R. Taylor Ripley, M.D.November 15, 2010

Pancreatic Cancer: Pancreaticoduodenectomy Only Chance for Long-Term Survival

Pancreatic Cancer: 10th Most Common Cancer

Life-Time Risk: 1.32%

Jemal et al. CA Cancer J Clin. 2010 September; 60: 277-300.

Pancreatic Cancer: 4th Most Common Cause of Cancer Death

Jemal et al. CA Cancer J Clin. 2010 September; 60: 277-300.

Pancreatic Cancer: Incidence Has Not Changed in Last 20 years

Death: Males Death: Females

Jemal et al. CA Cancer J Clin. 2010 September; 60: 277-300.

Localized Pancreatic Cancer: Amenable to Resection

Unfortunately, localized disease accounts for 8% of all patients with pancreatic cancer.

Controversy exists about extending resection to regional or borderline tumors.

Jemal et al. CA Cancer J Clin. 2010 September; 60: 277-300.

Overview

I. Survival after pancreaticoduodenectomy.

II. Comparison to similarly staged patients.

III. Survival after portal-mesenteric venous resections.

IV. Survival with perioperative therapy.

Pancreatic Cancer

Do patients experience long-term survival after this procedure?

Pancreatic Cancer: Survival

Riall et al. Surgery 2006; 140: 764-72

23% 5-yr Actual Survival:Periampullary Cancers

(n = 890)

17% 5-yr Actual Survival:Pancreatic Adenocarcinoma

(n = 564)

Long-Term Survivors Continue to Benefit from Pancreaticoduodenectomy

Riall et al. Surgery 2006; 140: 764-72

Pancreatic Cancer: Survival of Multiple Series

Katz et al. Ann Surg Oncol. 2009; 16: 836-47

Whipple Has Acceptable Perioperative Mortality

• Riall et al. Surgery 2006; 140: 764-72.– 890 patients– 1970’s: 30%– 1980’2: 3.6%– 1990’2: 2.3%

• Conlon et al. Ann Surg. 1996; 223: 273-9.– 1983 – 1989.– 118 patients– 3.4%

• Lygidakis et al. Hepato-Gastroenterology. 2004; 51: 427-33.– 1995 – 2002.– 56 patients with SMV resection.– 1/56 died: 2%.

Pancreatic Cancer

Long Term survival is obtainable after a Whipple.

Although only 17% of patients survive 5 years, the patients who survive continue to benefit from the

Whipple.

Would these patients have survived similarly without a Whipple? – Absolutely Not.

Overview

I. Survival after pancreaticoduodenectomy.

II. Comparison to similarly staged patients.

III. Survival after portal-mesenteric venous resections.

IV. Survival with perioperative therapy.

Comparative Study Highlighting Underutilization of Pancreatectomy for Pancreatic Cancer

Bilimoria et al. Ann Surg 2007; 246: 173-80

Significant Survival Advantage for Patients after Pancreatectomy for Stage I Disease

Bilimoria et al. Ann Surg 2007; 246: 173-80

Significant Survival Advantage for Patients after Pancreatectomy for Stage I Disease

Bilimoria et al. Ann Surg 2007; 246: 173-80

Pancreatic Cancer

Clearly, some patients achieve long-term survival after pancreaticoduodenectomy.

A highly significant improvement in survival exists for patients undergoing resection compared to

patients who do not undergo resection.

Do these survival advantageous exist for patients requiring vascular resection?

Overview

I. Survival after pancreaticoduodenectomy.

II. Comparison to similarly staged patients.

III. Survival after portal-mesenteric venous resections.

IV. Survival with perioperative therapy.

Portal-Mesenteric Venous Resection

Lygidakis et al. Hepato-Gastroenterology. 2004; 51: 427-33

Prospective RCT of Locally Advanced Pancreatic Head Cancer Treated by Resection Superior to Gastro-biliary Bypass

Lygidakis et al. Hepato-Gastroenterology. 2004; 51: 427-33

P = 0.0001

Prospective RCT of Portal-Mesenteric Venous Resection versus Radiochemotherapy

Imamura and Doi. Pancreas 2004; 28: 293-5

Pancreatic Cancer

Even operations requiring portal-mesenteric vascular resections impart a survival

advantage.

Overview

I. Survival after pancreaticoduodenectomy.

II. Comparison to similarly staged patients.

III. Survival after portal-mesenteric venous resections.

IV. Survival with perioperative therapy.

Adjuvant Therapy with Gemcitabine Increased Survival after Whipple

Oettle et al. JAMA 2007; 297: 267-77

Gemcitabine Increases DFS, yet Complete Surgical Resection More Significant Prognostic Factor

Oettle et al. JAMA 2007; 297: 267-77

Chemotherapy and Chemoradiotherapy Have Mixed Impact on Survival After Pancreatectomy

Neoptolemos et al. N. Engl J. Med 2004; 350: 1200-10

Pancreatic Cancer

Adjuvant chemotherapy imparts a modest survival advantage.

Would neoadjuvant protocols increase the efficacy of chemotherapy?

Multimodality Treatment Protocol

Evans et al. JCO 2008;26:3496-3502

Survival after Resection with Neoadjuvant Therapy

Evans et al. JCO 2008;26:3496-3502

Multimodality Treatment Protocol: Borderline Tumors

Katz et al. Ann Surg Oncol. 2009; 16: 836-47

27% 5-yr Actual Survival Rate.

Multimodality Treatment Protocol: Borderline Tumors

Katz et al. J Am Coll Surg. 2008; 206: 833-46

Summary of Neoadjuvant Therapy

• 27% survival rates highest ever achieved.

• 77% received neoadjuvant therapy.– Patients who progressed or did not tolerate therapy did not

undergo resection.

• Pre-operative staging improved compared to past series– Less unresectable and R2 resections performed.

• 33% underwent vascular reconstruction– Highlights complex cases not an exclusion criterion.

Katz et al. Ann Surg Oncol. 2009; 16: 836-47

Survival with Chemotherapy Alone

Cunningham et al. J Clin Oncol 2009; 20;27: 5513-8

Pancreatic Cancer

Despite advances in perioperative systemic treatment…

Surgery remains the foundation of survival for Pancreatic Cancer.

Is Peri-Operative, Intra-Arterial Chemotherapy the

Next Frontier of Pancreatic Surgery?

Regional Pancreatic Cancer: Any Hope?

Will perioperative regimens improve the resectability and survival of patients withregionally advanced disease?

Jemal et al. CA Cancer J Clin. 2010 September; 60: 277-300.

Perioperative Intra-Arterial and Systemic Chemotherapy for Pancreatic Cancer: Next Advancement?

Takamori et al. Ann Surg Oncol. Epub. November, 2010.

Summary• Almost no survivors exists with non-operative therapy for

pancreatic cancer.

• Long-term survival can only be achieved by resection for pancreatic cancer.

• Portal-mesenteric venous resections impart a survival advantage compared to chemotherapy and/or radiotherapy.

• Perioperative therapy adds a benefit, but the survival advantage is primarily secondary to resection.

• Will intra-arterial chemotherapy regimens increase the resectability and survival of patients with pancreatic cancer?

Thank You

Pancreatic Cancer: Adjuvant Therapy Pancreatic Cancer: Adjuvant Therapy (Completed Phase III Data)(Completed Phase III Data)

Study No Pts R1 Rxn (%)Treatment

Median SurvivalControl Arm

Median Survival P

GITSG(1985)

Kalser et al, Arch Surg 1985

49 0

5FU + XRT

21.0 months

No chemo/XRT

10.9 months0.035

EORTC-40891(1999)

Klinkenbijl et al, Ann Surg 1999

114 (214) 21

5FU + XRT

17.1 months

No chemo/XRT

12.6 months0.09

ESPAC-1(2004)

Neoptolmemos et al, N Eng J Med 2004

289 18

5FU + Leucovorin20.1 months

5FU + XRT15.9 months

No Chemo15.5

No Chemo/XRT17.9 months

0.009

0.05RTOG 9704

(2006)Regine et al,

J Clin Oncol 2007

380 (512)(head lesions)

>35

Gem-5FU/EBRT-Gem

20.6 months

5FU-5FU/EBRT-5FU

16.9 months0.33

CONKO-001(2007)

Oettle et al,JAMA 2007

368 19

Gemcitabine22.1 months

DFS 13.9 months

No chemo20.1 months

DFS 6.9 months

0.06

0.001

Kosuge(2006)

Jpn J Clin Oncol88

5-FU + cisplatin15.8

Observation12.5

0.94

Advanced Pancreatic Cancer Advanced Pancreatic Cancer (Gemzar vs. Gemzar / Platinum)(Gemzar vs. Gemzar / Platinum)

Study N Treatment RR(%) p Median PFS p Median survival p

ColucciCancer2002

107III

GemGem + cisplatin

9.2 26.4

0.020.02 2.05.0

0.0480.048 5.07.5

0.48

ViretJCO2004

83II

GemGem + cisplatin

57

- 2.52.2

ns 6.78.0

0.73

LouvetJCO2005

313III

GemGem + oxaliplatin(GERCOR/GISCAD)

17.326.8

0.040.04 3.75.8

0.040.04 7.19.0

0.13

PoplinJCO2006

832III

Gem (std 30 min iv)Gem (fixed dose rate)Gem + oxaliplatin

(GEMOX)

5109

- ---

- 4.96.05.9

ns

HeinemannJCO2006

195III

GemGem + cisplatin

8.210.2

- 3.15.3

0.053 6.07.5

0.15

Advanced Pancreatic CancerAdvanced Pancreatic Cancer (Gemzar vs. Gem + 5FU)(Gemzar vs. Gem + 5FU)

Study N Treatment RR p PFS p survival p

ECOG 2297JCO2002

322III

GemGem + 5-FU

5.66.9

- 2.23.4

0.022 5.46.7

0.09

ScheithauerAnn Oncol2003

83II

GemGem + Capecitabine

14 - 4.05.1

- 8.29.5

-

RiessJCO2005

473III

GemGem + 5-FU

7.24.8

- 3.53.5

0.44 6.25.9

0.68

GOIRCBJC2005

91II

GemGem + 5-FU

811

- 3.54.5

- 7.87.5

-

HerrmannJCO2007

319III

GemGem + Cap

7.910.1

- 4.04.8

0.21 7.38.4

0.31

CunninghamEJC2005

533III

GemGem + Cap

7.114.2

0.008 --

- 6.07.4

0.0260.026

42 days

Pancreatic Cancer: RCT Radiation TherapyPancreatic Cancer: RCT Radiation Therapy (Locally Advanced / Unresectable)(Locally Advanced / Unresectable)

Study N Treatment ResultsKarasawaRadiother Oncol2008

46 IORTVs.IORT + Doranidazol (hypoxic cell sensitizer)

IORT + Doranidazol might be moreeffective?3y 23% vs. 0% p=0.01

SunamuraPancreas2004

48 IORT aloneVs.IORT + PR-350 (radiosensitizer)

No difference in OSSlight better RR for IORT+PR-350

RosemurgyJ Gastrointest Surg2008

30 5-FU + gemcitabineVs.5-FU + gemcitabine + (32)P(intratumoral)

No difference in OS(32)P: more tumor necrosis observed

HishinumaJ hepatobil Panc Surg2005

65 Curative resectionVs.Resection + PHI (prophylactic hepatic irradiation)

PHI: Increased OS (p=0.045)Decreased risk of liver metastases

ChungInt J Rad Onc Bio Phy2004

48 Gemcitabine + RT + DoxifluridineVs.Paclitaxel + RT + Doxifluridine

No difference in OS