Transcript Role of Surgical Trials in Gynaecological Oncology

Role of Surgical Trials in
Gynaecological Oncology Research
Henry Kitchener, University of Manchester
ANZGOG, March 2013
Role of Surgery in Gynaecological
Oncology
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Curative
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Pallative
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Debulking and relief of obstruction.
Salvage
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The most sucessful primary treatment for early stage
disease.
Isolated metastasis; localised recurrence.
Cost effective
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Cheaper and less complex than many treatments.
Horizon scanning reveals a changing role
for surgery
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Ovarian cancer
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To follow chemotherapy (Grade I)
To treat recurrence (unproven)
More aggressive primary debulking (unproven)
Lymphadenectomy (unproven)
Endometrial cancer
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to rationalise staging by
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Full lymphadenectomy (unproven)
Sentinel node dissection (feasible)
Implications of obesity epidemic
Horizon scanning reveals a changing role
for surgery
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Cervical cancer
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Becoming ever rarer in GCIG (not in developing world)
Reduced role of radical hysterectomy
Sentinel node detection (feasible)
Vulval cancer
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Will become rarer following HPV vaccination
Sentinel node detection (feasible)
Completion surgery following chemo/radiation or antiviral
therapy
Influences on surgical trends
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Epidemiology
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Disease incidence
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Population characteristics (obesity, aging etc)
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Prevention strategies
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New non surgical treatments
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New techniques (eg laporoscopic, robotic)
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Extent of surgery
Surgical volume as current standard of
care
Setting
Trend
Upfront treatment of ovarian cancer
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Second line treatment for recurrence
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Primary treatment of endometrial cancer
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Primary treatment of cervical cancer
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Primary treatment of vulval cancer
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Extent of cancer surgery
Bipolar trend in surgery
More radical surgical attempt
 To debulk
 To salvage
Less radical surgery
 To conserve function
 To reduce morbidity
Drivers for clinical trials in surgery
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Surgical practice needs an evidence base
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Effectiveness
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Cost effectiveness
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Funders want to encourage surgical trials
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Need to address standard of care
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Need to evaluate new procedures
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(need to get into NEJM/Lancet)
Challenges facing surgical trials
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Surgical culture which does not demand evidence
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“Conviction based” resistance to trial design
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Reluctance to get involved in trials
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Lack of commercial sponsorship
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Except when new equipment is being evaluated
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Definition of a control arm
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Point in time of equipoise
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Randomisation
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The complexity of a surgical intervention
Types of clinical trials and other high
quality studies
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Randomised controlled trials
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Phase II (feasibility)
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Phase III (superiority, non inferiority, cost effectiveness)
Prospective non randomised studies
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Paired with standard of care e.g. sentinel node
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Stand alone with success self evident e.g. a new vaccine against
cervical cancer
Influences on surgical outcomes
Lancet 2009;374 1097-1104
Stage 0-1
Stage 2a
Stage 2b
Stage 3
Stage 4
(Innovation)
(Development)
(Exploration)
(Assessment)
(Long term)
Number and
types of patients
Single digit,
highly selected
(or pre-human)
Few, selected
Many, mixed but
not all
Many, variable
Almost all
Number of
surgeons
Very few
Few, innovators
Many
Many, early
majority
Most, late
majority
Ethics
Sometimes
Yes
Yes
Yes
No
Learning curve
in human beings
No
Yes
Yes
Maybe
No
Table 2: Stages of surgical innovation (IDEAL paradigm) Lancet 2009; 374: 1089-96
Ovarian cancer surgery trials (1)
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Hypothesis: super aggressive surgery does not improve
survival
Challenges
•Control arm
•Patient acceptance
•Feasible?
•Interface between “normal”
and “aggressive” surgical
effort
Randomise
Normal
debulking
effort
Aggressive
debulking
effort
Chemotherapy
Primary outcome: overall
survival
Ovarian cancer surgery trials (2)
Hypothesis: Surgery does not improve survival in ovarian
cancer
Platinum sensitive disease may not need debulking
Platinum resistant disease may not benefit from debulking
Surgery can be palliative
Challenges
•Timing of surgery
•Patient acceptance
•Doctor acceptance
•Feasible
•Need for palliation
RCT of primary surgery in ovarian
cancer
Neoadjuvant chemotherapy
If responding, randomise after 3 cycles
Surgery
No surgery
Continue chemo
Continue chemo
Relapse
Relapse
Primary outcome: progression free survival, quality of life
(1,6,12 months), overall survival
Primary Peritoneal cancer
R Clayton & S Kehoe for NCRI
•Hypothesis-
Surgery may be non contributory in
platinum sensitive women.
•Population-
Women with small ovarian mass and
obvious upper abdominal disease.
•Intervention-
Debulking surgery after 3 cycles of CP
if there has been a relapse.
•Primary Outcome- Progression free survival.
RCT of surgery in primary peritoneal
cancer
Eligible Women Registered
Laporoscopy & Biopsies
Chemo 3 Cycles
Response
Continue Chemo
Surgery
Follow Up
Chemo
Surgery trials in endometrial cancer (1)
To demonstrate whether lymphadenectomy directed
therapy is more beneficial than non selected adjuvant
therapy in high grade disease
Challenges
•Eligibility
•Quality control
•Extent of lymphadenectomy
•Choice of adjuvant therapy
Surgical trials in endometrial cancer
(2)
High-risk Endometrial Cancer
Clinical stage 1, grade 3 endometrioid
? Clinical stage 1, Serous cancer
? Clinical stage 1, grade 2 with deep invasion
Sentinel node
substudy
No
Lymphadenectomy
Lymphadenectomy
(pelvic/PA)
Lymph node
negative
Vaginal
Brachytherapy
Lymph node
positive
Lymph nodes
unknown
Chemotherapy and Radiation Therapy*
or Chemotherapy alone**
Follow-up, toxicity and quality of life
* EBRT + 2cylces of concurrent cisplatin, followed by 4 cycles of carboplatin/paclitaxel
** 6 cycles of carboplatin/paclitaxel; vaginal brachytherapy at group preference
Schedule by group preference, stated before and used consistently thoughout trial.
Surgical trials in endometrial cancer (3)
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To determine the clinical effectiveness of sentinel node
detection
Design: incorporate initial sentinel node detection into a
lymphadenectomy protocol
 Allows direct comparison of accuracy, reliability
 Enables controlled learning of technique
 Allows comparison of “SND outcomes” with trial
outcomes
 A positive SN/-ve lymphadenectomy counts as “lymph
node positive”
Role of surgical trials in cervical
cancer
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To determine the need for radical hysterectomy in small
volume (< 2cms) stage 1a2/1b
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SHAPE Trial
To determine the clinical effectiveness of sentinel node
detection
Cervical Tumour
< 2 cms across
> 1 cm margin
SHAPE Trial
Randomise
Rad Hyst
& PLND + SLN
Positive
Nodes
Simple Hyst
& PLND + SLN
Negative
Nodes
Adjuvant
treatment
policy
Negative
Nodes
HR
Chemoradiation
HR
IR
Radiation
IR
LR
Follow up only
LR
1° Outcome
Pelvic relapse free survival
(700 patients)
Conclusion
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Surgical trials in cancer are challenging but necessary
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Developments in cancer care require re-evaluation of
surgery
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Surgical trials may benefit from GCIG collaboration
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Several important trials can be considered which
challenge standard of care