Adjuvant Gemcitabine and Gemcitabine-based Chemoradiotherapy Versus Gemcitabine Alone After Pancreatic Cancer Resection: The Indiana University Experience.

ORIGINAL ARTICLE

Adjuvant Gemcitabine and Gemcitabine-based Chemoradiotherapy Versus Gemcitabine Alone After Pancreatic Cancer Resection The Indiana University Experience Muhammad R. Khawaja, MD, MPH,* Svetlana Kleyman, MD,* Zhangsheng Yu, PhD,w Thomas Howard, MD,z Matthew Burns,* Attila Nakeeb, MD,z Patrick J. Loehrer, Sr, MD,* Higinia R. Cardenes, MD,y and Elena Gabriela Chiorean, MD*8

Objectives: Adjuvant therapy after surgical resection is the current standard for pancreatic adenocarcinoma; however, the role of chemoradiotherapy (CRT) remains unclear. This study was conducted to compare the efficacy outcomes with adjuvant gemcitabine and gemcitabine-based CRT (CT-CRT) versus gemcitabine chemotherapy (CT) alone after pancreaticoduodenectomy. Methods: Among 165 patients who underwent surgical resection for pancreatic cancer at Indiana University Medical Center between 2004 and 2008, we retrospectively identified 53 consecutive patients who received adjuvant therapy (CT-CRT = 34 patients; CT = 19 patients) and had adequate follow-up medical records. The median follow-up was 19.1 months. Median disease-free (DFS) and overall survival (OS) were determined using Kaplan-Meier method, and a Cox-regression model was used to compare survival outcomes after adjusting for age, status of resection margins, and lymph node involvement. Results: The OS for the CT-CRT group was significantly higher compared with the CT group (median, 20.4 vs. 16.6 mo; hazard ratio, 2.42; 95% CI, 1.17-5.01). The median DFS for the CT-CRT group was 13.7 versus 11.1 months for the CT group (hazard ratio, 2.88; 95% CI, 1.376.06). On subgroup analyses, significantly superior OS and DFS were observed among patients younger than 65 years, T3/T4 tumor stage, negative resection margins, and positive lymph node involvement. Conclusion: Gemcitabine plus gemcitabine-based CRT compared with gemcitabine alone leads to superior DFS and OS for patients with resected pancreatic cancer. Key Words: pancreatic cancer, adjuvant treatment, gemcitabine, chemotherapy, chemoradiotherapy

(Am J Clin Oncol 2014;00:000–000)

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ancreatic cancer is among the 10 most common malignancies and fourth most common cause of cancer deaths in the United States.1 Although only 15% to 20% of patients qualify for surgical resection,2,3 most patients recur within 14 months.4,5 From the *Division of Hematology/Oncology; Departments of wBiostatistics; zSurgery; yRadiation Oncology, Indiana University School of Medicine, Indianapolis, IN; and 8Department of Medicine, Division of Hematology/Oncology, University of Washington, Seattle, WA. The authors declare no conflicts of interest. Reprints: E. Gabriela Chiorean, MD, Department of Medicine, Division of Hematology/Oncology, University of Washington, 825 Eastlake Ave East, G4830, Seattle, WA 98109. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000115

American Journal of Clinical Oncology

Adjuvant treatment after pancreatic cancer resection is the accepted standard of care.6–9 The choice of the most effective chemotherapeutic agent and the role of radiotherapy, however, remain uncertain. Approximately, 30% to 50% of pancreatic cancer recurrences involve local failure,4,5 and this can contribute to worse survival and quality of life. Recently, the EORTC-40013-22012 trial demonstrated that gemcitabine plus gemcitabine-based chemoradiotherapy (CT-CRT) can significantly reduce local recurrence (11% vs. 24%) compared with gemcitabine chemotherapy (CT) alone, but with no apparent benefit in disease-free (DFS) or overall survival (OS).10 Historically, CRT has shown benefit over surgery alone in several clinical studies. Both the Gastrointestinal Tumor Study Group (GITSG) and the EORTC-40891 trials demonstrated benefit from 5-fluorouracil (5-FU)-based CRT.6,11 Although the ESPAC-1 (European Study Group for Pancreatic Cancer) trial confirmed the value of adjuvant CT, it raised concerns that CRT may be detrimental.12 Prospective randomized trials regarding the role of adjuvant CRT for pancreatic cancer have yielded conflicting results and have been criticized due to complex study designs, outdated radiation techniques, absence of central quality assurance, and lack of restaging after surgical resection.6,11,12 Nonrandomized large retrospective studies have, however, yielded relatively consistent results regarding the value of CRT. Studies published from the Mayo Clinic, John Hopkins, and a population-based analysis of SEER data have all demonstrated better OS among patients receiving CRT compared with those undergoing surgery alone.13–16 Gemcitabine is the preferred chemotherapeutic agent in the adjuvant treatment of pancreatic cancer in the United States, due to a more favorable toxicity profile than 5-FU. The CONKO-1 trial confirmed the DFS and OS benefit from adjuvant gemcitabine versus observation after pancreatic cancer surgery,8,9 but the ESPAC-3 trial demonstrated equivalent results with either 5-FU or gemcitabine.17 The Radiation Therapy Oncology Group (RTOG 97-04) compared the combination of gemcitabine plus 5-FU-based CRT versus 5-FU plus 5-FU-based CRT. A trend toward higher OS was observed among patients receiving the gemcitabine-based regimen, but statistical significance was only seen for patients with pancreatic head tumors.18 Although most of the published adjuvant CRT regimens used 5-FU as radiosensitizer, at Indiana University we implemented gemcitabine-based CRT and have previously reported on its outcomes in locally advanced pancreatic cancer.19,20

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Khawaja et al

Gemcitabine-based CRT was not only a safe and feasible option, it also demonstrated a superior OS compared with gemcitabine CT alone.20 The advantage of gemcitabine over 5-FU among patients with advanced pancreatic cancer attracted attention to its possible benefit in the adjuvant setting as well.21 The question whether the addition of CRT to CT provides any benefit remains unanswered as control groups in most studies assessing the value of CRT consisted of patients undergoing surgery alone. Moreover, these studies have used 5-FU as the radiosensitizing chemotherapeutic agent. With the aforementioned background, this retrospective study was conducted to compare outcomes of adjuvant gemcitabine CT versus gemcitabine CT and gemcitabine-based CRT for patients with pancreatic adenocarcinoma who underwent surgical resection at Indiana University Medical Center (IUMC) between 2004 and 2008.

MATERIALS AND METHODS Study Design and Subjects A total of 165 patients underwent pancreaticoduodenectomy for pancreatic cancer at IUMC between 2004 and 2008. Fiftythree patients received adjuvant treatment at IUMC, had all medical records and follow-ups available, and were included in


this retrospective study. All patients had histologically proven pancreatic adenocarcinoma. The study was approved by the Institutional Review Board of Indiana University School of Medicine.

Treatment Groups Patients were retrospectively divided into 2 groups based on the adjuvant treatment they received. Patients receiving combination therapy (CT-CRT group) underwent 1 to 2 cycles of induction gemcitabine CT followed by CRT, followed by another 3 cycles of CT. Each cycle of CT was 4 weeks in duration and consisted of weekly doses of gemcitabine (1000 mg/m2) for 3 weeks followed by 1-week break. The CRT was administered in 28 fractions (median dose, 50.4 Gy) over 5 weeks together with weekly gemcitabine (600 mg/m2). The CT group received up to 6 cycles of gemcitabine CT (1000 mg/m2) for 3 weeks followed by 1-week break. Whether a patient received CT alone or CT-CRT was decided after detailed discussion regarding potential risks, benefits, and toxicities, and taking into consideration patient’s risk of recurrence, performance status, comorbidities, and his/her personal preference. If patients experienced recurrence, future treatment recommendations were made in multidisciplinary tumor board

TABLE 1. Patients and Disease Characteristics

n (%) Overall (n = 53) Age (y) Median < 65 Z65 Sex Male Female KPS Median (range) Location Head Body/tail Surgery Whipple Total pancreatectomy Distal pancreatectomy Margins R0 R1 R2 Pathologic tumor stage pT1 pT2 pT3 pT4 Nodal status Negative Positive Stage Ia Ib IIa IIb III

CT-CRT (n = 34)

CT (n = 19)

P

62 31 (58.5) 22 (41.5)

58 24 (70.6) 10 (29.4)

70 7 (36.8) 12 (63.2)

0.0168

28 (52.8) 25 (47.2)

17 (50) 17 (50)

11 (57.9) 8 (42.1)

0.5809

90 (50-100)

90 (80-100)

80 (50-90)

50 (94.3) 3 (5.6)

31 (91.2) 3 (8.8)

19 (100) 0

0.545w

47 (88.7) 2 (3.8) 4 (7.6)

30 (88.2) 1 (2.9) 3 (8.8)

17 (89.5) 1 (5.3) 1 (5.3)

0.8266

43 (81.1) 9 (16.9) 1 (1.9)

25 (73.5) 8 (23.5) 1 (2.9)

18 (94.7) 1 (5.3) 0 (0)

0.1629

7 12 33 1

6 6 22 0

1 6 11 1

(5.3) (31.6) (57.9) (5.3)

0.2270

(13.2) (22.6) (62.3) (1.9)

(17.7) (17.7) (64.7) (0)

0.0018*

< 0.001

5 (9.4) 48 (90.6)

4 (11.8) 30 (88.2)

1 (5.3) 18 (94.7)

0.4374

1 1 3 47 1

1 1 2 30 0

0 0 1 17 1

0.5717

(1.9) (1.9) (5.6) (88.7) (1.8)

(2.9) (2.9) (5.9) (88.2) (0)

(0) (0) (5.3) (89.5) (5.3)

*t test to compare average age; w2 for other variables. wFisher exact test P-value. KPS indicates Karnofsky performance status.

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Combined Gemcitabine and Chemoradiation Versus Gemcitabine Alone

after carefully considering their clinical and performance status, and patients’ preferences. All patients with recurrence were offered best supportive care, enrollment in clinical trials, or second-line systemic therapy. Radiation therapy was considered for patients with local recurrence only who have not previously received CRT.

Study Variables and Endpoints Patients and disease variables included age at diagnosis, sex, histologic type, pathologic TNM stage, Karnofsky performance status (KPS) at the start of adjuvant treatment, and margin status at resection. Resection margin status was classified as previously described22: R0 (absence of margin involvement on histopathology), R1 (microscopic involvement of resection margin), and R2 (macroscopic involvement of resection margin). Study endpoints included the DFS and OS. The DFS was defined as time from surgery to recurrence, death of any cause, or last follow-up. The OS was defined as time from surgery to death of any cause or last follow-up. Patients alive at last follow-up or October 8, 2010 were regarded as censored.

Statistical Analysis Patient characteristics were summarized by treatment group and compared using t test or w2 test as appropriate. Kaplan-Meier method was used to describe the median DFS and OS. For the overall sample, Cox proportional hazards model was used to compare the DFS and OS between CT-CRT and CT groups after adjusting for age, status of resection margins, and lymph node involvement. We also performed subgroup analyses by using Cox models adjusting for the same set of covariates except the grouping variable. A P-value of r0.05 was considered statistically significant. Data were analyzed using the Statistical Analysis Software (SAS 9.3). Kaplan-Meier plots were drawn using R software (2.14.0).

RESULTS Patients Characteristics Fifty-three patients were included in the study with the median follow-up of 19.1 months (range, 4.5 to 68.8 mo). Table 1 describes the patients’ characteristics. Forty-six patients had ductal adenocarcinoma, 2 mucinous ductal adenocarcinoma, 3 ductal adenocarcinoma with foci of intraductal papillary mucinous neoplasia, 1 adenocarcinoma with sarcomatoid features, and 1 had adenosquamous carcinoma. Median age at time of surgery was 62 years (range, 42 to 85 y); patients in the CT group were older than those in the CT-CRT group (Student t test P-value = 0.0018). Patients in the CT-CRT had a higher KPS than the CT group (median, 90% vs. 80%; Student t test < 0.001). Patients receiving CT-CRT were more likely to have positive (R1/R2) resection margins (26% vs. 5%; Fisher exact P-value = 0.076). The distribution of larger pathologic tumor stage (T3/T4) (65% in CTCRT group vs. 63% in CT group; P-value = 0.910) and positive lymph node status (88% in CT-CRT group vs. 95% in CT group; P-value = 0.437) were similar between groups.

Efficacy During the course of follow-up, 42 patients experienced disease recurrence (25 in CT-CRT vs. 17 in CT): 46% metastatic, 32% local, and 22% with metastatic and local recurrence. In the CT group, 57% of recurrences were local, 21% were metastatic, and 21% were both local and metastatic. In CT-CRT group, 17% of recurrences were local, 61% were metastatic, and 22% were both local and metastatic. Patients r


FIGURE 1. Comparison of survival outcomes between CT-CRT and CT groups using Kaplan-Meier curves (P-values from Cox proportional hazards models). DFS indicates disease-free survival; OS, overall survival.

receiving CT-CRT were less likely to recur locally compared with those receiving CT alone (28% vs. 69%; P-value = 0.007). In the overall sample, median DFS in the CT-CRT group was 13.7 months versus 11.1 months in the CT group, and the median OS was 20.4 months in the CT-CRT group versus 16.6 months with CT alone (Fig. 1). The CT-CRT group demonstrated a higher DFS (hazard ratio, 2.88; 95% CI, 1.37-6.06) and OS (hazard ratio, 2.42; 95% CI, 1.17-5.01) than the CT group after adjusting for age, status of resection margins, and lymph node involvement (Table 2). Among younger patients (age below 65 y), DFS and OS were significantly higher in the CT-CRT group (median DFS 13.2 vs. 10.1 mo with CT alone, and median OS 19.1 vs. 13.5 mo with CT alone). Numerical improvement in median DFS and median OS with CT-CRT were also observed among older patients (age 65 y and above). Patients with T3/T4 tumors derived increased benefit from CT-CRT compared with CT alone (median DFS 13.2 vs. 9.0 mo and median OS 20.4 vs. 15.4 mo). Similarly, patients with lymph node involvement, which comprised 91% of the study population, had improved outcomes with CT-CRT versus CT (median DFS 13.7 vs. 11.0 mo and median OS 20.4 vs. 16.6 mo, respectively). Improvement in DFS (median, 14.3 vs. 11.1 mo) and OS (median, 21.7 vs. 16.7 mo) with CT-CRT was also observed among patients with negative resection margins. Limited number of patients with positive resection margins (n = 10), or negative lymph node status (n = 5), preclude definitive conclusions in these subgroups.

DISCUSSION This retrospective study was conducted to compare survival outcomes of patients undergoing adjuvant therapy with gemcitabine versus gemcitabine plus gemcitabine-based CRT following resection of pancreatic adenocarcinoma. Earlier studies assessing the role of CRT in the adjuvant treatment of pancreatic cancer have primarily utilized 5-FU as the choice of chemotherapeutic agent and radiosensitizer. With the www.amjclinicaloncology.com |

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TABLE 2. Comparison of Survival Outcomes of CT-CRT (n = 34) Versus CT (n = 19) Groups

Median DFS (mo) Overall sample Age (y) < 65 (n = 31) Z65 (n = 22) Pathologic tumor stage T1/T2 (n = 19) T3/T4w (n = 34) Resection margins Negative (n = 43) Nodal status Positive (n = 48)

Median OS (mo)

CT-CRT

CT

HR (P)*

CT-CRT

CT

HR (P)*

13.7

11.1

2.88 (0.005)

20.4

16.6

2.42 (0.017)

13.2 17.8

10.1 13.9

4.91 (0.004) 1.85 (0.210)

19.1 22.51

13.5 16.7

2.97 (0.032) 1.81 (0.259)

14.0 13.2

11.0 9.0

1.56 (0.462) 4.91 (0.002)

18.3 20.4

17.7 15.4

1.28 (0.688) 4.15 (0.003)

14.3

11.1

2.56 (0.015)

21.7

16.7

2.13 (0.040)

13.7

11.0

3.58 (0.002)

20.4

16.6

2.45 (0.021)

*HR and P-value calculated by Cox proportional hazards models. wT4 (n = 1). DFS indicates disease-free survival; HR, hazards ratio; OS, overall survival.

increasing use of the gemcitabine in the adjuvant setting, studies are warranted to evaluate outcomes of patients receiving gemcitabine-based CRT. The phase II EORTC 40013-22012 trial demonstrated that the combination of gemcitabine-based CT and CRT (gemcitabine 300 mg/m2 weekly in combination with radiotherapy) was well tolerated and it improved the odds of local control, albeit with no OS benefit (24 mo in each group).10 Radiosensitizing doses of gemcitabine between 50 mg/m2 twice weekly to 1000 mg/m2 weekly have been used with radiotherapy, with overall good tolerability. The dose of 600 mg/m2 weekly used with radiotherapy in our institution comes from data previously determined to be safe and effective in locally advanced pancreatic cancer patients.19,20 The current retrospective analysis reports superior DFS and OS outcomes with gemcitabine plus gemcitabine-based CRT compared with gemcitabine CT alone in the adjuvant treatment of resected pancreatic adenocarcinoma patients. Superior outcomes with CT-CRT may, at least partially, be attributed to lower local recurrence (28% vs. 69%; P-value = 0.007). The benefit of CT-CRT was seen irrespective of age, but was significant in patients younger than 65 years, those with larger (T3 or T4) tumors, and positive lymph node involvement (N1 disease). Better outcomes with CT-CRT versus CT among patients with T3/T4 and N1 disease may be due to improved local tumor control in patients with more advanced stage who have a higher risk of local recurrence. These results are consistent with the previous results of CRT being more important for patients with higher risk of local recurrence.13,14,16 Herman et al13 have previously reported improvement in survival with CRT versus surgery alone among patients with positive resection margins, involvement of lymph nodes, and larger (> 3 cm) tumor size. Corsini et al16 similarly reported improvement in OS with CRT among patients with advanced (T3) tumor stage, lymph node involvement, and higher tumor grade compared with surgery alone. Merchant et al,14 in a large multicenter retrospective analysis, demonstrated that the improvement in OS with adjuvant CRT compared with surgery is observed irrespective of the status of resection margins, but is specific to patients with positive lymph nodes status. These earlier studies compared adjuvant CRT with surgery alone and utilized 5-FU-based CRT. Nonetheless, findings consistently suggest that adjuvant CRT may be particularly useful for patients at risk of microscopic residual disease and local recurrence. A recent report using weekly low-dose (100 mg/m2) gemcitabine-

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based CRT followed by gemcitabine CT for adjuvant pancreatic cancer noted high (> 80%) rates of local control, but no survival improvement (OS 22.5 mo) compared with historic controls.23 Although the current study has the advantage that all patients were treated uniformly at a single institution with appropriate follow-up, a relatively small number of patients might have led to a lower power to detect statistical differences. Secondly, the retrospective design of the study makes it difficult to eliminate bias; for instance, patients receiving CT-CRT in the current study were relatively younger, had higher KPS, and possibly fewer comorbid conditions, which may have affected outcomes with the combined therapy. It is also possible that the patients referred for CT-CRT had a higher risk of recurrence clinically. Thirdly, toxicities in either treatment group were not able to be captured in a retrospective analysis, but these were addressed in prospective studies such as Eastern Cooperative Oncology Group (ECOG) 4201.20 Nonetheless, given these limitations, our results warrant prospective randomized studies using CT-CRT versus CT to confirm these findings. The ongoing randomized RTOG 0848 study using gemcitabine with or without fluoropyrimidine-based CRT will help elucidate the contribution of CRT, albeit not gemcitabine based, for the adjuvant treatment of pancreatic cancer. In conclusion, our data demonstrate improvement in DFS and OS with adjuvant gemcitabine and gemcitabine-based CRT compared with gemcitabine alone after surgical resection of pancreatic adenocarcinoma, particularly for younger patients, and for those at higher risk for local recurrence.

REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. 2. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362: 1605–1617. 3. Li D, Xie K, Wolff R, et al. Pancreatic cancer. Lancet. 2004; 363:1049–1057. 4. Sperti C, Pasquali C, Piccoli A, et al. Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg. 1997;21: 195–200. 5. Griffin JF, Smalley SR, Jewell W, et al. Patterns of failure after curative resection of pancreatic carcinoma. Cancer. 1990;66:56–61. 6. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120:899–903. r





7. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001;358:1576–1585. 8. 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. 2007;297:267–277. 9. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473–1481. 10. Van Laethem JL, Hammel P, Mornex F, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol. 2010;28:4450–4456. 11. 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. 1999;230:776–782. 12. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200–1210. 13. Herman JM, Swartz MJ, Hsu CC, et al. Analysis of fluorouracilbased adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol. 2008;26:3503–3510. 14. Merchant NB, Rymer J, Koehler EA, et al. Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: who really benefits? J Am Coll Surg. 2009;208:829–838. 15. Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-

r


16.

17.

18.

19.

20.

21.

22. 23.

Combined Gemcitabine and Chemoradiation Versus Gemcitabine Alone

based, linked database analysis of 396 patients. Ann Surg. 2003;237:74–85. Corsini MM, Miller RC, Haddock MG, et al. Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975-2005). J Clin Oncol. 2008; 26:3511–3516. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs. gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073–1081. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs. gemcitabine chemotherapy before and after fluorouracilbased chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299: 1019–1026. Cardenes HR, Moore AM, Johnson CS, et al. A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study. Am J Clin Oncol. 2011;34:460–465. Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group Trial. J Clin Oncol. 2011;29:4105–4112. Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–2413. Chang DK, Johns AL, Merrett ND, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol. 2009;27:2855–2862. Mattiucci GC, Ippolito E, D’Agostino GR, et al. Long-term analysis of gemcitabine-based chemoradiation after surgical resection for pancreatic adenocarcinoma. Ann Surg Oncol. 2013; 20:423–429.

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Gemcitabine plus cisplatin versus gemcitabine alone in the treatment of pancreatic cancer: a meta-analysis.

Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: real-world analysis of Korean national database.

Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer.

Quality-adjusted survival with combination nab-paclitaxel + gemcitabine vs gemcitabine alone in metastatic pancreatic cancer: a Q-TWiST analysis.

III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

Patterns of Failure for Lymph Node-Positive Resected Pancreatic Adenocarcinoma After Adjuvant Radiotherapy or Gemcitabine-based Chemotherapy Alone.

Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia.

A Cost-Effectiveness Analysis of Gemcitabine plus Cisplatin Versus Gemcitabine Alone for Treatment of Advanced Biliary Tract Cancer in Japan.

A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea.

Comparison of gemcitabine combined with targeted agent therapy versus gemcitabine monotherapy in the management of advanced pancreatic cancer.

Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer.

Adjuvant temozolomide-based chemoradiotherapy versus radiotherapy alone in patients with WHO III astrocytoma: The Mainz experience.

Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer.

Risk factors for vertebral compression fractures in preoperative chemoradiotherapy with gemcitabine for pancreatic cancer.

Postoperative Adjuvant Therapy for Resectable Pancreatic Cancer With Gemcitabine and Adoptive Immunotherapy.

Mass spectrometry-based metabolic profiling of gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells.

Transport properties of pancreatic cancer describe gemcitabine delivery and response.

metastatic pancreatic cancer.

SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial.

Treatment outcomes of gemcitabine alone versus gemcitabine plus platinum for advanced biliary tract cancer: a Korean Cancer Study Group retrospective analysis.

Histopathological effects of preoperative chemoradiotherapy for pancreatic cancer: an analysis for the impact of radiation and gemcitabine doses.

Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme.

Genomic Testing for Gemcitabine-Based Treatment of Pancreatic Cancer.

Albumin-bound paclitaxel plus gemcitabine in pancreatic cancer.