should all patients be treated with adjuvant and/or neoadjuvant treatment?
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Should all patients be treated with adjuvant and/or neoadjuvant treatment?. Arnaud Roth MD Oncosurgery Geneva Switzerland. Gastric Barcelona 2012. Gastric Cancer Surgery Survival US vs. Japanese Centers. US (1982 – 1987) Japan (1971 – 1985) - PowerPoint PPT PresentationTRANSCRIPT
Taiwan 2000
Should all patients be treated with Should all patients be treated with adjuvant and/or neoadjuvant adjuvant and/or neoadjuvant
treatment?treatment? Arnaud Roth MDArnaud Roth MD
Oncosurgery Geneva SwitzerlandOncosurgery Geneva Switzerland
Gastric Barcelona 2012
Gastric Barcelona 2012
Gastric Cancer SurgerySurvival US vs. Japanese Centers
US (1982 – 1987) Japan (1971 – 1985)
Stage (%) 5-yr OS (%) 5-yr OS
I 2004 (18.1) 50% 1453 (45.7) 91%
II 1976 (16.2) 29% 377 (11.9) 72%
III 3945 (35.6) 13% 693 (21.8) 44%
IV 3342 (30.1) 3% 653 (20.6) 9%
Maruyama et al., World J Surg 1987;11:418-25
Gastric Barcelona 2012
We need to help our surgeons!
Gastric Barcelona 2012
Curative treatment programs
Neoadjuvant TTT(Chemotherapy and/or Radiation therapy)
Main TTT(SURGERY)
Adjuvant TTT(Chemotherapy and/or Radiation therapy)
Gastric Barcelona 2012
YES! Finally adjuvant chemotherapy in gastric cancer seems to work!
Gastric Barcelona 2012
Biostatistical constraints
5 years OS relative # events total patients accrual*Arm A Arm B OS ratio per arm 3y-2y (accr-fup) 5y-5y
20% 35% 1.533 93 298 pts 206 pts20% 30% 1.337 193 614 pts 434 pts
40% 55% 1.533 93 440 pts 264 pts40% 50% 1.332 209 964 pts 590 pts
*Two-sided alpha error = 0.05, beta error = 0.2
Gastric Barcelona 2012
Biostatistical constraints consequences
• Minimal accrual = 300 patients (for a 5 year study with relative OS ratio = 1.5)
• The required accrual increases when the prognosis of the control arm increases.
• A negative study with a power to observe a relative OS ratio of 1.5 does not reject a clinically meaningfull smaller difference.
Gastric Barcelona 2012
Gastric Cancer 1993 - 2003 4 Meta-Analysis on Adjuvant Chemotherapy
# of studies
# of patients ODDs ratio/hazard ratio for death (95% CI) Author
11 2,096 0.88 (0.78-1.08) Hermans (1993)
13 1,990 0.80 (0.66-0.97)* Earle (1999)
21 3,658 0.82 (0.75-0.89)* Mari (2000)
17 3,118 0.72 (0.62-0.84)* Panzini (2002)
*: p<0.05=> 3 / 4 positive and one ongoing with the « gastric » Meta-analysis group
Gastric Barcelona 2012JAMA. 2010;303(17):1729-1737
Adjuvant chemotherapy in gastric: OS Individual patient data meta-analysis
Gastric Barcelona 2012JAMA. 2010;303(17):1729-1737
Adjuvant chemotherapy in gastric: OS Individual patient data meta-analysis
Gastric Barcelona 2012
Adjuvant radio-chemotherapy in gastric cancer: INT 0116
– Long standing effect– Robust treatment effect in subset
analysis with an exception for diffuse histology
BUT– 54% of patients with insufficient surgery
(<D1)– Grade 3/4 toxicity 41%/32%!– 33% of inadequate RxTTT planning
(corrected by central review)
Smalley JS, JCO May 14th 2012, ahead of print
Gastric Barcelona 2012Lee J et al. JCO 2012;30:268-273
The ARTIST trial: adjuvant XP ± RxTTT
All patients
N+ patients
458 patients60% stage IB –II
DFS significant in N+ patients
Gastric Barcelona 2012
Be patient, CRITICS and other trials are coming up!
Gastric Barcelona 2012
Nutritional status after total gastrectomy:A nightmare for adjuvant chemotherapy
• 23 patients followed during 6 mois after gastrectomy
1st month 6th month
Mean calory intake (kcal/j) 1 ’458 2 ’118
Insufficient intake* (patients) 23/23 9/23
*according to RDA (Recommended dietary allowance)
Braga M. et al Br. J. Surg. 75:477-80 (1988)
Gastric Barcelona 2012
Adjuvant treatment in gastric cancer:The reality!
CONTROL
SURGERY
ADJUVANT TREATMENT
R
- Delayed surgical recovery- Poor food intake- Dumping syndrome etc.- Poor performance status- Treatment refusal
(~50%?)
BUT:frequent poor patient tolerance with
- Retreatment delays- Dose reductions- Early termination
=> Adjuvant TTT for fit patients only!
Gastric Barcelona 2012
What about neoadjuvant or perioperative chemotherapy?
Gastric Barcelona 2012
Perioperative chemotherapy for locally advanced Gastric Cancer:
The MAGIC and the French trials
Surgery alone
Stage ≥II
Chemoth Surgery Chemoth
• MAGIC trial: ECF x 3 => Surgery => ECF x 3 (Total 503 pts)
• French trial: FuP x 2 => Surgery => FuP x 4 (Total 224 pts)
R
Gastric Barcelona 2012
MAGIC trial
Gastric Barcelona 2012
Ychou M et al. JCO 2011;29:1715-1721
FNCLCC 94012 - FFCD 9703 Trial in gastric
Gastric Barcelona 2012
The Truth about the MAGIC and the French trials
Surgery alone
Stage ≥II
Chemoth Surgery Chemoth
• MAGIC trial: ECF x 3 => Surgery => ECF x 3 (Total 503 pts)
• French trial: FuP x 2 => Surgery => FuP x 4 (Total 224 pts)
R
40-50%40-50%
Gastric Barcelona 2012
Treatment
TCF X 4 Surgery (arm A)
T2N+M0T3-4anyN M0
Surgery TCF X 4 (arm B)
• TCF:
– Docetaxel 75mg/m2 d1
– Cisplatin 75 mg/m2 d1
– 5-Fluouracyl 300mg/m2 in continuous infusion d1-14
• Repeat cycle every 3 weeks
R
Biffi, R. World j Gastroenterol 18;868 2010
Gastric Barcelona 2012
Intensity of treatment administered per arm
‡ p<0.05, € p=0.07, # p<0.001, + p<0.003, * p<0.0003¥ Dose intensity corrected to actually given cycles
Biffi, R. World j Gastroenterol 18;868 2010
Gastric Barcelona 2012
Multidisciplinary approach for the cure of localised gastric cancer
Conclusions
• Adjuvant treatment is efficient but cumbersome and badly tolerated after gastrectomy
• The role of XRT in (neo)adjuvant TTT of gastric cancer is still unclear
• Peri-operative or neoadjuvant chemotherapy are better tolerated and leave less patients behind
• We needed huge meta-analyses to be convinced of adjuvant therapy while only few studies were sufficient for the peri-operative strategy!