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
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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
....
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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.

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Palliative Chemotherapy in Advanced Gastric
Cancer

• Innovative drugs and combinations are clearly
  needed !

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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

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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

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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

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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
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Taxotere Cisplatin Combinations
Grade 3/4 Nonhematologic Toxicity
Roth et al. Schüll et al.
Patients ()
Emesis Diarrhea Mucositis Asthenia
Alopecia Neuropathy
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Oxaliplatin FOLFOX Regimen
IRC confirmed RR 44.9
Median PFS 6.9 mos
Median OS 8.6 mos
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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 ?
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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.

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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
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Preoperative Chemotherapy in Locally Advanced
Gastric Cancer
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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.

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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

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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.

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Adjuvant Chemotherapy for Gastric Cancer
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Meta-analysis of Randomized Trialsof Adjuvant
Chemotherapy in Gastric Cancer
Pooled odds ratio 0.72 in favor
of adjuvant treatment
Treatment better Treatment worse
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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
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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)
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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.
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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.