This document discusses the role of systemic therapy in the management of laryngeal carcinoma. It begins with an introduction to chemotherapy and the goals of cancer treatment. It then reviews different chemotherapy regimens and targeted agents that have been studied in clinical trials for laryngeal cancer. It summarizes several landmark randomized controlled trials that have evaluated induction chemotherapy, concurrent chemoradiotherapy, and sequential chemoradiotherapy approaches. The document concludes by reviewing meta-analyses that have assessed the benefits of adding chemotherapy to radiotherapy for head and neck cancers.
1) The document discusses management of carcinoma of the hypopharynx, including pre-treatment evaluation, staging, treatment options of surgery, radiotherapy, chemotherapy, and biological therapy.
2) Key tests for pre-treatment evaluation are described, including endoscopy, CT/MRI scans, PET scans, and blood tests. Staging follows the AJCC 7th edition system.
3) Treatment recommendations are based on stage, with options including single modality therapy for early stages, and multi-modality therapy including chemoradiotherapy or induction chemotherapy followed by radiotherapy for advanced stages.
The document discusses considerations for larynx preservation approaches in treating head and neck cancers. It reviews milestones in the development of nonsurgical options, including the role of chemotherapy and radiation therapy. Two generations of larynx preservation trials are examined that evaluated induction chemotherapy followed by radiation therapy or concurrent chemoradiation, finding larynx preservation rates of 50-70% with equivalent survival outcomes to total laryngectomy. Ongoing questions remain around the most effective and least toxic treatment protocols.
Induction chemotherapy followed by concurrent ct rt versus ct-rt in advanced ...Santam Chakraborty
Induction chemotherapy followed by concurrent chemoradiation (CT-RT) has been studied as an alternative to primary CT-RT for locally advanced head and neck cancers. Meta-analyses have found induction chemotherapy provides no survival benefit compared to primary CT-RT and is associated with increased toxicity. Recent large randomized trials could not demonstrate an improvement with induction chemotherapy due to inadequate accrual and poor compliance with subsequent CT-RT. While induction chemotherapy may improve organ preservation or outcomes for select subgroups like HPV-negative cancers, current evidence indicates primary CT-RT remains the standard of care for most patients.
CURRENT STATUS OF ORGAN PRESERVATION IN CA LARYNXManu Babu
The document discusses treatment options for early stage laryngeal cancer, including radical radiotherapy, transoral laser surgery, and function preserving open partial laryngectomy. It notes that treatment selection depends on factors like disease extent, patient preference, occupational considerations, and physician expertise. For early glottic cancer specifically, radiotherapy and transoral laser surgery are standard options that provide equivalent cure rates, though there is debate around their relative efficacy and impact on voice quality. The document also discusses treatment approaches for supraglottic cancers and locally advanced laryngeal cancers, noting the importance of neck treatment for supraglottic cancers and the paradigm shift to organ preservation using induction chemotherapy.
This document discusses neoadjuvant chemotherapy in head and neck cancer. It provides background on when neoadjuvant chemotherapy is given, what regimens are used, and evidence from studies comparing neoadjuvant chemotherapy plus radiation/surgery versus radiation/surgery alone. Several large studies found that adding docetaxel, cisplatin and fluorouracil as neoadjuvant chemotherapy improved overall and progression-free survival compared to cisplatin and fluorouracil alone. However, other studies found no difference in outcomes between neoadjuvant chemotherapy followed by chemoradiation versus chemoradiation alone. Concomitant chemoradiation appears superior to induction chemotherapy for larynx preservation.
Management of carcinoma nasopharynx presents many challenges:
1) Detection is difficult due to its deep, silent location and treatment is challenging due to proximity to critical structures.
2) Radiotherapy alone was historically used but results in 5-year OS of only 35-50%.
3) The current standard of care is chemoradiotherapy which provides excellent tumor control and improves outcomes over radiotherapy alone, with 5-year OS of 70-80% for early stages and 50% for advanced stages.
This document summarizes guidelines for the management of carcinoma of the hypopharynx and larynx. It covers topics like NCCN guidelines, treatment options including surgery, radiotherapy, chemotherapy and biological therapy. It describes TNM staging according to AJCC 7th edition and provides general treatment recommendations based on tumor stage. It discusses the benefits of radiotherapy over surgery and indications for primary radiotherapy. It also summarizes various studies comparing altered fractionation radiotherapy with or without chemotherapy to conventional radiotherapy for improved survival outcomes in advanced stage disease.
This document discusses radiation therapy for laryngeal cancer preservation. It notes controversies in treatment approaches for early disease. While radiation therapy is a staple in organ preservation strategies, surgical preference remains for T3N0 glottic cancers. The document summarizes treatment approaches and outcomes for different T stages of laryngeal cancer based on studies. It also discusses dose fractionation schedules, advantages of intensity-modulated radiation therapy (IMRT), and technical issues in treating advanced laryngeal cancer with radiation therapy.
1) The document discusses management of carcinoma of the hypopharynx, including pre-treatment evaluation, staging, treatment options of surgery, radiotherapy, chemotherapy, and biological therapy.
2) Key tests for pre-treatment evaluation are described, including endoscopy, CT/MRI scans, PET scans, and blood tests. Staging follows the AJCC 7th edition system.
3) Treatment recommendations are based on stage, with options including single modality therapy for early stages, and multi-modality therapy including chemoradiotherapy or induction chemotherapy followed by radiotherapy for advanced stages.
The document discusses considerations for larynx preservation approaches in treating head and neck cancers. It reviews milestones in the development of nonsurgical options, including the role of chemotherapy and radiation therapy. Two generations of larynx preservation trials are examined that evaluated induction chemotherapy followed by radiation therapy or concurrent chemoradiation, finding larynx preservation rates of 50-70% with equivalent survival outcomes to total laryngectomy. Ongoing questions remain around the most effective and least toxic treatment protocols.
Induction chemotherapy followed by concurrent ct rt versus ct-rt in advanced ...Santam Chakraborty
Induction chemotherapy followed by concurrent chemoradiation (CT-RT) has been studied as an alternative to primary CT-RT for locally advanced head and neck cancers. Meta-analyses have found induction chemotherapy provides no survival benefit compared to primary CT-RT and is associated with increased toxicity. Recent large randomized trials could not demonstrate an improvement with induction chemotherapy due to inadequate accrual and poor compliance with subsequent CT-RT. While induction chemotherapy may improve organ preservation or outcomes for select subgroups like HPV-negative cancers, current evidence indicates primary CT-RT remains the standard of care for most patients.
CURRENT STATUS OF ORGAN PRESERVATION IN CA LARYNXManu Babu
The document discusses treatment options for early stage laryngeal cancer, including radical radiotherapy, transoral laser surgery, and function preserving open partial laryngectomy. It notes that treatment selection depends on factors like disease extent, patient preference, occupational considerations, and physician expertise. For early glottic cancer specifically, radiotherapy and transoral laser surgery are standard options that provide equivalent cure rates, though there is debate around their relative efficacy and impact on voice quality. The document also discusses treatment approaches for supraglottic cancers and locally advanced laryngeal cancers, noting the importance of neck treatment for supraglottic cancers and the paradigm shift to organ preservation using induction chemotherapy.
This document discusses neoadjuvant chemotherapy in head and neck cancer. It provides background on when neoadjuvant chemotherapy is given, what regimens are used, and evidence from studies comparing neoadjuvant chemotherapy plus radiation/surgery versus radiation/surgery alone. Several large studies found that adding docetaxel, cisplatin and fluorouracil as neoadjuvant chemotherapy improved overall and progression-free survival compared to cisplatin and fluorouracil alone. However, other studies found no difference in outcomes between neoadjuvant chemotherapy followed by chemoradiation versus chemoradiation alone. Concomitant chemoradiation appears superior to induction chemotherapy for larynx preservation.
Management of carcinoma nasopharynx presents many challenges:
1) Detection is difficult due to its deep, silent location and treatment is challenging due to proximity to critical structures.
2) Radiotherapy alone was historically used but results in 5-year OS of only 35-50%.
3) The current standard of care is chemoradiotherapy which provides excellent tumor control and improves outcomes over radiotherapy alone, with 5-year OS of 70-80% for early stages and 50% for advanced stages.
This document summarizes guidelines for the management of carcinoma of the hypopharynx and larynx. It covers topics like NCCN guidelines, treatment options including surgery, radiotherapy, chemotherapy and biological therapy. It describes TNM staging according to AJCC 7th edition and provides general treatment recommendations based on tumor stage. It discusses the benefits of radiotherapy over surgery and indications for primary radiotherapy. It also summarizes various studies comparing altered fractionation radiotherapy with or without chemotherapy to conventional radiotherapy for improved survival outcomes in advanced stage disease.
This document discusses radiation therapy for laryngeal cancer preservation. It notes controversies in treatment approaches for early disease. While radiation therapy is a staple in organ preservation strategies, surgical preference remains for T3N0 glottic cancers. The document summarizes treatment approaches and outcomes for different T stages of laryngeal cancer based on studies. It also discusses dose fractionation schedules, advantages of intensity-modulated radiation therapy (IMRT), and technical issues in treating advanced laryngeal cancer with radiation therapy.
The document discusses post-operative radiotherapy for oral cavity cancer. It notes that oral cavity cancer is the 11th most common cancer worldwide and is usually squamous cell carcinoma. For early stage disease, surgery or radiotherapy alone is effective, while advanced stages require multimodal therapy. Post-operative radiotherapy improves local control, especially for those with adverse features like positive margins or extracapsular nodal extension. Concurrent chemoradiotherapy using cisplatin is now standard for these high-risk patients based on trials showing improved survival outcomes.
Concomitant chemotherapy provides the greatest benefit for patients with locally advanced head and neck cancer according to the MACHNC 2021 meta-analysis. It improves 5-year overall survival by 6.5% and event-free survival by 5.8%, with the greatest decrease in locoregional failure rates. Induction chemotherapy provides smaller benefits of 2.2% for overall survival and 1.45% for event-free survival, as well as a significant decrease in distant failure rates. Adjuvant chemotherapy does not improve survival and increases 120-day mortality. Cisplatin-based regimens are preferred for concomitant and induction chemotherapy. This may be the final MACHNC analysis as no new patients have been
This document provides guidance on contouring for nasopharyngeal carcinoma (NPC) radiation treatment planning. It discusses the anatomy and patterns of spread of NPC, as well as staging. It describes how to delineate the primary gross tumor volume (GTVp), clinical target volumes (CTVs) including high-risk (CTVp1) and intermediate-risk (CTVp2) volumes. It also covers nodal CTV delineation (CTVn1, CTVn2, CTVn3) and discusses lymph node levels and risk of spread. Margins around critical organs and intracranial extension guidelines are also summarized. The document aims to provide a comprehensive overview of target volume delineation for NPC
The CROSS trial found that neoadjuvant chemoradiotherapy followed by surgery significantly improved long-term overall and progression-free survival compared to surgery alone for patients with resectable esophageal or esophagogastric junction cancer. At a minimum follow-up of 5 years, median overall survival was 48.6 months for chemoradiotherapy plus surgery versus 24 months for surgery alone. Both squamous cell carcinoma and adenocarcinoma subtypes benefited. Neoadjuvant chemoradiotherapy using carboplatin and paclitaxel is now considered the standard of care for these patients.
Radiotherapy plays an important role in the treatment of soft tissue sarcomas by improving local control rates when used adjuvantly with surgery. Post-operative radiotherapy reduces local recurrence rates compared to surgery alone, even for low-grade tumors. Pre-operative radiotherapy may provide a better chance of limb salvage for large or unresectable tumors but risks delaying wound healing. Positive surgical margins are associated with higher local recurrence rates, but margins within 1mm do not significantly impact outcomes. Adjuvant radiotherapy should be considered for all high-grade soft tissue sarcomas based on its ability to improve local control.
Role of Post-op Radiotherapy in Head and Neck CancersAshutosh Mukherji
This document discusses the role of adjuvant radiation therapy in head and neck cancers. It begins by outlining the use of radical and palliative treatment for stage III and IV diseases. It then reviews several landmark studies that established the benefits of postoperative radiation therapy (PORT) over surgery alone in improving local control and survival. Key factors that determine the need for adjuvant therapy like extracapsular extension, positive margins, and T3/T4 stage are discussed. The document also addresses optimal radiation dose, timing, use of concurrent chemotherapy and altered fractionation schedules based on evidence from clinical trials. While targeted therapies in the adjuvant setting have not proven beneficial so far, ongoing studies are exploring their potential role.
Reirradiation can provide local tumor control for recurrent head and neck cancer when surgery is not possible. Modern radiation techniques like IMRT allow higher radiation doses to be safely delivered to the tumor while minimizing risks of severe toxicity. Outcomes from reirradiation include a median survival of 10-12 months and 2-year local control rates of 40-64%. Patient selection is important to balance potential benefits of local tumor control against risks of treatment-related side effects.
This deals with novel molecular findings and their implications in Ewings sarcoma. The role of dose dense and dose intense chemotherapy and role of high dose chemotherapy. Additionally it also deals with survivor ship issues
This document summarizes key findings from several clinical trials on the treatment of anal squamous cell carcinoma. The UKCCCR ACT I trial showed improved local control and colostomy-free survival with chemoradiation (CRT) compared to radiation alone. Subsequent trials found improved outcomes with mitomycin-C compared to 5-FU alone. The RTOG 98-11 and ACT II trials found no advantage to cisplatin over mitomycin-C in CRT or with maintenance chemotherapy. The current standard is CRT with 5-FU and mitomycin-C.
Concurrent Chemoradiation in Postoperative Setting In LAHNC. A comparision of...Santam Chakraborty
A journal club presentation comparing and contrasting the EORTC and RTOG trials of concurrent chemoradiation in Head Neck Cancers in the post operative setting.
The RAPIDO trial tested a new experimental treatment for locally advanced rectal cancer that involved short-course radiotherapy followed by chemotherapy before surgery, compared to the standard treatment of long-course chemoradiotherapy followed by surgery and then chemotherapy. The results showed that the experimental treatment led to a lower rate of disease-related treatment failures and distant metastases, along with a doubled rate of pathologic complete responses, without increasing toxicities or compromising survival rates. This provides evidence that the experimental approach may be a new standard of care for high-risk locally advanced rectal cancer.
The document discusses lung cancer subtypes and molecular features that can guide treatment. It provides statistics on the distribution of histology types among lung cancer cases. It also summarizes several key studies investigating targeted therapies such as EGFR TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer, noting improved progression-free survival with TKIs in patients with EGFR mutations. Molecular testing is increasingly important for determining personalized treatment approaches in lung cancer.
This document summarizes key points from a presentation on watch and wait strategies after chemoradiotherapy for rectal cancer. It discusses principles of adjuvant therapy, indications for neoadjuvant therapy, assessment of treatment response, and outcomes data supporting watch and wait for patients who achieve a clinical complete response. The take home message emphasizes that watch and wait offers an alternative to surgery for some patients and should be discussed, but is best carried out in specialized cancer centers.
Evolving Role of Radiation Therapy in Hodgkins DiseaseSantam Chakraborty
1) Recent advances in radiation therapy for Hodgkin's lymphoma include reducing radiation volumes and doses based on clinical trials.
2) For early stage favorable Hodgkin's lymphoma, the standard is 2 cycles of ABVD chemotherapy followed by 20Gy involved field radiation.
3) For early stage unfavorable or poor prognosis disease, 4 cycles of ABVD plus 30Gy involved field radiation is standard based on clinical trials.
This document summarizes several key studies on the use of concurrent chemo-radiation therapy for carcinoma of the cervix. Five randomized controlled trials from the 1980s-1990s showed significantly improved progression-free and overall survival when cisplatin-based chemo-radiation was used compared to radiation alone. Subsequent larger trials like GOG 120 and RTOG 9001 reinforced these findings. Long term follow up data continued to show survival benefits with acceptable toxicity rates for concurrent chemo-radiation, which is now the standard of care for locally advanced cervical cancer.
- The document summarizes key landmark clinical trials investigating treatments for metastatic gastric cancer.
- The ToGA trial found that adding trastuzumab (Herceptin) to standard chemotherapy (cisplatin and fluoropyrimidine) significantly improved overall survival and progression-free survival in patients with HER2-positive metastatic gastric cancer compared to chemotherapy alone. Median overall survival was 13.8 months with chemotherapy plus trastuzumab versus 11.1 months with chemotherapy alone.
- The REAL-2 trial demonstrated that cisplatin plus capecitabine was as effective as cisplatin plus fluorouracil for advanced gastric cancer, with less toxicity. Cisplatin plus capecitabine has since
The document discusses the role of chemotherapy in carcinoma of the stomach. It outlines several key trials investigating neoadjuvant, adjuvant and perioperative chemotherapy approaches. The MAGIC trial showed significantly improved 5-year survival with perioperative chemotherapy compared to surgery alone. The French FNCLCC trial also demonstrated improved disease-free and overall survival with perioperative chemotherapy. Adjuvant chemoradiation was shown in the INT0116/SWOG 9008 trial to improve 5-year overall and disease-free survival compared to surgery alone. The Japanese S-1 trial found significant benefit in 5-year disease-free and overall survival with adjuvant S-1 chemotherapy compared to observation after surgery.
Organ preservation in laryngopharyngeal cancersRahul Pathade
This document discusses organ preservation in laryngopharyngeal cancers. It begins with an overview of the anatomy and staging of these cancers. It then reviews past treatment approaches involving total laryngectomy and highlights studies demonstrating the benefits of organ preservation strategies using induction chemotherapy and concurrent chemoradiation. Subsequent trials showed improved larynx preservation and survival with the addition of chemotherapy to radiation compared to radiation alone. More intensive chemotherapy regimens like docetaxel, cisplatin, and 5-FU were found to further improve outcomes over standard cisplatin and 5-FU. Overall, organ preservation approaches with chemotherapy have become the standard of care for locally advanced laryngopharyngeal cancers.
RADIOTHERAPY TARGET DELINEATION IN BREAST CANCERKanhu Charan
This document discusses guidelines for target delineation in breast cancer radiotherapy, including contours for the chest wall, breast, lymph nodes, and organs at risk. It describes guidelines from organizations like EORTC, RTOG, TROG, and ESTRO for delineating targets like the supraclavicular fossa, internal mammary nodes, and three levels of axillary lymph nodes. It also discusses techniques like custom immobilization and image guidance that can help reduce planning target volume and guidelines for target volumes in post-mastectomy and breast-conserving settings.
The document discusses head and neck cancer, focusing on individualizing treatment. It notes that head and neck cancer incidence is increasing, with some caused by HPV. EGFR is a molecular target in these cancers. Studies combining EGFR inhibitors like cetuximab with chemoradiation in locally advanced disease showed increased toxicity but uncertain efficacy benefits. Biomarker-selected treatment de-intensification may be appropriate for HPV-positive cancers.
Head and neck cancer accounts for 5-6% of all cancers, with over 90% being squamous cell carcinomas. Risk factors include tobacco, alcohol, and HPV. Treatment options include surgery, radiation therapy, chemotherapy, or combinations. While early stage cancer has a good prognosis with single modality treatment, advanced stages generally require combined modality treatment, though 5-year survival remains below 35%. New targeted therapies and improved radiation techniques have provided benefits in recent years.
The document discusses post-operative radiotherapy for oral cavity cancer. It notes that oral cavity cancer is the 11th most common cancer worldwide and is usually squamous cell carcinoma. For early stage disease, surgery or radiotherapy alone is effective, while advanced stages require multimodal therapy. Post-operative radiotherapy improves local control, especially for those with adverse features like positive margins or extracapsular nodal extension. Concurrent chemoradiotherapy using cisplatin is now standard for these high-risk patients based on trials showing improved survival outcomes.
Concomitant chemotherapy provides the greatest benefit for patients with locally advanced head and neck cancer according to the MACHNC 2021 meta-analysis. It improves 5-year overall survival by 6.5% and event-free survival by 5.8%, with the greatest decrease in locoregional failure rates. Induction chemotherapy provides smaller benefits of 2.2% for overall survival and 1.45% for event-free survival, as well as a significant decrease in distant failure rates. Adjuvant chemotherapy does not improve survival and increases 120-day mortality. Cisplatin-based regimens are preferred for concomitant and induction chemotherapy. This may be the final MACHNC analysis as no new patients have been
This document provides guidance on contouring for nasopharyngeal carcinoma (NPC) radiation treatment planning. It discusses the anatomy and patterns of spread of NPC, as well as staging. It describes how to delineate the primary gross tumor volume (GTVp), clinical target volumes (CTVs) including high-risk (CTVp1) and intermediate-risk (CTVp2) volumes. It also covers nodal CTV delineation (CTVn1, CTVn2, CTVn3) and discusses lymph node levels and risk of spread. Margins around critical organs and intracranial extension guidelines are also summarized. The document aims to provide a comprehensive overview of target volume delineation for NPC
The CROSS trial found that neoadjuvant chemoradiotherapy followed by surgery significantly improved long-term overall and progression-free survival compared to surgery alone for patients with resectable esophageal or esophagogastric junction cancer. At a minimum follow-up of 5 years, median overall survival was 48.6 months for chemoradiotherapy plus surgery versus 24 months for surgery alone. Both squamous cell carcinoma and adenocarcinoma subtypes benefited. Neoadjuvant chemoradiotherapy using carboplatin and paclitaxel is now considered the standard of care for these patients.
Radiotherapy plays an important role in the treatment of soft tissue sarcomas by improving local control rates when used adjuvantly with surgery. Post-operative radiotherapy reduces local recurrence rates compared to surgery alone, even for low-grade tumors. Pre-operative radiotherapy may provide a better chance of limb salvage for large or unresectable tumors but risks delaying wound healing. Positive surgical margins are associated with higher local recurrence rates, but margins within 1mm do not significantly impact outcomes. Adjuvant radiotherapy should be considered for all high-grade soft tissue sarcomas based on its ability to improve local control.
Role of Post-op Radiotherapy in Head and Neck CancersAshutosh Mukherji
This document discusses the role of adjuvant radiation therapy in head and neck cancers. It begins by outlining the use of radical and palliative treatment for stage III and IV diseases. It then reviews several landmark studies that established the benefits of postoperative radiation therapy (PORT) over surgery alone in improving local control and survival. Key factors that determine the need for adjuvant therapy like extracapsular extension, positive margins, and T3/T4 stage are discussed. The document also addresses optimal radiation dose, timing, use of concurrent chemotherapy and altered fractionation schedules based on evidence from clinical trials. While targeted therapies in the adjuvant setting have not proven beneficial so far, ongoing studies are exploring their potential role.
Reirradiation can provide local tumor control for recurrent head and neck cancer when surgery is not possible. Modern radiation techniques like IMRT allow higher radiation doses to be safely delivered to the tumor while minimizing risks of severe toxicity. Outcomes from reirradiation include a median survival of 10-12 months and 2-year local control rates of 40-64%. Patient selection is important to balance potential benefits of local tumor control against risks of treatment-related side effects.
This deals with novel molecular findings and their implications in Ewings sarcoma. The role of dose dense and dose intense chemotherapy and role of high dose chemotherapy. Additionally it also deals with survivor ship issues
This document summarizes key findings from several clinical trials on the treatment of anal squamous cell carcinoma. The UKCCCR ACT I trial showed improved local control and colostomy-free survival with chemoradiation (CRT) compared to radiation alone. Subsequent trials found improved outcomes with mitomycin-C compared to 5-FU alone. The RTOG 98-11 and ACT II trials found no advantage to cisplatin over mitomycin-C in CRT or with maintenance chemotherapy. The current standard is CRT with 5-FU and mitomycin-C.
Concurrent Chemoradiation in Postoperative Setting In LAHNC. A comparision of...Santam Chakraborty
A journal club presentation comparing and contrasting the EORTC and RTOG trials of concurrent chemoradiation in Head Neck Cancers in the post operative setting.
The RAPIDO trial tested a new experimental treatment for locally advanced rectal cancer that involved short-course radiotherapy followed by chemotherapy before surgery, compared to the standard treatment of long-course chemoradiotherapy followed by surgery and then chemotherapy. The results showed that the experimental treatment led to a lower rate of disease-related treatment failures and distant metastases, along with a doubled rate of pathologic complete responses, without increasing toxicities or compromising survival rates. This provides evidence that the experimental approach may be a new standard of care for high-risk locally advanced rectal cancer.
The document discusses lung cancer subtypes and molecular features that can guide treatment. It provides statistics on the distribution of histology types among lung cancer cases. It also summarizes several key studies investigating targeted therapies such as EGFR TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer, noting improved progression-free survival with TKIs in patients with EGFR mutations. Molecular testing is increasingly important for determining personalized treatment approaches in lung cancer.
This document summarizes key points from a presentation on watch and wait strategies after chemoradiotherapy for rectal cancer. It discusses principles of adjuvant therapy, indications for neoadjuvant therapy, assessment of treatment response, and outcomes data supporting watch and wait for patients who achieve a clinical complete response. The take home message emphasizes that watch and wait offers an alternative to surgery for some patients and should be discussed, but is best carried out in specialized cancer centers.
Evolving Role of Radiation Therapy in Hodgkins DiseaseSantam Chakraborty
1) Recent advances in radiation therapy for Hodgkin's lymphoma include reducing radiation volumes and doses based on clinical trials.
2) For early stage favorable Hodgkin's lymphoma, the standard is 2 cycles of ABVD chemotherapy followed by 20Gy involved field radiation.
3) For early stage unfavorable or poor prognosis disease, 4 cycles of ABVD plus 30Gy involved field radiation is standard based on clinical trials.
This document summarizes several key studies on the use of concurrent chemo-radiation therapy for carcinoma of the cervix. Five randomized controlled trials from the 1980s-1990s showed significantly improved progression-free and overall survival when cisplatin-based chemo-radiation was used compared to radiation alone. Subsequent larger trials like GOG 120 and RTOG 9001 reinforced these findings. Long term follow up data continued to show survival benefits with acceptable toxicity rates for concurrent chemo-radiation, which is now the standard of care for locally advanced cervical cancer.
- The document summarizes key landmark clinical trials investigating treatments for metastatic gastric cancer.
- The ToGA trial found that adding trastuzumab (Herceptin) to standard chemotherapy (cisplatin and fluoropyrimidine) significantly improved overall survival and progression-free survival in patients with HER2-positive metastatic gastric cancer compared to chemotherapy alone. Median overall survival was 13.8 months with chemotherapy plus trastuzumab versus 11.1 months with chemotherapy alone.
- The REAL-2 trial demonstrated that cisplatin plus capecitabine was as effective as cisplatin plus fluorouracil for advanced gastric cancer, with less toxicity. Cisplatin plus capecitabine has since
The document discusses the role of chemotherapy in carcinoma of the stomach. It outlines several key trials investigating neoadjuvant, adjuvant and perioperative chemotherapy approaches. The MAGIC trial showed significantly improved 5-year survival with perioperative chemotherapy compared to surgery alone. The French FNCLCC trial also demonstrated improved disease-free and overall survival with perioperative chemotherapy. Adjuvant chemoradiation was shown in the INT0116/SWOG 9008 trial to improve 5-year overall and disease-free survival compared to surgery alone. The Japanese S-1 trial found significant benefit in 5-year disease-free and overall survival with adjuvant S-1 chemotherapy compared to observation after surgery.
Organ preservation in laryngopharyngeal cancersRahul Pathade
This document discusses organ preservation in laryngopharyngeal cancers. It begins with an overview of the anatomy and staging of these cancers. It then reviews past treatment approaches involving total laryngectomy and highlights studies demonstrating the benefits of organ preservation strategies using induction chemotherapy and concurrent chemoradiation. Subsequent trials showed improved larynx preservation and survival with the addition of chemotherapy to radiation compared to radiation alone. More intensive chemotherapy regimens like docetaxel, cisplatin, and 5-FU were found to further improve outcomes over standard cisplatin and 5-FU. Overall, organ preservation approaches with chemotherapy have become the standard of care for locally advanced laryngopharyngeal cancers.
RADIOTHERAPY TARGET DELINEATION IN BREAST CANCERKanhu Charan
This document discusses guidelines for target delineation in breast cancer radiotherapy, including contours for the chest wall, breast, lymph nodes, and organs at risk. It describes guidelines from organizations like EORTC, RTOG, TROG, and ESTRO for delineating targets like the supraclavicular fossa, internal mammary nodes, and three levels of axillary lymph nodes. It also discusses techniques like custom immobilization and image guidance that can help reduce planning target volume and guidelines for target volumes in post-mastectomy and breast-conserving settings.
The document discusses head and neck cancer, focusing on individualizing treatment. It notes that head and neck cancer incidence is increasing, with some caused by HPV. EGFR is a molecular target in these cancers. Studies combining EGFR inhibitors like cetuximab with chemoradiation in locally advanced disease showed increased toxicity but uncertain efficacy benefits. Biomarker-selected treatment de-intensification may be appropriate for HPV-positive cancers.
Head and neck cancer accounts for 5-6% of all cancers, with over 90% being squamous cell carcinomas. Risk factors include tobacco, alcohol, and HPV. Treatment options include surgery, radiation therapy, chemotherapy, or combinations. While early stage cancer has a good prognosis with single modality treatment, advanced stages generally require combined modality treatment, though 5-year survival remains below 35%. New targeted therapies and improved radiation techniques have provided benefits in recent years.
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.
This document discusses balanced treatment approaches for esophageal cancer. It recommends that surgery plus additional therapy is required for pT3 N1 tumors. Definitive chemoradiotherapy is an acceptable standard for squamous cell carcinoma. Preoperative and postoperative combination chemotherapy is also an acceptable approach for resectable esophageal or GEJ adenocarcinoma. Preoperative concurrent chemoradiotherapy is a standard for resectable adenocarcinoma of the esophagus or GEJ. The role of preoperative chemotherapy alone for resectable squamous cell carcinoma is unclear and not recommended.
This document summarizes the state of the art in head and neck cancer treatment. It discusses epidemiology, risk factors, staging, treatment modalities including surgery, radiotherapy, chemotherapy, targeted therapy. It highlights recent findings like the role of HPV and molecular targeted agents. It also discusses the benefits of concurrent chemoradiation compared to radiotherapy alone as well as induction chemotherapy followed by chemoradiation for locally advanced disease.
Post-operative Radiotherapy for Esophageal Cancerfondas vakalis
The document discusses evidence from randomized trials and studies on the use of postoperative radiotherapy and chemoradiotherapy for esophageal cancer. It summarizes several key trials that have shown postoperative radiotherapy improves overall survival for stage III and node-positive esophageal cancer patients by decreasing locoregional recurrence rates. The largest trial discussed found that postoperative chemoradiotherapy improved both overall and relapse-free survival compared to surgery alone for gastric adenocarcinoma patients. Non-randomized studies also suggested benefits of postoperative chemoradiotherapy over radiotherapy alone or surgery alone for esophageal squamous cell carcinoma.
Optimizing Chemotherapy For Malignant Gliomafondas vakalis
The document discusses optimizing chemotherapy for malignant glioma. Meta-analyses showed that combining temozolomide (TMZ) with radiotherapy improved survival rates compared to radiotherapy alone. A phase III trial demonstrated that concomitant and adjuvant TMZ with radiotherapy significantly improved progression-free and overall survival. Subset analyses found the benefit was consistent across patient subgroups. Methylation of the MGMT gene promoter was identified as predictive of benefit from TMZ therapy.
Multimodality Treatment Of Stage Iii Nsclcfondas vakalis
1) Multimodality treatment including chemotherapy and radiotherapy has improved outcomes for stage III non-small cell lung cancer (NSCLC) over the past decade, increasing median survival by 5 months and 1-2 year survival by 10%.
2) Induction chemotherapy with a platinum agent and third-generation drug for 2-3 cycles followed by radiotherapy remains a good standard treatment for fit patients.
3) Concurrent chemoradiotherapy and combined modality approaches may offer further benefits but require more evidence, as they present increased toxicity risks that need to be weighed against uncertain survival gains.
The document discusses treatment options for a 66-year-old man from Nigeria diagnosed with locally advanced head and neck squamous cell carcinoma. The man was treated initially with induction chemotherapy consisting of a PF regimen, followed by concurrent chemoradiation with gemcitabine and radiotherapy, achieving a partial response. The document then outlines general treatment modalities and strategies for locoregionally advanced head and neck cancer.
The document discusses treatment options for a 66-year-old man from Nigeria diagnosed with locally advanced head and neck squamous cell carcinoma. The man was treated initially with induction chemotherapy consisting of a PF regimen, followed by concurrent chemoradiation with gemcitabine and radiotherapy, achieving a partial response. The document then outlines general treatment modalities and strategies for locoregionally advanced head and neck cancer.
This document provides information on a case presentation of anal squamous cell carcinoma, including staging, diagnostic workup, management, prognostic factors, and follow up. Key points include:
- The mean age of diagnosis is 62 years and most common symptom is rectal bleeding. Imaging includes CT, MRI, and PET scans to stage disease.
- Treatment depends on disease stage but typically involves chemoradiation with concurrent 5-FU and mitomycin C or cisplatin. Several trials have shown improved outcomes with chemoradiation compared to radiation alone.
- Follow up involves examination and imaging to monitor for recurrence or metastasis. Prognostic factors include tumor size, response to initial treatment, and presence of late
This Phase II trial assessed the safety and efficacy of the monoclonal antibody nimotuzumab combined with chemoradiation or radiation alone in patients with advanced head and neck cancer. The trial showed that concurrent use of nimotuzumab with chemoradiation enhanced long-term locoregional control and survival compared to chemoradiation alone, with nimotuzumab displaying a surprisingly benign toxicity profile. These encouraging results support conducting a Phase III trial to further evaluate nimotuzumab's potential clinical benefit in this cancer population.
This document discusses treatment approaches for locally advanced non-small cell lung cancer (NSCLC). It presents a case of stage IIIB NSCLC and reviews the history and evolution of combined modality therapy using chemotherapy and radiotherapy. Concurrent chemoradiotherapy is now the standard of care and research focuses on optimizing radiotherapy dose/fractionation and integrating targeted therapies and prophylactic cranial irradiation to further improve outcomes.
This document summarizes key findings from several studies on the treatment of rectal cancer with radiotherapy and chemoradiotherapy. It finds that preoperative chemoradiotherapy reduces local recurrence rates compared to postoperative chemoradiotherapy or no radiotherapy, with increased acute and late toxicity. Several large trials showed no difference in overall survival between treatment groups. Optimal patient selection and a balance between risk reduction and side effects are important considerations.
This document discusses adjuvant chemotherapy for colorectal cancer. It finds that for stage III cancer, 6 months of FU-FA + oxaliplatin is the standard treatment, based on evidence from trials like MOSAIC showing a 5-year disease-free and overall survival benefit. For stage II cancer, evidence is less clear but some benefit was seen in QUASAR from 5-FU regimens. FOLFOX showed minimal additional benefit over 5-FU for stage II in MOSAIC. Patient selection is important given heterogeneity in stage II prognosis.
This document discusses adjuvant chemotherapy for colorectal cancer. It finds that for stage III cancer, 6 months of FU-FA + oxaliplatin is the standard treatment, based on evidence from trials like MOSAIC showing a 5-6% improvement in disease-free and overall survival rates. For stage II cancer, evidence is less clear but trials like QUASAR showed a small (~3%) overall survival benefit from chemotherapy. The document questions whether shorter treatment durations could be equally effective.
This document summarizes information about radiotherapy for non-small cell lung cancer (NSCLC). It discusses the role of radiotherapy for early, locally advanced, and metastatic NSCLC. It describes stereotactic body radiotherapy (SBRT) for early-stage disease and concurrent chemoradiotherapy (CTRT) for locally advanced stages. It also reviews evidence on optimal radiotherapy techniques and dosing, as well as trials investigating induction, consolidation, and adjuvant chemotherapy combined with radiotherapy.
This document summarizes information about radiotherapy for non-small cell lung cancer (NSCLC). It discusses the role of radiotherapy for early, locally advanced, and metastatic NSCLC. It describes stereotactic body radiotherapy (SBRT) for early-stage disease and concurrent chemoradiotherapy (CTRT) for locally advanced stages. It also reviews evidence on optimal radiotherapy techniques and dosing, as well as trials investigating induction, consolidation, and adjuvant chemotherapy combined with radiotherapy.
Neoadjuvant therapy, including chemotherapy and chemoradiotherapy, is being investigated for the treatment of esophageal cancer. While some studies have shown improved survival rates with neoadjuvant therapy compared to surgery alone, the evidence from clinical trials remains conflicting. Achieving a complete pathological response after neoadjuvant therapy is associated with significantly improved long-term survival. Further research is still needed to determine the optimal neoadjuvant approaches and to improve outcomes by reducing distant metastases.
1) The document discusses the evidence and guidelines for use of radiation therapy (RT) in treatment of low-grade glioma.
2) Several practice-changing randomized controlled trials showed that for high-risk low-grade glioma, combining RT and chemotherapy improved outcomes over RT alone.
3) For anaplastic glioma, combining RT and chemotherapy improved survival compared to RT alone, especially for those with 1p/19q co-deletion.
4) Ongoing trials are exploring whether initial observation may be reasonable for some low-grade glioma patients after surgery, versus early adjuvant treatment.
Similar to Role of systemic therapy in management of laryngeal carcinoma (20)
This document discusses skin cancer, specifically melanoma. It notes that melanoma accounts for 1-5% of skin cancers but causes the majority of skin cancer deaths. Risk factors include family history, sun exposure, skin sensitivity, and immunosuppression. The main types of melanoma are superficial spreading, nodular, lentigo maligna, and acral lentiginous. Diagnosis involves examining lesions for characteristics like asymmetry, irregular border, multiple colors, diameter over 6mm, and changes over time. Treatment depends on cancer stage and may include surgery, radiation, immunotherapy, targeted therapy, chemotherapy, or a combination.
Sarcoma represents 1% of all malignant tumors and includes soft tissue sarcomas (STS), bone sarcomas, and visceral sarcomas. STS are more common than bone sarcomas by a ratio of 4:1. Risk factors for sarcoma include genetic syndromes, radiation exposure, and certain chemical exposures. Diagnosis involves imaging such as MRI or CT along with pathological confirmation. Treatment depends on the location and stage of disease, and may involve surgery, radiation therapy, chemotherapy, or targeted therapy. The goal is curative treatment for localized disease and palliation for metastatic disease.
Thyroid cancer is the most common cancer of the endocrine system. The three main types are papillary, follicular, and medullary thyroid carcinoma. Risk factors include radiation exposure, family history, and genetic conditions. Symptoms may include a neck mass, lymph node swelling, difficulty swallowing or breathing, and diarrhea. Diagnosis involves thyroid imaging tests, biopsy, and genetic testing. Treatment depends on cancer type and stage but commonly includes surgery, radioactive iodine therapy, and medication for differentiated cancers, and surgery plus other therapies for medullary and anaplastic thyroid cancers.
Head and neck cancer is the 6th most common cancer worldwide. The incidence increases with age, with most cases being diagnosed after age 60. It is also more common in men. Risk factors include cigarette smoking, HPV or EBV infection, alcohol intake, and prior history of head and neck cancer or radiation exposure. The most common type is squamous cell carcinoma. Symptoms depend on the location but may include masses, ulcers, pain, swallowing difficulties, voice changes, and sinus problems. Diagnosis involves endoscopy, imaging tests, and biopsy. Staging depends on tumor size and spread. Treatment options include surgery, radiation therapy, chemotherapy, and biological therapies depending on cancer type and stage.
Testicular tumors are the most common cancer in men aged 20-40. They make up about 1% of all cancers in men. Risk factors include family history, undescended testes, infertility, and genetic conditions. The majority are germ cell tumors which are divided into seminomas and non-seminomas. Common symptoms are a painless mass in the scrotum or painful enlargement of the testis. Diagnosis involves blood tests, ultrasound, and CT scans. Staging determines the appropriate treatment which may include surgery, radiation therapy, chemotherapy, or active surveillance depending on the stage and type of tumor.
Prostate cancer is the second most common cancer in men worldwide and the second most common cause of cancer death in men. It makes up around 10-15% of all male cancers. Hereditary factors like mutations in the BRCA1 and BRCA2 genes and a family history of prostate cancer can increase the risk. Screening tests for prostate cancer include a digital rectal exam and PSA blood test. Treatment depends on the stage and grade of cancer, and may include surgery, radiation therapy, hormone therapy, chemotherapy, and palliative care.
Bladder cancer is the 4th most common cancer in men worldwide, with a peak incidence around age 65. Risk factors include smoking, occupational exposure, and certain infections. Symptoms depend on whether the cancer is non-metastatic or metastatic, and may include blood in the urine, bladder irritability, and pelvic or flank pain. Diagnosis involves cystoscopy, imaging tests, and urine cytology. Treatment depends on the stage, and includes surgery, chemotherapy, and immunotherapy.
Renal cancer, also known as renal cell carcinoma (RCC), is the 12th most common cancer worldwide and the 4th most common cancer in adult males. Risk factors include hereditary conditions, smoking, obesity, and hypertension. Symptoms can include hematuria, flank mass, flank pain, and paraneoplastic syndromes in metastatic disease. Diagnosis involves imaging like CT scans and labs. Treatment depends on stage - surgery is recommended for localized disease while targeted drugs, immunotherapy, and surgery are options for metastatic renal cancer.
DNA repair systems help maintain the integrity of genetic material by correcting damage from mutagens. There are several types of DNA repair mechanisms, including direct damage reversal, mismatch repair, base excision repair, nucleotide excision repair, and recombination repair. Key DNA repair proteins like p53 play an important role in recognizing DNA damage and initiating cell cycle arrest to allow time for repair or inducing apoptosis if damage is irreparable. Double strand breaks are the most difficult to repair and can lead to chromosomal rearrangements if unrepaired.
Apoptosis is a genetically programmed cell death process that eliminates unwanted cells through activation of caspases. There are two main pathways that activate caspases - the extrinsic death receptor pathway where ligands bind to cell surface receptors, and the intrinsic mitochondrial pathway where increased permeability of mitochondria releases proteins that activate caspase. The Bcl-2 family of proteins regulate apoptosis by integrating both pro-apoptotic and anti-apoptotic signals to determine if a cell should undergo programmed cell death.
Cancer genes can be divided into two main classes: oncogenes and tumor suppressor genes. Oncogenes promote cell growth and proliferation when activated by mutations, while tumor suppressor genes normally inhibit cell growth and their inactivation allows for unchecked cell division. Dysfunction of multiple cancer genes is typically required for malignant transformation, as an imbalance between oncogene and tumor suppressor gene activity leads to cancer development. Common oncogenes include ras, myc, and HER2, while tumor suppressor genes include RB, p53, and APC. Mutations in DNA repair genes can also contribute to cancer by allowing genetic errors to persist.
The document discusses the cell cycle and its control. It describes the cell cycle as consisting of interphase (which includes G1, S, and G2 phases) and mitosis (M phase). Interphase involves cell growth and DNA replication, while mitosis involves the division of the cell into two daughter cells. Transition between phases is regulated by cyclins and cyclin-dependent kinases (Cdks). Key checkpoints ensure replication and division occur accurately. The centromere and chromatids are also described along with their behavior in the different mitotic phases.
1) Cancer metastasis is a multi-step process involving invasion of surrounding tissue, transportation through the bloodstream, and formation of tumors in distant organs.
2) Key steps include degradation of the extracellular matrix, entry and survival in the circulation, arrest and extravasation at distant sites, and induction of angiogenesis to establish blood supply for growing tumors.
3) Factors such as matrix metalloproteinases, integrins, and angiogenic growth factors regulate these steps by promoting degradation of barriers, cell adhesion, and new blood vessel formation to enable metastatic tumors to grow.
Cancer cells exhibit six hallmarks that allow tumor growth and metastasis. They are: self-sufficiency in growth signals, insensitivity to anti-growth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Cancer cells achieve these hallmarks through genetic and epigenetic alterations that disrupt normal cell signaling pathways.
1) Carcinogenesis is a multistep process involving initiation, promotion, and progression. Initiation involves genetic mutations from environmental factors like smoking. Promotion involves clonal expansion driven by growth factors in a reversible stage. Progression results in irreversible aneuploidy and cellular anaplasia.
2) The multihit hypothesis proposes cancer develops through accumulation of multiple genetic mutations in oncogenes and tumor suppressor genes, requiring 4-5 mutations for malignancy.
3) Cancers arise from a single cell of origin (monoclonal) that accumulates mutations over time, leading to intratumor heterogeneity as subclones evolve. Evidence for monoclonal origin includes single enzyme/immunoglob
This document discusses various diagnostic tools used in oncology, including tumor markers, immunohistochemistry, immunocytology, cytogenetics, molecular diagnosis, and gene expression analysis. It provides details on tumor markers including their definition, classification, factors that affect serum levels, and indications for use. It also discusses immunohistochemistry in detail, covering tumor antigens, immunoreactivity, clinical applications for diagnosis, predicting therapy response and prognosis, and specific carcinoma markers like cytokeratins, CEA, and hormone receptors.
There are 9 main classes of cancer: carcinomas, neuroectodermal tumors, sarcomas, hemolymphoid tumors, germ cell tumors, blastemal tumors, embryonal vestigal remnants tumors, uncertain histogenesis tumors, and undifferentiated tumors. Carcinomas are the most common type, arising from epithelial cells. Sarcomas arise from mesenchymal cells and grow more rapidly than carcinomas. Neuroectodermal tumors include tumors of neural, neuroendocrine, and primitive neuroectodermal origin. Hemolymphoid malignancies include lymphomas and leukemias. Other classes are defined by their origin from germ cells, embryonic rests, vestigial remnants
Neoplasia refers to abnormal tumor growth. There are two main types of tumors: benign tumors, which remain localized and do not recur after removal, and malignant tumors, which invade surrounding tissues and can metastasize to distant sites. Benign tumors are well-defined masses that grow slowly by expansion, while malignant tumors are poorly defined masses that grow rapidly by infiltration. Microscopically, benign tumor cells resemble normal cells and have few blood vessels and mitoses, whereas malignant tumor cells are poorly differentiated with irregular nuclei, frequent mitoses, and necrosis. Malignant tumors can recur after removal and are always a health risk.
This document discusses the etiology of cancer. It classifies etiological factors into extrinsic (chemical, physical, biological) and intrinsic (genetic, hormonal, immune) factors. Extrinsic factors predominate in causing adult cancers while intrinsic factors are more common in pediatric cancers. Major extrinsic factors include chemicals, radiation, infections, and tobacco. Chemicals can directly or indirectly damage DNA. Radiation can directly or indirectly ionize DNA. Certain viruses and bacteria are associated with specific cancer types. The interaction between multiple genetic and environmental factors usually leads to cancer development.
This document discusses various disorders of growth including hypertrophy, hyperplasia, metaplasia, dysplasia, carcinoma in situ, and precancerous lesions.
Hypertrophy is an increase in size of cells and organelles leading to organ enlargement. Hyperplasia is an increase in cell number, often with some hypertrophy. Metaplasia is a reversible change where one adult cell type replaces another of the same category. Dysplasia is a disorder of growth seen as abnormal cell maturation and arrangement. Carcinoma in situ represents severe dysplasia involving the entire epithelium but no invasion. Precancerous lesions are non-malignant conditions that may undergo malignant transformation.
Travel vaccination in Manchester offers comprehensive immunization services for individuals planning international trips. Expert healthcare providers administer vaccines tailored to your destination, ensuring you stay protected against various diseases. Conveniently located clinics and flexible appointment options make it easy to get the necessary shots before your journey. Stay healthy and travel with confidence by getting vaccinated in Manchester. Visit us: www.nxhealthcare.co.uk
Mercurius is named after the roman god mercurius, the god of trade and science. The planet mercurius is named after the same god. Mercurius is sometimes called hydrargyrum, means ‘watery silver’. Its shine and colour are very similar to silver, but mercury is a fluid at room temperatures. The name quick silver is a translation of hydrargyrum, where the word quick describes its tendency to scatter away in all directions.
The droplets have a tendency to conglomerate to one big mass, but on being shaken they fall apart into countless little droplets again. It is used to ignite explosives, like mercury fulminate, the explosive character is one of its general themes.
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
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• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
5-hydroxytryptamine or 5-HT or Serotonin is a neurotransmitter that serves a range of roles in the human body. It is sometimes referred to as the happy chemical since it promotes overall well-being and happiness.
It is mostly found in the brain, intestines, and blood platelets.
5-HT is utilised to transport messages between nerve cells, is known to be involved in smooth muscle contraction, and adds to overall well-being and pleasure, among other benefits. 5-HT regulates the body's sleep-wake cycles and internal clock by acting as a precursor to melatonin.
It is hypothesised to regulate hunger, emotions, motor, cognitive, and autonomic processes.
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
10 Benefits an EPCR Software should Bring to EMS Organizations Traumasoft LLC
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4. ZUCOD
This presentation will include a discussion of off-
label treatment , investigational agents not
approved by the FDA, and data were presented in
abstract form. These data should be considered
preliminary until published in a peer- reviewed
journal.
4
7. Positive Therapeutic Ratio (Gain)
Maximal probability
of tumor control
Minimal
(reasonably acceptable)
frequency of complications
(sequelae of therapy)
Therapeutic Ratio ZUCOD
7
8. D isea se
control
Im prov e
Overall
S urv iv a l
Ma inta in
f unction of
orga n
Good/Excellent
a esthetic
outcom e
Minim a l a dv erse
ef f ects/ toxicity
Goals
of
treatment
Ma inta in/
Im p ro v e
Qua lity o f
Lif e ( Qo L)
Goals of treatment ZUCOD
8
12. ZUCODCommonly Used Chemotherapeutic Agents
Class Agents Mechanism of action Clearance Toxicity
Platinum agents Cisplatin DNA adduct formation Renal Nausea
Carboplatin Nephrotoxicity
Ototoxicity
Neurotoxicity
Myelosuppression
Antifolates Methotrexate Depletion of precursors for purine Renal Myelosuppression
synthesis Gastrointestinal toxicity
Antimetabolites 5-Fluorouracil Depletion of precursors for DNA synthesis Renal Gastrointestinal toxicity
Incorporation into RNA (inactive drug) Myelosuppression
Taxanes Paclitaxel Mitotic arrest by microtubule Hepatobiliary Hypersensitivity
Docetaxel stabilization Peripheral neuropathy
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
12
13. ZUCOD
Multimodality treatment approaches using
Chemotherapy
Approach Definition
Induction chemotherapy The use of chemotherapy prior to definitive locoregional
management
Adjuvant chemotherapy The use of chemotherapy after definitive locoregional management
Concurrent chemoradiotherapy
Definitive chemoradiotherapy The use of concomitant chemotherapy and radiation as definitive
management
Adjuvant chemoradiotherapy The use of concomitant chemotherapy and radiation after definitive
locoregional management
Sequential treatment The use of induction chemotherapy followed by definitive
concomitant chemotherapy and radiation
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
13
14. ZUCOD
Randomized Larynx Preservation
Trial Designs and Outcomes
Forastiere AA et al, JCO. 2015; 33(29): 3262-3268.
Study
N
(period)
Site Stage Treatment
Response of
ICT
Larynx Preservation Overall Survival
VALCSG 332 Larynx III (57%) 3-year, 5-year
(1985- SG (63%) IV (43%) a) TL RT NA NA 56% 45%
Phase III 1988) G (37%) b) PF x 3 RT 85% CR+PR 3-year, 62% 53% 42%
RTOG 547 Larynx III (64%) 5-year 10-year 5-year 10-year
91-11 (1992- SG (69%) IV (36%) a) PF x 3 RT 85% CR+PR 71% 68% 58% 39%
Phase III 2000) G (31%) b) RT + P NA 84% 82% 55% 28%
c) RT NA 66% 64% 54% 32%
EORTC 450 Larynx (48%) II (4%) 3-year 3-year
24954-22950 (1996- Hypopharynx (52%) III (39%) a) PF x 4 RT 89% CR+PR 40% 62.2%
Phase III 2004) IV (58%) b) PF alternating/RT NA 45% 64.8%
GORTEC 213 Larynx (46%) III .002 3-year 3-year
2000-01 (2000 Hypopharynx (54%) IV a) PF x 3 RT 59.2% CR+PR 57.5% P= .03 60%
Phase III -2005) b) TPF x 3 RT 80% CR+PR 70.3% 60%
EORTC 202 Hypopharynx II (7%) 3-year 10-year 3-year 10-year
24891 (1986 III (57%) a) TLP RT NA NA NA 43% 14%
Phase III -1993) IV (37%) b) PF x 3 RT 54% CR 42% 27% 57% 13%
14
15. ZUCOD
Definitive Concurrent
Chemoradiation Trials
Study N F/U (years) CT
OS
RT
(control arm)
RT+CT
(experimental arm)
P-value
French trial 226 3 Carbo+5FU 31% 51% 0.002
German trial 270 3 Cis+5FU+LV 24% 48% <0.003
Duke U 116 5 Cis+5FU 28% 42% 0.05
Intergroup 199 3 Cis 23% 37% 0.01
Greek 83 3 Cis 18% 52% <0.001
15
23. ZUCODRTOG 68-01
Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 ;6(5):533-
Study Design
638 Patients
• H & N carcinoma.
• SGL: 12%.
• Squamous carcinoma.
• Previously untreated.
• Stage III or IV.
R
Radiation therapy
(5500 to 8000 cGy)
n = 326
Induction
Chemotherapy (MTX)*
n = 312
Radiation therapy
(5500 to 8000 cGy)
* MTX 25 mg every third day for five
doses
John T Fazekas, MD
23
24. ZUCODRTOG 68-01
Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 ;6(5):533-
Outcome
Primary site
RT
Median OS
MTX RT
Median OS
P-value
Oral cavity 11.8 mon 12.4 mon >0.05
Oropharynx 13.6 mon 13.1 mon >0.05
SGL 17.2 mon 19.2 mon >0.05
Hypopharynx 9.7 mon 13.4 mon >0.05
24
25. ZUCOD
This study taught
us• Minimal gain, induction methotrexate should not be used
RTOG 68-01
Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 ;6(5):533-
25
26. ZUCOD
Department of
Veterans Affairs Larynx
trialStudy Design
332 Patients
• Laryngeal carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Stage III or IV.
• Resectable.
Laryngectomy
N = 166
Induction chemotherapy
(Cis+5fu)* x 2 cycles
N = 166
Induction chemotherapy
(Cis+5fu)* x 1 more cycle
Salvage
Laryngectomy
Radiation therapy
(5400 cGy ± 1000 cGy)
Radiation therapy
(6600 to 7600 cGy)
Radiation therapy
(5400 cGy ± 1000 cGy)
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-
R
Responders
Non-responders
Salvage
Laryngectomy
Residual disease
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000
mg/m2 D1 to D5 (CIV) repeat cycle on days
22 & 43.
Median F/U of 33 months Gregory T Wolf, MD
26
28. ZUCOD
Disease Free
Survival
Department of
Veterans Affairs Larynx
trial
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-90.
P = 0.1195
64%
2-year Larynx Preservation Rate = 64%
Overall Survival
68%
P = 0.9846
28
29. ZUCOD
Department of
Veterans Affairs Larynx
trial
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-90.
Site of Recurrence
Surgery
(n = 166)
No. (%)
Chemotherapy
(n = 166)
No. (%)
p-value
All 42 (25%) 52 (31%)
Primary 4 (2%) 20 (12%) 0.0005
Regional 9 (5%) 14 (8%)
Distant 29 (17%) 18 (11%) 0.016
Site of Recurrence (pattern of failure)
Causes of Death
Cause of death
Surgery
(n = 166)
No. (%)
Chemotherapy
(n = 166)
No. (%)
All 58 (35%) 65 (39%)
Cancer 38 (23%) 42 (25%)
Complication of therapy 4 (2%) 4 (2%)
Other 14 (8%) 13 (8%)
Unknown 2 (1%) 6 (4%)
29
30. ZUCOD
This study taught
us
Department of
Veterans Affairs Larynx
trial
Wolf GT, et al. N Engl J Med. 1991 ;24(24):1685-90.
• The efficacy of chemotherapy followed by radiotherapy (with surgical
salvage) was similar to that of surgery followed by radiotherapy and
offered the added benefit of laryngeal preservation in two thirds of
patients treated by this approach.
• The higher rate of local recurrence indicates that more effective local
therapy is needed to improve rates of larynx preservation.
Chemotherapy regimens that achieve higher rates of complete
response, newer schemes of radiation fractionation, or other
combinations of radiation and chemotherapy may prove beneficial in
this regard.
30
31. ZUCODEORTC 24891
Study Design
202 Patients
• Pyriform fossa & AE fold
carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Stage II or IV (Non N2c).
• Resectable.
Total Laryngectomy + partial
pharyngectomy + neck
dissection
N =
Induction chemotherapy
(Cis+5fu)* x 2 cycles
N =
Induction chemotherapy
(Cis+5fu)* x 1 more cycle
Total Laryngectomy +
partial pharyngectomy +
neck dissection
Radiation therapy
(5000 to 7000 cGy)
Radiation therapy
(7000 cGy)
Radiation therapy
(5000 to 7000 cGy)
R
PR
SD or PD
Total Laryngectomy +
partial pharyngectomy +
neck dissection
PDCR
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000
mg/m2 D1 to D5 (CIV) repeat cycle on days
22 & 43.
Median follow-up of 51 months
Lefebvre JL, et al. J Natl Cancer Inst. 1996
CR
Jean-Louis Lefebvre, MD
31
32. ZUCODEORTC 24891
Lefebvre JL, et al. J Natl Cancer Inst. 1996
Outcome after 4 years
Parameters ICT RT Surgery HR (95% CI) p-value
Larynx preservation
Three-year 42%
Four-year 35%
Overall survival
Median (months) 44 25 0.86 >0.05
Three-year 38% 33%
Distant metastasis
Three-year 25% 36% 0.041
Local recurrence
Three-year 17% 12%
Regional recurrence
Three-year 23% 19%
Outcome after 10 years
Parameters ICT RT Surgery HR (95% CI) p-value
Larynx preservation
Five-year 22%
Ten-year 9%*
Overall survival
Five-year 13% 14%
Progression Free Survival
Five-year 32% 26% >0.05
* 69% survivors.
32
33. ZUCOD
This study taught
us
• Similar survival curves with larynx preservation as with conventional
total laryngectomy, with 2/3 survivors retaining their larynx.
EORTC 24891
• Induction chemotherapy reduce risk of distant metastasis.
Lefebvre JL, et al. J Natl Cancer Inst. 1996
33
34. ZUCOD
Study Design
68 Patients
• Laryngeal carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Stage III or IV.
• Resectable.
Laryngectomy
N = 32
Induction chemotherapy
(Cis+5fu)* x 2 cycles
N = 36
Induction chemotherapy
(Cis+5fu)* x 1 more cycle
Salvage
Laryngectomy
Radiation therapy
(5000 cGy to 7000 cGy)
Radiation therapy
(6500 to 7000 cGy)
N = 15
Radiation therapy
(5000 cGy to 7000 cGy)
R
No progression
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000
mg/m2 D1 to D5 (CIV) repeat cycle on days
22 & 43.
GETTEC trial
Richard JM, et al. Oral Oncol. 1998;34:224–8
Prematurely closed due to a
poor accrual
> 80% response
Progression
34
35. ZUCOD
Outcome
Parameters ICT RT Surgery p-value
Larynx preservation
Two-year 42%
Overall survival
Two-year 69% 84% 0.006
GETTEC trial
Richard JM, et al. Oral Oncol. 1998;34:224–8
35
36. ZUCODTAX323 (EORTC 24971)
Vermorken JB, et al, N Engl J Med 2007; 357:1695–1704.
Study Design
358 Patients
• H & N carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Unresectable.
R
Induction chemotherapy
(PF)* x 4 cycles
N = 177
Induction chemotherapy
(TPF)‡ x 4 cycles
N = 181
Radiation therapy
CF, AF or HF
Neck Dissection
Radiation therapy
CF, AF or HF
Neck Dissection
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1 to
D5 (CIV) repeat cycle 3weeks.
‡ Docetaxel 75 mg/m2 D1 + Cisplatin 75 mg/m2 D1 + Fluorouracil 750 mg/m2 D1 to
D5 (CIV) repeat cycle every 3 weeks
Stratify:-
• Primary site.
• Institution.
Median follow-up of 51 months
Jan B Vermorken, MD
36
38. ZUCOD
Vermorken JB, et al, N Engl J Med 2007; 357:1695–1704.
Progression Free Survival (PFS)
17% 14% P = 0.007
Overall Survival (OS)
37%
26% P = 0.02
TAX323 (EORTC 24971)
38
39. ZUCOD
This study taught
us
• The efficacy of adding docetaxel to PF as TPF demonstrated superior
response rate , increased 3-year PFS and increased 3-year OS.
• Patients who received TPF had less grades 3-4 toxicity and fewer toxic
deaths compared with those receiving PF, due to the reduced doses of
platinum and 5FU in the TPF regimen.
TAX323 (EORTC 24971)
Vermorken JB, et al, N Engl J Med 2007; 357:1695–1704.
39
40. ZUCODGORTEC 2000-01 trial
Pointreau Y, et al. J Natl Cancer Inst. 2009; 101(7):498-506
Study Design
213 Patients
• Larynx & Hypopharynx
carcinoma.
• Squamous carcinoma.
• Previously untreated.
• T2-4, N0-3.
• Resectable.
R
Induction chemotherapy
(CF)* x 3 cycles ± 1 more
N = 103
Induction chemotherapy
(TCF)‡ x 3 cycles ± 1 more
N = 110
Radiation therapy
(7000 cGy)
Radiation therapy
(7000 cGy)
* Cisplatin 100 mg/m2 D1 +
Fluorouracil 1000 mg/m2
D1 to D5 (CIV) repeat
cycle 3weeks.
‡ Paclitaxel 175 mg/m2 D1 +
Cisplatin 75 mg/m2 D1 +
Fluorouracil 750 mg/m2 D1 to
D5 (CIV) repeat cycle every
3 weeks
Median F/U of 3 years
≥ 50% response
≥ 50% response
< 50% response
Salvage
Laryngectomy
< 50% response
Radiation therapy
(5400 cGy ± 1000 cGy)
• Primary endpoint: 3-year laryngeal preservation.
• Secondary endpoint: Overall survival, Response to ICT, DFS,
Toxicity.
Yoann Pointreau, MD
40
46. ZUCODConclusions for Induction
Chemotherapy
• The addition of induction chemotherapy for larynx preservation did
not compromise the survival when compared with upfront surgery.
• None of the different induction chemotherapy regimens (PF or TPF)
has been able to improve survival in larynx preservation programs.
• Induction chemotherapy did not compromise subsequent treatment
(either salvage surgery of definitive irradiation) in terms of tolerance
or of efficacy.
46
47. ZUCODPros and Cons of Induction
Chemotherapy
• Improve distant control.
• Organ preservation.
• Higher rate of loco-regional failure.
Pros Cons
47
51. ZUCOD
Forastiere AA, etal, N Engl J Med 2003; 349:2091–2098
RTOG 91-11: Larynx Preservation
Trial
Preservation of the Larynx
88%
75%
70%
P = 0.005
P = 0.27
P < 0.001
Locoregional Control
78%
61%
56%
P = 0.003
P = 0.16
P < 0.001
51
55. ZUCODRTOG 91-11: Larynx Preservation
Trial
Locoregional control Overall Survival
Forastiere AA, etal, J Clin Oncol. 2013 Mar 1;31(7):845-52
55
56. ZUCOD
This study taught
us
• Preservation of the larynx significantly favored concurrent therapy.
• No improvement in overall survival with addition of chemotherapy to
radiotherapy.
RTOG 91-11: Larynx Preservation
Trial
Forastiere AA, etal, N Engl J Med 2003; 349:2091–2098
• Locoregional control significantly favored concurrent therapy.
56
57. ZUCODFrench Trial: Definitive Chemoradiation
Prades JM, et al. Acta Otolaryngol. 2009 ;15:1-6.
Study Design
75 Patients
• Pyriform fossa
carcinoma.
• Squamous carcinoma
• Previously untreated.
• Stage T3 N0-3.
• Resectable.
R
Induction chemotherapy
(Cis+5fu)* x 2 cycles
CR or PR Radiation therapy
(7000 cGy)
SD or PD
Salvage
Laryngectomy
Radiation therapy
(7000 cGy)
+ Chemotherapy (Cis)‡
Radiation therapy
(5000 to 7000 cGy)
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1 to
D5 (CIV) repeat cycle every 3weeks.
‡ Cisplatin 100 mg/m2 D1, 22, 43 of RT
Median F/U 2 years
Jean M Prades, MD
57
59. ZUCOD
This study taught
us
• Concurrent chemo-RT superior to induction chemotherapy then
radiotherapy as it improve local control, and preserve more larynx.
• No improvement in overall survival with concurrent use of
chemotherapy
Prades JM, et al. Acta Otolaryngol. 2009 ;15:1-6.
• Concurrent Chemo-RT had less distant control than induction strategy.
French Trial: Definitive Chemoradiation
59
60. ZUCOD
Conclusions for Concomitant
Chemoradiotherapy
• Concurrent chemoradiotherapy provides the highest larynx
preservation defined as the larynx in place.
• Concurrent chemoradiotherapy generates a substantial acute toxicity.
• Late toxicity after concurrent chemoradiotherapy may compromise
the laryngeal function. It is important to stress that for quality of life
only the preservation of a functioning larynx is meaningful.
• Neither concurrent nor alternating chemoradiotherapy improves
survival.
60
61. ZUCODPros and Cons of Definitive Chemoradiation
• Improve loco-regional control.
• Facilitates organ preservation.
• Beneficial impact on survival.
• Doubles the rate of sever acute
mucositis.
• Over-treatment based on stage.
• Long term functional deficit in voice
quality, swallowing.
Pros Cons
61
62. ZUCODRTOG 95-01: Postoperative Chemoradiation
Cooper JS, etal, N Engl J Med 2004; 350:1937–1944
Study Design
• Primary endpoint: Locoregional Control.
• Secondary endpoint: Disease-Free Survival, Overall
Survival.
459 Patients
• H & N carcinoma.
• Squamous carcinoma.
• Stage III-IV
(Resectable).
• Radical surgery.
• High risk feature:
histologic evidence of 2
or more LN &/or extra-
capsular extension
and/or microscopically
involved resection
margin
R
Radiation therapy
(6600 to 7000 cGy)
+ Chemotherapy (Cis)*
Radiation therapy
(6600 to 7000 cGy)
* Cisplatin 100 mg/m2 D1, 22, 43
of RT.
Median follow-up of 45.9 months
Jay S. Cooper, MD
62
68. ZUCOD
Combined Analysis of RTOG 95-01
& EORTC 22931
Bernier J , Cooper JS , et al, Head Neck 2005; 27:843–850
Pooled the data sets from RTOG
9501 and EORTC 22931 to analyze
the effect of possible predictors of
benefit from chemotherapy.
ECE and/or microscopically
involved surgical margins were the
only risk factors for which the
influence of concurrent chemo-RT
was significant in both trials.
• ≥2 positive
LN
• Stage III-IV
• OP or OC
with level 4
or 5 LN
• PNI
• Vascular
embolism
• Positive
margin
• ECE
EORTC 22931 RTOG 95-01 68
70. ZUCODTAX324 (Dana Farber trial)
Study Design
494 Patients
• H & N carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Unresectable.
R
Induction chemotherapy
(PF)* x 3 cycles
Induction chemotherapy
(TPF)* x 3 cycles
* Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1 to
D5 (CIV) repeat cycle 3weeks.
* Docetaxel 75 mg/m2 D1 + Cisplatin 100 mg/m2 D1 + Fluorouracil 1000 mg/m2 D1
to D5 (CIV) repeat cycle every 3 weeksMedian follow-up of 42 months
Posner MR, et al, N Engl J Med 2007; 357:1705–1715.
Radiation therapy
(7000 cGy) +
Chemotherapy ‡
‡ Carboplatin (AUC 1.5)weekly for 7 weeks. .
Radiation therapy
(7000 cGy) +
Chemotherapy ‡
‡ Carboplatin (AUC 1.5)weekly for 7 weeks. .
Marshall R Posner, MD
70
71. ZUCOD
Outcome
Parameters
TPF
(n = 255)
PF
(n = 246)
HR (95% CI) p-value
Progression-free survival
Median (months) 36 13 0.71 (0.56-0.90) 0.004
Two-year 53% 42%
Three-year 49% 37%
Overall survival
Median (months) 71 30 0.70 (0.54-0.90) 0.006
Two-year 67% 55%
Three-year 62% 48%
Time to progression
Median (months) NR 14% 0.66 (0.50-0.86) 0.002
Two-year 57% 43%
Three-year 54% 40%
Treatment failure
Any 35% 45% 0.70 (0.53-0.92) 0.01
Locoregional 30% 38% 0.73 (0.54-0.99) 0.04
Distant 5% 9% 0.60 (0.30-1.18) 0.14
Second primary 4% 4%
TAX324 (Dana Farber trial)
Posner MR, et al, N Engl J Med 2007; 357:1705–1715.
71
72. ZUCOD
This study taught
us
• The efficacy of adding docetaxel to PF as TPF demonstrated,
increased 3-year PFS and increased 3-year OS.
• Patients who received TPF had less local and regional failure.
TAX324 (Dana Farber trial)
Posner MR, et al, N Engl J Med 2007; 357:1705–1715.
72
73. ZUCOD
Study Design
382 Patients
• H & N carcinoma.
• Squamous carcinoma.
• Previously untreated.
• Locally advanced
• Resectable & unresectable.
R
Induction chemotherapy
(CF)* x 3 cycles ± 1 more
N = 193
Induction chemotherapy
(PCF)* x 3 cycles ± 1 more
N = 180
* Cisplatin 100 mg/m2 D1 +
Fluorouracil 1000 mg/m2
D1 to D5 (CIV) repeat
cycle 3weeks.
‡ Cisplatin 100 mg/m2 D1,
22, 43 of RT
* Paclitaxel 175 mg/m2 D1 +
Cisplatin 100 mg/m2 D2 +
Fluorouracil 500 mg/m2 D2 to
D6 (CIV) repeat cycle every
3 weeks.
‡ Cisplatin 100 mg/m2 D1, 22,
43 of RT
CR or PR ≥ 80% response
CR or PR ≥ 80% response
PR < 80% response or SD
Surgery
Neck dissection
PR < 80% response or SD
• Primary endpoint: Response to ICT.
• Secondary endpoint: Overall survival, TTP, Toxicity.
Spanish Intergroup Trial
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45.
Radiation therapy
(7000 cGy) +
Chemotherapy (Cis)‡
Radiation therapy
(7000 cGy) +
Chemotherapy (Cis)‡
Radiation therapy
(7000 cGy) +
Chemotherapy (Cis)‡
Ricardo Hitt, MD
73
74. ZUCOD
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45.
Spanish Intergroup Trial
Outcome
Parameters
PCF
(n = 189)
CF
(n = 193)
p-value
Response rate
ORR 80% 68% <0.001
CR 33% 14% <0.001
Time to progression (TTP)
Median (months) 20 12 0.006
Overall Survival (OS)
Median (months) 43 37 0.06
Median (months) (unresectable ) 36 26 0.04
Toxicity
Intolerable 2% 4% >0.05
Mucositis 16% 53% <0.001
Neutropenia (Febrile) 37% (8%) 36% (5%) >0.05
Alopecia 10% 2% <0.001
Peripheral neuropathy 8% 3% >0.05
Death due to toxicity 2% 4% >0.05
74
75. ZUCOD
This study taught
us
• Induction chemotherapy with PCF was better tolerated and resulted in
a higher CR rate than CF.
Spanish Intergroup Trial
Hitt R. et al, J Clin Oncol. 2005;23(34):8636-45. 75
76. ZUCOD
Conclusions for Sequential
Chemoradiotherapy
• Sequential chemoradiotherapy is potentially a new option.
• Delivering standard induction chemotherapy followed by the standard
concurrent chemoradiotherapy generates a substantial overall
toxicity..
76
78. ZUCODNew active* agents in R/M
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
Drug Response rates (%)
Edatrexate 6-21%
Pemetrexed 26%
Vinorelbine 6-16%
Irinotecan 21%
Capecitabine 8-24%
Orzel 21%
S-1 27%
Paclitaxel 20-43%
Docetaxel 12-20%
* Activity defined as >15 % responses
78
79. ZUCOD
Single-agent treatment in R/M
(Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
Author (year) No. of patients Drugs randomized Response rate (%) Median OS (months)
Grose (1985) 100 Methotrexate 16% 4.6
Cisplatin 8% 4.1
Hong (1983) 38 Methotrexate 23% 6.1
Cisplatin 29% 6.3
Schomagel (l995) 264 Methotrexate 16% 6.1
Edatrexate 21% 6.1
Vermorken (1999) 95 Methotrexate 16% 6.8
Paclitaxel 3 h (or 24h) 11% (23%) 6.5
Guardiola (2004) 57 Methotrexate 15% 3.9
Docetaxel 27% 3.7
79
80. ZUCOD
Platinum-based combinations vs. single-
agent chemotherapy (Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
Author (year) No. of patients Agents Response rate (%) Median OS (months)
Jacobs (1992) 249 PF 32%* 5.5
P 17% 5.0
F 13% 6.1
Forastiere (1992) 277 PF 32%† 6.6
CF 21% 5.0
M 10% 5.6
Clavel (1994) 382 CABO 34%‡ 8.2
PF 31%§ 6.2
P 15% 5.3
Urba (2012) 795 P + PEM 12.1% 7.3
P + placebo 8% 6.3
P cisplatin, C carboplatin, M methotrexate, B bleomycin, V vincristine, PEM pemetrexed, CABO=P+M + B+V
* p=0.035, † p<0.001, ‡p<0.001, § p=0.003
80
81. ZUCOD
Platinum-Taxanes combinations in R/M: two
vs. three drugs (Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
Paclitaxel Docetaxel
ORR CR ORR CR
Two drugs
Cisplatin 32-39% 0% 33-52% 9-11%
Carboplatin 33-33% 4-8% 25% NR
Three drugs
Cisplatin/5-FU 31-38% 13% 44% 12%
Cisplatin/Ifosfamide 58% 17% ----- -----
Carboplatin/Ifosfamide 59% 17% ----- -----
NR not reported
81
82. ZUCOD
Second-line treatment in R/M
(Randomized trials)
Head and Neck Cancer, Multimodality Management, second edition: Springer 2016: ISBN
Author (year) Drug
Prior chemotherapy
for R/M-SCCHN
Median PFS (months) Median OS (months)
Pivot (2001) MTX 62% 1.5 3.7
Stewart (2009) MTX Unclear N/A 6.7
Machiels (2011) BSC (MTX)a 83% (17%)b 1.9 5.2
Numico (2002) Docetaxel 61% 4.0 (TTP) 6.0
Zenda (2007) Docetaxel Unclear 1.7 4.6
Specenier (2011) Docetaxel 77% 1.7 4.1
Argiris (2013) Docetaxel Unclear 2.1 (TTP) 6.0
MTX methotrexate, BSC best supportive care, PFS progression-free survival,
N/A not assessable, TTP time to progression, OS overall survival.
a 78 % of the patients received MTX.
b 17 % of the patients relapsed <6 months after Chemoradiation.
82
90. ZUCOD
SCC of Larynx is an
Immunosuppressive Tumor
Freiser ME, et al. Immunol Res. 2013; 57:52-69.
Kang H, et al. Nat Rev Clin Oncol. 2015; 12:11-26.
Immune modulation occurs on multiple levels within the SCC
microenvironment a, b
CD8+ cells: reduced counts; display defects such as low
responsiveness to cytokines and reduced proliferative
ability.
CD+4 cells: Th2 phenotype favored.
TAMs: secrete immunosuppressive molecules, impair CD8+
cells, promote Tregs production.
Soluble factors: cytokine profile includes
immunosuppressive molecules such as TGF-B, VEGF, IL-6
and IL-10, as well as apoptosis-promoting factors that
induce T-cell death.
Tregs: secrete immunosuppressive molecules and induce T-
cell and DC dysfunction.
NK cells: activity is impaired
DC: tumors prevent maturation of DCs, promoting T-cell
dysfunction and promoting Treg production. 90
91. ZUCODTumor and Immune
Biomarkers
Blank CU, et al. Science. 2016; 352:658-
Biomarkers are being evaluated to predict better outcome to Immuno-oncology
therapy.
Tumor Antigens
• Biomarkers indicative of
hypermutaion and neoantigens may
predict response to IO treatment.
Examples:
-TMB, MSI-high, neoantigens
Tumor Immune Suppression
• Biomarkers that identify tumor
immune system evasion beyond PD-
1/CTLA-4 to inform new IO targets
and rational combinations
Examples:
-Treg, MDSCs, LAG-3
Inflamed Tumor Microenvironment
• Biomarkers (intratumoral or
peritumoral) indicative of an inflamed
phenotype may predict response to
IO treatment.
Examples:
-PD-L1, inflammatory signatures.
Host Environment
• Biomarkers that characterize the
host environment, beyond tumor
microenvironment, mar predict
response to IO treatment.
Examples:
-Microbiome, germline genetics.
91
92. ZUCODRelevance of Immunotherapies
a. Cooper JS, et al, N Engl J Med 2004; 350:1937–1944, b. Bernier J et al, N Engl J Med 2004; 350:1945–1952, c. Vermorken JB, et al. Ann Oncol.
Unmet medical need for effective systemic therapy.
• In postoperative setting, adding cisplatin to radiation improve disease
control(a) and improve survival by ~10% compared with radiation alone (b).
• In metastatic/recurrent disease, systemic therapy achieve median survival
of <11 mon(C).
• Second-line therapy in fit patients is associated with median survival of <6
mon(C).
• Targeted therapy has been limited by high prevalence of tumor suppressor
mutations.
• Agents that are active in the face of cisplatin-resistance or TS mutation are 92
93. ZUCODRelevance of Immunotherapies
Existing therapies are highly morbid
• Cisplatin induced renal injury, ototoxicity, and increased risk for non-cancer
mortality.
• Chronic sequelae of radiation include hypothyroidism, swallowing dysfunction,
chronic pain, xerostomia, soft tissue necrosis and osteonecrosis.
• Extensive surgery can be associated with neck and shoulder dysfunction,
pain, dysphagia and feeding tube dependence, risk for postoperative infection
and bleeding and graft failure.
• Psychological sequelae include PTSD-like syndrome, lower likelihood of
returning to work.
93
94. ZUCODRelevance of Immunotherapies
Have hallmarks of immune tolerance
• Inflamed phenotype with tumor infiltrating lymphocytes and transcription of
interferon response genes.
• Expression of PD-L1 and PD-L2.
• High mutational load.
• Viral antigens in HPV and EBV-driven cancer.
• Neoantigens predicted by mutational profile.
94
96. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
• Response assessment: every 8 weeks.
• Primary endpoints: ORR (RECIST v1.1, central imaging vendor),
safety.
• Secondary endpoints: ORR (investigator), PFS, OS, response
duration, ORR in patients who are HPV+‡.† Treatment beyond progression was
allowed.
‡ Initial cohort only.
Study Design
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Pembrolizumab
200 mg q3w
N = 132
Patients
• R/M HNSCC
• Measurable disease
(RECIST v1.1)
• ECOG PS 0-1
• PD-L+ (initial cohort)
• PD-L1+ or PD-L–
(expansion cohort)
Initial Cohort
Pembrolizumab
10 mg/kg q2w
N = 60
Expansion Cohort
Continue untill:
• 24 month of
treatment†
• PD
• Intolerable toxicity
Combined
analyses of
initial and
expansion
cohorts
ZUCOD
Laura Q.M. Chow, MD
96
97. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Baseline Demographics
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Characteristics All patients (n = 132)
Age, median (range), years 60 (25-84)
Male 110 (83%)
Race
White 95 (72%)
Asian 29 (22%)
Other 8 (6%)
ECOG performance status
0 38 (29%)
1 94 (71%)
Smoking
Smoked 81 (61%)
Sum of target lesions at baseline,
median (range), mm
99 (16-664)
Characteristics All patients (n = 132)
Primary location
Oropharynx 60 (49%)
Oral cavity 17 (13%)
Larynx 16 (12%)
Hypopharynx 12 (9%)
Nasal cavity 8 (6%)
Nasopharynx 5 (4%)
Previous Adj &/or NAT 53 (40%)
No. of previous lines
0 24 (18%)
1 33 (25%)
2 27 (21%)
3 20 (15%)
≥4 28 (21%)
ZUCOD
97
98. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Characteristics
All patients (n = 132)
No. (%) 95% CI
ORR 24 (18%) 12% to 26%
Best overall response
CR 4 (3%) 1% to 8%
PR 20 (15%) 10% to 22%
SD 26 (20%) 13% to 28%
Non-CR/Non-PD 1 (1%) 0% to 4%
PD 61 (46%) 38% to 55%
NA 18 (14%) 8% to 21%
NE 2 (2%) 0.2% to 5%
Response Rate
ZUCOD
Treatment exposure & Response
Duration
98
99. ZUCOD
Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Maximum percentage change from baseline in target lesions
99
100. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Progression Free Survival
(PFS)
Overall Survival
(OS)
ZUCOD
Median PFS 2 months Median OS 8 months
100
101. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
Association of efficacy and programmed death-ligand 1 (PD-L1)
expression
ZUCOD
PD-L1 Status Tumor and Immune Cells Tumor Cells Only
Nonresponders
No.
Responders,
No.
Response, %
(95% CI)
Nonresponders,
No.
Responders,
No.
Response, %
(95% CI)
Negative (< 1%) 24 1 4%
(0.1 to 20)
36 7 16%
(7 to 31)
Positive (≥1%) 84 23 22%
(14 to 31)
72 17 19 %
(12 to 29)
101
102. Keynote-012 Trial:
Pembrolizumab in R/M Head and
Neck Carcinoma
Chow LQ, et al. J Clin Oncol. 2016;34:3838-3845.
PFS by PDL-1 expression
ZUCOD
OS by PDL-1 expression
102
103. FDA Approval of Pembrolizumab
in R/M Head and Neck Carcinoma ZUCOD
• On August 5, 2016, U.S. Food and Drug Administration granted accelerated
approval to Pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme
Corp., Kenilworth, NJ)
• For treatment of patients with recurrent or metastatic head and neck
squamous cell carcinoma (HNSCC) with disease progression on or after
platinum‐containing chemotherapy.
• Approval was based on the objective response rate (ORR) and duration of
response (DoR) in a cohort of patients in a nonrandomized multi‐cohort trial
(KEYNOTE‐012) that included 174 patients. 103
104. CheckMate 141 Trial: Nivolumab
in R/M Head and Neck Carcinoma
Ferris RL, et al. N Engl J Med. 2016;375:1856-1867.
Study Design
ZUCOD
361 patients
• R/M HNSCC of oral cavity,
pharynx, or larynx
• Not amenable to curative
therapy
• Progression on or within 6
mon of last dose of platinum-
based therapy.
• ECOG PS 0-1
• Documentation of p16 to
determine HPV status.
• No active CNS metastasis.
R
2:1
Nivolumab
3 mg/kg IV q2w
Investigator’s Choice
• Methotrexate 40mg/m2
IV weekly
• Docetaxel 30 mg/m2 IV
weekly
• Cetuximab 400 mg/m2
IV once, then 250
mg/m2 weekly
Primary endpoint:-
• OS.
Secondary
endpoint:-
• PFS.
• ORR.
• Safety.
• DoR.
• Biomarkers.
• QoL.
Stratify by previous Cetuximab.
104
106. Overall Survival (OS)
CheckMate 141 Trial: Nivolumab
in R/M Head and Neck Carcinoma
Ferris RL, et al. N Engl J Med. 2016;375:1856-1867.
ZUCOD
Progression Free Survival (PFS)
106
107. FDA Approval of Nivolumab in
R/M Head and Neck Carcinoma ZUCOD
• On November 10, 2016, U. S. Food and Drug Administration approved Nivolumab
(OPDIVO Injection, Bristol-Myers Squibb Company)
• For the treatment of patients with recurrent or metastatic squamous cell carcinoma
of head and neck (SCCHN) with disease progression on or after a platinum-based
therapy.
• Approval was based on statistically significant and clinically meaningful improvement
in overall survival (OS) in international, multi-center, open-label, randomized trial
(CheckMate 141) that included 361patients.
107
121. ZUCOD
Not one size fit
allTailoring management strategy according to risk of disease
recurrence, impact of disease on overall survival, and impact
of management on quality of life of your patient.
Take Home Message
121