Paclitaxel-Eluting Polymer Film Reduces Locoregional Recurrence and Improves Survival in a Recurrent Sarcoma Model: A Novel Investigational Therapy
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Locoregional recurrences occur in up to 50% of patients after macroscopically complete (R0/R1) resections of abdominal, pelvic, and retroperitoneal sarcomas. Efficacy of a drug-eluting polymer film in reducing locoregional recurrence rates was assessed in a murine recurrent sarcoma model.
Poly(glycerol monostearate-co-caprolactone) polymer films were synthesized with and without 300 μg paclitaxel (Pax-film and unloaded film). Cytotoxicity was assessed against CS-1 (human chondrosarcoma) cells in vitro and in vivo in nude mice. Following R0/R1 resection of primary subcutaneous tumors, mice were blindly randomized to: (1) Pax-film implant, (2) unloaded film implant, (3) paclitaxel 300 μg IV (Pax IV), or (4) no other therapy (“untreated”). Locoregional recurrence, overall survival (OS), and tumor mitotic index were evaluated.
Pax-films, but not unloaded films, reduced CS-1 viability in vitro for >50 days (P < 0.001). In vivo, locoregional recurrence was observed in 2 of 12 Pax-film mice (17%), 9 of 13 unloaded film mice (69%), 8 of 9 Pax IV mice (89%), and 7 of 8 untreated mice (88%) (P < 0.01). Median OS was 81, 64, 48, and 56 days, respectively. Paclitaxel levels in local tissues were 50- to 300-fold greater in Pax-film mice compared with Pax IV mice. Tumor mitotic index adjacent to Pax-films was significantly lower than adjacent to unloaded films.
Tumor bed implantation of Pax-films after R0/R1 resection is superior to Pax IV as evidenced by reduced locoregional recurrence and improved OS in a murine recurrent sarcoma model. Continuous local drug exposure via polymer films represents a potentially novel approach for treatment of locally aggressive sarcomas.
- Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005;353:701–11. CrossRef
- Bonvalot S, Rivoire M, Castaing M, Stoeckle E, Le Cesne A, Blay JY, et al. Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol. 2009;27:31–7. CrossRef
- Gronchi A, Bonvalot S, Le Cesne A, Casali PG. Resection of uninvolved adjacent organs can be part of surgery for retroperitoneal soft tissue sarcoma. J Clin Oncol. 2009;27:2106–7; author reply 7–8. CrossRef
- Karakousis CP, Gerstenbluth R, Kontzoglou K, Driscoll DL. Retroperitoneal sarcomas and their management. Arch Surg. 1995;130:1104–9. CrossRef
- Karakousis CP, Velez AF, Gerstenbluth R, Driscoll DL. Resectability and survival in retroperitoneal sarcomas. Ann Surg Oncol. 1996;3:150–8. CrossRef
- Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: Analysis of 500 patients treated and followed at a single institution. Ann Surg. 1998;228:355–65. CrossRef
- Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, et al. Prognostic factors in retroperitoneal sarcoma: A multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer. 2001;92:359–68. CrossRef
- Lehnert T, Cardona S, Hinz U, Willeke F, Mechtersheimer G, Treiber M, et al. Primary and locally recurrent retroperitoneal soft-tissue sarcoma: local control and survival. Eur J Surg Oncol. 2009;35:986–93. CrossRef
- Catton CN, O’Sullivan B, Kotwall C, Cummings B, Hao Y, Fornasier V. Outcome and prognosis in retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 1994;29:1005–10. CrossRef
- Singer S, Corson JM, Demetri GD, Healey EA, Marcus K, Eberlein TJ. Prognostic factors predictive of survival for truncal and retroperitoneal soft-tissue sarcoma. Ann Surg. 1995;221:185–95. CrossRef
- Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet. 1997;350:1647–54.
- Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097–104. CrossRef
- Jones JJ, Catton CN, O’Sullivan B, Couture J, Heisler RL, Kandel RA, et al. Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol. 2002;9:346–54. CrossRef
- Baratti D, Pennacchioli E, Kusamura S, Fiore M, Balestra MR, Colombo C, et al. Peritoneal sarcomatosis: is there a subset of patients who may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy? Ann Surg Oncol. 2010;17:3220–8. CrossRef
- Lim SJ, Cormier JN, Feig BW, Mansfield PF, Benjamin RS, Griffin JR, et al. Toxicity and outcomes associated with surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with sarcomatosis. Ann Surg Oncol. 2007;14:2309–18. CrossRef
- Rossi CR, Deraco M, De Simone M, Mocellin S, Pilati P, Foletto M, et al. Hyperthermic intraperitoneal intraoperative chemotherapy after cytoreductive surgery for the treatment of abdominal sarcomatosis: clinical outcome and prognostic factors in 60 consecutive patients. Cancer. 2004;100:1943–50. CrossRef
- Liu R, Wolinsky JB, Walpole J, Southard E, Chirieac LR, Grinstaff MW, et al. Prevention of local tumor recurrence following surgery using low-dose chemotherapeutic polymer films. Ann Surg Oncol. 2010;17:1203–13. CrossRef
- Morioka H, Weissbach L, Vogel T, Nielsen GP, Faircloth GT, Shao L, et al. Antiangiogenesis treatment combined with chemotherapy produces chondrosarcoma necrosis. Clin Cancer Res. 2003;9:1211–7.
- Shao L, Kasanov J, Hornicek FJ, Morii T, Fondren G, Weissbach L. Ecteinascidin-743 drug resistance in sarcoma cells: transcriptional and cellular alterations. Biochem Pharmacol. 2003;66:2381–95. CrossRef
- Saad AG, Yeap BY, Thunnissen FB, Pinkus GS, Pinkus JL, Loda M, et al. Immunohistochemical markers associated with brain metastases in patients with nonsmall cell lung carcinoma. Cancer. 2008;113:2129–38. CrossRef
- Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81. CrossRef
- Gieschen HL, Spiro IJ, Suit HD, Ott MJ, Rattner DW, Ancukiewicz M, et al. Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2001;50:127–31. CrossRef
- Petersen IA, Haddock MG, Donohue JH, Nagorney DM, Grill JP, Sargent DJ, et al. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 2002;52:469–75. CrossRef
- Zlotecki RA, Katz TS, Morris CG, Lind DS, Hochwald SN. Adjuvant radiation therapy for resectable retroperitoneal soft tissue sarcoma: The University of Florida experience. Am J Clin Oncol. 2005;28:310–6. CrossRef
- Eilber F, Eckardt J, Rosen G, Forscher C, Selch M, Fu YS. Preoperative therapy for soft tissue sarcoma. Hematol Oncol Clin North Am. 1995;9:817–23.
- Pisters PW, Ballo MT, Fenstermacher MJ, Feig BW, Hunt KK, Raymond KA, et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol. 2003;21:3092–7. CrossRef
- Robertson JM, Sondak VK, Weiss SA, Sussman JJ, Chang AE, Lawrence TS. Preoperative radiation therapy and iododeoxyuridine for large retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys. 1995;31:87–92. CrossRef
- Bonvalot S, Cavalcanti A, Le Pechoux C, Terrier P, Vanel D, Blay JY, et al. Randomized trial of cytoreduction followed by intraperitoneal chemotherapy versus cytoreduction alone in patients with peritoneal sarcomatosis. Eur J Surg Oncol. 2005;31:917–23. CrossRef
- Raut CP, Pisters PW. Retroperitoneal sarcomas: combined-modality treatment approaches. J Surg Oncol. 2006;94:81–7. CrossRef
- Eroglu A, Kocaoglu H, Demirci S, Akgul H. Retroperitoneal soft tissue sarcoma: effect of hyperthermic total abdominal perfusion. Tumori. 1999;85:259–64.
- Dernell WS, Withrow SJ, Straw RC, Powers BE, Drekke JH, Lafferty M. Intracavitary treatment of soft tissue sarcomas in dogs using cisplatin in a biodegradable polymer. Anticancer Res. 1997;17:4499–505.
- Withrow SJ, Liptak JM, Straw RC, Dernell WS, Jameson VJ, Powers BE, et al. Biodegradable cisplatin polymer in limb-sparing surgery for canine osteosarcoma. Ann Surg Oncol. 2004;11:705–13. CrossRef
- Havlicek M, Straw RS, Langova V, Dernell WS. Intra-operative cisplatin for the treatment of canine extremity soft tissue sarcomas. Vet Comp Oncol. 2009;7:122–9. CrossRef
- Miura S, Mii Y, Miyauchi Y, Ohgushi H, Morishita T, Hohnoki K et al. Efficacy of slow-releasing anticancer drug delivery systems on transplantable osteosarcomas in rats. Jpn J Clin Oncol. 1995;25:61–71.
- Moses MA, Brem H, Langer R. Advancing the field of drug delivery: taking aim at cancer. Cancer Cell. 2003;4:337–41. CrossRef
- Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5:79–88.
- Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. 1995;345:1008–12. CrossRef
- Liu J, Meisner D, Kwong E, Wu XY, Johnston MR. A novel trans-lymphatic drug delivery system: implantable gelatin sponge impregnated with PLGA-paclitaxel microspheres. Biomaterials. 2007;28:3236–44. CrossRef
- Lu ZR, Parker DL, Goodrich KC, Wang X, Dalle JG, Buswell HR. Extracellular biodegradable macromolecular gadolinium(III) complexes for MRI. Magn Reson Med. 2004;51:27–34. CrossRef
- Manabe T, Okino H, Maeyama R, Mizumoto K, Tanaka M, Matsuda T. New infusion device for trans-tissue, sustained local delivery of anticancer agent to surgically resected tissue: potential use for suppression of local recurrence of pancreatic cancer. J Biomed Mater Res B Appl Biomater. 2005;73:203–7.
- Yeh TK, Lu Z, Wientjes MG, Au JL. Formulating paclitaxel in nanoparticles alters its disposition. Pharm Res. 2005;22:867–74. CrossRef
- Paclitaxel-Eluting Polymer Film Reduces Locoregional Recurrence and Improves Survival in a Recurrent Sarcoma Model: A Novel Investigational Therapy
Annals of Surgical Oncology
Volume 19, Issue 1 , pp 199-206
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- Author Affiliations
- 1. Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA
- 2. Departments of Chemistry and Biomedical Engineering, Boston University, Boston, MA, USA
- 3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- 4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
- 5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA