Pancreatic Cancer

Epidemiology

  • 26000 new cases a year with 26000 deaths a year.
  • 25% have locally advanced disease.
  • Risks: diet high in meat and fat, smoking, previous surgery for PUD,
  • Genetics: k-ras found in 95% of tumors
  • Head lesions are twice as common as tail lesions.

Anatomy

  • It is a retroperitoneal structure at the level L1 and L2
  • Divided in to the uncinate, head, neck, body, and tail.
  • A rich lymphatic network surrounds the pancreas including the celiac (T12), superior and inferior pancreaticosplenic, superior mesenteric (L1), porta hepatis, paraaortics, and splenic nodes.
  • With posterior tumor extension, the lateral aortic nodes are also at risk.

Pathology

  • 75% are of adenocarcinoma ductal in origin and less often exocrine in origin.
  • Others include acinar, giant cell, adenosquamous, and cystadenocarcinoma (good prognosis from the tail of the pancreas).
  • Tumors of the endocrine pancreas are islet cell or interacinar cell origin.
  • 85% are beyond gland at diagnosis.
  • DM typically to liver, lungs, and peritoneum.
  • 10% of patients with pancreatic tumors have mets from other sites. The most frequent primary sites are breast, lung, or melanoma.

Clinical Presentation

  • classic triad
    • pain
    • jaundice
    • weight loss
  • More than 80% present with pain, jaundice, or both.
  • Tumors in the body or tail may not cause jaundice or pain until far advanced and thus their prognosis is particularly poor.
  • Acinar tumors can have elevated lipase levels, eosinophilia, panniculitis, arthralgias, arthritis
  • 80-90% has nodal disease.
  • Infrequent Presentation
    • Trousseau's sign: migratory thrombophlebitis
    • Courvoisier’s sign: palpable gallbladder
    • Abnormal labs such as alteration in glucose, amylase, lipase, bilirubin, alkaline phosphatase, LDH, and aspartate aminotransferase levels

Workup

  • H/P
  • Labs: CBC, LFT, Renal studies, lipase and amylase, CEA, CA 19-9
  • endoscopic retrograde cholangiopancreatography (ERCP) with ultrasound is performed to obtain tissue, stent billiary system and obtain peritoneal fluid.
  • U/S of the upper abdomen can differentiate between obstructive and nonobstructive jaundice
  • CT is more helpful than U/S in providing definition of the tumor and surrounding structures.
  • Exploratory surgery (Laparaoscopy) for tissue with plan for Whipple.

Staging

T1 Confined to the pancreas <2 cm
T2 Confined to the pancreas >2 cm
T3 Extends to bile duct, duodenum, or peri-pancreatic tissues
T4 Extends to stomach, spleen, colon, or adjacent large vessels

N1a Single LN
N1b Multiple LNs

Stage Ia T1N0
Stage Ib T2N0
  • Positive cytology from washing obtained during laparoscopy should be considered M1

Evaluation for Resectability[4]

Test Accuracy
EUS 67%
helical CT 83%
MR 75%
Angiography 71%

Patterns of Spread for Resected Pancreatic Cancer

Study by Chicago[3]

  • 29.4% died with local only recurrence
  • 23.5% died with distant metastasis alone
  • 47.1% had both local and distant relpases.

Treatment Options with Outcomes

Surgical

Resectability

  • 5-20% of patients are resectable (ie. 85% have diease beyond the pancreas)
  • The most common extralymphatic sites of involvement are the liver and peritoneum; the lung is the most commonly involved extra-abdominal site.
  • Un-resectable tumor
    • celiac axis, direct extension into
    • superior mesenteric artery (SMA), direct extension into
    • inferior vena cava (IVC), direct extension into
    • portal vein, encasement or occlusion of
    • superior mesenteric vein (SMV), encasement or occlusion of
    • any distant metastases (liver, positive washing ect.)
    • extensive lymph node involvement
    • Splenic vein involvement does not necessarily preclude resection.

General

  • Whipple procedure (pancreaticoduodencectomy) is the standard surgery

Whipple procedure

  • The distal stomach, proximal jejunum, and head and part of the body of the pancreas, bile duct, and gallbladder are removed en bloc.
  • The bile duct is anastamosed to the jejunal remnant as is the pancreatic remnant.
  • A gastrojejunostomy is the performed along with a vagotomy to prevent upper GI hemorrhage.
  • Leave part of the pancreas.

Results

  • 5-year survival with surgery alone is less than 10%
  • median surivival of less than 1 year with surgery alone
  • Local failure with surgery alone is 50% to 80%. (Cox p.468)

Combined Modality

  • CMT: Most common adjuvant treatment is post-operative RT (40Gy) with concurrent chemotherapy (5FU) following surgery.
  • GITSIG has proven that post-op chemoradiation improved survival as opposed to surgery alone
  • 46% v. 18% 2-year survival for resectable tumors.

TX 2-YEAR SURVIVALS FOR RT ALONE
Surgery alone 18%
RT alone 15%
Post-op RT(40Gy) + 5FU 35%
Post-op RT(60Gy) + 5FU 50%

  • Problem with adjuvant therapy is distant metastases and that RT dose to this area is limited because of the critical structures.
  • A patient with unresectable disease typically live median 4-6 months without treatment and EBRT alone does not improve these results. However, another GITSIG trial showed chemo/RT better than RT alone (median survival 9.6 months v. 5.2 months)
  • Chemoradiation using Gemcitabine
  • Surgical respectability:5/53 who received Gemzar + XRT became resectable vs 1/61 for patients with concurrent 5FU and XRT. (MDA)

Treatment of Resectable Pancreatic Cancer

Chemotherapy (RTOG 9704)

Pre-chemoradiation

  • Starting 3-8 weeks after definitive, Gemcitabine at 1000 mg/m2 once a week x 3.

Chemoradiation (CRT)

  • Continuous infusion 5-FU, 250 mg/m2/d, during radiation.

Post-chemoradiation

  • Starting 3-5 weeks after completion of CRT; 3 cycles of gemcitabine (one cycle = 3 wks of gemcitabine at 1000 mg/m2, once weekly followed by 1 wk rest).

Radiation

Post-operative chemoradiation is considered standard of care.
Dose

  • 50.4 Gy.

Treatment fields

  • AP/PA with lightly weighted laterals. To ensure adequate coverage of the celiac nodes the superior border is T10-11. The inferior border is L2-3. The superior border may need to be a little higher for body lesions. Laterally a 3 cm margin on tumor should be used. Since > 50% of the right kidney is often in the field, care should be taken to exclude at least 2/3 of the left kidney. For the lateral fields the superior and inferior borders remain the same. The anterior border is 2-3 cm beyond gross disease. The posterior border is 1.5-2.0 cm behind the anterior aspect of the vertebral body.

Outcome

  • 5-yr OS 20%.
  • MST 20 months.

Studies of Resectable Pancreatic Cancer

GITSG 91-73 Arch surg 1985;120:899-903.

  • Prospective, randomized study comparing chemoradiation to no adjuvant therapy in patients undergoing Whipple resection
  • Initially only 43 pts accrued
  • An additional 30 patients were accrued as confirmation.

Treatment

  • radiation was 40 Gy split course combined with concurrent 5-FU.
Treatment Arms 2 yr OS 2 yr DFS 5-yr OS MST
Chemo/XRT 43% 48% 19% 21 mos
Confirmation 43% 32% 18 mos
No adjuvant TX 18% 14% 6% 11 mos
p-value 0.035 0.01

EORTC (Klinkenbijl Annals of Surgery 230(6)776, 1999)

  • prospective, randomized trial comparing observation to concurrent 5FU and RT for T1-T2, N0-N1a pancreatic head and T1-3, N0-1a peri-ampullary CA.
  • RT was 40 Gy split course as GITSG trial.
  • No benefit in LC or OS in treatment group.
  • Although there was a trend (p=0.099) for pts with pancreatic primaries.
  • Critisized due to split course RT and total dose.

European study Neoptolemos Lancet 358:1576, 2001

  • Interesting article which attempted to distinguish benefit of chemo, chemo/RT +/- adj chemo vs observation, but it had many problems (see comment by Ross Abrams)

Treatment of Unresectable Pancreatic Cancer

Surgery

  • For biopsy purposes.
  • Bypass is occasionally performed, but this will preclude any future attempts at curative surgery.
  • Debulking is of no benefit.

Chemotherapy

  • Has been shown to improve quality of life.
  • 5-FU and gemcitabine have been used.

Radiation

  • Radiation alone to doses high than 60Gy results in similar survival to surgery but high gastritis morbidity of 10%.
  • Intraoperative Radiation
    • Iodine 125 can be used + EBRT with similar survival but 20% with fistula formation.
    • NCI compared EBRT versus IORT post-operatively and OS was the same but LC was better with IORT.

ChemoRadiation

  • Doses of 50.4 Gy have been used along with 5-FU in an attempt to make tumors resectable.
  • Concurrent Gemcitabine with RT was found to be better than 5-FU/RT in a single institution retrospective study by MDACC.[2]
  • Studies of concurrent RT and Gemcitabine
    • Maximum Tolerated Dose (MTD) of Gemcitabine is 400 mg/m2 given in 40 mg/m2 twice-weekly for 5 weeks.[1]
    • GI toxicity is dose-limiting for Gemzar at it was reached at 60 mg/m2 twice-weekly

MDACC Retrospective Study [2]
Patients

  • Locally advanced

Therapy

  • 5-FU continuous infusion, 200 to 300 mg/m2 vs gemcitabine 250 to 500 mg/m2 weekly x 7
  • Concurrent with radiation

Results

  • 5/53 patients with gemcitabine/RT underwent surgical resection vs 1/61 patients in 5-FU/RT.
  • Median surival was similar 11 mo. vs 9 mo. p =.19
  • Fields are the same as for resectable lesions.

Outcome

  • Median survival is 4 months with bypass alone and 10 months with chemoradiation.

Studies of Unresectable Pancreatic Cancer

GITSG (Ann Surg 1979;189:205-208)

  • Prospective, randomized study of 106 patients receiving 60 Gy, 40 Gy + 5-FU, or 60 Gy + 5-FU. Split course
  • 5FU + RT improves median surival compared to RT alone
  • With 5-FU 60 Gy does not improve survival compared to 40 Gy.
Dose MST Med time to prog 1-yr OS
60 Gy 4 mos 3.5 mos 11%
40 Gy + 5-FU 9 mos 7 mos 36%
60 Gy + 5-FU 10 mos 8.5 mos 38%
p-value < 0.01 < 0.01

RTOG 88-01 (Komaki et al. Cancer 1992;69:2807.)

  • Prospective study of 81 patients with unresectable pancreatic cancer
  • Radiation 6120 cGy/34 fxs to the pancreas and 2340 cGy/13 fxs
  • prophylactically to the liver.
  • concurrent 5-FU.

Results

  • Overall hepatic mets occurred in 31% (13% as the first site), persistent or progressive pancreatic cancer was seen in 73%, and abdominal or extra-abdominal spread were reported in 27% and 8% respectively. Conclusion: PHI may reduce the frequency of hepatic mets, failure to control the primary and intra-abdominal spread remain overwhelming.

EORTC (Klinkenbijl J., Ann Surg. 230(6):776, 1999)

  • 40 Gy split course therapy
  • 20% did not receive intended treatment
  • only 114 pts with pancreatic cancer of 218 registered.

Treatment of Metastic Pancreatic Cancer

  • Standard treatment of patients with advanced metastatic or recurrent pancreatic adenocarcinoma and adequate performance stats, or both, is systemic chemotherapy.
  • Gemcitabine is the standard of care by itself or in combination
Bibliography
1. Blackstock AW, Bernard SA, Richards F, Eagle KS, Case LD, Poole ME, Savage PD, Tepper JE. Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol. 1999 Jul;17(7):2208-12.
2. Crane CH, Abbruzzese JL, Evans DB, Wolff RA, Ballo MT, Delclos M, Milas L, Mason K, Charnsangavej C, Pisters PW, Lee JE, Lenzi R, Vauthey JN, Wong AB, Phan T, Nguyen Q, Janjan NA. Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1293-302.
3. Michelassi F, Erroi F, Dawson PJ, Pietrabissa A, Noda S, Handcock M, Block GE. Experience with 647 consecutive tumors of the duodenum, ampulla, head of the pancreas, and distal common bile duct. Ann Surg. 1989 Oct;210(4):544-54; discussion 554-6. Review. PMID: 2679459
4. Soriano A, Castells A, Ayuso C, Ayuso JR, de Caralt MT, Gines MA, Real MI, Gilabert R, Quinto L, Trilla A, Feu F, Montanya X, Fernandez-Cruz L, Navarro S. Preoperative staging and tumor resectability assessment of pancreatic cancer: prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J Gastroenterol. 2004 Mar;99(3):492-501. PMID: 15056091
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