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

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)

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

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  1. Should all patients be treated with adjuvant and/or neoadjuvant treatment? Arnaud Roth MD Oncosurgery Geneva Switzerland Gastric Barcelona 2012

  2. Gastric Cancer Surgery Survival 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

  3. We need to help our surgeons!

  4. Curative treatment programs Neoadjuvant TTT (Chemotherapy and/or Radiation therapy) Main TTT (SURGERY) Adjuvant TTT (Chemotherapy and/or Radiation therapy)

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

  6. 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 pts 20% 30% 1.337 193 614 pts 434 pts 40% 55% 1.533 93 440 pts 264 pts 40% 50% 1.332 209 964 pts 590 pts *Two-sided alpha error = 0.05, beta error = 0.2

  7. 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.

  8. Gastric Cancer 1993 - 2003 4 Meta-Analysis on Adjuvant Chemotherapy => 3 / 4 positive and one ongoing with the « gastric » Meta-analysis group *: p<0.05

  9. Adjuvant chemotherapy in gastric: OS Individual patient data meta-analysis JAMA. 2010;303(17):1729-1737

  10. Adjuvant chemotherapy in gastric: OS Individual patient data meta-analysis JAMA. 2010;303(17):1729-1737

  11. 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

  12. The ARTIST trial: adjuvant XP ± RxTTT 458 patients 60% stage IB –II DFS significant in N+ patients All patients N+ patients Lee J et al. JCO 2012;30:268-273

  13. Be patient, CRITICS and other trials are coming up!

  14. 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)23/239/23 *according to RDA (Recommended dietary allowance) Braga M. et al Br. J. Surg. 75:477-80 (1988)

  15. 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!

  16. What about neoadjuvant or perioperative chemotherapy?

  17. 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

  18. MAGIC trial

  19. FNCLCC 94012 - FFCD 9703 Trial in gastric Ychou M et al. JCO 2011;29:1715-1721

  20. 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%

  21. Treatment TCF X 4 Surgery (arm A) T2N+M0 T3-4anyN 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 Gastroenterol18;868 2010

  22. 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 Gastroenterol18;868 2010

  23. Multidisciplinary approach for the cure of localised gastric cancerConclusions • 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!

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