Management of high risk early cervical cancer - a view of surgeon Dan DY Kim, M.D., Ph.D.

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1 Management of high risk early cervical cancer - a view of surgeon Dan DY Kim, M.D., Ph.D. Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

2 High risk cervical cancer bulky, node +, bad histology RH vs. CCRT Company Logo

3 Case 1. your choice? RH or CCRT 42, F para r/o both external iliac LN metastasis 4cm

4 Case 1 Metastatic lymphadenopathy in right obturator area most likely Mild hypermetabolic lymph node in left obturator area: reactive hyperplasia vs. metastasis

5 Case 2 your choice? RH or CCRT 45, F para s/p LEEP Enlarged lymph node in right external iliac vessel area, r/o metastatic lymphadenopathy 2cm mass (including conization mass)

6 Case 2 Hypermetabolic lesion in right side pelvic cavity, r/o LN metastasis

7 RH vs. CCRT Company Logo

8 1. 수술 + 방사선치료 vs. 방사선치료의치료효과가비슷하다면합병증을고려할때방사선치료가선택지이다 2. 수술전에추가방사선치료가예상된다면바로방사선치료를하는것이낮다. 3. 수술 + 방사선치료의합병증이방사선단독보다높다 4. 수술시암세포를전파시켜방사선 field 벗어날수있다. Company Logo

9 수술 + 방사선치료 vs. 방사선치료의치료효과가비슷 Company Logo

10 The only RCT comparing RH vs RT Objectives To evaluate 5-year survival and the rate and pattern of complications and recurrences associated with RH and RT in FIGO stage IB and IIA cervical cancer Landoni F et al. The Lancet 1997;350:535-40

11 Trial Profile Single institution in Italy Stage IB or IIA disease RT: 169 cases External RT + Brachytherapy RH: 158 cases Type III hysterectomy Adjuvant RT: External RT only Criteria for adjuvant RT Greater than pt2a uninvolved cervical stroma < 3 mm LN metastasis 54% in Tumor 4 cm 84% in Tumor > 4 cm Landoni F et al. The Lancet 1997;350:535-40

12 5-year Survival Median Follow-up Time : 87 months (Range, ) 74% 83% Landoni F et al. The Lancet 1997;350:535-40

13 Survival according to Tumor Size (RH vs RT) 87% vs 90% 70% vs 72% Landoni F et al. The Lancet 1997;350:535-40

14 Conclusion of This Study There is no treatment of choice for earlystage cervical carcinoma in terms of overall or disease-free survival. The combination of surgery and RT has the worst morbidity, especially urological complications. The optimum therapy should take account of clinical factors such as MP status, age, medical illness, histology and tumor size. Landoni F et al. The Lancet 1997;350:535-40

15 Limitations of This RCT The primary endpoint of this study was not to compare RH vs RT in IB2 & IIA2 disease. This study included only small number of IB2 & IIA2 disease. Unacceptable high rate of complications in RH alone group. Generalization of the conclusion of this study is not possible. Further RTC should be performed in bulky early cervical cancer in the era of CCRT Landoni F et al. The Lancet 1997;350:535-40

16 Protocol GOG-0201 Treatment of patients with stage IB2 carcinoma of the cervix: A randomized comparison of radical hysterectomy and tailored chemo-radiation versus primary chemo-radiation (in 2003) Randomization 1:1 Cervical cancer IB2 > 4 cm SCCa, AdenoCa, AdenoSCCa Radical Hysterecto my CCRT wcddp No risk Intermediate or High risk 3yr PFS: 78% vs 70%, HR & α = 0.05 β = sided Log rank test Gompertz model Total 740 (370:370) 7yr accrual, 2 yr FU Observatio n CCRT wcddp Terminated in 2004 due to very slow rate of enrollment

17 KGOG 1029-Study scheme A randomized controlled trial comparing radical hysterectomy plus tailored adjuvant therapy versus primary chemo-radiation therapy in non-bulky node-positive early cervical cancer No risk Observation Randomization 1:1 Radical Hysterectomy Intermediate risk Pelvic RT Cervical cancer IB1 or IIA1 (<4 cm) and pelvic lymphadenopath y in MRI/PET SCCa, AdenoCa, AdenoSCCa ARH, L(V)RH, RLRH Sentinel LN mapping allowed CCRT wcddp 6 Pelvic RT + ICR + Boost Extended-filed RT if PALN+ CDDP 40mg/m 2 High risk CCRT wcddp 6 Pelvic RT Extended-filed RT if PALN+ CDDP 40mg/m 2

18 Recent Large Population-based Retrospective Studies of RH and (CC)RT for IB2 & IIA2 Cx Ca Ryu HS et al. Int J Gynecol Cancer 2007;17:132-6

19 Survival Outcomes 34% in surgery group did not received adjuvant therapy Surgery alone group had the best survival outcome Ryu HS et al. Int J Gynecol Cancer 2007;17:132-6

20 Survival Outcomes Potential survival benefits in RH group : In IB2 Cx Ca, the best survival outcome in RH group Ryu HS et al. Int J Gynecol Cancer 2007;17:132-6

21 Recent Large Population-based Retrospective Studies of RH and (CC)RT for IB2 & IIA2 Cx Ca Surveillance, Epidemiology, and End Results (SEER) date Stage IB-IIA Cervical Cancer RH: 4012 RT/CCRT: 873 Bansal N et al. Am J Obstet Gynecol 2009;201:184.e1-9

22 Survival Outcomes: Total Patients RH=4012 RH=4012 RT=873 RT=873 In Multivariable analysis, OR 0.41 (95% CI, ) Bansal N et al. Am J Obstet Gynecol 2009;201:184.e1-9

23 Survival Outcomes: Total Patients RH=135 RH=3186 < 4 cm 4-6 cm RT=365 RH=653 RT=353 RH=38 Suggested potential survival benefits in RH group : Cx Ca < 6 cm, RH is superior to (CC)RT RT= cm > 8 cm RT=23 In Multivariable analysis, <4cm OR 0.38 (95% CI, ) 4-6cm OR 0.51 (95%CI, ) Bansal N et al. Am J Obstet Gynecol 2009;201:184.e1-9

24 Korean retrospective study Nam JH et al. J Gynecol Oncol 2012;23:226-34

25 Patients flow 34% of patients in surgery group were cured by surgery alone n=248 Radical Hysterectomy 370 Cervical Cancer Patients with 1) FIGO stage IB and IIA 2) Tumor size > 4 cm in MRI 3) SCCa, AdenoCa or AdenoSCCa n=122 RT / CCRT n=50 Low Risk Group n=84 Intermediate Risk Group n=114 High Risk Group n=50 n=77 RT CCRT Adjuvant treatment n=50 No n=42 n=11 n=22 n=9 No CT RT CCRT n=21 n=23 n=70 CT RT CCRT Recurrence 10% (5/50) 14.3% (6/42) 27.3% (3/11) 22.7% (5/22) 0% (0/9) 14.3% (3/21) 43.5% (10/23) 24.3% (17/70) 16% (8/50) 37.7% (29/77) Death 6% (3/50) 9.5% (4/42) 27.3% (3/11) 22.7% (5/22) 0% (0/9) 14.3% (3/21) 39.1% (9/23) 21.4% (15/70) 16% (8/50) 32.5% (25/77) Nam JH et al. J Gynecol Oncol 2012;23:226-34

26 Survival comparison 76% 74% 78% 71% 64% 64% 66% 62% Nam JH et al. J Gynecol Oncol 2012;23:226-34

27 Survival comparison Nam JH et al. J Gynecol Oncol 2012;23:226-34

28 수술전에추가방사선치료가예상된다면바로방사선치료를하는것이낮다. Company Logo

29 non-bulky Lymphadenopathy Cervical Cancer in AMC RFS Overal survival 2years OS 93% 3years OS 90% 2years RFS 86% Under 1/3 patients had not been underwent RT after surgery in AMC

30 Lymph node assessment with 18 F-FDG-PET and MRI in uterine cervical cancer MRI : PPV 50% NPV 91% FDG-PET : PPV 50% NPV 85% * AMC data * MRI PPV 41.7% NPV 80% FDG-PET PPV 50% NPV 72.7% J.Monteil et al. Anticancer Research 2011;31:

31 Treatment-related Morbidity :RH vs. CCRT

32 Low rate of complications in RH+RT group in stage IB Cx Ca In GOG 98 Protocol (Randomized trial of pelvic RT vs no further therapy in selected patients with stage IB Cx Ca after RH + PLND) Contrary to previously reported 20-40% rates of serious toxicity when RT is combined with RH, grade 3-4 toxicity was only 7%, including 2% and 3% rates for GI and GU complication, respectively Sedlis A et al. Gynecol Oncol 1999;73:

33 Low rate of complications in RH+RT group in stage IB Cx Ca In GOG 98 Protocol RH + RT RH alone Sedlis A et al. Gynecol Oncol 1999;73:

34 Complications P-value RH alone (n=50) RH+(CC)RT (n=101) (CC)RT (n=116) RH alone vs RH+RT RH alone vs. CRT RH + RT vs. CRT Acute complications, grade (3.4) 29 (23.4) 27 (22.1) < < Chronic complications, grade (1.6) 8 (6.5) 12 (9.8) Nam JH et al. J Gynecol Oncol 2012;23:226-34

35 Lower rate of complications in RH+CRT than CRT in stage IB Cx Ca Ziebarth et al. Gynecol Oncol 2012;126:69-72

36 Lower rate of complications in RH+CRT than CRT in stage IB Cx Ca RH + WPRT + Cisplatin (not receive BT) WPRT + Cisplatin + BT Ziebarth et al. Gynecol Oncol 2012;126:69-72

37 Lower rate of complications in RH+CRT than CRT in stage IB Cx Ca RH + WPRT + Cisplatin WPRT + Cisplatin + BT Ziebarth et al. Gynecol Oncol 2012;126:69-72

38 Conclusion of This Study RH + LND decreases RT exposure (BT is not required) and thus RT related complication without compromising safety and outcomes. The morbidity of RH + CRT is lower than CRT because of the less exposure to radiation. Ziebarth et al. Gynecol Oncol 2012;126:69-72

39 Longterm morbidity of Radiation secondary malignancy 30yr survival rate Company Logo

40 Preference of patients and Doctors Company Logo

41 Guidelines for management of cx ca Treatment of FIGO stage IB2, IIA2: The role of RH is still controversial Pelvic RT + Cisplatin + Brachytherapy (Total point A dose > 85 Gy) RH + PLND + PALND Category 1 Category 2B Pelvic RT + Cisplatin + Brachytherapy (Total point A dose 75-80) + Adjuvant hysterectomy Category 3 NCCN Guidelines Version

42 Clinical Practice Guideline NCCN 2012 NIC 2010 ESMO 2012 AGO 2008 JSGO 2011 KSGO 2010 USA USA Europe Germany Japan Korea IB2 & IIA2 CCRT RH CCRT + Hysterectomy CCRT CCRT RH RH CCRT RH CCRT NAC + RH Optimal treatment is controversial Recommendation is different depending on the regions North America & Europe: CCRT Asia: RH or CCRT

43 Pattern of Practice in Korea KGOG 1005: Efficacy of different types of treatment in FIGO stage IB2 cervical cancer in Korea: Results of a multicenter retrospective Korean study 43.9% (70.1%) The most frequently employed primary treatment modality for stage IB2 cervical cancer in Korea during past 10 years was radical hysterectomy. Ryu HS et al. IJGC 2007;17:132-6

44 Have you seen irradiated bowel and vulva? Company Logo

45 Company Logo

46 Adjuvant chemotherapy Phase II study of adjuvant chemotherapy with paclitaxel and nedaplatin for FIGO stage IB-IIA uterine cervical cancer with lymph node metastasis following radical hysterectomy: A Kansai Clinical Oncology Group study (KCOG-G1101). The 2-year overall survival rate was 93.3% (95% CI, 86.8% to 99.8%). Adverse events were almost acceptable. Company Logo

47 Company Logo

48 GOG 258 Trial Profile TH, BSO, Pelvic and paraaortic LNS optional Inclusion Stage III or IVA, EC Stage I or II, Serous, Clear, + cytology Exclusion Carcinosarcoma Recurrent EC Residual tumor after surgery > 2cm Randominization 1:1 Regimen I: C-RT (n=404) Cisplatin 50mg/m2 IV Days 1 and 29 plus External 45Gy ± Brachytherapy followed by CBDCA AUC 5 + Paclitaxel 175mg/2 q 21 days for 4 cycles with G-CSF Regimen II (n=406) CBDCA AUC 6 plus Paclitaxel 175m/m2 q 21 days for 6 cycles 5YRFS NO diff. (V: 3% vs 7%, LN: 10% vs 19%, D: 27% vs 21%) 3YRFS CTX about 65% 5YOVS 70% (CRT) vs 73%(CTX) 49 th SGO 2018

49 NEW Protocol : Study scheme No risk Observation Radical Hysterectomy Local risk factors Adj RT Bulky ± LN (> 4 cm) ARH, L(V)RH, RLRH Sentinel LN mapping allowed Distant risk factor (LN) Adj chemo Non bulky +LN SCCa, AdenoCa, AdenoSCCa CCRT wcddp 6 Pelvic RT + ICR + Boost Extended-filed RT if PALN+ CDDP 40mg/m 2

50 RH vs. CCRT Adjuvant chemo Company Logo