should all patients be treated with adjuvant and/or neoadjuvant treatment?

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 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


We need to help our surgeons!


Curative treatment programs

Neoadjuvant TTT(Chemotherapy and/or Radiation therapy)

Main TTT(SURGERY)

Adjuvant TTT(Chemotherapy and/or Radiation therapy)


YES! Finally adjuvant chemotherapy in gastric cancer seems to work!


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


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 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


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


Be patient, CRITICS and other trials are coming up!


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)


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!


What about neoadjuvant or perioperative chemotherapy?


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


MAGIC trial


Ychou M et al. JCO 2011;29:1715-1721

FNCLCC 94012 - FFCD 9703 Trial in gastric


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%


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


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


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!

should all patients be treated with adjuvant and/or neoadjuvant treatment?

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