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Gemcitabine For High Grade Bladder Cancer

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Combining Bcg And Intravesical Gemcitabine For Patients With Bcg

Controversies in Non Muscle Invasive Bladder Cancer

May 5, 2021

Biographies:Related Content:Read the Full Video TranscriptAshish Kamat:Eugene Pietzak:Ashish Kamat:Eugene Pietzak:Ashish Kamat:Eugene Pietzak:Ashish Kamat:Eugene Pietzak:Ashish Kamat:Eugene Pietzak:Ashish Kamat:Eugene Pietzak:

If Treatment Does Not Work

Full recovery from bladder cancer is not always possible. If the cancer cannot be cured or controlled, the disease may be called advanced or metastatic.

This diagnosis is stressful, and for many people, advanced cancer is difficult to discuss. However, it is important to have open and honest conversations with your health care team to express your feelings, preferences, and concerns. The health care team has special skills, experience, expertise, and knowledge to support patients and their families, and is there to help. Making sure a person is physically comfortable, free from pain, and emotionally supported is extremely important.

Patients who have advanced cancer and who are expected to live less than 6 months may want to consider hospice care. Hospice care is a specific type of palliative care designed to provide the best possible quality of life for people who are near the end of life. You and your family are encouraged to talk with the health care team about hospice care options, which include hospice care at home, a special hospice center, or other health care locations. Nursing care and special equipment can make staying at home a workable option for many families. Learn more about advanced cancer care planning.

After the death of a loved one, many people need support to help them cope with the loss. Learn more about grief and loss.

Gemcitabine And Associated Combinations

4.3.1 Gemcitabine as a sole agent

Gemcitabine has been studied in BCG refractory cases in two trials. Lorenzo et al. conducted a multi-center prospective randomized phase 2 trial in which 80 patients failing one course of BCG were randomly allocated to Gemcitabine arm and 2nd course of BCG arm. Kaplan Meier statistics of 2-year recurrence-free survival showed a significant difference between the gemcitabine and BCG group . Seven of 21 patients in gemcitabine group and 13 of 35 patients in group had disease progression and underwent radical cystectomy . No significant safety concern was seen in both groups. The authors concluded that gemcitabine might be considered a second-line treatment after BCG failure in a high-risk non-muscle-invasive group .

Addeo et al. conducted a phase III randomized control trial in 120 high-risk NMIBC patients previously treated with BCG from march 2003 to November 2005. They received 40 mg of mitomycin C or 2000 mg of gemcitabine diluted in 50 mL of normal saline. The median follow-up was 36 months. In the gemcitabine arm, 39 of 54 patients remained free of recurrence versus 33 of 55 in the mitomycin C arm. Progression was seen in 10 patients in the mitomycin C arm and 6 in the gemcitabine arm. The incidence of chemical cystitis in the mitomycin C arm was statistically higher than in the gemcitabine arm .

4.3.2 Gemcitabine plus cabazitaxel plus cisplatin

6-wk induction regimen of sequentially administered cabazitaxel, gemcitabine, and cisplatin

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Gemcitabine/radiation Shows Sustained Success For Bladder Preservation In Mibc

In patients with muscle-invasive bladder cancer, gemcitabine plus once daily radiation showed a low cystectomy rate and high overall survival rate at long-term follow-up.

Gemcitabine plus once daily radiation continued to achieve a low cystectomy rate and high overall survival rate in selected patients with muscle-invasive bladder cancer , according to long-term follow-up data from the phase 2 NRG-RTOG 0712 trial presented during the 2020 ASTRO Annual Meeting.1,2

The study evaluated both the GD regimen and the previous standard of fluorouracil plus cisplatin and radiation twice a day . The results showed that the 2 regimens were equally effective at a median follow-up time of 7.3 years. The rate of freedom from distant metastasis at 3 years was 79% with FCT versus 85% with GD. The rates at 5 years were 70% versus 77%, respectively.

The 3-year bladder-intact distant metastasis free rates were 67% with FCT versus 72.5% with GD, and the 5-year rates were 65.1% versus 72.5% respectively. In the FCT cohort, the post-induction complete response rate was 88% versus 76% in the GD arm. The 5-year OS rates were 74% versus 71%, respectively.

The study was not powered to compare the 2 regimens head-to-head however, it was observed that the safety profile was better in the GD arm.

Among the 70 randomized patients, 66 were eligible for the efficacy and safety analyses. Of the 66 patients, 3 patients in the FCT arm and 6 patients in the GD arm underwent cystectomy.

New Treatments For Bladder Cancer In 2020

intravesical Gemcitabine in High risk non muscle invasive bladder can

In 2019 and early 2020, the U.S. Food and Drug Administration approved a number of new drugs for bladder cancer of all stages, and more treatments are on the horizon. Heres a snapshot of whats happening right now in bladder cancer treatment:

Non-muscle invasive bladder cancer treatments

In patients with NMIBC, tumors are confined to the inner cell layer of the bladder and have not invaded the thick muscle tissue of the bladder. NMIBC is usually treated by surgical excision in a procedure known as trans urethral resection of bladder tumor , followed by repeated drug injections into the bladder most commonly with a drug called Bacillus Calmette-Guerin .

BCG is a bacterial vaccine that is primarily used to immunize against tuberculosis, but may also trigger a broader immune response against cancer cells. BCG certainly improves outcomes for patients whose tumors have been resected nevertheless, over a half of these patients will experience recurrence within one year, and some do not respond to BCG at all. Intravesical chemotherapy drugs are used for higher-grade NMIBC.

Newly emerging treatment options for NMIBC include:

Of course, the biggest news for NMIBC is the recent FDA approval of the immune checkpoint drug pembrolizumab for systemic treatment of high grade NMIBC that is not responsive to BCG. In clinical testing, 41% of patients experienced complete responses with median duration of 16 months.

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Bcg Or Gemcitabine For Bladder Cancer: When Should They Be Used

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In 1976, Bacillus Calmette-Guérin became known as an effective treatment for non-muscle invasive bladder cancer . Since then, BCG has been used throughout the world for preventing NIMBC. Tice® BCG is the brand name, though most people simply refer to this treatment as BCG.1

After transurethral resection surgery , placing BCG inside the bladder prevents NMIBC from getting worse. BCG also prevents tumors from coming back once they are removed. This process is called intravesical treatment.2,3

In the last decade, issues with BCG availability have led to the use of other treatments, such as intravesical gemcitabine. Gemzar® is also used when BCG no longer works or when it is not tolerated.4

Intravesical Therapy For Bladder Cancer

With intravesical therapy, the doctor puts a liquid drug right into your bladder rather than giving it by mouth or injecting it into your blood. The drug is put in through a soft catheter that’s put into your bladder through your urethra. The drug stays in your bladder for up to 2 hours. This way, the drug can affect the cells lining the inside of your bladder without having major effects on other parts of your body.

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Intravesical Immunotherapy With Bcg

BCG is a live attenuated strain of Mycobacterium bovis, originally developed as a vaccine for tuberculosis. There are several strains available from different manufacturers with the commonest used in the UK being Oncotice BCG®. The content of a vial is reconstituted with 50 ml of saline and then administered through a urethral catheter to remain in the urinary bladder for about 2 h time. The mechanism of action is incompletely understood but it is postulated to work via a local immune response characterised by induced expression of cytokines in the urine and bladder wall . Before starting BCG in new patients, it is important to adequately debulk all visible tumour and re-resect T1 high grade tumours to reduce understaging. BCG strain may have an impact on treatment outcome in NMIBC immunotherapy. A recent prospective randomised study of 142 high-risk NMIBC patients with two of the commonest BCG strains showed that treatment with BCG Connaught conferred significantly greater 5-year recurrence-free survival compared with treatment with BCG Tice .

Rrm1 And Rrm2 Expression Analysis By Ihc

Neoadjuvant chemotherapy in patients with high-grade upper tract urothelial carcinoma

Immunohistochemical analysis was performed to assay RRM1 and RRM2 expression in bladder cancer, as described previously. Anti-RRM1 and Anti-RRM2 antibodies were both used at a dilution of 1:100. Negative controls consisted of slides where the primary antibody had been omitted. Cases were evaluated as having positive staining if > 10% of the cytoplasm of the tumor cells was stained. Tumor grade and stage were evaluated using standard hematoxylin and eosin staining.

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Global Gene Expression Analysis In Rt112 And Rt112

RT112-Gr cells were 350-fold less sensitive to gemcitabine than the parental cell lines, which IC50 was 4.2 umol/l in former. KU7-Gr cells were 15-fold less sensitive to gemcitabine than the parental cell lines, which IC50 was 0.285umol/l in former. Microarray analysis was performed to obtain broad spectrum information about the genes differentially expressed in RT112 and RT112-Gr cells. The RNAs obtained from RT112 and RT112-Gr cells were amplified, fragmented, labeled, and hybridized to GeneChip microarrays. Of the 55752 genes represented on the Human OneArray® GeneChip, 442 showed significantly up-regulated and 235 down-regulated. Among them, P-value of RRM1 is 0.046, and RRM2 is 0.021, while EG5 is 0.323. Our microarray results have been successfully loaded into a public repository named ArrayExpress, Data Review URL: .

Clustering was performed to visualize the correlations among the replicates and varying sample conditions. A subset of differential genes were selected for clustering analysis. An intensity filter was used to select genes where the difference between the maximum and minimum intensity values exceeds 1000 among all microarrays. For this microarray project, the number of genes clustered was 227 .

Clustering analysis of microarray.

Efficacy Of Bladder Intravesical Chemotherapy With Three Drugs For Preventing Non

Zhixin Ling

1Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China

Abstract

1. Introduction

Bladder cancer has the clinical characteristics of high recurrence rate, high progression rate, and high mortality rate. Most of it comes from epithelial tissue. The urothelial cell carcinoma accounts for nearly 90% of bladder cancer worldwide . According to the extent of cancer cells invading the bladder wall, non-muscle-invasive bladder cancer and muscle-invasive bladder cancer are the two main types of bladder cancer, and non-muscle-invasive bladder cancer is among the most common types of bladder cancer. The non-muscle-invasive bladder cancer is responsible for 75%85% of newly diagnosed cases .

2. Materials and Methods

2.1. Research Object

This study retrospectively analyzed a total of 335 intermediate- and high-risk patients who underwent transurethral bladder tumor resection in our hospital from October 2015 to October 2019, and they were regularly perfused with epirubicin, gemcitabine, and pirarubicin. The risk of patients was classified with intermediate- or high-risk non-muscle-invasive bladder cancer. According to the different perfusion drugs, the patients were divided into an epirubicin group , gemcitabine group , and pirarubicin group .

2.1.1. Inclusion Criteria
2.1.2. Exclusion Criteria
2.2. Surgical Plan
2.3. Perfusion Scheme
2.4. Follow-Up
2.5. Observation Indicators
2.6. Data Analysis

3. Results

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Rrm1 And Rrm2 Expression Analysis In Bladder Cancer Tissues And Cell Lines

Immunohistochemical analysis was performed to assay RRM1 and RRM2 expression in surgically resected specimens of bladder cancer. RRM1 and RRM2 staining was localized in the cytoplasm. There were 98 male and 42 female, with 65 low-grade cases and 75 high-grade cases in histological grade. The staining reactivity of anti-RRM1 and anti-RRM2 were showed in the Table 1 and Fig 2, respectively. RT-PCR analysis was plotted to identify RRM1 mRNA and RRM2 mRNA expression in RT112 and RT112-Gr cell lines. RT-PCR further demonstrated that RT112-Gr cells had significant increases in the levels of RRM1 and RRM2 mRNA compared with the parental cells , respectively .

Physical Emotional And Social Effects Of Cancer

intravesical Gemcitabine in High risk non muscle invasive bladder can

Cancer and its treatment cause physical symptoms and side effects, as well as emotional, social, and financial effects. Managing all of these effects is called palliative care or supportive care. It is an important part of your care that is included along with treatments intended to slow, stop, or eliminate the cancer.

Palliative care focuses on improving how you feel feels during treatment by managing symptoms and supporting patients and their families with other, non-medical needs. Any person, regardless of age or type and stage of cancer, may receive this type of care. And it often works best when it is started right after an advanced cancer diagnosis. People who receive palliative care along with treatment for the cancer often have less severe symptoms, better quality of life, report that they are more satisfied with treatment, and they may live longer.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional and spiritual support, and other therapies. You may also receive palliative treatments similar to those meant to get rid of the cancer, such as chemotherapy, surgery, or radiation therapy.

Before treatment begins, talk with your doctor about the goals of each treatment in the treatment plan. You should also talk about the possible side effects of the specific treatment plan and palliative care options.

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Subgroup Analysis And Sensitivity Analysis

Subgroup analysis in reference to RFS is conducted to examine the sources of heterogeneity . Subgroups include study, intervention, and tumor characteristics, such as study design, study origin, study center, schedule, and risk of recurrence. However, the level of heterogeneity for the subgroup is similar to that for the total effect, indicating that the heterogeneity is not originated from these study features. Figure 4 shows the results of sensitivity analysis for both RFS and PFS. All the pooled effect sizes after omitting study are in the 95% CI range of overall effect size, reflecting the robustness of the results.

Nonmuscle Invasive Bladder Cancer

High-grade or T1 disease:

  • For T1 tumors, TURBT alone is generally not adequate treatment use of intravesical bacillus Calmette-Guerin after TURBT is recommended

Intravesical adjuvant immunotherapy for nonmuscle-invasive bladder cancer :

  • BCG 81 mg or 50 mg in 50 mL sterile saline instilled into the bladder through a catheter and held for 2 h instilled weekly for 6 wk

  • Maintenance therapy: 81 mg intravesically given on days 1, 8, and 15 of months 3, 6, 12, 18, 24, and 36 after initiation

BCG-unresponsive nonmuscle-invasive bladder cancer:

  • Pembrolizumab is indicated for treatment of BCG-unresponsive, high-risk NMIBC with carcinoma in situ with or without papillary tumors in patients who are ineligible for, or have elected not to undergo, cystectomy.
  • Pembrolizumab 200 mg IV q3wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression
  • Valrubicin is indicated for intravesical therapy of BCG-refractory CIS of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.
  • Valrubicin 800 mg added to 55 mL sterile saline instilled into the bladder through a catheter and held for 2 h instilled weekly for 6 wk

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References To Studies Excluded From This Review

Jump to:

Autorino 2009

Bartoletti 2005a

Bartoletti 2005b

Boehle 2009b

Boehle 2010

Bohle 2009c

Cho 2009

Faiola 2008

Gardmark 2003

Gardmark 2005b

Gardmark 2005c

Gardmark 2005d

Hadley 2008

Kim 2008

Montella 2008

Morabito 2006

Rampersaud 2011

Herr 2000

Higgins 2008

Jemal 2007

Kilani 2002

Addeo 2010

Methods

A prospective randomised study. No method of randomisation presented. Stratification was by age, stage and tumour grade

Participants

One hundred and twenty patients with recurrent transitional cell carcinoma stages Ta or T1, Grades 13 were enrolled from March 2003 to November 2005. Included were those with disease that had progressed or relapsed after intravesical BCG. Mean age of Gemcitabine group 64.9 + 10.7, Mitomycin C group 67.9 + 10.2. Eleven were excluded.

Interventions

Patients randomised to Gemcitabine 2000mg/50ml saline instilled for 1 hour given weekly for 6 weeks or Mitomycin C 40mg/50mL instilled for 1 hour and within 2 days of TUR then weekly for 4 weeks . Responders in each group had 10 monthly treatments.

Outcomes

No conflict of interest stated by authors.

Establishment Of The Gemcitabine

Understanding the Evolving Treatment Landscape in Bladder Cancer

Gemcitabine-resistant cells were developed by chronic, repeated exposure to gemcitabine though gradient culture. The established resistant cell line was maintained in medium containing 45 nmol/L of gemcitabine. For all studies, resistant cells were cultured in drug-free medium for 1 week to eliminate gemcitabine. Gemcitabine-resistant cells are referred as RT112-Gr cells and KU7-Gr. IC50 of Gemcitabine-resistant RT112 cells to Gemcitabine is 4.2umol/L. IC50 of Gemcitabine-resistant KU7 cells to Gemcitabine is 0.285umol/L. So we choose RT112-Gr cells as a subject in the following experiments.

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Intravesical Chemotherapy With Hyperthermia

Thermal energy appears to improve the absorption of several intravesical agents, and as such adjunctive hyperthermia has been shown to increase cytotoxicity in bladder cells in in vitro and animal models . Several devices are available to deliver thermochemotherapy for NMIBC with the commonest used heat delivery system being Synergo® . This machine delivers local hyperthermia in conjunction with intravesical chemotherapy using a 915-MHz intravesical radiofrequency energy applicator placed on a thermocouple-controlled 20 F urethral catheter . Other HT systems include the BSD-2000 , the ALBA hyperthermia system , the BWT system by Elmedical, the Sonotherm 1000 and the Combat BRS system .

A recent systemic review and meta-analysis of 22 trials examining intravesical chemohyperthermia for NMIBC showed a 59 % reduction in recurrence rate for TURB + CHT compared to TURBT + chemotherapy alone . However, due to short follow-up, no conclusions could be drawn about time to recurrence and progression. In addition, the overall bladder preservation rate after CHT was 87.6 %.

In one of the few studies with long-term follow-up, Colombo et al. reported on a cohort of 83 patients with intermediate/high grade NMIBC with a median follow-up of 91 months . They showed a significantly better 10-year disease-free survival rate for thermochemotherapy . Bladder preservation rates for thermochemotherapy were also significantly higher .

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