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Can a Less Radical Surgery Using Photodynamic Therapy With Acridine Orange Be Equal to a Wide-margin Resection?

  • Symposium: Papers Presented at the 2011 ISOLS Meeting in Beijing, China
  • Published:
Clinical Orthopaedics and Related Research®

Abstract

Background

Wide-margin resections are an accepted method for treating soft tissue sarcoma. However, a wide-margin resection sometimes impairs function because of the lack of normal tissue. To preserve the normal tissue surrounding a tumor, we developed a less radical (ie, without a wide margin) surgical procedure using adjunctive photodynamic therapy and acridine orange for treating soft tissue sarcoma. However, whether this less radical surgical approach increases or decreases survival or whether it increases the risk of local recurrence remains uncertain.

Questions/purposes

We determined the survival, local recurrence, and limb function outcomes in patients treated with a less radical approach and adjunctive acridine orange therapy compared with those who underwent a conventional wide-margin resection.

Methods

We treated 170 patients with high-grade soft tissue sarcoma between 1999 and 2009. Fifty-one of these patients underwent acridine orange therapy. The remaining 119 patients underwent a conventional wide-margin resection for limb salvage surgery. We recorded the survival, local recurrence, and functional score (International Society of Limb Salvage [ISOLS]) score) for all the patients.

Results

The 10-year overall survival rates in the acridine orange therapy group and the conventional surgery group were 68% and 63%, respectively. The 10-year local recurrence rate was 29% for each group. The 5-year local recurrence rates for Stages II, III, and IV were 8%, 36%, and 40%, respectively, for the acridine orange group and 13%, 27%, and 33%, respectively, for the conventional surgery group. The average ISOLS score was 93% for the acridine orange group and 83% for the conventional therapy group.

Conclusion

Acridine orange therapy has the potential to preserve limb function without increasing the rate of local recurrence. This therapy may be useful for eliminating tumor cells with minimal damage to the normal tissue in patients with soft tissue sarcoma.

Level of Evidence

Level IV, therapeutic study. See Guidelines for Authors for a complete description of the levels of evidence.

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References

  1. Brooks AD, Gold JS, Graham D, Boland P, Lewis JJ, Brennan MF, Healey JH. Resection of the sciatic, peroneal, or tibial nerves: assessment of functional status. Ann Surg Oncol. 2002;9:41–47.

    Article  PubMed  CAS  Google Scholar 

  2. Cairnduff F, Stringer MR, Hudson EJ, Ash DV, Brown SB. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. Br J Cancer. 1994;69:605–608.

    Article  PubMed  CAS  Google Scholar 

  3. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213.

    Article  PubMed  Google Scholar 

  4. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247.

    Article  PubMed  CAS  Google Scholar 

  5. Enneking WF, Dunham W, Gebhardt MC, Malawar M, Pritchard DJ. A system for the functional evaluation of reconstructive procedures after surgical treatment of tumors of the musculoskeletal system. Clin Orthop Relat Res. 1993;286:241–246.

    PubMed  Google Scholar 

  6. Fuchs B, Davis AM, Wunder JS, Bell RS, Masri BA, Isler M, Turcotte R, Rock MG. Sciatic nerve resection in the thigh: a functional evaluation. Clin Orthop Relat Res. 2001;382:34–41.

    Article  PubMed  Google Scholar 

  7. Ghert MA, Davis AM, Griffin AM, Alyami AH, White L, Kandel RA, Ferguson P, O’Sullivan B, Catton CN, Lindsay T, Rubin B, Bell RS, Wunder JS. The surgical and functional outcome of limb-salvage surgery with vascular reconstruction for soft tissue sarcoma of the extremity. Ann Surg Oncol. 2005;12:1102–1110.

    Article  PubMed  Google Scholar 

  8. Grimer R, Judson I, Peake D, Seddon B. Guidelines for the management of soft tissue sarcomas. Sarcoma. 2010;2010:506182.

    PubMed  Google Scholar 

  9. Gustafson P. Soft tissue sarcoma. Epidemiology and prognosis in 508 patients. Acta Orthop Scand Suppl. 1994;259:1–31.

    PubMed  CAS  Google Scholar 

  10. Hashiguchi S, Kusuzaki K, Murata H, Takeshita H, Hashiba M, Nishimura T, Ashihara T, Hirasawa Y. Acridine orange excited by low-dose radiation has a strong cytocidal effect on mouse osteosarcoma. Oncology. 2002;62:85–93.

    Article  PubMed  CAS  Google Scholar 

  11. Herbert SH, Corn BW, Solin LJ, Lanciano RM, Schultz DJ, McKenna WG, Coia LR. Limb-preserving treatment for soft tissue sarcomas of the extremities. The significance of surgical margins. Cancer. 1993;72:1230–1238.

    CAS  Google Scholar 

  12. Kato H, Horai T, Furuse K, Fukuoka M, Suzuki S, Hiki Y, Ito Y, Mimura S, Tenjin Y, Hisazumi H, et al. Photodynamic therapy for cancers: a clinical trial of porfimer sodium in Japan. Jpn J Cancer Res. 1993;84:1209–1214.

    Article  PubMed  CAS  Google Scholar 

  13. Kawaguchi N, Ahmed AR, Matsumoto S, Manabe J, Matsushita Y. The concept of curative margin in surgery for bone and soft tissue sarcoma. Clin Orthop Relat Res. 2004;419:165–172.

    Article  PubMed  Google Scholar 

  14. Kawaguchi N, Matumoto S, Manabe J. New method of evaluating the surgical margin and safety margin for musculoskeletal sarcoma, analysed on the basis of 457 surgical cases. J Cancer Res Clin Oncol. 1995;121:555–563.

    Article  PubMed  CAS  Google Scholar 

  15. Kotilingam D, Lev DC, Lazar AJ, Pollock RE. Staging soft tissue sarcoma: evolution and change. CA Cancer J Clin. 2006;56:282–291; quiz 314–385.

    Article  PubMed  Google Scholar 

  16. Kusuzaki K, Aomori K, Suginoshita T, Minami G, Takeshita H, Murata H, Hashiguchi S, Ashihara T, Hirasawa Y. Total tumor cell elimination with minimum damage to normal tissues in musculoskeletal sarcomas following photodynamic therapy with acridine orange. Oncology. 2000;59:174–180.

    Article  PubMed  CAS  Google Scholar 

  17. Kusuzaki K, Minami G, Takeshita H, Murata H, Hashiguchi S, Nozaki T, Ashihara T, Hirasawa Y. Photodynamic inactivation with acridine orange on a multidrug-resistant mouse osteosarcoma cell line. Jpn J Cancer Res. 2000;91:439–445.

    Article  PubMed  CAS  Google Scholar 

  18. Kusuzaki K, Murata H, Matsubara T, Miyazaki S, Okamura A, Seto M, Matsumine A, Hosoi H, Sugimoto T, Uchida A. Clinical trial of photodynamic therapy using acridine orange with/without low dose radiation as new limb salvage modality in musculoskeletal sarcomas. Anticancer Res. 2005;25:1225–1235.

    PubMed  CAS  Google Scholar 

  19. Kusuzaki K, Murata H, Matsubara T, Miyazaki S, Shintani K, Seto M, Matsumine A, Hosoi H, Sugimoto T, Uchida A. Clinical outcome of a novel photodynamic therapy technique using acridine orange for synovial sarcomas. Photochem Photobiol. 2005;81:705–709.

    Article  PubMed  CAS  Google Scholar 

  20. Kusuzaki K, Murata H, Matsubara T, Satonaka H, Wakabayashi T, Matsumine A, Uchida A. Acridine orange could be an innovative anticancer agent under photon energy. In Vivo. 2007;21:205–214.

    PubMed  CAS  Google Scholar 

  21. Kusuzaki K, Murata H, Takeshita H, Hashiguchi S, Nozaki T, Emoto K, Ashihara T, Hirasawa Y. Intracellular binding sites of acridine orange in living osteosarcoma cells. Anticancer Res. 2000;20:971–975.

    PubMed  CAS  Google Scholar 

  22. Kusuzaki K, Suginoshita T, Minami G, Aomori K, Takeshita H, Murata H, Hashiguchi S, Ashihara T, Hirasawa Y. Fluorovisualization effect of acridine orange on mouse osteosarcoma. Anticancer Res. 2000;20:3019–3024.

    PubMed  CAS  Google Scholar 

  23. Kusuzaki K, Takeshita H, Murata H, Gebhardt MC, Springfield DS, Mankin HJ, Ashihara T, Hirasawa Y. Polyploidization induced by acridine orange in mouse osteosarcoma cells. Anticancer Res. 2000;20:965–970.

    PubMed  CAS  Google Scholar 

  24. Lam S, Kostashuk EC, Coy EP, Laukkanen E, LeRiche JC, Mueller HA, Szasz IJ. A randomized comparative study of the safety and efficacy of photodynamic therapy using Photofrin II combined with palliative radiotherapy versus palliative radiotherapy alone in patients with inoperable obstructive non-small cell bronchogenic carcinoma. Photochem Photobiol. 1987;46:893–897.

    Article  PubMed  CAS  Google Scholar 

  25. Mandard AM, Petiot JF, Marnay J, Mandard JC, Chasle J, de Ranieri E, Dupin P, Herlin P, de Ranieri J, Tanguy A, et al. Prognostic factors in soft tissue sarcomas. A multivariate analysis of 109 cases. Cancer. 1989;63:1437–1451.

    Article  PubMed  CAS  Google Scholar 

  26. Matsubara T, Kusuzaki K, Matsumine A, Murata H, Marunaka Y, Hosogi S, Uchida A, Sudo A. Photodynamic therapy with acridine orange in musculoskeletal sarcomas. J Bone Joint Surg Br. 2010;92:760–762.

    Article  PubMed  CAS  Google Scholar 

  27. Matsubara T, Kusuzaki K, Matsumine A, Murata H, Nakamura T, Uchida A, Sudo A. Clinical outcomes of minimally invasive surgery using acridine orange for musculoskeletal sarcomas around the forearm, compared with conventional limb salvage surgery after wide resection. J Surg Oncol. 2010;102:271–275.

    Article  PubMed  Google Scholar 

  28. Matsubara T, Kusuzaki K, Matsumine A, Murata H, Satonaka H, Shintani K, Nakamura T, Hosoi H, Iehara T, Sugimoto T, Uchida A. A new therapeutic modality involving acridine orange excitation by photon energy used during reduction surgery for rhabdomyosarcomas. Oncol Rep. 2009;21:89–94.

    Article  PubMed  Google Scholar 

  29. Matsubara T, Kusuzaki K, Matsumine A, Shintani K, Satonaka H, Uchida A. Acridine orange used for photodynamic therapy accumulates in malignant musculoskeletal tumors depending on pH gradient. Anticancer Res. 2006;26:187–193.

    PubMed  CAS  Google Scholar 

  30. Monk BJ, Brewer C, VanNostrand K, Berns MW, McCullough JL, Tadir Y, Manetta A. Photodynamic therapy using topically applied dihematoporphyrin ether in the treatment of cervical intraepithelial neoplasia. Gynecol Oncol. 1997;64:70–75.

    Article  PubMed  CAS  Google Scholar 

  31. Muramatsu K, Ihara K, Miyoshi T, Yoshida K, Taguchi T. Clinical outcome of limb-salvage surgery after wide resection of sarcoma and femoral vessel reconstruction. Ann Vasc Surg. 2008;25:1070–1077.

    Article  Google Scholar 

  32. Nakamura T, Kusuzaki K, Matsubara T, Matsumine A, Murata H, Uchida A. A new limb salvage surgery in cases of high-grade soft tissue sarcoma using photodynamic surgery, followed by photo- and radiodynamic therapy with acridine orange. J Surg Oncol. 2008;97:523–528.

    Article  PubMed  Google Scholar 

  33. Parsons HM, Habermann EB, Tuttle TM, Al-Refaie WB. Conditional survival of extremity soft-tissue sarcoma: results beyond the staging system. Cancer. 2011;117:1055–1060.

    Article  PubMed  Google Scholar 

  34. Peabody TD, Gibbs CP Jr, Simon MA. Evaluation and staging of musculoskeletal neoplasms. J Bone Joint Surg Am. 1998;80:1204–1218.

    PubMed  CAS  Google Scholar 

  35. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol. 1996;14:859–868.

    PubMed  CAS  Google Scholar 

  36. Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14:1679–1689.

    PubMed  CAS  Google Scholar 

  37. Singer S, Demetri GD, Baldini EH, Fletcher CD. Management of soft-tissue sarcomas: an overview and update. Lancet Oncol. 2000;1:75–85.

    Article  PubMed  CAS  Google Scholar 

  38. Sternberg ED, Dolphin D. Second generation photodynamic agents: a review. J Clin Laser Med Surg. 1993;11:233–241.

    PubMed  CAS  Google Scholar 

  39. Stinson SF, DeLaney TF, Greenberg J, Yang JC, Lampert MH, Hicks JE, Venzon D, White DE, Rosenberg SA, Glatstein EJ. Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 1991;21:1493–1499.

    Article  PubMed  CAS  Google Scholar 

  40. The JOA Committee of Tumors. General Rules for Clinical and Pathological Studies on Malignant Bone Tumors [in Japanese]. 3rd ed. Tokyo: Kanehara shuppan; 2000.

    Google Scholar 

  41. Trovik CS, Bauer HC, Alvegard TA, Anderson H, Blomqvist C, Berlin O, Gustafson P, Saeter G, Walloe A. Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 559 surgically-treated patients from the Scandinavian Sarcoma Group Register. Eur J Cancer. 2000;36:710–716.

    Article  PubMed  CAS  Google Scholar 

  42. Tsukushi S, Nishida Y, Sugiura H, Nakashima H, Ishiguro N. Results of limb-salvage surgery with vascular reconstruction for soft tissue sarcoma in the lower extremity: comparison between only arterial and arteriovenous reconstruction. J Surg Oncol. 2008;97:216–220.

    Article  PubMed  Google Scholar 

  43. Wang J, Gao M, Wen S, Wang M. Photodynamic therapy for 50 patients with skin cancers or precancerous lesions. Chin Med Sci J. 1991;6:163–165.

    PubMed  CAS  Google Scholar 

  44. Weiss SW, Goldblum JR. Enzinger and Weiss’ Soft Tissue Tumors. 5th ed. St Louis, MO, USA: Mosby; 2008:15–31.

  45. Yamada Y, Nishida Y, Nakashima H, Sugiura H, Tsukushi S, Kamei Y, Toriyama K, Ishiguro N. Oncologic and functional outcomes of soft tissue sarcomas of the distal upper extremity: comparison with those of the proximal upper extremity. Int Surg. 2010;95:33–39.

    PubMed  Google Scholar 

  46. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, DeLaney T, Glatstein E, Steinberg SM, Merino MJ, Rosenberg SA. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998;16:197–203.

    PubMed  CAS  Google Scholar 

  47. Yoshida K, Kusuzaki K, Matsubara T, Matsumine A, Kumamoto T, Komada Y, Naka N, Uchida A. Periosteal Ewing’s sarcoma treated by photodynamic therapy with acridine orange. Oncol Rep. 2005;13:279–282.

    PubMed  Google Scholar 

  48. Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS, Evans HL. Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer. 2003;97:2530–2543.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Atsumasa Uchida MD and Kunihiro Asanuma MD for their surgical management and data collection assistance.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie, 514-8507, Japan

    Takao Matsubara MD, Akihiko Matsumine MD, Tomoki Nakamura MD & Akihiro Sudo MD

  2. Department of Orthopaedic Surgery, Kyoto Kujo Hospital, Kyoto, Japan

    Katsuyuki Kusuzaki MD

Authors
  1. Takao Matsubara MD
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  2. Katsuyuki Kusuzaki MD
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  3. Akihiko Matsumine MD
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  4. Tomoki Nakamura MD
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  5. Akihiro Sudo MD
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Corresponding author

Correspondence to Takao Matsubara MD.

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Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

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Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.

This work was performed at Mie University Hospital, Mie, Japan.

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Matsubara, T., Kusuzaki, K., Matsumine, A. et al. Can a Less Radical Surgery Using Photodynamic Therapy With Acridine Orange Be Equal to a Wide-margin Resection?. Clin Orthop Relat Res 471, 792–802 (2013). https://doi.org/10.1007/s11999-012-2616-9

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  • DOI: https://doi.org/10.1007/s11999-012-2616-9

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