Sunday, December 16, 2012

Ovarian Cancer

Stanford Hospital Cancer Physicians
UCSF Medical Center Cancer Specialists

National Cancer Institute, Comprehensive Cancer CentersClinical TrialsCancer Trials Support Unit,
NCI's Clinical Trials Cooperative Group Program

1. TRINOVA-3: A Study of AMG 386 or AMG 386 Placebo in Combination With Paclitaxel and Carboplatin to Treat Ovarian Cancer
2. Bevacizumab (Avastin), American Society of Clinical Oncology (ASCO)
Stanford Cancer Institute, Clinical Research Groups, Gynecology, Eligibility Flowcharts Gynecologic Cancer
 
National Comprehensive Cancer Network, NCCN Member InstitutionsGuidelines with Evidence Blocks
NCI Ovarian Cancer Treatments - Intraperitoneal Therapy, Angiogenesis Inhibitors (Bevacizumab)
Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review - anti-angiogenesis

List of trauma centers in the United States Adult Level I

ClinicalTrials.gov 

癌症研究所-臺灣癌症臨床研究合作組織 癌症臨床指引
婦女醫學資料庫 - 卵巢癌
European Society for Medical Oncology Guideline Gynaecologic Cancers

Peritoneal Cancer Index (PCI)
2007 Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systematic review with metaanalyses. 
2008 Why i.p. therapy cannot yet be considered as a standard of care for the first-line treatment of ovarian cancer: a systematic review.  
2009 Advanced cancer of the ovary: intraperitoneal chemotherapy as a new therapeutical option.
2009 Pros and cons of intraperitoneal chemotherapy in the treatment of epithelial ovarian cancer.
2010 Intraperitoneal catheter leads to prolongation of the time to normalization of serum CA125 levels.
2012 CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study. 
* 2011 Ovarian Cancer Diagnosis and Treatment

Postoperative nausea and vomiting NeiGuan Pericardium Meridian 6 accupressure, Zofran (5-HT3 antagonists)
Chyle - milky bodily fluid consisting of lymph and emulsified fats, or free fatty acids (FFAs).  A chyle fistula is a leakage of lymphatic fluid from the lymphatic vessels, typically accumulating in the thoracic or abdominal cavities, possibly leading to a chylothorax or chylous ascites, respectively.

HemOnc.org - A Free Hematology/Oncology Reference

Dosage:
Body Surface Area calculator 100lb 61" = 1.4 m^2
AUC (area under curve) serum creatinine (0.5-1.0) AUC6 = 460mg

全民健康保險藥品給付規定
Drugs@FDA FDA Approved Drug Products

FDA Hematology/Oncology (Cancer) Approvals & Safety Notifications recently approved drugs

Approved Drugs, Drugs used in UK
cisplatin 1978, carboplatin 1989, taxol 1992, doxil 1995, topotecan 1996, gemzar 2006, bevacizumab 2014, olaparib 2014

*TAXOL (paclitaxel) *1992+cisplatin
西藥許可證 衛署藥製字, 衛署藥輸字 抗癌藥
PACLITAXEL Paclitaxel Shortage
太平洋紫杉醇 Taiwan price 175mg/m^2 * 1.4 = 245mg = $8000
corticosteroids, diphenhydramine, and H2 antagonists.
premedication: corticosteroids (steroid dexamethasone 20 mg [causing stomach upset and effects of dexamethasone on the proliferation and apoptosis]) PO administered approximately 12 and 6 hours before TAXOL, diphenhydramine-Benadryl (or its equivalent) 50 mg IV 30 to 60 minutes prior to TAXOL, and fast-acting acid reducer H2 antagonists (cimetidine-Tagamet 300 mg [Tagamet HB 200], ranitidine-Zantac 50 mg [Zantac 150], famotidine-Pepcid [Pepcid AC 20mg]) IV 30 to 60 minutes before TAXOL.
Neutropenia - 500 - 1000 - 1500, G-CSF - Filgrastim (Neupogen), Pegfilgrastim (Neulasta), Tbo-filgrastim (Neutroval)
Anemia - blood transfusion, Epoetin alfa (Epogen/Procrit), Darbepoetin alfa (Aranesp) - erythropoiesis-stimulating agents (ESA) are not for cure
Thrombocytopenia -
Peripheral neuropathyGlutamin 10g*3/day, Pyridoxine (Vitamin B6 100mg) - might affect response and remission

aluminum hydroxide and magnesium hydroxide [Maalox]Bismuth subsalicylate [Pepto-Bismol]
fast-acting acid reducer H2 antagonists: cimetidine-Tagamet 300 mg [Tagamet HB 200], famotidine-Pepcid [Pepcid AC 20mg]
slow-acting Proton pump inhibitor (H2 antagonists) (Omeprazole [Prilosec OTC, Zegerid OTC])

European Human Medicines for Ovarian Neoplasms: Avastin (bevacizumab) and others

*ABRAXANE nab-paclitaxel protein-bound particles albumin-bound, 2005 breast, NSCLC

*TAXOTERE (docetaxel) breast, 1999 NSCLC, prostate, ..
歐洲紫杉醇 75mg/m^2 * 1.4 = 105mg = $21000

Cynviloq paclitaxel polymeric micelle in trial

*PARAPLATIN (carboplatin) *1989+cyclophosphamide
西藥許可證 衛署藥製字, 衛署藥輸字 卵巢癌
Carboplatin shortage
佳鉑帝 Taiwan price 460mg = $4000
allergic reactions - epinephrine (adrenaline), corticosteroid (dexamethasone), and antihistamine therapy: Benadryl (diphenhydramine)
Chemotherapy-induced nausea and vomiting (emesis) 24 hour premedication: antiemetics - 5-HT3 antagonists: Zofran (Ondansetron) 1991, Aloxi (Palonosetron delayed CINV 2-5 days) 2003; Dopamine antagonist Reglan metoclopramide (older)

*CISPLATIN *1978+cyclophosphamide [ETHYOL (amifostine) reducing renal toxicity]
西藥許可證 衛署藥輸字 轉移性睪丸腫瘤,轉移性卵巢腫瘤,膀胱內轉移型細胞腫瘤
順鉑 Taiwan price 75mg/m^2 * 1.4 = 105mg = $400
PLATINOL (cisplatin) Guidelines for Hospitalization for Chemotherapy outpatient 75mg/m^2
Mannitol
Emend (aprepitant) NK1 antagonists 2003 +  5-HT3 antagonists: Zofran (Aloxi) + Dexamethasone (steroid)
Epinephrine (adrenaline), corticosteroids, and antihistamines: Benadryl (diphenhydramine)

*Tamoxifen 2x20mg daily, increasing CA125

*relapsed at least 6 months after platinum-based treatment
GEMZAR (gemcitabine) *1996(non-small cell lung)-2006 (ovarian+carboplatin) last cytotoxic drug
西藥許可證 衛署藥製字, 衛署藥輸字 1.非小細胞肺癌2.胰臟癌3.膀胱癌4.乳癌5.卵巢癌
健澤, 吉西他滨 1000mg/m^2 * 1.4 * 2 = 2800mg = $13000
GEMCITABINE *
1. with carboplatin, bevacizumab (ascites) dosage C AUC4, G 1000mg/m^2 D1,D8, BEV 15mg/kg D1, q21D x 6c -> BEV q21DTrial, recurred 6 month after maintenanceduring maintenanceHE4, CA125
2. with cisplatin, bevacizumab Gemcitabine in Ovarian Cancer C 75mg/m^2, G 1250mg/m^2 D1, D8, BEV 15mg/kg D1...

*after 3 chemo
Lynparza Olaparib *2014 PARP-inhibitor for germline BRCA mutated, best for platinum sensitive, not somatic cells 
400mg*2 daily, Proton pump inhibitor (Pantoprazole) or H2 antagonists for dyspepsia, diarrhea, or nausea

*platinum-resistant, first or second relapse
Bevacizumab (Avastin) *2014 (with Taxol, Gemzar, PLD, Topotecan)
癌思停 15mg/kg/3weeks * 45kg = 675mg = $65000
Seeking Alpha: Roche's Avastin Should Get The Nod From The FDA On November 19

*after platinum
DOXIL (Liposomal Doxorubicin Hydrochloride) *1995 (also multiple myeloma)
微脂體小紅莓化療藥物合併鉑金藥物, 多柔比星脂质体
康利斯微脂粒 Caelyx 50mg/m^2 * 1.4 = 70mg = $43000
Doxil with Carboplatin - 30mg/m^2 + AUC 5 (4 weekly), escalated to AUC 6 and then 40mg
Maintenance 30–40 mg/m^2 given every 4–8 weeks, heart failure after cumulative 550mg/m^2
Early changes in CA125 after treatment with pegylated liposomal doxorubicin or topotecan do not always reflect best response in recurrent ovarian cancer patients
Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

*metastatic, failure of initial and subsequent chemotherapy
HYCAMTIN (topotecan) *1996 (also cervical, small cell lung cancer) Caris no
癌康定, 托泊替康 1.5mg/m^2 * 1.4 * 5 day = 10.5mg = $21500
with Bevacizumab schedule
1, topotecan 4mg/m^2 days 1, 8, 15 every 4 weeks + Avastin 10mg every 2 weeks
2. topotecan 1.25mg/m^2 days 1-5 every 3 weeks + Avastin 15mg every 3 weeks

Etoposide trial 1983 SCLC oral 50-60mg/m2/d for 21 days per 28 days
抑特癌 50*1.4*21 = 70m2*21 = $5000

Alkylating antineoplastic agent
*Cyclophosphamide Cytoxan *1959 (malignant disease)
癌德星
-Ifosfamide *1988 
-Melphalan

*Altretamine *1990

Other 3rd line
Pemetrexed Caris no
Vinorelbine
Capecitabine Caris no

Pazopanib (Votrient) tyrosine kinase inhibitor, angiogenesis inhibitor VEGF-R 800mg daily, 2009 renal, sarcoma
福退癌 200mg*4 $677 = $56868 / 3 weeks maintenance
result not as good for East Asian Womenreportbad for Asian WomenNeutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed more frequently in patients of East Asian descent 亞洲

Nivolumab Opdivo anti-PD-1, 3 mg/kg IV every 2 weeks

Side-effect Adverse-effects:
Carbo: Nausea, Vomiting, Electrolytes (sodium, magnesium) loss, Bone Marrow (Leukopenia, Neutropenia, Thrombocytopenia) (Transfusions)
Taxol: Alopecia, Peripheral Neuropathy, Myalgia (muscle pain), Neutropenia, Nausea
Gemzar: Nausea, Hematologic (Anemia, Neutropenia), Hepatic, Proteinuria, Fever
Doxil: Hand-foot syndrome, Nausea, Stomatitis, Asthenia (fatigue)
Topotecan: Neutropenia, Nausea, Alopecia, Infections

Cancer Focus Forum: Cancer Forums and News by PhD's

Chemotherapy sensitivity/resistance assays and other biomarker assays - Inspire Cancer FocusCSN
Human Tumor Stem Cell Drug Sensitivity Assays (190.7)
Retrospective Case Study to Validate Existing Chemoresponse Marker Test in Ovarian, Peritoneal or Fallopian Cancer Cases
Precision Therapeutics, Inc. ChemoFxRational Therapeutics, Weisenthal Cancer Group

HIPEC
Hyperthermia therapy
Hyperthermia in Cancer Treatment
Treatment Types Hyperthermia
Hyperthermia: Using Heat to Treat Cancer
Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Continuous hyperthermic peritoneal perfusion
Surgeon performs controversial cancer surgery named after him Sugarbaker
NYT: Hot Chemotherapy Bath: Patients See Hope, Critics Hold Doubts
OncLive: Chemo Controversy: An Inside Look at the 'Hot Chemotherapy Bath' 
A Patient’s Guide to HIPEC

2004 Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from ovarian cancer
* 2009 The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer. 
* 2009 Peritoneal carcinomatosis: patients selection, perioperative complications and quality of life related to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy
2012 Cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy in the treatment of advanced epithelial ovarian cancer.
2012 Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Where are we?
2012 Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Intraoperative Chemotherapy in the Treatment of Advanced Epithelial Ovarian Cancer
2015 Hyperthermic intraperitoneal chemotherapy for ovarian cancer: is there a role?

Recurrent 
2011 HIPEC in recurrent ovarian cancer patients: Morbidity-related treatment and long-term analysis of clinical outcome
2012 Survival benefit of adding HIPEC at the different time-points of treatmtnt of ovarian cencer: review of evidence  secondary CRS for stage III ovarian cancer and salvage CRS for recurrent ovarian cancer
2015 A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer
2015 Cytoreductive surgery and HIPEC in recurrent epithelial ovarian cancer: a prospective randomized phase III study
2015 The role of cytoreductive surgery and HIPEC in epithelial ovarian cancer CRS and HIPEC offer a significant survival benefit in patients with recurrent EOC. This observation applies to both platinum-sensitive and platinum-resistant disease.

American Society of Peritoneal Surface Malignancies
Peritoneal Surface Malignancies Conference
Peritoneal Malignancies Pals

aetna: hyperthermia for cancer therapy
Cigna: hyperthermia treatment for cancer
Anthem: hyperthermia for cancer therapy

2012 Survival benefit of adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer: review of evidence.

Consolidation / Maintenance treatment
2003 12 versus 3 months of maintenance paclitaxel
2006 9 Pegylated liposomal doxorubicin HCL (PLD; Caelyx/Doxil®): Experience with long-term maintenance in responding patients with recurrent epithelial ovarian cancer 30–40 mg/m2 given every 4–8 weeks
** 2009 follow-up of 12 versus 3 months
** 2010 Current status of maintenance therapy for advanced ovarian cancer 
2010 The addition of new drugs to standard therapy in the first-line treatment of ovarian cancer.
2010 Current academic clinical trials in ovarian cancer: Gynecologic Cancer Intergroup (GCIG) and United States National Cancer Institute (NCI) clinical trials planning meeting, May, 2009
2010 Practical considerations in ovarian cancer chemotherapy 
2011 Rethinking Ovarian Cancer: Recommendations for Improving Outcomes  
* 2011 Current and future directions of clinical trials for ovarian cancer.
** 2011 Maintenance therapy in ovarian cancer: Molecular basis and therapeutic approach (Review).
Opaxio, Oxytax, CT-2103, Polyglutamate Paclitaxel, Paclitaxel Poliglumex 
** 2011 Incorporation of bevacizumab in the primary treatment of ovarian cancer GOG-218
2012 Major clinical research advances in gynecologic cancer in 2011
2012 Therapeutic strategies in epithelial ovarian cancer
2013 Advanced ovarian cancer: what should be the standard of care?
** 2013 Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance
** 2015 Ovarian cancer standard of care: are there real alternatives?

CA125
Definitions for Response and Progression in Ovarian Cancer Clinical Trials Incorporating RECIST 1.1 and CA 125 response (partial) PR: 50% reduction for 4 weeks, a month; complete response CR: 35; stable disease SD; progressive disease PD
2000 Prognostic significance of CA 125 and TPS levels after 3 chemotherapy courses in ovarian cancer patients. < 35U/mL after 3 courses
2005 A multicenter study of CA 125 level as a predictor of non-optimal primary cytoreduction of advanced epithelial ovarian cancer.  400
2006 Pretreatment CA-125 and risk of relapse in advanced ovarian cancer nadir <=10 U/mL, 11-20, 21-35, PFS 24, 17, 7
2007 An early signal of CA-125 progression for ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy. >= 20 and double of nadir 56 days earlier
2008 CA125 velocity at relapse is a highly significant predictor of survival post relapse: results of a 5-year follow-up survey to a randomized placebo-controlled study of maintenance oregovomab immunotherapy in advanced ovarian cancer. CA125 < or =65 U/mL before cycle 3
2008 Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer  nadir <= 10 U/mL, PFS 42 vs 20, OS 84 vs 40
2008 Serum CA-125 level after 6 cycles of primary adjuvant chemotherapy is a useful prognostic factor for complete responders' survival in patients with advanced epithelial ovarian cancer nadir < 10, 10-21, 21-35, PFS 26, 14, 10, OS 105, 42, 37
2009 Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels. increase by 5 U/mL of nadir 58 days earlier
2009 Nadir CA-125 level is an independent prognostic factor in advanced epithelial ovarian cancer nadir <= 10, PFS 32.4 vs 16.8
2010 Preoperative serum CA-125 levels and risk of suboptimal cytoreduction in ovarian cancer: a meta-analysis. > 500U/mL neo-adjuvant
2010 CA125 nadir concentration is an independent predictor of tumor recurrence in patients with ovarian cancer: a population-based study nadir <= 5 U/mL
2010 Doubling time of serum CA125 is an independent prognostic factor for survival in patients with ovarian cancer relapsing after first-line chemotherapy.
2011 Possible use of CA-125 level normalization after the third chemotherapy cycle in deciding on chemotherapy regimen in patients with epithelial ovarian cancer: brief report. < 35U/mL after 3rd cycle
2011 Abagovomab: an anti-idiotypic CA-125 targeted immunotherapeutic agent for ovarian cancer
2011 Role of neutrophil to lymphocyte ratio as a prognostic indicator for epithelial ovarian cancer.  NLR should be less than 2.6
2011 Interaction between preoperative CA-125 level and survival benefit of neoadjuvant chemotherapy in advanced epithelial ovarian cancer. > 2000
2011 Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.
2011 Prediction of a high-risk group based on postoperative nadir CA-125 levels in patients with advanced epithelial ovarian cancer < nadir 18 U/mL
2012 The value of serum CA125 for the development of virtual follow-up strategies for patients with epithelial ovarian cancer: a retrospective study doubling of value and nadir > 10 
2012 Platelet to lymphocyte ratio as a prognostic factor for epithelial ovarian cancer should be less than 200-300

Progression Free Survival
2011 Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective
2011 Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort

Recurrence, resistant
2016 ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells P-glycoprotein inhibitors Tariquidar
2015 Novel Agents Signal Progress in the Management of Platinum-Resistant Ovarian Cancer, Topotecan+Avastin, Docetaxel+Avastin, Pemetrexed, Nab-Paclitaxel, Etirinotecan Pegol, low-dose oral cyclophosphamide, Olaparib, Rucaparib

Platinum Resistance in Ovarian Cancer OncLive
2011 Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort
2012 The Role of Secondary Surgery in Recurrent Ovarian Cancer
2013 CA-125–indicated asymptomatic relapse confers survival benefit to ovarian cancer patients who underwent secondary cytoreduction surgery 1.68 * nadir
2013 Should studies of maintenance therapy be maintained in women with ovarian cancer?
2014 Treatment options in recurrent ovarian cancer: latest evidence and clinical potential

2010 Weight, Physical Activity, Diet, and Prognosis in Breast and Gynecologic Cancers
2010 What surveillance plan should be advised for patients in remission after completion of first-line therapy for advanced ovarian cancer? 3, 3, 4, 6

2015 Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells
2014 Quercetin enhances apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway
2010 The prosurvival activity of ascites against TRAIL is associated with a shorter disease-free interval in patients with ovarian cancer

PARP, BRCAness, BRCA-like
2015 Olaparib in the management of ovarian cancer
2015 Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes.
2015 Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial
2014 PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies

Metronomic
metronomic ovarian papers
2014 Metronomic chemotherapy
2013 Bevacizumab and oral metronomic cyclophosphamide in platinum-resistant ovarian cancer
2013 The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum-resistant recurrent ovarian cancer

Immunotherapy
PD-1 Nivolumab, Pembrolizumab
2015 Immunotherapeutic approaches to ovarian cancer treatment Antibody, Immune checkpoint inhibitors, Vaccine strategies, Adoptive cell therapy, Combinatorial immunotherapy
2013 Antibody-based immunotherapy for ovarian cancer: where are we at?trial results, Abagovomab, Oregovomab

The Consequence of Oncomorphic TP53 Mutations in Ovarian Cancer

Ketogenic Diet carbohydrate restriction, metabolic therapy
2015 Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy
2014 Ketogenic diet does not “beat chemo for almost all cancers”
Thomas Seyfried Cancer as a Metabolic Disease
2014 Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism
2013 Tumor glycolysis as a target for cancer therapy: progress and prospects
2011 Is there a role for carbohydrate restriction in the treatment and prevention of cancer?

Women's Cancer Network, Find a Gynecologic Oncologist
台灣婦癌醫學會, 專科醫師名單, 成員服務醫院
台灣癌症臨床研究發展基金會
KingNet 國家網路醫院

日本婦人科腫瘍学会 卵巣がん治療ガイドライン

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