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Palliative Chemotherapy for Advanced Gastric Cancer

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Innovative drugs and combinations are clearly needed ! UFT ... The number of potentially active new drugs & combinations has increased, but their future role ... – PowerPoint PPT presentation

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Title: Palliative Chemotherapy for Advanced Gastric Cancer


1
Palliative Chemotherapy for Advanced Gastric
Cancer
2
Limitations of Published Clinical Trials in
Advanced Gastric Cancer
  • non-measurable lesions
  • variable study inclusion criteria
  • heterogeneous patient populations
  • inadequate number of patients
  • response rate rather than survival

3
Palliative Chemotherapy in Advanced Gastric
Cancerversus Best Supportive Care alone
Treatment Regimen No. of Pts. Median
Survival (mos) 1 yr. 2 yrs. FAMTX 30
10 40 6 BSC 10 3 10 0 FEMTX 17
12 -- -- BSC 19 3 -- -- ELF 10
10 -- -- BSC 8 4 -- -- EpiLF 52
10.2 34.6 9.6 BSC 51 5 7.8 0
4
Palliative Chemotherapy in Advanced Gastric
CancerSelected Phase III Studies during the
last 10 Years
  • 1991 FAM 9 7.2 mos
  • (n213) FAMTX 41 0.001 10.5 mos
    0.004
  • 1992 EAP 20 6.1 mos
  • (n60) FAMTX 33 n.s. 7.3 mos
    n.s.
  • 1997 FAMTX 21 5.7 mos
  • (n274) ECF 45 0.0002 8.9 mos
    0.009
  • 2000 FAMTX 12 6.7 mos
  • (n245) ELF 9 n.s. 7.2 mos
    n.s
  • FUP 20
    7.2 mos
  • 2001 FAMTX 21 6.9 mos
  • (n200) PELF 38 0.009
    7.7 mos n.s

These results make ECF a sort of standard regimen
....
5
However,
  • Most patients with gastric cancer are elderly
    (about 60 gt70 yrs.) and may have cardial,
    renal or neurological comorbidities,
    precluding use of an anthracycline or
    cisplatin-containing regimen.
  • Objective results with several different
    established combinations are similar regarding
    response rate and very unsatisfactory in terms of
    survival.
  • In a recent internet survey (2002), only 33 of
    all participating international oncologists
    recommended ECF, while others preferred
    5-FU/doxorubicin/methotrexate or 5-FU/cisplatin
    or docetaxel/cisplatin 5-FU.

6
Palliative Chemotherapy in Advanced Gastric
Cancer
  • Innovative drugs and combinations are clearly
    needed !

7
UFT Leucovorin
  • 3 trials with UFTLV in 16-45 pts RR 10-42
  • UFT-Combination regimens
  • UFT 400/m2 d1-12 CDDP 80/m2 d8 (n43)
    51
  • UFT 375/m2 cont. MMC 5/m2/wk (n91)
    25
  • UFT 390/m2 d1-14 VP-16 LV (n46)
    35
  • UFT 360/m2 d1-21 EPI CDDP (n37)
    54

8
Irinotecan
  • 3 trials with CPT-11 in 26-40 pts RR 14-18
  • Irinotecan Combination Regimens
  • CPT-11 65/m2/wk CDDP 30/m2/wk
    (n14) 18
  • CPT-11 65/m2/wk CDDP 30/m2/wk
    (n38) 58
  • CPT-11 100/m2 CDDP 40/m2 d1d15
    MMC 6 mg/m2 d1
    (n31) 50
  • CPT-11 125/m2 LV 20/m2 FU 500/m2/wk (n38)
    22
  • CPT-11 125/m2 LV 20/m2 FU 500/m2/wk (n62)
    23

9
Paclitaxel
  • 7 trials with Paclitaxel in 15-60 pts RR 4-23
  • Paclitaxel-Combination Regimens
  • PTX 175/m2 d1 FU 1500/m2 d2
    (n29) 65
  • PTX 175/m2 d1 FU 750 CI d1-5
    CDDP 20/m2 d1-5
    (n41) 51
  • PTX 80/m2 d1815 FU 2600/ LV 300/m2 (n26)
    46
  • PTX 175/m2 d122 LV 500/m2 FU 24h CI
    CDDP 50/m2 d8 29
    (n45) 51

10
Taxotere Cisplatin Combinations
Reference Regimen (mg/m2) No. of pts
ORR Survival
11
Taxotere Cisplatin Combinations
Grade 3/4 Hematotoxicity
Roth et al. Schüll et al.
Patients ()
Leukopenia Neutro Anemia Thrombopenia
12
Taxotere Cisplatin Combinations
Grade 3/4 Nonhematologic Toxicity
Roth et al. Schüll et al.
Patients ()
Emesis Diarrhea Mucositis Asthenia
Alopecia Neuropathy
13
Oxaliplatin FOLFOX Regimen
IRC confirmed RR 44.9
Median PFS 6.9 mos
Median OS 8.6 mos
14
Advanced Gastric CancerNew Drug Combination
Regimens
Promising, though only preliminary results have
become available about these new drugs and
combinations in phase II studies.
  • PELF
  • FOLFOX
  • HLFP
  • CPT-11 P
  • MLP-F
  • FAME
  • FLAME,...

Phase III ?
15
Palliative Chemotherapy - Conclusions
  • Chemotherapy improves survival and quality of
    life
  • compared to BSC alone.
  • Considerable efforts have been undertaken in
  • comparing and refining treatment schedules.
  • The number of potentially active new drugs
  • combinations has increased, but their future
    role
  • has to be defined in comparative phase II/III
    trials.
  • Every effort should be undertaken to enter
    patients
  • into such prospective randomized clinical
    trials.

16
Strategies to Improve ECFREAL-2 Trial Design for
Advanced Gastro-Oesophageal Cancer
ECF
EEF
E Eloxatin 130 mg/m2every 3 weeks
EEX
ECX
X Xeloda 1000 mg/m2daily
2x2 multifactorial design
17
Preoperative Chemotherapy in Locally Advanced
Gastric Cancer
18
Rationale for Preoperative Chemotherapy
  • ? Poor long-term results of conventional
    treatment
  • Better effectiveness due to intact tumor
    vascularisation.
  • Improved tolerance
  • Better general condition of the patients
  • ? Downstaging of the primary tumor / better
    resectability.
  • Response to therapy also adds prognostic
    information.

19
Preoperative Chemotherapy
Preop. Regimen Postop. Ther. Pts. R0
Res. Survival
  • Ajani JA 1991
  • EFP x2 EFP x3 25 72
    15 mos
  • Ajani JA 1993
  • EAP x3 EAP x2 48 77
    16 mos
  • Rougier P 1994
  • FUP x1-6 None 30 59 16
    mos
  • Crookes P 1997
  • FU/LV/P x2 ip FUDR/P 59 71 gt48
    mos
  • Kelsen D 1996
  • FAMTX x3 ip FU/P 56 61
    15 mos

20
Preoperative Chemotherapy - Conclusions
  • Feasible without increase in perioperative
  • morbidity and mortality.
  • About 50 chance of a R0 resection in patients
    with primarily not curatively resectable tumors.
  • Larger randomized trials with prospectively
    defined endpoints will be needed.

21
Adjuvant Chemotherapy for Gastric Cancer
22
Meta-analysis of Randomized Trialsof Adjuvant
Chemotherapy in Gastric Cancer
Pooled odds ratio 0.72 in favor
of adjuvant treatment
Treatment better Treatment worse
23
Postoperative Chemoradiation vs. Observation
Intergroup 116 Trial
OBSERVATION
R a n d o m i z e
FU/LV
FU/LV
T1,2,3,4

FU/LV (Mayo)
R A D I A T I O N
FU/LV x2 (Mayo)
N0, 1-3 LNN, or gt4 LNN,
4,500 cGy
In 7 years, 603 patients were accrued from stage
1B through IV
24
Postoperative Chemoradiation vs. Observation
Intergroup 116 Trial
Median time to relaps 19 vs.30 mos (P.0001)
Median survival 28 vs.35 mos (P.01)
25
Comments to the Intergroup 116 Trial
Inadequate surgery was performed in the large
majority of patients (D0 resection in gt 50) and
balance between the 2 arms uncertain.
Outcome of the surgery-only arm was exeptionally
poor.
Stratification according to tumor stage was
meaningless, because the surgical approach was
not uniform.
Chemoradiotherapy was associated with a
substantial number of major side effects, and
only 64 could complete the treatment.
32 of patients required a change in radiation
planning after central review. Without that
life-threatening toxicity might have occurred in
up to 10 of patients.
Because of the too small subgroups
(IB,II,IIIA,IIIB,IV), a meaningful conclusions
about the effectiveness of therapy by stage seems
difficult.
26
Adjuvant Chemotherapy - Conclusions
  • A recent meta-analysis the Intergroup 116
    trial
  • (with all its limitations) give us hope that
    the long-
  • term prognosis of resectable gastric cancer
    patients
  • can be improved.
  • Better systemic chemotherapy (that may become
  • available in the near future) would be
    particularly
  • helpful to improve the control of regional and
  • distant sites.
  • Postoperative intraperitoneal chemotherapy may
  • be an alternative to RT to decrease the risk of
  • peritoneal failure, and continues to be studied.
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