1. Less Radical Surgery for Patients with Early-Stage Cervical Cancer Dr Marie Plante NCIC CTG, Cervix Working Group GCIG meeting Belgrade, Oct 10-11, 2009

2. Less Radical Surgery  Rationale  Trial proposal  Areas of controversies

3. Less radical surgery  Morbidity of the radical hysterectomy and nodes comes from l Lymphadenectomy Lymphocele/lymphoedema, nerve/vessel injury l Parametrectomy Damage to autonomic nerve fibers a/w bladder, bowel and sexual dysfunction Late urological/rectal dysfunctions: 20-30% Magrina 1995, Sood 2002, Benedetti-Panici 2005

4. Less Radical Surgery  In low risk disease l Stage Ib1 l < 2 cm l LVSI -  Rate of lymph node metastasis: < 5% Kinney WK. Gynecol Oncol 57:3-6, 1995

5. Less Radical Surgery  Review of 1063 cases of stage IA2 l Rate of lymph node mets: < 5% 12% in ptes with LVSI + 1.3% in ptes with LVSI - l Recurrence rate: 3.6% Van Meurs H et al. Int J Gynecol Cancer 19: 21, 2009

6. Less Radical Surgery  Review of 1565 cases of IA1/IA2 adenoca l Rate LN mets: 1.5% l Recurrence rate: 2.4% l Cone alone appears to be safe l PLND may be avoided in LVSI - patients Bisseling K and Quinn M. Gynecol Oncol 107: 424, 2007

7. Less radical surgery  Parametrial invasion (PI) l Retrospective study of 842 ptes l Risk of PI was 0.6% if Tumor size < 2 cm Negative pelvic nodes Depth of stromal invasion < 10 mm Covens et al. Gynecol Oncol 2002; 84: 145

8. Less radical surgery  Parametrial invasion l Retrospective review of 594 ptes l PI in node + and node - ptes : 48 vs 6% l PI was found in 0.4% if Node negative ptes No LVSI Tumors < 2 cm Wright JD et al. Cancer 2007; 110: 1281

9. Less radical surgery  Parametrial invasion l Literature review of ptes with low-risk pathological characteristics: Tumor size < 2 cm Stromal invasion < 10 mm Negative pelvic nodes No LVSI l Risk of PI was 0.63% (5/799) Stegeman et al. Gynecol Oncol 2007; 105: 475

10. Less radical surgery  Hard to justify the morbidity of a radical hysterectomy and parametrectomy in very low risk patients l Risk of PI < 1%  Lymphadenectomy probably still justified although LN mets low < 5% l Could possibly be omitted in IA2/LVSI -

11. Less radical surgery  Sentinel node mapping l Particularly effective in small lesions (< 2 cm) Detection rate: 100% False negative rate: 0% l Could reduce the radicality/morbidity of the PLND in this low risk group Rob L et al. Gynecol Oncol 98: 281, 2005

12. Less radical surgery  Relationship between SN vs PI status l 158 ptes IA2/IB1 If SN +: risk of PI 28% If SN - : risk of PI 0% if –Tumor < 2 cm –Stromal invasion < 50% Strnad P et al. Gynecol Oncol 2008; 109: 280

13. Less radical surgery  Pilot study : n=60 l Procedure Laparoscopic SLN followed by PNLD in SN- ptes on FS and simple vaginal hysterectomy l Selection criteria IA1/VSI (3), IA2 (11), IB1 < 2 cm and SI < 50% (46) Diagnosis by leep/cone (75%) or cx biopsy (25%) MRI after to identify residual disease LVSI not excluded Pluta M et al. Gynecol Oncol 2009; 113: 181

14. Less radical surgery  Pilot study n=60 l 5 ptes had + SLN (8.3%) 3 detected on FS: rad hyst / nodes + RT 2 missed on FS (micromets); one had RT l Median F/U: 47 mo (12-92) No recurrences Pluta M et al. Gynecol Oncol 2009; 113: 181

15. Less radical surgery  Pilot study n=60 l « Parametrectomy » Medial part of the lateral parametrium –Between cervical fascia and obliterated umbilical artery Resection of parametrial « blue node » with ex-vivo radioactive count and parametrial « blue channels » Pluta M et al. Gynecol Oncol 2009; 113: 181

16. Parametrial SN Right obturator SNRight parametrial SN Ureter uterine artery Sup. vesical arteryObturator nerve

17. Less radical surgery  Proposed protocol

18. Proposed Protocol

19. Less radical surgery  Study design: randomized trial l Modified rad hyst/nodes vs. simple hyst/nodes Outcome primary endpoint: 1500 ptes (80% power to show a difference of 2% in pelvic relapse, i.e, 2 vs 4%) Toxicity primary endpoint: 320 ptes *** (favoured) (80% power to show a difference of 10% in acute severe toxicity, i.e, 15 vs 5%) l A prospective cohort to be compared with similar sized contemporaneous cohort of ptes treated by rad hyst: 160 ptes (least favoured)

20. Less radical surgery  Study design l Modified rad hyst/nodes vs. simple hyst/nodes Toxicity primary endpoint: 320 ptes (80% power to show a difference of 10% in acute severe toxicity, i.e, 15 vs 5%) Expected to be primarily bladder complications, with smaller numbers of post-operative and operative events (infection, bleeding, thromboembolic etc.) Early stopping if relapse in the experimental arm exceeds an agreed upon threshold (e.g. more than 4%, stats pending)

21. Less radical surgery  Question l Would more limited surgery reduce morbidity without jeopardizing outcome  Objective l Feasibility/safety of less radical surgery l Oncologic outcome and treatment-related morbidity  Inclusion criteria l Stage IA1/LVSI, IA2- IB1 < 2 cm with < 50% SI l Adeno and squamous l All grades l LVSI

22. Less radical surgery  Primary endpoints l Operative morbidity l Severe toxicity (< 12 months)  Secondary endpoints l SLN detection rate l Rates of PI, positive SLN, positive margins l Relapse (site) and survival l QoL (NCI-CTC version 3)

23. Less radical surgery  Points of discussion l Imaging requirement Pelvic MRI ? l Sentinel node mapping « parametrial node » resection. Is it reproducible ? l Stratification IA2 vs IB1 With/without LVSI Surgical approach (abdominal vs vaginal/laparoscopic/robotic)

24. Less radical surgery  Points of discussion l Exclusion criteria IA1 with LVSI If not doing nodes in stage IA2 and LVSI- Cone alone for fertility preservation –Can’t really compare morbidity of rad hyst vs. cone l Central pathology review ? Diagnostic cone/LEEP mandatory to assess depth of stromal invasion and size ? Do we consider depth of stromal invasion or not

26. MD Anderson Trial  Prospective multi-institutional trial l MSKCC l Texas (El Paso) l Czech Republic (2 centers) l Colombia  Sample size l 20-100 cases Schmeler Kathleen et al

27. MD Anderson Trial  Criteria differ l IA1 (VSI) excluded l Grade 3 adenoca excluded l LVSI excluded l Diagnostic cone/ECC with negative margins for cancer or ACIS If +, 2nd cone allowed l Inclusion of women who wish to preserve fertility SN and PLND only Schmeler Kathleen et al

28. MD Anderson Trial  Objectives: l Safety, feasibility, recurrence at 2 years l Nodal involvement and tx-related morbidity compared to historical data from matched patients treated with rad hyst l QoL (5 questionnaires !)

30. Pluta M et al. Gynecol Oncol 2009; 113: 181 Prague protocol