Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer (GYNE Paclitaxel + Carbo (dose-dense))

Transcription

1 Practice Guideline: Systemic Therapy Summary Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer (GYNE Paclitaxel + Carbo (dose-dense)) Gynecologic Oncology Disease Site Group Effective: February 2013 Required Update: April 2016 Annual Review: April 2015

2 Systemic Therapy Summary 2 ACKNOWLEDGEMENT AND SPONSORSHIP DISCLAIMERS There are no relevant conflicts of interest to disclose. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 2

3 Systemic Therapy Summary 3 Preface This document has been prepared by the Winnipeg Regional Health Authority/CancerCare Manitoba (WRHA/CCMB) Oncology Pharmacotherapeutic (P&T) Subcommittee s Systemic Therapy Summaries Working Group, as a means of disseminating drug information and formulary decisions made by the Subcommittee. The CCMB Provincial Pharmacy Program, Provincial Oncology Drug Program (PODP) and Clinical Practice Guidelines Initiative (CPGI) have contributed to the development of this summary. Systemic Therapy Summaries (STS) are being developed for drugs/or indications where the P&T Subcommittee, based on scientific data, has accepted clinical benefit. The P&T Subcommittee Chair and the CPGI Lead/Advisory Panel Chair approve all STS documents. The content of this STS was in large part adapted from the Formulary Addition Request submitted to the P&T Subcommittee by the CCMB Gynecologic Oncology (GYNE) Disease Site Group (DSG), February This document will be reviewed, and updated as necessary, once in every twelve-month period; unless emerging evidence from scientific research dictates otherwise. Purpose This document is intended as a guide to facilitate the safe and effective clinical use of dose-dense paclitaxel combined with carboplatin for advanced/metastatic ovarian cancer. For this purpose, it may be used by qualified and licensed healthcare practitioners involved with the care of oncology patients, which may include (but is not limited to): physicians, nurses, and pharmacists at CancerCare Manitoba, Community Cancer Programs Network (CCPN) sites and WRHA Community Oncology Program sites. Disclaimer Use of this document should not preclude the practitioner s independent clinical judgment, nor should it replace consultation with the oncologist. It is the responsibility of the practitioner to develop an individualized treatment plan for each patient under his/her care, and ideally this should take place within the context of a multidisciplinary team. The unique needs and preferences of the patient and the family should always be reflected in the plan of care. This document is not a comprehensive drug monograph. Practitioners must refer to other sources for complete drug information. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 3

4 Systemic Therapy Summary 4 Dose-Dense Paclitaxel combined with Carboplatin for Advanced/Metastatic Ovarian Cancer Protocol Code: G Y N E P a c l i t a x e l + C a r b o ( d o s e - d e n s e ) Developed by: Gynecologic Oncology Disease Site Group Date of Presentation to P&T Subcommittee: February 19, 2013 Treatment Recommendations The Gynecologic Oncology DSG recommends dose-dense paclitaxel with carboplatin be used for advanced stage ovarian/fallopian tube/peritoneal serous carcinoma who meet the inclusion criteria (see below). Treatment Intent Curative Prolongation of overall survival (OS) and progression free survival (PFS) Rationale The current standard of treatment for advanced stage ovarian cancer remains carboplatin and paclitaxel and more recently intraperitoneal (IP) chemotherapy. Dose-dense therapy is thought to act by shortening the interval between drug doses and therefore, be more effective for cell kill, although the combined dose remains the same. Dose-dense weekly paclitaxel has been studied in breast cancer and has shown an obvious benefit. 1-3 Clinical Benefit (Level Ib Evidence see Appendix I) A phase I study was performed investigating weekly paclitaxel for recurrent ovarian cancers. 4 A total of 77 cycles in 16 patients were analyzed and found a 66.6% response rate with a 33.3% complete response rate. The authors concluded that carboplatin (area under the curve [AUC] 5) and paclitaxel (80 mg/m 2 weekly) is well tolerated and a feasible regimen. 4 Several phase II trials were also performed showing promising results. 5-7 A phase II trial of weekly paclitaxel and carboplatin q3 weeks in 28 patients reported 77% of patients had a clinical response with 58% achieving a complete response. 5 Another large phase II trial examined 129 patients at 17 centers with weekly paclitaxel and carboplatin. 6 This study found a biochemical response of 74% and a clinical response of 56%. Median PFS was 21 months and OS was 43 months. Dose-dense paclitaxel has also been studied in recurrent ovarian cancer with promising results, and has quickly become a standard treatment for recurrent ovarian cancers. 8,9 Armstrong et al. performed a large study on IP cisplatin and paclitaxel for ovarian cancer. 10 Although this study concentrated on IP chemotherapy combined with IV therapy, the treatment arm included IV paclitaxel on day 1, IP cisplatin on day 2, and IP paclitaxel on day 8; versus the control arm of cisplatin on day 2, and paclitaxel on day 1. The IP arm of the trial showed a PFS advantage of 23.8 compared to 18.3 months and an OS advantage of 65.6 CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 4

5 Systemic Therapy Summary 5 compared to 49.7 months. Although this advantage was in the IP arm, many gynecologic oncologists feel that part of the survival advantage was due to the dose intensity of the chemotherapy. A large National Cancer Institute of Canada (NCIC) trial (OV-21) is currently underway further examining the utility of IP chemotherapy specifically. The treatment arms consist of IP chemotherapy (IP/IV CarboTaxol) versus IV chemotherapy (on days 1 and 8). Many new trials in the U.S.A are now incorporating dose-dense chemotherapy into their treatment protocols (e.g., GOG 252 and GOG 262). Further support for dose-dense paclitaxel combined with carboplatin for advanced/metastatic ovarian cancer comes from a large phase III randomized controlled trial at 85 centers. 11 This study included stage 2-4 epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancers. Patients were randomized to carboplatin with either weekly paclitaxel (80 mg/m 2 ) or routine paclitaxel (180 mg/m 2 q3 weeks). A total of 631 patients were enrolled in the study. The preliminary results showed a median PFS improvement of 28 versus 17.2 months (HR, 0.71) and a higher 3 year OS (75.1 versus 65.1%; Hazard Ratio [HR], 0.75). An update was also presented in 2012 with continued PFS advantage of 28.1 versus 17.5 months (p = ) and a 5 year OS advantage of 58.6 versus 51% (p = ). This large randomized phase III trial in primary treatment of ovarian cancer has been influential in gynecologic oncology. It showed that the combination of carboplatin with weekly paclitaxel was superior to standard therapy with an increase in OS of 7.6% at 5 years and an increase of PFS of 10.6 months. As a result of this study, dose-dense paclitaxel with carboplatin is becoming the standard of care for ovarian cancer and has become actively incorporated into all new research protocols. Patient Population and Selection Criteria Inclusion criteria Stage 2-4 ovarian/fallopian/peritoneal cancer (see Appendix IV); AND Serous adenocarcinoma; AND An Eastern Cooperative Oncology Group (ECOG) score of 0-3 (see Appendix II); AND Normal blood work (see Dose Modifications) Exclusion criteria Borderline ovarian tumour Synchronous malignancies Age > 75 years old Previous pelvic radiation therapy or chemotherapy (with the exception of neoadjuvant chemotherapy) Pre-existing peripheral neuropathy CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 5

6 Systemic Therapy Summary 6 CCMB Formulary Status 1. Formulary definition Formulary Implementation and Safety Considerations The regimen may be administered at all CancerCare Manitoba Facilities and Community Cancer Program Sites under the supervision of a Gynecologic Oncologist. Treatment may continue for up to 6 cycles dependent upon response. Treatment Regimen GYNE Paclitaxel + Carboplatin 1 cycle = 21 days Drug Dose CCMB Administration Guideline Paclitaxel 80 mg/m 2 on Days 1, 8 and 15 IV in 250 ml normal saline (NS) polyvinylchloride (PVC)-free over 1 hour Carboplatin AUC 5 on Day 1 IV in 250 ml NS over 1 hour CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 6

7 Systemic Therapy Summary 7 Pre-Medications and Supportive Care Drug Dose CCMB Administration Guideline Diphenhydramine 50 mg once on Days 1, 8 and 15 Orally Ranitidine 150 mg once on Days 1, 8 and 15 Orally Methylprednisolone 100 mg once on Days 1, 8 and 15 IV once over 15 min in 50 ml of NS Ondansetron 16 mg once on Days 1, 8 and 15 Orally Suggested Outpatient Prescriptions Aprepitant 125 mg on Day 1, prior to chemotherapy 80 mg on Days 2 and 3 Orally Dexamethasone 4 mg on Days 1-3, 9, 10, 16 and 17 of chemotherapy Orally, twice daily Metoclopramide 10 mg Orally, 4 times a day, prn for nausea Granisetron 1 mg on Days 9 and 16 Orally, twice daily Filgrastim mcg on Days 4-6, 9-11 and starting after cycle 2 Subcutaneous injection CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 7

8 Systemic Therapy Summary 8 Clinical Monitoring and Follow-Up Recommendations Hematology, chemistry and required tests 2 days prior to Day 1: o CBC, creatinine, urea, liver function tests (LFTs) (bilirubin, AST, alkaline phosphatase, ALT, lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT)), electrolytes, calcium, magnesium and phosphate Day 6 and Day 13: o CBC, creatinine Clinical toxicity assessment (CTCAE version 4.0, see Appendix III) Prior to each cycle: o Toxicity assessment includes nausea and vomiting, ototoxicity, allergic reaction, nephrotoxicity, myelosuppression and neurotoxicity Assessment of treatment response Treatment may continue for up 6 cycles dependent upon response Response will be assessed clinically, biochemically (CA125) and with selective diagnostic imaging (e.g., CT scan, MRI and PET scan) Common or Clinically Important Adverse Events 12,13 (Refer to individual drug monographs for full details of adverse events) Myelosuppression ± infection/ bleeding Severe neutropenia occurs in 27-50% of patients receiving paclitaxel. Myelosuppression is dose- and schedule-dependent but is not cumulative. Toxicity may be more severe in HIV patients, especially infection and neutropenia Occurs in 25% of patients receiving carboplatin. Patients with renal dysfunction, those receiving nephrotoxic drugs, with poor performance status, elderly or those with prior exposure to cisplatin may experience more prolonged and severe myelosuppression. Anemia is more common than with cisplatin, may be cumulative and transfusions may be required Neuropathy Occurs in 64% of patients (4% severe) receiving paclitaxel. It is dose-related and cumulative. Common symptoms include numbness, tingling and/or burning pain in a glove-and-stocking distribution CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 8

9 Systemic Therapy Summary 9 Mild symptoms usually improve or resolve completely within several months after discontinuation of therapy. Pre-existing neuropathies are not a contraindication to treatment with paclitaxel. The development of severe symptoms may occur and requires a 20% dose reduction for each subsequent course of paclitaxel Alopecia Occurs in 93% of patients receiving paclitaxel. Rarely permanent Diarrhea, mucositis Occurs in 38% and 31% of patients, respectively, receiving paclitaxel Edema Occurs in 21% of patients receiving paclitaxel Fatigue Occurs in 17% of patients receiving paclitaxel Nausea, vomiting Occurs in 52% of patients receiving paclitaxel Occurs in 53% of patients receiving carboplatin Hypersensitivity Anaphylaxis occurs in 41% of patients (2% severe) receiving paclitaxel Myalgia, arthralgia Occurs in 60% of patients (12% severe) receiving paclitaxel Increases in LFTs Occurs in 22% of patients (severe rare) receiving paclitaxel Occurs in 36% of patients (transient) receiving carboplatin Nephrotoxicity, electrolyte abnormalities Electrolyte imbalance occurs in 37% of patients receiving carboplatin. May cause decrease in Na, K (16%), Ca (5%) and Mg (37%). Nephrotoxicity occurs in 25% of patients. May be severe and exacerbated in patients receiving concomitant aminoglycosides Cardiovascular Hypotension and bradycardia have been observed during infusion of paclitaxel and are usually asymptomatic, but not dose or schedule-dependent. Severe events should be managed appropriately and dose interrupted/discontinued. Continuous ECG monitoring should be performed if patient receives subsequent paclitaxel therapy *CTCAE v.4.0 See Appendix III CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 9

10 Systemic Therapy Summary 10 Precautions 12,13 Pregnancy Paclitaxel is clastogenic, genotoxic, embryotoxic, fetotoxic and should not be used during pregnancy. Carboplatin is embryotoxic, mutagenic, teratogenic, carcinogenic and should not be used during pregnancy. Breast-feeding Paclitaxel is not recommended due to potential secretion into breast milk. Carboplatin is not recommended due to potential secretion into breast milk. Fertility Paclitaxel reduces fertility. Carboplatin s effect on fertility has not yet been established. Contraindications In patients with a severe hypersensitivity reaction to paclitaxel or other drugs formulated in Cremophor EL (polyethoxylated castor oil) or in patients with severe baseline neutropenia (ANC < 1.5 x 10 9 /L; < 1 x 10 9 /L in patients with AIDS-related Kaposi s). Congestive heart failure (including left ventricular ejection fraction decrease) has been reported in patients who have received other chemotherapy agents, especially anthracyclines. In patients with severe renal impairment, severe myelosuppression, bleeding tumours and those with a history of severe allergic reactions to carboplatin or other platinum-containing compounds. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 10

11 Systemic Therapy Summary 11 Dose Modifications 14 Hematological Day 1 ANC (x 10 9 /L) Platelets (x 10 9 /L) Chemotherapy Dose 1.0 and > % < 1.0 or < 75 Hold chemotherapy for one week. If persistent, decrease dose of chemotherapy by 20% Days 8 and 15 ANC (x 10 9 /L) Platelets (x 10 9 /L) Chemotherapy Dose 0.5 and > % < 0.5 or < 50 Hold chemotherapy for one week. If persistent, decrease dose of chemotherapy by 20% Neuropathy Grade Chemotherapy Dose 1 100% 2 Decrease paclitaxel by 20% 3 or 4 Hold chemotherapy and consider switching regimen Ototoxicity Grade Chemotherapy Dose 1 Decrease carboplatin by 20% 2-4 Discontinue carboplatin and consider switching regimen CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 11

12 Systemic Therapy Summary 12 Adequate liver function Serum bilirubin x ULN Serum transaminases x ULN If the abnormal liver function tests are clearly attributable to liver metastases then serum transaminases (ALT and/or AST) values < 5 x ULN are permitted Adequate renal function Serum creatinine ULN or calculated creatinine clearance > 50 ml/min Hypersensitivity reactions For mild symptoms it is possible to complete the infusion of paclitaxel under close supervision. For moderate symptoms: Stop infusion and give diphenhydramine mg IV and methylprednisolone 125 mg IV Once symptoms have resolved, resume paclitaxel infusion at a rate of 10% of original rate for 15 minutes, then at 25% of original rate for 15 minutes, and if no further symptoms develop, continue at original rate until infusion is complete For severe symptoms: Stop infusion; give diphenhydramine and methylprednisolone as above. Use epinephrine and bronchodilators if indicated Do not rechallenge with paclitaxel Desensitization and/or antihistamine/steroid prophylaxis may allow retreatment of carboplatin CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 12

13 Systemic Therapy Summary 13 Drug Interactions 12,13 Drug-drug interactions For paclitaxel Cisplatin - increases toxicity of paclitaxel if cisplatin given prior (within hours) to paclitaxel. Give paclitaxel before cisplatin. May also increase risk of renal failure in gynecological cancers. Doxorubicin (after paclitaxel with prolonged infusions) - increases neutropenia and stomatitis. Epirubicin - increases systemic exposure to epirubicin or its metabolites. May be schedule-dependent. Give epirubicin first. Cyclophosphamide (given after paclitaxel) - increases myelosuppression. Radiation - radiation pneumonitis. Carboplatin (given after paclitaxel) - decreases thrombocytopenia. CYP 2C8 substrates (e.g, paclitaxel, sorafenib, amiodarone) - may increase/decrease effects of substrates of paclitaxel. CYP 3A4 substrates (e.g., verapamil, etoposide, dexamethasone, vincristine) - may increase/decrease effects of substrates of paclitaxel. Inducers of CYP 2C8 - may decrease paclitaxel levels and effects. CYP 2C8 inhibitors (e.g., gemfibrozil, montelukast) - may increase paclitaxel levels and effects. CYP 3A4 inducers (e.g., phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John s Wort) - may decrease paclitaxel levels and effects. CYP 3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir) - may increase paclitaxel effects. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 13

14 Systemic Therapy Summary 14 Drug-drug interactions For carboplatin Aminoglycosides - exacerbates nephro- and ototoxicity. Phenytoin - decreases serum phenytoin level. Other nephrotoxic drugs - increases incidence of renal dysfunction. Warfarin - risk of increased international normalized ratio (INR) or bleeding. Drug-food interactions For paclitaxel Fruit or juice from grapefruit, Seville oranges or starfruit - may increase paclitaxel levels and effects. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 14

15 Systemic Therapy Summary 15 References 1. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21(6): Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol J Clin Oncol 2008;26(10): Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008;358(16): Erratum in: N Engl J Med 2008;359(1):106. N Engl J Med 2009;360(16): Leiser AL, Maluf FC, Chi DS, et al. A phase I study evaluating the safety and pharmacokinetics of weekly paclitaxel and carboplatin in relapse ovarian cancer. Int J Gynecol Cancer 2007;17(2): Rose PG, Smrekar M, Fusco N. A phase II trial of weekly paclitaxel and every 3 weeks of carboplatin in potentially platinum-sensitive ovarian and peritoneal carcinoma. Gynecol Oncol 2005;96(2): Sehouli J, Stengel D, Mustea A, et al. Weekly paclitaxel and carboplatin (PC-W) for patients with primary advanced ovarian cancer: results of a multicenter phase-ii study of the NOGGO. Cancer Chemother Pharmacol 2008;61(2): Pignata S, Breda E, Scambia G, et al. A phase II study of weekly carboplatin and paclitaxel as first-line treatment of elderly patients with advanced ovarian cancer. A Multicentre Italian Trial in Ovarian cancer (MITO-5). Crit Rev Oncol Hematol 2008;66(3): Baird RD, Tan DS, Kaye SB. Weekly paclitaxel in treatment of recurrent ovarian cancer. Nat Rev Clin Oncol 2010;7(10): Lortholary A, Largillier R, Weber B, et al. Weekly paclitaxel as a single agent or in combination with carboplatin or weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial from Groupe d Investigateurs Nationaux pour l Etude des Cancer Ovarians (GINECO). Ann Oncol 2012; 23(2): Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med Jan;354(1): Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K; Japanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009;374(9698): CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 15

16 Systemic Therapy Summary CancerCare Ontario Chemotherapy Regimen Carboplatin. Updated March [Accessed 26 Sept 2014]. 13. CancerCare Ontario Chemotherapy Regimen Paclitaxel. Updated March [Accessed 26 Sept 2014]. 14. CancerCare Ontario Chemotherapy Regimen CRBPPACL. Updated August [Accessed 26 Sept 2014]. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 16

17 Systemic Therapy Summary 17 CCMB Contributors Miss. Lisa Havixbeck, BSc (Pharm) Mrs. Kristi Hofer, BSc (Pharm), Senior Pharmacist, Operations Contact Physician Dr. Robert Lotocki, Gynecologic Oncologist, Gynecologic Oncology Disease Site Group Approved By Dr. Ralph Wong, Medical Oncologist Chair, WRHA/CCMB Oncology Pharmacotherapeutic Subcommittee Dr. Piotr Czaykowski, Medical Oncologist Co-Lead and Advisory Panel Chair, CCMB Clinical Practice Guidelines Initiative Dr. Vallerie Gordon, Medical Oncologist Co-Lead and Advisory Panel Chair, CCMB Clinical Practice Guidelines Initiative We gratefully acknowledge the support of CancerCare Manitoba, the CancerCare Manitoba Foundation and the Provincial Oncology Clinical Practice Guidelines Initiative. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 17

18 Systemic Therapy Summary 18 Appendix I Levels of Evidence Ia Evidence obtained from meta-analysis of randomised controlled trials Ib Evidence obtained from at least one randomised controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomisation IIb Evidence obtained from at least one other type of well-designed, quasi- experimental study III Evidence obtained from well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities British Committee for Standards in Haematology CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 18

19 Systemic Therapy Summary 19 Appendix II ECOG Performance Status Scale 0 Fully active, able to carry on all pre-disease activities without restriction (Karnofsky ) 1 Restricted in physical strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework or office work (Karnofsky 70-80) 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about greater than or equal to 50% of waking hours (Karnofsky 50-60) 3 Capable of only limited self-care, confined to bed or chair greater than or equal to 50% of waking hours (Karnofsky 30-40) 4 Completely disabled, cannot carry on any self-care, totally confined to bed or chair (Karnofsky 10-20) Oken MM, Creech RH, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5: , Eastern Cooperative Oncology Group Robert Comis M.D., Group Chair CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 19

20 Systemic Therapy Summary 20 Appendix III Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Publish Date: 18 May 2009 Grades Grade refers to the severity of the AE. The CTCAE displays grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. A semi-colon indicates or within the description of the grade. A single dash (-) indicates a grade is not available. Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for grade selection. Grade 5: Grade 5 (Death) is not appropriate for some AEs and therefore is not an option Activities of Daily Living (ADL): * Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. ** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. CTCAE document available at: Accessed 10 September 2010 CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 20

21 Systemic Therapy Summary 21 Appendix IV FIGO Ovarian, Fallopian Tube and Peritoneal Cancer Staging System Stage Definition I IA Tumour limited to one ovary IB Tumour limited to both ovaries or fallopian tubes IC One or both ovaries with a ruptured capsule, tumour on ovarian surface, malignant cells in ascites or peritoneal washings II IIA Pelvic extension and/or implants on uterus and/or fallopian tube(s) IIB Pelvic extension to and/or implants on other pelvic intraperitoneal tissues III IIIA(i) Regional lymph node metastasis and/or microscopic peritoneal involvement beyond the pelvis IIIA IIIA (ii) Metastasis > 10 mm in greatest dimension IIIA2 Microscopic peritoneal involvement above the pelvic brim and/or regional lymph node metastasis IIIB Peritoneal metastasis beyond pelvic brim 2 cm in greatest dimension and/or regional lymph node metastasis IIIC Peritoneal metastasis beyond pelvis > 2 cm in greatest dimension and/or regional lymph node metastasis IV IVA Pleural effusion with positive cytology IVB Metastases to extra-abdominal organs National Cancer Institute. Updated 08 February Accessed 02 March CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 21

22 Systemic Therapy Summary 22 CancerCare Manitoba 675 McDermot Avenue Winnipeg, Manitoba, Canada R3E 0V9 CCMB STS: GYNE Paclitaxel + Carbo (dose-dense) February 2013 Effective: February 2013 Approved: April 2015 CancerCare Manitoba, February All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organization, or for commercial purposes is allowed without written permission of CancerCare Manitoba. CCMB, STS: Dose-Dense Paclitaxel Combined with Carboplatin for Advanced/Metastatic Ovarian Cancer p. 22