Tag: Urothelial Cancer (Bladder-Ureters-Renal-Pelvis)

E-Cigarettes Can Increase the Risk of Bladder Cancer

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SUMMARY: The American Cancer Society estimates that tobacco use is responsible for nearly 1 in 5 deaths in the United States and accounts for at least 30% of all cancer deaths. Smokeless tobacco products are a major source of cancer causing nitrosamines, and increase the risk of developing cancer of the oropharynx, esophagus, and pancreas. Cigarette smoke contains more than 7,000 chemicals, many of which are toxic and some linked to cancer. E-cigarettes or Electronic Nicotine Delivery Systems (ENDS) were first developed in China and introduced to the U.S. market in 2007. When a smoker inhales through the mouth piece of an e-cigarette, the air flow triggers a sensor that switches on a small lithium battery powered heater, which in turn vaporizes liquid nicotine along with PolyEthylene Glycol (PEG) present in a small cartridge. The PEG vapor looks like smoke. The potent liquid form of nicotine extracted from tobacco is tinctured with fragrant flavors such as chocolate, cherry and bubble gum, coloring substances, as well other chemicals and these e-liquids are powerful neurotoxins.

With the rapid growth of the e-cigarette industry and the evidence of potential dangers and risk to public health, particularly children, experts from the world's leading lung organizations were compelled to release a position statement on electronic cigarettes, specifically focusing on their potential adverse effects on human health and calling on government organizations to ban or restrict the use of e-cigarettes, until their impact on health is better understood. According to the National Youth Tobacco Survey, the use of e-cigarettes has tripled from 2013 to 2014 among middle school and high school students. Epidemiological data have shown that nicotine use is a gateway to the use of cocaine and marijuana and subsequent lifelong addiction. E-cigarettes and other Electronic Nicotine Delivery Systems (ENDS), unlike combustible cigarettes and many other tobacco products are not currently regulated by the U.S. Food and Drug Administration.

Smoking more than one pack of cigarettes a day has been associated with an increased risk of mortality among patients with bladder cancer. E-cigarettes have been advertised and promoted as a safer way of delivering the stimulating effects of tobacco smoke, without the harmful health risks. Contrary to this claim, over 90% of inhaled nicotine is excreted to urine. Nicotine can be nitrosatized in urothelial cells and then further metabolized into carcinogenic nitrosamines and formaldehyde, which in turn can induce DNA damage in the bladder mucosa. Additionally, these metabolites can also block DNA repair, increasing cancer risk.

The authors in this study compared the urine of e-cigarette users to that of nonsmokers, for known bladder carcinogens. There are five known bladder carcinogens that are either present in traditional cigarettes or common solvents believed to be used in some e-cigarette formulations, and they include (benz(a)anthracene, benzo(a)pyrene, 1-hydroxypyrene, o-toluidine and 2-naphthylamine. The limit of detection of these carcinogens in this study was 10-100 ng/ml. Urine samples were collected from 13 e-cigarette users and 10 non-smoking, non e-cigarette using controls. The mean age was 39 years and participants were predominantly male and had abstained completely from traditional cigarettes, for at least 6 months prior to specimen collection.

It was noted that the urine from 92% of e-cigarette users tested positive for two of the five carcinogenic compounds whereas none of the controls tested positive for these carcinogens. Interestingly, all study participants considered e-cigarettes were safe, when interviewed by the study investigators.

It was concluded that in this important pilot study, majority of the e-cigarette users had carcinogenic metabolites in the urine, which can contribute to the development of bladder cancer. This study underscores the importance both traditional and e-cigarette smoking cessation, for bladder cancer prevention. MP88-14 EVALUATION OF E-CIGARETTES USERS URINE FOR KNOWN BLADDER CARCINOGENS. Fuller T, Acharya A, Bhaskar G, et al. DOI: http://dx.doi.org/10.1016/j.juro.2017.02.2739

KEYTRUDA® (Pembrolizumab)

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The FDA on May 18, 2017 granted regular approval to KEYTRUDA® for patients with locally advanced or metastatic Urothelial Carcinoma, who have disease progression during or following Platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with Platinum-containing chemotherapy. KEYTRUDA® is a product of Merck and Co., Inc.

FDA Approves IMFINZI® for Advanced Bladder Cancer

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SUMMARY: The FDA on May 1, 2017, granted accelerated approval to IMFINZI® (Durvalumab) for the treatment of patients with locally advanced or metastatic Urothelial Carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA also approved the VENTANA PD-L1 (SP263) Assay as a complementary diagnostic for the assessment of the PD-L1 protein in Formalin-Fixed, Paraffin-Embedded Urothelial Carcinoma tissue. Urothelial Carcinoma accounts for 90% of all bladder cancers and can originate in the renal pelvis, ureter and urethra. The American Cancer Society estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

The treatment paradigm for solid tumors has been rapidly evolving, with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), as well as Programmed cell Death Ligands (PD-L1) that are expressed by cells in the tumor micro environment. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with Urothelial Carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

IMFINZI® is a selective, high-affinity human IgG1 monoclonal antibody directed against PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. The accelerated FDA approval of IMFINZI® was based on evaluation of 182 patients in the bladder cancer cohort of Study 1108, which is a single-arm Phase I/II trial. This study evaluated the safety and efficacy of IMFINZI® in patients with locally-advanced or metastatic Urothelial Carcinoma of the bladder, who had progressed while on or after a platinum-containing chemotherapy regimen. This study included patients who had progressed within 12 months of receiving therapy, in a neoadjuvant or adjuvant setting. Treatment consisted of IMFINZI® 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. Tumor PD-L1 expression was assessed using the validated VENTANA SP263 Assay, in Formalin-Fixed, Paraffin-Embedded Urothelial Carcinoma tissue. High PD-L1 expression was defined as 25% or more expression on tumor and immune cells. The Primary endpoints were Objective Response Rate and Safety. Secondary endpoints included Duration of Response (DoR) and Overall Survival (OS).

The confirmed Objective Response Rate as assessed by blinded Independent Central Review was 17% and the median response duration was not reached. Objective Response Rate was also analyzed by PD-L1 expression status. In the 182 patients, the confirmed Objective Response Rate was 26.3% in patients with a high PD-L1 score and 4.1% in patients with a low or negative PD-L1 score. The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection.

The authors concluded that IMFINZI® has significant clinical activity and an excellent safety profile in patients with locally advanced or metastatic Urothelial Carcinoma. Clinical trials are underway, evaluating IMFINZI® as monotherapy and in combination with other checkpoint inhibitors, in the first line treatment of patients with advanced bladder cancer. Updated Efficacy and Tolerability of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma. Powles T, O’Donnell PH, Massard C, et al. J Clin Oncol. 2017;35 (suppl 6S; abstract 286).

BAVENCIO® (Avelumab)

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The FDA on May 9, 2017 granted accelerated approval to BAVENCIO® for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. BAVENCIO® is a product of EMD Serono, Inc.

IMFINZI® (Durvalumab)

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The FDA on May 1, 2017 granted accelerated approval to IMFINZI®, for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. IMFINZI® is marketed by AstraZeneca UK Limited.

FDA Approves OPDIVO® for Bladder Cancer

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SUMMARY: The FDA on February 2, 2017 granted accelerated approval to OPDIVO® (Nivolumab), for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. Urothelial carcinoma accounts for 90 percent of all bladder cancers and can originate in the renal pelvis, ureter and urethra. The American Cancer Society’s estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

The treatment paradigm for solid tumors has been rapidly evolving, with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), as well as Programmed cell Death Ligands (PD-L1) that are expressed by cells in the tumor micro environment. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that has demonstrated antitumor efficacy in multiple tumor types. The FDA approval of OPDIVO® for patients with previously treated locally advanced or metastatic urothelial carcinoma, was based on CheckMate-275 trial which is an international, multicenter, phase II study, in which 270 patients with metastatic or surgically unresectable locally advanced urothelial carcinoma received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. All patients had prior platinum based therapy. The median age was 66 years. The primary endpoint was overall Objective Response Rate confirmed by blinded independent review committee, in all treated patients and by tumor PD-L1 expression (5% or more and 1% or more). The follow up for this study is still ongoing. The median follow up for overall survival was 7 months.

The Objective Response Rate across all treated patients was 19.6% and the responses were durable and the median duration of response has not been reached. There was a higher likelihood of response with increasing tumor PD-L1 expression. The Objective Response Rate was 28.4% in patients with PD-L1 expression of 5% or greater, 23.8% in patients with PD-L1 expression of 1% or greater and 16.1% in those with PD-L1 expression of less than 1%. The most common adverse events were fatigue, musculoskeletal pain, nausea, and decreased appetite.

The authors concluded that single agent therapy with OPDIVO® in previously treated patients with metastatic or surgically unresectable urothelial carcinoma, resulted in durable response rate, irrespective of PD-L1 expression and was associated with an acceptable safety profile. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Sharma P, Retz M, Siefker-Radtke A, et al. The Lancet Oncology. Published: 25 January 2017, DOI: http://dx.doi.org/10.1016/S1470-2045(17)30065-7

OPDIVO® (Nivolumab)

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The FDA on February 2, 2017 granted accelerated approval to OPDIVO® for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. OPDIVO® is marketed by Bristol-Myers Squibb company.

TECENTRIQ® (Atezolizumab)

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The FDA on May 18, 2016 granted accelerated approval to TECENTRIQ® injection for the treatment of patients with locally advanced or metastatic Urothelial carcinoma, who have disease progression during or following Platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with Platinum-containing chemotherapy. TECENTRIQ® is a Programmed Death-ligand 1 (PD-L1) blocking antibody and is a product of Genentech, Inc.

FDA Approves TECENTRIQ® for Advanced Urothelial Carcinoma

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SUMMARY: The FDA on May 18, 2016 approved TECENTRIQ® (Atezolizumab) for the treatment of patients with locally advanced or metastatic urothelial carcinoma, whose disease has worsened during or following platinum containing chemotherapy, or within 12 months of receiving platinum containing chemotherapy, either before (neoadjuvant) or after (adjuvant) surgical treatment. Urothelial carcinoma accounts for 90 percent of all bladder cancers and can originate in the renal pelvis, ureter and urethra. The National Cancer Institute estimates that in 2016, approximately 76,960 new cases of Bladder Cancer will be diagnosed and 16,390 patients will die of the disease. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The treatment paradigm for solid tumors has been rapidly evolving, with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, Immune checkpoints or gate keepers inhibit an intense immune response by switching off the T cells of the immune system. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), as well as Programmed cell Death Ligands (PD-L1) that are expressed by cells in the tumor micro environment. By doing so, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.
TECENTRIQ® (Atezolizumab) is an anti-PDL1 monoclonal antibody designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating Immune Cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. The FDA approval was based on IMvigor 210 trial which is an open label, single arm, multicenter, phase II study in which the safety and efficacy of TECENTRIQ® was evaluated in patients with locally advanced or metastatic urothelial carcinoma, regardless of PD-L1 expression. In this study, 310 patients whose disease had progressed during or following previous treatment with a platinum based chemotherapy regimen received TECENTRIQ® 1200 mg as an intravenous dose once every 21 days cycles until disease progression. The primary endpoint of the study was Objective Response Rate (ORR) and secondary endpoints included Duration of Response (DOR), Overall Survival (OS), Progression Free Survival (PFS) and safety. PD-L1 expression on tumor-infiltrating Immune Cells (IC) was assessed prospectively by ImmunoHistoChemistry using Formalin-Fixed Paraffin-Embedded tumor specimens. PD-L1 positivity was defined as follows – IC 2/3 (5% or more), IC 1 (1-5%) and IC 0 (<1%).
In an updated analysis, with a median follow of 11.7 months, the ORR was 15% for the entire cohort of patients (P=0.0058). The ORR in the IC 2/3 group was 26% (P<0.0001) and 18% in the IC 1 group (P=0.0004). Ongoing responses were noted in 84% of the responding patients. The most common side effects associated with TECENTRIQ® included fatigue, decreased appetite, nausea, urinary tract infection, fever and constipation.
The authors concluded that TECENTRIQ® significantly improves Objective Response rate (ORR) in metastatic urothelial cancers and this benefit is even more so in those tumors with a higher level of PD-L1 expression. Rosenberg JE, Hoffman-Censits, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; Published online 4 March. DOI: http://dx.doi.org/10.1016/S0140-6736(16)00561-4

Clinical Guidelines for the Evaluation of Hematuria as a Marker of Occult Urinary Tract Cancer

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SUMMARY: Hematuria is a common finding in clinical practice and millions of patients have routine urine evaluation. However, the magnitude of the risk for an underlying malignancy can vary significantly. Screening healthy, asymptomatic patients with urinalysis for malignancy is not currently recommended by any major health organization. This article describes the indications for the evaluation of hematuria, as a marker of occult urinary tract cancer, and is meant to help Health Care Providers make appropriate referral of patients, for urologic evaluation. The information in this article was gathered following a review of published clinical guidelines that addressed the evaluation of hematuria as a marker of occult urinary tract cancer, as well as other relevant studies, from the peer-reviewed literature. The American College of Physicians' High Value Care Task Force put this information together, with the intent to increase awareness and provide practical advice, based on the best available evidence.

High-Value Care Advice 1: Clinicians should include gross hematuria in their routine review of systems and specifically ask all patients with microscopic hematuria about any history of gross hematuria.

High-Value Care Advice 2: Clinicians should not use screening urinalysis for cancer detection in asymptomatic adults.

High-Value Care Advice 3: Clinicians should confirm heme-positive results of dipstick testing with microscopic urinalysis that demonstrates 3 or more erythrocytes per high-powered field before initiating further evaluation in all asymptomatic adults.

High-Value Care Advice 4: Clinicians should refer all adults with gross hematuria, even if self-limited, for further urologic evaluation.

High-Value Care Advice 5: Clinicians should consider urology referral for cystoscopy and imaging in adults with microscopically confirmed hematuria, in the absence of some demonstrable benign cause.

High-Value Care Advice 6: Clinicians should pursue evaluation of hematuria even if the patient is receiving antiplatelet or anticoagulant therapy.

High-Value Care Advice 7: Clinicians should not obtain urinary cytology or other urine-based molecular markers for bladder cancer detection in the initial evaluation of hematuria.

Hematuria as a Marker of Occult Urinary Tract Cancer: Advice for High-Value Care from the American College of Physicians. Nielsen M, Qaseem A, for the High Value Care Task Force of the American College of Physicians. Ann Intern Med. 2016;164:488-497.