This document summarizes the therapeutic approach to colorectal cancer according to Dr. Jose Alfredo Almenarez Gomez. It discusses staging of colorectal cancer, surgical and adjuvant treatment options based on stage, including chemotherapy regimens. It also covers factors to consider for stage IV cancer and the importance of KRAS and BRAF biomarkers in determining treatment approach.
This document summarizes various cutaneous (skin) toxicities that can result from cancer therapies such as chemotherapy, radiation therapy, and targeted therapies. It discusses side effects including alopecia (hair loss), hyperpigmentation, hand-foot syndrome, radiation sensitivity and recall effects, hypersensitivity reactions, nail dystrophies, and extravasation injuries. Prevention and treatment strategies are provided for many of these side effects. The conclusion emphasizes the importance of recognizing both the physical and psychological impacts of cutaneous toxicities from cancer treatment.
This case study describes a 7-year-old Thai boy who presented with a rash, fever, and seizures. He was initially diagnosed with epilepsy and treated with phenytoin, cef-3, and azithromycin. His condition worsened with the development of Steven Johnson Syndrome. Testing found he was positive for phenytoin on an ELISPOT test. The document discusses SJS pathogenesis, definitions, investigations including the ALDEN algorithm and ELISPOT test, and management of the patient's condition.
Prompt withdrawal of the culprit drug is essential in managing toxic epidermal necrolysis (TEN). Wound care including sterile handling and antibiotics according to culture results are also important. Systemic steroids are contraindicated due to risk of infection and poor wound healing. Cyclosporine may provide a survival benefit but requires further study. A tumor necrosis factor inhibitor such as a single dose of etanercept can halt skin detachment and induce rapid healing in some cases.
Toxic epidermal necrolysis (TEN) is a rare and potentially fatal skin reaction characterized by skin tenderness, redness, and extensive shedding of the skin's outer layer. It is caused by apoptosis of skin cells triggered by certain drugs like antibiotics, NSAIDs, and anticonvulsants. TEN affects over 30% of the body surface area and has a high mortality rate of 25-35%. Treatment focuses on discontinuing the culprit drug, providing intensive wound and skin care, and supportive care in an ICU. No specific treatments have been proven effective, and corticosteroids may increase mortality risk.
This document provides guidelines for the diagnosis and management of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). It outlines the definition, epidemiology, etiology, pathogenesis, symptoms, examination findings, investigations, management, complications and prognosis. Key points include that anti-fas drugs may be promising treatments and steroids are still controversial. Management involves supportive care, stopping causative medications, and intravenous immunoglobulin may improve survival. Complications can include infections, ocular issues, strictures and death.
Erythromelalgia: A New Password For Old MysterySamir Mounir
This document summarizes the case presentation of a 3-year-old boy who presented with intermittent attacks of bilateral intense pain, warmth and flushing of the feet that was exacerbated by exercise, heat exposure, and stopping medication. Testing ruled out other conditions and a skin biopsy supported a diagnosis of erythromelalgia. Treatment with the antihistamine cetirizine hydrochloride provided partial relief of symptoms. The case highlights the challenges of diagnosing and treating pediatric erythromelalgia.
Pathogenesis And Clinical Manifestations Of Juvenile Dermatomyositis And Poly...franklinaranda
This document provides an overview of juvenile dermatomyositis (JDM) and polymyositis (JPM), which are rare autoimmune disorders affecting children. It discusses the epidemiology, pathogenesis, clinical manifestations and complications of JDM and JPM. Key points include:
- JDM is more common than JPM and involves vascular damage in muscles, while JPM involves direct immune invasion of muscle fibers.
- JDM typically presents with a characteristic rash and proximal muscle weakness. Common rashes include heliotrope and Gottron's papules. Long term complications can include calcinosis and lipodystrophy.
- The cause is unknown but likely involves genetic susceptibility and
This document summarizes various cutaneous (skin) toxicities that can result from cancer therapies such as chemotherapy, radiation therapy, and targeted therapies. It discusses side effects including alopecia (hair loss), hyperpigmentation, hand-foot syndrome, radiation sensitivity and recall effects, hypersensitivity reactions, nail dystrophies, and extravasation injuries. Prevention and treatment strategies are provided for many of these side effects. The conclusion emphasizes the importance of recognizing both the physical and psychological impacts of cutaneous toxicities from cancer treatment.
This case study describes a 7-year-old Thai boy who presented with a rash, fever, and seizures. He was initially diagnosed with epilepsy and treated with phenytoin, cef-3, and azithromycin. His condition worsened with the development of Steven Johnson Syndrome. Testing found he was positive for phenytoin on an ELISPOT test. The document discusses SJS pathogenesis, definitions, investigations including the ALDEN algorithm and ELISPOT test, and management of the patient's condition.
Prompt withdrawal of the culprit drug is essential in managing toxic epidermal necrolysis (TEN). Wound care including sterile handling and antibiotics according to culture results are also important. Systemic steroids are contraindicated due to risk of infection and poor wound healing. Cyclosporine may provide a survival benefit but requires further study. A tumor necrosis factor inhibitor such as a single dose of etanercept can halt skin detachment and induce rapid healing in some cases.
Toxic epidermal necrolysis (TEN) is a rare and potentially fatal skin reaction characterized by skin tenderness, redness, and extensive shedding of the skin's outer layer. It is caused by apoptosis of skin cells triggered by certain drugs like antibiotics, NSAIDs, and anticonvulsants. TEN affects over 30% of the body surface area and has a high mortality rate of 25-35%. Treatment focuses on discontinuing the culprit drug, providing intensive wound and skin care, and supportive care in an ICU. No specific treatments have been proven effective, and corticosteroids may increase mortality risk.
This document provides guidelines for the diagnosis and management of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). It outlines the definition, epidemiology, etiology, pathogenesis, symptoms, examination findings, investigations, management, complications and prognosis. Key points include that anti-fas drugs may be promising treatments and steroids are still controversial. Management involves supportive care, stopping causative medications, and intravenous immunoglobulin may improve survival. Complications can include infections, ocular issues, strictures and death.
Erythromelalgia: A New Password For Old MysterySamir Mounir
This document summarizes the case presentation of a 3-year-old boy who presented with intermittent attacks of bilateral intense pain, warmth and flushing of the feet that was exacerbated by exercise, heat exposure, and stopping medication. Testing ruled out other conditions and a skin biopsy supported a diagnosis of erythromelalgia. Treatment with the antihistamine cetirizine hydrochloride provided partial relief of symptoms. The case highlights the challenges of diagnosing and treating pediatric erythromelalgia.
Pathogenesis And Clinical Manifestations Of Juvenile Dermatomyositis And Poly...franklinaranda
This document provides an overview of juvenile dermatomyositis (JDM) and polymyositis (JPM), which are rare autoimmune disorders affecting children. It discusses the epidemiology, pathogenesis, clinical manifestations and complications of JDM and JPM. Key points include:
- JDM is more common than JPM and involves vascular damage in muscles, while JPM involves direct immune invasion of muscle fibers.
- JDM typically presents with a characteristic rash and proximal muscle weakness. Common rashes include heliotrope and Gottron's papules. Long term complications can include calcinosis and lipodystrophy.
- The cause is unknown but likely involves genetic susceptibility and
This study examined 213 patients presenting with post-burn contractures in Pakistan over four years. The commonest site of contracture was the neck. Most patients (92) had received initial burn injury management in general surgery units rather than plastic surgery units, and few (26) received appropriate treatment like skin grafts, splinting, or physiotherapy. None of the patients received proper anti-deformity splinting or physiotherapy during acute burn treatment. This highlights the need for improved initial burn management to prevent severe, long-standing contractures in developing countries like Pakistan.
This document provides an overview of inflammatory diseases of muscle, specifically polymyositis and dermatomyositis. It discusses the pathophysiology, clinical manifestations, diagnosis, treatment and prognosis of these conditions. Key points include that they present with proximal muscle weakness, increased muscle enzymes, characteristic findings on electromyography and muscle biopsy. Diagnosis is based on criteria including skin lesions, muscle symptoms and testing. Treatment involves corticosteroids and immunosuppressive agents. Prognosis can be poorer if complications like interstitial lung disease are present.
This document discusses muscle weakness and skin rash (dermatomyositis). It provides information on the clinical presentation, causes, diagnostic criteria and classification, investigations, histopathological findings, treatment and prognosis of dermatomyositis. Key points include that dermatomyositis involves proximal muscle weakness and a skin rash. Diagnosis involves elevated muscle enzymes, electromyography, muscle biopsy and the presence of a skin rash. Treatment primarily involves oral steroids. Prognosis depends on factors like age, presence of malignancy and disease recalcitrance.
1. Rheumatoid arthritis is a chronic inflammatory autoimmune disease that targets the synovial tissue, with a prevalence of 0.8% in adults worldwide.
2. Current therapeutic approaches for rheumatoid arthritis focus on early, aggressive intervention and include medications such as DMARDs, biologics, corticosteroids, and surgery.
3. DMARDs are first-line medications and include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. Biologics that target cytokines like TNF-alpha and IL-6 are used if DMARDs are ineffective or for severe disease.
This document provides an overview of the management of rheumatoid arthritis (RA). It discusses the etiology and pathology of RA and describes the diagnostic criteria. It then outlines various treatment approaches for RA including physical therapies, medications like NSAIDs, glucocorticoids, DMARDs, and biologics. Newer targeted biologic therapies that inhibit cytokines like TNF-α, IL-1, IL-6 are discussed. The goals of RA treatment and factors influencing treatment choice are also summarized.
Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation of the joints which can lead to joint damage and physical disability. It is a progressive disease affecting the synovial lining of peripheral joints, causing symmetrical inflammation and potentially deforming polyarthritis. Symptoms include tender swollen joints, morning stiffness lasting hours, fatigue, and rheumatoid nodules under the skin. Treatment focuses on relieving pain, reducing inflammation, protecting joints, maintaining function, and controlling systemic effects through use of drugs like NSAIDs, DMARDs, biologics, glucocorticoids, and surgery.
Rheumatoid arthritis current diagnosis and treatmentAnkur Varshney
This document provides information on the diagnosis and management of rheumatoid arthritis (RA). It begins with an introduction to RA, noting that it is a chronic inflammatory joint disease affecting approximately 1% of the population. It then discusses the clinical presentation and manifestations of RA, including onset, patterns of joint involvement, and articular and extra-articular symptoms. The document reviews the diagnostic criteria for RA and covers laboratory investigations and radiographic features. It concludes with an overview of the goals and various treatment modalities for RA, including NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs), immunosuppressive therapies, and biological therapies.
A 40-year-old woman presented with difficulty using her limbs over the last 7 months, discoloration of her face and hands for 6 months, and swallowing difficulties for 2 months. She was diagnosed with dermatomyositis based on her symptoms and signs of muscle weakness, characteristic rashes, and positive autoantibodies. She is being treated with steroids and immunosuppressants and is improving. Dermatomyositis is an autoimmune disease characterized by muscle inflammation and weakness along with skin rashes.
Dermatomyositis is an inflammatory myopathy that affects the skin and muscles. It is characterized by progressive proximal muscle weakness, elevated muscle enzymes, abnormal electromyography and muscle biopsy findings. The cause is unknown but genetic, immunological, infectious and environmental factors may play a role. Treatment involves sun protection, immunosuppressants like hydroxychloroquine and methotrexate, and corticosteroids like prednisone to control muscle and skin symptoms.
This document provides an overview of rheumatoid arthritis (RA). It discusses the history and first descriptions of RA. The epidemiology section notes that RA affects 0.5-1% of adults worldwide and is more common in females. Genetics plays a role, as the risk is increased in relatives and twin studies show a 60% genetic contribution. The HLA-DRB1 gene confers the greatest risk. Environmental factors like smoking can also increase risk. The pathogenesis involves a breakdown of self-tolerance leading to autoantibodies like rheumatoid factor and anti-CCP antibodies. T cells and cytokines like TNF-alpha promote inflammation and joint damage. Clinical features include variable onset patterns and progressive joint damage over time, sometimes leading
Carpal tunnel syndrome is caused by increased pressure on the median nerve as it passes through the carpal tunnel in the wrist. It is commonly seen in conditions that increase pressure in the tunnel such as diabetes, hypothyroidism, pregnancy, and anatomical variations. Symptoms include pain, numbness and tingling in the hand, especially at night. Diagnosis involves physical exam tests like Tinel's sign and Phalen's maneuver as well as electrodiagnostic studies. Treatment begins with splinting, lifestyle changes and medications but may require carpal tunnel release surgery to divide the transverse carpal ligament if conservative measures fail.
Dermatomyositis is a rare inflammatory myopathy with characteristic skin manifestations and muscular weakness.
Polymyositis is a similar disease without skin lesions.
Amyopathic dermatomyositis: typical cutaneous manifestation of DM without clinical and/or laboratory findings of muscle involvement for at least 6 months after the onset of skin rash.
Rheumatoid arthritis is a chronic inflammatory disease that affects the joints and causes pain, stiffness, and swelling. It impacts around 1% of the adult population worldwide. While conventional disease-modifying antirheumatic drugs (DMARDs) like methotrexate are usually the first line of treatment, biological DMARDs or biologics targeting molecules like tumor necrosis factor (TNF) are used for cases that are resistant to conventional DMARDs. Biologics have revolutionized RA treatment by providing rapid relief and preventing long-term joint damage. The monoclonal antibody rituximab depletes B cells and is effective for RA by reducing inflammation and rheumatoid factor levels. It is administered as two 1000 mg intravenous
Rheumatoid arthritis (RA) is a progressive inflammatory disorder characterized by symmetric synovitis and joint erosions. Approximately 1% of adults are affected. RA results in significant costs, morbidity, and mortality. The pathogenesis involves genetic and immunological factors. Early diagnosis and treatment can slow structural damage. Disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are first-line treatments, with the goal of controlling disease activity and slowing progression. Combination DMARD therapy may provide superior outcomes to single agents. New therapies are still needed to further improve safety profiles and disease control.
TED (thyroid eye disease) or Graves' ophthalmopathy is an autoimmune disorder where the eyes and area around the eyes become inflamed and swollen. It is commonly associated with Graves' hyperthyroidism but can also occur in euthyroid or hypothyroid patients. Common symptoms include eye dryness, pain, and bulging of the eyes. Signs include eyelid retraction, muscle weakness, and in severe cases, optic nerve compression. Treatment involves supportive care, medications like steroids to reduce inflammation, and in some cases orbital decompression surgery or eye muscle surgery to correct muscle weakness and eye alignment issues.
Recent advances in idiopathic inflammatory myopathies by Dr. Naman MadaanNaman Madaan
This document summarizes recent advances in idiopathic inflammatory myopathies (IIM). IIM are a heterogeneous group of autoimmune muscle disorders characterized by chronic muscle weakness and fatigue. Recent research has provided insights into the pathogenesis of IIM, including the roles of humoral and cellular immune responses as well as class 1 MHC expression. Advances in imaging modalities such as ultrasound, MRI, PET, and MRS have also enhanced understanding of IIM. Key IIM subtypes - including dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and inclusion body myositis - are described in terms of their clinical features, investigations, and histopathology. New diagnostic
The document discusses various challenges in treating psoriasis, including balancing treatment goals of reducing disease severity and burden while managing risks of long-term treatment and adverse effects. It presents 10 case studies highlighting issues such as treating psoriasis that presents or worsens with certain drugs, managing chronic or recurrent disease, and treating special populations like children and pregnant women. Treatment options and their risks/benefits are evaluated based on each patient's individual circumstances.
Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disorder of unknown etiology characterized by polyarticular symmetric joint involvement and systemic manifestations.
Rheumatoid arthritis is an autoimmune disease that causes inflammation and destruction of joints. Early diagnosis through laboratory tests like rheumatoid factor, anti-CCP antibodies, erythrocyte sedimentation rate, and C-reactive protein is important so aggressive treatment can be started to control symptoms and prevent joint damage. The 2010 ACR/EULAR classification criteria uses scores based on the number and type of joints involved, serology results, markers of inflammation, and duration of symptoms to classify a patient as having rheumatoid arthritis.
This document provides an overview of rheumatoid arthritis (RA), including its definition, pathophysiology, clinical presentation, risk factors, diagnosis, treatment options, and complications. RA is a chronic inflammatory disorder that commonly affects the joints, causing pain, swelling, stiffness and loss of mobility. Treatment involves both pharmacological and non-pharmacological approaches, with disease-modifying antirheumatic drugs (DMARDs) like methotrexate as first-line options. If DMARDs are ineffective, biological DMARDs may be used. Managing risk factors and treating complications can help improve outcomes for those living with RA.
Asco 2006 Update Genitourinary Cancer Selected Abstractsfondas vakalis
The document summarizes several studies on targeted therapies for kidney cancer presented at the 2006 ASCO conference. Key findings include:
- Sunitinib and temsirolimus were shown to be superior to interferon for metastatic kidney cancer in phase 3 trials, with longer progression-free and overall survival.
- The TARGET trial found sorafenib increased progression-free survival compared to placebo in advanced RCC and improved overall survival after patients on placebo crossed over.
- A global phase 3 trial found temsirolimus alone or with interferon improved overall survival over interferon in poor-risk metastatic RCC patients.
Renal Cell Carcinoma A New Standard Of Carefondas vakalis
This document summarizes the current standard of care for renal cell carcinoma (RCC), focusing on targeted therapies such as anti-angiogenesis agents. It reviews the biology and risk factors for RCC, the clinical efficacy and safety profiles of drugs like sorafenib and sunitinib, and phase III trial results demonstrating improved progression-free and overall survival compared to interferon-alpha. It concludes that anti-angiogenic therapies such as sorafenib, sunitinib, and temsirolimus have become the new standard first-line treatment for metastatic RCC based on superior clinical outcomes over existing immunotherapy options.
This study examined 213 patients presenting with post-burn contractures in Pakistan over four years. The commonest site of contracture was the neck. Most patients (92) had received initial burn injury management in general surgery units rather than plastic surgery units, and few (26) received appropriate treatment like skin grafts, splinting, or physiotherapy. None of the patients received proper anti-deformity splinting or physiotherapy during acute burn treatment. This highlights the need for improved initial burn management to prevent severe, long-standing contractures in developing countries like Pakistan.
This document provides an overview of inflammatory diseases of muscle, specifically polymyositis and dermatomyositis. It discusses the pathophysiology, clinical manifestations, diagnosis, treatment and prognosis of these conditions. Key points include that they present with proximal muscle weakness, increased muscle enzymes, characteristic findings on electromyography and muscle biopsy. Diagnosis is based on criteria including skin lesions, muscle symptoms and testing. Treatment involves corticosteroids and immunosuppressive agents. Prognosis can be poorer if complications like interstitial lung disease are present.
This document discusses muscle weakness and skin rash (dermatomyositis). It provides information on the clinical presentation, causes, diagnostic criteria and classification, investigations, histopathological findings, treatment and prognosis of dermatomyositis. Key points include that dermatomyositis involves proximal muscle weakness and a skin rash. Diagnosis involves elevated muscle enzymes, electromyography, muscle biopsy and the presence of a skin rash. Treatment primarily involves oral steroids. Prognosis depends on factors like age, presence of malignancy and disease recalcitrance.
1. Rheumatoid arthritis is a chronic inflammatory autoimmune disease that targets the synovial tissue, with a prevalence of 0.8% in adults worldwide.
2. Current therapeutic approaches for rheumatoid arthritis focus on early, aggressive intervention and include medications such as DMARDs, biologics, corticosteroids, and surgery.
3. DMARDs are first-line medications and include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. Biologics that target cytokines like TNF-alpha and IL-6 are used if DMARDs are ineffective or for severe disease.
This document provides an overview of the management of rheumatoid arthritis (RA). It discusses the etiology and pathology of RA and describes the diagnostic criteria. It then outlines various treatment approaches for RA including physical therapies, medications like NSAIDs, glucocorticoids, DMARDs, and biologics. Newer targeted biologic therapies that inhibit cytokines like TNF-α, IL-1, IL-6 are discussed. The goals of RA treatment and factors influencing treatment choice are also summarized.
Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation of the joints which can lead to joint damage and physical disability. It is a progressive disease affecting the synovial lining of peripheral joints, causing symmetrical inflammation and potentially deforming polyarthritis. Symptoms include tender swollen joints, morning stiffness lasting hours, fatigue, and rheumatoid nodules under the skin. Treatment focuses on relieving pain, reducing inflammation, protecting joints, maintaining function, and controlling systemic effects through use of drugs like NSAIDs, DMARDs, biologics, glucocorticoids, and surgery.
Rheumatoid arthritis current diagnosis and treatmentAnkur Varshney
This document provides information on the diagnosis and management of rheumatoid arthritis (RA). It begins with an introduction to RA, noting that it is a chronic inflammatory joint disease affecting approximately 1% of the population. It then discusses the clinical presentation and manifestations of RA, including onset, patterns of joint involvement, and articular and extra-articular symptoms. The document reviews the diagnostic criteria for RA and covers laboratory investigations and radiographic features. It concludes with an overview of the goals and various treatment modalities for RA, including NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs), immunosuppressive therapies, and biological therapies.
A 40-year-old woman presented with difficulty using her limbs over the last 7 months, discoloration of her face and hands for 6 months, and swallowing difficulties for 2 months. She was diagnosed with dermatomyositis based on her symptoms and signs of muscle weakness, characteristic rashes, and positive autoantibodies. She is being treated with steroids and immunosuppressants and is improving. Dermatomyositis is an autoimmune disease characterized by muscle inflammation and weakness along with skin rashes.
Dermatomyositis is an inflammatory myopathy that affects the skin and muscles. It is characterized by progressive proximal muscle weakness, elevated muscle enzymes, abnormal electromyography and muscle biopsy findings. The cause is unknown but genetic, immunological, infectious and environmental factors may play a role. Treatment involves sun protection, immunosuppressants like hydroxychloroquine and methotrexate, and corticosteroids like prednisone to control muscle and skin symptoms.
This document provides an overview of rheumatoid arthritis (RA). It discusses the history and first descriptions of RA. The epidemiology section notes that RA affects 0.5-1% of adults worldwide and is more common in females. Genetics plays a role, as the risk is increased in relatives and twin studies show a 60% genetic contribution. The HLA-DRB1 gene confers the greatest risk. Environmental factors like smoking can also increase risk. The pathogenesis involves a breakdown of self-tolerance leading to autoantibodies like rheumatoid factor and anti-CCP antibodies. T cells and cytokines like TNF-alpha promote inflammation and joint damage. Clinical features include variable onset patterns and progressive joint damage over time, sometimes leading
Carpal tunnel syndrome is caused by increased pressure on the median nerve as it passes through the carpal tunnel in the wrist. It is commonly seen in conditions that increase pressure in the tunnel such as diabetes, hypothyroidism, pregnancy, and anatomical variations. Symptoms include pain, numbness and tingling in the hand, especially at night. Diagnosis involves physical exam tests like Tinel's sign and Phalen's maneuver as well as electrodiagnostic studies. Treatment begins with splinting, lifestyle changes and medications but may require carpal tunnel release surgery to divide the transverse carpal ligament if conservative measures fail.
Dermatomyositis is a rare inflammatory myopathy with characteristic skin manifestations and muscular weakness.
Polymyositis is a similar disease without skin lesions.
Amyopathic dermatomyositis: typical cutaneous manifestation of DM without clinical and/or laboratory findings of muscle involvement for at least 6 months after the onset of skin rash.
Rheumatoid arthritis is a chronic inflammatory disease that affects the joints and causes pain, stiffness, and swelling. It impacts around 1% of the adult population worldwide. While conventional disease-modifying antirheumatic drugs (DMARDs) like methotrexate are usually the first line of treatment, biological DMARDs or biologics targeting molecules like tumor necrosis factor (TNF) are used for cases that are resistant to conventional DMARDs. Biologics have revolutionized RA treatment by providing rapid relief and preventing long-term joint damage. The monoclonal antibody rituximab depletes B cells and is effective for RA by reducing inflammation and rheumatoid factor levels. It is administered as two 1000 mg intravenous
Rheumatoid arthritis (RA) is a progressive inflammatory disorder characterized by symmetric synovitis and joint erosions. Approximately 1% of adults are affected. RA results in significant costs, morbidity, and mortality. The pathogenesis involves genetic and immunological factors. Early diagnosis and treatment can slow structural damage. Disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are first-line treatments, with the goal of controlling disease activity and slowing progression. Combination DMARD therapy may provide superior outcomes to single agents. New therapies are still needed to further improve safety profiles and disease control.
TED (thyroid eye disease) or Graves' ophthalmopathy is an autoimmune disorder where the eyes and area around the eyes become inflamed and swollen. It is commonly associated with Graves' hyperthyroidism but can also occur in euthyroid or hypothyroid patients. Common symptoms include eye dryness, pain, and bulging of the eyes. Signs include eyelid retraction, muscle weakness, and in severe cases, optic nerve compression. Treatment involves supportive care, medications like steroids to reduce inflammation, and in some cases orbital decompression surgery or eye muscle surgery to correct muscle weakness and eye alignment issues.
Recent advances in idiopathic inflammatory myopathies by Dr. Naman MadaanNaman Madaan
This document summarizes recent advances in idiopathic inflammatory myopathies (IIM). IIM are a heterogeneous group of autoimmune muscle disorders characterized by chronic muscle weakness and fatigue. Recent research has provided insights into the pathogenesis of IIM, including the roles of humoral and cellular immune responses as well as class 1 MHC expression. Advances in imaging modalities such as ultrasound, MRI, PET, and MRS have also enhanced understanding of IIM. Key IIM subtypes - including dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and inclusion body myositis - are described in terms of their clinical features, investigations, and histopathology. New diagnostic
The document discusses various challenges in treating psoriasis, including balancing treatment goals of reducing disease severity and burden while managing risks of long-term treatment and adverse effects. It presents 10 case studies highlighting issues such as treating psoriasis that presents or worsens with certain drugs, managing chronic or recurrent disease, and treating special populations like children and pregnant women. Treatment options and their risks/benefits are evaluated based on each patient's individual circumstances.
Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disorder of unknown etiology characterized by polyarticular symmetric joint involvement and systemic manifestations.
Rheumatoid arthritis is an autoimmune disease that causes inflammation and destruction of joints. Early diagnosis through laboratory tests like rheumatoid factor, anti-CCP antibodies, erythrocyte sedimentation rate, and C-reactive protein is important so aggressive treatment can be started to control symptoms and prevent joint damage. The 2010 ACR/EULAR classification criteria uses scores based on the number and type of joints involved, serology results, markers of inflammation, and duration of symptoms to classify a patient as having rheumatoid arthritis.
This document provides an overview of rheumatoid arthritis (RA), including its definition, pathophysiology, clinical presentation, risk factors, diagnosis, treatment options, and complications. RA is a chronic inflammatory disorder that commonly affects the joints, causing pain, swelling, stiffness and loss of mobility. Treatment involves both pharmacological and non-pharmacological approaches, with disease-modifying antirheumatic drugs (DMARDs) like methotrexate as first-line options. If DMARDs are ineffective, biological DMARDs may be used. Managing risk factors and treating complications can help improve outcomes for those living with RA.
Asco 2006 Update Genitourinary Cancer Selected Abstractsfondas vakalis
The document summarizes several studies on targeted therapies for kidney cancer presented at the 2006 ASCO conference. Key findings include:
- Sunitinib and temsirolimus were shown to be superior to interferon for metastatic kidney cancer in phase 3 trials, with longer progression-free and overall survival.
- The TARGET trial found sorafenib increased progression-free survival compared to placebo in advanced RCC and improved overall survival after patients on placebo crossed over.
- A global phase 3 trial found temsirolimus alone or with interferon improved overall survival over interferon in poor-risk metastatic RCC patients.
Renal Cell Carcinoma A New Standard Of Carefondas vakalis
This document summarizes the current standard of care for renal cell carcinoma (RCC), focusing on targeted therapies such as anti-angiogenesis agents. It reviews the biology and risk factors for RCC, the clinical efficacy and safety profiles of drugs like sorafenib and sunitinib, and phase III trial results demonstrating improved progression-free and overall survival compared to interferon-alpha. It concludes that anti-angiogenic therapies such as sorafenib, sunitinib, and temsirolimus have become the new standard first-line treatment for metastatic RCC based on superior clinical outcomes over existing immunotherapy options.
1. Colon cancer is the second and third most common cancer in males and females respectively and accounts for 9% of cancer deaths.
2. Screening and lifestyle changes have led to improved outcomes, with a 55% reduction in late-stage colon cancer cases over 3 decades from screening.
3. Adjuvant chemotherapy regimens including FOLFOX, CAPOX and XELOX have improved disease-free and overall survival rates compared to 5-FU/LV alone, particularly for stage III disease.
4. Ongoing research focuses on shortening treatment duration, identifying high-risk patients who may benefit from more intensive regimens, and incorporating molecular markers to optimize adjuvant therapy
Medicinal Mushroom Preparations against Lung CancerNeven Jakopovic
In this cohort study, 13 patients with advanced small cell lung carcinoma and 52 with non-small cell lung carcinoma used medicinal mushroom extract (Dr Myko San company) from 2004 to 2007, and their status was assessed in 2009.
Using medicinal mushroom extracts with standard oncological therapy resulted in these significant dose-depended effects:
improved cancer survival and delayed mortality
decreases in tumor size
improved quality of life scores
when compared with standard therapy alone. Significant side effects or decreases in performance status, tolerance to therapy or outcome was not observed.
This work was presented by Dr. Ivan Jakopovic at the 5th International Medicinal Mushroom Conference in Nantong, China, in 2009.
This document summarizes information about immunotherapy for non-small cell lung cancer (NSCLC). It provides data on key clinical trials that evaluated immunotherapy drugs like nivolumab and pembrolizumab in previously treated NSCLC. It shows the efficacy results including overall survival benefits from these trials compared to chemotherapy. Long-term survival outcomes are also presented from pooled analyses of nivolumab trials with over 3 years of follow-up data.
1) The document discusses several studies presented at the ASCO 2020 conference regarding prostate cancer treatment updates. These include studies on chemo-hormonal therapy, androgen signaling inhibitors, and immunotherapy combinations.
2) A key study found that combining pembrolizumab and enzalutamide showed activity in patients with metastatic castration-resistant prostate cancer whose disease had progressed on enzalutamide, with an objective response rate of 12% and durable disease control.
3) Additional results from the conference included findings on predictive biomarkers, outcomes based on site of metastasis, and safety data from combination immunotherapy and targeted therapy trials for advanced prostate cancer.
Describes the changes made over years in the management of advanced renal cell carcinoma with special focus on re-empowering of the concept of immunotherapy
The document summarizes information about lung cancer, including:
1) Lung cancer subtypes are small cell carcinoma (13%), large cell carcinoma (5%), adenocarcinoma (38.3%), and squamous cell carcinoma (19.7%).
2) Adjuvant chemotherapy in resected early-stage non-small cell lung cancer (NSCC) improves survival compared to surgery alone, though benefits vary by stage. Platinum-based regimens like cisplatin and vinorelbine are commonly used.
3) For locally advanced unresectable NSCLC, concurrent chemoradiotherapy is superior to sequential chemotherapy and radiotherapy, improving median and 5-year survival.
1. The document discusses individualized systemic therapy for non-small cell lung cancer (NSCLC), focusing on biomarkers like ERCC1, BRCA1, and EGFR mutations that can help customize chemotherapy based on a patient's tumor genetics.
2. Clinical trials show that targeting therapies like EGFR tyrosine kinase inhibitors provide significant benefits for NSCLC patients with EGFR mutations, with response rates over 70% in some studies.
3. Ongoing research aims to identify additional biomarkers to further personalize treatment selection and overcome resistance to targeted therapies.
The Role of Radiotherapy in the Treatment of Early Stage Ocular Marginal Zone...daranisaha
To evaluate the benefit of radiotherapy, compared with other treatment in ocular marginal zone lymphoma, retrospectively we analyzed our experience, with the end-points: efficacy, measured for complete response, Progression-Free Survival (PFS) and Overall Survival
The document discusses combined chemoradiotherapy for non-small cell lung cancer (NSCLC). It describes the evolution of radiotherapy techniques from older 2D techniques to modern 3D conformal radiation and IMRT. Studies show combined chemoradiotherapy improves survival over radiotherapy alone or sequential chemotherapy and radiotherapy by reducing locoregional recurrence rates. However, concurrent chemoradiotherapy is associated with increased toxicity risks which must be balanced against survival benefits.
The document discusses several clinical studies on the use of intensity-modulated radiation therapy (IMRT) to treat head and neck cancers and gynecological cancers. It finds that IMRT reduces toxicity compared to conventional radiation therapy by better sparing nearby organs-at-risk. Specifically, IMRT is shown to reduce xerostomia, dysphagia, and gastrointestinal or genitourinary toxicity both acutely and chronically for these cancer types compared to older radiation techniques. Local control and survival outcomes are also encouraging with IMRT combined with chemotherapy for advanced cases.
1. Advanced testicular cancer has a variable prognosis depending on factors like tumor markers and site of metastases. First-line chemotherapy typically consists of bleomycin, etoposide, and cisplatin (BEP).
2. For good prognosis metastatic seminoma or non-seminoma, 3 cycles of BEP is usually sufficient. For poor prognosis, 4 cycles of BEP is standard despite trials finding no benefit to more treatment.
3. For relapsed or refractory disease, salvage regimens including ifosfamide and cisplatin offer around 25% chance of cure, with prognostic factors predicting outcome. Intensive approaches show no clear benefit.
This document discusses treatment approaches for bladder cancer including radiotherapy and cystectomy. It summarizes results from several studies comparing outcomes of radiotherapy versus cystectomy, and studies combining radiotherapy with chemotherapy. The key findings are:
1) Long-term survival rates after radiotherapy or cystectomy are comparable.
2) A study found neoadjuvant chemotherapy prior to radiotherapy improved 2-year loco-regional disease-free survival compared to radiotherapy alone.
3) Bladder preserving therapy can provide good long-term bladder function for patients who are not candidates for cystectomy.
Robert P. Edwards, MD, Chair of OB/GYN/RS, Co-Director of Women's Cancer Program at University of Pittsburgh, offers information about the current state of immunotherapy for recurrent ovarian cancer patients.
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1. ABORDAJE TERAPEUTICO DEL CANCER COLORECTAL DR. JOSE ALFREDO ALMENAREZ GOMEZ ONCOLOGIA CLINICA I.P.S. UNIVERSITARIA – U. DE ANTIOQUIA CENTRO ONCOLOGICO DE ANTIOQUIA MEDELLIN - ANTIOQUIA
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18. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
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20. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
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22. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
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24. ESTADIO T N M DUKES MAC 0 is 0 0 - - I 1 2 0 0 0 0 A A A B1 IIA 3 0 0 B B2 IIB 4a 0 0 B B2 IIC 4b 0 0 B B3 IIIA 1 - 2 1 1 - 1c 2a 0 0 C C C1 C1 IIIB 3 - 4a 2 - 3 1 - 2 1 - 1c 2a 2b 0 0 0 C C C C2 C1 - C2 C1 IIIC 4a 3 - 4a 4b 2a 2b 1 - 2 0 0 0 C C C C2 C2 C3 IVA ANY ANY 1a - - IVB ANY ANY 1b - -
28. The Angiogenic Switch and Antiangiogenic Therapy Somatic mutation Small avascular tumor Tumor secretion of angiogenic factors stimulates angiogenesis Rapid tumor growth, invasion and metastasis Angiogenic inhibitors may reverse this vascularization Carmeliet and Jain. Nature. 2000;407:249 .
41. Correlation of Rash and Survival After Treatment With Cetuximab 1. Saltz L, et al. Proc ASCO. 2001. 2. Saltz L, et al. J Clin Oncol. 2004;22:1201-1208. 3. Cunningham D, et al. N Engl J Med. 2004;351:337-345. 4. Van Cutsem E, et al. EORTC/NCI Geneva. 2004. 5. Xiong H, et al. J Clin Oncol. 2004;22:2610-2616. 6. Kies MS, et al. Proc ASCO. 2002. 0 No reaction Grade 2 Grade 1 Grade 3 Survival (Months) 16 12 8 4 CRC 9923 Saltz (2001) [1] CRC 0141 Saltz (2004) [2] CRC BOND Cunningham [3] CRC Van Cutsem (2004) [4] Pancreatic Xiong (2004) [5] SCCHN Kies (2002) [6]
42. Pooled Analysis: Predictive Value of Skin Toxicity With Panitumumab *Berlin study is interim. † Patients who developed progressive disease while receiving best supportive care in the phase III study were allowed to cross over to this extension study to receive panitumumab until disease progression or drug intolerability. Michelini T, et al. ASHP 2007. Abstract P141D. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664. Berlin J, et al. ASCO 2006. Abstract 3548. Mitchell EP, et al. ASCO 2007. Abstract 4082. Hecht JR, et al. Cancer. 2007;110:980-988. Van Cutsem, et al. 2007 Berlin, et al. 2006* Mitchell, et al. 2007 Hecht, et al. 2007 Phase III Panitumumab Crossover Phase III III (ES † ) II II II Patients enrolled, n 231 177 93 160 150 Patients included in current analysis, n 218 166 52 145 146 Dose schedule 6 mg/kg q2w 6 mg/kg q2w 6 mg/kg q2w 6 mg/kg q2w 2.5 mg/kg qw Response assessment RECIST central review RECIST local review WHO central review WHO central review RECIST central review Assessment schedule Wks 8-48 and q3m after until PD q8w ~ q8w for Wks 8-48 and q3m after until PD ~ q8w for Wks 8-48 and q3m after until PD q9w
43. Severity of Skin Toxicity Throughout Treatment Is Associated With PFS Michelini T, et al. ASHP 2007. Abstract P141D. 2.6 8.4 1.8 5.4 0 2 4 6 8 10 12 PFS OS Median Survival (months) Grade 2-4 Grade 0-1 Hazard ratio (grade 2-4:0-1): 0.66 (95% Cl: 0.56-0.78); P < .0001 Hazard ratio (grade 2-4:0-1): 0.62 (95% Cl: 0.5-0.74); P < .0001 Skin Toxicity
44. CRYSTAL: PFS by On-Study Skin Reactions: Cetuximab + FOLFIRI *There were no grade 4 skin reactions. Van Cutsem E, et al. ASCO 2007. Abstract 4000. Skin reaction grade 0 or 1 (n = 244) 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 PFS Time (Months) 1.00 0.75 0.50 0.25 0.00 PFS Estimate Skin reaction grade 2 (n = 243) Skin reaction grade 3* (n = 112) 11.3 months 5.4 months 9.4 months
45. EVEREST: Study Design Day 22 Not eligible for randomization All patients continued to receive irinotecan Treatment until disease progression, unacceptable toxicity or withdrawal of consent. Skin and tumor biopsy at baseline, Week 3 and, in Arm B, at maximum cetuximab dose. Van Cutsem E, et al. WCGIC 2007. Abstract 0-034. Arm C Standard Cetuximab regimen (250 mg/m 2 /wk) Cetuximab 400 mg/m 2 initial dose then 250 mg/m 2 /wk + Irinotecan (180 mg/m 2 q2w) Arm A Standard cetuximab regimen (250 mg/m 2 /wk) Arm B Cetuximab dose escalation (dose increases of 50 mg/m 2 q2w up to maximum 500 mg/m 2 /wk) Screening
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49. 0 10 20 30 40 50 22.9 20.0 22.2 24.2 20.8 24.7 22.7 7.1 31.3 0 9.4 4.8 12.7 11.8 10 > 10 - 20 > 35 Faint Weak/ moderate Strong Irinotecan/cetuximab Cetuximab > 20 - 35 0 10 20 30 40 50 Percentage Percentage EGFR-expressing Cells (%) EGFR-staining Intensity Clinical Response Rate Clinical Response Rate Correlation of Response Rate and EGFR Expression (IHC): BOND Data Cunningham D…Van Cutsem D, et al. N Eng J Med. 2004; 351:337-345. P for trend = .87 P for trend = .64
50. OS for Panitumumab by EGFR Tumor Membrane Staining Categories (IHC) 0.0 0.2 0.4 0.6 0.8 1.0 Months From Randomization 0 2 4 6 8 10 12 14 16 18 20 22 24 Survival Probability Van Cutsem E, et al. WCGIC 2005. Abstract O-027. EGFR Tumor Membrane Staining Category (IHC) > 35% (n = 76) 10% - 35% (n = 63) 1% - < 10% (n = 43)
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58. Predictive Role of KRAS in CRC Patients Treated With Cetuximab Khambata-Ford S, et al. J Clin Oncol. 2007;25:3230 - 3237. P = .003 11 51 89 46 0 20 40 60 80 100 Disease Control Group Patients (%) Mutant at KRAS codon 12 or 13 Wild-type KRAS Nonresponders
59. Single-Arm Studies: KRAS as a Biomarker for EGFR Inhibitors Treatment (Panitumumab or Cetuximab) No. of Patients (WT:MT) Objective Response n (%) MT WT Li é vre, et al (AACR Proceedings 2007) Cmab ± CT 76 (49:27) 0 (0) 24 (49) Benvenuti, et al (Cancer Res, 2007) Pmab or cmab or cmab + CT 48 (32:16) 1 (6) 10 (31) De Roock, et al (Ann Oncol. 2007;Epub) Cmab or cmab + irinotecan 113 (67:46) 0 (0) 27 (40) Capuzzo, et al (Ann Oncol. 2007;Epub) Cmab ± CT 81 (49:32) 2 (6) 13 (26) Di Fiore, et al (Br J Cancer. 2007) Cmab + CT 59 (43:16) 0 (0) 12 (28) Khambata-Ford, et al (J Clin Oncol. 2007) Cmab 80 (50:30) 0 (0) 5 (10)
60. Outcome & KRAS Status in Iri-Refractory mCRC Treated With Cmab Lièvre A, et al. J Clin Oncol. 2008;26:374-379. KRAS status Median PFS (95% CI), n = 88 Median OS (95% CI), n = 88 KRAS mutation 10.1 weeks (8-16) 10.1 months (5.1-13) Wild type 31.4 weeks (19.4-36) 14.3 months (9.4-20) P Value .0001 .026
61. Survival & Skin Toxicity in Iri-Refractory CRC Treated With Cmab N = 113 Lièvre A, et al. J Clin Oncol. 2008;26:374-379. Skin toxicity 2-3 Skin toxicity 0-1 P = .029 13.9 8.2 0 5 10 15 20 Median Survival (months) Median OS
62. OS in Iri-Refractory CRC Treated With Cmab: KRAS and Skin Toxicity Lièvre A, et al. J Clin Oncol. 2008;26:374-379. P = .0008 5.6 10.7 15.6 0 5 10 15 20 Median OS Median Survival (months) 0 good prognostic factors (KRAS mutation and grade 0-1 skin toxicity) 1 good prognostic factors (wild type or grade 2-3 skin toxicity) 2 good prognostic factors (wild type and grade 2-3 skin toxicity)
63. KRAS in Irinotecan-Refractory mCRC Treated With Cetuximab and Irinotecan P = .020; HR: 0.620 (95% CI: 0.41-0.92) De Roock W…Van Cutsem E, et al. Ann Oncol. 2007;Epub. 43.0 10.7 0 10 20 30 40 50 Median Survival (weeks) KRAS wild type KRAS mutant 17 26 42 74 39 2 0 20 40 60 80 100 Wild type KRAS Mutant KRAS CR PR SD PD Best Response (%)
68. EGFR Ligand Expression: A Predictor for Increased PFS? EGFR Ligand Expression High Low 0 20 40 60 80 100 120 140 Median PFS (Days) 103.5 days 115.5 days 57 days 57 days EREG (P = .0002) AREG (P = .0002) Single study data, further validation required in prospective studies n = 110, cetuximab monotherapy. Khambata-Ford S, et al. J Clin Oncol 2007;25:3230 - 3237.
69. EVEREST Study: Analysis of Epiregulin Expression Association of PFS and OS with the baseline expression level of epiregulin (EREG) Van Cutsem E, et al. WCGIC 2007. Abstract 0 – 034. PFS Survival High Low 1.0 0.8 0.6 0.4 0.2 0.0 0 100 200 300 400 500 0 200 400 600 800 High Low Refseq NM_001432 (EREG), 205767_at P = .013 Refseq NM_001432 (EREG), 205767_at P = .00033 Time (Days) Time (Days) Proof of PFS Proof of OS 1.0 0.8 0.6 0.4 0.2 0.0
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Editor's Notes
The EGFR pathway is very complex pathway. Inhibitors to EGFR have proven antitumor activity in colorectal cancer.
2 2 Simplified diagram of the EGFR pathway consisting of the EGFR signal transduction cascade, and cellular effects of stimulation through the EGFR. 5 The ligand binding site serves as the receptor for ligands such as EGF and TGF- Upon ligand binding, subsequent receptor signaling, including autophosphorylation of the receptor and phosphorylation of target proteins, occurs downstream in the signal transduction cascade. 2 • EGFR is expressed in a significant percentage of human tumors. Expression has been correlated with poor prognosis, decreased survival, and/or increased metastases. 2 • EGFR plays a critical role in cellular growth, repair, and survival and has been demonstrated to function as a key pathway for the regulation of growth in many tumor types. 2 • Current therapies have significant therapeutic and safety limitations in the management of solid tumors. The use of EGFR targeted therapy is a potentially important addition to standard anticancer therapy. 2 • It has been postulated that EGFR inhibitors may synergize with radiation and certain chemotherapeutic agents, possibly through apoptotic, antiangiogenic, and/or cell cycle effects. 2
2 2 Simplified diagram of the EGFR pathway consisting of the EGFR signal transduction cascade, and cellular effects of stimulation through the EGFR. 5 The ligand binding site serves as the receptor for ligands such as EGF and TGF- Upon ligand binding, subsequent receptor signaling, including autophosphorylation of the receptor and phosphorylation of target proteins, occurs downstream in the signal transduction cascade. 2 • EGFR is expressed in a significant percentage of human tumors. Expression has been correlated with poor prognosis, decreased survival, and/or increased metastases. 2 • EGFR plays a critical role in cellular growth, repair, and survival and has been demonstrated to function as a key pathway for the regulation of growth in many tumor types. 2 • Current therapies have significant therapeutic and safety limitations in the management of solid tumors. The use of EGFR targeted therapy is a potentially important addition to standard anticancer therapy. 2 • It has been postulated that EGFR inhibitors may synergize with radiation and certain chemotherapeutic agents, possibly through apoptotic, antiangiogenic, and/or cell cycle effects. 2
EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. Clinical data suggest that several factors are of potential use in predicting the activity of EGFR inhibitors. These include skin rash, EGFR status, and EGFR activation.
EGFR, epidermal growth factor receptor. Skin rash appears early in treatment with EGFR inhibitors; more than 80% of patients treated with cetuximab or panitumumab develop a rash that eventually improves. Longer treatment durations are associated with other skin toxicity, such as fissures or paronychia, which are more difficult to treat.
CRC, colorectal cancer; SCCHN, squamous cell carcinoma of the head and neck. Multiple clinical trials in multiple indications, including retrospective studies, have shown a correlation between the severity of rash and the activity of cetuximab and panitumumab. Increasing rash severity has been correlated with longer survival time across these analyses.
ES, extension study; PD, progressive disease; q2w, every 2 weeks; q3m, every 3 months; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization. This slide shows a pooled analysis of 5 different clinical trials that evaluated panitumumab-associated skin toxicity in patients with chemorefractory colorectal cancer. In these trials, panitumumab was administered as a single agent.
CI, confidence interval; OS, overall survival; PFS, progression-free survival. This analysis shows that, across these 5 studies, patients with a grade 2-4 rash had longer progression‑free survival and longer overall survival than patients with no rash or with a grade 1 rash.
FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; PFS, progression-free survival. The Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial evaluated FOLFIRI with and without cetuximab as first-line treatment for patients with metastatic colorectal cancer. Results showed a correlation between progression-free survival and rash. The upper line shows that patients with grade 3 rash had the longest progression-free survival time whereas the lower line shows that patients without rash or with grade 1 rash had the shortest survival without progression. For more information on this study, go online to: clinicalcareoptions.com/Oncology/Conference%20Coverage/Clin%20Onc%20June%202007/Tracks/Gastrointestinal%20Cancer/Capsules/4000.aspx
q2w, every 2 weeks. The data on the correlation between rash and activity led to the question of whether the dose of an EGFR inhibitor could be adjusted according to presence and severity of rash. The phase II EVEREST study evaluated the activity of escalating doses of cetuximab in irinotecan-refractory colorectal cancer patients with no rash or with only a slight rash. Patients were evaluated on Day 22 of treatment with cetuximab and irinotecan. Those patients with a severe rash (ie, ≥ grade 2) or other toxicity received the classic standard dose of cetuximab plus irinotecan. Patients with no rash or grade 1 rash and no other toxicity were randomized to either the standard regimen of cetuximab plus irinotecan or to irinotecan plus gradually escalating doses of cetuximab.
AE, adverse event. Results from EVEREST show slightly more toxicity in the dose-escalation arm, although the toxicity was acceptable. Toxicity included slightly more diarrhea and slightly more skin rash.
CI, confidence interval; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. Among the interesting findings from EVEREST was a 30% response rate in the dose-escalation arm, which received up to a double dose of cetuximab. By contrast, patients with no rash or grade 1 rash receiving the standard dose of cetuximab plus irinotecan had a response rate of 16%. Median progression-free survival times were 3.9 months with standard cetuximab dosing vs 4.8 months in the dose-escalation arm; however, overlapping confidence intervals and the sample size of the study did not allow a formal statistical comparison. Despite the lack of statistical power, this study produced valuable hypothesis-generating data.
EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. Regarding molecular markers that can help predict the effect of EGFR inhibitors, the initial trials with cetuximab and panitumumab were based in part on the idea that EGFR receptor status, as determined by immunohistochemistry, could help enrich or predict for activity. However, as I will show, that turned out not to be the case.
EGFR, epidermal growth factor receptor. The BOND study showed no correlation between EGFR receptor status and clinical response, as determined by immunohistochemistry. For instance, the data showed that patients given irinotecan plus cetuximab had a consistent response rate of 20% to 25%, regardless of whether they had a low or high percentage of EGFR-expressing cells or a low or strong EGFR staining intensity. In other words, EGFR receptor expression did not help to distinguish and predict for higher or lower toxicity. Other published data also suggest that patients not expressing the EGFR receptor, at least by immunohistochemistry, can respond as well as patients that have a high expression of the receptor.
EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; OS, overall survival. Similarly, in the pivotal study of panitumumab vs best supportive care, there was no difference in activity for panitumumab based on EGFR staining intensity. However, further analysis evaluated whether other factors might predict efficacy.
EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization. Moroni and colleagues published interesting data on the possible role of EGFR gene copy number in the treatment of metastatic colorectal cancer. Indeed, this study and later studies demonstrated a correlation between EGFR copy number and activity of anti-EGFR agents.
EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; mCRC, metastatic colorectal cancer; OS, overall survival; TTP, time to progression. There were clear methodologic issues in studies evaluating the use of FISH to determine EGFR expression, and there is no consensus on the use of the FISH test to help select patients. Therefore, it is not currently of use in clinical practice. Various groups that conducted different, relatively small, studies are now working together to combine these data to generate clear consensus recommendations on the use of FISH in colorectal cancer treatment.
CR, complete response; EGFR, epidermal growth factor receptor; PD, progressive disease; PR, partial response; SD, stable disease. Sartore‑Bianchi and colleagues conducted a retrospective study in which they looked at the EGFR copy number and outcomes with panitumumab therapy. They came to the same conclusions as the previously discussed studies: Patients with a high EGFR copy number have longer progression-free and overall survival times when treated with panitumumab. This was demonstrated both by looking directly at EGFR copy number and by evaluating chromosome 7 polysomy/amplification, another marker of EGFR level.
CRC, colorectal cancer; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer. Among patients with non-small-cell lung cancer, a subset of patients has been identified that exhibit EGFR gene mutations. The presence of these mutations is associated with the efficacy of EGFR-targeting therapies . Although these EGFR gene mutations also have been identified in colorectal cancer, they are rare, and their predictive role in this setting is as-yet unclear.
EGFR, epidermal growth factor receptor. Few data exist regarding EGFR phosphorylation. This slide shows data from a very small study that suggested that EGFR phosphorylation might be of predictive value in the future. However, further studies are needed.
CRC, colorectal cancer; EGFR, epidermal growth factor receptor. Another parameter becoming validated as a prognostic factor is KRAS mutation status. Data on KRAS mutations have been collected from more than 800 patients with chemorefractory colorectal cancer. KRAS is important in the EGFR pathway potentially in part because when the KRAS gene is mutated, the KRAS protein is active regardless of EGFR activation. On the other hand, KRAS mutations are an early event and are found in only approximately 40% of colorectal cancer patients.
mCRC, metastatic colorectal cancer; OS, overall survival. Lievre and colleagues conducted one of the first studies of KRAS mutations in colorectal cancer. This was a small retrospective study, with only 30 patients, all of whom were refractory and treated with cetuximab plus irinotecan. In this study, approximately 40% of the patients had a KRAS mutation. Strikingly, patients with wild-type KRAS had much longer survival than patients with mutated KRAS .
CRC, colorectal cancer. A more recent study by Khambata-Ford and colleagues evaluated the importance of KRAS mutations in a series of chemorefractory patients with colorectal cancer. The majority of patients in this study who achieved disease control following treatment with cetuximab monotherapy had wild-type KRAS .
Cmab, cetuximab; CT, chemotherapy; EGFR, epidermal growth factor receptor; MT, mutated type; WT, wild type. Five other recently published studies looked at patients treated with EGFR inhibitors. This slide shows that across all 5 studies, almost no responses were seen in patients with a KRAS mutation. Conversely, response rates were substantial in patients with wild-type KRAS . Although these are relatively small, retrospective studies, the results as a whole suggest that responses seen after treatment with cetuximab or panitumumab are essentially confined to patients with wild-type KRAS .
Cmab, cetuximab; CI, confidence interval; Iri, irinotecan; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival. Liévre and colleagues conducted a retrospective study of cetuximab in irinotecan-refractory patients that demonstrated striking differences in progression-free and overall survival times for patients with wild-type tumor vs KRAS -mutated tumor.
Cmab, cetuximab; CRC, colorectal cancer; Iri, irinotecan; OS, overall survival. Similar to other studies of cetuximab, the investigators also reported a correlation between skin toxicity and outcome.
Cmab, cetuximab; CRC, colorectal cancer; Iri, irinotecan; OS, overall survival. When Liévre and colleagues looked at skin rash and KRAS status, patients with wild-type KRAS and grade 2/3 rash had superior survival times vs patients with poor prognostic factors (ie, mutated KRAS or less severe rash).
CI, confidence interval; CR, complete response; HR, hazard ratio; mCRC, metastatic colorectal cancer; PD, progressive disease; PR, partial response; SD, stable disease. Our recently published study from Leuven included 113 chemorefractory colorectal cancer patients treated with cetuximab. In our study, as well as in other studies, a response rate of 30% to 35% was seen in patients with wild-type KRAS following treatment with cetuximab plus irinotecan.
BSC, best supportive care; ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; q2w, every 2 weeks. In this analysis of the pivotal trial of panitumumab, the KRAS status of more than 400 patients with chemorefractory colorectal cancer was determined.
BSC, best supportive care; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; Pmab, panitumumab. This slide shows progression-free survival results by KRAS status in this study. Overall, patients with colorectal cancer had superior progression-free survival times when treated with panitumumab vs best supportive care alone (hazard ratio: 0.59). However, with a hazard ratio of 0.45 and a median difference of 5 weeks between populations, panitumumab was clearly more effective in those patients with wild-type KRAS . In fact, panitumumab-treated patients with mutated KRAS had very similar progression-free survival times to patients who received best supportive care alone.
BSC, best supportive care; CR, complete response; PD, progressive disease; Pmab, panitumumab; PR, partial response; SD, stable disease. The response rate to panitumumab across all evaluable patients was 10%. Patients with mutated KRAS experienced no objective responses to panitumumab whereas those with wild-type KRAS had an objective response rate of 17%. An analysis of the same data with waterfall plots showed that virtually no patients with mutated KRAS had tumor regression vs a considerable number of patients with wild-type KRAS. Clearly, at least in chemorefractory patients with colorectal cancer, the activity of EGFR inhibitors appears confined to those with wild-type KRAS . This also suggests that KRAS mutations are a marker for resistance. However, KRAS is not the only potential predictive factor, although data on other markers are limited.
CRC, colorectal cancer; TTP, time to progression. BRAF is another candidate biomarker for resistance in colorectal cancer, although BRAF mutations occur in far fewer patients than KRAS mutations. A recent study by Benvenuti and colleagues suggested that BRAF status could help distinguish some patients who are more likely to benefit from treatment.
AREG, amphiregulin; EGFR, epidermal growth factor receptor; EREG, epiregulin; PFS, progression-free survival. Khambata-Ford and colleagues published a study looking at the EGFR ligands epiregulin and amphiregulin, which showed that patients with high expression of these ligands have better progression-free survival outcomes. More data are emerging on the possible predictive role of EGFR ligands.
OS, overall survival; PFS, progression-free survival. The EVEREST study evaluated many possible predictive markers in colorectal cancer patients. These data confirm the results from Khambata-Ford and colleagues by showing that patients with a high vs low epiregulin expression have superior progression-free survival rates.
ADCC, antibody-dependent cell-mediated cytotoxicity; PFS, progression-free survival. Results from a small study by Zhang and colleagues suggested a positive association between progression-free survival and FC polymorphism in colorectal cancer patients receiving cetuximab, but it is too early to use FC status in clinical practice today.
CRC, colorectal cancer; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; PFS, progression-free survival; RR, response rate. This presentation discussed potential predictors of clinical activity of cetuximab and panitumumab in metastatic colorectal cancers, including the correlation between skin rash and outcome. It is clear that EGFR status by immunohistochemistry is not useful in selecting patients and that there appears to be no role of somatic EGFR gene mutations. However, an increased EGFR gene copy number, as assessed by FISH, correlates with response rates and progression-free survival. These data comprise retrospective evidence from different studies in chemorefractory patients and major methodologic issues need to be addressed before implementing this knowledge in clinical practice. There is strong evidence from different studies for an association between KRAS mutation and lack of activity in chemorefractory patients. However, more data from first-line trials will be needed to definitively ascertain the validity of these results. Finally, EGFR ligand expression is emerging as a predictive marker for treatment with cetuximab or panitumumab.