A.D. Roth, R. Biffi, R. Stupp, R. Morant, J.C. Schuller, F. De Braud, O. Huber, N. Fazio

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


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)


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


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


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

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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


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


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%)


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


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%


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%


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])


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)

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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%)


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)


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)


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

A.D. Roth, R. Biffi, R. Stupp, R. Morant, J.C. Schuller, F. De Braud, O. Huber, N. Fazio

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