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

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. Locally advanced unresectable pancreatic cancer. Background Definitions and statistics

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

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  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: casesdeaths 1-Prostate 179,000 1-Lung 158,900 12-Pancreas 28,600 5-Pancreas 28,600

  4. Pancreatic cancerPresentation • Extent of disease at diagnosis: • Resectable20% • Locally advanced unresectable 40% • Metastatic 40%

  5. Pancreatic cancerSurvival Survival: Median (m)5-y (%) • Resectable15-19 5-20 • Locally advanced6-100 • Metastatic3- 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 ptsMedian(m) • Moertel, 1969 5FU+RT • GITSG, 1979 RT(60 Gy) 25 6 RT(40 Gy)+5FU83 9 RT(60 Gy)+5FU86 12 • GITSG, 1988 SMF24 8 SMF+5FU+RT24 11

  8. 5FU-based chemoradiotherapy (2)No. ptsMedian(m)1-y s(%) • 5FU+RT13-34 7-13 31, 32 • 5FU/PLT+RT22-38 7.5-14 31, 53 • 5FU/ADM/PLT19 14 +5FU+RT • 5FU/STZ/PLT+RT18, 35 5, 15 50

  9. Locally advanced unresectable pancreatic cancerResectability rate after 5FU + RT • Jessup (Boston) 5FU + RT2/16= 12.5 % Arch Surg, 1993 • Bajetta (Milan) 5-DFUR + RT5/32= 15.6 % Inter J Radiat Oncol Biol Phys, 1999

  10. Resectability rate after5FU-Based chemotherapy+RT Kamthan(NY) 5FU/STZ/PLT5/35= 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%

  11. 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. • 2’2’-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 G=1000 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 G=300 mg/m2/w+ RT 70/50 Gy ASCO, 1997 in H&N cancer Toxicity:GIII-IV acute skin toxicity(7/8),gastric feedingtubes(8/8) pharyngeal strictures(3/8) • Eisbruch Phase I G=150 mg/m2/w+ RT 70/50 Gy ASCO, 1998 Toxicity:complete pharyngeal obstruction(2/12)pharyngeal strictures(6/12).

  15. Gemcitabine and RT in pancreatic cancerPhase I studies Treatment MTD • Wolf(MDACC)3000cGy+G 400mg/m2  350mg/m2 ASCO, 1998 • Abad(Spain)4500+cGy+G 200mg/m2  200mg/m2 ESMO, 1998 • Maurer (Germany)5040cGy+G 200mg/m2  350mg/m2 ECCO, 1999 • McGinn (USA)5040cGy+G 300mg/m2  700mg/m2 ASCO, 1998 • Blackstock(USA)5040cGy+G 20mg/m2 X 2/wk 40mg/m2 JCO, 1999 • Kudrimoti(USA)4000+cGy+G 50mg/m2 CI 150mg/m2 ASCO, 1999 • McGinn(USA) 2400cGy+G 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. Background:The 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 (n=20) 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%)

  24. 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 >10 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, >1000-2 pts NR 123-31290, med-1070, >1000-5pts

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