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Taiwan 2000
Comparative evaluation in tolerance of Comparative evaluation in tolerance of neoadjuvant versus adjuvant docetaxel neoadjuvant versus adjuvant docetaxel
based chemotherapy in resectable based chemotherapy in resectable gastric cancer in a randomized trial gastric cancer in a randomized trial
of the Swiss Group for Clinical Cancer of the Swiss Group for Clinical Cancer Research (SAKK) and the European Research (SAKK) and the European
Institute of Oncology (EIO)Institute of Oncology (EIO)
A.D. Roth, R. Biffi, R. Stupp, R. Morant, J.C. Schuller, F. De Braud, O. Huber, N. Fazio
SAKK 43/99 Barcelona 2007
SAKK 43/99 Barcelona 2007
Background
• Adjuvant chemotherapy has been reported as minimally effective in the curative treatment of gastric cancer
• Adjuvant chemotherapy is often difficult to start on time and to conduct after gastrectomy because of delayed recovery
• Neoadjuvant chemotherapy has been shown to be feasible and to induce tumor response before surgery (Van Cutsem et al, Ann Oncol 2006)
• Very short time to response are highly desirable in this setting and can be obtained with docetaxel containing regimens (Roth AD et al, J Clin Oncol 2007)
SAKK 43/99 Barcelona 2007
Objectives
• To compare the feasibility in term of tolerance and toxicity of the same chemotherapeutic regimen administered in an adjuvant and neoadjuvant setting in a randomized phase III trial
• To evaluate the efficacy and tolerance of a docetaxel based combination used with surgery in the curative treatment of locally advanced gastric cancer
SAKK 43/99 Barcelona 2007
Methods
• Patient inclusion criteria– Locally advanced resectable gastric cancer (LARGC)
T2N+M0 or T3-4anyN M0– PS ≤2, normal blood count, normal renal and hepatic
functions– Absence of macroscopic peritoneal carcinomatosis
• Staging work up– Body CT-scan– Gastroscopy with echoendoscopy– Bone scintigraphy– Peritoneal lavage and/or laparoscopy
SAKK 43/99 Barcelona 2007
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
SAKK 43/99 Barcelona 2007
Statistical considerations
• The trial was planned to recruit 252 patients allowing to detect 15% difference in event free rate at 3 years (arm A 35%, arm B 20%) but was interrupted due to slow accrual after 70 patients were enrolled
• Tolerance and toxicity results are compared between the 2 arms. Analyses are exploratory, p-value are two sided and not adjusted for multiple testing
SAKK 43/99 Barcelona 2007
Patient Characteristics
Arm A (n=34) Arm B (n=35)
Age (y): median (range) 57 (25-75) 59 (39-76)
Male (%) 68 71
PS 0/1/2 (%) 91/6/3 86/14/0
Tumor Localization (%)
Cardia 21 20
Fundus/corpus 38 40
Antrum/pylorus 41 40
Stage (by echoendoscopy + CTscan)
IB 2 1
II 14 13
III 18 21
SAKK 43/99 Barcelona 2007
TCF => SN = 34
Preop CT (4 cycles)Started N=33 (97%)(97%)
Completed N= 25 (74%)(74%)
SurgeryN = 32 (94%)(94%)
Postop CT (4 cycles)Started N = 23 (66%)(66%)
Completed N = 12 (34%)(34%)
S =>TCF N = 35
SurgeryN = 35 (100%)(100%)
Trial profile
pCR in 4 patients (12.9%)
SAKK 43/99 Barcelona 2007
Intensity of treatment administered per arm
Arm A (n=33) Arm B (n=23)
Total number of cycles 118 71
Mean number of cycles/patient 3.6 2.2‡
Median cycle duration (days) 21 21
Cycle delays (> 7 days, % cycles) 3 7
¥Dose intensity docetaxel, median(range) 97 (81-108) 94 (76-113)€
¥Dose intensity cisplatin, median(range) 98 (62-104) 90 (0-100)#
¥Dose intensity 5-FU, median (range) 96 (28-102) 72 (10-100)+
Overall dose intensity¥ (median) 94.6 82.8*
‡ p<0.05, € p=0.07, # p<0.001, + p<0.003, * p<0.0003¥ Dose intensity corrected to actually given cycles
SAKK 43/99 Barcelona 2007
Hematotoxicity (NCIC grade 3/4)
Arm A Arm B(% per patient / % per cycle)
• Neutropenia 79%/41% 61%/34%• Thrombocytopenia 0% 4%/1%
• Febrile neutropenia 15%/8% 9%/3%
SAKK 43/99 Barcelona 2007
Non-hematological toxicity (NCIC grade 3/4)
Arm A Arm B (% per patient / % per cycle)
Nausea/vomiting 3%/1% 13%/4%
Alopecia 55%/ - 35%/ -
Diarrhea 9%/3% 4%/3%
Stomatitis 0% 9%/3%
Neurosensory 0% 0%
Neuromotor 0% 0%
Plantar-palmar 0% 0%
Other skin 0% 0%
SAKK 43/99 Barcelona 2007
Discussion
• This is the only available trial comparing head to head the feasibility and tolerability of the same systemic regimen in a neoadjuvant and adjuvant setting
• Neoadjuvant chemotherapy is feasible in gastric cancer while adjuvant chemotherapy is difficult to conduct after gastrectomy
• Our data are consistent with the results of the published trials of perioperative chemotherapy in gastric cancer
(MAGIC trial [NEJM july 2006] and FNLCC-ACCORD trial [ASCO 2007 abstr #4510])
SAKK 43/99 Barcelona 2007
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
SAKK 43/99 Barcelona 2007
MAGIC trial: Compliance to chemotherapy
(Cunningham, D. NEJM 355: 11-20 2006)
• Preop. chemotherapy:– Started: 237 pts– Completed 3 cycles: 215 pts (90.7%)
• Surgery: 209 pts
• Postop. Chemotherapy:– Started: 137 pts (65.6%)– Completed 3 cycles: 104 pts (49.7%)
SAKK 43/99 Barcelona 2007
CT + SN = 113
Preop CT (2-3 cycles)N = 98 (87%)
SurgeryN = 109 (96%)
Postop CT (1-4 cycles)N = 54 (50%)
SN = 111
SurgeryN = 110 (99%)
Trial profile
(Boige V. ASCO 2007, abstr #4510)
SAKK 43/99 Barcelona 2007
Nutritional status after total gastrectomy
• 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)
SAKK 43/99 Barcelona 2007
Conclusions
• In the multidisciplinary approach to the cure of locally advanced gastric cancer a neo-adjuvant strategy should be preferred to an adjuvant strategy whenever possible
• Additional trials establishing the role of neoadjuvant (radio-)chemotherapy in the curative approach of gastric cancer are warranted