preoperative fluorouracil (fu)-based chemoradiation +/- weekly oxaliplatin in locally advanced...
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Preoperative fluorouracil (FU)-based chemoradiation +/-
weekly oxaliplatin in locally advanced rectal cancer.
Pathologic response analysis of the STAR (Studio Terapia
Adiuvante Retto)-01 randomized phase III trial.
C. Aschele, C. Pinto, S. Cordio, G. Rosati, A. Tagliagambe,
S. Artale, P. Rosetti, S. Lonardi, L. Boni, L. Cionini, on behalf of STAR Network Investigators.
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BACKGROUND AND RATIONALE
Locally-advanced rectal cancer
high rates of distant metastases (30 - 35 %)
+ve CRM in 10-30 % of “resectable” tumors
Oxaliplatin
improves the efficacy of FU-based CT (colon ca.)
radiosensitizing properties (exp. models) promising activity with pre-op RT and FU
(phase I-II studies)
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STUDY OUTLINE
R
RT 50.4 GyFU 225 mg/m2/day PVI OXA 60 mg/m2 weekly x 6
RT 50.4 GyFU 225 mg/m2/day PVI
TME
FU/LV(bolus or CI, center choice)
6-8wks
• stage• center
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MAIN INCLUSION CRITERIA
adenocarcinoma within 12 cm from anal verge cT3-T4 and/or cN+ resectable (no infiltration of
the pelvic wall, prostate, bladder base)
cM0
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STUDY END-POINTS
primary: overall survival- 30% RR in mortality rates (3-y S: 75 --> 82%)- 80% power - alpha error: 0.05
secondaries:• pathologic complete response (pCR):- all path reports available (cut-off data 01/03/09)- 12% --> 25%; 90% power
• disease-free survival • safety
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STUDY POPULATION
747: randomizedresponse/survival analyses
379FU/RT
368FU/OXA/RT
379 353
5 never started- consent withdrawal (2)- squamous histology (1)- immediate surgery (2)
10 never started (3) consent withdrawal(2) squamous /melanoma(1) immediate surgery(2) only RT(2) different chemo
5 received FU alone
732: treatedsafety/compliance analyses
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PATIENTS CHARACTERISTICS
FU/RT FU/OXA/RT
(n=379)(n=368)
Age, yearsmedian 63 62
Sex, %males 68 67 females 32 33
ECOG PS, %0 87 88 1-2 13 12
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FU/RT FU/OXA/RT(n=379) (n=368)
T stage, %T1-2 2 5 T3 78 78 T4 20 17
N +, % 64 67
cm from anal verge
median 6 6TRUS: 33; pelvic CT scan: 261; both 453
TUMORS CHARACTERISTICS
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TREATMENT COMPLIANCE:OXALIPLATIN
weekly courses patients, n*
1 3 2 6
3 26 4 24 5 60
83% > 6 233 66%
* missing data=1
mean actually delivered dose intensity:58.3 mg/mq/wk
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patients, % FU/RT FU/OXA/RT
(n=379) (n=353)FU > 5 weekly courses 95 88
RT full dose +/- 10 % 97 90
TREATMENT COMPLIANCE:5-FU and RT
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TOXICITY % of patients
FU/RT FU/OXA/RT (n=379) (n=353)
pgrade III-IV any type 8 24<.0001 diarrhea 4 15<.0001 radiation dermatitis 2 5
0.038grade II-IIIneurosensory 0.5/0 36/1<.0001
Tx related deaths 0.3 (1) 0.6 (2)
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patients, % FU/RT
FU/OXA/RT (n= 379) (n= 368)Operated 9696 LAR 72 73 APR 19 18 other 4 5
Median interval 52 days 53 days
Deaths < 60 d 0.8 (3) 0.8 (3)
SURGERY
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patients, % FU/RT FU/OXA/RT
(n= 379) (n= 368) p
ypT0N0 16 16 0.94(95% cl) (13-20) (13-20)
pathologic CR
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patients, % FU/RT
FU/OXA/RT (n= 379) (n= 368)
pT0 17 18pT1-2 35 35 pT3-4 44 42
diameter, mm median (range) 26 (1-100) 24 (2-80)
CRM+ 6 4*
PATHOLOGY (T)
* p=0.13
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patients, % FU/RT
FU/OXA/RT (n= 379) (n= 368)examined median 12 11 range 0-47 0-42
pN0 70 68
pN1 17 17 pN2 8 10
PATHOLOGY (N)
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patients, n FU/RT FU/OXA/RT (n=379) (n=368) p
pM1 11 (3%) 2 (0.5%) 0.014 liver 6 1 peritoneal 4 1 nodes 1 -
cM1 5 - liver 4 - liver+lung 1 -
Overall 16 2
M+ at SURGERY (unplanned / exploratory)
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SUMMARY
The addition of OXA to FU-based preop CRT:
- does not improve local tumor response
- significantly increases toxicity (still manageable) and slightly reduces treatment compliance (but surgery OK)
- is associated with a lower frequency of occult distant metastases at surgery
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CONCLUSIONS
These data do not support the addition of OXA to pre-op FU/RT to maximize tumor shrinkage in LARC (radiosensitizing properties unconfirmed)
OXA-based regimens may not be the optimal back-bone for incorporation of new radiosentizing agents
The observation of a lower number of distant mts at surgery lends support to the study primary hypothesis (confirmation with more mature data is required)
Follow-up is ongoing to assess the impact on efficacy end-points. Stay tuned!
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StudioTerapia
Adiuvante
Retto
ALBA
AREZZO
AVIANO
BERGAMO
BOLOGNA RAVENNA
BOLZANO RIMINI
CAMPOSAMPIERO RIONERO VULTURE
CASTELLANZA LUGO ROMA
CATANIA MANTOVA SANREMO
CATANZARO MASSA CARRARA SARONNO
CATTOLICA MILANO HUMANITAS SAVONA
CUNEO MILANO NIGUARDA SONDRIO
FAENZA MILANO SAN PAOLO TARANTO
FANO MODENA THIENE
FELTRE MONZA TORINO
FORLI' NOVARA TRENTO
GENOVA PADOVA UDINE
LEGNAGO PISA VENEZIA
LIVORNO POTENZA VIGEVANO
THANKS TO ALL THE PATIENTS,
INVESTIGATORS and DATA-MANAGEMENT
STAFF!