Chemotherapy for Cervical Cancer. Matsue City Hospital Junzo Kigawa

Transcription

1 Chemotherapy for Cervical Cancer Matsue City Hospital Junzo Kigawa

2 Introduction Worldwide, cervical cancer is the second most common cancer in women and affects 530,000 new patients and 275,000 deaths. Concurrent chemoradiotherapy is considered standard treatment for FIGO Stages IB2 and higher. Unfortunately, the 5-year survival for stages are approximately 76% for IB2, 66% for IIB, 42% for IIIB, and 22% for IVA. New strategy of treatment for advanced cervical cancer is necessary. FIGO CANCER REPORT 2012International Journal of Gynecology and Obstetrics journal homepage:

3 Mystery in Cervical Cancer Outcome Standard treatment Chemotherapy

4 Mystery in Cervical Cancer Outcome Standard treatment Chemotherapy

5 5- year Survival Rate for Cervical Cancer FIGO Stage I 83.3 (%) 82.1 (%) 91.8(%) II III IV Japan Society of OB GY, 2015

6 Mystery in Cervical Cancer Outcome Standard treatment Chemotherapy

7 Treatment for Cervical Cancer in USA 0-Ib1 Surgery Ib2 II III Radiation (Chemoradiation) IV

8 Treatment for Cervical Cancer in Japan(Asia) 0-Ib1 Ib2 Surgery II NAC Neoadjuvant chemotherapy III IV Radiation (Chemoradiation)

9 Treatment for Ib-II Cervical Cancer in Japan Surgery RT CT Othres Total n % n % n % n % n % Ib Ib IIa IIb Japan Society of OB & GY 2011Report

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11 Mystery in Cervical Cancer Outcome Standard treatment Chemotherapy

12 Chemotherapy agents used in the 30 trials Shoji et al., 2013 Shen et al., 2012 Yamaguchi et al., Pinheiro et al., 2011 Vizza et al., 2011 Mossa et al., 2010 Shoji et al., 2010 Cho et al., 2009 Kokawa et al., 2007 Sláma et al., Eddy et al., 2007 Choi et al., 2006 Cai et al., 2006 Termrungruanglert et al., 2005 Taneja et al., 2005 DeSouza et al., 2004 Huang et al., 2003 Napolitano et al., 2003 D Agostino et al., 2002 Benedetti-Panici et al., 2002 Duenas-Gonzalez et al., 2003 Duenas-Gonzalez et al., 2002 Costa et al., 2001 MacLeod et al., 2001 Aoki et al., 2001 Hwang et al., 2001 Chang et al., 2000 Zanetta et al., 1998 Sardi et al., 1997 Lacava et al., 1997 Carboplatin (AUC6), paclitaxel (175 mg/m2)/ docetaxel (70 mg/m2) Cisplatin (20 mg/m2 D1-4)/carboplatin (AUC5), paclitaxel (150 mg/m2) Nedaplatin (80 mg/m2), irinotecan (60 mg/m2 D1,8 Mitomycin C (10 mg/m2), methotrexate (300 mg/m2 with folonic acid), bleomycin (15 mg/m2 D1,8) Cisplatin (75 mg/m2), paclitaxel (175 mg/m2), ifosfamide (5 g/m2, mesna) Cisplatin (50 mg/m2), vincristine (1 mg/m2), bleomycin (25 mg/m2 D1,8) Cisplatin (70 mg/m2), irinotecan (70 mg/m2 D1,8) Cisplatin (75 mg/m2)/carboplatin (AUC5), paclitaxel (135 mg/m2) Cisplatin (75 mg/m2)/carboplatin (AUC5), paclitaxel (135 mg/m2) Mitomycin-C (10 mg/m2), irinotecan (100 mg/m2) D1,8,15 2 (28 patients) Cisplatin (50 mg/m2), ifosfamide (5 g/m2, mesna) Cisplatin, vincristine Cisplatin (100 mg/m2), 5-fluorouracil (1000 mg/m2/day D2-5) Cisplatin (100 mg/m2), 5-fluorouracil (1000 mg/m2/day D2-5) Cisplatin (70 mg/m2), gemcitabine (1000 mg/m2 D1,8) Cisplatin (50 mg/m2), bleomycin (15 mg/m2 D1, 2), vincristine (1 mg/m2) Cisplatin (60 mg/m2), methotrexate (300 mg/m2 with folonic acid), bleomycin (30 mg/m2 twice weekly) Cisplatin (50 mg/m2), bleomycin (15 mg/m2 D1, 2), vincristine (1 mg/m2) Cisplatin (50 mg/m2), bleomycin (15 mg/m2 D1, 2), vincristine (1 mg/m2) Cisplatin (100 mg/m2), epirubicin (100 mg/m2), paclitaxel (175 mg/m2) Cisplatin (80 mg/m2), vincristine (1 mg/m2), bleomycin (25 mg/m2 3 days) Carboplatin (AUC 6), paclitaxel (175 mg/m2) Cisplatin (100 mg/m2), gemcitabine (1 mg/m2 D1,8) Cisplatin (40 mg/m2), epirubicin(30 mg/m2), etoposide(75 mg/m2), bleomycin (15 mg D1,2) Cisplatin (50 mg/m2)/carboplatin (AUC5) based combination Cisplatin (60 mg/m2), vinblastine (4 mg/m2 D1, 2), bleomycin (25 mg/m2 3 days) Cisplatin (50 mg/m2), vinblastine (6 mg/m2), bleomycin (25 mg/m2 3 days) Cisplatin (50 mg/m2), vincristine (1 mg/m2), bleomycin (25 mg/m2 for 3 days) Cisplatin (50 mg/m2) (75 mg/m2 in 10 patients), paclitaxel (175 mg/m2), ifosfamide (5 g/m2, mesna) Cisplatin (50 mg/m2), vincristine (1 mg/m2), bleomycin (25 mg/m2 D1-3) Vinrolbine (30 mg/m2 weekly) Mohammed Osman, Oncology Reviews (2):

13 JCOG 0505 Kitagawa R et al. JCO 33: , 2015

14 JCOG 0505 TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.

15 GOG 240 Tewari KS et al. N Engl J Med. 370:734-43, 2014

16 GOG 240 The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.

17 GOG 240 Benefit of BEV was not observed in patients with AC.

18 FIGO stage Histological type and Outcome Histological type n 5-yrs OS P value HR (95%CI) IB1 SCC 1, % ( ) non SCC 1, % IB2 SCC % ( ) non SCC % IIA SCC % < ( ) non SCC % IIB SCC % < ( ) non SCC % JGOG

19 Surgical principles for managing stage IB2, IIA2, and IIB uterine cervical cancer (Bulky Tumors) in Japan: a survey of the Japanese Gynecologic Oncology Group. Treatment for Stage IIb SCC Non-SCC Mikami M et al. Int J Gynecol Cancer;

20 Surgical principles for managing stage IB2, IIA2, and IIB uterine cervical cancer (Bulky Tumors) in Japan: a survey of the Japanese Gynecologic Oncology Group. NAC No 54.5% Yes 45.5% Mikami M et al. Int J Gynecol Cancer;

21 Internal pudendal artery Internal iliac artery Obturator vein Internal iliac vein Superradical hyesterctomy Complete removal of pelvic vessels

22 NAC + Surgery vs RT hazard ratio p OS PFS But too small data 1,605 patients (15 trials) MRC Eur J Cancer 39, 2003

23 Conclusions of MRC NAC followed by RT is not effective. The future trial is necessary for NAC followed by surgery.

24 Phase III randomized trial of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy (RH) versus RH for bulky stage I/II cervical cancer (JCOG 0102) NAC arm BOMP q3wks, 2 or 4cycles Cervical cancer Ib2-IIb SCC R A N D O M I Z E BLM 7mg/body d1-5 VCR 0.7mg/m 2 d5 MMC 7mg/body d5 CDDP 14mg/m 2 d1-5 Control (RH) arm Radical Hysterectomy ± RT Radical Hysterectomy ± RT 200 patients Katsumata et al. Br J Cancer. 108:

25 Result of JCOG Over all survival RH arm (n=54), 1-year OS; 94.5% NAC arm (n=54), 1-year OS; 94.2% HR of NAC Arm: 2.11 (adjusted 99%CI; ) Days on Study Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival.

26 Response to BOMP CR or PR after 2 cycles; 33 patients Response Rate; 61.1% (33/54) (95%CI, %) Clinical response to chemotherapy was evaluated using MRI measurement according to RECIST criteria.

27 Hypothesis Cisplatin combined with paclitaxel is the most promising regimen for advanced cervical cancer. Dose-dense weekly administration of paclitaxel has been shown to prolong survival in ovarian and breast cancer. Therefore, cisplatin plus dose-dense paclitaxel (ddtp) may be the most promising regimen for locally advanced cervical cancer, and that neoadjuvant ddtp plus radical hysterectomy followed by adjuvant ddtp without radiotherapy might show better recurrence-free survival rate and QoL than concurrent chemoradiotherapy (CCRT).

28 Cisplatin with dose-dense paclitaxel before and after radical hysterectomy for locally advanced cervical cancer Final results of a multicenter phase II study (Sankai Gynecology Study Group 013) Satoshi Yamaguchi 1, Kiyoshi Fujiwara 1, Shinya Sato 3, Shoji Nagao 4, Kazuhiro Takehara 5, Masato Nishimura 6, Muneaki Shimada 3, Junzo Kigawa 3, Maki Tanioka 2 : Sankai Gynecologic Oncology Group 1 Gynecologic Oncology, 2 Medical Oncology, Hyogo Cancer Center, Akashi, Japan, 3 Gynecologic Oncology Division, Tottori University Hospital, Yonago, Japan 4 Gynecologic Oncology Division, Saitama Medical University International Medical Center, Hidaka, Japan, 5 Obstetrics and Gynecology, Kure Medical Center/Chugoku Cancer Center, Kure, Japan, 6 Obstetrics and Gynecology, School of Medicine University of Tokushima, Tokushima, Japan,

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30 Patient characteristics (N=51) Median age, years 52 (30-70) Performance status 0 1 Stage IB2 IIA2 IIB Histology Squamous Adenocarcinoma Adenosquamous Small cell carcinoma % 16% 27% 6% 67% 80% 14% 4% 2% Presented by: Satoshi Yamaguchi Hyogo Cancer Center, Akashi, Japan

31 Response & Feasibility Response rate (RECIST1.1, best response) PD SD PR CR Objective Response rate N=51 (Evaluable, N=50) 0% (0/50) 6% (3/50) 58% (29/50) 36% (18/50) 94% (47/50) pathological CR 28% (14/50) Completion rate of surgery Completion rate of 5 cycles of ddtp and surgery Discontinuation before surgery Grade 4 hypersensitivity for paclitaxel Inoperable CCRT Discontinuation after surgery Withdrawal due to pcr or good PR at surgery Adverse effects of adjuvant ddtp Positive surgical margin CCRT Presented by: Satoshi Yamaguchi Hyogo Cancer Center, Akashi, Japan 98% (50/51) 69% (35/51) 2% (1/51) 2% (1/51) 16% (8/51) 10% (5/51) 2% (1/51)

32 Outcome 2 year RFS: 88.2% 2 year OS: 94.1%

33 Conclusions of SGSG013 Administering with ddtp before and after RH for locally advanced cervical cancer achieves good survival and is feasible. Phase III studies should compare this with concurrent chemoradiation. Presented by: Satoshi Yamaguchi Hyogo Cancer Center, Akashi, Japan

34 Histological type and Outcome Shimada M et al. Mol Clin Oncol 2013

35 Treatment for Non-SCC Non-SCC, including adenocarcinoma and adenosquamous carcinoma, accounts for approximately 20%, and the incidence of Non-SCC has gradually increased over the past 3 decades. Chemotherapy Surgery Radiation

36 Treatment for Non-SCC Non-SCC, including adenocarcinoma and adenosquamous carcinoma, accounts for approximately 20%, and the incidence of Non-SCC has gradually increased over the past 3 decades. Chemotherapy Surgery Radiation

37 Response rate to recurrent/ advanced cervical non SCC SGSG006/TGCU DTX/CBDCA for IVB and recurrent uterine cervical non SCC (Phase II) docetaxel at a dose of 60mg/m 2 followed by carboplatin at a dose based on an AUC of 6.

38 Response rate to recurrent/ advanced cervical non SCC SGSG006/TGCU DTX/CBDCA for IVB and recurrent uterine cervical non SCC (Phase II) CR PR SD PD NE IVb (N=24) recurrent (N=24) total (N=48) 5 (10.4%) 18 (37.5%) 14 (29.2%) 6 (12.5%) 5 (10.4%) Response rate 47.9% (23/48) Therapeutic benefit rate 77.1% (37/48) Shoji T et al. ECCO 2013

39 SGSG 008 Adjuvant chemotherapy containing taxane/ CBDCA for high-risk non SCC of uterine cervix after radical hysterectomy FIGO stage IB1: 14 IB2: 9 IIA: 3 IIB: 11 RH (n=37) High risk Adjuvant chemotherapy PTX/CBDCA: 22 DTX/CBDCA: 15 Risk factors PLN: 20 PI: 6 Both: 11 6 cycles every 3wks Histology Mucinous: 20 ASC: 11 Endo: 2 Others: 4 Sato S, et al. Int J Gynecol Cancer in press 2016

40 PFS Percent survival P=0.14(Log-rank Test) PTX DTX PFS 2yr-PFS DTX/CBDCA:80.0% PTX/CBDCA:50.0%

41 SGSG 005 (non SCC) (%) Response rate: 69% (95%CI: 57-82%) Out of 52, 50 patients (96.1%) underwent radical surgery DTX/CBDCA :CR :PR :SD :PD (Phase II) (n=52) Nagao S, et al. ASCO 2012

42 SGSG005 (non SCC) docetaxel at a dose of 60mg/m 2 followed by carboplatin at a dose based on an AUC of 6. 2 years OS rate (median follow-up: 1,151 days) IB2: 85.7%, IIA2: 71.4%, IIB: 87.0%

43 Gastric type cervical adenocarcinoma Histologic subtype (n=47) RECIST (ver. 1.0) CR PR SD PD RR Usual-type adenocarcinoma (n=20) % Gastric-type adenocarcinoma (n=13) % Adenosquamous carcinoma (n=12) % Neuroendocrine tumors (n=1) (100%) Serous adenocarcinoma (n=1) (100%) Kojima A, et al. ASCO 2013

44 Conclusions The prognosis of patients with cervical cancer, particularly advanced cases, has not improved. New chemotherapeutic regimens (i.e bevacizumab, ddtp ) improved the outcome of patients with cervical cancer. However, survival benefit was not observed in patients with cervical adenocarcinoma. Neoadjuvant chemotherapy with docetaxel and carboplatin followed by radical hysterectomy may be a useful strategy for patients with non-squamous cell carcinoma. Gastric type cervical adenocarcinoma will be a next focus for improving the prognosis of cervical adenocarcinoma.