This document discusses a 44-year-old female patient diagnosed with stage IV non-small cell lung cancer (NSCLC) that was found to be positive for ALK gene rearrangement. She was started on the ALK inhibitor crizotinib (Xalkori) as first-line treatment. Crizotinib is an effective targeted therapy for NSCLC tumors with ALK rearrangement, having shown improved progression-free survival compared to chemotherapy in clinical trials. The document reviews dosing, monitoring, adverse effects and dose modifications for crizotinib treatment.
The document discusses new aspects of adjuvant therapy for endometrial cancer based on recent clinical trials. It summarizes three major randomized controlled trials from 2007-2008 that evaluated the role of external beam radiation therapy in early stage endometrial cancer and found no improvement in survival with its addition to surgery alone. Risk group stratification is important to identify patients most likely to benefit from adjuvant treatment.
Immunotherapy maintenence for advanced urothelial cancerChandan K Das
- JAVELIN Bladder 100 was a phase 3 trial investigating avelumab maintenance therapy after platinum-based chemotherapy in patients with advanced urothelial carcinoma.
- The trial found avelumab maintenance significantly improved overall survival compared to best supportive care alone, with a 31% reduction in risk of death. Progression-free survival was also significantly improved.
- Subgroup analyses found overall survival benefits were consistent across all patient subgroups, including those with PD-L1-negative tumors. Response rates were also higher with avelumab maintenance.
- The safety profile of avelumab was manageable, with most treatment-related adverse events being grade 1-2 in severity and no new safety signals
This document summarizes targeted therapies for ovarian cancer, including anti-angiogenic agents and PARP inhibitors. It discusses several studies evaluating bevacizumab, an anti-VEGF monoclonal antibody, in the first-line and recurrent platinum-sensitive settings. The GOG218 and ICON7 trials showed improved progression-free survival when bevacizumab was added to chemotherapy as first-line treatment. The OCEANS trial found that adding bevacizumab to chemotherapy significantly prolonged progression-free and overall survival compared to chemotherapy alone for platinum-sensitive recurrent ovarian cancer. Adverse events with bevacizumab were consistent with its known safety profile.
Journal club: Durvalumab as Consolidation therapy in Advanced NSCLCAnimesh Agrawal
This study evaluated the addition of durvalumab consolidation therapy following chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer. The study found that durvalumab improved progression-free survival compared to placebo, with median progression-free survival of 16.8 months versus 5.6 months respectively. Overall survival was also improved with durvalumab, though final analysis is still pending. Safety profiles were similar to other PD-L1 inhibitors, with immune-related adverse events in approximately 25% of durvalumab patients. This study provides evidence that durvalumab consolidation improves outcomes for stage III NSCLC following chemoradiotherapy.
Hitting the Target in HER2-Positive Metastatic Colorectal Canceri3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck will share the latest data and strategies for hitting the target in HER2-positive metastatic colorectal cancer. Dr. Christopher Lieu, Associate Professor at the University of Colorado Cancer Center, explores actionable targets to inform personalized care plans, guideline-recommended combination and sequencing strategies, adverse event monitoring and management, and more.
STATEMENT OF NEED
An estimated 153,020 new cases of colorectal cancer (CRC) are diagnosed annually, and 52,550 people die of the disease (Siegel et al, 2023). Approximately 22% of patients present with metastatic disease, which is associated with a dismal 5-year survival rate of 15% (SEER, 2022). Targeting biomarkers is a key strategy for expanding therapeutic options and improving outcomes in metastatic CRC. Human epidermal growth factor receptor 2 (HER2) amplification status and treatments targeting HER2 are some of the most recent additions to the arsenal of targeted therapy for this disease. This activity chaired by Christopher Lieu, MD, Associate Director of Clinical Research at the University of Colorado Cancer Center, will provide expert perspectives and practical guidance on treating HER2-positive metastatic CRC.
TARGET AUDIENCE
Oncologists, gastroenterologists, nurse practitioners, physician assistants, oncology nurses, and other health care professionals involved in the treatment of patients with colorectal cancer (CRC).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to
Distinguish actionable targets that can inform personalized care plans in metastatic CRC
Evaluate practice guidelines on treatment combinations and sequences for patients with metastatic CRC
Appraise emerging efficacy and safety data on novel targeted therapies for patients with HER2-positive metastatic CRC
Assess strategies for optimizing the safety and tolerability of novel targeted therapies for HER2-positive metastatic CRC
This document discusses treatment approaches for metastatic triple negative breast cancer. It notes that chemotherapy is currently the standard treatment but that the disease is heterogeneous. Several new targeted treatment approaches are discussed that are being explored in clinical trials, including PARP inhibitors targeting DNA repair, platinum agents, anti-androgens targeting the androgen receptor, immune checkpoint inhibitors, and antibody-drug conjugates. Ongoing research aims to improve outcomes by identifying biomarkers to match patients to effective targeted therapies.
1) Anti-angiogenic therapy targets tumor angiogenesis and has become an established treatment for metastatic colorectal cancer (mCRC).
2) Bevacizumab, a monoclonal antibody targeting VEGF, has shown efficacy in multiple phase III trials in combination with chemotherapy as first-line and maintenance therapy for mCRC.
3) Additional anti-angiogenic agents approved for mCRC include aflibercept, ramucirumab, and regorafinib, which have demonstrated benefits in later lines of therapy.
The document discusses new aspects of adjuvant therapy for endometrial cancer based on recent clinical trials. It summarizes three major randomized controlled trials from 2007-2008 that evaluated the role of external beam radiation therapy in early stage endometrial cancer and found no improvement in survival with its addition to surgery alone. Risk group stratification is important to identify patients most likely to benefit from adjuvant treatment.
Immunotherapy maintenence for advanced urothelial cancerChandan K Das
- JAVELIN Bladder 100 was a phase 3 trial investigating avelumab maintenance therapy after platinum-based chemotherapy in patients with advanced urothelial carcinoma.
- The trial found avelumab maintenance significantly improved overall survival compared to best supportive care alone, with a 31% reduction in risk of death. Progression-free survival was also significantly improved.
- Subgroup analyses found overall survival benefits were consistent across all patient subgroups, including those with PD-L1-negative tumors. Response rates were also higher with avelumab maintenance.
- The safety profile of avelumab was manageable, with most treatment-related adverse events being grade 1-2 in severity and no new safety signals
This document summarizes targeted therapies for ovarian cancer, including anti-angiogenic agents and PARP inhibitors. It discusses several studies evaluating bevacizumab, an anti-VEGF monoclonal antibody, in the first-line and recurrent platinum-sensitive settings. The GOG218 and ICON7 trials showed improved progression-free survival when bevacizumab was added to chemotherapy as first-line treatment. The OCEANS trial found that adding bevacizumab to chemotherapy significantly prolonged progression-free and overall survival compared to chemotherapy alone for platinum-sensitive recurrent ovarian cancer. Adverse events with bevacizumab were consistent with its known safety profile.
Journal club: Durvalumab as Consolidation therapy in Advanced NSCLCAnimesh Agrawal
This study evaluated the addition of durvalumab consolidation therapy following chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer. The study found that durvalumab improved progression-free survival compared to placebo, with median progression-free survival of 16.8 months versus 5.6 months respectively. Overall survival was also improved with durvalumab, though final analysis is still pending. Safety profiles were similar to other PD-L1 inhibitors, with immune-related adverse events in approximately 25% of durvalumab patients. This study provides evidence that durvalumab consolidation improves outcomes for stage III NSCLC following chemoradiotherapy.
Hitting the Target in HER2-Positive Metastatic Colorectal Canceri3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck will share the latest data and strategies for hitting the target in HER2-positive metastatic colorectal cancer. Dr. Christopher Lieu, Associate Professor at the University of Colorado Cancer Center, explores actionable targets to inform personalized care plans, guideline-recommended combination and sequencing strategies, adverse event monitoring and management, and more.
STATEMENT OF NEED
An estimated 153,020 new cases of colorectal cancer (CRC) are diagnosed annually, and 52,550 people die of the disease (Siegel et al, 2023). Approximately 22% of patients present with metastatic disease, which is associated with a dismal 5-year survival rate of 15% (SEER, 2022). Targeting biomarkers is a key strategy for expanding therapeutic options and improving outcomes in metastatic CRC. Human epidermal growth factor receptor 2 (HER2) amplification status and treatments targeting HER2 are some of the most recent additions to the arsenal of targeted therapy for this disease. This activity chaired by Christopher Lieu, MD, Associate Director of Clinical Research at the University of Colorado Cancer Center, will provide expert perspectives and practical guidance on treating HER2-positive metastatic CRC.
TARGET AUDIENCE
Oncologists, gastroenterologists, nurse practitioners, physician assistants, oncology nurses, and other health care professionals involved in the treatment of patients with colorectal cancer (CRC).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to
Distinguish actionable targets that can inform personalized care plans in metastatic CRC
Evaluate practice guidelines on treatment combinations and sequences for patients with metastatic CRC
Appraise emerging efficacy and safety data on novel targeted therapies for patients with HER2-positive metastatic CRC
Assess strategies for optimizing the safety and tolerability of novel targeted therapies for HER2-positive metastatic CRC
This document discusses treatment approaches for metastatic triple negative breast cancer. It notes that chemotherapy is currently the standard treatment but that the disease is heterogeneous. Several new targeted treatment approaches are discussed that are being explored in clinical trials, including PARP inhibitors targeting DNA repair, platinum agents, anti-androgens targeting the androgen receptor, immune checkpoint inhibitors, and antibody-drug conjugates. Ongoing research aims to improve outcomes by identifying biomarkers to match patients to effective targeted therapies.
1) Anti-angiogenic therapy targets tumor angiogenesis and has become an established treatment for metastatic colorectal cancer (mCRC).
2) Bevacizumab, a monoclonal antibody targeting VEGF, has shown efficacy in multiple phase III trials in combination with chemotherapy as first-line and maintenance therapy for mCRC.
3) Additional anti-angiogenic agents approved for mCRC include aflibercept, ramucirumab, and regorafinib, which have demonstrated benefits in later lines of therapy.
Recent advances in targeted therapy for metastatic lung cancerAlok Gupta
This document discusses recent advances in targeted therapy for metastatic lung cancer. It summarizes key findings from several clinical trials evaluating third-generation EGFR TKIs like osimertinib for patients with EGFR mutation-positive NSCLC. The document highlights that osimertinib provides significantly longer progression-free survival compared to earlier generation EGFR TKIs, with a median PFS of 18.9 months versus 10.2 months. Osimertinib also demonstrated a higher objective response rate and longer duration of response. Benefits were consistent across patient subgroups.
The CLEOPATRA trial was a phase III randomized controlled trial that compared the efficacy and safety of pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel in patients with previously untreated HER2-positive metastatic breast cancer. The study found that adding pertuzumab to trastuzumab and docetaxel significantly extended progression-free survival by 6 months and improved overall response rates compared to the placebo group. Overall survival was also improved with the pertuzumab regimen. While rates of adverse events were similar between the groups, the pertuzumab regimen represented a substantial improvement over the standard of care.
The Changing Role of PARP Inhibitors in the Treatment of Ovarian Cancerbkling
In recent years, researchers have been looking into using a class of drugs called PARP inhibitors to prevent the progression and recurrence of ovarian cancer. Dr. Kathleen Moore of Stephenson Cancer Center, Principal Investigator of the SOLO-1 trial, explains how the results of this trial may affect ovarian cancer patients and where research on ovarian cancer treatment is headed next.
What's the latest in breast cancer treatment and research? Erica Mayer, MD, MPH, a medical oncologist in the Susan F. Smith Center for Women's Cancers, shares the latest breast cancer news.
This presentation was originally given on Oct. 16, 2015, at the annual Young Women with Breast Cancer Forum, hosted by the Program for Young Women with Breast Cancer in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston, Mass.
Learn more: http://www.susanfsmith.org
ADC’s - What Everyone with MBC Should Know about Antibody Drug Conjugatesbkling
Antibody drug conjugates (ADC’s), a novel class of anticancer agents, have been around for decades but recently great strides have been made in metastatic breast cancer. Next generation ADC’s, sometimes referred to as ' Trojan Horses' have shown promising efficacy in all subtypes of MBC. Join Dr. Erika Hamilton, Director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, and partner with Tennessee Oncology PLCC, as she presents an overview of ADC’s, biomarkers and clinical mapping, current treatment options, as well as the promising trials to keep an eye on. There will be time for your questions throughout the presentation.
Next-generation DNA sequencing (NGS) provides high-throughput sequencing of DNA fragments in parallel to determine sequences exponentially faster and cheaper than Sanger sequencing. NGS can be used for whole genome, whole exome, or targeted gene panel sequencing. It has various clinical applications including cancer screening and management, diagnosis of complex genetic diseases, and identification of pathogenic variants. Tumor mutation burden (TMB) quantifies total mutations per tumor genome and higher TMB may predict better response to immunotherapy by expressing more neoantigens.
Chair and Presenter, Jonathan D. Spicer, MD, PhD, FRCSC, Sara Najmeh, MD, and Paula A. Ugalde Figueroa, MD, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “Neoadjuvant, Adjuvant, or Both: How to Solve the Puzzle of Perioperative Immunotherapy, Individualize Treatment Plans, and Improve Cure Rates in Resectable NSCLC.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3K8tKH9. CME/MOC credit will be available until June 5, 2024.
Update on Management of Triple Negative Breast Cancerspa718
This document provides an update on the management of triple negative breast cancer from Dr. Banu Arun at MD Anderson Cancer Center. It discusses that triple negative breast cancer is a heterogeneous disease comprised of several molecular subtypes with different characteristics and potential treatment targets. Clinical trials exploring chemotherapy regimens, platinum agents, PARP inhibitors, anti-angiogenic drugs, and immunotherapies are summarized. Ongoing research aims to better define the subtypes in order to personalize treatment for triple negative breast cancer patients.
Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and HER2 receptors. It represents 15% of breast cancers and has a higher sensitivity to chemotherapy than other subtypes. New targeted therapies are being developed and tested in clinical trials based on TNBC's defective DNA repair pathways. These include PARP inhibitors, platinum chemotherapy, and angiogenesis inhibitors. TNBC is a heterogeneous disease with multiple molecular subtypes, each with different treatment responses. Participation in clinical trials is important to advance new targeted therapies for TNBC.
This document summarizes treatment approaches for metastatic castration-resistant prostate cancer (mCRPC). It discusses definitions of CRPC and mechanisms of resistance. For mCRPC patients with PSADT >10 months and no symptoms, secondary hormonal therapies are recommended, while those with PSADT <10 months receive second-generation antiandrogens. Docetaxel remains first-line for symptomatic mCRPC, while abiraterone, enzalutamide, radium-223, and sipuleucel-T are also options. Detection of AR-V7 in circulating tumor cells may help determine if taxanes or AR-targeted therapies are most suitable. Ongoing treatment, monitoring of
Pharmaceutical prospectives of anti estrogen, m-tor, CDK 4/6 in Breast CancerNoha El Baghdady
This document discusses various treatments for breast cancer, including anti-estrogen therapies, mTOR inhibitors, and CDK 4/6 inhibitors. It describes how these drugs work and their side effects. For anti-estrogens, it compares aromatase inhibitors like anastrozole and tamoxifen. It also discusses managing side effects like hot flashes. For mTOR inhibitors, it provides details on everolimus, including dosing and drug interactions through CYP450 pathways. Finally, it compares the first three CDK 4/6 inhibitors approved - palbociclib, ribociclib, and abemaciclib - in terms of their pharmacokinetics, dosing, and drug interaction profiles.
Immunotherapy for Metastatic Triple Negative Breast Cancerbkling
Sylvia Adams, MD, medical oncologist, and associate professor at the NYU School of Medicine, discusses the latest research including the role of immunology in the treatment of triple negative metastatic breast cancer. This webinar was hosted on October 19, 2016.
Strategies for Managing Recurrent Ovarian Cancerbkling
When ovarian cancer returns, it's not uncommon to experience a range of emotions and feel overwhelmed. But it's important to remember that recurrent ovarian cancer can often be successfully treated. Dr. Shannon N. Westin, gynecologic oncologist and clinical investigator at MD Anderson Cancer Center, goes over the latest treatment options for recurrent disease.
This phase 3 randomized trial investigated the incorporation of bevacizumab and nonplatinum combination chemotherapy in the treatment of advanced cervical cancer. It found that the addition of bevacizumab to chemotherapy significantly improved median overall survival compared to chemotherapy alone, from 13.3 months to 16.8 months. Bevacizumab also significantly improved progression-free survival and response rates. The benefit was observed across patient subgroups and did not negatively impact quality of life. Higher rates of gastrointestinal fistulas and thromboembolic events occurred with bevacizumab. The trial demonstrated that bevacizumab provided meaningful clinical benefit when added to chemotherapy for advanced cervical cancer.
Biomarkers can be used for screening, diagnosis, prognosis, and predicting response to treatment for cancer. In bladder cancer, screening biomarkers could identify high-risk groups but population screening may lead to many false positives. Diagnostic biomarkers are needed because hematuria is non-specific, and cystoscopy is expensive. Prognostic biomarkers help determine disease course as response can vary between patients with similar pathology. Predictive biomarkers identify subgroups likely to benefit from specific therapies.
This document discusses the management of luminal breast cancers. It covers several topics:
1) The different breast cancer subtypes, including luminal A and B cancers, which make up 50-60% and 15-20% of cases respectively. Luminal A has a better prognosis while luminal B is more aggressive.
2) The need for molecular signatures to better classify cancers and predict outcomes. Trials have shown certain gene expression profiles can determine if chemotherapy is needed.
3) Guidelines for adjuvant systemic therapies for luminal cancers, including chemotherapy, endocrine therapy, radiation, and duration of treatment. Trials support extended endocrine therapy to lower recurrence risk.
4) Neoadjuvant endocrine therapy
Treatment landscape of alk+ nsclc 12 novemberssuser4c22ca
This document provides an overview of treatments for ALK+ non-small cell lung cancer (NSCLC). It discusses the epidemiology of ALK+ NSCLC, occurring in 3-5% of NSCLC cases worldwide. First generation ALK inhibitors like crizotinib provided significant benefits for patients. Current NCCN guidelines recommend first-line treatment with newer ALK inhibitors such as alectinib, brigatinib, or lorlatinib which have led to median overall survival rates of over 5 years for some patients with metastatic ALK+ NSCLC. The document reviews the classes of ALK inhibitors including first, second, and third generation treatments and their effectiveness against ALK+ NSCLC.
molecular biology and Target therapy in lung cancerRikin Hasnani
This document summarizes molecular biology and targeted therapies in lung cancer. It discusses that lung cancer is a leading cause of cancer death worldwide. Historically, lung cancers were classified by histology alone, but it is now known they are driven by specific mutations. Key driver mutations were discovered in the EGFR, ALK, KRAS genes. These mutations activate intracellular signaling pathways like RAS/RAF/MEK/ERK and regulate cell growth. Targeted therapies like EGFR TKIs erlotinib and gefitinib or the ALK inhibitor crizotinib have significantly improved outcomes for patients with specific driver mutations. However, resistance often develops through secondary mutations like T790M, requiring new
Recent advances in targeted therapy for metastatic lung cancerAlok Gupta
This document discusses recent advances in targeted therapy for metastatic lung cancer. It summarizes key findings from several clinical trials evaluating third-generation EGFR TKIs like osimertinib for patients with EGFR mutation-positive NSCLC. The document highlights that osimertinib provides significantly longer progression-free survival compared to earlier generation EGFR TKIs, with a median PFS of 18.9 months versus 10.2 months. Osimertinib also demonstrated a higher objective response rate and longer duration of response. Benefits were consistent across patient subgroups.
The CLEOPATRA trial was a phase III randomized controlled trial that compared the efficacy and safety of pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel in patients with previously untreated HER2-positive metastatic breast cancer. The study found that adding pertuzumab to trastuzumab and docetaxel significantly extended progression-free survival by 6 months and improved overall response rates compared to the placebo group. Overall survival was also improved with the pertuzumab regimen. While rates of adverse events were similar between the groups, the pertuzumab regimen represented a substantial improvement over the standard of care.
The Changing Role of PARP Inhibitors in the Treatment of Ovarian Cancerbkling
In recent years, researchers have been looking into using a class of drugs called PARP inhibitors to prevent the progression and recurrence of ovarian cancer. Dr. Kathleen Moore of Stephenson Cancer Center, Principal Investigator of the SOLO-1 trial, explains how the results of this trial may affect ovarian cancer patients and where research on ovarian cancer treatment is headed next.
What's the latest in breast cancer treatment and research? Erica Mayer, MD, MPH, a medical oncologist in the Susan F. Smith Center for Women's Cancers, shares the latest breast cancer news.
This presentation was originally given on Oct. 16, 2015, at the annual Young Women with Breast Cancer Forum, hosted by the Program for Young Women with Breast Cancer in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston, Mass.
Learn more: http://www.susanfsmith.org
ADC’s - What Everyone with MBC Should Know about Antibody Drug Conjugatesbkling
Antibody drug conjugates (ADC’s), a novel class of anticancer agents, have been around for decades but recently great strides have been made in metastatic breast cancer. Next generation ADC’s, sometimes referred to as ' Trojan Horses' have shown promising efficacy in all subtypes of MBC. Join Dr. Erika Hamilton, Director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, and partner with Tennessee Oncology PLCC, as she presents an overview of ADC’s, biomarkers and clinical mapping, current treatment options, as well as the promising trials to keep an eye on. There will be time for your questions throughout the presentation.
Next-generation DNA sequencing (NGS) provides high-throughput sequencing of DNA fragments in parallel to determine sequences exponentially faster and cheaper than Sanger sequencing. NGS can be used for whole genome, whole exome, or targeted gene panel sequencing. It has various clinical applications including cancer screening and management, diagnosis of complex genetic diseases, and identification of pathogenic variants. Tumor mutation burden (TMB) quantifies total mutations per tumor genome and higher TMB may predict better response to immunotherapy by expressing more neoantigens.
Chair and Presenter, Jonathan D. Spicer, MD, PhD, FRCSC, Sara Najmeh, MD, and Paula A. Ugalde Figueroa, MD, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “Neoadjuvant, Adjuvant, or Both: How to Solve the Puzzle of Perioperative Immunotherapy, Individualize Treatment Plans, and Improve Cure Rates in Resectable NSCLC.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3K8tKH9. CME/MOC credit will be available until June 5, 2024.
Update on Management of Triple Negative Breast Cancerspa718
This document provides an update on the management of triple negative breast cancer from Dr. Banu Arun at MD Anderson Cancer Center. It discusses that triple negative breast cancer is a heterogeneous disease comprised of several molecular subtypes with different characteristics and potential treatment targets. Clinical trials exploring chemotherapy regimens, platinum agents, PARP inhibitors, anti-angiogenic drugs, and immunotherapies are summarized. Ongoing research aims to better define the subtypes in order to personalize treatment for triple negative breast cancer patients.
Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and HER2 receptors. It represents 15% of breast cancers and has a higher sensitivity to chemotherapy than other subtypes. New targeted therapies are being developed and tested in clinical trials based on TNBC's defective DNA repair pathways. These include PARP inhibitors, platinum chemotherapy, and angiogenesis inhibitors. TNBC is a heterogeneous disease with multiple molecular subtypes, each with different treatment responses. Participation in clinical trials is important to advance new targeted therapies for TNBC.
This document summarizes treatment approaches for metastatic castration-resistant prostate cancer (mCRPC). It discusses definitions of CRPC and mechanisms of resistance. For mCRPC patients with PSADT >10 months and no symptoms, secondary hormonal therapies are recommended, while those with PSADT <10 months receive second-generation antiandrogens. Docetaxel remains first-line for symptomatic mCRPC, while abiraterone, enzalutamide, radium-223, and sipuleucel-T are also options. Detection of AR-V7 in circulating tumor cells may help determine if taxanes or AR-targeted therapies are most suitable. Ongoing treatment, monitoring of
Pharmaceutical prospectives of anti estrogen, m-tor, CDK 4/6 in Breast CancerNoha El Baghdady
This document discusses various treatments for breast cancer, including anti-estrogen therapies, mTOR inhibitors, and CDK 4/6 inhibitors. It describes how these drugs work and their side effects. For anti-estrogens, it compares aromatase inhibitors like anastrozole and tamoxifen. It also discusses managing side effects like hot flashes. For mTOR inhibitors, it provides details on everolimus, including dosing and drug interactions through CYP450 pathways. Finally, it compares the first three CDK 4/6 inhibitors approved - palbociclib, ribociclib, and abemaciclib - in terms of their pharmacokinetics, dosing, and drug interaction profiles.
Immunotherapy for Metastatic Triple Negative Breast Cancerbkling
Sylvia Adams, MD, medical oncologist, and associate professor at the NYU School of Medicine, discusses the latest research including the role of immunology in the treatment of triple negative metastatic breast cancer. This webinar was hosted on October 19, 2016.
Strategies for Managing Recurrent Ovarian Cancerbkling
When ovarian cancer returns, it's not uncommon to experience a range of emotions and feel overwhelmed. But it's important to remember that recurrent ovarian cancer can often be successfully treated. Dr. Shannon N. Westin, gynecologic oncologist and clinical investigator at MD Anderson Cancer Center, goes over the latest treatment options for recurrent disease.
This phase 3 randomized trial investigated the incorporation of bevacizumab and nonplatinum combination chemotherapy in the treatment of advanced cervical cancer. It found that the addition of bevacizumab to chemotherapy significantly improved median overall survival compared to chemotherapy alone, from 13.3 months to 16.8 months. Bevacizumab also significantly improved progression-free survival and response rates. The benefit was observed across patient subgroups and did not negatively impact quality of life. Higher rates of gastrointestinal fistulas and thromboembolic events occurred with bevacizumab. The trial demonstrated that bevacizumab provided meaningful clinical benefit when added to chemotherapy for advanced cervical cancer.
Biomarkers can be used for screening, diagnosis, prognosis, and predicting response to treatment for cancer. In bladder cancer, screening biomarkers could identify high-risk groups but population screening may lead to many false positives. Diagnostic biomarkers are needed because hematuria is non-specific, and cystoscopy is expensive. Prognostic biomarkers help determine disease course as response can vary between patients with similar pathology. Predictive biomarkers identify subgroups likely to benefit from specific therapies.
This document discusses the management of luminal breast cancers. It covers several topics:
1) The different breast cancer subtypes, including luminal A and B cancers, which make up 50-60% and 15-20% of cases respectively. Luminal A has a better prognosis while luminal B is more aggressive.
2) The need for molecular signatures to better classify cancers and predict outcomes. Trials have shown certain gene expression profiles can determine if chemotherapy is needed.
3) Guidelines for adjuvant systemic therapies for luminal cancers, including chemotherapy, endocrine therapy, radiation, and duration of treatment. Trials support extended endocrine therapy to lower recurrence risk.
4) Neoadjuvant endocrine therapy
Treatment landscape of alk+ nsclc 12 novemberssuser4c22ca
This document provides an overview of treatments for ALK+ non-small cell lung cancer (NSCLC). It discusses the epidemiology of ALK+ NSCLC, occurring in 3-5% of NSCLC cases worldwide. First generation ALK inhibitors like crizotinib provided significant benefits for patients. Current NCCN guidelines recommend first-line treatment with newer ALK inhibitors such as alectinib, brigatinib, or lorlatinib which have led to median overall survival rates of over 5 years for some patients with metastatic ALK+ NSCLC. The document reviews the classes of ALK inhibitors including first, second, and third generation treatments and their effectiveness against ALK+ NSCLC.
molecular biology and Target therapy in lung cancerRikin Hasnani
This document summarizes molecular biology and targeted therapies in lung cancer. It discusses that lung cancer is a leading cause of cancer death worldwide. Historically, lung cancers were classified by histology alone, but it is now known they are driven by specific mutations. Key driver mutations were discovered in the EGFR, ALK, KRAS genes. These mutations activate intracellular signaling pathways like RAS/RAF/MEK/ERK and regulate cell growth. Targeted therapies like EGFR TKIs erlotinib and gefitinib or the ALK inhibitor crizotinib have significantly improved outcomes for patients with specific driver mutations. However, resistance often develops through secondary mutations like T790M, requiring new
1. Chronic myeloid leukemia (CML) is a cancer of the white blood cells characterized by the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22.
2. CML progresses through chronic, accelerated, and blast crisis phases and presents with splenomegaly, basophilia and elevated white blood cell count.
3. Treatment has advanced significantly with tyrosine kinase inhibitors like imatinib that target the BCR-ABL1 fusion protein resulting from the Philadelphia chromosome. These drugs have improved survival rates and altered the treatment landscape for CML.
This document describes alkylating agents, a class of chemotherapy drugs that work by alkylating DNA and proteins. It discusses their mechanism of action, including how they crosslink DNA and cause DNA damage, leading to cell death. It also covers resistance mechanisms, adverse effects like bone marrow toxicity and nausea/vomiting, and important alkylating agents like cisplatin, carboplatin, oxaliplatin, cyclophosphamide, and carmustine. For each drug, it provides absorption, indications, dosage ranges, and special considerations.
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the proliferation of immature lymphocytes. It most commonly affects children aged 2-6 years and has a peak incidence in adults at around 35 years of age. The disease involves replacement of normal bone marrow by leukemic blasts. Treatment involves chemotherapy with regimens depending on risk stratification including induction, consolidation, CNS prophylaxis and maintenance phases. Prognosis depends on factors like age, white blood cell count, genetics and response to initial treatment.
The document discusses platinum compounds, specifically cisplatin and its mechanism of action. Cisplatin coordinates to DNA and forms adducts, inhibiting replication and transcription and inducing apoptosis. It is renally excreted and can cause nephrotoxicity. Carboplatin and oxaliplatin are two derivatives that are less nephrotoxic but more myelosuppressive. Both exert their effects by forming DNA adducts but have different leaving groups, affecting their reactivity.
This document compares hypokalemic periodic paralysis (Hypo PP) and hyperkalemic periodic paralysis (Hyper PP). Hypo PP is caused by mutations in the CACNA1S or SCN4A genes and is characterized by acute onset flaccid paralysis, low serum potassium levels, and triggers including high carbohydrate intake and exercise. Hyper PP is caused by mutations in the SCN4A gene and presents with weakness of proximal muscles, normal or high potassium levels, and triggers including rest after exercise and potassium intake. Both involve defective sodium or calcium channels and can be distinguished based on clinical features, laboratory findings, and genetic testing.
- ALK gene mutations can cause lymphomas such as ALCL and rare cases of DLBCL. The ALK gene encodes a tyrosine kinase receptor important for neural development. In ALCL, the ALK gene often fuses with other genes like NPM, forming chimeric proteins that drive uncontrolled cell growth. ALCL with ALK mutations has a better prognosis and responds well to chemotherapy, with many patients achieving long-term remission or cure. New targeted therapies that inhibit ALK are also under development.
This document discusses hepatocellular carcinoma (HCC), including its risk factors, methods of inducing HCC in mice for research purposes, biomarkers for detecting HCC, and assays used to study oxidative stress related to HCC development. Specifically, it covers the four main risk factors for HCC, common ways to induce HCC in mice, biomarkers like AFP, AST, and ALT that indicate liver damage and cancer, and assays measuring enzymes and lipid peroxidation involved in the body's response to oxidative stress.
This document discusses five key developments in oncology since 2000:
1. The rise of targeted therapies that selectively inhibit molecular cancer drivers
2. Tumor stratification based on driver mutations and molecular profiles to select targeted treatments
3. Emergence of resistance to targeted therapies due to secondary mutations or activation of alternative pathways
4. Cancer genome sequencing revealing high mutation burdens and heterogeneity within tumors
5. Discovery of tumor heterogeneity with subclones evolving over time, challenging targeted treatment approaches
Dr. Angela Christiano presents an update on genetic and immunological studies in alopecia areata. Dr. Christiano’s research has helped clarify the immunologic mechanisms behind the disease. Now, early clinical trials with existing drugs that specifically target these mechanisms are showing promising hair regrowth. Dr. Christiano is the Richard and Mildred Rhodebeck Professor of Dermatology and Professor of Genetics & Development, and Vice Chair for Basic Science Research in Dermatology at Columbia University.
The document discusses the mechanism of action, resistance mechanisms, and adverse effects of alkylating agents and anti-metabolites. Alkylating agents work by transferring alkyl groups to biologically important molecules like DNA, RNA, and proteins. This impairs cell function and can cause cross-linking of DNA. Anti-metabolites inhibit key enzymes in folate and purine synthesis pathways, interfering with DNA, RNA, and protein production. Both classes of drugs can cause myelosuppression and gastrointestinal toxicity as main adverse effects. Resistance can develop through increased DNA repair, reduced drug uptake, or alterations in target enzymes.
Smart radiotherapy aims to precisely target tumor cells while sparing healthy cells. New techniques described in the document include using hypoxic cell sensitizers to target hypoxic tumor regions, anti-angiogenic agents to inhibit tumor blood vessels, and nanoparticles to enhance radiation dose and selectively deliver drugs. Molecular imaging helps optimize treatment by identifying tumor characteristics. Combining radiotherapy with immunotherapy or targeted depletion of host cells may also improve outcomes. Overall, the document discusses developing more precise radiation approaches through better understanding of tumor biology and microenvironment.
Lung cancer development is a multistep process involving genetic and environmental factors. Tobacco smoke contains carcinogens like benzo(a)pyrene and nitrosamines that cause DNA damage leading to mutations in genes like EGFR, KRAS, ALK and ROS1. These mutations drive cancer growth through pathways like EGFR, PI3K-AKT-mTOR. Targeted therapies have been developed that inhibit these mutated genes and pathways, improving outcomes for patients. Identification of genetic changes can help determine prognosis and optimize treatment selection.
This document provides an overview of the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). For AML, it discusses pre-treatment evaluation, induction therapy including various chemotherapy regimens, post-remission consolidation therapy stratified by risk factors, and management of relapsed or refractory disease. It also covers special situations in AML including differentiation syndrome, tumor lysis syndrome, and hyperleucocytosis. For CML, it outlines prognostic scoring, treatment goals, available tyrosine kinase inhibitors and their dosing and side effects, monitoring response levels, and options for treatment discontinuation or allogeneic stem cell transplant.
While some studies have found correlations between elevated triglycerides and improved psychiatric symptoms with Clozapine, the evidence does not conclusively demonstrate that triglyceride elevations directly cause or account for Clozapine's therapeutic effects. Further research is needed to fully understand these complex relationships.
This document summarizes current treatment guidelines for lupus nephritis. It defines lupus nephritis based on ACR criteria and recommends an early renal biopsy. For initial treatment of proliferative lupus nephritis (classes III/IV), guidelines differ on whether cyclophosphamide or mycophenolate mofetil is preferred. Maintenance therapy with mycophenolate mofetil or azathioprine with low-dose steroids is recommended, with mycophenolate mofetil showing better outcomes. Immunosuppression should be continued for at least one year after complete remission is achieved.
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ROLE OF DARATUMUMAB IN NEWLY DIAGNOSED MULTIPLE MYELOMA.pptxSeraj Aldeen
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2. The MAIA trial showed that in transplant-ineligible newly diagnosed multiple myeloma patients, daratumumab with lenalidomide and dexamethasone (D-Rd) resulted in significantly longer progression-free survival compared to lenalidomide and dexamethasone (Rd) alone, with median PFS not reached for D-Rd versus 34.4 months for Rd.
3. D-Rd also resulted in higher overall response and complete response rates compared to Rd.
1) The document discusses renal cell carcinoma (RCC), providing details on incidence, risk factors, genetics, histology, staging, and management approaches.
2) Management depends on disease extent and includes active surveillance for low-risk localized or metastatic RCC, surgery for localized RCC or oligometastatic disease, and systemic therapies such as immune checkpoint inhibitors or tyrosine kinase inhibitors for metastatic RCC.
3) Adjuvant pembrolizumab showed improved recurrence-free survival compared to placebo for high-risk localized RCC based on the KEYNOTE-564 trial. Oligometastasectomy may provide survival benefits, especially for favorable prognostic factors like long disease-free interval
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1) Colorectal cancer is the third most common cancer worldwide, with over 1.36 million new cases and 694,000 deaths annually. Survival has improved over the last decade due to earlier detection and new treatments.
2) Approximately 20-50% of CRC patients will develop metastases. Integration of chemotherapy, biological agents, and surgery can cure up to 30-40% of patients with limited metastatic disease.
3) Several clinical trials demonstrated improved progression-free and overall survival when bevacizumab was added to first-line chemotherapy regimens for metastatic colorectal cancer. However, the benefit was limited to irinotecan-based regimens.
Differentiated Thyroid Cancer Treatment.pptxSeraj Aldeen
- Locally advanced or metastatic radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) is difficult to treat. Until tyrosine kinase inhibitors (TKIs) became available, patients with RAI-R DTC had limited treatment options.
- The SELECT trial was a phase III study of lenvatinib versus placebo in patients with RAI-R DTC. Lenvatinib showed significantly improved progression-free survival and objective response rate compared to placebo and was well tolerated.
- The DECISION trial was a phase III study of sorafenib versus placebo in patients with RAI-R DTC. Sorafenib showed significantly improved progression-free survival compared to
This document discusses the anatomy and surgical treatment options for rectal cancer. It describes the rectum and anal canal anatomically. There are three main types of surgery for rectal cancer - abdominoperineal resection (APR) for lower tumors, which results in a permanent colostomy, low anterior resection (LAR) for upper tumors, which aims to preserve the anus, and total mesorectal excision (TME), the gold standard technique which completely removes the rectum and surrounding tissue. TME results in lower recurrence rates than other approaches. Neoadjuvant chemoradiation is often used in addition to surgery to improve local control and reduce distant metastasis.
TREATMENT OPTIONS FOR TNBC ESMO 2022.pptxSeraj Aldeen
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer defined by a lack of estrogen, progesterone, and HER2 receptors. It accounts for 15-20% of breast cancers and is associated with poorer prognosis and shorter survival. Current treatment options for TNBC include chemotherapy. Immunotherapy with PD-1 inhibitors such as pembrolizumab shows promise based on results from the KEYNOTE-355 trial showing improved progression-free survival compared to chemotherapy alone in patients with TNBC. PARP inhibitors in combination with platinum-based chemotherapy may provide a preferred treatment option for patients with BRCA1/2 mutated TNBC based on clinical trial results and NCCN guidelines.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Kat...rightmanforbloodline
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
2. CANCER RELATED DEATH WORLDWIDE.
-NSCLC ACCOUNTS FOR ABOUT 85% OF LUNG
CANCER.
-UNFORTUNTLY, ABOUT 75% OF NSCLC ARE
DIAGNOSED LATE WITH METASTATIC DISEASE,
WITH 5 YEARS SURVIVAL RATE IS ONLY 5 %.
-SMOKING,TOGEATHER WITH OTHER
CARCINOGENS E.G “ CHROMIUM, ARSENIC ,
NICKLE, RADON” STILL THE MOST COMMON
CAUSE.
-AND , WE ALL NOW KNOW THAT THERE ARE
11. -LUNG CANCER IN LAUNGUAGE OF
NUMBERS:
A.WORLDWIDE:
.MOST COMMON CANCER IN MALES WORLDWIDE
.MOST COMMON CAUSE OF CANCER RELATED DEATH IN MALES
WORLDWIDE
. 3RD MOST COMMON CANCER IN WOMEN WORLDWIDE
.2ND MOST COMMON CAUSE OF CANCER RELATED DEATH IN
WOMEN WORLDWIDE
B. JORDANIAN:
.3RD MOST COMMON CANCER IN BOTH SEXES AND MOST COMMON
CANCER IN JORDANIAN MALES
.MOST COMMON CANCER ELATED DEATH IN JORDANIAN MALES
C. LUNG CANCER:
12.
13. 44 YEARS OLD FEMALE PATIENT
HOUSEWIFE, MARRRIED WITH 3 OFF-SPRINGS
NEITHER SMOKER , NOR ALCOHOLIC
HYPOTHYROIDISM ON L.TYROXIN
NEGATIVE FAMILY HISTORY FOR LUNG OR
OTHER CANCERS
NO NKDA AND NOT ON OTHER MEDICATIONS
14. -HISTORY OF COVID-19 INFECTION 4 MONTHS
PRIOR TO PRESENTATION , COVID-19 RELATED
RESPIRATORY SYMPTOMS IMRPOVED GRADUALLY
BUT DIDN’T DISAPPERED, PATIENT MAINLY HAD
RESIDUAL SHORTNESS OF BREATH AND EASY
FATIGUE
.SHE SOUGHT HELP AT PULMONARY TEAM FOR
FOLLOW UP AS ” POST COVID-19 CASE”: NOTES
1.POST COVID-19
2. DYSPNEA ON ORDINARY EFFORT
3.INTERMITTENT DRY COUGHING
4.O2SAT 95%
5. DULL PERCUSSION LEFT LOWER LUNG FIELD
26. -OUR PATIENT WAS TESTED FOR :
1. EGFR: WILD TYPE
2. PDL-1:NEGATIVE
+
3. ALK –EML FUSION:POSITIVE
27.
28. .The ALK gene is located at chromosome 2
.ALK GENE CODES FOR ALK-TYROSIN KINASE RECEPTOR
.There is great similarity to insulin receptors and togeather with it
belongs to the insulin receptor subfamily of the whole tki-receptors
superfamily
. ALK-TK RECEPTOR consists of 3 domains:
an extracellular domain , transmembrane and intracellular domain
. Pleiotrophin and midkine display neurotrophic functions on receptor
binding, so this binding results in proliferation of nerve cells during
embryogenesis
.SO, The receptor ALK plays a pivotal role in cellular
communication and in the normal development and function of the
nervous system.
29. Different mutations occurs in Alk gene This results in ligand-independent
dimerization and, thus, continuous activation of the ALK-tyrosin kinase receptor:
A. POINT MUTATION :
.Point mutations have been found in 6 to 8% of primary neuroblastomas
B. GENE RE-ARRANGEMENT:
Several types of ALK gene rearrangements (ALK fusion genes) have been found
in many types of cancers:
. ALK was first identified as the fusion gene nucleophosmin (NPM)1-ALK in
ALCL in 1994:
.2;5 chromosomal translocation is associated with approximately 60% ALCL
. In 2007, a novel ALK fusion gene, EML4-ALK, was discovered in lung cancers
as a strong driver oncogene
+. EML-4 gene : is a member of the echinoderm microtubule family. encode
protein that is involved in microtubule formation AND stabilization
30. Tumor type ALK alteration Incidence
Lung cancer EML4-ALK 3–7%
Breast cancer EML4-ALK
0–2.4% FUSION GENE
Colorectal cancer EML4-ALK 0–2.4%
ALCL NPM-ALK 60–80%
Neuroblastoma Point mutations 6–8%, 4.4%
point
31.
32. -IHC:
A laboratory method that uses antibodies to check for
certain antigens (markers) in a sample of tissue. The
antibodies are usually linked to an enzyme or a fluorescent
dye.
After BINDING OF antibodies to the antigen in the tissue
sample, the enzyme or dye is activated, and the antigen can
then be seen under a microscope.
.
-IHC analysis using anti-ALK antibodies (such as clone 5A4),
which recognize the tyrosine kinase domain of ALK.
33.
34.
35. -Fluorescence in situ hybridization (FISH) :
.is a laboratory technique for detecting and locating a
complementary DNA sequence on a chromosome.
.The technique relies on exposing chromosomes to a
small DNA sequence called a probe that has a
fluorescent molecule attached to it.
.(This probe) sequence binds to its corresponding
sequence (ALK-EML FUSION GENE)
SEQUENCE.
39. .ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1). This proto-
oncogene is located on chrmosome 6.
.mutation in this gene results in over activation of ROS1-TKR..ROS-1 FUSION is
the most common mutation that occured with many other different genes .
. ROS1-TKR :has structural similarity to the anaplastic lymphoma kinase (ALK)
protein and it is mutually exclusive to ALK rearrangement
. in 2007 a ROS1 fusion was 1stly identified in a cell line derived from a lung
adenocarcinoma patient.
. Accounts for about 2% of NSCLC , 7patients tend to be younger, with a median
age of 49.8 years, never-smokers , Asian ethnicity and patients with Stage IV
disease ,
. The ROS1ders : is a worldwide collaboration of ROS1+ cancer patients and
caregivers with a goal of improving patient outcomes and accelerating research for
any type of ROS1+ cancer. It is the first such collaboration focused on cancers
driven by a single oncogene.
42. -ALK INHIBITORS:
1st GENERATION : PFIZER :investigated Crizotinib as MEK -inhibitors
,But then Pfizer shifted its investigations to focus on ALK-positive + ROS-posstive
NSCLC ,it was approved in Aug 2011 by the US FDA for this indication./
PROFILE 1007 TRIAL
-2nd GENERATION
AFTER this significant crizotinib success, there was a need to conceive new drugs
with better brain penetrance and can overcome the newly developed resistance
mutation, thus:
.Novartis: ceritinib was approved by the FDA in 2014 for treatment of NSCLC/
ASCEND-4 trial.
.Roche : alectinib was FDA approved in 2017 FOR treatment for ALK-positive
NSCLC./alex trial
. Ariad's and Takeda: brigatinib which was the latest second-generation
inhibitor and was approved in April 2017 by the US FDA for ALK-positive
NSCLC
-3rd GENERATION:
43. -Profile 1004 was published on June 1,2013
From February 2010
through February
2012
48. -CONCLUSION OF PROFILE 1007:
. This study showed that crizotinib, as compared
with chemotherapy, prolonged progression-free
survival, increased response rates, and improved
the quality of life in patients with advanced,
previously treated ALK-positive non–small-cell
lung cancer.
57. -DOSAGE:
.The recommended dosage of XALKORI for patients with NSCLC is 250 mg
orally twice daily, with or without food, until disease progression or TOXICTY
-STRENGTHS: Capsules: 250 mg, 200 mg.
-THE Recommended Dosage Reductions: ALK- or ROS1-positive metastatic
NSCLC ARE:
First dose reduction: XALKORI 200 mg taken orally twice daily
Second dose reduction: XALKORI 250 mg taken orally once daily
Permanently discontinue if unable to tolerate XALKORI 250 mg taken orally once
daily.
-MONITORING:
. Baseline: CBC, creatinine, alkaline phosphatase, ALT, total bilirubin, LDH,
calcium, magnesium, sodium, potassium, ECG
.should be checked every two weeks during cycle 1 and cycle 2 and at each
subsequent visit thereafter
. PREMEDICATIONS: no premedications needed
58. - ADVERSE REACTIONS:
The most common adverse reactions (≥25%) in
patients with NSCLC are :
1.GIT :
nausea, diarrhea, vomiting, edema, constipation,
elevated transaminases, fatigue, decreased appetite,
2. VISIUAL DISORDERES
3. Embryo-Fetal Toxicity: Can cause fetal harm.
Advise females of reproductive potential of the
potential risk to a fetus and use of effective
contraception
59. ANC (x109 /L)+- Platelets (x109 /L) Dose
greater than or
equal to 1.0
and greater than or equal to 50 250 mg twice daily
0.5 to less than 1.0 or 25 to less than 50 Withhold until
recovery, then
resume at same dose
schedule
less than 0.5 or less than 25 Withhold until
recovery, then
resume at 200 mg
twice daily
-a In case of recurrence , withhold until recovery, then resume at 250 mg once daily
-Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose
reductions.
1. Hematological:
- WARNINGS ,PRECAUTIONS AND DOSE MODIFICATIO
Severity of Adverse Reaction DOSE MIDIFICATION
Grade 3
Withhold until recovery to Grade 2 or less,
then resume at the same dosage.
Grade 4
Withhold until recovery to Grade 2 or less,
then resume at next lower dosage.
60. Baseline bilirubin > 1.5 x ULN
and ≤ 3 x ULN (with any ALT or
AST)
Reduce starting dose to dose level
-1 (200 mg twice daily)
Baseline bilirubin > 3 x ULN (with
any ALT or AST)
Reduce starting dose to dose level -
2 (250 mg once daily)
ALT elevation to > 5.0 x ULN with
bilirubin ≤1.5 x ULN
Withhold until recovery of ALT to
≤ 3.0 x ULN or baseline, then
resume at the next lower dosea
ALT elevation to > 3.0 x ULN and
concurrent bilirubin elevation to >
1.5 x ULN
Permanently discontinue
2. Hepatic Dysfunction: : Crizotinib is extensively metabolized in the liver and
hepatic impairment may result in higher plasma concentrations.
3-RENAL IMPAIRMENT: The recommended dosage of XALKORI in patients
with severe renal impairment ( (CLcr) less than 30 mL/min, not requiring dialysis)
is : 250 mg orally once daily
61. 4.CARDIOTOXOCITY:
-QT interval prolongation and symptomatic bradycardia have been observed in
patients treated with crizotinib. SO IT should be administered with caution in
patients with pre-existing LONG QT or symptomatic bradycardia . And , in
those who are taking medications that are known to prolong the QT interval or
bradycardia
-treatment interruption and subsequent dose reduction is required UNTIL QTc ≥
500 msec AND HEART RATE > 60.
-PERMANENT D/C IF PERSISTANT QTc ≥ 500 msec AND
HEART RATE > 60 DESPITE 2nd dose reduction or if torse de
point , polymorphic v.tach
-5.RESPIRATORY:
-Crizotinib has been associated with severe, life-threatening pneumonitis. occurred within
3m
-3 % of XALKORI-treated patients had ILD of any grade, 1% had Grade 3 or 4 ILD, and
0.5% had fatal ILD
62. 7.Ocular Toxicity, including Visual Loss
Visual Symptoms, Grade 1 (mild symptoms)
or Grade 2 (moderate symptoms affecting
ability to perform age-appropriate activities
of daily living)
Monitor symptoms and report any symptoms
to an eye specialist. Consider dose reduction
for Grade 2 visual disorders.
Visual Loss (Grade 3 or 4 Ocular Disorder,
marked decrease in vision) the incidence of
Grade 4 visual field defect with visual loss was
0.2%
Permanently discontinue XALKORI for
Grade 3 or 4 ocular disorders, if no other
cause found on evaluation
8.Gastrointestinal Toxicity: Grade 3 and more occurred in 27% of patients
Vomiting (Grade 3: more than 6 episodes in 24
hours for more than 3 days, , Grade 4: life-
threatening consequences, urgent intervention
indicated)
Grade 3 or 4 (despite maximum medical therapy):
Withhold until resolved, and then resume at the next
lower dose level.§
Diarrhea (Grade 3: increase of 7 or more stools
per day Grade 4: life-threatening
consequences, urgent intervention indicated)
Grade 3 or 4 (despite maximum medical therapy):
Withhold until resolved, and then resume at the next
lower dose level.
63. -Drug interactions: Crizotinib is a substrate of CYP3A. The concurrent use of
strong CYP3A inhibitors may increase crizotinib plasma concentration and
should be avoided. The concurrent use of strong CYP3A inducers may decrease
crizotinib plasma concentration and should be avoided:
64.
65.
66.
67. -FOLLOW-UP PET SCAN SHOWED:
1.DIS-APPEARANCE OF INTRA
ABDOMINAL LNS
2.ONLY MILD LEFT SIDED PLEURAL
EFFUSION
3.DECREASE IN SIZE AND
METABOLIC ACTIVITY OF LEFT
PLEURAL THICKENING
69. -CONCLUSION:
.CRIZOTINIB WAS WELL-TOLERATED
.DRAMATIC REPSONSE WAS SEEN
AFTER 4 MONTHS ONLY OF XALKORI
.THE RESPONSE WAS OBSERVED IN BOTH
SYSTEMIC AND BRAIN METASTATIC
LESIONS
.WE AND THE PATIENT ARE SATISFIFED
WITH THIS CURRENT STATUS.