Study proposal

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Study proposal
NSGO
After 4 A Phase III intergroup trial on adjuvant
therapy in radically operated endometrial cancer
patients (FIGO stage IC-IIIC) with high risk for
micro- metastatic disease
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What we know from randomized studies

• Aalders et al. (1980), GOG-99 (Keys et al.
  2003), PORTEC (Creutzberg et al. 2000) ASTEC/EN.5
  (Blake et al. 2009) Better loco-regional control
  but no (or very small) effect on OS.
• GOG-34 (Morrow et al. 1990) Prematurely
  terminated
• GOG-122 (Randall et al. 2006) CT is better than
  WAR (more advan-ced disease)
• Maggi et al. 2006
  Failed to show superiority
• JGOG-2033 (Susumi et al. 2008) of either
  CT or RT
• RTOG-9708 (Greven et al. 2006) ChemoRT (CMT) is
  feasible
• NSGO-EC-9501/EORTC-55991 (Hogberg et al. ASCO
  2007) The sequential addition of CT to RT
  improves PFS
• Kouppala et al 2008 Failed to show superiority
  of CTRT vs RT n150
• PORTEC-3 (ongoing) is CMT better than RT?

Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991
May 1996 to January 2007
RT
Randomization
n196
44 Gy XRT optional VBT (39)
n382
Radical surgery TAHBSO (PLA)
RTCT
n186
(VBT 44)
OR
Surgical stage I, II, IIIA (positive peritoneal
fluid cytology only), or IIIC (positive pelvic
lymph nodes only) with high risk for
micro-metastatic disease
CTRT
CT intially AP Later AP, TcP, TAP, TEcP

Patients with serous, clear cell, or anaplastic
carcinomas were eligible regardless of other risk
factors
Primary endpoint Progression-free survival (PFS)
Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991
PFS progression-freee survival (PFS)
Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991
PFS progression-freee survival (PFS) serous/clear
cell ca
Thomas Hogberg, Lund Univ Hosp Oct 2009
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MANGO ILIADE
October 1998 to July 2007
RT
Randomization
n76
45 Gy XRT (VBT If st IIB or IIIB)
n156
Radical surgery TAHBSO (PLA)
CTRT
n80
Surgical stage IIB, IIIA-C endometrioid
carcinomas (IIIA with only pos per cytol not
eligible
CT APX3 q 3 weeks
Primary endpoint Progression-free survival
(PFS) and overall survival (OS)
Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991/MANGO
Pooled data failure-free survival (FFS)
endometrioid carcinoma
Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991/MANGO
Pooled results failure-free survival (FFS)
endometrioid carcinoma
Randomization Observed Expected events events R
T n187 50 37.15 RTCT n197 29
41.85 Total n384 79 79.00
HR 0.46 (95 CI 0.28-0.74) p0.001 which
translates to an estimated absolute difference in
5-year FFS of 13 from 71 84
Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991/MANGO
Pooled data cancer-specific survival (CCS)
endometrioid carcinoma
Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991/MANGO
Pooled results cancer-specific survival (CCS)
endometrioid carcinoma
Randomization Observed Expected events events R
T n187 36 27.33 RTCT n197 21
29.67 Total n384 57 57.00
HR 0.51 (95 CI 0.29-0.91) p0.02 which
translates to an estimated absolute difference in
5-year CSS of 10 from 77 87
Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO EC-9501/EORTC-55991
Lokoregional progressions 4.1 in the RT-arm vs.
1,1 in the RTCT-arm additive effects?
The combination of RT CT is better than RT
An additive interaction between RT CT could
explain the difference in the EORTC/NSGO/MANGO-stu
dy And the lack of difference in the Italian and
Japanese studies
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Conclusions questions

• PORTEC-3
• Unless there is something fundamentally wrong
  with NSGO-9501/EORTC-55991 PORTEC-3 will most
  probably show that CMT is better than RT

The question about the contribution of RT will
remain unanswered
When PORTEC-3 is published CMT will probably
become standard treatment
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Proposition
We have a time-frame in which we can resolve
the question of the value of addition of
radiotherapy to chemotherapy
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Proposed study
RT
Randomization
N1000
Radical surgery TAHBSOLA CTx4
CTx2
Main inclusion criteria a. Endometrioid
carcinoma b. Stage 1C grade 3 c. Stage IIA grade
3 and MI50, IIB d. Stage IIIA-C Radical
surgery, LA recommended but optional Main
exclusion criteria Serous or clear cell
carcinoma IIIA with only pos fluid cytology
CT Paclitaxel 175 mg/m2, carboplatin AUC 5-6
(calculated) q 3 weeks
Primary endpoint Overall survival (OS)
Thomas Hogberg, Lund Univ Hosp Oct 2009
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After 4

• Informed consent and registration after surgery
  before CT. All patients are followed
• If there is extensive neurotoxicity the patient
  will not be randomized but will be treated with
  RT
• If severely detoriated general condition
  protocol therapy is stopped
• These patients will then not be drop-outs after
  randomization
• Negative consequence of after 4 randomization.
  The therapy will only evaluated in a subgroup
  with better general condition who tolerate 4
  cycles of CT

Thomas Hogberg, Lund Univ Hosp Oct 2009
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End-points

• Primary
• To compare overall survival (OS) of patients
  treated with either 2 more courses of CT versus
  sequential RT after 4 courses of CT
• Secondary
• Cause-specific survival (CSS) (time to death of
  endometrial carcinoma or of treatment
  complications), progression-free survival (PFS)
  (time to relapse of endometrial carcinoma or
  death all causes), failure-free survival (FFS)
  (time to relapse or death of endometrial
  carcinoma or of treatment complications, with
  deaths unrelated to endometrial carcinoma
  censored)
• Toxicity
• Patterns of progression
• Quality of life evaluated by EORTC QLQ-30
• Fraction of registered patients that could be
  randomized and reasons for non-randomization.
  Survival for non-randomized patients

Thomas Hogberg, Lund Univ Hosp Oct 2009
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Inclusion criteria

• Histologically confirmed endometrial carcinoma
  with no macroscopic remaining tumor after primary
  surgery (systematic lymph node exploration
  optional), with one of the following
  postoperative FIGO 1988 stage and grade
• FIGO 1988 stage IC grade 3.
• FIGO 1988 stage IIA MI50 , IIB.
• FIGO 1988 stage IIIA, IIIB, IIIC all grades.

IIIA only because of positive peritoneal lavage
fluid is included if there is also grade 3 and
MI50
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Inclusion criteria
According to the new proposed FIGO staging
Stage IB grade 3. Stage II all
grades. Stage IIIA, IIIB, IIIC1, and IIIC2 all
grades
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Exclusion criteria

• Any postoperative residual macroscopic tumor
• Clear cell, serous, squamous carcinoma or small
  cell carcinoma with neuroendocrine
  differentiation
• Preoperative irradiation
• Previous or concurrent malignant disease except
  for curatively treated carcinoma in situ of the
  cervix or basal cellosquamous carcinoma of the
  skin
• Active infection or other serious underlying
  medical condition, which might prevent the
  patient from receiving treatment or to be
  followed
• Uncontrolled or potentially active site of pelvic
  infection (e.g. fistula or abscesses)
• Inadequate bone marrow, liver, or kidney
  function
• Previous extensive abdominal surgery or other
  condition that might give a substantial increase
  in the risk for complications from RT or CT
• Whatever reasons which interferes with an
  adequate follow-up.
• Longer interval than 3 weeks between last CT
  and randomization

Thomas Hogberg, Lund Univ Hosp Oct 2009
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Surgical procedure
Hysterectomy with bilateral salpingo-oophorectomy
and extirpation of macroscopic palpable
suspicious lymph nodes must be done. Pelvic and
paraaortic lymph node exploration is recom-mended
but is not mandatory. Stratification depending on
lymph node exploration
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Chemotherapy

• Adjuvant CT should start as soon as possible or
  within 2 weeks after registration. Registration
  after the start of CT is not allowed.
• Schedule for CT
• Paclitaxel 175 mg/m2 i.v./3 hours.
• Carboplatin AUC 5-6 i.v. infusion over 30-60
  minutes.
• Both drugs are given on the same day and the
  treatment is to be repeated every 3-weeks for
  four cycles to all patients. Patients who are
  randomized to further CT will receive two more
  cycles, i.e. 6 in all.
• The minimum allowed starting dose of carboplatin
  is AUC 5.
• Calculated GFR.

Thomas Hogberg, Lund Univ Hosp Oct 2009
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Radiotherapy
External radiotherapy (preliminary) The dose,
fractionation and radiation technique is a matter
of departmental preference, but at least CT-based
computer-aided 3-dimensional dose planning and
4-field technique is recommended. The advised
prescribed dose to the target volume should be at
least 44 Gy specified according to ICRU or NACP.
If other fractionations than 2.0 Gy 5 times per
week are used, the dose should be converted to a
2 Gy equivalent dose according to the linear
quadratic formula Brachytherapy Vaginal
brachytherapy should be added for patients with
FIGO 1988 stage IIB (proposed new FIGO stage II)

Thomas Hogberg, Lund Univ Hosp Oct 2009
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Statistical issues
We suppose that a 10 increase in OS from about
65-70 to 75-80 would be regarded as
convincing evidence to accept the addition of
RT Significance level and power are usually set
to 5 and 80. In this case it is very important
not to miss a difference if it exists thus it is
suggested power is set to 90
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Statistical issues
Suppose a trial propulation with somewhat more
advanced cases than in NSGO/EORTC/MANGO-study
with 65 5 year survival in the control group,
recruitment period 3 years, and 3 additional
years for observation power 0.9 and significance
level 0.05, two sided test
Survival experimental arm N 70 4002 75
968 80 414
About 1000 patients would be needed and 266
events need to be observed
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Statistical issues

• With 50 participating departments each
  depart-ment would have to randomize 7
  patients/year for 3 years
• Possible collaborations ?????....

Thomas Hogberg, Lund Univ Hosp Oct 2009
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Stratification
1. Study group 2. Institution 3. Stage FIGO
1988 stage I-IIA FIGO 1988 stage IIB, IIIA,
IIIC According to the new proposed FIGO
staging FIGO stage IB FIGO stage II-IIIC2 4.
Lymph node exploration Yes No
Thomas Hogberg, Lund Univ Hosp Oct 2009
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We have to get used to doing big randomized
trials also in endometrial cancer
Thomas Hogberg, Lund Univ Hosp Oct 2009
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These guys are eagerly waiting for results from
clinical trials in endometrial cancer!
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CONTACT INFORMATION Thomas Hogberg Dept Cancer
Epidemiology Lund University Hospital 221 85
Lund Sweden thomas.hogberg_at_med.lu.se NSGO DATA
CENTER J.B. Winsløws Vej 9, DK-5000 Odense C,
Denmark Phone [phone] Fax 45 6550
4348 gandersen_at_health.sdu.dk
Thomas Hogberg, Lund Univ Hosp Oct 2009
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Problem

• This is a disease with generally good prognosis
• OS8 yr PORTEC 75
• OS5 yr GOG-122 50
• OS5 yr Susumo 90
• OS5 yr Maggi 70
• NSGO/EORTC-5591 80
• AZTEC/EN.5 85
• PORTEC recorded 15 mortality rate at 8 years
  related to intercurrent causes (10 at 5-years)
  (which is more than in AZTEC and NSGO 5)

Thomas Hogberg, Lund Univ Hosp Oct 2009
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Example

• Suppose we have 30 5-year mortality in a risk
  group of endometrial cancer
• 20 would be cancer related and 10
  unrelated to cancer
• Suppose that we have an adjuvant therapy that
  prevents 50 of the cancer related deaths
• The effect on OS will be a change from 70 to
  80 (10 absolute difference).

Thomas Hogberg, Lund Univ Hosp Oct 2009
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NSGO-MITO Proposals - Issues

• Eligibility include IBG3LVSI (as in PORTEC3)?
• include serous pap./clear cell types?
• Stratification Center, LA?
• Design Two-arm trial (RTCT vs CT)?
• three-arm (CTRTCT vs CTRT
  vs CT)?
• VBT To allow or not to allow? Decision before
  randomization
• Statistics To be re-evaluated according with
  trial design, strata at randomization
• POSSIBLE COLLABORATIONS GEICO, AGO-Austria?,
  KGOG

Thomas Hogberg, Lund Univ Hosp Oct 2009
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Thomas Hogberg, Lund Univ Hosp Oct 2009