Radiation Oncology/Pancreas/Randomized

Randomized Evidence for Pancreatic Cancer

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Resectable Disease

Biliary Drain

• The Netherlands (2003-2008) -- preop biliary drainage vs. surgery only
  • 2010 PMID 20071702 -- "Preoperative biliary drainage for cancer of the head of the pancreas." (van der Gaag NA, N Engl J Med. 2010 Jan 14;362(2):129-37.)
  • Randomized. 202 patients, obstructive jaundice and bilirubin 2.3 - 14.6 mg/dl. Arm 1) Preoperative biliary drainage for 4-6 weeks vs. Arm 2) No drainage. Both arms followed by surgical resection. Drainage primarily by ERCP placed endoprosthesis. Primary outcome rate of serious complications
    • Outcome: Complications drain 74% vs. no drain 39% (RR 0.54, SS). Mortality and LOS no difference
    • Conclusion: Routine pre-op biliary drainage increases rate of complications

Extent of surgical resection

• Mayo Clinic (1997-2003) -- standard LND vs. extended LND
  • Randomized. 79 patients with resectable pancreatic head cancer, peri-ampullary and islet cell excluded. Distal gastrectomy, pylorus preservation not allowed. Arm 1) standard LND (D1) removed first-echelon lymph nodes en bloc vs. Arm 2) extended LND (D2) which in addition dissected second-echelon lymph nodes
  • 2005 PMID 16269290 -- "A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma." (Farnell MB, Surgery. 2005 Oct;138(4):618-28; discussion 628-30.)
    • Outcome: Median OR time D1 6.2 hrs vs. D2 7.6 hrs (SS), blood transfusions 22% vs. 44% (SS), median LN resected 15 vs. 36 (SS), LOS ~11 days (NS). Median OS 2.2 years vs. 1.6 years (NS), 1-year OS 82% vs. 71% (NS)
    • Toxicity: Diarrhea, body appearance, bowel control better (SS) with D1 resection
    • Conclusion: No difference, extended LND unattractive for further evaluation

• Johns Hopkins (1996-2001) - Pancreaticoduodenectomy: pylorus preservation with standard LND vs. distal gastrectomy with retroperitoneal LND
  • Randomized. 299 patients with periampullary carcinoma (57% pancreatic, 22% ampullary, 17% distal bile duct, 3% duodenal). Initially treated with pylorus-preserving pancreaticoduodenectomy then Arm 1) pylorus preservation and standard LND (distal gastrectomy only if inadequate margin) vs. Arm 2) radical resection with gastrectomy and extended LND
  • 2002 PMID 12192322 -- "Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality." (Yeo CJ, Ann Surg. 2002 Sep;236(3):355-66; discussion 366-8.)
    • Complication rate: standard 29% vs. radical 43%
    • LN+ 74%, SM+ 10% (standard 21% vs. radical 5%)
  • 5-years; 2005 PMID 16332474 -- "Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part 3: update on 5-year survival." (Riall TS, J Gastrointest Surg. 2005 Dec;9(9):1191-204; discussion 1204-6.). Median live F/U 5.3 years
    • Outcome: 5-year OS standard 25% vs. radical 31% (NS); pancreatic CA - standard 13% vs. radical 29% (NS). SM+ standard 21% vs. radical 5% (SS)
    • Conclusion: Pylorus-preserving pancreaticoduodectomy without retroperitoneal lymphadenectomy procedure of choice, but higher SM+ in standard resection

• Milan (Italy)(1991-1994) -- standard LND vs extended LND
  • Randomized. 81 patients with resectable head of pancreas CA. Pancreatoduodenectomy, then Arm 1) standard LND vs. Arm 2) extended LND and retroperitoneal soft-tissue clearance (hepatic hilum, along aorta from the diaphragm to the IMA, laterally to both renal hila, with clearance of the celiac axis and SMA). IORT in 19 patients (NS)
  • 1998 PMID 9790340 -- "Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group." Pedrazzoli S, Ann Surg. 1998 Oct;228(4):508-17.)
    • Outcome: No difference in peri-operative outcomes. LN sampled standard 13 vs. extended 20 (SS). Median OS standard 11.0 months vs. 16.4 (NS)
    • Post-hoc analysis: N1 patients significantly better survival if extended vs standard; no difference in N0 patients
    • Predictors of survival: Grade, size (>2.0 cm), N1, >=4 transfused units of blood
    • Conclusion: Extended resection doesn't improve survival, although trend in N1 patients

Surgery +/- Chemo-RT

• Erasmus MC (2000-2007) -- intra-arterial chemo-RT vs observation
  • Randomized. 120 patients, pancreatic head (52%) or periampullary (48%) cancer. After pancreaticoduodenectomy, randomized to Arm 1) intra-arterial mitoxantrone, 5-FU, leucovoring, and cisplatin x6 cycles with RT 54/30 after first cycle vs Arm 2) observation
  • 2008 PMID 19092348 -- "Adjuvant intra-arterial chemotherapy and radiotherapy versus surgery alone in resectable pancreatic and periampullary cancer: a prospective randomized controlled trial." (Morak MJ, Ann Surg. 2008 Dec;248(6):1031-41.) Median F/U 1.5 years
    • Outcome: Median OS 19 months vs 18 months (NS), PFS 37% vs 20% (SS). Significantly fewer liver mets on subgroup analysis
    • Conclusion: Intra-arterial chemo-RT prolongs time to progression, but no impact on survival

• ESPAC-1 (1994-2000) -- 2x2 surgery +/- chemotherapy and +/- chemo-RT
  • Randomized, 2x2 design + 2 other randomizations to improve accrual. 541 patients total, treated with pancreaticoduodenectomy (R0 81%, R1 19%). Physicians could choose a randomization. 285 patients randomized to 2x2 factorial (observation, chemotherapy x6 cycles, chemo-RT, chemo-RT followed by adjuvant chemo x6 cycles). 68 patients randomized to +/- adjuvant chemo-RT. 188 patients randomized to +/- adjuvant chemo. Patients could be given other "background" therapy, which could be chemo or RT. RT AP/PA split course 20/10 + 20/10 (GITSG regimen, although up to 60 Gy could be given). Chemotherapy concurrent bolus 5-FU 500 mg/m2 + leucovorin, adjuvant 5-FU 425 mg/m2 x6 months
  • All patients; 2001 PMID 11716884 -- "Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial." (Neoptolemos JP, Lancet. 2001 Nov 10;358(9293):1576-85.) Median F/U of alive patients 10 months
    • Analysis: Combined group chemo-RT (n=178) vs. no chemo-RT (n=175); combined group chemo (n=235) vs. no chemo (n=238).
    • Outcome: median OS chemo-RT 15 months vs. no chemo-RT 16 months (NS); median OS chemo 20 months vs. no chemo 14 months (SS)
    • Conclusion: No survival benefit for adjuvant chemo-RT, significant benefit for adjuvant chemo
  • 2x2 subset; 2004 PMID 15028824 — "A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer" (Neoptolemos JP, N Engl J Med. 2004 Mar 18;350(12):1200-10.)
    • Analysis of 2x2 factorial patients only. 289 patients, not powered for individual group comparison. 82% deaths recorded. Median F/U 3.9 years
    • Outcome: median OS observation 17 months vs. chemo-RT 14 months vs. 22 months chemo vs. 20 months chemo-RT + chemo (not powered for statistics)
      • Chemo-RT comparison: median OS chemo-RT 16 months vs. no chemo-RT 18 months (NS), 5-year OS chemo-RT 10% vs. no chemo-RT 20% (p=0.05); no benefit regardless of chemo
      • Chemo comparison: median OS chemo 20 months vs. no chemo 15 months (SS), 5-year OS chemo 21% vs. no chemo 8% (p=0.009); benefit regardless of RT
    • Pattern of failure: LR 35%, LR+DM 27%, DM 34%
    • Conclusion: Adjuvant chemotherapy significant survival benefit; adjuvant chemo-RT had deleterious effect on survival

• EORTC 40891 (1987-95) -- surgery +/- chemo-RT
  • Randomized. 218 patients. Pancreatic T1-2 N0-1a (55%) or periampullary (ampulla, distal CBD, duodenum) T1-3 N0-1a (45%). Arm 1) Chemo-RT vs. Arm 2) observation. RT split course 20/10 + 20/10 (GITSG regimen). Chemo 5-FU C.I. 25 mg/kg over 5 days at the beginning of each RT course. No maintenance (vs. 2 years in GITSG). SM+ 21%, LN+ 50%
  • 1999 PMID 10615932 — "Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group." (Klinkenbijl JH, Ann Surg. 1999 Dec;230(6):776-82.)
    • For all tumors: Median PFS chemo-RT 17 months vs observation 16 months (NS); median OS 24 months vs 19 months (NS). 2-year OS 51% vs 41%, 5-year OS 28% vs 22% (NS)
    • Pancreas tumor subset: median OS 17 months vs 13 months (NS). 2-year OS 37% vs 23%, 5-year OS 20% vs 10% (p=0.09).
    • Periampullary tumor subset: median OS 39 months vs 40 months (NS). 5-year OS 38% vs. 36% (NS)
    • Site of failure: LR both arms 15% (NS), LRR+DM ~20%, DM ~30%
    • Conclusion: Routine use of post-op chemo-RT not warranted
  • 12-years; 2007 PMID 17968163 -- "Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891." (Smeenk HG, Ann Surg. 2007 Nov;246(5):734-40.) Median F/U 11.7 years
    • Outcome: Death reported in 79% (malignant disease cause of death in chemo-RT 79% vs. observation 86%); median OS chemo-RT 1.8 years vs. observation 1.6 years (NS), 5-year OS 25% vs. 22% (NS), 10-year OS 17% vs. 18% (NS) - pancreatic subset 8% vs. periampullary subset 29%; median PFS 1.5 years vs. 1.2 years (NS)
    • Conclusion: No benefit for adjuvant chemo-RT
  • Criticisms: No maintenance chemotherapy. About 20% of pts assigned to chemo-RT arm did not receive that treatment, although 93% received RT. Benefit was diluted by inclusion of favorable periampullary cancers, although on exploratory pancreatic cancer subset analysis there was no difference.

• GITSG 9173 (1974-82) -- surgery +/- chemo-RT
  • Randomized. Terminated early due to poor accrual. 42 patients with adenocarcinoma of the pancreas (ampulla excluded), who were resected, margins negative, no peritoneal mets. Head of pancreas 95%, SM+ 38%, LN+ 28%, Grade 3 5%. Subtotal Whipple 68%, Stage I 35%. Randomized to Arm 1) RT + 5-FU vs Arm 2) observation. RT was supravoltage 40/20 split course (2 week break after 20/10). Fields included the pancreatic bed and regional nodes AP/PA. 5-FU (500 mg/m2) bolus on days 1-3 of each cycle. Adjuvant chemotherapy given weekly x 2 years beginning 1 month after RT.
  • 1985 PMID 4015380 — "Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection." (Kalser MH, Arch Surg. 1985 Aug;120(8):899-903.) Median F/U 5.5 years
    • Median OS: chemo-RT 20 months vs observation 11 months (SS). 2-year OS 42% vs 15%; 5-yr OS vs 15% and 5%; median DFS 11 months vs. 9 months (SS)
    • Recurrence: overall 71% vs. 86%; local 47%; hepatic 32% vs. 50%; DM 40% vs 52%.
    • Conclusion: Adjuvant chemo-RT may prolong survival time

Surgery + Chemo-RT: Adjuvant Chemo Alternatives

• RTOG 97-04 / Intergroup (1998-2002) -- sandwich chemo-RT adjuvant 5-FU vs. gemcitabine
  • Randomized. 451 patients, with complete GTR of pancreas. Arm 1) CI 5-FU (250 mg/m2) x3 weeks -> chemo-RT -> CI 5-FU (250 mg/m2) x12 weeks vs. Arm 2) gemcitabine (1000 mg/m2) x3 weeks -> chemo-RT -> gemcitabine (1000 mg/m2) x12 weeks. Chemo-RT was same for both arms (RT 50.4 Gy + concurrent 5-FU 250 mg/m2), 1-2 weeks after induction chemo. Compliance with both >85%
  • 2008 PMID 18319412 -- "Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial." (Regine WF, JAMA. 2008 Mar 5;299(9):1019-26.)
    • Outcome: median OS 5-FU 17 months vs. gemcitabine 20 months (p=0.09)
    • Toxicity: Grade 4 hematologic 5-FU 1% vs. gemcitabine 14% (SS)
    • Conclusion: Trend to survival for gemcitabine (but NS), and significantly more toxic

Surgery +/- Adjuvant Chemotherapy

• CONKO-001 (Germany)(1998-2004) -- adjuvant gemcitabine vs observation
  • Randomized. 354/368 patients. Pancreas carcinoma T1-4 N0-1 M0 s/p gross complete resection (R0 or R1 allowed). Arm 1) adjuvant gemcitabine (1000 mg/m2) x 6 cycles vs Arm 2) no adjuvant treatment. R0 resection in 80%
  • 2007 PMID 17227978 — "Adjuvant Chemotherapy With Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer." (Oettle H, JAMA. 2007 Jan 17;297:267-277.) Median F/U 4.4 years
    • Relapse: chemo 74% vs control 92%; LR (with/without DM) in 34% vs 41%. DM alone in 56% vs 49%.
    • Survival: Median DFS 13 vs 7 months (SS); 1-year DFS 58% vs. 31%, 3-year 23% vs. 7%, 5-year 16% vs. 5%. Median OS 22 months vs. 20 months (NS) but 5-year OS 22% vs. 11% (p=0.06)
    • Subgroup analysis shows benefit for gemzar for DFS for all subgroups. In subgroup analysis, OS benefit thus far for gemzar for R0 resection and T3-4 and N- pts.
    • Conclusion: Adjuvant gemcitabine significantly improved DFS (primary endpoint), and trial supports its use as adjuvant therapy

• JSAP (Japan)(1992-2000) -- adjuvant cisplatin/5-FU vs. observation
  • Randomized. 85 patients, s/p complete resection (R1 not allowed). Arm 1) adjuvant cisplatin 80 mg/m2 + 5-FU 500 mg/m2 x2 cycles. Intraop RT used but not discussed.
  • 2006 PMID 16490736 -- "A multicenter randomized controlled trial to evaluate the effect of adjuvant cisplatin and 5-fluorouracil therapy after curative resection in cases of pancreatic cancer." (Kosuge T, Jpn J Clin Oncol. 2006 Mar;36(3):159-65. Epub 2006 Feb 20.)
    • Outcome: median OS chemo 12 months vs. observation 16 months (NS); 5-year OS chemo 26% vs. observation 15%
    • Prognostic factors: Grade 1, no LN+. T-stage, size not prognostic
    • Toxicity: Grade 3+ 16%
    • Conclusion: Postop adjuvant cisplatin/5-FU safe, but no survival benefit

• Japan (1986-1992) -- adjuvant MF vs. observation
  • Randomized. 508 patients (pancreatic n=173, cholangio n=139, n=140, ampulla n=56), s/p surgery. Stage II-IV, pancreas LN+ 80%, liver+ 10%, curative resection 58%. Arm 1) adjuvant chemo with mitomycin C + 5-FU C.I. x2 courses, followed by 5-FU until recurrence vs. Arm 2) observation
  • 2002 PMID 12365016 -- "Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma." (Takada T, Cancer. 2002 Oct 15;95(8):1685-95.)
    • Outcome: 5-year OS pancreatic chemo 11% vs. observation 18%; for curative resection chemo 18% vs. observation 27% (NS)
    • Conclusion: No benefit for adjuvant systemic chemotherapy in pancreatic cancer

• Norway (1984-1987) -- adjuvant AMF vs. observation
  • Randomized. 61 patients with pancreatic (77%) or papilla (23%), s/p radical resection. Arm 1) adjuvant chemo (AMF) x6 cycles vs. Arm 2) control.
  • 1993 PMID 8471327 -- "Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater--results of a controlled, prospective, randomised multicentre study." (Bakkevold KE, Eur J Cancer. 1993;29A(5):698-703.)
    • Outcome: median OS chemo 23 months vs. observation 11 months (SS); 2-year OS 43% vs. 32% (NS); 5-year OS 4% vs. 8% (NS)
    • Conclusion: Adjuvant chemo postpone incidence of recurrence during first 2 years; no difference on ultimate cure rate

Surgery vs. Chemo-RT

• Japan Pancreatic Cancer Study Group -- Surgery vs. Chemo-radiation
  • Randomized. Stopped early after survival benefit to surgery. 42/150 patients, locally advanced but resectable pancreatic cancer, no involvement of SMA or common hepatic artery, no para-aortic LN+. Arm 1) Surgery (pancreaticoduodenectomy or distal pancreatectomy + dissection of regional lymphatics) vs. Arm 2) Concurrent RT 50.4/28 and C.I. 5-FU 200 mg/m2 to primary tumor + 1-3 cm margin to cover regional lymph nodes
  • 5-years; 2008 PMID 18958561 -- "Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: Final results of a randomized multi-institutional trial." (Doi R, Surg Today. 2008 Nov;38(11):1021-1028. Epub 2008 Oct 29.) Minimum F/U alive patients 5 years
    • Outcome: median OS surgery 12 months vs. chemo-RT 9 months (NS); 3-year OS 20% vs. 0% (SS); 5-year OS 10% vs. 0% (NS)
    • Conclusion: Locally invasive resectable pancreatic cancer is treated more effectively by resection than by chemo-radiation

Unresectable Disease

RT vs. Chemo-RT

• GITSG 9273 (1970's) -- RT 60 Gy vs. RT 40 Gy + 5-FU vs. RT 60 Gy + 5-FU
  • Randomized, 3 arms. 194 patients with locally unresectable pancreatic CA. Arm 1) RT alone 60/30 Gy split course (On interim analysis found inferior and was discontinued) vs. Arm 2) RT 40/20 Gy split course + concurrent 5-FU vs. Arm 3) RT 60/30 Gy split course + concurrent 5-FU. Concurrent 5-FU 500 mg/m2, followed by maintenance 5-FU 500 mg/m2 x2 years
  • 1981 PMID 7284971 "Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group," Moertel CG et al. Cancer. 1981 Oct 15;48(8):1705-10.
    • Outcome: DFS RT-60 2.9 months vs. C-RT-40 7.0 months vs. C-RT 60 7.6 months (SS); median OS 5.3 months vs. 9.7 months vs. 9.3 months (SS); 1-year OS 10% vs. 35% vs. 46%
    • Toxicity: No severe GI toxicity >10%
    • Conclusion: Concurrent chemo-RT superior to RT alone; C-RT 40 Gy comparable to C-RT 60 Gy

• Mayo Clinic (1960's) -- RT alone vs. RT + 5-FU
  • Randomized. 64 patients with unresectable cancers of the stomach, pancreas, and large bowel. Arm 1) EBRT 35-40 Gy vs. Arm 2) Same EBRT + concurrent 5-FU
  • 1969 PMID 4186452 -- "Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer." (Moertel CG, Lancet. 1969 Oct 25;2(7626):865-7.)
    • Outcome: median OS RT alone 6.3 months vs. chemo-RT 10.4 months (SS); 1-year OS 6% vs. 22%
    • Conclusion: Concurrent chemo-RT significantly augments RT alone

Chemo-RT: Chemo Choices

• PACT -- 5-FU + RT +/- TNFerade
  • Randomized. 330 patients with locally advanced pancreatic CA. Treated with 1) TNFerade (adenoviral vector carrying TNF-a regulated by radiation-inducible promoter Egr-1) + C.I. 5-FU 200 mg/m2/d + RT 50.4 Gy vs 2) 5-FU + RT, randomized 2:1
  • 2007 ASCO Abstract -- "Multi-center phase II/III randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC)." (Posner M, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4518)
    • First 50 patients assessed for response. 1-year OS (primary endpoint): 71% vs. 28%; median OS 1.4 years vs. 0.9 years
    • Conclusion: Preliminary data encouraging

• Taipei (1998-2001) -- 5-FU + RT vs. GEM + RT
  • Randomized. 34 patients. Unresectable pancreatic CA. Arm 1) 5-FU 500 mg/m2 + RT vs. Arm 2) Gemcitabine 600 mg/m2 + RT. RT 50.4 - 61.2 Gy @ 1.8 Gy/fx. All patients received maintenance GEM 1000 mg/m2 thereafter
  • 2003 PMID 12909221 "Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study." (Li CP, Int J Radiat Oncol Biol Phys. 2003 Sep 1;57(1):98-104.)
    • Outcome: median OS 5-FU 7 months vs. GEM 14 months (SS). 1-year OS 31% vs. 56%. 2-year OS 0% vs. 15%. Also improvement in pain control, performance status, and QoL
    • Toxicity: No difference
    • Conclusion: Gemcitabine + RT more effective than 5-FU + RT, comparable tolerability

• GITSG 9277 (1980's) -- RT + 5-FU vs. RT + adriamycin
  • Randomized. 143 patients with locally unresectable pancreatic CA, surgically staged. Arm 1) RT 60/30 split course + concurrent 5-FU bolus 500 mg/m2 + maintenance 5-FU vs Arm 2) RT 40/20 continuous course + concurrent adriamycin 10 mg/m2 + maintenance adriamycin x5 courses + maintenance 5-FU
  • 1985 PMID 2864997 "Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group," ([No Authors Listed], Cancer. 1985 Dec 1;56(11):2563-8.)
    • Outcome: Median OS 5-FU 8.5 months vs. adriamycin 7.6 months (NS). Initial recurrence LRR 5-FU 58% vs. adriamycin 51%
    • Toxicity: 5-FU 36% vs. adriamycin 53% (SS)
    • Conclusion: No difference in outcome, but adriamycin significantly more toxic

Chemo-RT vs. Chemo Alone

• LAP 07 (not reported, 2x2 rand.) induction gem vs. induction gem + erolotonib --> stable disease --> gemcitabine vs. gemcitabine + RT
  • 2013 ASCO Abstract -- "Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study." (Hammel P, J Clin Oncol 31: 2013 (suppl; abstr LBA4003))
  • Randomized. 269 patients reached 2nd randomization. Arm 1) Chemotherapy alone. Arm 2) RT 54 Gy + Xeloda 1600 mg/m2
    • Outcome: Median OS 16.5 months vs. 15.3 months (p=0.83)
    • Conclusion: CRT is not superior to chemotherapy alone in LAPC

• ECOG E4201 (2003-2005) -- gemcitabine vs. gemcitabine + RT
  • 2008 ASCO Abstract -- "A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201." (Loehrer PJ, J Clin Oncol 26: 2008 (May 20 suppl; abstr 4506))
  • Randomized. Closed early due to slow accrual. 69 of planned 316 patients with unresectable disease. Arm 1) Gemcitabine alone 1000 mg/m2 x7 cycles vs. Arm 2) RT 50.4/28 + gemcitabine 600 mg/m2, then gemcitabine alone 1000 mg/m2 x5 cycles
    • Outcome: PFS GEM 6.1 months vs. GEM/RT 6.3 months (NS). Median OS 9 months vs. 11 months (SS)
    • Toxicity: Grade 4 GEM 6% vs. GEM/RT 41% (SS)
    • Conclusion: Gem+RT had increased but generally manageable toxicity, with improved OS over Gem alone

• FFCD-SFRO (2000-2005) -- 5-FU + RT vs. Gemcitabine alone
  • Randomized. Stopped prematurely due to worse survival in Chemo-RT arm. 119 patients with unresectable pancreatic CA. Arm 1) 3D-RT 60/30 + concurrent 5-FU C.I. 300 mg/m2 + cisplatin 20 mg/m2 vs Arm 2) Gemcitabine 1000 mg/m2 alone x7 weeks. Both arms then maintenance Gemcitabine 1000 mg/m2 until disease progression/toxicity
  • 2008 PMID 18467316 -- "Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study." (Chauffert B, Ann Oncol. 2008 May 7. [Epub ahead of print])
    • Outcome: median OS Chemo-RT 8.6 months vs. GEM 13 months (SS); 1-year OS 32% vs. 53%
    • Toxicity: higher in Chemo-RT arm 36% vs. GEM 22% (SS)
    • Conclusion: Chemo-RT is more toxic and less effective than Gemcitabine alone

• GITSG 9283 (1980's) -- 5-FU + RT vs. SMF (Streptozocin, mytomycin, 5-FU)
  • Randomized. 43 patients with locally unresectable pancreatic CA. Arm 1) Streptozocin + mitomycin + 5FU (SMF) vs Arm 2) RT 54 Gy + concurrent 5FU, followed by SMF.
  • 1988 PMID 2898536 "Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group," ([No Authors Listed], J Natl Cancer Inst. 1988 Jul 20;80(10):751-5.)
    • Outcome: median OS Chemo-RT 9.7 months vs. SMF alone 7.4 months (SS); 1-year OS 41% vs. 19% (SS)
    • Conclusion: Combined chemo-RT superior to SMF chemotherapy alone

• ECOG (1970's) -- 5-FU alone vs. 5-FU + RT
  • Randomized. 148/191 patients with locally unresectable adenoCA of stomach (n=57) or pancreas (n=91). Arm 1) 5-FU 600 mg/m2 alone vs. Arm 2) RT 40/20 + concurrent 5-FU bolus 600 mg/m2 + adjuvant 5-FU 600 gm/m2
  • 1985 PMID 3973648 -- "Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study." (Klaassen DJ, J Clin Oncol. 1985 Mar;3(3):373-8.)
    • Outcome: median OS 5-FU 6.5 months vs. chemo-RT 5.1 months (NS); pancreas subgroup 8.2 months vs. 8.3 months (NS)
    • Toxicity: 5-FU alone 27% vs. chemo-RT 51% (SS)
    • Conclusion: Adding RT to 5-FU didn't improve survival, and was more toxic