Sunitinib Plus Paclitaxel in Patients with Advanced Esophageal Cancer: A Phase II Study from the Hoosier Oncology Groupe 760 Journal of Thoracic Oncology • Volume 7, Number 4, April 2012 BRIEF REPoRT Abstract: The combination of sunitinb (37.5 mg orally daily) + pacli- taxel (90 mg/m2 intravenously on days 1, 8, 15 every 4 weeks) was examined in patients with advanced esophageal or gastroesophageal junction cancer, and progression-free survival (PFS) was compared to that of historical controls. The end points included response rate, overall survival, and toxicities. Twenty-eight patients were enrolled at six centers. Median age was 59.5 years. The 24-week PFS rate was 25% (90% confidence interval [CI], 12–42%). Three (11%) of 23 evaluable patients had a response (1 complete response and 2 partial response) (90% CI, 3−25%). Median overall survival was 228 days (90% CI, 140–283 days). Grade 3/4 toxicities included leukopenia/ neutropenia (25%), anemia (18%), fatigue (11%), and hemorrhage (11%). There were four grade 5 toxicities including upper gastroin- testinal hemorrhage (n = 2), gastrointestinal/esophageal fistula (n = 1), and unexplained death (n = 1). In our study, we found that suni- tinib + paclitaxel in patients with advanced esophageal or gastroe- sophageal junction cancer had a 24-week PFS no better than the PFS of historical controls. The combination also had a high rate of serious toxicities and will not be pursued. Key Words: Sunitinib, Paclitaxel, Esophageal, Gastroesophageal junction, Angiogenesis, Tyrosine kinase inhibitors. (J Thorac Oncol. 2012;7: 760–763) Despite advances in staging and treatment for patients with esophageal cancer, the relative 5-year survival rate for all stages remained at an estimated 19% between 1999 and 2005.1 Response rates (RRs) to classic chemotherapeutic regimens range from 15 to 48% and are typically short in duration.2,3 Angiogenesis is a critical factor in tumor growth and meta- static spread. In patients with esophageal cancer, 30 to 60% of them have overexpression of vascular endothelial growth fac- tor (VEGF), which has been correlated with greater microves- sel density, advanced disease, and poor prognosis.4 Inhibition of angiogenesis with compounds like sunitinib maleate, a well-tolerated oral inhibitor of tyrosine kinase with activity against VEGF receptors (types 1–3), platelet-derived growth factor a and platelet-derived growth factor , c-kit, and fetal liver tyrosine kinase receptor 3,5 is a novel therapeutic approach that has demonstrated activity in a variety of malig- nancies. In preclinical studies, gastric and esophageal cancer cell lines overexpressed VEGF, proliferated in the presence of recombinant VEGF, and were inhibited in a dose-dependent manner by sunitinib.6 Sunitinib has been studied for locally advanced esophageal cancer7 and studies in patients with relapsed/refractory metastatic disease are ongoing. on the basis of this preclinical and clinical work, the known overex- pression of VEGF in esophageal cancer, the hypothesized syn- ergy between VEGF inhibition, and the antiangiogenic effects of taxane therapy,4 we conducted this multi-institutional phase II study to evaluate the efficacy of sunitinib + paclitaxel in patients with advanced esophageal or gastroesophageal (GE) junction carcinoma. PATIENTS AND METHODS Patients enrolled on study included adults with histo- logically proven recurrent or metastatic esophageal or GE junction squamous cell or adenocarcinoma, who had received less than two chemotherapy regimens for locally advanced or metastatic disease, and had measurable and/or evaluable dis- ease as per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. All patients had an Eastern Cooperative oncology Group performance status of 0 to 2. Key exclusion criteria included prior exposure to an epidermal growth factor receptor inhibitor or any other antiangiogenic agents. Each treatment cycle was defined as 28 days and included paclitaxel 90 mg/m2 intravenous infusion over 60 minutes on *Indiana University Simon Cancer Center, Indianapolis, Indiana; †Indiana University Medical Center, Indianapolis, Indiana; ‡South Carolina oncology Associates PA, Columbia, South Carolina; §Hoosier oncology Group,  Indianapolis,  Indiana;  •Medical  Consultants,  PC,  Muncie,  Indiana; ¶Northern Indiana Cancer Research Consortium, South Bend, Indiana; #Community Hospital, Munster, Indiana; **Cancer Care Center of Southern Indiana, Bloomington, Indiana; ††Medical and Surgical Specialists, LLC, Galesburg, Illinois; and ‡‡Indiana University Division of Biostatistics Indianapolis, Indiana. Disclosure: This work was supported by Pfizer. Address for correspondence: Jordan Schmitt, MD, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202. E-mail: jmw8@iupui.edu Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0704-0760 Sunitinib Plus Paclitaxel in Patients with Advanced Esophageal Cancer A Phase II Study from the Hoosier Oncology Group Jordan M. Schmitt, MD,*† Scott R. Sommers, MD,‡ William Fisher, MD,§• Rafat Ansari, MD,§¶ Erwin Robin, MD,§# Karuna Koneru, MD,§** John McClean, MD,§†† Ziyue Liu, PhD,‡‡ Yan Tong, MS,‡‡ and Nasser Hanna, MD*†§ 761Copyright © 2012 by the International Association for the Study of Lung Cancer Journal of Thoracic Oncology • Volume 7, Number 4, April 2012 Sunitinib Plus Paclitaxel in Esophageal Cancer Patients days 1, 8, and 15 and sunitinib maleate 37.5 mg orally daily.8 Participants were scheduled to receive four cycles of the com- bination therapy. Treatment was discontinued upon disease progression or unacceptable toxicity. After four cycles, pacli- taxel was discontinued and each patient was allowed to con- tinue on sunitinib maleate for two more cycles provided he/ she did not have disease progression, intolerable side effects, or adverse reactions. Patients were evaluated at the beginning of each treat- ment cycle. Before odd-numbered cycles, a disease evalu- ation per RECIST criteria was performed. At the end of the study, patients, including those who discontinued pro- tocol therapy early, were evaluated 30 days after the last dose. Patients were then serially followed up for duration of response and for survival. All toxicities were measured according to the National Cancer Institute Common Toxicity Criteria version 3.0. The primary end point was the rate of nonprogressive disease at 6 months. Nonprogressive disease was defined as a complete response, partial response, or stable disease. A pre- determined improvement from 25 to 50% in nonprogressive disease rate was deemed reasonable for the proposed regimen as two prior phase II trials of paclitaxel therapy alone dem- onstrated a median duration of response ranging from 119 to 172 days9,10 and we anticipated prolonged duration of response with the addition of antiangiogenic therapy. With 26 subjects, the study had more than 80% power based on one-sided test with error rate controlled at 5%. RESULTS Twenty-eight patients were enrolled at six participating centers. Patient demographics and disease characteristics are summarized in Table 1. over 80% of the participants were men, with a median age at enrollment of 59.5 years (age range of 40–84 years). All tumors were located in the esophagus (22/28 or GE junction [6/28]). Ninety-three percent of the tumors (n = 26) were adenocarcinoma and 7% (n = 2) were squamous cell carcinoma. Nine of 28 patients had received prior chemotherapy. The median follow-up was 222 days, with a range of 15 to 629 days. Six patients (22%) completed less than one cycle of therapy. Seven patients (25%) finished all four cycles and went on to receive maintenance treatment (median length of maintenance treatment was 54 days). At the end of the study, 23 patients (82%) were evaluable. Five patients were not evaluable owing to no postbase- line assessment. Reasons for coming off study included death caused by progressive disease (n = 20 [71%]), death caused by other reasons (n = 2 [7%]), and refusal to fol- low-up (n = 1 [4%]). Among the 28 patients, 10 (36%) had dose modification and 16 (57%) had dose delay of sunitinib. Fifteen (54%) had dose modification of paclitaxel, and 14 (50%) had dose delay of paclitaxel. Toxicity data for all patients are summarized in Tables 2 through 4. The most common toxicities reported included fatigue, anemia, and leukopenia/neutropenia. Grade 3 and grade 4 toxicities included leukopenia/neutropenia (25%), anemia (18%), fatigue (11%), and hemorrhage (11%). There were four grade 5 toxicities including two deaths caused by upper gastrointestinal hemorrhage and one caused by gastro- intestinal/esophageal fistula (Table 4). Three of the four events were considered treatment-related deaths. Sunitinib-related toxicities including diarrhea, rash, hemorrhage, thrombosis, and hypertension were also observed. The 24-week progression-free survival (PFS) rate was 25% (7/28) (90% CI, 12–42%) for the combined regimen. of the 23 evaluable patients, 3 (11%) had a measurable response by RECIST criteria (90% CI, 3−25%). A complete response was observed in one patient and partial response observed in two patients. For the three patients who responded, the dura- tions of response were 29, 56, and 72 days, respectively. For the 28 intention-to-treat patients, the 1-year overall survival (oS) rate was 20% (90% CI, 9−34%). Median oS was 228 days (90% CI, 140–283 days). The median PFS was 112 days (90% CI, 54–150). TABLE 1. Demographics (Intention to Treat n = 28) Characteristics Category/ Statistics n/Value % Sex Female 5 18 Male 23 82 Race Caucasian 27 96 African American 1 4 Ethnicity Non-Hispanic 27 96 Not reported 1 4 Age Median 59.5 yr Range 40–84 yr ECoG PS 0 15 54 1 11 39 2 2 7 Tumor site Esophagus 22 79 Gastroesophageal junction 6 21 Histology Adenocarcinoma 26 93 Squamous cell carcinoma 2 7 Prior treatment Yes 11 (9 with prior chemo) 39 No 17 61 ECoG PS, Eastern Cooperative oncology Group performance status. TABLE 2. Selected Hematologic Toxicities Irrespective of Causality Attributed (n = 28) Grade 3 Grade 4 Grade 3/4 Leukopenia/neutropenia 6 21% 1 4% 7 25% Anemia 3 11% 2 7% 5 18% Thrombocytopenia 1 4% 0 — 1 4% Febrile neutropenia (fever without clinically or microbiologically documented infection) (ANC <1.0, fever ≥38.5°C) 1 4% 0 — 1 4% ANC, absolute neutrophil count. 762 Copyright © 2012 by the International Association for the Study of Lung Cancer Schmitt et al. Journal of Thoracic Oncology • Volume 7, Number 4, April 2012 DISCUSSION The results of this multi-institutional phase II trial are, to our knowledge, the first reported study of sunitinib in advanced esophageal/GE junction cancer. This combination did not meet our predetermined goal of improved nonprogres- sive disease from 25 to 50% at 24 weeks. The majority of the patients completed less than two cycles and toxicities were significant with at least three treatment-related deaths. Paclitaxel alone as first-line therapy for metastatic disease has demonstrated an RR ranging from 15 to 32% in two prior phase II studies of patients with advanced esophageal cancer.9,10 This is inferior to RRs reported with use of regimens such as epirubicin + cisplatin + fluorouracil and epirubicin + oxaliplatin + capecitabine or paclitaxel containing combination regimens that have yielded higher RRs (40–54%) at the expense of higher toxicity rates, including docetaxel + cisplatin + 5-fluorouracil,11 and oxaliplatin + paclitaxel.12 our study failed to show similar RRs with a reported overall RR of only 11% and a 24-week PFS rate estimated at 25% with increased toxicities. VEGF inhibitors have been studied in patients with advanced esophageal cancer. In a phase II study combining irino- tecan, cisplatin and bevacizumab,13 a 65% overall RR was noted with a median time to progression of 8.3 months and a median survival of 12.3 months. A second study looking at docetaxel + cisplatin + 5-FU + bevacizumab demonstrated an improvement in PFS at 6 months from a historic control of 43% for docetaxel + cisplatin + fluorouracil alone to 79% with the addition of beva- cizumab.14 Grade 3 or 4 toxicities in both of these studies were fewer than appreciated in our study. Another study evaluating bevacizumab + cisplatin and capecitabine in advanced gastric cancer reported fewer serious toxicities than observed in our study, and although this study showed significant improvements in the overall RR and PFS, it failed to meet its primary end point of improved oS (10.1 versus 12.1 months [p = 0.1]).15 Sunitinib has been evaluated in esophageal cancer in the adjuvant setting, looking at neoadjuvant irinotecan + cisplatin combined with radiation followed by esophagectomy followed by adjuvant sunitinib therapy. In this phase II study, 70 patients were enrolled; following esophagectomy only 20 patients were fit enough to receive sunitinib therapy. Median oS in this locally advanced population was 26 months with a 2-year oS of around 50%. Specific toxicity data are not yet available.7 Currently, there is an ongoing phase II study comparing suni- tinib single agent to placebo therapy in relapsed or refractory esophageal or GE junction carcinoma (ClincalTrials.gov ID #NCT00702884). The sunitinib-specific toxicities observed in our study were similar to those previously reported; however, the increased incidence of grade 3/4/5 hemorrhage was con- cerning with this combination and was not previously reported in therapy with taxanes alone, combination regimens contain- ing taxanes, or with other VEGF inhibitors. In conclusion, our study of the combination of sunitinib + paclitaxel in advanced esophageal and GE junction cancer was negative as it did not meet our primary end point of 50% PFS at 24 weeks, and with a high rate of serious toxicities, including four grade-5 events, this combination will not be pursued further. REFERENCES 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. 2. Shah MA, Schwartz GK. Treatment of metastatic esophagus and gastric cancer. Semin Oncol 2004;31:574–587. TABLE 3. Selected Nonhematologic Toxicities Irrespective of Causality Attributed (n = 28) Grade 3 Grade 4 Grade 3/4 Grade 5 Hemorrhage/bleeding 1 4% 2 7% 3 11% 2 7% Thrombosis/thrombus/embolism 0 — 2 7% 2 7% 0 — Fistula, GI/esophagus 1 4% 0 — 1 4% 1 4% Rash/dermatologic complaints 0 — 1 4% 1 4% 0 — Dyspnea 0 — 1 4% 1 4% 0 — Neuropathy: motor 1 4% 0 — 1 4% 0 — Allergic reaction/hypersensitivity (including drug fever) 2 7% 0 — 2 7% 0 — Pulmonary (effusion, pneumonitis NoS) 2 7% 1 4% 3 11% 0 — Fatigue (asthenia, lethargy, and malaise) 3 11% 0 — 3 11% 0 — Diarrhea 2 7% 0 — 2 7% 0 — Dysphagia 2 7% 0 — 2 7% 0 — Hyponatremia 2 7% 0 — 2 7% 0 — Hyperglycemia 2 7% 0 — 2 7% 0 — Death NoS 0 — 0 0% 0 — 1 4% GI, gastrointestinal; NoS, not otherwise specified. TABLE 4. Grade 5 Toxicity and Treatment-Related Death Evaluable Population (n = 23) N % Cycle Consequence Attribution Hemorrhage, GI/ upper GI NoS 1 4 Maintenance Death Possible Fistula, GI/ esophagus 1 4 1 Death Unrelated Death NoS 1 4 2 Death Probably Hemorrhage, GI/ stomach 1 4 2 Death Possible GI, gastrointestinal. 763Copyright © 2012 by the International Association for the Study of Lung Cancer Journal of Thoracic Oncology • Volume 7, Number 4, April 2012 Sunitinib Plus Paclitaxel in Esophageal Cancer Patients 3. Cunningham D, Starling N, Rao S, et al.; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36–46. 4. Kleespies A, Guba M, Jauch KW, Bruns CJ. Vascular endothelial growth factor in esophageal cancer. J Surg Oncol 2004;87:95–104. 5. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. 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Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol 2007;18:898–902. 11. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006;24:4991–4997. 12. Kaechele V, Moehler M, Lutz MP, et al. A phase I/II study of oxaliplatin and paclitaxel in patients with non-resectable cancer of the oesophagus and adenocarcinoma of the gastro-oesophageal junction: a study of the Arbeitsgemeinschaft Internistische onkologie. Cancer Chemother Pharmacol 2010;66:191–195. 13. Shah MA, Ramanathan RK, Ilson DH, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006;24:5201–5206. 14. Shah MA, Jhawer M, Ilson DH, et al. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol 2011;29:868–874. 15. ohtsu A, Shah MA, Van Cutsem E , et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011;29:3968–3976. Sunitinib Plus Paclitaxel in Patients with Advanced Esophageal Cancer: A Phase II Study from the Hoosier Oncology Group PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES