Gemcitabine combined with radiation therapy in patients with locally advanced unresectable pancreatic cancer

1
Gemcitabine combined with radiation therapy in
patients with locally advanced unresectable
pancreatic cancer

• Ron Epelbaum,M.D.
• Department of Oncology
• Rambam Medical Center
• Haifa, Israel
• January 2001

2
Locally advanced unresectable pancreatic cancer

• Background
• Definitions and statistics
• Chemoradiotherapy with 5FU
• Gemcitabine combined with radiation therapy
• The literature
• The Rambam Medical Center experience

3
Pancreatic cancerIncidence and mortality

• Incidence 5-10/100,000 (2 of all cancers)
• Change from 1991 to 1995
• ? 6.5 white males
• ? 4.3 white females
• Estimated incident cancer cases and deaths, 1999
• cases deaths
• 1-Prostate 179,000 1-Lung 158,900
• 12-Pancreas 28,600 5-Pancreas 28,600

4
Pancreatic cancerPresentation

• Extent of disease at diagnosis
• Resectable 20
• Locally advanced unresectable 40
• Metastatic 40

5
Pancreatic cancerSurvival

• Survival
• Median (m)
  5-y ()
• Resectable 15-19 5-20
• Locally advanced 6-10 0
• Metastatic 3- 6 0

6
Locally advanced unresectable pancreatic
cancerAims of treatment

• Improvement of quality of life clinical benefit
  response
• Local control prolongation of survival ?
• Downstaging resectability ?

7
Locally advanced unresectable pancreatic
cancer5FU-based chemoradiotherapy (1)
No pts Median(m)

• Moertel, 1969 5FURT
• GITSG, 1979 RT (60 Gy) 25 6
• RT (40 Gy)5FU 83 9
• RT (60 Gy)5FU 86 12
• GITSG, 1988 SMF 24 8
• SMF5FURT 24 11

8
5FU-based chemoradiotherapy (2) No. pts
Median(m) 1-y s()

• 5FURT 13-34 7-13 31, 32
• 5FU/PLTRT 22-38 7.5-14 31, 53
• 5FU/ADM/PLT 19 14
• 5FURT
• 5FU/STZ/PLTRT 18, 35 5, 15
  50

9
Locally advanced unresectable pancreatic
cancerResectability rate after 5FU RT

• Jessup (Boston) 5FU RT 2/16 12.5
• Arch Surg, 1993
• Bajetta (Milan) 5-DFUR RT 5/32 15.6
• Inter J Radiat Oncol Biol Phys, 1999

10
Resectability rate after5FU-Based
chemotherapyRT

• Kamthan (NY) 5FU/STZ/PLT 5/35 14.2 JCO,
  1997 (2)
• Todd (UCLA) 5FU/LEUC/MIT 4/38 10.5
• J Gastro Surg, 1998
• Bousquet (France) 5FU/PLT 2/7 28.0
• Chirurgie, 1998
• Martin (Duke) 5FU/STZ/PLT 0/18 0.0
• Am J Clin Oncol, 1999
• White (Hershey) 5FU/MIT or PLT 1/25 4.0
  Ann Surg Oncol, 1999 (1)
• Andre (Paris) 5FU/PLT 3/32 9.3
• Inter J Radiat Oncol Biolog Phys,2000 (1)
• 15/155 10

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Gemcitabine in pancreatic cancer

• Clinical benefit response in 30-40 of pts
• Objective response in 5-11 of pts
• Radiosensitization

12
Radiosensitization by gemcitabine

• Gemcitabine is a potent radiosensitizer in both
  laboratory studies and in the clinic
• Radiosensitization can be achieved under
  noncytotoxic conditions.
• Enhancement ratio of 1.8
• Mechanisms deoxyadenosine triphosphate (dATP)
  pool depletion and redistribution into S phase.
• 22-Difluoro-2-deoxycitidine (gemcitabine) is
  phosphorylated by deoxycitidine kinase to
  gemcitabine mono-, di- (dFdCDP) and
  triphosphate.dFdCDP inhibits ribonucleotide
  reductase, resulting in perturbation of
  deoxynucleotide triphosphate (dNTP) pools, mainly
  dATP depletion. DNA damage, then, might be
  improperly repaired.

13
Gemcitabine and RTEarly clinical trials (1)

• Goor (Belgium) Phase II G1000 mg/m2/w RT 60
  Gy
• Ann Oncol, 1996 in stage III NSCLC
• Toxicity lethal lung insufficiency (1/8),
  severe lung fibrosis(2/8), severe weight loss
  (8/8).

14
Gemcitabine and RTEarly clinical trials (2)

• Eisbruch (USA) Phase I G300 mg/m2/w RT 70/50
  Gy
• ASCO, 1997 in HN cancer
• Toxicity GIII-IV acute skin toxicity(7/8),gastri
  c feeding tubes(8/8) pharyngeal strictures(3/8)
• Eisbruch Phase I G150 mg/m2/w RT 70/50 Gy
• ASCO, 1998
• Toxicity complete pharyngeal obstruction(2/12)
  pharyngeal strictures(6/12).

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Gemcitabine and RT in pancreatic cancerPhase I
studies
Treatment MTD

• Wolf (MDACC) 3000cGyG 400mg/m2 ?
  350mg/m2
• ASCO, 1998
• Abad (Spain) 4500cGyG 200mg/m2 ?
  200mg/m2
• ESMO, 1998
• Maurer (Germany) 5040cGyG 200mg/m2 ?
  350?mg/m2
• ECCO, 1999
• McGinn (USA) 5040cGyG 300mg/m2 ?
  700?mg/m2
• ASCO, 1998
• Blackstock(USA) 5040cGyG 20mg/m2 X 2/wk?
  40mg/m2
• JCO, 1999
• Kudrimoti (USA) 4000cGyG 50mg/m2 CI
  150mg/m2
• ASCO, 1999
• McGinn (USA) 2400?cGyG 1000mg/m2
  3000?cGy
• ASCO, 1999

16
A PHASE II STUDY OF GEMCITABINE COMBINED WITH
RADIATION THERAPY IN PATIENTS WITH LOCALIZED
UNRESECTABLE PANCREATIC CANCER.

• Ron Epelbaum, Edward Rosenblatt, Abraham Kuten.
• Dept. of Oncology. Rambam Medical Center and
  Faculty of
• Medicine. Technion - Israel Institute of
  Technology.
• Haifa, Israel.

17
BackgroundThe rationale for combining
Gemcitabine with radiation therapy.

• Combined chemo-radiotherapy may improve local
  control and long term survival.
• Gemcitabine is an active agent in advanced
  pancreatic cancer resulting in clinical benefit
  in 30-50 of pts. and an objective response rate
  of 5-11.
• Gemcitabine has known radiosensitizing properties.

18
Eligibility Criteria

• 1. Locally advanced unresectable
  adenocarcinoma of the
• pancreas.
• 2. Performance status 0 - 3.
• 3. Bilirubin 2.0 mg/dl

19
Treatment plan

• Phase I - Induction chemotherapy.
• Phase II - Combined Radio-chemotherapy.
• Phase III - Maintenance chemotherapy.

20
Treatment planPhase I - Induction chemotherapy

• Gemcitabine 1000 mg/m2 iv weekly for 7
• weeks followed by one week rest.
• (to achieve clinical benefit, select the
  favorable patients for the combined phase, and
  allow for radiotherapy planning)

21
Treatment planPhase II - Combined
Radio-chemotherapy

• Starting on week 9 - Radiation therapy to 50.4
  Gy in 28 1.8 Gy fractions, in 5.5 weeks
  Gemcitabine 400 mg/m2 iv weekly x 3 every 4 weeks.

22
Treatment planPhase III - Maintenance
chemotherapy

• Gemcitabine 1000 mg/m2 iv weekly x 3 every 4
  weeks starting on week 17, until severe toxicity
  or disease progression.

23
Patient characteristics (n20)

• Age 66 (38-84)
• Male/Female 8/12
• Head of pancreas 8 (40)
• Stage II (T3 N0) 1 (5)
• III (T1-T3, N1) 4 (20)
• IV (T4, N0-1) 15 (75)
• Biopsy 9 (45)
• Cytology 8 (40)
• Unresectability by
• CT 12 (60)
• Operation 8 (40)

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Locally advanced unresectable pancreatic Ca

• Encasement of celiac axis or blood vessels (SMA
  or SMPV confluence) 13 (65)
• Peripancreatic lymph nodes 6 (30)
• Extension to adjacent organs 4 (20)

25
Results

• No Clinical benefit response 10/20 (50)
• Objective response - tumor progression in all
• Median survival 4 mo (1-12 mo)
• Clinical Benefit Response 10/20 (50)
• Objective Response
• Partial response 4/20 (20)
• Stable disease 6/20 (30)
• Tumor progression 10/20 (50)
• Resection Rate 3/20 (15)
• Median Survival All pts. 8 mo
• Responders not
  reached

26
Absolute survival all patients
27
Results

• Latest Status
• Alive, no evidence of disease 3/20 (15)
• Alive, with disease 3/20 (15)
• Dead with disease 14/20 (70)

28
Surgery

• Pt. 1- PR and release of major vessels encasement
  by the tumor ? pancreatectomy fibrotic mass with
  no viable tumor. NED at 24 months.
• Pt. 2- PR and release of major vessels encasement
  ? pancreatectomy complete tumor resection. NED
  at 14 months.
• Pt. 3- PR ?patient refused re-exploration- rise
  in CA 19-9 and positive FDG ? pancreatectomy
  complete tumor resection. NED at 33 months.

29
Results Toxicity

• DI RT dose and duration
• Median WBC nadir 3400-2950-2400
• Median PLT nadir 133-96-99x10³
• Grade III-IV GI toxicity 4/20 (20)
• Late myositis of the
• abdominal wall 3/20 (15)

30
Conclusions

• This schedule of Gemcitabine and radiation
  therapy is well tolerated, and has shown to
  provide prolonged clinical benefit response and
  disease stabilization in patients with localized,
  unresectable pancreatic carcinoma.
• The potential of this regimen to downstage a
  subset of previously unresectable patients,
  rendering them resectable should be further
  investigated.

31
Locally advanced unresectable pancreatic cancer-
whereto ?

• ESTRO 2000, McGinn 5/22 (23) pts were resected,
  following concurrent gemcitabine/radiation
  therapy (two phase I trials).
• New gemcitabine-combination chemotherapy
• Feasibility studies of gemcitabine-based
  chemotherapy combined with radiotherapy
• Modern techniques of radiation delivery
• ?
• Further improvement in local control of disease
  and cure for more pts ??

32
Locally advanced pancreatic cancerCBR vs CB non-R

• 0 1 2 3
• PS R 0 7 3 0
• NR 1 2 4 3
• 0 1-5 5-10 gt10
• Weight loss R 3 2 2 3
• NR 2 1 3 4
• no mild mod sev
• Pain R 2 1 6 1
• NR 0 1 6 3
• CA 19-9 R 54-1119, med-148, gt1000-2 pts
• NR 123-31290, med-1070, gt1000-5pts