Journal of Gastrointestinal Surgery

, 13:26

Surgical Resection Versus Palliative Chemoradiotherapy for the Management of Pancreatic Cancer with Local Venous Invasion: A Decision Analysis

Authors

  • Michael A. Abramson
    • Department of SurgeryBrigham and Women’s Hospital, Harvard Medical School
  • Edward W. Swanson
    • Department of SurgeryBrigham and Women’s Hospital, Harvard Medical School
    • Department of SurgeryBrigham and Women’s Hospital, Harvard Medical School
2008 ssat poster presentation

DOI: 10.1007/s11605-008-0648-y

Cite this article as:
Abramson, M.A., Swanson, E.W. & Whang, E.E. J Gastrointest Surg (2009) 13: 26. doi:10.1007/s11605-008-0648-y

Abstract

Background

Benefit from pancreaticoduodenectomy (PD) combined with superior mesenteric-portal vein (SMV-PV) resection in the management of pancreatic adenocarcinoma with local venous invasion remains controversial.

Methods

Using formal decision analysis, we compared survival associated with PD plus SMV-PV resection when applied to patients with pancreatic adenocarcinoma with isolated local venous invasion (Group 1) versus that achieved with palliative chemoradiotherapy when applied to patients with locally advanced pancreatic cancer (Group 2). Individual studies were identified using Medline. A total of 1,324 and 709 patients were analyzed for Groups 1 and 2, respectively. Patients with distant metastases were excluded.

Results

Overall decision analysis favored surgical resection (Group 1) over palliative chemoradiotherapy (Group 2). Sensitivity analyses indicated that this decision is sensitive to the perioperative mortality rate and the percentage of surgical resections with microscopic (R1) or macroscopic (R2) residual tumor at the resection margin. In contrast, sensitivity analysis revealed that the decision is not sensitive to the percentage of cases in which true venous invasion by cancer is documented histologically.

Conclusions

Surgical resection may confer a survival advantage over palliative chemoradiotherapy in select patients with pancreatic cancers with presumed local venous invasion.

Keywords

Pancreatic adenocarcinomaPancreaticoduodenectomySurvivalDecision analysis

Introduction

Pancreatic cancer is the fifth leading cause of cancer-related deaths in the USA, causing an estimated 33,370 deaths in 2007.1 Surgical resection offers the only potential for cure for patients with this disease.

The benefit of surgical resection for the subset of patients with locally advanced pancreatic cancers with isolated portal vein and/or superior mesenteric vein (PV-SMV) invasion is controversial. Although it has been suggested that resection of these lesions can be performed safely (with acceptable long-term survival rates), the survival benefit of surgical resection over palliative chemoradiotherapy has not been confirmed in a randomized controlled trial.

As such, in this study, we conducted formal decision analysis in order to compare survival in patients with pancreatic cancer based on two competing treatment strategies; Group 1 patients underwent surgical resection (pancreaticoduodenectomy (PD) with venous resection and reconstruction) for pancreatic adenocarcinoma with isolated local venous invasion and Group 2 patients underwent palliative chemoradiotherapy for locally advanced pancreatic cancer.

Materials and Methods

Decision analysis is a quantitative method for estimating the effectiveness of alternative management strategies. Decision analysis was performed according to published guidelines.26

Data Sources

A systematic Medline search was conducted using the search term “pancreatic cancer AND vein resection” to identify English language publications containing data relevant to Group 1. Despite an extensive search of the literature, we were unable to identify studies reporting survival data specifically for patients with isolated local venous invasion treated solely with chemoradiation. As such, we used survival data for patients with locally advanced cancers treated with palliative chemoradiation as a proxy for survival among Group 2 patients. We believe this is an appropriate strategy, given that nonresected patients with Stage IIA (locally invasive; resectable; T3, N0, M0), Stage IIB (locally invasive; resectable; T1,2, or 3, N1, M0), and Stage III (locally advanced; unresectable; T4, any N, M0) disease are reported to have nearly identical 1-year survival rates (25.0%, 26.9% and 27.0%, respectively).7,8 Upon detailed review of the selected articles for both groups, additional articles were subsequently identified that met inclusion criteria. Critical appraisal of each study was performed by the authors, and studies were selected on the basis of the inclusion criteria used for this analysis.

Inclusion and Exclusion Criteria

Letters, reviews without original data, animal studies, studies without survival data, and overlapping studies were all eliminated from the analysis. In studies that did not explicitly state survival time periods in the text, we have estimated survival using Kaplan–Meier Survival curves.

Perioperative mortality was defined as death within 30 days of the surgery. However, in-hospital or operative mortality was used as a substitute for perioperative mortality when death within 30 days of surgery was not reported.

Studies used for Group 1 included patients having pancreatic cancer with local invasion into the portal vein and/or superior mesenteric veins. All studies meeting these criteria were included regardless of the extent of lymph node dissection and/or venous resection. In some of the studies, survival data included patients undergoing simultaneous vein and arterial resections. Additionally, some studies included in our analysis included patients undergoing additional neoadjuvent and/or adjuvant therapies. Studies used for Group 2 included patients with locally advanced pancreatic cancers who received palliative chemoradiotherapy. Studies were included regardless of the type or duration of the treatment regimen. Some studies in this group included patients with incompletely resected pancreatic cancer with residual disease. Patients were excluded from both Groups 1 and 2 if there was any evidence of metastatic disease.

Decision Analysis Models and Calculations

Decision tree design and analysis was performed using TreeAge Pro 2007 software (TreeAge Software, Williamstown, MA, USA). Decision trees used in this analysis are shown in Figs. 1, 2, and 3. Figure 1 shows the decision tree comparing 1-year survival of all patients treated with PD plus PV-SMV resection versus those patients treated with palliative chemoradiotherapy. Figure 2 shows the decision tree comparing 1-year survival of the subset of patients treated with PD plus PV-SMV resection accounting for documented histopathologic invasion status of tumor into the portal and/or superior mesenteric vein versus those patients treated with palliative chemoradiotherapy. Figure 3 shows the decision tree comparing 1-year survival of the subset of patients treated with PD plus PV-SMV resection accounting for documented R-status at the surgical resection margin versus those patients treated with palliative chemoradiotherapy.
https://static-content.springer.com/image/art%3A10.1007%2Fs11605-008-0648-y/MediaObjects/11605_2008_648_Fig1_HTML.gif
Figure 1

Decision tree comparing 1-year survival of all patients treated with PD plus PV-SMV resection versus those patients treated with palliative chemoradiotherapy.

https://static-content.springer.com/image/art%3A10.1007%2Fs11605-008-0648-y/MediaObjects/11605_2008_648_Fig2_HTML.gif
Figure 2

Decision tree comparing 1-year survival of the subset of patients treated with PD plus PV-SMV resection accounting for documented histopathologic invasion status of cancer into the portal and/or superior mesenteric vein and versus those patients treated with palliative chemoradiotherapy.

https://static-content.springer.com/image/art%3A10.1007%2Fs11605-008-0648-y/MediaObjects/11605_2008_648_Fig3_HTML.gif
Figure 3

Decision tree comparing 1-year survival of the subset of patients treated with PD plus PV-SMV resection accounting for documented R-status at the surgical resection margin versus those patients treated with palliative chemoradiotherapy.

Weighted means were calculated for each variable and used as baseline estimates, taking into account the number of patients contributing to each outcome. As the outcome of interest in this analysis was survival at a given time point, a utility (payoff) of 1 was assigned for a patient surviving to that time point, and a utility of 0 was assigned for a patient surviving less than to that time point.

Sensitivity Analysis

One-way sensitivity analysis was performed for variables in the decision models to determine the impact of uncertainty in the estimates of probabilities. Threshold values were calculated for variables that would lead to a change in the preferred strategy when traversed. If the decision outcome to select one treatment strategy over the other did not change over the range of the variable being manipulated, the decision was considered to be not sensitive to this variable and, thus, no threshold was identified for that variable. Alternatively, if the decision outcome to select one treatment strategy over the other did change over the range of the variable being manipulated, the decision was considered to be sensitive to this variable, and the value at which the optimal strategy changed was considered to be the “threshold value.”

Results

Analysis of Data Used

Studies used in the analysis are shown in Tables 1 and 2 for Groups 1 and 2, respectively. Overall, a total of 32 studies including 1,324 patients and 19 studies including 709 patients were used to calculate baseline probabilities for Groups 1 and 2, respectively.
Table 1

Published Studies Included in the Surgical Resection Group (Group 1)

Year published

Inclusion period

Authors

Institution

Patients

2008

1994–2005

Yekebas et al.10

University Medical Centre Hamburg-Eppendorf (Germany)

100

2007

1998–2005

Al-Haddad et al.11

Mayo Clinic (Jacksonville)

22

2006

1996–2004

Shimada et al.12

National Cancer Center (Tokyo, Japan)

86

2006

1989–2003

Carrere et al.13

Hopital Beaujon, University Paris VII (France)

45

2006

1981–2005

Nakao et al.14

Nagoya University (Japan)

186

2006

1994–2004

Riediger et al.15

University Hospitals of Rostock and Freiburg (Germany)

26

2005

1999–2003

Zhou et al.16

Shanghai Institute of Digestive Surgery (China)

32

2005

 

Koniaris et al.17

University of Miami School of Medicine

11

2004

1998–2002

Poon et al.18

Queen Mary Hospital, University of Hong Kong (China)

12

2004

1990–2002

Tseng et al.19

University of Texas, M.D. Anderson Cancer Center

110

2004

1994–2003

Bin Li et al.20

Multiple hospitals in China

79

2003

 

Howard et al.21

Indiana University School of Medicine

13

2003

1992–2001

Nakagohri et al.22

National Cancer Center East (Japan)

33

2003

1983–2000

Aramaki et al.23

Oita Medical University (Japan)

22

2002

1990–1997

Kawada et al.24

Hokkaido University (Japan)

28

2002

1987–2000

Sasson et al.25

Fox Chase Cancer Center and Temple University

25

2002

1980–2001

Hartel et al.26

University-Hospital Mannheim (Germany)

68

2001

1983–1998

Shibata et al.27

Sendai City Medical Center and Iwate Medical University (Japan)

28

2001

1992–1998

van Geenen et al.28

Academic Medical Center (Netherlands)

34

2001

1990–1999

Bachellier et al.29

Hopital Universitaire de Hautepierre (France)

21

2001

1996–1999

Park et al.30

Samsung Medical Center (Korea)

25

2001

1965–1998

Kinoshita et al.31

Kurume University School of Medicine (Japan)

37

1999

1973–1992

Launois et al.32

Centre Medico Chirurgical Saint Vincent (France)

14

1998

1981–1996

Civello et al.33

Catholic University School of Medicine (Rome, Italy)

7

1998

1976–1997

Naganuma et al.34

Mie University School of Medicine (Japan)

30

1996

1983–1995

Harrison et al..35

Memorial Sloan-Kettering Cancer Center

58

1996

 

Roder et al.36

Technische Universitat Munchen (Germany)

31

1996

1971–1993

Klempnauer et al.37

Hannover Medical School (Germany)

18

1995

1970–1994

Yeo et al.38

Johns Hopkins Medical Institutions

10

1994

1983–1992

Allema et al.39

Academic Medical Centre (Netherlands)

20

1994

1976–1992

Takahashi et al.40

Keio University School of Medicine (Japan)

63

1992

1984–1989

Ishikawa et al.41

The Center for Adult Diseases (Osaka, Japan)

30

Table 2

Published Studies Included in the Chemoradiotherapy Group (Group 2)

Year published

Inclusion period

Authors

Institution

Patients

Treatment Regimen

2007

2004–2005

Ikeda et al.42

Nat Cancer Center Hosp. East, Japan

21

Radiation+S-1

2007

2001–2003

Haddock et al.43

Mayo Clinic

48

Radiation+Gemciabine+Cisplatin

2005

1983–1989

Cohen et al.44

Fox Chase Cancer Center

55

Raditation+5-FU+MMC

2005

2000–2003

Mishra et al.45

Wake Forest

20

Radiation+Gemcitabine+Irinotecan

2004

1998–2000

Rich et al.46

University of Virgina

109

Radiation+Paclitaxel

2003

1999

Blackstock et al.47

Wake Forest

43

Radiation+Gemcitabine

2003

1998–2001

Martenson et al.48

Mayo Clinic

26

Radiation+Gemciabine+Cisplatin

2002

1997–1999

Epelbaum49

Technicon-Israel Institute of Tech

20

Radiation+Gemcitabine

2001

1996–1998

Wolff et al.50

MD Anderson

18

Radiation+Gemcitabine

2001

 

Safran et al.51

Brown University

44

Radiation+Paclitaxel

2000

 

Talamonti et al.52

Northwestern University

7

Radiation+5-FU+Gemcitabine

1997

1993–1996

Ishii et al.53

Nat. Cancer Center Hosp., Tokyo

20

Radiation+5-FU

1995

 

Whittington et al.54

University of Pennsylvania

16

Radiation+5-FU

1981

 

Moertel et al.55

Mayo Clinic

86

6000 rads+5-FU

1969

 

Moertel et al.56

Mayo Clinic

32

Radiation+5-FU

2005

2001–2003

Louvet et al.57

Hospital St. Antoine

51

Gemcitabine+Oxaliplatin

2004

 

Rocha Lima et al.58

University of Miami

24

Gemcitabine

2002

1997–1998

Bramhall et al.59

Queen Elizabeth Hospital

32

Gemcitabine

2001

1997–2000

McGinn et al.60

University of Michigan

37

Radiation+Gemcitabine

Variables used in the decision trees, calculated weighted means, and ranges found in the literature are shown in Table 3. Overall decision analysis favored surgical resection over palliative chemoradiotherapy with 1-year survival probabilities of 55% and 39% for Groups 1 and 2, respectively. Similarly, analysis favored surgical resection over palliative chemotherapy when 3- and 5-year survivals were used as the outcome of interest (data not shown).
Table 3

Study Variables

Variable

Studies analyzed

Patients

Weighted mean (%)

Range (%) in the literature

1-year survival for treatment with chemoradiation

13

567

39

17–51

1-year survival for treatment with surgical resection

26

1151

57

22–94

Perioperative mortality

28

1303

3

0–15

Histopathologic proven vein invasion

23

852

61

3–100

1-year survival for treatment with surgical resection given true histopathologic vein invasion

10

219

53

14–80

1-year survival for treatment with surgical resection given no histopathologic vein invasion

9

109

62

0–81

R1 or R2 resections

22

921

34

8–85

1-year survival for treatment with surgical resection given an R0 resection

3

63

62

45–75

1-year survival for treatment with surgical resection given an R1 or R2 resection

3

50

34

17–61

Sensitivity Analysis

One-way sensitivity analyses varying the: (1) perioperative mortality rate, (2) the percentage of cases in which true venous invasion by cancer is documented histologically, and (3) the percentage of surgical resections with microscopic (R1) or macroscopic (R2) residual tumor at the resection margin are shown in Figs. 4, 5, and 6, respectively.
https://static-content.springer.com/image/art%3A10.1007%2Fs11605-008-0648-y/MediaObjects/11605_2008_648_Fig4_HTML.gif
Figure 4

One-way decision analysis varying the perioperative mortality rate over a range of values. The decision to perform surgical resection versus chemoradiation was sensitive to manipulation of this variable. Decision analysis favored treatment with chemoradiation over surgical resection at a perioperative mortality rate higher than 30% (intersection of two lines).

https://static-content.springer.com/image/art%3A10.1007%2Fs11605-008-0648-y/MediaObjects/11605_2008_648_Fig5_HTML.gif
Figure 5

One-way decision analysis varying the percentage of tumors with histopathologic proven invasion into the portal and/or superior mesenteric veins. As this variable increased, the 1-year survival of those patients undergoing surgical resection decreased (note the negative slope of the line marked with triangles). However, the decision analysis favored surgical resection over chemoradiation regardless of the percentage of tumors with histopathologic proven invasion (i.e., no threshold was reached).

https://static-content.springer.com/image/art%3A10.1007%2Fs11605-008-0648-y/MediaObjects/11605_2008_648_Fig6_HTML.gif
Figure 6

One-way sensitivity analysis varying the percentage of surgical resections with either microscopic (R1) or macroscopic (R2) residual tumor at the resection margin. At a probability of R1 plus R2 resection greater than 80%, surgical resection was no longer the favored treatment strategy.

The decision to perform surgical resection versus chemoradiation is sensitive to manipulation of the perioperative mortality rate. At the baseline perioperative mortality of 3.3%, decision analysis favors resection over chemoradiation. However, at a perioperative mortality rate higher than 31%, (intersection of lines in Fig. 4), decision analysis favors treatment with chemoradiation over surgical resection.

One-way sensitivity analysis revealed that an increase in the percentage of cases in which true venous invasion by cancer is documented histologically resulted in a decrease in the 1-year survival of those patients undergoing surgical resection (Fig. 5). However, the decision analysis favored surgical resection over chemoradiation regardless of the percentage of tumors with histopathologically proven invasion, and thus, the decision is not sensitive to this variable.

Finally, one-way sensitivity analysis demonstrated the decision to treat with surgical resection over chemoradiation is sensitive to the percentage of surgical resections with either microscopic (R1) or macroscopic (R2) residual tumor at the resection margin. At a probability of R1 plus R2 resections greater than 77%, surgical resection is no longer the favored strategy (Fig. 6).

Discussion

As far as we are aware, this is the first study to utilize decision analysis to assess the potential survival benefit of surgical resection for patients with pancreatic cancer with local venous invasion. Given a lack of randomized controlled trials, decision analysis provides a useful alternative method for comparing these two treatments.

In their recent article, Siriwardana et. al. performed a systematic review of the literature of outcomes associated with synchronous portal-superior mesenteric vein resection during pancreatectomy for cancer.9 The authors pooled data on categories relating to the operation, complications, histopathology, and overall outcome and concluded that even with radical resection, cures are unlikely for patients with tumors involving the portal vein.8

A decision analysis study, such as ours, is not without potential limitations, which we enumerate here. As we have pooled many studies in order to determine baseline probabilities, there is considerable variability within both groups compared in this study, along with some overlap of the two groups in this study. In the surgical group, studies differed in the types of adjuvant and/or neoadjuvant therapies, criteria used for resectability, preoperative imaging studies, curative-resection rates, surgical techniques (e.g., venous reconstructive procedures), extent of resection (e.g., removal of lymph nodes), and tumor location, for example. Similarly, the patient selection and treatment regimens varied widely in the palliative chemoradiotherapy group. To account for this variability in published study data, we completed sensitivity analyses over a wide range of values for the probability of perioperative mortality, probability of histopathologic vein invasion and the probability of an R1 or R2 resection to determine threshold values that would lead to a change in the preferred strategy when traversed.

Decision analysis studies can be limited by paucity of data for specific patient subgroups. Although there are several published reports containing survival data for surgically treated patients based on histopathologically documented invasion status of cancer into the portal and/or superior mesenteric vein, there are fewer reports containing survival data for surgically treated patients (those treated with portal and/or superior mesenteric vein resection) based on documented R-status at the surgical resection margin (Table 3). Furthermore, as far as we are aware, there are no published reports that contain survival data based on both of these variables in the same patient cohort. To overcome this limitation, we elected to analyze survival data using three separate decision trees instead of a single tree. This strategy allowed us to include many more studies than would have been possible for a single decision tree approach.

Finally, as we have noted earlier in our methods and discussion, our study compared two groups of patients that may not be identical with respect to stage distribution, comorbidity profiles, and other variables. For example, although most patients categorized into Group 1 of our study had cancer invasion limited to the portal vein and/or superior mesenteric vein (stage IIA or IIB disease), some of these patients had invasion into the superior mesenteric artery (stage III disease) for which arterial resection was performed.7 For Group 2, the reported data do not permit determination of the distribution of patients among stages IIA, IIB, and III; therefore, it is possible that a greater percentage of Group 2 than Group 1 patients had stage III disease. Nonetheless, patients with nonresected stages IIA, IIB, and III pancreatic adenocarcinoma have virtually indistinguishable 1-year survival rates (25.0%, 26.9%, and 27.0%, for stages IIA, IIB, and III, respectively).8 Given that the primary endpoint of our study was 1-year survival and all patients included in our study had stage IIA, IIB or III disease, we believe that Groups 1 and 2 are comparable for the purposes of this analysis.

Conclusion

In conclusion, we have determined that surgical resection may confer a survival advantage over palliative chemoradiotherapy in select patients with pancreatic cancers with presumed invasion into local veins. We recommend that authors report survival statistics based on histopathologic proven vein invasion and R-status so that a more through evaluation of this data may be completed in the future.

Copyright information

© The Society for Surgery of the Alimentary Tract 2008