scholarly journals “PROBE”ing the Role of Cytoreductive Nephrectomy in Advanced Renal Cancer

Kidney Cancer ◽  
2021 ◽  
pp. 1-7
Author(s):  
Hannah Bell ◽  
Brittney H. Cotta ◽  
Simpa S. Salami ◽  
Hyung Kim ◽  
Ulka Vaishampayan
Keyword(s):  
Combination Therapy ◽  
Systemic Therapy ◽  
Immune Checkpoint ◽  
Primary Tumor ◽  
Immune Therapy ◽  
Cell Cancer ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Cytoreductive Nephrectomy

The Southwest Oncology Group (SWOG)1931 trial, also known as PROBE (ClinicalTrials.gov Identifier: NCT04510597) is a phase III study evaluating the role of cytoreductive nephrectomy (CN) in metastatic renal cell cancer (RCC). Kidney cancer presenting with synchronous metastases has demonstrated shorter survival outcome compared to the patients relapsing with metastases after nephrectomy. Previously, CN has been associated with survival improvement when interferon-based systemic therapy was used. In the setting of antivascular therapy sunitinib, a prospective randomized clinical trial demonstrated no benefit of CN. Immune checkpoint-based combination therapy has now become the standard-of-care in the frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint-based systemic therapy. The sequence and optimal timing of nephrectomy is also not established. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in RCC within the context of immune checkpoint-based combination regimens. The study requires starting with systemic therapy; any one of the FDA approved immunotherapy-based regimens at the time the study was activated are permitted. The disease status and response are evaluated at 9–12 weeks of therapy and then consented patients are randomized 1:1 to receive CN or to continue systemic therapy. The patients who have rapid disease progression are considered ineligible for randomization as they need a switch in systemic therapy. Both groups should continue systemic therapy as long as they are tolerating the treatment and continuing to derive clinical benefit. Quality-of-life, tumor genomic testing, microbiome, radiomics and circulating tumor DNA assessments as predictive biomarkers are planned as study correlatives. The study hypothesis is that CN will improved OS in synchronous metastatic RCC when surgery is performed after starting systemic immune checkpoint-based combination therapy. A potential mechanism leading to improved survival is the broader antigen spread and higher neoantigen load enabled by the primary tumor enhancing the efficacy of the immune therapy. CN after initial systemic therapy would help select the patient subset most likely to benefit and will potentially enable eradication of immune resistant clones within the primary tumor.

scholarly journals Role of Immune Checkpoint Inhibitors in Cervical Cancer: From Preclinical to Clinical Data

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2089
Author(s):  
Simona Duranti ◽  
Antonella Pietragalla ◽  
Gennaro Daniele ◽  
Camilla Nero ◽  
Francesca Ciccarone ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Hpv Infection ◽  
Phase Iii ◽  
Screening Programs ◽  
Cervical Cancers ◽  
Relapsed Disease

Human papillomavirus (HPV) infection is the recognized cause of almost all cervical cancers. Despite the reduction in incidence due to a wide use of screening programs and a specific vaccine, the prognosis of cervical cancer remains poor, especially for late-stage and relapsed disease. Considering the elevated rates of PD-L1 expression in up to 80% of cervical cancers, a strong rationale supports the use of immunotherapy to restore the immune response against tumor. The aim of this review is to analyze the possible role of immune checkpoint inhibitors in cervical cancer treatment, with a particular focus on the rationale and on the results of phase I and II clinical trials. An overview of ongoing phase III studies with possible future areas of development is also provided.

scholarly journals Role of fluoroquinolones in the treatment of tuberculosis

2011 ◽  
Vol 3 (1) ◽  
pp. 17-31
Author(s):  
Suhail Ahmad ◽  
Eiman Mokaddas
Keyword(s):  
Combination Therapy ◽  
Phase Iii ◽  
Cross Resistance ◽  
Phase Ii Trials ◽  
First Line ◽  
Duration Of Treatment ◽  
Pulmonary Tb ◽  
Mdr Tb ◽  
Tract Infections

INTRODUCTION: The increasing incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis is hampering efforts to control the global tuberculosis (TB) epidemic. Although treatment of drug-susceptible TB is possible in ≥ 95% of disease cases, long (≥ 6 months) duration of supervised combination therapy is challenging. Non-adherence to treatment often results in much lower cure rates. Treatment of MDR-TB and XDR-TB is far less effective. The aim of this review is to summarize the current status of fluoroquinolones in shortening the duration of drug-susceptible pulmonary TB and in improving the outcome of MDR-TB/XDR-TB.METHODS: All the relevant articles were identified through a search of PubMed and Scopus databases by using search terms like tuberculosis (or M. tuberculosis), fluoroquinolones, drug-susceptible TB, MDR-TB, XDR-TB, combination therapy, treatment regimens, treatment duration, drug target and drug resistance. The current literature on the role of fluoroquinolones in the treatment of TB was reviewed.RESULTS: The fluoroquinolones, particularly newer compounds such as levofloxacin, moxifloxacin and gatifloxacin, have bactericidal activity against M. tuberculosis, excellent oral bioavailability, favorable safety profile and no cross-resistance with other first-line anti-TB drugs. Data from phase II trials of fluoroquinolones-containing regimens for shortening the duration of treatment for pulmonary TB are encouraging and phase III trials are currently underway. The fluoroquinolones are also effective as substitute agents for those individuals who are intolerant to first-line drugs. Several studies and clinical trials have also supported the use of fluoroquinolones in patients with MDR-TB/XDR-TB.DISCUSSION: The fluoroquinolones-containing regimens are being tested to shorten the duration of treatment for pulmonary TB to 4 months. They are also regarded as one of the two cornerstone drugs for the treatment of MDR-TB/XDR-TB. However, they are also among the commonly prescribed antibiotics for lower respiratory tract infections and are becoming increasingly associated with delayed treatment and resistance in TB. If these trends are not reversed soon, we may lose fluoroquinolones as effective anti-TB agents very rapidly.

scholarly journals The role of hormone therapy and chemotherapy in oligometastatic prostate cancer

ESMO Open ◽  
2019 ◽  
Vol 4 (Suppl 1) ◽  
pp. e000471 ◽  
Author(s):  
Yuji Miura ◽  
Shigeo Horie
Keyword(s):  
Prostate Cancer ◽  
Hormone Therapy ◽  
Systemic Therapy ◽  
Local Therapy ◽  
High Volume ◽  
Phase Iii ◽  
Clinical State ◽  
Current Evidence ◽  
Oligometastatic Prostate Cancer

Oligometastatic disease was proposed by Hellman and Weichselbaum in 1995 as an intermediate tumour state between localised lesions and widespread metastases, characterised by the limited number and size of metastases in specific organs such as lung, liver, bone or even brain. The oligometastatic state has increasingly been recognised as a unique clinical state during which local ablative treatment can be effective in several types of cancer, including prostate cancer. However, the role of systemic therapy, such as hormone therapy and chemotherapy, is not yet well known. Some promising data for local ablative therapy have emerged, but it remains unclear whether local therapy can eliminate the need for, androgen-deprivation therapy (ADT), or reduce the required duration. In addition, several randomised phase III trials have demonstrated survival benefits from the addition of docetaxel or abiraterone to ADT in patients with metastatic hormone-sensitive prostate cancer. These findings suggest that such aggressive treatments may improve clinical outcomes for patients with oligometastatic prostate cancer. However, the efficacy of these treatments may depend on the volume of metastases, with higher efficacy for high-volume disease. Therefore, further investigation including stratification by disease volume is warranted. This review will discuss the current evidence and controversies surrounding the role of systemic therapy in patients with oligometastatic prostate cancer.

Neoadjuvant imatinib in patients with locally advanced GIST in the prospective BFR14 trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10551-10551 ◽  
Author(s):  
P. A. Cassier ◽  
A. A. Blesius ◽  
D. Perol ◽  
I. Ray-Coquard ◽  
A. Adenis ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Primary Tumor ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Primary Gist ◽  
Advanced Gist

10551 Background: The role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains unknown. We sought to assess the outcome of patients with locally advanced primary GIST tumors without metastases treated with IM in the neoadjuvant setting within the prospective BFR14 phase III trial. Methods: The data base of the BFR14 trial was searched for patients with locally advanced disease and no metastases. Patients with recurrent disease were excluded. Results: Twenty five patients (9 females, 16 males) met these criteria. Twenty patients were PS 0 or 1, primary tumor sites were: small intestine (n=7), peritoneum (n=7), rectum (n=4), stomach (n=4), esophagus (n=2), and pelvis (n=1). Nine of the 25 patients underwent surgical resection of the primary tumor after a median of 7.3 (range 3.4–12.1) months of treatment with IM. There was a significant improvement in progression-free survival (PFS) for patient who underwent surgical resection versus those who did not: median PFS: 28.7 month vs 12.9 months respectively (p=0.0463) this benefit did not however translate into a significant benefit in overall survival (OS), although the trend favoured the resected group: median OS median not reached vs 29.4 months (p=0.0677). Conclusions: Surgery may increase progression-free survival in patients with locally advanced GIST who become resectable following treatment with IM. [Table: see text]

Lentiviral interferon with immune checkpoint blockade: A novel method for gene therapy in bladder cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 33-33
Author(s):  
Sharada Mokkapati ◽  
Andrea Kokorovic ◽  
Jonathan J. Duplisea ◽  
Devin Plote ◽  
Amy Lim ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bladder Cancer ◽  
Combination Therapy ◽  
Cell Viability ◽  
Immune Checkpoint ◽  
Target Genes ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Control Virus

33 Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. LV can infect non-dividing cells and integrate into the host’s genome, making it more efficient gene delivery vectors. As treatment with IFN upregulates checkpoint inhibitors, we also wanted to investigate the role of checkpoint inhibitors with and without IFN gene therapy. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα (MOI 2:1). IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, the MB49 intravesical tumor model and p53+/- C57/B6 mouse model were employed. We also assessed the role of combination therapy with immune checkpoint blockade using PD1 antibody using our MB49 intravesical model. Results: Efficient LV-IFNα transduction of BLCA cells resulted in increased expression of IFNα and its target genes and reduced cell viability vs. controls (p<0.001). Mechanistically, TRAIL dependent cytotoxicity in the LV-IFNα cells was rescued by Caspase8 inhibition. Urinary IFNα levels were elevated in mice receiving LV-IFNα compared with control virus. Overall survival improved in the MB49 model and BBN model in treated mice. LV-IFN induced intratumoral CD8+ T cell infiltration, high expression of PD-L1, and inhibited angiogenesis in BBN model whereas in the MB49 tumor response was mediated by TRAIL. Combination therapy with PD1 resulted in further improved survival. Conclusions: LV-IFNα effectively upregulated IFNα target genes, was cytotoxic to murine BLCA cells, and improved the survival in mouse models. Combining it with PD1 therapy appears to further improve survival.

Prognostic value of simple blood biomarkers of systemic inflammation for metastatic renal cell carcinoma (mRCC) patients who undergo cytoreductive nephrectomy (CNx).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 350-350
Author(s):  
Jigi Moudgil-Joshi ◽  
Mark Stares ◽  
Alex Laird ◽  
Steve Leung ◽  
Jahangeer Malik ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Inflammatory Response ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Cytoreductive Nephrectomy

350 Background: The role of cytoreductive nephrectomy (CNx) in patients with metastatic renal cell carcinoma (mRCC) is currently in question. Assessing the benefits and risks of CNx is challenging, with a lack of validated prognostic tools. Biomarkers of the systemic inflammatory response have prognostic utility in mRCC and are included in the IMDC score used to predict survival in patients with mRCC treated with systemic therapy. We sought to investigate their role in patients with mRCC who had undergone CNx. Methods: A cohort of 68 patients, suitable for first-line VEGFR inhibitor (VEGFRi) systemic therapy, who had undergone CNx for mRCC, were identified from a clinical database of patients referred to a regional mRCC service. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and overall survival and time to VEGFRi (tVEGFRi) was examined using Kaplan-Meier and Cox-regression methods. Results: Data were available for 68 patients. Median survival was 33.7 months. On multivariate analysis, albumin ( < 35g g/dL v ≥35 g/dL) and CRP (≤ 10 mg/L v > 10 mg/L) were independently associated with overall survival (p = 0.027 and p = 0.034 respectively). Albumin stratified survival from 24.7 to 87.2 months (p < 0.0001) and CRP from 29.4 to 82.3 months (p = 0.004). 40 (59%) patients subsequently commenced VEGFRi therapy. Median tVEGFRi was 18.1 months, with only 5 (7%) patients commencing treatment within 3 months. 16 (24%) patients yet to receive systemic therapy remain alive after a median 54.0 months follow-up. On multivariate analysis, albumin was also predictive of tVEGFRi (p = 0.037), stratifying tVEGFRi from 6.07 to 45.7 months (p = 0.002). Conclusions: These results highlight that biomarkers of the systemic inflammatory response are strong prognostic factors in mRCC patients who have undergone CNx. Albumin and CRP, but not IMDC, predict survival in this patient group. Significantly, the population investigated here differ from those included in the CARMENA and SURTIME studies, with a majority undergoing surveillance prior to VEGFRi therapy. Our results support a role for CNx in patients where deferred systemic therapy strategies may be employed. Albumin may assist in clinical decision making when considering when to start systemic therapy. We advocate further studies to investigate the prognostic role of these simple, routine clinical tests in patients with mRCC undergoing CNx.

scholarly journals The Role of Nephrectomy for Kidney Cancer in the Era of Targeted and Immune Therapies

2016 ◽  
pp. e16-e20 ◽  
Author(s):  
Ulka N. Vaishampayan
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Annual Meeting ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Cytoreductive Nephrectomy ◽  
Education Session ◽  
Immune Therapies ◽  
Pros And Cons

Editor's Note: The following article is based on the 2016 ASCO Annual Meeting Education Session “Cytoreductive Nephrectomy in Renal Cell Carcinoma: A Debate.” The author reviews the pros and cons of cytoreductive nephrectomy and whether recent advances in systemic therapy warrant physicians to proceed directly to systemic therapy as in other metastatic solid tumors, without the integral step of cytoreductive nephrectomy.

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