Annals of Surgical Oncology

, Volume 17, Issue 4, pp 1203–1213 | Cite as

Prevention of Local Tumor Recurrence Following Surgery Using Low-Dose Chemotherapeutic Polymer Films

  • Rong Liu
  • Jesse B. Wolinsky
  • Joseph Walpole
  • Emily Southard
  • Lucian R. Chirieac
  • Mark W. Grinstaff
  • Yolonda L. ColsonEmail author
Translational Research and Biomarkers



To evaluate the efficacy of a polymer film designed for prolonged paclitaxel release at surgical margins to prevent local recurrence in non-small-cell lung cancer (NSCLC) following complete surgical resection in a murine model.


Poly(glycerol monostearate co-ε-caprolactone) polymer films were prepared with or without 10% (w/w) paclitaxel and characterized for prolonged tumor cytotoxicity in vitro against several NSCLC cell lines including LLC, NCI-H460, and NCI-H292. Films were implanted following complete LLC tumor resection and assessed in vivo for prevention of local tumor recurrence, impact on wound healing, and extent of local drug delivery. Plasma and local tissue concentrations of paclitaxel were compared following systemic administration and film implantation.


The flexible polymeric films eluted paclitaxel over several weeks and remained cytotoxic to LLC, NCI-H460, and NCI-H292 cells in vitro for 50 days, while unloaded films did not impair tumor cell growth. Implanted paclitaxel films prevented local tumor recurrence in vivo in 83.3% of animals, compared with unloaded films (12.5%), systemic (22.2%) or locally administered paclitaxel (0%) (P < 0.005). Although minimal paclitaxel remained in either plasma or tissue 10 days after systemic injection, local paclitaxel concentration at the site of surgical resection was significantly greater (3,000-fold) at 10 days when paclitaxel was locally delivered via films (P = 0.024).


Local application of paclitaxel-loaded polymer films following surgical resection can prevent local tumor recurrence without impairing wound healing.


Paclitaxel Drug Release BCNU Lewis Lung Carcinoma Local Tumor Recurrence 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Y.L.C. is supported by the Center for Integration of Medicine and Innovative Technology (CIMIT grants 06-006, 07-004, and 09-433), the American College of Surgeon’s George H. A. Clowes, Jr., MD, FACS, Memorial Research Career Development Award. M.W.G. is supported by the Wallace H. Coulter Foundation. We thank Dr. Paul Catalano of the Dana-Farber/Harvard Cancer Center for his statistics consulting, the Animal Resources Facility at Dana-Farber Cancer Institute, and Jessica Rickards for assistance with document preparation.


None of the authors have conflict of interest.

Supplementary material

10434_2009_856_MOESM1_ESM.doc (48 kb)
Supplementary material 1 (DOC 49 kb)


  1. 1.
    Harpole DH, Jr., Herndon JE, 2nd, Young WG, Jr., Wolfe WG, Sabiston DC, Jr. Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer. 1995;76:787–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Martini N, Burt ME, Bains MS, McCormack PM, Rusch VW, Ginsberg RJ. Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg. 1992;54:460–5; discussion 466.PubMedCrossRefGoogle Scholar
  3. 3.
    Sugimura H, Nichols FC, Yang P, et al. Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection. Ann Thorac Surg. 2007;83:409–17; discussion 417–8.CrossRefPubMedGoogle Scholar
  4. 4.
    El-Sherif A, Fernando HC, Santos R, et al. Margin and local recurrence after sublobar resection of non-small cell lung cancer. Ann Surg Oncol 2007;14:2400–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1995;60:615–22; discussion 622–3.Google Scholar
  6. 6.
    Landreneau RJ, Sugarbaker DJ, Mack MJ, et al. Wedge resection versus lobectomy for stage I (T1 N0 M0) non-small-cell lung cancer. J Thorac Cardiovasc Surg. 1997;113:691–8; discussion 698–700.CrossRefPubMedGoogle Scholar
  7. 7.
    Warren WH, Faber LP. Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg. 1994;107:1087–93; discussion 1093–4.PubMedGoogle Scholar
  8. 8.
    Sawabata N, Ohta M, Matsumura A, et al. Optimal distance of malignant negative margin in excision of nonsmall cell lung cancer: a multicenter prospective study. Ann Thorac Surg. 2004;77:415–20.CrossRefPubMedGoogle Scholar
  9. 9.
    Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Tsuboi M, Ohira T, Saji H, et al. The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer. Ann Thorac Cardiovasc Surg. 2007;13:73–7.PubMedGoogle Scholar
  11. 11.
    Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL. the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37:1590–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs. 1996;7:78–86.CrossRefPubMedGoogle Scholar
  13. 13.
    Lee W, Daly BD, DiPetrillo TA, et al. Limited resection for non-small cell lung cancer: observed local control with implantation of I-125 brachytherapy seeds. Ann Thorac Surg. 2003;75:237–42; discussion 242–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Santos R, Colonias A, Parda D, et al. Comparison between sublobar resection and 125Iodine brachytherapy after sublobar resection in high-risk patients with stage I non-small-cell lung cancer. Surgery. 2003;134:691–7; discussion 697.CrossRefPubMedGoogle Scholar
  15. 15.
    Langer R, Tirrell DA. Designing materials for biology and medicine. Nature. 2004;428:487–92.CrossRefPubMedGoogle Scholar
  16. 16.
    Wu P, Grainger DW. Drug/device combinations for local drug therapies and infection prophylaxis. Biomaterials. 2006;27:2450–67.CrossRefPubMedGoogle Scholar
  17. 17.
    Brem H, Piantadosi S, Burger PC, 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.Google Scholar
  18. 18.
    Dong Y, Chin SF, Blanco E, et al. Intratumoral delivery of {beta}-lapachone via polymer implants for prostate cancer therapy. Clin Cancer Res. 2009;15:131–139.CrossRefPubMedGoogle Scholar
  19. 19.
    Harper E, Dang W, Lapidus RG, Garver RI, Jr. Enhanced efficacy of a novel controlled release paclitaxel formulation (PACLIMER delivery system) for local-regional therapy of lung cancer tumor nodules in mice. Clin Cancer Res. 1999;5:4242–8.PubMedGoogle Scholar
  20. 20.
    Ogura Y, Mizumoto K, Tanaka M, et al. Strategy for prevention of local recurrence of pancreatic cancer after pancreatectomy: antitumor effect of gemcitabine mixed with fibrin glue in an orthotopic nude mouse model. Surgery. 2006;140:66–71.CrossRefPubMedGoogle Scholar
  21. 21.
    Pradilla G, Wang PP, Gabikian P, et al. Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model. J Neurooncol. 2006;76:131–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Ruel-Gariepy E, Shive M, Bichara A, et al. A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel. Eur J Pharm Biopharm. 2004;57:53–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Westphal M, Hilt DC, Bortey E, 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.CrossRefPubMedGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    Okino H, Maeyama R, Manabe T, Matsuda T, Tanaka M. Trans-tissue, sustained release of gemcitabine from photocured gelatin gel inhibits the growth of heterotopic human pancreatic tumor in nude mice. Clin Cancer Res. 2003;9:5786–93.PubMedGoogle Scholar
  26. 26.
    Wolinsky JB, Ray WC, Colson YL, Grinstaff MW. Poly(carbonate ester)s based on units of 6-hydroxyhexanoic acid and glycerol. Macromolecules. 2007;40:7065–8.CrossRefGoogle Scholar
  27. 27.
    Drachman DE, Edelman ER, Seifert P, et al. Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months. J Am Coll Cardiol. 2000;36:2325–32.CrossRefPubMedGoogle Scholar
  28. 28.
    Fonseca C, Simoes S, Gaspar R. Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity. J Control Release. 2002;83:273–286.CrossRefPubMedGoogle Scholar
  29. 29.
    Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317–24.CrossRefPubMedGoogle Scholar
  30. 30.
    Qadri SS, Wang JH, Coffey JC, et al. Can surgery for cancer accelerate the progression of secondary tumors within residual minimal disease at both local and systemic levels? Ann Thorac Surg. 2005;80:1046–50; discussion 1050–1.CrossRefPubMedGoogle Scholar
  31. 31.
    Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science. 2008;319:195–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Kolb BA, Buller RE, Connor JP, DiSaia PJ, Berman ML. Effects of early postoperative chemotherapy on wound healing. Obstet Gynecol. 1992;79:988–92.PubMedGoogle Scholar
  33. 33.
    Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005;91:173–80.CrossRefPubMedGoogle Scholar
  34. 34.
    Obara K, Ishihara M, Ozeki Y, et al. Controlled release of paclitaxel from photocrosslinked chitosan hydrogels and its subsequent effect on subcutaneous tumor growth in mice. J Control Release. 2005;110:79–89.CrossRefPubMedGoogle Scholar
  35. 35.
    Baguley BC, Finlay GJ. Pharmacokinetic/cytokinetic principles in the chemotherapy of solid tumours. Clin Exp Pharmacol Physiol. 1995;22:825–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Cao Q, Li ZB, Chen K, et al. Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide-paclitaxel conjugate in mice with breast cancer. Eur J Nucl Med Mol Imaging. 2008;35:1489–98.CrossRefPubMedGoogle Scholar
  37. 37.
    Bota DA, Desjardins A, Quinn JA, Affronti ML, Friedman HS. Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas. Ther Clin Risk Manag. 2007;3:707–15.PubMedGoogle Scholar
  38. 38.
    Knemeyer I, Wientjes MG, Au JL. Cremophor reduces paclitaxel penetration into bladder wall during intravesical treatment. Cancer Chemother Pharmacol. 1999;44:241–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Baguley BC, Marshall ES, Finlay GJ. Short-term cultures of clinical tumor material: potential contributions to oncology research. Oncol Res. 1999;11:115–24.PubMedGoogle Scholar
  40. 40.
    Baguley BC, Marshall ES, Holdaway KM, Rewcastle GW, Denny WA. Inhibition of growth of primary human tumour cell cultures by a 4-anilinoquinazoline inhibitor of the epidermal growth factor receptor family of tyrosine kinases. Eur J Cancer. 1998;34:1086–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Grossman SA, Reinhard C, Colvin OM, et al. The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers. J Neurosurg. 1992;76:640–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer. 2000;88:2619–28.CrossRefPubMedGoogle Scholar
  43. 43.
    Jordan MA, Toso RJ, Thrower D, Wilson L. Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations. Proc Natl Acad Sci U S A. 1993;90:9552–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Benoit MA, Baras B, Gillard J. Preparation and characterization of protein-loaded poly(epsilon-caprolactone) microparticles for oral vaccine delivery. Int J Pharm. 1999;184:73–84.CrossRefPubMedGoogle Scholar
  45. 45.
    Lilenbaum RC, Herndon JE, 2nd, List MA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol. 2005;23:190–6.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2009

Authors and Affiliations

  • Rong Liu
    • 1
  • Jesse B. Wolinsky
    • 2
  • Joseph Walpole
    • 1
  • Emily Southard
    • 1
  • Lucian R. Chirieac
    • 3
  • Mark W. Grinstaff
    • 2
  • Yolonda L. Colson
    • 1
    Email author
  1. 1.Division of Thoracic Surgery, Department of SurgeryBrigham and Women’s HospitalBostonUSA
  2. 2.Department of Biomedical Engineering and ChemistryBoston UniversityBostonUSA
  3. 3.Department of PathologyBrigham and Women’s HospitalBostonUSA

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