Muscle Invasive Bladder Cancer : Bladder conservation protocols
Bladder cancer group c10 (1)
1
Combination Therapies 1 • A cycle of MVAC given as 14 days (2 weeks) or 28 days (4 weeks) – up to 3-6 cycles • Shorter cycle i.e. accelerated or dose dense MVAC given with growth factors to speed up recovery of white blood cells Dosing Regimen (given IV) Bladder Cancer; Introduction Prognosis of Bladder Cancer The table below shows the different survival rates for both males and females. Between gender and depending on what stage of cancer, the survival rates vary. Bladder Cancer Stage 5 Year Survival Rate Male Female Stage 1 90% 90% Stage 2 50% 33% Stage 3 33% 15% However, each patients prognosis is individual and depends on the following factors: Exactly how far the cancer cells have gone into the bladder lining Number of tumours Size of the tumours How abnormal the cancer cells look under the microscope Whether this a recurrence, and how often the tumour has recurred Review of Treatment Options in Invasive Bladder Cancer Safia Khan, Noor Mujahid, Xia Qi Pook, Umar Malik, James Kumar, Wura Oguntoye Session 1 Group C Combination Therapies 2 Gemcitabine and Cisplatin (GC) • Single use of drugs is limited by low, short-lived response rates, with few complete responses and median survival between 4 and 6 months • Systemic combination therapy improves survival to 8-12 months • MVAC is standard first-line treatment for advanced bladder cancer • It can be given as adjuvant or neoadjuvant therapy • A newer 2-drug regimen used for better tolerance but not efficacy • A cycle of GC lasts 21 days (3 weeks) - up to 6 cycles GC vs. MVAC • As effective as each other • GC and MVAC have prolonged survival of 13.8 and 14.8 months respectively Neoadjuvant therapy improves survival by 5% absolute benefit at 5 years (45% to 50%) MVAC Methotrexate Mechanism of Resistance Mechanism of Action • Inhibitor of tetrahydrofolate dehydrogenase • Prevents the formation of tetrahydrofolate • Tetrahydrofolate is needed for thymidine synthesis which is required for DNA synthesis Myelosuppression (major DLT*) so needs CBC** monitoring Mucositis occurs 5-10 days after treatment initiation so needs daily oral care Nephrotoxicity at high dose so needs creatinine monitoring Drug Toxicities Hepatotoxicity where serum ALT level rises so needs prior liver evaluation • Microtubule inhibitor • Prevents spindle formation during metaphase • Leading to incomplete mitosis and apoptotic cell death Mechanism of Action Adriamycin (Doxorubicin) Mechanism of Action • Stabilises the topoisomerase II-DNA complex • Prevents re-ligation of double stranded DNA • Accumulation of double stranded DNA breaks leading to apoptotic cell death Cardiotoxicity (DLT*) leads to cardiomyopathy and arrhythmias Extravasation if occurs, administer dexrazoxane at the site as soon as possible Drug Toxicities Myelosuppression can be severe so needs CBC** monitoring Cisplatin Mechanism of Resistance • “Alkylating like” agent • Chlorine displaced by water to form aqua ligand (aquation) • Aqua ligand is displaced by Guanine. This can occur also with the second chlorine atom • Hence formation of 1-2 intrastrand crosslinks between G-G bases and G-A bases Nausea and vomiting (level 4) so should be given with antiemetic Nephrotoxicity (major DLT*) reduced by keeping patients hydrated Drug Toxicities Neuropathies may be irreversible and is more susceptible in elderly Ototoxicity at high doses and cumulative doses which can be severe Bladder cancer incidence in men Bladder cancer incidence in women Mechanism of Action Resistance mechanisms,, arise as a consequence of intracellular changes that either prevent cisplatin from interacting with DNA, interfere with DNA damage signals from activating the apoptotic machinery, or both. Mechanism of Resistance Mechanism of Resistance 1: Efflux of drug by a membrane pump. 2: Altered metabolism or distribution of agent. 3: Altered interaction of agent with microtubules. 4: Inadequate induction of apoptotic signal. Vinblastine Thought to involve, in particular, ABCB1 and ABCC1 and transporters.ABCB1 confers resistance by acting as an ATP-dependent drug efflux pump causing increased drug efflux via altered or increased expression Invasive bladder cancer through cytoscope Types of Bladder Cancer Transitional Cell Squamous Cell Adenocarcinoma Rare Types Cancer that has Spread Non Muscle Invasive Invasive Causes and Risk Factors Age Smoking Gender Family History Infection Previous Treatment for Cancer Exposure to Chemicals at Work Symptoms of Bladder Cancer Hematuria Pain when passing urine Swelling of Legs Pelvic and/or Back Pain Weight loss Bladder cancer is where a growth of a tumour, develops in the bladder lining. In some cases, the tumour spreads through the lining into the surrounding muscles. MVAC Methotrexate Vinblastine Doxorubicin (Adriamycin) Cisplatin Drug Dose/frequency per cycle Methotrexate 30 mg/m 2 , days 1, 15, 22 Vinblas?ne 3mg/m 2 , days 2, 15, 22 Doxorubicin 30mg/m 2 , day 2 Cispla?n 70mg/m 2 , day 2 Common Side Effects Myelosuppression Fatigue Neurotoxicity and ototoxicity Alopecia Nausea and Vomiting Mucositis Nephrotoxicity Drug Toxicities Neuropathies not common or permanent but can be disabling Neutropenia (major DLT*) so needs WBC*** count before administration Eye problems rarely but may affect vision and may be permanent Conclusion Each drug of the MVAC combination therapy brings about different potential drug toxicities that can cause harm to the patients even if they exert therapeutic efficacy when used together. This is why it is so important to constantly monitor the patients when they are given with this therapy and provide supportive measurements. Types of Toxicity Dose Alterations Myelotoxicity Delay treatment cycle until WBC and platelet count back to ideal levels Neurologic toxocity Reduce VINBLASTIN dose in severe neurotoxicity Mucositis Reduce DOXORUBICIN dose by 33% if it is grade 3 or 4 Cardiotoxicity Discontinue DOXORUBICIN if develop heart failure Nephrotoxicity May reduce CISPLATIN dose Clinical Monitoring CBC**; baseline and regular Liver; baseline and regular Renal; baseline and regular Cardiac function test Clinical toxicity test eg infection, bleeding MVAC Main treatments: • Surgery to remove all or part of the bladder • Radiotherapy on its own or combined with chemotherapy (combination therapy) References: Cancer, C. (2015). Cisplatin - Drug Information - Chemocare. [online] Chemocare.com. Available at: http://chemocare.com/chemotherapy/drug-info/cisplatin.aspx [Accessed 2 Dec. 2015]. Cancer Research UK. (30/05/2014). Bladder cancer statistics and outlook. Available: http://www.cancerresearchuk.org/about-cancer/type/bladder-cancer/treatment/bladder-cancer-statistics-and-outlook. Last accessed 4th December 2015. cancer, T. (2015). Types of bladder cancer | Cancer Research UK. [online] Cancerresearchuk.org. Available at: http://www.cancerresearchuk.org/about-cancer/type/bladder-cancer/about/types-of-bladder-cancer [Accessed 8 Dec. 2015]. cancer, T. (2015). Types of treatment for invasive bladder cancer | Cancer Research UK. [online] Cancerresearchuk.org. Available at: http://www.cancerresearchuk.org/about-cancer/type/bladder-cancer/treatment/invasive/which-treatment-for-invasive-bladder-cancer [Accessed 7 Dec. 2015]. Chennaiurology.com, (2015). [online] Available at: http://www.chennaiurology.com/images/bladder_cancer2.jpg [Accessed 3 Dec. 2015]. Cursoenarm.net, (2015). [online] Available at: http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?6/13/6364 [Accessed 3 Dec. 2015]. Drugs.com, (2015). Doxorubicin - FDA prescribing information, side effects and uses. [online] Available at: http://www.drugs.com/pro/doxorubicin.html [Accessed 4 Dec. 2015]. Drugs.com, (2015). Methotrexate (Amethopterin; MTX) (Professional Patient Advice) - Drugs.com. [online] Available at: http://www.drugs.com/ppa/methotrexate-amethopterin-mtx.html [Accessed 1 Dec. 2015]. Drugs.com, (2015). Vinblastine - FDA prescribing information, side effects and uses. [online] Available at: http://www.drugs.com/pro/vinblastine.html [Accessed 3 Dec. 2015]. Dumontet, C. and Sikic, B. (1999). Mechanisms of Action of and Resistance to Antitubulin Agents: Microtubule Dynamics, Drug Transport, and Cell Death. Journal of Clinical Oncology, [online] 17(3), pp.1061-1061. Available at: http://jco.ascopubs.org/content/17/3/1061.long?hwshib2=authn%3A1449611210%3A20151207% -bc77-67d41c9e433a%3A0%3A0%3A0%3Aqce1zj1REXh0YQ6khoESlw%3D%3D [Accessed 6 Dec. 2015]. Macmillan.org.uk, (2015). Causes of bladder cancer - Cancer Information - Macmillan Cancer Support. [online] Available at: http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Bladder/Aboutbladdercancer/Causes.aspx [Accessed 1 Dec. 2015]. Manski, D. 2015. MVAC chemotherapy for bladder cancer [Online]. Available at: http://www.urology-textbook.com/mvac.html [Accessed: 6 December 2015]. Nature.com, (2015). Oncogene - Figure 5 for article: Cisplatin: mode of cytotoxic action and molecular basis of resistance. [online] Available at: http://www.nature.com/onc/journal/v22/n47/fig_tab/1206933f5.html [Accessed 6 Dec. 2015]. Netty Cracknell. 2014. MVAC chemotherapy [Online]. Available at: http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Chemotherapy/Combinationregimen/MVAC.aspx [Accessed: 6 December 2015]. NHS Choices. (11/05/2015). Bladder cancer . Available:http://www.nhs.uk/conditions/cancer-of-the-bladder/Pages/Introduction.aspx. Last accessed 4th December 2015. Roberts, J.T. et al. 2006. Long term survival results of a randomised trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer. Annals of Oncology 17(5), pp. 118-122. Salam, MA. 2013. Principles and Practice of Urology. Vol. 7. London: JP Medical Ltd. Vale, C. et al. 2003. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. The Lancet. Vol. 361(9373) pp. 1927-1934. http://www.nature.com/nrc/journal/v5/n1/images/nrc1529-f3.jpg https:// upload.wikimedia.org/wikipedia/commons/2/2d/Microtubules_and_alkaloids.png http://www2.lbl.gov/Science-Articles/Archive/assets/images/2007/Dec/19-Wed/Topo-II-mechanism.gif http://pubs.sciepub.com/bb/2/1/1/image/fig8.png *DLT : Dose Limiting Toxicity **CBC : Complete Blood Count ***WBC : White Blood Cell MTX enters cells by the reduced folate carrier (1), is polyglutamylated (2), and MTX or its polyglutamylated forms are potent inhibitors (3). MTX polyglutamates are broken down and effluxed from the cell. Pa?ent Centric Approach Services available for patients with advanced bladder cancer (referrals) Palliative care Counseling and emotional support Social and disability services
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Transcript of Bladder cancer group c10 (1)
Combination Therapies 1
• A cycle of MVAC given as 14 days (2 weeks) or 28 days (4 weeks) – up to 3-6 cycles
• Shorter cycle i.e. accelerated or dose dense MVAC given with growth factors to speed up recovery of white blood cells
Dosing Regimen (given IV)
Bladder Cancer; Introduction
Prognosis of Bladder Cancer The table below shows the different survival rates for both males and females. Between gender and depending on what stage of cancer, the survival rates vary.
Bladder Cancer Stage 5 Year Survival Rate
Male Female
Stage 1 90% 90%
Stage 2 50% 33%
Stage 3 33% 15%
However, each patients prognosis is individual and depends on the following factors: Ø Exactly how far the cancer cells have gone into the bladder lining Ø Number of tumours Ø Size of the tumours Ø How abnormal the cancer cells look under the microscope Ø Whether this a recurrence, and how often the tumour has recurred
Review of Treatment Options in Invasive Bladder Cancer Safia Khan, Noor Mujahid, Xia Qi Pook, Umar Malik, James Kumar, Wura Oguntoye
Session 1 Group C
Combination Therapies 2
Gemcitabine and
Cisplatin (GC)
• Single use of drugs is limited by low, short-lived response rates, with few complete responses and median survival between 4 and 6 months
• Systemic combination therapy improves survival to 8-12 months
• MVAC is standard first-line treatment for advanced bladder cancer
• It can be given as adjuvant or neoadjuvant therapy
• A newer 2-drug regimen used for better tolerance but not efficacy
• A cycle of GC lasts 21 days (3 weeks) - up to 6 cycles
GC vs. MVAC • As effective as each other • GC and MVAC have
prolonged survival of 13.8 and 14.8 months respectively
Neoadjuvant therapy improves survival by 5% absolute benefit at 5 years (45% to 50%)
MVAC
Methotrexate
Mechanism of Resistance
Mechanism of Action
• Inhibitor of tetrahydrofolate dehydrogenase • Prevents the formation of tetrahydrofolate • Tetrahydrofolate is needed for thymidine
synthesis which is required for DNA synthesis
Myelosuppression
(major DLT*) so needs CBC** monitoring
Mucositis occurs 5-10 days after treatment initiation so needs daily oral care
Nephrotoxicity at high dose so needs creatinine monitoring
Drug Toxicities
Hepatotoxicity where serum ALT level rises so needs prior liver evaluation
• Microtubule inhibitor
• Prevents spindle formation during metaphase • Leading to incomplete mitosis and apoptotic
cell death
Mechanism of Action
Adriamycin (Doxorubicin)
Mechanism of Action
• Stabilises the topoisomerase II-DNA complex • Prevents re-ligation of double stranded DNA • Accumulation of double stranded DNA breaks
leading to apoptotic cell death
Cardiotoxicity (DLT*) leads to
cardiomyopathy and arrhythmias
Extravasation if occurs, administer dexrazoxane at the site as soon as possible
Drug Toxicities
Myelosuppression can be severe so needs CBC** monitoring
Cisplatin
Mechanism of Resistance
• “Alkylating like” agent • Chlorine displaced by water to form aqua
ligand (aquation) • Aqua ligand is displaced by Guanine. This can
occur also with the second chlorine atom • Hence formation of 1-2 intrastrand crosslinks
between G-G bases and G-A bases
Nausea and vomiting
(level 4) so should be given with antiemetic
Nephrotoxicity (major DLT*) reduced by keeping patients hydrated
Drug Toxicities
Neuropathies may be irreversible and is more susceptible in elderly
Ototoxicity at high doses and cumulative doses which can be severe
Bladder cancer incidence in men
Bladder cancer incidence in women
Mechanism of Action
Resistance mechanisms,, arise as a consequence of intracellular changes that either prevent cisplatin from interacting with DNA, interfere with DNA damage signals from activating the apoptotic machinery, or both.
Mechanism of Resistance
Mechanism of Resistance
1: Efflux of drug by a membrane pump. 2: Altered metabolism or distribution of agent. 3: Altered interaction of agent with microtubules. 4: Inadequate induction of apoptotic signal.
Vinblastine
Thought to involve, in particular, ABCB1 and ABCC1 and transporters.ABCB1 confers resistance by acting as an ATP-dependent drug efflux pump causing increased drug efflux via altered or increased expression
Invasive bladder cancer through cytoscope
Types of Bladder Cancer
Transitional Cell Squamous Cell
Adenocarcinoma Rare Types Cancer that has Spread
Non Muscle Invasive Invasive
Causes and Risk Factors
Age
Smoking
Gender
Family History
Infection
Previous Treatment for Cancer
Exposure to Chemicals at Work
Symptoms of Bladder
Cancer
Hematuria
Pain when passing urine
Swelling of Legs
Pelvic and/or Back Pain Weight loss
Bladder cancer is where a growth of a tumour, develops in the bladder lining. In some cases, the tumour spreads through the lining into the surrounding muscles.
MVA
C
Methotrexate
Vinblastine
Doxorubicin (Adriamycin)
Cisplatin
Drug Dose/frequency per cycle
Methotrexate 30 mg/m2, days 1, 15, 22
Vinblas?ne 3mg/m2, days 2, 15, 22
Doxorubicin 30mg/m2, day 2
Cispla?n 70mg/m2, day 2
Common Side Effects
Myelosuppression Fatigue Neurotoxicity and ototoxicity
Alopecia Nausea and Vomiting
Mucositis Nephrotoxicity
Drug Toxicities
Neuropathies not common or permanent but can be disabling
Neutropenia (major DLT*) so needs WBC*** count before administration
Eye problems rarely but may affect vision and may be permanent
Conclusion
Each drug of the MVAC combination therapy brings about different potential drug toxicities that can cause harm to the patients even if they exert therapeutic efficacy when used together. This is why it is so important to constantly monitor the patients when they are given with this therapy and provide supportive measurements.
Types of Toxicity
Dose Alterations
Myelotoxicity Delay treatment cycle until WBC and platelet count back to ideal levels
Neurologic toxocity
Reduce VINBLASTIN dose in severe neurotoxicity
Mucositis Reduce DOXORUBICIN dose by 33% if it is grade 3 or 4
Cardiotoxicity Discontinue DOXORUBICIN if develop heart failure
Nephrotoxicity May reduce CISPLATIN dose
Clinical Monitoring
CBC**; baseline and regular
Liver; baseline and regular
Renal; baseline and regular
Cardiac function test
Clinical toxicity test eg infection, bleeding
MVAC
Main treatments: • Surgery to remove all or part of the bladder • Radiotherapy on its own or combined with
chemotherapy (combination therapy)
References: Cancer, C. (2015). Cisplatin - Drug Information - Chemocare. [online] Chemocare.com. Available at: http://chemocare.com/chemotherapy/drug-info/cisplatin.aspx [Accessed 2 Dec. 2015]. Cancer Research UK. (30/05/2014). Bladder cancer statistics and outlook. Available: http://www.cancerresearchuk.org/about-cancer/type/bladder-cancer/treatment/bladder-cancer-statistics-and-outlook. Last accessed 4th December 2015. cancer, T. (2015). Types of bladder cancer | Cancer Research UK. [online] Cancerresearchuk.org. Available at: http://www.cancerresearchuk.org/about-cancer/type/bladder-cancer/about/types-of-bladder-cancer [Accessed 8 Dec. 2015]. cancer, T. (2015). Types of treatment for invasive bladder cancer | Cancer Research UK. [online] Cancerresearchuk.org. Available at: http://www.cancerresearchuk.org/about-cancer/type/bladder-cancer/treatment/invasive/which-treatment-for-invasive-bladder-cancer [Accessed 7 Dec. 2015]. Chennaiurology.com, (2015). [online] Available at: http://www.chennaiurology.com/images/bladder_cancer2.jpg [Accessed 3 Dec. 2015]. Cursoenarm.net, (2015). [online] Available at: http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?6/13/6364 [Accessed 3 Dec. 2015]. Drugs.com, (2015). Doxorubicin - FDA prescribing information, side effects and uses. [online] Available at: http://www.drugs.com/pro/doxorubicin.html [Accessed 4 Dec. 2015]. Drugs.com, (2015). Methotrexate (Amethopterin; MTX) (Professional Patient Advice) - Drugs.com. [online] Available at: http://www.drugs.com/ppa/methotrexate-amethopterin-mtx.html [Accessed 1 Dec. 2015]. Drugs.com, (2015). Vinblastine - FDA prescribing information, side effects and uses. [online] Available at: http://www.drugs.com/pro/vinblastine.html [Accessed 3 Dec. 2015]. Dumontet, C. and Sikic, B. (1999). Mechanisms of Action of and Resistance to Antitubulin Agents: Microtubule Dynamics, Drug Transport, and Cell Death. Journal of Clinical Oncology, [online] 17(3), pp.1061-1061. Available at: http://jco.ascopubs.org/content/17/3/1061.long?hwshib2=authn%3A1449611210%3A20151207% -bc77-67d41c9e433a%3A0%3A0%3A0%3Aqce1zj1REXh0YQ6khoESlw%3D%3D [Accessed 6 Dec. 2015]. Macmillan.org.uk, (2015). Causes of bladder cancer - Cancer Information - Macmillan Cancer Support. [online] Available at: http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Bladder/Aboutbladdercancer/Causes.aspx [Accessed 1 Dec. 2015]. Manski, D. 2015. MVAC chemotherapy for bladder cancer [Online]. Available at: http://www.urology-textbook.com/mvac.html [Accessed: 6 December 2015]. Nature.com, (2015). Oncogene - Figure 5 for article: Cisplatin: mode of cytotoxic action and molecular basis of resistance. [online] Available at: http://www.nature.com/onc/journal/v22/n47/fig_tab/1206933f5.html [Accessed 6 Dec. 2015]. Netty Cracknell. 2014. MVAC chemotherapy [Online]. Available at: http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Chemotherapy/Combinationregimen/MVAC.aspx [Accessed: 6 December 2015]. NHS Choices. (11/05/2015). Bladder cancer . Available:http://www.nhs.uk/conditions/cancer-of-the-bladder/Pages/Introduction.aspx. Last accessed 4th December 2015. Roberts, J.T. et al. 2006. Long term survival results of a randomised trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer. Annals of Oncology 17(5), pp. 118-122. Salam, MA. 2013. Principles and Practice of Urology. Vol. 7. London: JP Medical Ltd. Vale, C. et al. 2003. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. The Lancet. Vol. 361(9373) pp. 1927-1934. http://www.nature.com/nrc/journal/v5/n1/images/nrc1529-f3.jpg https://upload.wikimedia.org/wikipedia/commons/2/2d/Microtubules_and_alkaloids.png http://www2.lbl.gov/Science-Articles/Archive/assets/images/2007/Dec/19-Wed/Topo-II-mechanism.gif http://pubs.sciepub.com/bb/2/1/1/image/fig8.png
*DLT : Dose Limiting Toxicity **CBC : Complete Blood Count ***WBC : White Blood Cell
MTX enters cells by the reduced folate carrier (1), is polyglutamylated (2), and MTX or its polyglutamylated forms are potent inhibitors (3). MTX polyglutamates are broken down and effluxed from the cell.
Pa?ent Centric Approach
Services available for patients with advanced
bladder cancer (referrals)
Palliative care
Counseling and emotional support
Social and disability services
