Less Radical Surgery for Patients with Early-Stage Cervical Cancer

Dr Marie PlanteNCIC CTG, Cervix Working Group

GCIG meetingBelgrade, Oct 10-11, 2009

Less Radical Surgery

Rationale Trial proposal Areas of controversies

Less radical surgery

Morbidity of the radical hysterectomy and nodes comes from Lymphadenectomy• Lymphocele/lymphoedema, nerve/vessel injury

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

Less Radical Surgery

In low risk disease Stage Ib1 < 2 cm LVSI -

Rate of lymph node metastasis: < 5%

Kinney WK. Gynecol Oncol 57:3-6, 1995

Less Radical Surgery

Review of 1063 cases of stage IA2 Rate of lymph node mets: < 5%• 12% in ptes with LVSI +

• 1.3% in ptes with LVSI - Recurrence rate: 3.6%

Van Meurs H et al. Int J Gynecol Cancer 19: 21, 2009

Less Radical Surgery

Review of 1565 cases of IA1/IA2 adenoca Rate LN mets: 1.5% Recurrence rate: 2.4% Cone alone appears to be safe PLND may be avoided in LVSI - patients

Bisseling K and Quinn M. Gynecol Oncol 107: 424, 2007

Less radical surgery

Parametrial invasion (PI) Retrospective study of 842 ptes 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

Less radical surgery

Parametrial invasion Retrospective review of 594 ptes PI in node + and node - ptes : 48 vs 6% PI was found in 0.4% if• Node negative ptes

• No LVSI

• Tumors < 2 cm

Wright JD et al. Cancer 2007; 110: 1281

Less radical surgery Parametrial invasion

Literature review of ptes with low-risk pathological characteristics: • Tumor size < 2 cm

• Stromal invasion < 10 mm

• Negative pelvic nodes

• No LVSI Risk of PI was 0.63% (5/799)

Stegeman et al. Gynecol Oncol 2007; 105: 475

Less radical surgery

Hard to justify the morbidity of a radical hysterectomy and parametrectomy in very low risk patients Risk of PI < 1%

Lymphadenectomy probably still justified although LN mets low < 5% Could possibly be omitted in IA2/LVSI -

Less radical surgery

Sentinel node mapping Particularly effective in small lesions (< 2 cm)• Detection rate: 100%

• False negative rate: 0% Could reduce the radicality/morbidity of the

PLND in this low risk group

Rob L et al. Gynecol Oncol 98: 281, 2005

Less radical surgery

Relationship between SN vs PI status 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

Less radical surgery

Pilot study : n=60 Procedure

• Laparoscopic SLN followed by PNLD in SN- ptes on FS and simple vaginal hysterectomy

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

Less radical surgery

Pilot study n=60 5 ptes had + SLN (8.3%)• 3 detected on FS: rad hyst / nodes + RT• 2 missed on FS (micromets); one had RT

Median F/U: 47 mo (12-92)• No recurrences

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

Less radical surgery

Pilot study n=60 « 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

Parametrial SN

Right obturator SNRight parametrial SN

Ureter

uterine artery

Sup. vesical artery Obturator nerve

Less radical surgery

Proposed protocol

Proposed Protocol

Less radical surgery

Study design: randomized trial 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%)

A prospective cohort • to be compared with similar sized

contemporaneous cohort of ptes treated by rad hyst: 160 ptes (least favoured)

Less radical surgery

Study design 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)

Less radical surgery

Question Would more limited surgery reduce morbidity without

jeopardizing outcome Objective

Feasibility/safety of less radical surgery Oncologic outcome and treatment-related morbidity

Inclusion criteria Stage IA1/LVSI, IA2- IB1 < 2 cm with < 50% SI Adeno and squamous All grades LVSI

Less radical surgery

Primary endpoints Operative morbidity Severe toxicity (< 12 months)

Secondary endpoints SLN detection rate Rates of PI, positive SLN, positive margins Relapse (site) and survival QoL (NCI-CTC version 3)

Less radical surgery

Points of discussion Imaging requirement • Pelvic MRI ?

Sentinel node mapping• « parametrial node » resection. Is it reproducible ?

Stratification • IA2 vs IB1• With/without LVSI• Surgical approach (abdominal vs

vaginal/laparoscopic/robotic)

Less radical surgery

Points of discussion 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

Central pathology review ?• Diagnostic cone/LEEP mandatory to assess depth of stromal

invasion and size ?

• Do we consider depth of stromal invasion or not

MD Anderson Trial

Prospective multi-institutional trial MSKCC Texas (El Paso) Czech Republic (2 centers) Colombia

Sample size 20-100 cases

Schmeler Kathleen et al

MD Anderson Trial

Criteria differ IA1 (VSI) excluded Grade 3 adenoca excluded LVSI excluded Diagnostic cone/ECC with negative margins for

cancer or ACIS• If +, 2nd cone allowed

Inclusion of women who wish to preserve fertility• SN and PLND only

Schmeler Kathleen et al

MD Anderson Trial

Objectives: Safety, feasibility, recurrence at 2 years Nodal involvement and tx-related morbidity • compared to historical data from matched

patients treated with rad hyst QoL (5 questionnaires !)

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

Prague protocol