A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large ce
The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the rituximab era however, this treatment approach has shown only limited benefit. In particular, patients relapsing after rituximab-containing primary treatment have an adverse prognosis, especially if this occurs within the first year after therapy or if the disease is primarily refractory. Therefore there is an ultimate need for improved salvage treatment approaches.
L'efficacia clinica del trattamento con ixabepilone nel carcinoma mammario me...Merqurio
1) Approximately 30% of women diagnosed with early-stage breast cancer will progress to metastatic breast cancer, for which treatment options are limited after anthracycline and taxane chemotherapy.
2) Resistance to chemotherapy is a major challenge, as responses to subsequent treatments are typically low (20-30%) and last less than 6 months.
3) Ixabepilone is a potential treatment for taxane-resistant metastatic breast cancer due to its activity against microtubules and lack of cross-resistance with other chemotherapies. It may provide an option for patients with limited remaining treatment options.
This document summarizes recent developments in molecular targeted therapies for head and neck cancer. It discusses two primary strategies - blocking EGFR signaling and angiogenesis pathways. Epidermal growth factor receptor (EGFR) is overexpressed in many head and neck cancers and associated with poorer outcomes. Cetuximab, an anti-EGFR monoclonal antibody, has shown efficacy in combination with radiation for locally advanced disease and in extending survival when added to chemotherapy for metastatic disease. Other targeted agents discussed include tyrosine kinase inhibitors and anti-angiogenic drugs.
Cancer Chemoprevention and Molecular Targeting Drug Delivery for CancerSukriti Singh
This document discusses cancer chemoprevention and molecular targeting for drug delivery in cancer treatment. It defines chemoprevention as using agents to reverse, suppress or prevent cancer development. Molecular targeting delivers medication selectively to target tissues to improve efficacy and reduce side effects. Various targeting strategies and carrier systems are described for achieving targeted delivery of chemopreventive and chemotherapeutic agents, including passive, active, ligand-mediated and physical targeting using nanoparticles, liposomes, dendrimers and other carriers. The advantages and challenges of targeted drug delivery systems for cancer are also summarized.
Chemotherapeutic agents pharmacology /certified fixed orthodontic courses by...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Indian dental academy provides dental crown & Bridge,rotary endodontics,fixed orthodontics,
Dental implants courses.for details pls visit www.indiandentalacademy.com ,or call
0091-9248678078
Bridging the Gap in Personalized Oncology using Omics Data and Epidemiology_C...CrimsonpublishersCancer
This document discusses advances in personalized oncology and challenges in implementing personalized medicine. It reviews how personalized oncology has been applied to several cancers including leukemia, melanoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer using biomarkers and high-throughput technologies. However, challenges remain in integrating omics data with epidemiology to fully realize personalized healthcare. Barriers include the need to analyze large datasets from different sources and effectively translate genomic findings into clinical practice.
Metronomic chemotherapy involves the chronic administration of low, minimally toxic doses of chemotherapy drugs on a frequent schedule with no prolonged breaks. This contrasts with conventional chemotherapy which uses maximum tolerated doses with breaks to allow for bone marrow recovery. Metronomic chemotherapy aims to target the tumor vasculature through its anti-angiogenic effects and has shown efficacy in palliative settings with less toxicity. Several drugs have been used in metronomic chemotherapy regimens with the most common being cyclophosphamide and methotrexate. Ongoing research is focused on optimizing dosing schedules and biomarkers to evaluate treatment response and resistance.
Principles of chemotherapy(types, indications and complications)ashirwad karigoudar
This document provides an overview of the principles of chemotherapy. It discusses the historical origins of chemotherapy beginning in the 1960s when combination chemotherapy was found to cure childhood leukemias and lymphomas. It also addresses the main obstacles of toxicity and drug resistance. The document then covers the clinical applications of chemotherapy including primary induction, neoadjuvant, adjuvant, and site-directed treatments. It concludes by discussing principles of cancer kinetics, drug resistance biology, and methods for assessing clinical response.
This document discusses pharmacology of antineoplastic agents. It begins by classifying antineoplastic agents into cell cycle specific agents, cell cycle non-specific agents, and miscellaneous agents like antibodies. It then discusses mechanisms of action, side effects, and drug resistance. Specific agents and their mechanisms, uses, and side effects are outlined. Alkylating agents like cyclophosphamide and mechanisms like crosslinking DNA are explained in detail.
L'efficacia clinica del trattamento con ixabepilone nel carcinoma mammario me...Merqurio
1) Approximately 30% of women diagnosed with early-stage breast cancer will progress to metastatic breast cancer, for which treatment options are limited after anthracycline and taxane chemotherapy.
2) Resistance to chemotherapy is a major challenge, as responses to subsequent treatments are typically low (20-30%) and last less than 6 months.
3) Ixabepilone is a potential treatment for taxane-resistant metastatic breast cancer due to its activity against microtubules and lack of cross-resistance with other chemotherapies. It may provide an option for patients with limited remaining treatment options.
This document summarizes recent developments in molecular targeted therapies for head and neck cancer. It discusses two primary strategies - blocking EGFR signaling and angiogenesis pathways. Epidermal growth factor receptor (EGFR) is overexpressed in many head and neck cancers and associated with poorer outcomes. Cetuximab, an anti-EGFR monoclonal antibody, has shown efficacy in combination with radiation for locally advanced disease and in extending survival when added to chemotherapy for metastatic disease. Other targeted agents discussed include tyrosine kinase inhibitors and anti-angiogenic drugs.
Cancer Chemoprevention and Molecular Targeting Drug Delivery for CancerSukriti Singh
This document discusses cancer chemoprevention and molecular targeting for drug delivery in cancer treatment. It defines chemoprevention as using agents to reverse, suppress or prevent cancer development. Molecular targeting delivers medication selectively to target tissues to improve efficacy and reduce side effects. Various targeting strategies and carrier systems are described for achieving targeted delivery of chemopreventive and chemotherapeutic agents, including passive, active, ligand-mediated and physical targeting using nanoparticles, liposomes, dendrimers and other carriers. The advantages and challenges of targeted drug delivery systems for cancer are also summarized.
Chemotherapeutic agents pharmacology /certified fixed orthodontic courses by...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Indian dental academy provides dental crown & Bridge,rotary endodontics,fixed orthodontics,
Dental implants courses.for details pls visit www.indiandentalacademy.com ,or call
0091-9248678078
Bridging the Gap in Personalized Oncology using Omics Data and Epidemiology_C...CrimsonpublishersCancer
This document discusses advances in personalized oncology and challenges in implementing personalized medicine. It reviews how personalized oncology has been applied to several cancers including leukemia, melanoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer using biomarkers and high-throughput technologies. However, challenges remain in integrating omics data with epidemiology to fully realize personalized healthcare. Barriers include the need to analyze large datasets from different sources and effectively translate genomic findings into clinical practice.
Metronomic chemotherapy involves the chronic administration of low, minimally toxic doses of chemotherapy drugs on a frequent schedule with no prolonged breaks. This contrasts with conventional chemotherapy which uses maximum tolerated doses with breaks to allow for bone marrow recovery. Metronomic chemotherapy aims to target the tumor vasculature through its anti-angiogenic effects and has shown efficacy in palliative settings with less toxicity. Several drugs have been used in metronomic chemotherapy regimens with the most common being cyclophosphamide and methotrexate. Ongoing research is focused on optimizing dosing schedules and biomarkers to evaluate treatment response and resistance.
Principles of chemotherapy(types, indications and complications)ashirwad karigoudar
This document provides an overview of the principles of chemotherapy. It discusses the historical origins of chemotherapy beginning in the 1960s when combination chemotherapy was found to cure childhood leukemias and lymphomas. It also addresses the main obstacles of toxicity and drug resistance. The document then covers the clinical applications of chemotherapy including primary induction, neoadjuvant, adjuvant, and site-directed treatments. It concludes by discussing principles of cancer kinetics, drug resistance biology, and methods for assessing clinical response.
This document discusses pharmacology of antineoplastic agents. It begins by classifying antineoplastic agents into cell cycle specific agents, cell cycle non-specific agents, and miscellaneous agents like antibodies. It then discusses mechanisms of action, side effects, and drug resistance. Specific agents and their mechanisms, uses, and side effects are outlined. Alkylating agents like cyclophosphamide and mechanisms like crosslinking DNA are explained in detail.
While the incorporation of pertuzumab to a chemotherapy and trastuzumab backbone (dual HER2
blockade) yielded a robust improvement in the outcomes of HER2-positive metastatic patients in the
CLEOPATRA study, in the adjuvant setting the same magnitude of benefit was not reproduced with the
addition of pertuzumab in the overall population of the APHINITY study, being the reasons for this discrepancy unknown so far. In the present manuscript, we discuss biological and clinical differences between metastatic and early-stage HER2-positive breast cancer that may potentially explain the different magnitudes of benefit observed with pertuzumab in the different disease settings.
Nick chen ppt presentation metronomic chemotherapy 2015CNPS, LLC
Metronomic chemotherapy provides several advantages over conventional chemotherapy:
- It is associated with lower toxicity due to more frequent lower doses, allowing better treatment consistency.
- It has enhanced anti-cancer effects through anti-angiogenesis and improved immune response against tumors.
- Targeting both the tumor and tumor microenvironment makes it less likely to encounter chemo-resistance.
Targeted therapy aims to inhibit specific molecular targets involved in cancer cell growth and survival. Chemotherapy treats the whole body but is less specific, while targeted therapy inhibits more specific cancer cell targets like tyrosine kinases, genes, angiogenesis factors, and survival signals. Examples include imatinib for CML and trastuzumab for HER2-positive breast cancer. Resistance can develop but may be overcome through combinations of targeted agents that inhibit multiple cancer cell pathways and processes. New targeted agents continue to be developed that exploit vulnerabilities in cancer signaling networks or stimulate anti-tumor immune responses.
Dose selection trial of metronomic oral vinorelbine monotherapy in patients w...Enrique Moreno Gonzalez
Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer.
This study compared eribulin mesylate to capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracycline and taxane chemotherapy. The open-label, randomized, phase III study found no statistically significant differences between eribulin and capecitabine in overall survival or progression-free survival. Both drugs demonstrated similar safety profiles and effects on quality of life as expected based on their known adverse effect profiles. The study concluded that eribulin was not shown to be superior to capecitabine for overall survival or progression-free survival in this patient population.
Metronomic Chemotherapy Vs Best Supportive Care in Progressive Pediatric Tumors.Pranav Sopory
Journaal Club discussing the Randomised Clinical Trial (RCT) of metronomic chemotherapy in extra cranial, non-hematopoietic solid malignancies in paediatric population (aged 5-18 years). Courtesy Dr Atul Batra, Asst. Prof. Medical Oncology, IRCH, AIIMS.
Cancer chemoprevention uses natural or laboratory-made substances to prevent cancer from developing. It is typically used by people at higher risk of cancer, such as those with a family history or previous cancer. Some chemopreventive agents studied include tamoxifen, raloxifene, aspirin and other NSAIDs. While chemoprevention may lower cancer risk, it also carries risks of side effects that must be weighed against the individual's cancer risk. Clinical trials test chemopreventive agents' safety and efficacy in delaying or preventing cancer. Targeted drug delivery seeks to concentrate medication in tissues of interest while reducing side effects by specifically targeting cancer cells over normal cells. Strategies include passive,
- The document summarizes adjuvant therapies for malignant melanoma that have been presented by Dr. v.veeranath reddy and moderated by Dr. G.Puranik at a journal club meeting.
- Traditional adjuvant therapies included wide local excision, lymph node dissection, and radiotherapy to lymph node basins. However, evidence for their impact on survival is lacking.
- Recent therapies that have shown improved survival include targeted BRAF and MEK inhibitors for BRAF mutant tumors, and immuno therapies like anti-PD-1 inhibitors for BRAF wild type tumors. These are now established as first line therapies for stage 4 disease.
- Ongoing adjuvant trials are investigating
Metronomic chemotherapy involves administering lower doses of chemotherapy drugs more frequently to target tumor growth. This summary approach has three potential mechanisms of action - inhibiting angiogenesis, stimulating the immune system, and directly targeting tumor cells. It yields long-term improved outcomes despite slower initial decreases in tumor size compared to maximum tolerated dose regimens. Clinical trials have shown metronomic chemotherapy to be an effective treatment approach in several cancer types including breast, colon, ovarian and prostate cancer when used as a single agent or in combinations.
This document provides treatment algorithms for multiple myeloma based on the latest evidence from clinical trials and expert opinion. It summarizes:
1) Treatment approaches are guided by eligibility for stem cell transplantation and risk stratification based on cytogenetic abnormalities.
2) For transplant-eligible patients, initial therapy is usually bortezomib, lenalidomide, dexamethasone followed by stem cell collection and transplantation. Daratumumab combinations may be preferred for high-risk disease.
3) For transplant-ineligible patients, bortezomib, lenalidomide, dexamethasone or daratumumab, lenalidomide, dexamethasone are standard initial options, followed
Nanoparticle (NP) Delivery of Chemotherapy
Drugs to Prostate Cancer Patients by Toluleke Oloruntobi Famuyiwa* and James Kwasi Kumi-Diaka in Integrative Journal of Conference Proceedings
Pharmacogenomics uses a patient's genetic profile to select optimal drug therapies and dosages. Gene polymorphisms like substitutions, deletions and insertions can affect drug efficacy and toxicity. Biomarkers can help predict cancer prognosis and treatment response. For example, EGFR mutations predict response to EGFR inhibitors in NSCLC, while BRAF mutations indicate response to BRAF inhibitors in melanoma. Resistance often develops from additional mutations that prevent drug binding. Combination therapies can overcome resistance by targeting alternate pathways.
Chemotherapy is the main treatment for disseminated cancers. It involves using multiple drugs in cycles to target rapidly dividing cancer cells. Common drugs include alkylating agents, antimetabolites, microtubule inhibitors, and monoclonal antibodies. Combination chemotherapy aims to maximize responses while avoiding overlapping toxicities. Doses are based on body surface area and adjusted for individual factors. Treatment intervals allow time for normal tissues to recover between cycles. Toxicities include myelosuppression, nausea/vomiting, and alopecia. Response is evaluated based on tumor shrinkage or progression.
FinalImpact of Comorbidities in Decision Making in Multiple Myeloma ManagementRasha Ibrahim
This document discusses the impact of comorbidities on decision making in the management of multiple myeloma. It notes that multiple myeloma occurs most commonly in older adults, who often have other medical conditions. Comorbidities like diabetes, renal failure, peripheral neuropathy, cardiovascular disease, and venous thromboembolism can affect treatment outcomes in multiple myeloma. The document provides guidance on managing multiple myeloma treatment for patients with these common comorbidities.
First immunotherapy for early stage triple-negative breast cancerDoriaFang
On July 27, Merck (MSD) announced that the FDA approved its blockbuster PD-1 antibody therapy Keytruda in combination with chemotherapy, as a neoadjuvant therapy before surgery, then continued as single agent as an adjuvant therapy after surgery, to treat high-risk early-stage triple-negative breast cancer (TNBC) patients.
The document discusses cancer prevention through diet and lifestyle factors. It notes that cancer risks can be reduced through not smoking, limiting red meat, exercising regularly, and modifying one's diet to include foods with anticancer compounds like fruits, vegetables, soy, tea, and wine in moderation. Choosing a diet with these anticancer foods is presented as one of the best ways to fight cancer and prevent its growth.
This deals with the current paradigm of treatment of osteosarcoma. It is an honest effort to clear the prevailing confusion in the treatment of osteosarcoma. I would be happy to get anyone
Principles of cancer chemotherapy: a deep insight, by RxVichuZ!!RxVichuZ
This presentation deals with PRINCIPLES OF CANCER CHEMOTHERAPY.
The following headings are included:
A. PRINCIPLES OF ONCOLOGY
B. CELL-CYCLE
C. PRINCIPLES OF CANCER CHEMOTHERAPY
Precise details have been provided.
Do go through!!
This document discusses targeted cancer therapy. It begins with an introduction to cancer classification and targeted therapy. It then discusses the epidemiology of cancer in India, signs and symptoms, and risk factors. It describes the goals and challenges of targeted therapy development. Targets for targeted therapy include monoclonal antibodies and small molecule inhibitors that target proteins involved in cancer signaling pathways. Treatment involves administration of targeted drugs through pills or IV. Side effects and limitations of targeted therapy are also discussed. The document concludes that targeted therapies provide more selective treatment compared to chemotherapy.
Zauderer, M.G., et al. Clinical Cancer Research, 2017.sellasq4
1. This randomized phase II trial evaluated the WT1 peptide vaccine galinpepimut-S combined with GM-CSF and Montanide in patients with malignant pleural mesothelioma after multimodality therapy.
2. The trial randomized 41 patients to galinpepimut-S plus adjuvants or adjuvants alone. The control arm was stopped early due to a futility analysis showing progression within 1 year in over 10 of the first 20 patients.
3. Trends toward improved progression-free survival (10.1 vs 7.4 months) and overall survival (22.8 vs 18.3 months) were observed in the vaccine arm compared to control, but the trial was
While the incorporation of pertuzumab to a chemotherapy and trastuzumab backbone (dual HER2
blockade) yielded a robust improvement in the outcomes of HER2-positive metastatic patients in the
CLEOPATRA study, in the adjuvant setting the same magnitude of benefit was not reproduced with the
addition of pertuzumab in the overall population of the APHINITY study, being the reasons for this discrepancy unknown so far. In the present manuscript, we discuss biological and clinical differences between metastatic and early-stage HER2-positive breast cancer that may potentially explain the different magnitudes of benefit observed with pertuzumab in the different disease settings.
Nick chen ppt presentation metronomic chemotherapy 2015CNPS, LLC
Metronomic chemotherapy provides several advantages over conventional chemotherapy:
- It is associated with lower toxicity due to more frequent lower doses, allowing better treatment consistency.
- It has enhanced anti-cancer effects through anti-angiogenesis and improved immune response against tumors.
- Targeting both the tumor and tumor microenvironment makes it less likely to encounter chemo-resistance.
Targeted therapy aims to inhibit specific molecular targets involved in cancer cell growth and survival. Chemotherapy treats the whole body but is less specific, while targeted therapy inhibits more specific cancer cell targets like tyrosine kinases, genes, angiogenesis factors, and survival signals. Examples include imatinib for CML and trastuzumab for HER2-positive breast cancer. Resistance can develop but may be overcome through combinations of targeted agents that inhibit multiple cancer cell pathways and processes. New targeted agents continue to be developed that exploit vulnerabilities in cancer signaling networks or stimulate anti-tumor immune responses.
Dose selection trial of metronomic oral vinorelbine monotherapy in patients w...Enrique Moreno Gonzalez
Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer.
This study compared eribulin mesylate to capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracycline and taxane chemotherapy. The open-label, randomized, phase III study found no statistically significant differences between eribulin and capecitabine in overall survival or progression-free survival. Both drugs demonstrated similar safety profiles and effects on quality of life as expected based on their known adverse effect profiles. The study concluded that eribulin was not shown to be superior to capecitabine for overall survival or progression-free survival in this patient population.
Metronomic Chemotherapy Vs Best Supportive Care in Progressive Pediatric Tumors.Pranav Sopory
Journaal Club discussing the Randomised Clinical Trial (RCT) of metronomic chemotherapy in extra cranial, non-hematopoietic solid malignancies in paediatric population (aged 5-18 years). Courtesy Dr Atul Batra, Asst. Prof. Medical Oncology, IRCH, AIIMS.
Cancer chemoprevention uses natural or laboratory-made substances to prevent cancer from developing. It is typically used by people at higher risk of cancer, such as those with a family history or previous cancer. Some chemopreventive agents studied include tamoxifen, raloxifene, aspirin and other NSAIDs. While chemoprevention may lower cancer risk, it also carries risks of side effects that must be weighed against the individual's cancer risk. Clinical trials test chemopreventive agents' safety and efficacy in delaying or preventing cancer. Targeted drug delivery seeks to concentrate medication in tissues of interest while reducing side effects by specifically targeting cancer cells over normal cells. Strategies include passive,
- The document summarizes adjuvant therapies for malignant melanoma that have been presented by Dr. v.veeranath reddy and moderated by Dr. G.Puranik at a journal club meeting.
- Traditional adjuvant therapies included wide local excision, lymph node dissection, and radiotherapy to lymph node basins. However, evidence for their impact on survival is lacking.
- Recent therapies that have shown improved survival include targeted BRAF and MEK inhibitors for BRAF mutant tumors, and immuno therapies like anti-PD-1 inhibitors for BRAF wild type tumors. These are now established as first line therapies for stage 4 disease.
- Ongoing adjuvant trials are investigating
Metronomic chemotherapy involves administering lower doses of chemotherapy drugs more frequently to target tumor growth. This summary approach has three potential mechanisms of action - inhibiting angiogenesis, stimulating the immune system, and directly targeting tumor cells. It yields long-term improved outcomes despite slower initial decreases in tumor size compared to maximum tolerated dose regimens. Clinical trials have shown metronomic chemotherapy to be an effective treatment approach in several cancer types including breast, colon, ovarian and prostate cancer when used as a single agent or in combinations.
This document provides treatment algorithms for multiple myeloma based on the latest evidence from clinical trials and expert opinion. It summarizes:
1) Treatment approaches are guided by eligibility for stem cell transplantation and risk stratification based on cytogenetic abnormalities.
2) For transplant-eligible patients, initial therapy is usually bortezomib, lenalidomide, dexamethasone followed by stem cell collection and transplantation. Daratumumab combinations may be preferred for high-risk disease.
3) For transplant-ineligible patients, bortezomib, lenalidomide, dexamethasone or daratumumab, lenalidomide, dexamethasone are standard initial options, followed
Nanoparticle (NP) Delivery of Chemotherapy
Drugs to Prostate Cancer Patients by Toluleke Oloruntobi Famuyiwa* and James Kwasi Kumi-Diaka in Integrative Journal of Conference Proceedings
Pharmacogenomics uses a patient's genetic profile to select optimal drug therapies and dosages. Gene polymorphisms like substitutions, deletions and insertions can affect drug efficacy and toxicity. Biomarkers can help predict cancer prognosis and treatment response. For example, EGFR mutations predict response to EGFR inhibitors in NSCLC, while BRAF mutations indicate response to BRAF inhibitors in melanoma. Resistance often develops from additional mutations that prevent drug binding. Combination therapies can overcome resistance by targeting alternate pathways.
Chemotherapy is the main treatment for disseminated cancers. It involves using multiple drugs in cycles to target rapidly dividing cancer cells. Common drugs include alkylating agents, antimetabolites, microtubule inhibitors, and monoclonal antibodies. Combination chemotherapy aims to maximize responses while avoiding overlapping toxicities. Doses are based on body surface area and adjusted for individual factors. Treatment intervals allow time for normal tissues to recover between cycles. Toxicities include myelosuppression, nausea/vomiting, and alopecia. Response is evaluated based on tumor shrinkage or progression.
FinalImpact of Comorbidities in Decision Making in Multiple Myeloma ManagementRasha Ibrahim
This document discusses the impact of comorbidities on decision making in the management of multiple myeloma. It notes that multiple myeloma occurs most commonly in older adults, who often have other medical conditions. Comorbidities like diabetes, renal failure, peripheral neuropathy, cardiovascular disease, and venous thromboembolism can affect treatment outcomes in multiple myeloma. The document provides guidance on managing multiple myeloma treatment for patients with these common comorbidities.
First immunotherapy for early stage triple-negative breast cancerDoriaFang
On July 27, Merck (MSD) announced that the FDA approved its blockbuster PD-1 antibody therapy Keytruda in combination with chemotherapy, as a neoadjuvant therapy before surgery, then continued as single agent as an adjuvant therapy after surgery, to treat high-risk early-stage triple-negative breast cancer (TNBC) patients.
The document discusses cancer prevention through diet and lifestyle factors. It notes that cancer risks can be reduced through not smoking, limiting red meat, exercising regularly, and modifying one's diet to include foods with anticancer compounds like fruits, vegetables, soy, tea, and wine in moderation. Choosing a diet with these anticancer foods is presented as one of the best ways to fight cancer and prevent its growth.
This deals with the current paradigm of treatment of osteosarcoma. It is an honest effort to clear the prevailing confusion in the treatment of osteosarcoma. I would be happy to get anyone
Principles of cancer chemotherapy: a deep insight, by RxVichuZ!!RxVichuZ
This presentation deals with PRINCIPLES OF CANCER CHEMOTHERAPY.
The following headings are included:
A. PRINCIPLES OF ONCOLOGY
B. CELL-CYCLE
C. PRINCIPLES OF CANCER CHEMOTHERAPY
Precise details have been provided.
Do go through!!
This document discusses targeted cancer therapy. It begins with an introduction to cancer classification and targeted therapy. It then discusses the epidemiology of cancer in India, signs and symptoms, and risk factors. It describes the goals and challenges of targeted therapy development. Targets for targeted therapy include monoclonal antibodies and small molecule inhibitors that target proteins involved in cancer signaling pathways. Treatment involves administration of targeted drugs through pills or IV. Side effects and limitations of targeted therapy are also discussed. The document concludes that targeted therapies provide more selective treatment compared to chemotherapy.
Similar to A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large ce
Zauderer, M.G., et al. Clinical Cancer Research, 2017.sellasq4
1. This randomized phase II trial evaluated the WT1 peptide vaccine galinpepimut-S combined with GM-CSF and Montanide in patients with malignant pleural mesothelioma after multimodality therapy.
2. The trial randomized 41 patients to galinpepimut-S plus adjuvants or adjuvants alone. The control arm was stopped early due to a futility analysis showing progression within 1 year in over 10 of the first 20 patients.
3. Trends toward improved progression-free survival (10.1 vs 7.4 months) and overall survival (22.8 vs 18.3 months) were observed in the vaccine arm compared to control, but the trial was
This document summarizes recent advances in immunotherapy for solid tumors. It discusses how immunotherapy has established itself as an effective treatment strategy, building on William Coley's pioneering work in the late 1800s using bacteria to elicit anti-tumor immune responses. The document outlines several key immunotherapy approaches, including immune checkpoint inhibitors, adoptive cellular therapy, strategies to enhance tumor immunogenicity like radiotherapy and oncolytic viruses, and cancer vaccines. It also discusses how tumor-infiltrating lymphocytes and immunoscore can help predict cancer prognosis and how the immune system interacts with tumors.
Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “How to Integrate Perioperative Immunotherapy Into Multimodal Treatment Plans to Improve Outcomes 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/3xb6WS1. CME/MOC credit will be available until June 14, 2023.
Chair & Moderator, Prof. Solange Peters, MD, PhD, Mark M. Awad, MD, PhD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to Cancer Immunotherapy for this CME/MOC/CC activity titled “Parsing the Practicalities of Pathologic Response Assessment After Neoadjuvant Immunotherapy to Facilitate Progress in Early-Stage Cancers.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/3uRHyjk. CME/MOC/CC credit will be available until May 9, 2023.
Lenalidomide maintenance compared with placebo in responding elderlyravi jaiswal
This randomized phase III trial compared lenalidomide maintenance therapy versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) who achieved a response to first-line R-CHOP induction therapy. The trial found that lenalidomide maintenance led to a statistically significant improvement in progression-free survival compared to placebo, with a median PFS not reached in the lenalidomide arm versus 58.9 months in the placebo arm. There was no significant difference in overall survival between the arms. Lenalidomide maintenance was associated with more grade 3-4 adverse events compared to placebo. The benefit of lenalidomide maintenance was seen across patient subgroups.
Thank you for the detailed case presentation. Based on the investigations:
- Serum monoclonal protein >2g/dL
- Clonal BM plasma cells >20%
- FLC ratio >20
The patient meets criteria for high risk smoldering myeloma as per Mayo 2018 criteria.
Diagnosis is high risk smoldering myeloma.
Treatment options would include enrollment in a clinical trial or treatment with a proteasome inhibitor like bortezomib or immunomodulatory drug like lenalidomide. Close monitoring at 3 monthly intervals would also be recommended.
Safety and clinical activity of pembrolizumab for treatmentMarwa EL-Sayed
Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 receptor. This study evaluated the safety and efficacy of pembrolizumab in 104 patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The results showed that pembrolizumab had a manageable safety profile, with 63% of patients experiencing drug-related adverse events mostly grade 1-2. Pembrolizumab also demonstrated promising anti-tumor activity with an 18% overall response rate. Progression-free survival was 13 months. This study provides evidence that pembrolizumab is a potential new treatment option for this patient population.
Pediatric patients are often faced with resistant or recurrent cancers that cannot be cured by chemotherapy, radiation, or surgery.
Immunotherapies have become viable therapeutic options for many cancer patients.
Some of these new pharmacologic medications are changing the landscape of treatment for pediatric cancers, while the utility of others is not yet known.
1. The study analyzed treatment patterns over time in patients receiving first-line chemotherapy for advanced or metastatic esophageal or gastric cancer based on data from 2,808 patients documented in Therapiemonitor from 2006-2013.
2. Treatment intensity increased over time, with 49.3% of patients receiving triplet chemotherapy in 2013 compared to just 10.1% in 2006. HER2 testing rates increased from 49.1% in earlier studies to 79.1% in 2012-2013, though testing was still not always performed according to guidelines.
3. Usage of fluoropyrimidine/cisplatin combinations with trastuzumab declined from 67% in 2010-2011 to 50% in 2012-2013
This document discusses immunotherapies for hepatocellular carcinoma (HCC). It begins by explaining that HCC typically develops in the context of chronic liver disease and cirrhosis. For early-stage HCC, surgical resection and liver transplantation can be curative, while radiofrequency ablation and transarterial chemoembolization are common local therapies for intermediate-stage HCC. Systemic therapies were historically ineffective for advanced HCC, but tyrosine kinase inhibitors like sorafenib were found to provide a survival benefit. More recent immunotherapies like nivolumab, pembrolizumab, and combinations with ipilimumab have shown response rates of 15-31% in advanced HCC
Targeted therapy is a new generation of cancer treatment that is more specific to tumor cells than traditional chemotherapy. It works by blocking critical molecular targets involved in processes like uncontrolled cell growth, angiogenesis, tissue invasion and metastasis. Several types of targeted therapies have been developed including monoclonal antibodies, tyrosine kinase inhibitors, angiogenesis inhibitors and proteasome inhibitors. Monoclonal antibodies in particular have shown effectiveness against cancers like breast, colorectal and lymphoma cancers when used alone or in combination with other treatments. They work by direct action on signaling pathways in tumor cells or by delivering toxic compounds specifically to tumor sites. Targeted therapies are an important new approach in cancer treatment and integrating them with other treatments offers potential benefits.
Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally ad...Enrique Moreno Gonzalez
Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.
Differentiation of irradiation and cetuximab induced skin reactions in patien...Enrique Moreno Gonzalez
In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before.
This memorandum discusses the management of meningeal myeloma, a lethal condition involving the membranes surrounding the brain and spinal cord. While optimal treatment is unclear, three modalities consistently appear effective: intrathecal chemotherapy administered directly into the cerebrospinal fluid (CSF), radiation therapy, and systemic chemotherapy. Intrathecal chemotherapy with cytarabine, methotrexate and dexamethasone is the preferred method and should be administered until the CSF normalizes. Radiation therapy provides a survival benefit and should be considered part of treatment. Systemic chemotherapy, such as the D(T)PACE regimen, also has a role in management.
Lenalidomide has shown promising activity against various types of lymphoma in clinical trials. It achieved objective response rates of 44% in relapsed/refractory peripheral T-cell lymphoma and 53% in mantle cell lymphoma. Bortezomib also achieved durable responses as a single agent in relapsed/refractory mantle cell lymphoma. The addition of rituximab to standard chemotherapy such as CHOP has improved outcomes in diseases like DLBCL and increased 5-year survival rates. Combining epratuzumab with rituximab has also shown high response rates in recurrent indolent lymphomas. Radioimmunotherapy with 90Y-ibritumomab tiuxetan following R-
This document discusses the clinical development of monoclonal antibody therapies for cancer treatment. It focuses on five FDA-approved antibodies - rituximab, trastuzumab, bevacizumab, cetuximab, and panitumumab. The document summarizes the clinical trials that led to the approval of rituximab for treating lymphoma, including early phase trials showing efficacy as a single agent and a pivotal trial demonstrating an overall response rate of 48%. It also discusses the mechanisms of action of antibody cancer therapies and opportunities and challenges for developing such therapies in China.
This document summarizes the results of a clinical trial investigating the efficacy and safety of pembrolizumab (anti-PD-1 antibody) in patients with advanced melanoma that progressed after treatment with ipilimumab. The overall response rate was 26% in the 2 mg/kg group and 10% in the 10 mg/kg group, with responses ongoing after 1 year. Pembrolizumab demonstrated a manageable safety profile, with grade 3-4 drug-related adverse events occurring in 12% of patients. This trial provides evidence that pembrolizumab is an effective treatment option for patients with advanced melanoma who have progressed on ipilimumab.
Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “Can the Addition of Immunotherapy to Multimodal Management of Stage I-III NSCLC Help Break the Stalled Cycle of Poor Outcomes?” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3m1OV2m. CME/MOC credit will be available until February 27, 2023.
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Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
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This study compared the expression of E-cadherin, β-catenin, and MUC1 in multicentric/multifocal breast cancers versus unifocal breast cancers of identical tumor size and grade. The study found significantly downregulated expression of E-cadherin in multicentric/multifocal cancers compared to unifocal cancers. In contrast, no significant differences were seen in β-catenin expression between the two groups. Within the unifocal group, E-cadherin and β-catenin expression were positively correlated, but this was not seen in the multicentric/multifocal group. The results suggest multicentric/multifocal and unifocal breast cancers differ in E-
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It is widely recognized that spiritual care plays an important role in physical and psychosocial well-being of cancer patients, but there is little evidence based research on the effects of spiritual care. We will conduct a randomized controlled trial on spiritual care using a brief structured interview scheme supported by an e-application. The aim is to examine whether an assisted reflection on life events and ultimate life goals can improve quality of life of cancer patients.
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Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
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4) The results suggest p53
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These lecture slides, by Dr Sidra Arshad, offer a simplified look into the mechanisms involved in the regulation of respiration:
Learning objectives:
1. Describe the organisation of respiratory center
2. Describe the nervous control of inspiration and respiratory rhythm
3. Describe the functions of the dorsal and respiratory groups of neurons
4. Describe the influences of the Pneumotaxic and Apneustic centers
5. Explain the role of Hering-Breur inflation reflex in regulation of inspiration
6. Explain the role of central chemoreceptors in regulation of respiration
7. Explain the role of peripheral chemoreceptors in regulation of respiration
8. Explain the regulation of respiration during exercise
9. Integrate the respiratory regulatory mechanisms
10. Describe the Cheyne-Stokes breathing
Study Resources:
1. Chapter 42, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 36, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 13, Human Physiology by Lauralee Sherwood, 9th edition
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
- 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
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large ce
2. A phase I/II trial to evaluate the safety, feasibility
and activity of salvage therapy consisting of the
mTOR inhibitor Temsirolimus added to standard
therapy of Rituximab and DHAP for the treatment
of patients with relapsed or refractory diffuse large
cell B-Cell lymphoma – the STORM trial
Mathias Witzens-Harig1*
*
Corresponding author
Email: Mathias.Witzens-Harig@med.uni-heidelberg.de
Marie Luise Memmer1
Email: marie-luise.memmer@med.uni-heidelberg.de
Martin Dreyling2
Email: Martin.Dreyling@med.uni-muenchen.de
Georg Hess3
Email: Georg.Hess@unimedizin-mainz.de
1
Department of Internal Medicine V, University of Heidelberg, INF 410, 69120
Heidelberg, Germany
2
Department of Internal Medicine III, University of Munich (LMU),
Marchioninistr. 15, Munich 81377, Germany
3
Department of Hematology, Oncology, and Pneumology, University of Mainz,
Langenbeckstr 1, 55131 Mainz, Germany
Abstract
Background
The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell
lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is
chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the
rituximab era however, this treatment approach has shown only limited benefit. In particular,
patients relapsing after rituximab-containing primary treatment have an adverse prognosis,
especially if this occurs within the first year after therapy or if the disease is primarily
refractory. Therefore there is an ultimate need for improved salvage treatment approaches.
3. Methods/design
The STORM study is a prospective, multicentre phase I/II study to evaluate the safety,
feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus
added to the standard therapy rituximab and DHAP for the treatment of patients with relapsed
or refractory DLBCL. The primary objective of the phase I of the trial is to establish the
maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP.
The secondary objective is to demonstrate that stem cells can be mobilized during this
regimen in patients scheduled to proceed to high dose therapy. In phase II, the previously
established maximum tolerated dose of temsirolimus will be used. The primary objective is to
evaluate the overall response rate (ORR) in patients with relapsed DLBCL. The secondary
objective is to evaluate progression free survival (PFS), overall survival (OS) and toxicity.
The study will be accompanied by an analysis of lymphoma subtypes determined by gene
expression analysis (GEP).
Discussion
The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of
the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the
treatment of patients with relapsed or refractory DLBCL. It also might identify predictive
markers for this treatment modality.
Trial Registration
ClinicalTrials.gov NCT01653067
Background
Non-Hodgkin’s Lymphomas are the fifth most common tumor type worldwide, and their
incidence is still increasing [1]. Although in recent years advances in tumor therapy and
supportive care have improved overall survival, a large proportion of patients will ultimately
die of their disease. The prognosis of diffuse large B-cell lymphoma (DLBCL) has improved
with the advent of the monoclonal antibody rituximab. However, there is increasing evidence
that treatment of patients with relapsed and refractory disease remains challenging. The
current standard treatment of patients with relapsed or refractory DLBCL primarily consists
of intensified salvage therapy using widely accepted regimens like R-DHAP or R-ICE. For
chemo-sensitive disease high dose therapy followed with either autologous [2] or, in selected
cases, allogeneic transplantation is applied. In the rituximab era however, high dose therapy
and autologous transplantation have only been of limited benefit in relapsed and refractory
disease, and allogeneic transplantation is limited to a selected small subset of patients. The
dismal prognosis was recently underlined by the interim analysis of the CORAL trial, in
which patients with relapsed DLBCL were randomized to either receive salvage R-DHAP or
R-ICE: it was demonstrated that patients relapsing after rituximab-containing primary
treatment had an adverse prognosis, especially if this occured within the first year after
therapy or if the disease was primarily refractory. Even with this intensive treatment in this
patient subset only 10-15% of patients achieve long-term survival [3].
4. Recently, the specific mTOR inhibitor temsirolimus has shown to be clinical active in
relapsed mantle cell lymphoma in a large multicenter phase III trial, which included patients
with up to 7 prior lines of therapy. In this poor-risk population, the ORR was 22% using a
regimen consisting of 175mg temsirolimus for 3 weeks given weekly, followed by
75mg/weekly or 25mg/weekly until tumor progression or unacceptable toxicity occured.
During the later therapy phase the average dose was 52mg/week. The most prominent side
effect in this trial was thrombocytopenia. PFS, which was the primary endpoint of this trial,
was significantly superior using this regimen, in comparison to a standard treatment arm,
which consisted of a variety of commonly accepted single agents. Interestingly, the
superiority of temsirolimus appeared to be accentuated in patients with a lower number of
pre-treatments [4]. In another trial, the combination of rituximab and even low dosis of
temsirolimus resulted in impressive response rates in relapsed and refractory mantle cell
lymphoma [5].
Furthermore, a recently presented phase II trial by Smith and colleagues demonstrated single
agent activity of temsirolimus in DLBCL and follicular lymphoma by achieving a ORR of
56% in relapsed patients. Especially a single agent activity of 28% in relapsed aggressive
lymphoma is promising and merits further evaluation [6].
It seems therefore a logical consequence to incorporate temsirolimus into earlier treatment
lines or to combine it with other therapies. Accordingly, a combination of temsirolimus with
bendamustine and rituximab achieved a response in all patients evaluable with relapsed
mantle cell and follicular lymphoma [7]. Of note, in recent in vitro experiments, additive
action of temsirolimus, dexamethasone, cytarabine and platinum could be demonstrated [8].
Building on to this, the STORM trial combines temsirolimus with a well-established salvage
treatment protocol (R-DHAP) with a known safety profile for the treatment of patients with
refractory or relapsed DLBCL. The aim of this trial is to determine the safety, feasibility and
clinical activity of the proposed regimen.
Methods/design
Trial organization
The STORM trial has been designed by the Trial Centre of the Department of Hematology
and Oncology of the University of Heidelberg in cooperation with the Department of
Hematology and Oncology of the University of Mainz and the other participating centres.
The trial is an investigator initiated trial, and is sponsored by the University Hospital of
Heidelberg. The trial is coordinated by the Department of Hematology and Oncology of the
University of Heidelberg, which is responsible for the overall trial management, trial
registration (ClinicalTrials.gov Identifier NCT01653067) and the scientific program of all
trial-related meetings. Database management, quality assurance, monitoring and reporting is
performed by the Interdisciplinary Centre for Clinical Trials (IZKS) at the University of
Mainz.
A total of 9 German centres participate in this trial. The centres are (listed alphabetically):
University Hospital Charité, Berlin; University Hospital Erlangen; University Hospital
Frankfurt, University Hospital Freiburg; University Hospital Heidelberg; University Hospital
Mainz; University Hospital Munich LMU; University Hospital Munich TU and University
Hospital Ulm.
5. On-site monitoring
During recruitment on-site monitoring is performed following good clinical practice (GCP)
guidelines. The data management will be performed by the Interdisciplinary Centre for
Clinical Trials (IZKS) at the University of Mainz.
Ethics, informed consent and safety
The final protocol was jointly approved by the central ethics committee of this trial at the
University of Heidelberg, Medical School (AFmu-017/2012, http://www.klinikum.uni-
heidelberg.de) and by the ethics committees of all participating centres. This study complies
with the Helsinki Declaration in its most recent German version, the Medical Association's
professional code of conduct, the principles of Good Clinical Practice (GCP) guidelines and
the Federal Data Protection Act. The trial will also be carried out in keeping with local legal
and regulatory requirements. The medical secrecy and the Federal Data Protection Act will be
followed.
Informed consent is obtained from each patient in oral and written form before inclusion in
the trial and after the nature, scope, and possible consequences of the trial have been
explained by a physician. The investigator will refrain from any measures specifically
required only for the clinical trial until valid consent has been obtained.
Study design and objectives
The STORM study is a prospective phase I/II study to evaluate the safety, feasibility and
activity of a salvage therapy consisting of the mTOR inhibitor temsirolimus added to
standard therapy of rituximab and DHAP for the treatment of patients with relapsed or
refractory DLBCL. The STORM-trial consists of two phases.
Phase I is a dose-escalation study of temsirolimus. The primary objective is to establish the
maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP.
The secondary objective is to demonstrate that stem cells can be mobilized during this
regimen in patients scheduled to proceed to high dose therapy.
In phase II, the previously established maximum tolerated dose of temsirolimus will be used.
The primary objective is to evaluate the overall response rate (ORR) in patients with relapsed
DLBCL. The secondary objective is to evaluate progression free survival (PFS), overall
survival (OS) and toxicity.
Patient selection
To be included into the STORM trial, patients must be at least 18 years old and have a
histologically confirmed diagnosis of DLBCL according to the World Health Organization
classification. There must be a documented relapse or progression after at least one prior
treatment but a maximum of two prior treatments. Prior treatment must have included at least
three cycles of anthracycline-containing chemotherapy (e.g. CHOP-like). The histology has
to be confirmed by a reference pathologist. Evaluation of CD20 status is compulsory. At least
one measurable tumor mass (>1.5 cm x >1.0 cm), involvement of any organ or bone marrow
infiltration must be present. In addition, adequate organ function and a Eastern Cooperative
6. Oncology Group [ECOG] performance Status of less than 3 are essential for inclusion into
the trial. Patients are required to use adequate contraception before entry and throughout the
study, if appropriate. Naturally, patients must have signed an informed consent document
indicating that they understand the purpose of and procedures required for the study and are
willing to participate in the study.
Patients with lymphoma other than DLBCL or active central nervous system lymphoma are
not eligible. Other exclusion criteria are severe concomitant diseases, active uncontrolled
infections including HIV, active hepatitis B or C or other malignant disease (except:
adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix,
DCIS of the breast, or other solid tumors curatively treated with no evidence of disease for >5
years). Prior treatment with temsirolimus, known CD20 negativity, disease refractory to
DHAP in a prior treatment line, severe psychiatric illness, peripheral neuropathy or
neuropathic pain grade 2 or worse, prior autologous or allogeneic stem cell or bone marrow
transplantation, concurrent treatment with another investigational agent during the conduct of
the trial or known intolerance to sirolimus or derivates, cytarabine, cisplatine or rituximab
will prohibit inclusion, as well as pregnancy or breast feeding.
Statistical design
In phase I of the study, a 6 + 6 standardized design is chosen to establish the MTD of the
investigational product (temsirolimus). A maximum of 48 patients can consequently be
included into this phase. In phase II of the study, 40 patients will be included, receiving two
to four cycles of the full target dose of temsirolimus in combination with R-DHAP, as
established in phase I of the trial. The number of cycles will depend on the evaluation of
activity and toxicity of the regimen by the investigator in each individual patient. Based on
published data on rituximab in combination with DHAP, a response rate of at least 60 to 65
% (40% CR and CRu) can be expected. The study will be terminated if the number of non-
responders exceeds a critical value determined by Wald´s Sequential probability ratio test. In
both phases of this trial explorative statistics are used to calculate remission and response
rates. Median progression free survival, overall survival etc. are calculated by the Kaplan and
Meier method. Adverse events will be classified according to MedDRA terminology. The
frequency of adverse events will be calculated, and there will be further analyses to determine
their seriousness, intensity, duration, relationship to trial treatment, actions taken and clinical
outcome. Patients with and without consolidating high dose therapy and autologous stem cell
transplantation will be analysed separately.
Work up
Patients with histologically documented diagnosis of DLBCL receive a complete work-up
which includes cervical, thoracic, abdominal and pelvic CT scans, bone marrow histology
and extensive laboratory testing. The IPI risk score will be calculated for each patient. All in-
and exclusion criteria are evaluated. If patients meet all inclusion criteria, they will be
informed about the study and all associated risks and benefits, and their written consent is
sought. If patients decline treatment within the STORM trial, an adequate alternative
treatment regimen is offered.
7. Treatment
This is a multicenter, open label, single arm, phase I/II study. Placebo will not be used within
this trial. In phase I, the dose escalation phase of this trial, 6 patients will be included in each
dose level. There will be four cohorts, administering up to a maximum of four cycles with 25
mg, 50 mg, 75mg or 100mg temsirolimus on day 1 and 8 in combination with rituximab (375
mg/m2
day 2) and DHAP (dexamethasone 40mg day 3–6, cisplatin 100 mg/m2
day 3,
cytarabine 2 × 2 g/m2
day 4). Treatment is repeated on day 22 for up to a maximum of 4
cycles.
After inclusion of six patients, each patient has to receive at least one complete cycle without
experiencing any dose limiting toxicity, until the enrolment into the next cohort can be
initiated. In phase II of the trial 40 patients will be included to receive the previously
established full target dose. Special attention in phase I and phase II of the study is brought to
monitoring of adverse events. Stem cell mobilization and subsequent high dose therapy and
autologous stem cell transplantation can be performed in eligible patients (Figure 1).
Figure 1 Treatment algorithm of the STORM trial.
Safety and discontinuation of treatment
Toxicities are classified by grade, type, duration, onset, and relationship to study treatment
using the NCI Common Toxicity Criteria (CTC). Dose limiting toxicities of STORM in the
context of the trial treatment are defined as any CTCAE grade V toxicity that are potentially
related to the trial treatment, any hematological toxicity not recovering to at least NCI
CTCAE grade II after 28 days after start of the last STORM-cycle (except as a consequence
of bone marrow insufficiency due to bone marrow infiltration) and any non-hematological
toxicity NCI CTCAE grade III/IV not recovering to grade II within 14 days after initial
occurrence and potentially related to the trial treatment.
In phase I of the trial 6 patients will be included at each dose level. After inclusion of six
patients, each patient has to receive at least one complete cycle without experiencing any
dose limiting toxicity (DLT), until the enrolment into the next cohort can be initiated. If one
DLT occurs, this is discussed with the data safety monitoring board (DSMB). The DSMB
may recommend that six additional patients will be added to the specific dose level. If two
DLTs occur in the first six patients of a cohort, six additional patients will be added to the
specific dose level and this will be discussed with the DSMB. If three DLTs occur in the 6 +
6 cohort, the DSMB will be informed and will recommend further action. If a fourth DLT
appears in the 6 + 6 cohort, the last dose level with three or less than three DLTs will be
considered the standard dose for the phase II trial. If four DLTs occur in cohort A, the study
will continue with an additional Cohort X with a temsirolimus dose of 15 mg. If the final
dose level is achieved without any DLT, there will be no further dose escalation.
Additionally, cumulated data of each dose level will be presented to the DSMB prior to
proceeding to the next dose level. The 6 + 6 design was chosen to provide a more robust data
basis than a 3 + 3 design.
8. Trial duration
Patient recruitment is planned to be completed after 24 months. Patients will be monitored for
three years after study entry. The total duration of the trial is estimated to be five years.
Recruitment will begin in April 2013.
Assessment of therapeutic efficiency
Assessments including patient history, physical exam, CT of neck, chest and abdomen, bone
marrow biopsy and serological tumor markers are scheduled before, during and after
treatment and during follow up. Response is evaluated in accordance with the Cheson Criteria
[9]:
• Complete response (CR) is the complete disappearance of all detectable evidence of
disease on CT, and all disease-related symptoms, and normalization of biochemical
abnormalities, and normal bone marrow biopsy (BMB). Previously involved nodes on CT
more than 1.5 cm in their greatest axial diameter must regress to less than 1.5 cm, and
previously measured nodes of 1.1–1.5 cm must decrease to less than 1 cm.
• CRu (uncertain) corresponds to CR criteria but with a residual mass more than 1.5 cm in
greatest axial diameter that has regressed by more than 75%.
• Partial response (PR) is at least 50% reduction in the sum of the product of the greatest
diameters (SPD) of the six largest nodes with no increase in the size of other nodes and no
new sites of disease. Splenic and hepatic nodules must regress by at least 50% in the SPD.
• Stable disease (SD) is less than a PR but is not progressive disease. Progressive disease
(PD) is more than 50% increase in the sum of the product of the greatest diameters of any
previously abnormal node, or appearance of any new lesions during or at the end of
therapy.
• Relapsed disease (RD) is the appearance of any new lesion or increase in size of more than
50% of previously involved sites or nodes in patients who achieved CR or CRu.
PET-data will be collected if available upon discretion of the individual physician.
Quality assurance program
Quality assurance, database management, monitoring and reporting is performed by the
Interdisciplinary Centre for Clinical Trials (IZKS) at the University of Mainz.
Discussion
The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of
the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the
treatment of patients with relapsed or refractory DLBCL. It also might identify predictive
markers for this treatment modality.
9. Competing interests
The trial is funded by Pfizer Inc., New York, USA. Funding includes trial organization and
monitoring by the IZKS Mainz, the statistical analysis, data management and the supply of
the study medication. There is no other funding of the trial. The authors also participate in
other scientific trials which are supported by Pfizer Inc., New York, USA.
Authors’ contribution
MWH, MD and GH planned the study and wrote the manuscript. MLM coordinated and
conducted the study. All authors read and approved the final manuscript.
Acknowledgments
Study protocol committee:
Agnieszka Korfel (Berlin), Stefan Krause (Erlangen), Johannes Atta (Frankfurt), Gerald
Illerhaus (Freiburg), Ulrich Keller (München), Andreas Viardot (Ulm).
Trial medication (Temsirolimus, Torisel®) is supplied by Pfizer Inc., New York, USA. The
trial is supported by Pfizer Inc., New York, USA.
We thank Dr. Fabienne McClanahan for linguistic revision.
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