they can be sequenced in the context of available chemotherapeutic options. For cisplatin-eligible patients, platinum-based chemotherapy remains the standard first-line treatment. For patients progressing on platinum-based therapy, phase III trials have been performed comparing pembrolizumab and atezolizumab separately with standard chemotherapy, and results favor the use of pembrolizumab.
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http://dx.doi.org/10.1177/1758835918788310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066800PMC
July 2018

Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies.

Mol Cancer Ther 2018 07;17(7):1355-1364

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Renal cell carcinoma (RCC) is the most common form of kidney cancer. It is categorized into various subtypes, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. The lack of sensitivity to chemotherapy and radiation therapy prompted research efforts into novel treatment options. The development of targeted therapeutics, including multi-targeted tyrosine kinase inhibitors (TKI) and mTOR inhibitors, has been a major breakthrough in ccRCC therapy. More recently, other therapeutic strategies, including immune checkpoint inhibitors, have emerged as effective treatment options against advanced ccRCC. Furthermore, recent advances in disease biology, tumor microenvironment, and mechanisms of resistance formed the basis for attempts to combine targeted therapies with newer generation immunotherapies to take advantage of possible synergy. This review focuses on the current status of basic, translational, and clinical studies on mechanisms of resistance to systemic therapies in ccRCC. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-1299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034114PMC
July 2018

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.

J Immunother Cancer 2018 05 9;6(1):32. Epub 2018 May 9.

Department of Biomedical Informatics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Background: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.

Methods: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8 T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.

Results: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

Conclusions: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.
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http://dx.doi.org/10.1186/s40425-018-0344-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944039PMC
May 2018

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA.

Cancer 2018 05 8;124(10):2115-2124. Epub 2018 Mar 8.

Division of Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

Methods: Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes.

Results: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC.

Conclusions: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857169PMC
May 2018

Effect of Single-agent Daily Prednisone on Outcomes and Toxicities in Metastatic Castration-resistant Prostate Cancer: Pooled Analysis of Prospective Studies.

Clin Genitourin Cancer 2018 04 27;16(2):e277-e287. Epub 2017 Dec 27.

Dana Farber Cancer Institute, Boston, MA. Electronic address:

The clinical effect of prednisone in metastatic castration-resistant prostate cancer (mCRPC) is unknown. We performed a pooled analysis of control arms of randomized controlled trials that had or had not administered single-agent prednisone. Randomized controlled trials with a control arm that included single-agent placebo (or no anticancer therapy) or single-agent prednisone (with or without placebo) were eligible for analysis. Patients receiving prednisone combined with other agents in the control arm were excluded. The trial characteristics, baseline demographic data, overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) response, Response Evaluation Criteria In Solid Tumors response, and toxicities were recorded. The effect of prednisone was investigated for significance in bivariate models, adjusting for age, pre- and post-docetaxel status, Eastern Cooperative Oncology Group performance status, and trial publication year. Eighteen trials were included; 9 had control arms that contained prednisone (n = 2831) and 9 did not (n = 2784). No significant differences were identified for OS or toxicities of any grade. A significantly greater PSA response rate (18.8% vs. 2.5%; P = .023) and a trend toward more frequent grade ≥ 3 fluid retention (1.0% vs. 0.4%; P = .097) was seen in the prednisone group. Prednisone was also significantly associated with PFS after adjusting for docetaxel status. Single-agent prednisone for mCRPC did not improve OS but was associated with a greater PSA response rate and PFS. Overall and grade ≥ 3 toxicities were not significantly different with prednisone. With the exception of concurrent use with abiraterone or for palliative purposes, the routine use of prednisone for mCRPC appears unnecessary.
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http://dx.doi.org/10.1016/j.clgc.2017.12.006DOI Listing
April 2018
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