Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma

Joseph M Herman, Daniel T Chang, Karyn A Goodman, Avani S Dholakia, Siva P Raman, Amy Hacker-Prietz, Christine A Iacobuzio-Donahue, Mary E Griffith, Timothy M Pawlik, Jonathan S Pai, Eileen O'Reilly, George A Fisher, Aaron T Wild, Lauren M Rosati, Lei Zheng, Christopher L Wolfgang, Daniel A Laheru, Laurie A Columbo, Elizabeth A Sugar, Albert C Koong, Joseph M Herman, Daniel T Chang, Karyn A Goodman, Avani S Dholakia, Siva P Raman, Amy Hacker-Prietz, Christine A Iacobuzio-Donahue, Mary E Griffith, Timothy M Pawlik, Jonathan S Pai, Eileen O'Reilly, George A Fisher, Aaron T Wild, Lauren M Rosati, Lei Zheng, Christopher L Wolfgang, Daniel A Laheru, Laurie A Columbo, Elizabeth A Sugar, Albert C Koong

Abstract

Background: This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC).

Methods: A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2)) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT.

Results: The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥ 2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections.

Conclusions: Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy.

Keywords: chemoradiation; locally advanced; pancreatic cancer; positron emission tomography; stereotactic body radiotherapy; unresectable.

© 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Figures

Figure 1
Figure 1
Consolidated Standards Of Reporting Trials (CONSORT) flow diagram showing enrollment and outcomes is shown.
Figure 2
Figure 2
Kaplan-Meier estimates of the survival function for (A) overall survival and (B) progression-free survival are shown. The 95% confidence intervals are included as dotted lines.

References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.
    1. Tempero MA, Arnoletti JP, Behrman SW. National Comprehensive Cancer Networks. Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2012;10:703–713. et al;
    1. Herman JM, Wild AT, Wang H. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013;31:886–894. et al.
    1. Loehrer PJ, Sr, Feng Y, Cardenes H. 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. et al.
    1. Ben-Josef E, Schipper M, Francis IR. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2012;84:1166–1171. et al.
    1. Treatment of locally unresectable carcinoma of the pancreas. comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst. 1988;80:751–755.
    1. Huguet F, Andre T, Hammel P. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol. 2007;25:326–331. et al.
    1. Chauffert B, Mornex F, Bonnetain F. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008;19:1592–1599. et al.
    1. Huguet F, Hammel P, Vernerey D. Impact of chemoradiotherapy (CRT) on local control and time without treatment in patients with locally advanced pancreatic cancer (LAPC) included in the international phase III LAP 07 study [abstract] J Clin Oncol. 2014;32 , et al. (suppl 5):Page. Abstract 4001.
    1. Timmerman RD, Kavanagh BD, Cho LC, Papiez L, Xing L. Stereotactic body radiation therapy in multiple organ sites. J Clin Oncol. 2007;25:947–952.
    1. Koong Le ho ACQT. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;58:1017–1021. et al.
    1. Koong AC, Christofferson E, Le QT. Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2005;63:320–323. et al.
    1. Schellenberg D, Goodman KA, Lee F. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2008;72:678–686. et al.
    1. Chang DT, Schellenberg D, Shen J. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer. 2009;115:665–672. et al.
    1. Schellenberg D, Kim J, Christman-Skieller C. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2011;81:181–188. et al.
    1. Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol. 2009;16:1727–1733.
    1. Khashab MA, Kim KJ, Tryggestad EJ. Comparative analysis of traditional and coiled fiducials implanted during EUS for pancreatic cancer patients receiving stereotactic body radiation therapy. Gastrointest Endosc. 2012;76:962–971. et al.
    1. Murphy JD, Christman-Skieller C, Kim J, Dieterich S, Chang DT, Koong AC. A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys. 2010;78:1420–1426.
    1. Aaronson NK, Ahmedzai S, Bergman B. The European Organization for Research and Treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–376. et al.
    1. Fitzsimmons D, Johnson CD, George S. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life. Eur J Cancer. 1999;35:939–941. et al.
    1. Eisenhauer EA, Therasse P, Bogaerts J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. et al.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10.
    1. Hoyer M, Roed H, Sengelov L. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol. 2005;76:48–53. et al.
    1. Polistina F, Costantin G, Casamassima F. Unresectable locally advanced pancreatic cancer: a multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration. Ann Surg Oncol. 2010;17:2092–2101. et al.
    1. Mahadevan A, Jain S, Goldstein M. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2010;78:735–742. et al.
    1. Lominska CE, Unger K, Nasr NM, Haddad N, Gagnon G. Stereotactic body radiation therapy for reirradiation of localized adenocarcinoma of the pancreas. Radiat Oncol. 2012;7:74.
    1. Tozzi A, Comito T, Alongi F. SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience. Radiat Oncol. 2013;8:148. et al.
    1. Gurka MK, Collins SP, Slack R. Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety. Radiat Oncol. 2013;8:44. et al.
    1. Chuong MD, Springett GM, Freilich JM. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys. 2013;86:516–522. et al.
    1. Shin SH, Kim SC, Hong SM. Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. Pancreas. 2013;42:216–222. et al.
    1. McCarthy DM, Brat DJ, Wilentz RE. Pancreatic intraepithelial neoplasia and infiltrating adenocarcinoma: analysis of progression and recurrence by DPC4 immunohistochemical labeling. Hum Pathol. 2001;32:638–642. et al.
    1. Iacobuzio-Donahue CA, Fu B, Yachida S. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–1813. et al.

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