study proposal after 4 a phase iii intergroup trial on adjuvant therapy in radically operated...

Study proposal

After 4A Phase III intergroup trial on adjuvant therapy in radically operated endometrial cancer patients (FIGO stage IC-IIIC) with high risk for micro-metastatic disease

NSGO

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 CT+RT vs RT n=150

• PORTEC-3 (ongoing) is CMT better than RT?

Thomas Hogberg, Lund Univ Hosp Oct 2009

Radical surgeryTAH+BSO (+PLA)

RT+CT

RT

CT+RTOR

Randomization

Primary endpointProgression-free survival (PFS)

Surgical stage I, II, IIIA (positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) with high risk for micro-metastatic disease

Patients with serous, clear cell, or anaplastic carcinomas were eligible regardless of other risk factors

≥ 44 Gy XRT ± optional VBT (39%)

CT : 　 intially APLater AP, TcP, TAP, TEcP

n=196

n=186

n=382

May 1996 to January 2007

(VBT 44%)

NSGO EC-9501/EORTC-55991



PFS progression-freee survival (PFS)


HR 0.63 (95 % CI 0.41 - 0.98) p = 0.04

0.72

0.790.

000.

250.

500.

751.

00

prob

abili

ty o

f sur

viva

l

186 175 158 143 119 82random = 1191 170 149 123 110 84random = 0

Number at risk

0 1 2 3 4 5years

random = 0 random = 1

PFS NSGO-EC-9501/EORTC-5591


PFS progression-freee survival (PFS) serous/clear cell ca


HR 0.81 (95 % CI 0.41 - 1.61) p=0.55

0.73

0.71

0.00

0.25

0.50

0.75

1.00

65 62 55 48 43 27random = 176 70 59 47 43 35random = 0

Number at risk

0 1 2 3 4 5analysis time


PFS serous/cc carcinoma NSGO-EC-9501/EORTC-55991

Radical surgeryTAH+BSO (+PLA)

CT+RT

RTRandomization

Primary endpointProgression-free survival (PFS)and overall survival (OS)

Surgical stage IIB, IIIA-C endometrioid carcinomas(IIIA with only pos per cytol not eligible

45 Gy XRT (+VBTIf st IIB or IIIB)

CT : APX3 q 3 weeks

n=76

n=80

n=156

October 1998 to July 2007

MANGO ILIADE


NSGO EC-9501/EORTC-55991/MANGO

Pooled data failure-free survival (FFS) endometrioid carcinoma


HR 0.46 (95 % CI 0.28 -0.74) p= 0.001

0.71

0.840.

000.

250.

500.

751.

00

197 176 156 145 114 84random = 1187 159 138 117 93 68random = 0

Number at risk



FFS endometrioid carcinomas POOLED DATA

Pooled results failure-free survival (FFS) endometrioid carcinoma

Randomization Observed Expectedevents events

RT n=187 50 37.15RT+CT n=197 29 41.85Total n=384 79 79.00

HR 0.46 (95% CI 0.28-0.74) p=0.001 which　translates　to　an　estimated　absolute　difference　in　5-year　FFS　of　13　%　from　　71　–　84　%



Pooled data cancer-specific survival (CCS) endometrioid carcinoma



HR 0.51 (95 % CI 0.29-0.91) p=0.02

0.77

0.870.

000.

250.

500.

751.

00

197 187 164 149 118 87random = 1187 175 153 130 106 75random = 0

Number at risk



CSS endometrioid carcinomas POOLED DATA

Pooled　results　cancer-specific　survival　(CCS)　endometrioid　carcinoma

Randomization Observed Expectedevents events

RT n=187 36 27.33RT+CT n=197 21 29.67Total n=384 57 57.00

HR 0.51 (95% CI 0.29-0.91) p=0.02 which translates to an estimated absolute difference in 5-year CSS of 10 % from 77 – 87 %




Lokoregional progressions 4.1 % in the RT-arm vs. 1,1 % in the RT+CT-arm – additive effects?


The combination of RT + CT is better than RT

An additive interaction between RT + CT could explainthe difference in the EORTC/NSGO/MANGO-study

And the lack of difference in the Italian and Japanese studies

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

When　PORTEC-3　is　published　CMT　will　probably　become　standard　treatment

The　question　about　the　contribution　of　RT　will　remain　unanswered


Proposition

We　have　a　time-frame　in　which　we　can　resolve　the　question　of　the　value　of　addition　of　

radiotherapy　to　chemotherapy


Primary　endpointOverall　survival　(OS)

Radical surgeryTAH+BSO±LA

CTx4

CTx2

RTRandomization

Main inclusion criteriaa. Endometrioid carcinomab. Stage 1C grade 3 c. Stage IIA grade 3 and MI≥50%, IIB d. Stage IIIA-CRadical surgery, LA recommended but optionalMain exclusion criteriaSerous or clear cell carcinomaIIIA with only pos fluid cytology

CT : Paclitaxel 175 mg/m2, carboplatin AUC 5-6 (calculated) q 3 weeks

N=1000

Proposed study


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


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: 1. 　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)

2. 　Toxicity

3. 　Patterns　of　progression

4. Quality　of　life　evaluated　by　EORTC　QLQ‑30

5. 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

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　MI≥50　%,　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　MI≥50　%

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


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　followedUncontrolled　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


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　


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.


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)　　


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　%


Statistical issues

About　1000　patients　would　be　needed　and　266　events　need　to　be　observed


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

Survivalexperimental　arm N70　% 　　　　　　400275　% 　　　　　　　　96880　% 　　　　　　　　414

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

•　　Possible　collaborations:　　?????....

Statistical issues


1.　Study　group

2.　Institution

3.　Stage

FIGO　1988　stage　I-IIAFIGO　1988　stage　IIB,　IIIA,　IIIC

According　to　the　new　proposed　FIGO　stagingFIGO　stage　IBFIGO　stage　II-IIIC2

4.　Lymph　node　exploration

YesNo

Stratification


We　have　to　get　used　to　doing　big　randomized　trials　also　in　endometrial　cancer


These　guys　are　eagerly　waiting　for　results　from　clinical　trials　in　endometrial　cancer!

CONTACT　INFORMATION

Thomas　HogbergDept　Cancer　EpidemiologyLund　University　Hospital

221　85　LundSweden

[email protected]

NSGO　DATA　CENTERJ.B.　Winsløws　Vej　9,　DK-5000　Odense　C,　Denmark

Phone:　 +　45　6550　4346Fax:　 +　45　6550　4348

[email protected]


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%)


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).


• Eligibility: include　IBG3+LVSI　(as　in　PORTEC3)?include　serous　pap./clear　cell　types?

• Stratification:　 Center,　LA?

• Design:　 Two-arm　trial　(RT+CT　vs　CT)?　　　　　　　　　　　　　　　　　　 three-arm　(CTRT+CT　vs　CT+RT　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

NSGO-MITO　　Proposals - Issues


Baseline within 14 days prior to enrolment

During RT Before each course

(up to –3 days)

Between courses

Day 14±2

End of Therapy

During Follow-upat 3, 6, 12, 18… months up to 5 years

Determination of FIGO stage X -- -- -- -- --

Informed consent X -- -- -- -- --

Performance status WHO X X X -- X X

Height X -- -- -- -- --

Weight X -- X -- -- --

Physical + gynecologic examination

X -- -- -- X X

CTC v2.0 scale toxicity X X X -- X X

Blood counts a X Departmental praxis

X X Xuntil

recovery

--

Calculationb (or measurement) of GFR

X -- X -- -- --

Chemistry c X Departmental praxis

XS-creatinine within 7

days

-- Xuntil

recovery

--

CT chest and abdomen X d -- -- -- -- Yearly

ECG X

EORTC QLQ‑30 X Xe X X


study proposal after 4 a phase iii intergroup trial on adjuvant therapy in radically operated...

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