Dr Marie Plante
NCIC CTG, Cervix Working Group
GCIG meeting
Belgrade, Oct 10-11, 2009


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

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


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


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
Ureter Sup. vesical artery Obturator nerve uterine artery
Right parametrial SN Right obturator SN

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 !)

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