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Adjuvant Radiotherapy and Chemotherapy for Pancreatic Carcinoma: The Mayo Clinic Experience (1975-2005)

Michele M. Corsini, Robert C. Miller, Michael G. Haddock, John H. Donohue, Michael B. Farnell, David M. Nagorney, Aminah Jatoi, Robert R. McWilliams, George P. Kim, Sumita Bhatia, Matthew J. Iott, Leonard L. Gunderson

From the Department of Radiation Oncology; the Divisions of Gastroenterologic and General Surgery, Surgical, and Medical Oncology, Mayo Clinic, Rochester, MN; the Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL; and the Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ

Corresponding author: Robert C. Miller, MD, MS, Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: miller.robert{at}mayo.edu

	ABSTRACT

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Purpose To determine prognostic factors and impact of adjuvant chemotherapy (CT) and radiotherapy (RT) on overall survival (OS) after resection of pancreatic adenocarcinoma.

Patients and Methods We performed a retrospective review 472 consecutive patients who underwent complete resection with negative margins (R0) for invasive carcinoma (T1-3N0-1M0) of the pancreas between 1975 and 2005 at the Mayo Clinic in Rochester, MN. Exclusion criteria included metastatic or unresectable disease at surgery, positive surgical margins, and indolent tumor types (islet cell tumors and mucinous cystadenocarcinoma). Median RT dose was 50.4 Gy in 28 fractions; 98% of RT patients also received concurrent fluorouracil-based CT.

Results Six patients died within 30 days of surgery. For the 466 surviving patients, median follow-up was 32.4 months; median OS was 21.6 months. Median OS after adjuvant CT-RT was 25.2 versus 19.2 months after no adjuvant therapy (P = .001). Two-year OS was 50% versus 39%, and 5-year OS was 28% versus 17%. Adverse prognostic factors identified by univariate and multivariate analysis included positive lymph nodes (risk ratio [RR] = 1.3; P < .001), high histologic grade (RR = 1.2; P < .001), and no adjuvant therapy (RR = 1.3; P < .001). Tumor extension beyond the pancreas was an adverse prognostic factor by univariate analysis alone (P = .03). Patients receiving adjuvant therapy had more adverse prognostic factors than those not receiving adjuvant therapy (P = .001).

Conclusion This study represents one of the largest, single-institution, retrospective reviews of adjuvant therapy in patients after R0 resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CT-RT.

	INTRODUCTION

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Pancreatic cancer is the fourth leading cause of cancer mortality in the Western world, with an estimated 37,170 new cases and an estimated 33,370 deaths projected in the United States for 2007.¹ Despite current multimodality therapy, treatment outcomes are poor. Surgical resection is the most important curative treatment, but only 10% to 15% of patients are candidates for potentially curative resection.^2-4 Even among this more favorable subset, survival rates after surgical resection remain poor, with less than 20% surviving 5 years.^3-5

To improve survival after resection, researchers have explored adjuvant chemotherapy (CT) and radiotherapy (RT) for pancreatic adenocarcinoma. Adjuvant CT plus RT (concurrent with or without maintenance), which is called chemoradiotherapy (CT-RT), is used in the United States on the basis of the results of the GI Tumor Study Group (GTSG) and European Organisation for Research and Treatment of Cancer (EORTC) trials. However, outcomes from the European Study Group for Pancreatic Cancer (ESPAC-1) trial have raised doubts about the utility of adjuvant RT in pancreatic malignancies.^6-8

To better define the role of adjuvant RT in patients with fully resected, nonmetastatic pancreatic adenocarcinoma, we conducted a retrospective review of patients who underwent laparotomy plus complete resection with negative margins. Our intent was to determine prognostic factors and compare patient outcomes after surgery alone versus surgery plus adjuvant therapy.

	PATIENTS AND METHODS

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Patients
This study was approved by the Mayo Foundation Institutional Review Board. The institutional database was retrospectively searched for records of consecutively treated patients with pancreatic carcinoma who underwent surgery at Mayo Clinic in Rochester, MN, between January 1975 and December 2005. Of the approximately 1,030 patients who underwent laparotomy in this 30-year period, 472 patients with invasive pancreatic carcinoma underwent potentially curative resection with negative margins (R0) and no evidence of metastatic disease (T1-3N0-1M0) at surgery. Patients with indolent tumor types such as islet-cell tumors and mucinous cystadenocarcinoma were excluded. Six patients died within 30 days of surgery and therefore were also excluded from analysis.

This sample of 466 patients was first analyzed to determine prognostic factors and outcomes independent of adjuvant therapy. Next, we analyzed the effect of adjuvant therapy. In the analysis of the effect of adjuvant therapy, 12 of the 466 patients were excluded, nine because they received adjuvant CT alone, usually because of early distant relapse, and three because adjuvant therapy could not be verified. Of the remaining 454 patients, 180 received no adjuvant therapy and 274 received adjuvant RT. Of the 274 who received adjuvant RT, 268 (98%) received concurrent fluorouracil (FU)-based CT during RT. Twenty-eight of these 268 patients received additional adjuvant CT after completion of CT-RT. All 274 patients treated with RT were considered to have received adjuvant therapy; therefore, our definition of adjuvant therapy was receipt of adjuvant RT (with 98% of patients also receiving concurrent CT).

Surgery
All patients underwent surgery at Mayo Clinic in Rochester, MN. Standard pancreaticoduodenectomy was performed in 240 patients, pylorus-preserving pancreaticoduodenectomy in 146, total pancreatectomy in 27, and distal pancreatectomy in 53.

Pathologic specimens were reviewed internally by the Department of Pathology. Staging was based on the sixth edition of the guidelines of the American Joint Committee on Cancer (AJCC)⁹ in use at the time of chart review.

All pathology and operative reports were reviewed to determine the extent of resection. Margin status was reported as R0 for no residual tumor, R1 for microscopic residual tumor less than 1 mm from margin (if quantitative margin data were available), and R2 for macroscopic residual tumor, consistent with AJCC definitions.⁹

Adjuvant Radiotherapy
Adjuvant external-beam RT was delivered in 274 patients with linear accelerators using multiple-field techniques. The median RT dose was 50.4 Gy in 28 fractions, with 93% of patients receiving 45 to 55 Gy (range, 13.8 to 60 Gy). Adjuvant RT was performed internally at Mayo Clinic facility in 139 cases and externally in 135 cases. For patients treated at the Mayo Clinic, the initial irradiation field, defined as the tumor bed plus regional nodes, was usually administered 45 Gy in 25 fractions with a four-field technique (anteroposterior, posteroanterior, and paired laterals) using 10- or 18-mV photons, and the tumor bed boost field received an additional 5.4 to 9 Gy in three to five fractions of 1.8 Gy.¹⁰

Outcomes Measures and Statistical Analysis
Overall survival (OS) was calculated from the date of surgery. Prospectively chosen prognostic factors investigated by univariate analysis (UVA) included age, sex, presence or absence of local and regional lymph node (LN) metastases, histologic grade high (grade 3 or 4) versus low (grade 1 or 2), extension of disease outside the pancreas (T3 v T1 or T2), site of disease (head of pancreas v other), type of surgery, and adjuvant therapy. Factors found to be adversely prognostic by UVA were further investigated by multivariate analysis (MVA). OS was calculated for each prospectively chosen prognostic factor. After prognostic factors were validated for risk stratification, the effect of adjuvant therapy on OS was evaluated sequentially for each adverse variable. Information on patterns of failure or first site of recurrence was not consistently documented, and thus was not reviewed.

The distribution of prognostic variables among treatment groups was compared using the Fisher's exact test. The Kaplan-Meier method was used to estimate OS. Log-rank testing was used to calculate univariate differences in outcomes, and a proportional hazards model was used to estimate relative risk (RR). MVA was performed using a Cox regression model. P < .05 was considered statistically significant.^11,12

	RESULTS

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For the 466 patients who met inclusion criteria, the median age at surgery was 67 years (range, 29 to 90 years). There were more men (n = 250) than women (n = 216; Table 1). Pathology was consistent with adenocarcinoma in 463 (99%) patients. Two patients had carcinoma, not otherwise specified, and one patient had acinar cell carcinoma. Three hundred twenty-three patients (69%) had high-grade tumors. Approximately half the 466 patients had tumors that extended outside the pancreas (T3 tumors; n = 243), whereas 223 patients had either T1 or T2 tumors. Pathologic LN evaluation identified 241 patients with negative LNs, 224 patients with positive LNs, and one patient who either had no LNs removed or none identified during pathologic evaluation. At least one adverse prognostic factor was present in 379 (82%) patients.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Overall survival (OS) of 454 patients with R0 resection for pancreatic cancer who received adjuvant therapy (median OS, 25.2 months) or did not receive adjuvant therapy (median OS, 19.2 months; P = .001). (B) OS by number of adverse prognostic factors (zero, one, or two) in patients with R0 resection for pancreatic cancer independent of adjuvant therapy (median OS, 40.8 months, 22.8 months, or 15.6 months, respectively; P < .001). (C) OS in patients with two adverse prognostic factors (both lymph node involvement and high histologic grade) in relation to adjuvant therapy. OS with adjuvant therapy (median OS, 18 months) or without adjuvant therapy (median OS, 12 months; P < .001).

	DISCUSSION

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Our findings demonstrate significantly better survival in patients with pancreatic cancer who received adjuvant CT-RT after R0 resection; this result is consistent with those of several previous studies.^6,13-17 Patients who received adjuvant CT-RT had improved median, 2-year, and 5-year OS rates relative to patients who had an R0 surgical resection alone, with an 11% absolute survival benefit at both 2 years (50% v 39%) and 5 years (28% v 17%; P = .001). An OS difference was still present at 10 years (20% v 14% for adjuvant therapy versus observation, respectively). Our intent was to assess the impact of CT-RT on OS in a truly adjuvant setting where no known identifiable primary tumor remained (R0 resection).

Although there is potential bias in patient selection in any retrospective analysis from a single institution (eg, patient performance status may affect referral patterns, with healthier patients more likely to be referred for adjuvant therapy), this bias may be offset by a competing bias to refer patients for adjuvant CT-RT when they have a higher risk for relapse after surgery alone. We found a statistically significant difference in the number of adverse prognostic factors in patients who received adjuvant therapy (P = .001). Nonetheless, as noted previously, these patients still had an improved survival rate compared with those not receiving adjuvant therapy.

In the current investigation, the most significant negative prognostic factors for patient survival after R0 resection for pancreatic cancer were LN involvement and histologically proved high-grade tumor. Tumor extension beyond the pancreas failed to retain statistical significance by MVA, perhaps because of the exclusion of patients with known microscopic or macroscopic positive margins. These findings are similar to those published elsewhere.² The variables of age, sex, type of surgical procedure (Whipple v non-Whipple), location of adjuvant therapy (Mayo Clinic facility or elsewhere), and time of adjuvant therapy (before or after 1995) were not found to be negatively associated with outcomes. The 28 patients who received additional adjuvant CT after completion of concurrent CT-RT had the highest mean number of adverse prognostic factors, yet the best median, 2-year, and 5-year survival rates—almost double those of patients who had postoperative observation alone. Despite having the lowest mean number of adverse prognostic factors, the observation group had worse survival.

The medical literature includes several randomized controlled trials, as well as various single-institution, nonrandomized, and retrospective studies addressing the efficacy of adjuvant therapy for resected pancreatic cancer.^18-24 Whereas the randomized trials (GTSG, EORTC, and ESPAC-1) have shown conflicting results about the benefits of adjuvant therapy over surgery alone followed by observation, other studies have consistently indicated an OS benefit with adjuvant CT-RT.^14-17

The GTSG phase III trial was the first randomized trial designed to evaluate the role of postoperative adjuvant treatment.⁶ This US-based multi-institutional trial conducted between 1974 and 1982 sought to determine the value of postoperative adjuvant RT combined with bolus FU CT (concurrent with RT, then 2 years of maintenance) versus surgery alone with observation for resected adenocarcinoma of the pancreas. This trial demonstrated a statistically significant survival advantage for the 43 eligible patients who underwent resection followed by adjuvant CT-RT (P = .04), leading to the adoption of adjuvant CT-RT as the standard of care in the United States for resected adenocarcinoma of the pancreas.

The EORTC phase III trial⁷ was a somewhat larger study designed to validate the results of the GTSG trial, but it also included patients with periampullary carcinoma. Analyses demonstrated a trend toward improved survival (P = .099) in patients with pancreatic head adenocarcinoma who received adjuvant CT-RT versus observation. A recent reanalysis of these data, using a one-sided log-rank test instead of a two-sided log-rank test, revealed a statistically significant (P = .049) 2-year overall survival benefit in patients who received postoperative CT-RT, which supports the earlier findings of the GTSG trial.¹³

In contrast to the results of prior randomized trials, the findings of the ESPAC-1 study suggest that adjuvant RT is not beneficial, and is possibly even deleterious, for resected pancreatic cancer. The study used a complex design involving three simultaneous phase III trials. In two of the trials, physicians could choose to deliver background adjuvant therapy before random assignment, which led some authors to suggest that the resultant bias in patient selection negated the phase III design. The third trial involved a 2 x 2 design in which 289 patients were randomly assigned to one of four treatment arms (surgery alone, adjuvant CT, concurrent CT-RT, or concurrent CT-RT followed by adjuvant CT). Two- and 5-year survival for patients randomly assigned to receive CT-RT versus no CT-RT was 29% versus 41% and 10% versus 20%, respectively. Whereas the ESPAC-1 authors concluded that adjuvant RT was harmful and reduced survival time,⁸ the adjuvant concurrent CT-RT arm in this trial produced extremely poor results compared with those of other phase III and single-institution series. In addition, there were significant flaws in both the study design and the quality-control aspects of the trial (background therapy was allowed in two of the three trials; no radiation-field design parameters were included in the protocol, nor was there central review of the designed radiation field; and restaging studies were not performed before initiation of adjuvant therapy).

Despite the heterogeneous results of the three previously reported phase III trials, several nonrandomized and retrospective US series have consistently demonstrated an OS benefit with the addition of adjuvant therapy for resected pancreatic cancer. These series include single-institution series from Mayo Clinic (present study) and from Johns Hopkins University,¹⁴ and two separate analyses of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database.^2,15

In 1997, Yeo et al¹⁴ published a single-institution experience from Johns Hopkins University of more than 170 patients that compared adjuvant CT-RT to observation. A statistically significant (P = .003) OS benefit was demonstrated with a median survival of 19.5 months after adjuvant therapy, consistent with the findings of the GTSG and EORTC trials, versus 14 months after surgery alone; 2-year survival was 40% versus 31%. This survival benefit was most significant in patients with negative surgical margins, node-positive disease, and primary tumors 3 cm or more in size,^14,25 which is similar to the findings in the current Mayo Clinic series. The Johns Hopkins investigators subsequently evaluated patient outcomes in more than 160 patients at their institution,¹⁶ again demonstrating a significant survival benefit (P < .001) associated with adjuvant CT-RT compared with observation in patients with resected pancreatic cancer.

Two separate analyses of the SEER database suggest an advantage for adjuvant therapy over surgery alone. Lim et al² reported findings in 396 patients older than age 65 years who were diagnosed with nonmetastatic pancreatic adenocarcinoma and underwent surgical resection with curative intent between 1991 and 1996 while enrolled in one of the 11 SEER registries. The strongest predictor of survival was the addition of adjuvant CT-RT. Greco et al¹⁵ recently reviewed data from the SEER database for more than 2,600 patients treated between 1988 and 2003 who had received RT after resection of adenocarcinoma of the head of the pancreas. RT was associated with longer median OS (18 v 11 months; P < .01).

In our analysis, although only 11% of patients received additional systemic therapy after completion of concurrent CT-RT, the median survival in this cohort was increased by more than 9 months compared with that of patients treated with CT-RT alone. Although continued use of adjuvant FU-based concurrent CT-RT is supported for patients with resected pancreatic adenocarcinoma by the findings of the phase III GTSG and EORTC trials, the SEER results, and the single-institution analyses from Mayo Clinic and Johns Hopkins, survival rates remain poor, primarily because of high distant metastatic failure rates. Recent results of the CONKO-001 (Charite’ Onkolgie²⁶) phase III trial from Germany and Austria, as well as the Radiation Therapy and Oncology Group (RTOG) 9704 phase III GI Intergroup trial in the United States, have shown modest improvements in survival with adjuvant gemcitabine CT after resection of pancreatic cancer.^26,27 Accordingly, there is a need for more effective systemic therapy.

Future advances in adjuvant treatment after resection will include the discovery of more active, yet tolerable, systemic regimens. The recent negative phase III trials in patients with metastatic cancer do not necessarily exclude specific biologic agents as components of adjuvant treatment.^28-30 There is an obvious distinction between the bulky tumors found in metastatic disease and the micrometastases present in resectable patients. Although the survival benefit with biologic agents (such as erlotinib hydrochloride, an inhibitor of the epidermal growth factor receptor) is marginal in metastatic patients, this benefit may be amplified in the smaller, potentially more vulnerable tumors residually present after resection. The relative greater dependency of tumor cells on specific biologic processes (eg, angiogenesis) argues for future evaluation of biologic agents for adjuvant treatment of pancreatic cancer.

This large, single-institution analysis demonstrates an OS benefit with the addition of adjuvant CT-RT after R0 resection of adenocarcinoma of the pancreas. MVA identified adjuvant CT-RT, nodal status, and tumor histology as the primary independent predictors of survival after pancreaticoduodenectomy for pancreatic adenocarcinoma.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Michele M. Corsini, Robert C. Miller, Sumita Bhatia

Provision of study materials or patients: Michele M. Corsini, Robert C. Miller, Michael G. Haddock, John Donohue, Michael B. Farnell, David M. Nagorney, Aminah Jatoi, Leonard L. Gunderson

Collection and assembly of data: Michele M. Corsini, Robert C. Miller

Data analysis and interpretation: Michele M. Corsini, Robert C. Miller, Michael G. Haddock, Robert C. McWilliams, Leonard L. Gunderson

Manuscript writing: Michele M. Corsini, Robert C. Miller, Michael G. Haddock, David M. Nagorney, Aminah Jatoi, Sumita Bhatia, Matthew J. Iott, Leonard L. Gunderson, George P. Kim

Final approval of manuscript: Michele M. Corsini, Robert C. Miller, John Donohue, Michael B. Farnell, David M. Nagorney, Aminah Jatoi, Robert C. McWilliams, George P. Kim, Matthew J. Iott, Leonard L. Gunderson

	ACKNOWLEDGMENTS

 
Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic.

	NOTES

 
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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2. Lim JE, Chien MW, Earle CC: Prognostic factors following curative resection for pancreatic adenocarcinoma: A population-based, linked database analysis of 396 patients. Ann Surg 237:74-85, 2003[CrossRef][Medline]

3. Trede M, Schwall G, Saeger HD: Survival after pancreatoduodenectomy: 118 consecutive resections without an operative mortality. Ann Surg 211:447-458, 1990[Medline]

4. Geer RJ, Brennan MF: Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 165:68-72, 1993[CrossRef][Medline]

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7. Klinkenbijl JH, Jeekel J, Sahmoud T, et al: 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. Ann Surg 230:776-782, 1999[CrossRef][Medline]

8. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004[Abstract/Free Full Text]

9. Greene FL, Page DL, Fleming ID, et al (eds): AJCC cancer staging manual (ed 6). New York, NY, Springer-Verlag, 2002

10. Gunderson LL, Martenson JA, Smalley SR, et al: Upper gastrointestinal cancers: Rationale, results, and techniques of treatment. Front Radiat Ther Oncol 28:121-139, 1994[Medline]

11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

12. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187-220, 1972

13. Garofalo MC, Regine WF, Tan MT: On statistical reanalysis, the EORTC trial is a positive trial for adjuvant chemoradiation in pancreatic cancer. Ann Surg 244:332-333, 2006[CrossRef][Medline]

14. Yeo CJ, Abrams RA, Grochow LB, et al: Pancreaticoduodenectomy for pancreatic adenocarcinoma: Postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225:621-633, 1997

15. Greco JA, Castaldo ET, Feurer ID, et al: Survival benefit with adjuvant radiation therapy in surgically resected pancreatic cancer. Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 19-21, 2007, Orlando, FL

16. Swartz MJ, Abrams RA, Winter J, et al: Adjuvant chemoradiation for adenocarcinoma of the pancreas: The Johns Hopkins experience. Int J Radiat Oncol Biol Phys 66:582, 2006 (suppl)

17. Corsini MM, Miller RC, Haddock MG, et al: Adjuvant radiation and chemotherapy for pancreatic adenocarcinoma: The Mayo Clinic experience. Int J Radiat Oncol Biol Phys 69:S79, 2007 (suppl; abstr)[Medline]

18. Bhatia S, Miller RC, Haddock MG, et al: Adjuvant therapy for ampullary carcinomas: The Mayo Clinic experience. Int J Radiat Oncol Biol Phys 66:514-519, 2006[Medline]

19. Garofalo M, Flannery T, Regine W: The case for adjuvant chemoradiation for pancreatic cancer. Best Pract Res Clin Gastroenterol 20:403-416, 2006[CrossRef][Medline]

20. Stocken DD, Buchler MW, Dervenis C, et al: Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer. Br J Cancer 92:1372-1381, 2005[CrossRef][Medline]

21. Bergenfeldt M, Albertsson M: Current state of adjuvant therapy in resected pancreatic adenocarcinoma. Acta Oncol 45:124-135, 2006[Medline]

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23. Chu QD, Khushalani N, Javle MM, et al: Should adjuvant therapy remain the standard of care for patients with resected adenocarcinoma of the pancreas? Ann Surg Oncol 10:539-545, 2003[CrossRef][Medline]

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25. Winter JM, Cameron JL, Campbell KA, et al: 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg 10:1199-1210, 2006[CrossRef][Medline]

26. Oettle H, Post S, Neuhaus P, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA 297:267-277, 2007[Abstract/Free Full Text]

27. Regine WF, Winter KW, Abrams R, et al: RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs gemcitabine (G) for resected pancreatic adenocarcinoma. J Clin Oncol 24:180S, 2006 (suppl; abstr 4007)

28. Poplin E, Levy DE, Berlin J, et al: Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201). J Clin Oncol 24:180S, 2006 (suppl; abstr LBA4004)

29. Kindler HL, Niedzwiecki D, Hollis D, et al: A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB). J Clin Oncol 25:199S, 2007 (suppl; abstr 4508)

30. Philip PA, Benedetti J, Fenoglio-Preiser C, et al: Phase III study of gemcitabine (G) plus cetuximab (C) versus gemcitabine in patients (pts) with locally advanced or metastatic pancreatic adenocarcinoma (Pca): SWOG S0205 study. J Clin Oncol 25:199S, 2007 (suppl; abstr LBA4509)

Submitted December 27, 2007; accepted March 3, 2008.

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