GYNECOLOGIC MALIGNANCIES

Transcription

1 GYNECOLOGIC MALIGNANCIES Nuttapat Saengsukkasemsak, BP, Pharm.D, BCOP Clinical oncology pharmacist Department of Pharmacy, Siriraj hospital 29 th March 2018

2 Outline 1. Epithelial Ovarian Cancer 2. Cervical Cancer 3. Endometrial Cancer

3 Epithelial Ovarian Cancer

4 Etiology and Pathogenesis 85-90% ovarian cancers are sporadic Incessant ovulation is related to her number of ovulatory cycles Lifetime risk < 2% of developing Ovarian Cancer 10-15% ovarian cancers are familial and hereditary syndromes BRCA1, BRCA2 mutation Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) Lifetime risk > 50% of developing Ovarian Cancer Lancet (London, England). 1971;2(7716):163. Human pathology. 2011;42(7):

5 BRCA 1 mutation BRCA 2 mutation HNPCC Chromosome 17q21 13q12 MSH2, MSH6, PMS2 and MLH1 (chromosome 3) Breast CA risk 65-74% 65-74% - Ovarian CA risk 39-46% 12-20% 10-15% Other cancer risk - - Colon 80% Endometrial 60% Breast CA the 10- year actuarial risk of developing Ovarian Cancer Hereditary Ovarian Cancer 12% 6% - Histology ACOG Practice Bulletin #103, Serous and Endometrioid Serous and Endometrioid - 5

6 Risk Factors Increased risk Increased age Nulliparity due to increased number or duration of ovulatory cycles Early menarche, late menopause Use of fertility drug Estrogen alone hormone replacement therapy Decrease risk Tubal Ligation Hysterectomy, oophorectomy and/or salpingectomy Multiple pregnancies and breast-feeding Prolonged oral contraceptives (OCP): decreases risk of ovarian cancer > 50% after 5 years of use American journal of epidemiology. 1988;128(3): Lancet (London, England). 2008;371(9609):

7 Pathophysiology/Pathology Most common type of ovarian cancer Epithelial adenocarcinoma (> 90%) Germ cell tumors (15-20%) Sex-cord Stromal tumors (5%) 75-80% of patients are diagnosed with Stage III or IV disease 7

8 Subtypes of Adenocarcinoma Five primary histopathology subtypes 1) High-grade serous (70%) most common type 2) Endometrioid (10%) 3) Clear-cell (10%) associated with a poor prognosis 4) Mucinous (3%) 5) Low-grade serous (<10%) 8

9 Grading of Adenocarcinoma Grade 1 well differentiated Grade 2 moderately differentiated Grade 3 poorly differentiated; most virulent 9

10 Stage of disease Prognostic Factor Stage 5-years survival (%) I II III IV Volume of residual disease Histology subtype and grade High-grade tumors are worse than low-grade tumors Clear cell and carcinosarcoma >> poor prognosis 10

11 Screening for Ovarian Cancer There is no evidence that screening for Ovarian Cancer leads to earlier detection or improved survival Nonetheless, the following have been or are being used TVS CA125 Pelvic examination 11

12 PLCO Trail Buys et al. Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian cancer screening randomized controlled trial. JAMA 2011; 305: ,216 women aged ,105 : annual screening (CA years, TVS 4 years) 39,111 : no screening Maximum follow-up 13 years (median 12.4 years) Primary outcome: mortality from ovarian cancer Secondary outcome: incidence of ovarian cancer and complications from screening examinations and diagnostic procedures 12

13 PLCO Trail Screening Observation RR Ovarian cancer (Cl 95%, ) Death from ovarian Cancer (Cl 95%, ) 3285 women had false-positive results; resulting in 1080 surgeries 163 women experienced at least one serious complication (15%) [infectious complications 40%] Conclusion: simultaneous screening with CA125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. 13

14 Screening (Symptoms) Goff BA et al. Development of an ovarian cancer screening index, possibilities for earlier detection. Cancer 2007; 109: Pelvic pain Increased abdominal size Difficulty eating Abdominal pain Bloating Feeling full A symptom index was considered positive if these 6 symptoms were reported >12 days a month for two consecutive months but were present for <1 year Sensitivity Early stage disease (56.7%) Late stage disease (79.5%) Specificity Women >50 (90%) Women <50 (86.7%) 14

15 Prevention Oral contraceptives Use 5 yrs, decreases risk 50% Protection up to 30 yrs after stop Lancet 2008;371(9609):

16 Prevention Salpingo-oophorectomy used by carriers of BRCA1 or BRCA2 mutations (high-risk patient) to reduce risks of ovarian cancer Not recommended for low-risk patients Domchek et al. JAMA 2010; 304:

17 Diagnosis 1. Present adnexal mass and elevated CA-125 (normal CA-125 = 0-35 IU/mL) 2. Diagnosis workup : Pelvic examination Imaging: pelvic ultrasound, CT or MRI Barium enema (if colon cancer is in the differential diagnosis) Family history (for genetic counseling) 17

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19 Treatment of early stage ovarian cancer (stage I and II) Goal is cure Comprehensive surgical staging for all patients Pathology divided into favorable vs. unfavorable Favorable Unfavorable Stage IA or IB grade 1 Stage IA or IB grade 2 or 3 Stage IC Stage II with ascites, rupture capsule or clear cell No further therapy Adjuvant Chemotherapy 19

20 Surgical staging TAH/BSO, omentectomy, pelvic and para-aortic lymph node sampling, appendectomy, peritoneal biopsies, cytologic washings 20

21 Trials of adjuvant treatment in early stage ovarian cancer Trial Patients Regimen Outcome Comments ICON newly diagnosed - Stage I or II EOC Sx >> - Single agent carboplatin x 6 cycle - Cyclophosphamide, Adriamycin and Cisplatin x 6 cycle - Observation PFS and 5-year survival statistically improved with chemotherapy Included patient with gr. 1 tumors (not currently treated in US) ACTION newly diagnosed - Stage IA, grade 2 or 3 - Stage IB, grade 2 or 3 - Stage IC, any grade - Stage II, any grade, complete resection - Clear cell histology Sx>> - 4 cycles of a platinum-agent (single carboplatin or cisplatin ) + cyclophosphamide - Observation PFS statistically significantly improved with adjuvant CMT in patients with nonoptimal staging Excluded patient with stage IA or IB grade 1 21

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23 Early ovarian cancer (Stage I) Comprehensive surgical staging followed by treatment based on stage Current standard is Taxane plus Platinum Taxane (paclitaxel or docetaxel) plus a platinum (cisplatin or carboplatin) administered intravenously for 3-6 cycles 23

24 Early ovarian cancer (Stage I) GOG 157: Randomized phase III trial of evaluate 3 vs. 6 cycles of adjuvant treatment in early stage EOC Eligibility: Stage IA, grade 3 Stage IB, grade 3 Stage IC, any grade Stage II, any grade, complete resection Clear cell histology Unfavorable Surgery: TAH/BSO Peritoneal washings for cytology Omentectomy Bilateral pelvic and aortic node dissections Peritoneal biopsies Carboplatin (AUC 7.5) + Taxol (175 mg/m2) Q21 days x 3 cycles Carboplatin (AUC 7.5) + Taxol (175 mg/m2) Q21 days x 6 cycles Gynecol Oncol 2006: 102:

25 GOG 157: Results 25

26 3 vs. 6 : Subgroup analysis Gynecologic oncology. 2010; 116(3):

27 Advanced ovarian cancer (Stage III, Stage IV) Key topics for advanced ovarian cancer History of GOG studies/rise of Carboplatin/Taxol Intraperitoneal chemotherapy Dense dose chemotherapy Neoadjuvant chemotherapy Bevacizumab in the first line of EOC Maintenance therapy 27

28 Treatment of Advanced ovarian cancer (Stage III, Stage IV) Goal is cure (cure decrease in Stage IV or unresectable) Prognosis is poor 20% 5-year survival, mo. Of median overall survival Comprehensive surgical staging by a gynecological oncologist for all patient Optimal cytoreduction: < 1 cm residual tumor Sub-optimal cytoreduction: > 1 cm residual tumor Adjuvant CMT with 6 cycle of taxane + platinum is standard of care Intraperitoneal CMT : appropriately selected pt. 28

29 Trials of adjuvant treatment in advanced stage ovarian cancer Trail Patients Regimen Outcomes Comments GOG-111 (1996) 485 pts with EOC Stage III Stage IV Residual disease > 1cm Cyclophosphamide 750 mg/m2 + Cisplatin 75 mg/m2 Q 21 days x 6 cycles vs. Paclitaxel 135 mg/m2 over 24 hrs + Cisplatin 75 mg/m2 Q 21 days x 6 cycles Paclitaxel + cisplatin Statistically significantly improved CR PFS OS Standard of care shifted to Paclitaxel and Cisplatin GOG-158 (2003) 792 pts with optimal debulked Stage III Residual disease < 1 cm Cisplatin 75 mg/m2 + Paclitaxel 135 mg/m2 over 24 hrs infusion Q 21 days X 6 cycles vs. Carboplatin (AUC 7.5) + Paclitaxel 175 mg/m2 over 3 hrs infusion Q 21 days X 6 cycles Carboplatin + paclitaxel is not inferior to cisplatin + paclitaxel CR and OS not different between arms Carboplatin + paclitaxel preferred Equal efficacy reduced hematologic toxicity (accept thrombocytopenia) Less non-hematologic toxicity 29

30 Trials of adjuvant treatment in advanced stage ovarian cancer Trail Patients Regimen Outcomes Comments SCOTROC (2004) 1077 patients Stage III/IV (80%) Serous histology (44%) Residual disease Microscopic (33%) 2 cm (30%) > 2cm (37%) Carboplatin (AUC 5) + Docetaxel 75 mg/m2 over 1 hr infusion, Q 21 days X 6 cycles vs. Carboplatin (AUC 5) + Paclitaxel 175 mg/m2 over 3 hrs infusion, Q 21 days X 6 cycles No different in PFS Docetaxel significantly with More gr.3-4 neutropenia Less gr.2-4 neurotoxicity QOL better than paclitaxel (less weakness, pain, and neurotoxicity) Docetaxel: Equal efficacy Less neurotoxicity Less hypersensitivity 30

31 Trials of adjuvant treatment in advanced stage ovarian cancer Trail Patients Regimen Outcomes Comments Pignata (2014) 822 patients Stage IC IV ovarian and primary peritoneal cancer Optimal surgical ECOG 0-2 Carboplatin (AUC 6) + Paclitaxel 175 mg/m2 over 3 hrs infusion, q 3 weeks X 6 cycles VS. Carboplatin (AUC 2) + Paclitaxel 60 mg/m2 IV once weekly for 18 weeks No different in PFS Every 3 wks significantly with More gr.3-4 hematologic toxicity More gr.2 neurotoxicity QOL was worse for patient treated with q 3 wks. NCCN recommends : weekly regimen for elderly or poor ECOG performance status 31

32 Intraperitoneal Chemotherapy Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. Methods- Eligibility: Stage III Residual disease 1cm Primary endpoint PFS- measured from the date of randomization OS- measured from the date of randomization Treatment groups Paclitaxel (135 mg/m 2 for 24 hours) IV and Cisplatin (75 mg/m 2 ) IV Q 21 days for 6 cycles Paclitaxel (135 mg/m 2 for 24 hours) IV and Cisplatin (100 mg/m 2 ) IP D2, Paclitaxel (60 mg/m 2 ) IP D8 Q 21 days for 6 cycles NEJM 2006; 354:

33 Intraperitoneal Chemotherapy IV IP P value N Completed 6 cycles 83% 42% Grade 3-4 Leukopenia GI Fatigue Metabolic Pain Thrombocytopenia Neuropathy Infection 64% 24% 4% 7% 1% 4% 9% 6% 76% 46% 18% 27% 11% 12% 19% 16% Deaths 127 (60%) 101 (49%) p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p=0.002 p=0.001 p=0.001 PFS 18.3 mo 23.8 mo RR 0.77 (95% CI), p=0.05 OS 49.7 mo 65.6 mo RR 0.73 (95% CI), p=

34 Intraperitoneal Chemotherapy Candidates for IP therapy: 1. Adjuvant therapy for EOC stage IIIC (optimal surgical cytoreduction <1 cm residual disease) 2. Good performance status 3. No history of prior bowel surgery or bowel surgery at the time of primary therapy 4. Age < 65 34

35 Dose-dense Chemotherapy Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open label, randomized controlled trial Methods: Eligibility Stage II-IV Residual disease > 1cm included Primary endpoint PFS- measured from the date of randomization Secondary endpoint OS- measured from the date of randomization Response rate Adverse events Treatment groups Paclitaxel (180 mg/m 2, 3 hour infusion) and Carboplatin (AUC 6) IV Q 21 days for 6 cycles Paclitaxel (80 mg/m 2, 1 hour infusion) D1,8,15 and Carboplatin (AUC 6) D1 IV Q 21 days for 6 cycles 35 Lancet 2009; 374:

36 Dose-dense Chemotherapy Results 632 patients Stage II (19%) III (66%) IV (15%) Serous histology (56%) Grade 3 (24%) Residual disease 1 cm (46%) Primary debulking surgery (89%) Standard Dosedense N Completed 6 cycles 73% 62% P value Grade 3-4 Anemia 44% 69% p< Response rate Complete response Partial response 54% 16% 38% 56% 20% 36% Deaths 124 (39%) 96 (30%) PFS 17.2 mo 28 mo HR 0.71 (95% CI, ), p= OS (3-year) 65.1% 72.1% HR 0.75 (95% CI ), p=

37 Dose-dense Chemotherapy plus Bevacizumab GOG-262 : Weekly vs. Every-3-Week paclitaxel and carboplatin for ovarian cancer addition of bevacizumab to both treatment arms. Methods: Eligibility Stage II-IV Residual disease > 1cm included Non-Asian patient population Primary endpoint PFS- measured from the date of randomization Secondary endpoint OS- measured from the date of randomization Treatment groups Paclitaxel (175 mg/m 2, 3 hour infusion) and Carboplatin (AUC 6) IV Q 21 days for 6 cycles Paclitaxel (80 mg/m 2, 1 hour infusion) D1,8,15 and Carboplatin (AUC 6) D1 IV Q 21 days for 6 cycles Bevacizumab, 15 mg/kg IV every 3 wk until progression (starting from cycle 2) 37 N Engl J Med 2016;374:

38 GOG-262 Overall, weekly paclitaxel vs paclitaxel administered every 3 weeks, did not prolong PFS among patients with ovarian cancer. N Engl J Med 2016;374:

39 Neoadjuvant chemotherapy Methods: Eligibility Stage IIIC - IV Primary endpoint OS Secondary endpoint PFS Quality of life Adverse events Treatment groups Primary debulking surgery followed by at least 6 courses of platinum-based chemotherapy 3 Courses of neoadjuvant platinum-based chemotherapy followed by interval debulking surgery, followed by at least 3 courses of platinum-based chemotherapy. 39

40 Neoadjuvant chemotherapy Conclusions: No difference in overall survival Reduced perioperative morbidity and mortality 40

41 Bevacizumab in 1 st line of EOC Trail Patients Regimen Outcomes Comments GOG 218 (2011) ICON patients stage III or IV macroscopic residual disease 1528 patients stage I-IV optimal or suboptimal disease allowed Surgery >> paclitaxel + carboplatin x 6 cycles and placebo (cycle 2-5) followed by placebo (cycle 7-22) paclitaxel + carboplatin x 6 cycles and bevacizumab 15 mg/kg (cycle 2-5) followed by placebo (cycle 7-22) paclitaxel + carboplatin x 6 cycles and bevacizumab 15 mg/kg (cycle 2-5) followed by bevacizumab 15 mg/kg (cycle 7-22) Surgery >> paclitaxel + carboplatin x 6 cycles paclitaxel + carboplatin x 6 cycles and bevacizumab 7.5 mg/kg (cycle 2-6) followed by bevacizumab 7.5 mg/kg maintenance (12 more cycles) Statistically significant increase in PFS for Arm 3 OS not different between the groups. Small but significant differences in QOL for bevacizumab compared to placebo Median PFS was improved in treatment arm vs. control arm No difference in OS Median OS improved with suboptimal disease Bevacizumab significant higher: GI event Hypertension Bevacizumab significant higher: GI event Hypertension Significantly worse QOL in bevacizumab arm 41

42 Bevacizumab toxicity GOG-218 (Bevacizumab 15 mg/kg) Toxicity Placebo (%) BEV (cycle 2-22) (%) ICON-7 (Bevacizumab 7.5 mg/kg) Placebo (%) BEV (cycle 2-18) (%) Hypertension GI Event (gr. >2) <1 1 Bleeding (gr.1) NR NR 6 36 Thrombosis Fatal events 6 deaths 14 deaths 1 death 4 deaths 42

43 Regimen for the primary adjuvant treatment Regimen Paclitaxel 175 mg/m2 IV over 3 hr + carboplatin IV (AUC=5-7.5) every 21 days for 6 cycles Docetaxel mg/m2 + carboplatin IV (AUC=5-6) every 21 days for 6 cycles Paclitaxel 135 mg/m2 IV over 3 or 24 hours (day 1) + cisplatin mg/m2 IP (day 2) + paclitaxel 60 mg/m2 IP (day 8) every 21 days for 6 cycles Paclitaxel 80 mg/m2 IV over 1 hour days 1, 8, 15 + carboplatin (AUC=6) IV day 1; repeat every 21 days for 6 cycles (dose dense regimen) Paclitaxel 60 mg/m2 IV + carboplatin (AUC =2) IV once weekly for 18 weeks. Comments NCCN category 1 recommendation for patients who are not candidates for IP therapy NCCN category 1 recommendation. Recommended in patients at risk for peripheral neuropathy NCCN category 1 recommendation for patients with Stage III disease who are candidates for IP chemotherapy NCCN category 1 recommendation NCCN category 1 recommendation for elderly patient or poor performance status 43

44 Maintenance therapy Bevacizumab may be continued after primary upfront chemotherapy plus bevacizumab as in the GOG-218 or ICON-7. 44

45 AGO-OVAR patients - Randomized, double-blind, placebo controlled, phase III trial - Age 18 yrs. - Stage II-IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma - No PD after primary therapy (surgery and > 5 cycles of platinum-taxane) - ECOG 2 Randomized 1:1 24 months Pazopanib 800 mg PO daily Placebo 45

46 Maintenance therapy : AGO-OVAR16 P = ; 17.9 vs 12.3 mos, Improved PFS, no OS J Clin Oncol 32:

47 East Asian locations are China, Korea, Taiwan and Hong Kong. Japanese patients enrolled in AGO-OVAR16 Limited evidence that postremission Pazopanib may be less effective in east Asian woman with ovarian cancer. Int J Gynecol Cancer

48 Maintenance Therapies X Discontinue bevacizumab before initiating maintenance therapy with PARP inhibitor. 48

49 Recurrent, Refractory and Resistant Start CMT CR recurrent recurrent 3 6 Platinum-sensitive disease Platinum-resistant disease Platinum-refractory disease 2 nd line 49

50 Recurrence Therapies 50

51 Trial for platinum-sensitivity 1 st relapse Trial Patients Regimen Outcome Comments ICON-4/AGO-OVAR (2003) AGO/OVAR/EORTC (2006) 802 patients 1 st relapse TFI > 6-12 mo. 356 patients 1 st relapse TFI > 6 mo. Conventional platinum base (non-taxane) vs. Paclitaxel + platinum Carboplatin (AUC=5) vs. Gemcitabine 1000 mg/m2 IV D1, 8 + carboplatin (AUC=4) IV D1 PFS and OS statistically better in paclitaxel + platinum Overall response and PFS better in combination arm. No difference in OS Paclitaxel + platinum based is more toxic than conventional platinum-based Alopecia Neuropathy Pain More bone marrow toxicity Consider for Pt with neuropathy (can t tolerate taxane) 51

52 Trial for platinum-sensitivity 1 st relapse Trial Patients Regimen Outcome Comments CALYPSO OCEANS 976 patients 1 st or 2 nd relapse TFI > 6 mo. 484 patients 1 st relapse with measurable disease Liposomal doxorubicin 30 mg/m2 IV + carboplatin (AUC=5) q 4 wks. vs. Paclitaxel 175 mg/m2 IV + carboplatin (AUC=5) q 3 wks. Gemcitabine 1000 mg/m2, D1,8 + Carboplatin (AUC 4) D1 x 6-10 cycle + bevacizumab 15 mg/kg, D1 until to PD vs. Gemcitabine 1000 mg/m2, D1,8 + Carboplatin (AUC 4) D1 x 6-10 cycle + placebo Improved PFS in liposomal doxorubicin arm. No difference in OS PFS significantly longer in bevacizumab treated patients OS was not an endpoint Liposomal doxorubicin arm: less carboplatin hypersensitivity less peripheral neuropathy More mucositis, NV and PPE Bevacizumab arm: Hypertension Proteinuria GI events 52

53 Regimen for platinum sensitivity EOC in 1 st relapse Regimen Paclitaxel mg/m2 + carboplatin (AUC=5-6) IV q 3 wks. Gemcitabine 1000 mg/m2 IV days 1 & 8 + carboplatin (AUC=4) day 1 Gemcitabine mg/m2 + cisplatin 30 mg/m2 days 1 & 8, repeat q 21 days Liposomal doxorubicin 30 mg/m2 + carboplatin (AUC=5) both on Day 1; repeat every 28 days Cisplatin 75 mg/m2 IV q 21 day for 6 cycles Comments ICON-4 trial: Platinum free interval >12 months Only trial in recurrent disease documenting overall survival benefit NCCN category 1 recommendation Good choice for patients with pre-existing peripheral neuropathy Gemcitabine reverses platinum resistance Based on the CALYPSO Trial NCCN category 1 recommendation Can not tolerate combination chemotherapy Carboplatin (AUC=5-6) IV q 21 day for 6 cycles Can not tolerate combination chemotherapy 53

54 Recurrence Therapies 54

55 Platinum resistant disease or 2 nd relapse Pujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum resistant recurrent ovarian cancer: The Aurelia open-label randomized phase iii trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014; 32(13): Phase III, randomized, controlled trial Objective- to evaluate efficacy, safety, and quality of life (QoL) of combining bevacizumab with chemotherapy for platinumresistant recurrent ovarian cancer 55

56 Platinum resistant disease or 2 nd relapse 56

57 Platinum resistant disease or 2 nd relapse Results: Overall response rate PFS and RR were statistically significantly better in the chemotherapy + bevacizumab arm OS was not significantly different between arms. 57

58 Platinum-resistant or platinumrefractory ovarian cancer PFS was significantly longer in the combination arm (p=0.0002). And adverse events were higher in the combination arm. (neutropenia, fatigue, leucopenia, hypertension, anemia, elevated liver function tests) 58

59 Platinum-resistant or platinumrefractory ovarian cancer 59

60 PARP Inhibitor Jane de Lartigue, PhD August 30,

61 Olaparib FDA accelerated approval December 2014 For women who have received three or more prior chemotherapy regimen treatments for advance ovarian cancer. Germline BRCA mutation Oral drug: 400 mg (eight 50 mg capsules) twice a day with or without food Pharmacokinetics: Strong CYP3A4 inhibitor >> reduced to 150 mg twice daily Moderate CYP3A4 inhibitor >> reduced to 200 mg twice daily Clin Cancer Res; 21(19);

62 Olaparib Gynecologic Oncology 140 (2016)

63 Rucaparib Elizabeth M Swisher PFS was significantly longer in the BRCA mutant (HR 0 27, 95% CI , p<0 0001). The most common grade 3 or worse treatment-emergent adverse events were anemia and AST/ALT elevated. 63

64 Platinum-resistant or platinumrefractory ovarian cancer 64

65 Salvage agent for platinum resistant Agent Dose/Schedule Altretamine 260 mg/m2/day, orally, divided tid days 1-14; repeat every 28 days Bevacizumab Docetaxel Etoposide (oral) Gemcitabine Nanoparticle albumin-bound paclitaxel Olaparib Oxaliplatin Paclitaxel Pegylated liposomal doxorubicin (PLD) Tamoxifen Topotecan 15 mg/kg IV every 3 weeks mg/m2 every 21 days or 30 mg/m2 days 1, 8, 15; repeat q 28 days 50 mg/m2/day PO days 1-21; repeat every 28 days mg/m2 days 1, 8, 15; repeat q 28 days 260 mg/m2 IV every 3 weeks 400 mg PO twice daily 130 mg/m2 IV every 3 weeks 80 mg/m2 days 1, 8, 15; repeat every 28 days 40 mg/m2 every 28 days 20 mg PO BID 1.25 mg/m2/day x 5 days; repeat every days or 3-4 mg/m2/week days 1, 8, 15; repeat every 28 days Vinorelbine 30 mg/m2 days 1 & 8; repeat every 21 days 65

66 Michael Friedlander Method: Pt with CA-125 CA U/mL (N2 ULN) were treated with pazopanib 800 mg once daily until PD or unacceptable toxicity. Further studies evaluating the potential role of pazopanib in patients with ovarian cancer are ongoing. 66

67 Platinum-resistant or platinumrefractory ovarian cancer 67

68 Immunotherapy 68

69 Pembrolizumab Highly selective against PD-1 designed to block interaction with PD-L1 inhibition of T-cell activation against cancer. PD-L1 was found to be overexpressed in ovarian cancer. Recommended used: MSI-H or mismatch repairdeficient(dmmr) solid tumors. Dose: 10 mg/kg was given every 2 weeks for up to 2 years or until PD or unacceptable toxicity. ECOG PS 0-1. Overall response rate: 11.5% Adverse event: fatigue (42.3%), anemia (30.8%), and decreased appetite (30.8%). Journal of Clinical Oncology 33, no. 15_suppl (May 2015)

70 Symptom Management: Hypersensitivity Carboplatin Onset: Higher after 6-8 exposures Carboplatin desensitization Docetaxel Onset same Paclitaxel Premedication: Dexamethasone 8 mg po BID x 3 days, beginning day prior to docetaxel. Paclitaxel Onset: first or second administration Standard premedication: Dexamethasone po 20 mg given 12 and 5 hrs. prior to paclitaxel or Dexamethasone 20 mg 30 min prior to paclitaxel + Diphenhydramine 50 mg + H 2 -antagonist. 70

71 Summary Points Stage IA or IB grade 1 : no further treatment Standard for treatment : Paclitaxel 175 mg/m2 IV over 3 hr + Carboplatin IV (AUC=5-7.5) every 21 days for 6 cycles, alternative Tx in pt at risk for PN : Docetaxel mg/m2 + Carboplatin IV (AUC=5-6) every 21 days for 6 cycles IP therapy for select pt (stage IIIC, optimal surgical, ECOG 0-1, no history of bowel surgery) Bevacizumab is improvement in PFS with no change in OS, but significantly HTN and GI events. 71

72 Summary Points Taxane hypersensitivity: Paclitaxel, albumin bound Carboplatin hypersensitivity : Cisplatin Maintenance therapy: bevacizumab or pazopanib (NCCN category 2B) Relapse-platinum sensitive : Paclitaxel + Carboplatin, alternative Tx in pt at risk for PN : Gemcitabine + Carboplatin BRCA1, 2 mutation received three or more chemotherapy treatments : PARP inhibitor (Olaparib 400 mg BID) improved PFS MSI-H or dmmr solid tumors: pembrolizumab 72

73 Cervical Cancer

74 Etiology and Pathogenesis Related to infection with oncogenic human papillomavirus (HPV) strains HPV-16 and HPV-18 are responsible for more than 70% of invasive cervical cancers HPV-6 and HPV-11 are also associated with the development of genital warts Infection with HPV is associated with the development of other cancers including oropharyngeal, anal, vaginal, vulvar, penile and non-melanoma skin cancers 74

75 Evolution of an HPV infection Transient Infection Persistent Infection Normal Precancerous, potential to regress or persist to severe disease Invasive HPV Infection CIN 1,2 CIN 2,3 1 Cervical Cancer y 1 10 y 2 HPV Disappearance 1-2 y 3,4,6 ~6 9 mo 5,6 Colposcopy demonstrates abnormal vasculature and angiogenesis dependent progression CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HR, high risk. 1. Schiffman M, Kjaer SK. J Int Cancer Natl Monogr. 2003;31:14-19; 2. Ostör AG. Int J Gynecol Pathol. 1993;12: ; 75

76 Risk Factors Increased risk HPV (16,18) Multiparity ( 3 pregnancies) Smoking Early onset of sexual activity Cervical cancer Multiple sexual partners History of STD Lower socioeconomic due to poor health care HIV 76

77 Risk Factors Decrease risk Abstinence Nulliparity HPV vaccine Intrauterine device 77

78 Histology Histology Prevalence Comment Squamous cell 65-86% Highly associated with HPV Adenocarcinoma 10-25% Screening may be less effective; HPV vaccination effective against this subtype as well. Associated with a worse prognosis. Adenosquamous <5% Poor prognosis Other subtypes (neuroendocrine small cell, glassy cell, primary sarcoma) Rare Poor prognosis; not likely to be associated with HPV infection Most common distant metastatic : lungs, mediastinal, and supraclavicular lymph nodes, bones and liver 78

79 Screening by Age Recommended Method Comments Age < 21 No screening - Age Cytology alone every 3 years Age Cytology alone every 3 years (acceptable) Age > 65 After hysterectomy HPV vaccinated females Cytology and HPV test every 5 years (preferred) No screening : negative prior screening No screening Co-testing preferred to identify both adenocarcinoma and squamous cell carcinoma Follow age specific recommendation as above

80 Prevention : HPV Vaccination Vaccine Bivalent (Cervarix ) Quadrivalent (Gardasil ) 9-Valent (Gardasil 9) HPV strains 16,18 6,11,16,18 6,11,16,18,31, 33,45,52,58 FDA-female age FDA-male age Not approved Administration Age 9-14 Age Enhancer immune response IM at 0 and 6 months IM at 0, 2, and 6 months A s O4 - - Guideline from America recommend that vaccination should begin between years of age. 80

81 Diagnosis Physical exam & history Pelvic exam PAP test HPV test Endocervical curettage Colposcopy Biopsy 81

82 Staging 3-5 mm < 3 mm Cancer growth into the top part of the vagina Parametrial invasion Pelvic wall Cancer growth into the 2/3 of the vagina Tumor invades mucosa of bladder or rectum Spread to peritoneal and distant organs 82

83 Prognosis (with treatment) Poor prognosis 1. Large primary tumor 2. Positive lymph nodes 3. Adenocarcinoma or adenosquamous carcinoma 4. Lymphovascular space invasion Stage IA IB II III IV 5-yr. Survival 93% 80% 60-65% 30% 15% 83

84 Treatment 1. CIN-III (Carcinoma in situ; high grade dysplasia) (Stage 0) 1) Excision: Cold knife cone biopsy (CKC) Loop electrosurgical excision procedure (LEEP) Total hysterectomy 2) Ablative: Cryotherapy Laser ablation 84

85 Treatment 2. Early stage disease (Stage I-IIA) 1) Surgery: PLND and PALN 85

86 Treatment 2. Early stage disease (Stage I-IIA) 1) Surgery: Stage Stage IA 1 (Margin negative) Surgery Fertility Non-fertility Cone biopsy +/- PLND Simple hysterectomy Stage IA 1 (Margin positive = LVSI) Radical trachelectomy + PLND Modified radical hysterectomy + PLND Stage IA 2 Radical trachelectomy + PLND Stage IB 1 Tumor < 2 cm. : radical trachelectomy + PLND +/- PALN Tumor 2 to 4 cm. : abdominal trachelectomy + PLND +/- PALN Radical hysterectomy + bilateral PLND Radical hysterectomy + bilateral PLND +/- PALN 86

87 Treatment 2. Early stage disease (Stage I-IIA) 1) Surgery: Stage Stage IIA 1 Treatment Radical hysterectomy + PLND +/- PALN sampling Or Pelvic radiation with brachytherapy +/- Cisplatin 87

88 Treatment 2. Early stage disease (Stage I-IIA) Stage 2) Adjuvant radiation: Stage IA 2, IB 1, IIA 1, node negative with no high risk features Stage IA 2, IB 1, IIA 1, node negative with high risk features Stage IA 2 -IIA 1 with positive lymph nodes, positive surgical margins +/- positive parametrium Recommended Treatment Observation Adjuvant pelvic RT (NCCN category 1 recommendation) Adjuvant pelvic RT with concurrent cisplatin based chemotherapy (NCCN category 1 recommendation) with or without vaginal brachytherapy High risk : lymphovascular space invasion (LVSI), cervical tumor diameter > 4 cm, or greater than one-third stromal invasion 88

89 Treatment 3. Advanced stage disease (Bulky stage IIB, III and IVA) Primary treatment = Radiation Whole pelvic radiation (WPRT) and brachytherapy (ICRT) with chemosensitization External beam radiation plus ICRT plus cisplatin containing chemosensitization is a National Comprehensive Cancer Network (NCCN ) category 1 recommendation 89

90 Chemosensitization CCRT : improves RR and survival Cisplatin 40 mg/m 2 weekly for 5-6 weeks (cap dose at 70 mg) Increase effectiveness of radiation Direct cell cytotoxicity Tumor cell synchronization Inhibition of sub-lethal radiation repair Initiated cisplatin within hrs of starting radiation Pain may increase during first 1-2 weeks of RT (pain usually improves tumor shrinkage occurs) Parameter for holding cisplatin: ANC < 1000, and platelet < 75,000 90

91 Alternative chemosensitizing agents Paclitaxel mg/m 2 /week Mitomycin mg/m 2 Fluorouracil Hydroxyurea Carboplatin** mg/m2 IV Or 4200 mg/m 2 PO (3x during radiation) 2 g/m 2 (twice weekly during radiation) mg/m 2 /week ** recommended by NCCN 92

92 Chemotherapy for Recurrent Cervical Cancer - Lessons Learned in the 80 s and 90 s Platinum-based therapies most effective Cisplatin more active than carboplatin Single agent cisplatin at 50 mg/m 2 became standard

93 Phase III Trial for Advanced Stage or Recurrent Cervical Cancer P=

94

95 JCOG 0505: The non-inferiority Trial of Paclitaxel + Carboplatin vs Paclitaxel + Cisplatin 96

96 JCOG 0505: The non-inferiority Trial of Paclitaxel + Carboplatin vs Paclitaxel + Cisplatin 97

97

98 GOG 240: Non-platinum doublet objective Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 ANC 1500/µL Platelets 100,000/µL Serum creatinine 1.5 mg/dl No CNS disease No past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation) R A N D O M I Z E Regimen 1** Paclitaxel* + CDDP 50 mg/m 2 Regimen 2** Paclitaxel* + CDDP 50 mg/m 2 + Bevacizumab 15/mg/kg Regimen 3** Paclitaxel 175 mg/m 2 over 3 hrs on day 1 + Topotecan 0.75 mg/m 2 over 30 mins days 1-3 Regimen 4** Paclitaxel 175 mg/m 2 over 3 hrs on day 1 + Topotecan 0.75 mg/m 2 over 30 mins days Bevacizumab 15/mg/kg Open to enrollment April 6, 2009 Closed to enrollment Jan 3, 2012 Sample size = 452 OS HR reduction of 30% Study Chair = KS Tewari ClinicalTrials.gov Identifier: NCT ALL REGIMENS * 135 mg/m2 over 24 or 175 mg/m2 over 3 hours Quality of life Assessment: ** Cycles repeated q21 days to progression/toxicity Baseline Before cycle 2 Before cycle 5 9 mo. after study entry at follow-up visit Tewari KS et al N Engl J Med Feb 20;370(8):

99 GOG 240: Bevacizumab objective Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 ANC 1500/µL Platelets 100,000/µL Serum creatinine 1.5 mg/dl No CNS disease No past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation) R A N D O M I Z E Regimen 1** Paclitaxel* + CDDP 50 mg/m2 Regimen 2** Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg Regimen 3** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan 0.75 mg/m2 over 30 mins days 1-3 Regimen 4** Paclitaxel 175 mg/m2 over 3 hrs on day 1 + Topotecan 0.75 mg/m2 over 30 mins days Bevacizumab 15/mg/kg Open to enrollment April 6, 2009 Closed to enrollment Jan 3, 2012 Sample size = 452 OS HR reduction of 30% Study Chair = KS Tewari ClinicalTrials.gov Identifier: NCT ALL REGIMENS * 135 mg/m2 over 24 or 175 mg/m2 over 3 hours Quality of life Assessment: ** Cycles repeated q21 days to progression/toxicity Baseline Before cycle 2 Before cycle 5 9 mo. after study entry at follow-up visit Tewari KS et al N Engl J Med Feb 20;370(8):

100 GOG 240 : Results of Non-platinum objective 101

101 GOG 240: Results of Bevacizumab Objective Bevacizumab plus CMT arm improved PFS and OS 102

102 Progress in Survival in Advanced and Recurrent Cervical Cancer 104

103 Summary 1 st line CMT for advanced or recurrent cervical cancer Regimen Cisplatin 50 mg/m2 + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg Carboplatin AUC 5 + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg Topotecan 0.75 mg/m2 (Day 1 to 3) + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg Comment NCCN category 1 recommendation based on data from GOG NCCN category 2A recommendation based on data from GOG- 240 and JCOG0505. NCCN category 1 recommendation based on data from GOG Cisplatin 50 mg/m2 + paclitaxel mg/m2 NCCN category 1 recommendation. Cisplatin 50 mg/m2 + Topotecan 0.75 mg/m2 (Day 1-3) Topotecan 0.75 mg/m2 (Day 1 to 3) + paclitaxel 175 mg/m2 Paclitaxel 175 mg/m2 + carboplatin (AUC=5) Cisplatin 50 mg/m2 single agent Paclitaxel mg/m2 Carboplatin (AUC 5-7.5) * All regimens repeat every 21 days to progression or toxicity NCCN category 2A recommendation for patients who cannot tolerate taxanes. NCCN category 2A recommendation for patients who are not candidates for cisplatin. NCCN category 1 recommendation for patients who have received prior cisplatin therapy and 2A for those who have not. NCCN category 2A recommendation for patients deemed unable to tolerate combination therapy. NCCN category 2A recommendation for patients unable to tolerate combination chemotherapy or cisplatin. NCCN category 2A recommendation for patients unable to tolerate combination chemotherapy or cisplatin. 105

104 Summary Points HPV-16 and HPV-18 are also associated with the development of cervical cancer Prevention by HPV vaccine Screening start at age 21 until age > 65 no screening Stage IA 1 Fertility : Cone biopsy with negative margins and Radical trachelectomy No fertility : Simple hysterectomy Stage IA 2, IB 1, IIA Radical hysterectomy -> observe (node negative, low risk) Radical hysterectomy -> WPRT/ICRT (node negative, high risk) -> observe Stage IIB, IIIA, IIIB WPRT/ICRT with Cisplatin -> observe Stage IVA,IVB Combination CMT 107

105 Summary Points CCRT : improves RR and survival Cisplatin 40 mg/m2 weekly for 5-6 weeks (cap dose at 70 mg) 1 st line CMT for advance or recurrent Cisplatin 50 mg/m2 + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg Topotecan 0.75 mg/m2 (Day 1 to 3) + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg Cisplatin 50 mg/m2 + paclitaxel mg/m2 Paclitaxel 175 mg/m2 + carboplatin (AUC=5) All patient with recurrent disease, treatment is continued for as long as the patient responds. Therapy is stopped or change due to progression or toxicity. 108

106 Endometrial Cancer

107 Etiology and Pathogenesis 1. Estrogen has been a suspected carcinogen Endometrial adenocarcinoma Type I 80% of all endometrial cancers Endometrioid adenocarcinoma Type II 20% of all endometrial cancers Serous and clear cell adenocarcinoma Histology Low grade, well differentiated High grade, poor differentiated Tumor develop form Hyperplasic epithelium Atrophic epithelium Clinical course Indolent Aggressive Hormone dependency Estrogen dependent Not estrogen-dependent Usually diagnosed in Younger, obese, perimenopausal women Older women Cancer Letters 319 (2012) US Pharm. 2014;39(9):

108 Etiology and Pathogenesis 2. Genetic mutations: 5% of endometrial cancers are caused by inherited genetic susceptibility. Defective DNA mismatch repair (MSH2, MSH6, MLH1) is associated with Lynch Syndrome. Women that carry this mutation have a 40-60% lifetime risk of developing endometrial cancer 111

109 Risk Factor Increased risk Nulliparity (never had children) Early menarche/late menopause Obesity (increased production of estrogen from peripheral adipose tissue) Complex atypical hyperplasia (CAH) Anovulatory or oligoovulatory syndromes Tamoxifen (29% higher) Diabetes (insulin-resistance pathway) Lynch mutation Decreased risk Oral contraceptive use The longer duration of use, the greater the protective effect Protection persists for several years after use Reduced risk presumably >> progesterone Reducing the risk of obesity Healthy eating Maintaining a normal body weight 112

110 Tamoxifen Tamoxifen effects can range from benign endometrial proliferation to the development of invasive uterine adenocarcinoma or sarcoma. Phase III trial of the NSABP- P-1 study : increased risk of endometrial cancer was 29% in patients treated with tamoxifen (not statistically significant) Post-menopausal higher risk of endometrial cancer than premenopausal 113

111 Tamoxifen RR=2.7 95% CI (1.94 to 3.75) J GEN INTERN MED 2003; 18:

112 Histology The Lancet Oncology , e268-e278doi: ( /S (13) ) 115

113 Screening Healthy women: No screening recommended, except an annual pelvic examination. Women on tamoxifen: prefer for postmenopausal women An annual pelvic examination is recommended. Routine screening endometrial biopsies are not recommended. ACOG recommends: endometrial sampling only if they become symptomatic (i.e., develop abnormal bleeding) Lynch mutation with asymptomatic: ACS Age : endometrial biopsy every 1-2 yrs. NCCN Annual endometrial biopsy Hysterectomy and BSO immediately after completion of childbearing 116

114 Prevention Hysterectomy in women with Complex atypical hyperplasia (CAH) Hysterectomy in women with Lynch mutations after childbearing is completed Progesterone challenge in women with CAH Endometrial hyperplasia Normal endometrium 117

115 Symptoms Unusual vaginal bleeding, spotting, or other discharge 90% of women diagnosed with endometrial cancer have abnormal vaginal bleeding Such as a change in their periods or bleeding between periods or after menopause Pelvic pain and/or mass and weight loss Most common metastasis to lung 118

116 Diagnosis Transvaginal ultrasound that indicates a thickened endometrium Endometrium biopsy CA 125 useful as a marker in pt with clear cell or papillary serous tumors ER/PR status for endometrioid adenocarcinoma 119

117 Staging < 50% of myometrium 1A > 50% of myometrium 1B Invades stromal connective tissue of the cervix 2 Involved serosa or adnexa Vagina Bladder mucosa/bowel Pelvic/para-aortic lymph nodes Obstet Gynecol 2010;116:1141 4A 4B Inguinal lymph nodes, intraperitoneal disease, or lung, liver, or bone 120

118 Poor prognosis Serous and clear cell : most likely to metastasis High grade (grade 2-3), or poorly differentiated Myometrial invasion >50% : high rate of spread to extra-uterine tissue (metastases), treatment failure, and recurrence. Extension to the cervix: the risk of pelvic nodal involvement Vascular space invasion: pelvic and para-aortic node involvement and myometrial invasion. Positive peritoneal cytology: positive washing associated with an increased risk of regional or distant metastases. Pelvic and para-aortic lymph node involvement: represents regional spread and a higher likelihood of distant metastases. Endometrial cancer stage IB due to poor prognosis 121

119 Treatment Goal : Cure in early stage (90% of 5-yrs survival) Stage Surgery Adjuvant RT Adjuvant CMT Stage I-II - Stage III-IV ± Surgery: Total hysterectomy + bilateral salpingo-oophorectomy + pelvic lymph node dissection ± para-aortic lymph node dissection for high risk tumors (TH/BSO + PLND ± PAND) Omentectomy, and intra-abdominal tumor stripping in advanced stage (stage III and IV) 122

120 Treatment Radiation: external beam RT and/or brachytherapy Adjuvant RT after surgery for pt high risk for recurrence. Reduces risk of local pelvic recurrence, but not improve OS Chemotherapy: not only used for the treatment of advanced and recurrent disease Hormone therapy: most useful in well-differentiated adenocarcinoma such as endometrioid tumors and elderly who cannot tolerate CMT. 123

121 Stage I Adverse risk factor: 1. High-grade tumors (grade 2 or 3) 2. Deep myometrial invasion 3. Lymphovascular space invasion (LVSI) 4. Papillary serous histology or Clear cell histology or Carcinosarcoma (MMMT) Endometrial carcinoma. NCCN. V

122 Uterine Risk Factors and Recurrence Rate Uterine Factor Recurrence Rate (%) Grade 1, 2, 3 4%, 9%, 16% Deep myometrial invasion 15% Isthmus/cervix involvement 16% Lympho/vascular space involvement 27% 125

123 Stage II Endometrial carcinoma. NCCN. V Chemotherapy alone is no benefit in adjuvant setting for pt with stage I and II 126

124 GOG-99 : Adjuvant WPRT Phase III RCT 392 women Staging with or without post-op WPRT Defined intermediate risk Stage IB, IC, IIA/IIB (occult) 5 year recurrence rate of 20-25% Excluded serous and clear cell No Adjuvant Treatment Adjuvant WPRT P Value Progression Free : 2 yrs 88% 96% Survival: 3 yrs 89% 96% 0.09 Keys HM et al. Gynecol Oncol

125 Stage III and IV Primary treatment : Total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, omentectomy, pelvic washings and peritoneal biopsies Endometrial carcinoma. NCCN. V

126 Adjuvant treatment of advanced stage endometrial cancer Chemotherapy with AP significantly improved progression-free and overall survival compared with WAI. Randall et all, J Clin Oncol Jan 1;24(1):

127 Stage III and IV Extra-uterine Factor Recurrence Rate (%) Adnexal Metastasis 14 + Peritoneal Cytology 19 + Peritoneal Disease 25 Pelvic Nodal Metastases 28 Para-aortic Nodal Metastases 40 High-grade tumors: Adjuvant therapy with chemotherapy and vaginal brachytherapy or pelvic radiation. Chemotherapy may be give fist, followed by radiation 130

128 Clinical trial for systemic therapy for recurrent, metastasis and high-risk disease. Trail Regimen Outcome Comment GOG 184 (AP vs TAP) Doxorubicin 45 mg/m2 + cisplatin 50 mg/m2 every 21 days for 6 cycles (AP) or Doxorubicin 45 mg/m2 (day 1) + cisplatin 50 mg/m2 (day 1) + Paclitaxel 160 mg/m2 over 3 hr (day 2) + filgrastim (or equivalent) or pegfilgrastim (day 3 or later); repeat every 21 days for 6 cycles (TAP) ORR, PFS and OS were all statistically improved in the TAP arm (15 months vs. 12 months, P=0.037 for survival) TAP : but more neurotoxicity and BMS. GOG 209 (CBP/PAC vs TAP) Doxorubicin 45 mg/m2 (day 1) + cisplatin 50 mg/m2 (day 1) + Paclitaxel 160 mg/m2 over 3 hr (day 2) + filgrastim (or equivalent) or pegfilgrastim (day 3 or later); repeat every 21 days for 6 cycles (TAP) or Paclitaxel 175 mg/m2 + carboplatin (AUC 6) every 21 days for 6-8 cycles Same efficacy and less toxicity in CBP/PAC treatment arm. *** Paclitaxel plus Carboplatin : preferred regimen. 131

129 Systemic chemotherapy 132

130 Systemic Chemotherapy Regimen Doxorubicin 60 mg/m2 plus Cisplatin 50 mg/m2 (AP) repeated every 21 days Doxorubicin 45 mg/m2 (Day 1) plus Cisplatin 50 mg/m2 (Day 1) plus Paclitaxel 160 mg/m2 over 3 hr (Day 2) (TAP); plus filgrastim (or equivalent) or pegfilgrastim; repeat every 21 days Paclitaxel 175 mg/m2 plus Carboplatin (AUC=6); repeat every 21 days Docetaxel 75mg/m2 IV + carboplatin AUC 5 IV every 21 days for 6 cycles Paclitaxel 135 mg/m2/3-hr Day 1 + ifosfamide 1.6 g/m2/d (Day 1-3) + mesna + filgrastim (or equivalent) or pegfilgrastim Cisplatin 20 mg/m2/d + ifosfamide 1.5 g/m2/d for days mesna Comments Reduce doxorubicin to 45 mg/m2 in patients previously treated with pelvic radiation. Increased toxicity makes this regimen difficult to tolerate in elderly patients or patients with comorbid diseases. Commonly used due to reduce toxicity. May be considered in patients whom paclitaxel is contraindicated (ie. severe neuropathy) Used for carcinosarcoma histologies only. Reduce ifosfamide dose 25% for any history of prior pelvic radiation. NCCN category 1 recommendation. Used for carcinosarcoma histologies only. 133

131 Single agent chemotherapy Cisplatin, carboplatin, doxorubicin and paclitaxel are the most active Used in the management of women who have failed prior primary treatment, hormonal therapy and/or who are unable to tolerate combination chemotherapy. 134

132 Single agent chemotherapy 135

133 Recurrent Prognosis is worse if there is extravaginal extension or pelvic lymph node involvement All patients should be considered for enrollment in clinical trials Radiation at recurrence site (confined to the vagina or pelvis alone): pelvic external beam radiation therapy (EBRT) plus brachytherapy (if no prior radiation therapy) Surgery role at isolated relapse. Endocrine therapy Progestins and tamoxifen act as anti-estrogens. Agents of choice for treatment of 1 st recurrence in patients with long disease-free intervals, well differentiated and estrogen and/or progesterone-receptor positive tumors. Overall response rates are approximately 10-25%. 136

134 Systemic chemotherapy 137

135 Endocrine therapy Agent Dose Adverse reactions Medroxyprogesterone acetate Medroxyprogesterone acetate alternative with tamoxifen Megestrol acetate Tamoxifen mg orally Daily for 14 days; repeat monthly Medroxyprogesterone acetate 80 mg PO BID x 3 weeks alternating with tamoxifen 20 mg PO BID x 3 weeks 160 mg orally daily (in divided dose) 20 mg BID or 40 mg orally once daily Breast tenderness, irregular bleeding, abnormal glucose control Weight gain, appetite stimulation, nausea, abnormal glucose control Hot flashes, nausea, irregular bleeding, weight gain Anastrazole 1 mg PO daily Hot flashes, asthenia, nausea, depression, osteoporosis, peripheral edema, arthralgia Letrozole 2.5 mg PO daily Hot flashes, asthenia, nausea, depression, osteoporosis, peripheral edema, arthralgia 138

136 Summary points Serous and clear cell : poor prognosis Obesity, DM and Tamoxifen : increase risk Oral contraceptive : decrease risk Primary treatment : Total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection (omentectomy, pelvic washings and peritoneal biopsies for advanced stage) Standard CMT : Paclitaxel 175 mg/m2 plus Carboplatin (AUC=6); repeat every 21 days 139

137 Summary points Adverse risk factor: High-grade tumors, myometrial and lymphovascular space invasion (LVSI) and serous or Clear cell histology or Carcinosarcoma (MMMT) Stage Primary Treatment EBRT ± ICRT Adjuvant treatment chemotherapy Stage IA Observe Stage IB +/- - Surgery Stage II + - Stage IIIA Tumor direct-rt + Stage IIIB Surgery If you can Tumor direct-rt + Stage IV Surgery If you can

138 ขอบพระ ค ณออ เจ าท ก ท านเจ า ค ะ 141