Pre-operative chemoradiation followed by post-operative adjuvant therapy with tetrathiomolybdate, a novel copper chelator, for patients with resectable esophageal cancer
Tóm tắt
Introduction This phase II trial investigated chemoradiation followed by surgery and 2 years of adjuvant tetrathiomolybdate (TM) for resectable esophageal cancer. Methods Patients with resectable, locally advanced esophageal cancer received neoadjuvant cisplatin 60 mg/m2 (days 1 and 22), paclitaxel 60 mg/m2 (days 1, 8, 15, and 22), and 45 Gy hyperfractionated radiotherapy for 3 weeks followed by transhiatal esophagectomy. TM 20 mg PO QD was started 4 weeks post-op, and continued for 2 years to maintain the ceruloplasmin level between 5 and 15 mg/dl. Results Sixty-nine patients were enrolled (median age, 60 years). Sixty-six patients underwent surgery and 61 patients had a complete resection. Histologic complete response rate was 10 %. Twenty-one patients did not receive TM (metastases noted in the peri-operative period, prolonged post-operative recovery time, or patient refusal). Forty-eight patients started TM; 14 completed 24 months of treatment, 11 completed 10–18 months, 15 completed 2–8 months, and 8 completed ≤1 month. Twenty-seven patients had disease recurrence. With a median follow-up of 55 months, 25 patients were alive without disease, 1 was alive with disease, and 43 have died. Three-year recurrence-free survival was 44 % (95 % CI, 32–55 %) and the three-year overall survival was 45 % (95 % CI 33–56 %). Conclusions TM is an antiangiogenic agent that is well tolerated in the adjuvant setting. Disease-free survival and overall survival are promising when compared to historical controls treated at our institution with a similar regimen that did not include TM. However, the challenges associated with prolonged administration limit further investigation.
Tài liệu tham khảo
Jemal A, Siegel R, Xu J et al (2010) Cancer statistics. CA Cancer J Clin 60:277–300
Urba SG, Orringer MB, Ianettonni M et al (2003) Concurrent cisplatin, paclitaxel and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Cancer 98:2177–2183
Gaast AV, van Hagen P, Hulshof M, et al. (2010) Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: Results from a multicenter randomized phase III study. J Clin Oncol 28:15s, (Suppl; abstr 4004)
Sharma R, Yang GY, Nava HR, et al. (2009) A single institution experience with neoadjuvant chemoradiation (CRT) with irinotecan (I) and cisplatin (C) in locally advanced esophageal carcinoma (LAEC), J Clin Oncol 27:15s, (Suppl; abstr 15619)
Brewer GJ, Hedera P, Kluin KJ et al (2003) Treatment of Wilson’s disease with tetrathiomolybdate III. Initial therapy in a total of 55 neurology affected patients and follow-up with zinc therapy. Arch Neurol 60:378–385
Brewer GJ, Askari F, Lorincz MT et al (2006) Treatment of Wilson’s disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double blind study of treatment of neurologic presentation of Wilson’s disease. Arch Neurol 63:521–527
Pan Q, Kleer CG, van Golen KL et al (2002) Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res 62:4854–4859
Pan Q, Bao LW, Merajver SD (2003) Tetrathiomolybdate inhibits angiogenesis and metastasis through suppression of the NFκB signaling cascade. Mol Canc Res 1:701–706
Brewer GJ, Dick RD, Grover DK et al (2000) Treatment of metastatic cancer with tetrathiomolybdate, and anticopper, antiangiogenic agent: Phase I study. Clin Cancer Res 6:1–10
Henry NL, Dunn R, Merajver S et al (2006) Phase II trial of copper depletion with tetrathiomolybdate as an antiangiogenesis strategy in patients with hormone-refractory prostate cancer. Oncology 71:168–175
Redman BG, Esper P, Pan Q et al (2003) Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer. Clin Cancer Res 9:1666–1672
Gartner EM, Griffith KA, Pan Q et al (2009) A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-fluorouracil and leucovorin for metastatic colon cancer. Investig New Drugs 27:159–165
Brewer GJ (2003) Tetrathiomolybdate anticopper therapy for Wilson’s disease inhibits angiogenesis, fibrosis and inflammation. J Cell Mol Med 7:11–20
Brewer GJ, Merajver S (1999) Treatment of metastatic cancer with the anticopper, antiangiogenic, tetrathiomolybdate. J Investig Med 47:223A
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephro 16:31–41
Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481
Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019
Sandler A, Gray R, Perry MC et al (2007) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550
Miller K, Wang M, Gralow J et al (2007) Paclitaxel Plus Bevacizumab Versus Paclitaxel Alone for Metastatic Breast Cancer. N Engl J Med 35:2666–2676
Hassouneh B, Islam M, Nagel T et al (2007) Tetrathiomolybdate promotes tumor necrosis and prevents distant metastases by suppressing angiogenesis in head and neck cancer. Mol Cancer Ther 6:1039–1045
Pass HI, Brewer GJ, Dick R et al (2008) A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results. Ann Thorac Surg 86:383–390
Cunningham D, Allum WH, Stenning SP et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20