Annals of Surgical Oncology

, Volume 14, Issue 8, pp 2411–2421 | Cite as

Use of an Artificial Lymphatic System During Carboplatin Infusion to Improve Canine Osteosarcoma Blood Flow and Clinical Response

  • Gene R. DiResta
  • Sean W. Aiken
  • Holly K. Brown
  • Philip J. Bergman
  • Ann Hohenhaus
  • E. J. Ehrhart
  • Keith Baer
  • John H. Healey
Laboratory Research

Abstract

Background

The artificial lymphatic system (ALS), a mechanical system designed to reduce increased interstitial fluid pressure in solid tumors and enhance the delivery of chemotherapy, was evaluated within a randomized clinical trial treating spontaneously occurring canine appendicular osteosarcoma (OS), a tumor similar to its human OS counterpart.

Methods

An ALS was investigated for its ability to increase OS blood flow and increase uptake of intravenously administered carboplatin.

Results

Blood flow increased by 314% in tumors with active ALS drains versus 126% in control tumors (P < .03). Tumor carboplatin uptake increased by 51% after drain activation (P = .07). Microvascular density (MVD) was measured in tumors after surgical amputation and in corresponding bone regions in a cohort of normal dogs. The OS tumors had equivalent MVD as normal bone, and MVD was higher in the humerus than the femur (P < .03) in both tumor and normal bone. Median survival between the ALS-treated and control cohorts was not different despite increased drug uptake or ALS manipulation. Compared with historic controls, ALS drain insertion into tumors to reduce interstitial fluid pressure did not worsen the prognosis.

Conclusions

The findings in canine spontaneously occurring OS indicate that an ALS may be of value as a chemotherapy adjunct for enhancing the delivery of chemotherapy to tumor interstitium.

Keywords

Osteosarcoma Carboplatin Blood flow Interstitial fluid pressure Microvessel density Canine Artificial lymphatic system 

References

  1. 1.
    Baxter LT, Jain RK. Transport of fluid and macromolecules in tumors: I. Role of interstitial pressure and convection. Microvasc Res 1989; 37:77–104PubMedCrossRefGoogle Scholar
  2. 2.
    DiResta GR, Lee J, Healey JH, et al. The artificial lymphatic system: a new approach to reduce interstitial hypertension and increase blood flow, pH and Po2 in solid tumors. Ann Biomed Eng 2000; 28:543–55PubMedCrossRefGoogle Scholar
  3. 3.
    Weinmann M, Belka C, Plasswilm L. Tumour hypoxia: impact on biology, prognosis and treatment of solid malignant tumours. Onkologie 2004; 27:83–90PubMedCrossRefGoogle Scholar
  4. 4.
    DiResta GR, Lee J, Larson SM, et al. Characterization of neuroblastoma xenograft in rat flank: I. Growth, interstitial fluid pressure and interstitial fluid velocity distribution profiles. Microvasc Res 1993; 46:158–77PubMedCrossRefGoogle Scholar
  5. 5.
    Arbit E, Lee J, DiResta GR. 1994; Interstitial hypertension in human brain tumors: possible role in peritumoral edema formation. In: Nagai H, Kamiya K, Ishii S, eds. Intracranial Pressure. Nagoya, Japan: Springer-Verlag, 610–4Google Scholar
  6. 6.
    Healey JH and DiResta GR. Measurement of interstitial fluid pressure and blood flow in human bone tumors and adjacent normal tissue. Paper presented at: Orthopedic Research Society, 44th Annual Meeting; March 16–19, 1998; New Orleans, LAGoogle Scholar
  7. 7.
    Zachos TA, Aiken SW, DiResta GR, et al. Interstitial fluid pressure and blood flow in canine osteosarcoma and other tumors. Clin Orthop Relat Res 2001; 385:230–6PubMedCrossRefGoogle Scholar
  8. 8.
    Salnikov AV, Iversen VV, Koisti M, et al. Lowering of tumor interstitial fluid pressure specifically augments efficacy of chemotherapy. FASEB J 2003; 17:1756–8PubMedGoogle Scholar
  9. 9.
    DiResta GR, Lee J, Healey JH, et al. Enhancing the uptake of chemotherapeutic drugs into tumors using an artificial lymphatic system. Ann Biomed Eng 2000; 28:556–64PubMedCrossRefGoogle Scholar
  10. 10.
    Process and device to reduce interstitial fluid pressure in tissue. US patents 5,484,399, 16 January 1996, 6,547,777, 15 April 2003Google Scholar
  11. 11.
    Withrow SJ, Powers BE, Straw RC, et al. Comparative aspects of osteosarcoma: dog versus man. Clin Orthop Relat Res 1991; 270:159–68PubMedGoogle Scholar
  12. 12.
    Ehrhart NE, Dernell WS, Hoffmann WE, et al. Prognostic importance of alkaline phosphatase activity in serum from dogs with appendicular osteosarcoma: 75 cases (1990–1996). J Am Vet Med Assoc 1998; 213:1002–6PubMedGoogle Scholar
  13. 13.
    Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 1977; 101:14–8PubMedGoogle Scholar
  14. 14.
    Zachos TA, Chiaramonte D, DiResta GR, et al. Canine osteosarcoma: treatment with surgery, chemotherapy and/or radiation therapy, The Animal Medical Center, 1993–1998. Proceedings, 19th Annual Veterinary Cancer Society Conference. November 13–19, 1999, Wood’s Hole, MAGoogle Scholar
  15. 15.
    Wong NACS, Willott J, Kendall MJ, Sheffield EA. Measurement of vascularity as a diagnostic and prognostic tool for well-differentiated thyroid tumours: comparison of different methods of assessing vascularity. J Clin Pathol 1999; 52:593–7PubMedCrossRefGoogle Scholar
  16. 16.
    Bergman PJ, MacEwen EG, Kurzman ID, et al. Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991 to 1993). J Vet Intern Med 1996; 10:76–81PubMedCrossRefGoogle Scholar
  17. 17.
    Hecquet B, Caty A, Fournier C, et al. Comparison of platinum concentrations in human head and neck tumours following administration of carboplatin, iproplatin or cisplatin. Bull Cancer 1987;74:433-6PubMedGoogle Scholar
  18. 18.
    Takeda S, Ikeba K, Ohokubo T, et al. [Clinical effect of intra-arterial carboplatin-combined chemotherapy for advanced uterine cervical cancer and increased tissue platinum levels with Lipo PGE1 administration before chemotherapy]. Gan To Kagaku Ryoho 1996; 23:1697–703PubMedGoogle Scholar
  19. 19.
    Abe I, Suzaki M, Hori K, et al. Some aspect of size-dependent differential drug response in primary and metastatic tumors. Cancer Metast Rev 1985; 4:27–39CrossRefGoogle Scholar
  20. 20.
    Eriksen J, Tondevold E, Jansen E, et al. Relationship between oxygen and carbon dioxide tensions and acid-base balance in arterial blood and in medullary blood from long bones in dogs. Acta Orthop Scand 1979; 50:519–25PubMedCrossRefGoogle Scholar
  21. 21.
    Li G, Bronk JT, Kelly PJ. Canine bone blood flow estimated with microspheres. J Orthop Res 1989; 7:61–7PubMedCrossRefGoogle Scholar
  22. 22.
    Evans HE, ed. Miller’s Anatomy of Dog. 3rd ed. Philadelphia: WB Saunders, 1993Google Scholar
  23. 23.
    Brookhart JM, Parmeggiani PL, Petersen WA, et al. Postural stability in the dog. Am J Physiol 1965; 208:1047–57PubMedGoogle Scholar
  24. 24.
    Meyers PA, Heller G, Healey J, et al. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 1992; 10:5–15PubMedGoogle Scholar
  25. 25.
    Bailey D, Erb H, Williams L, et al. carboplatin and doxorubicin combination chemotherapy for the treatment of appendicular osteosarcoma in the dog. J Vet Int Med 2003; 17:199–205CrossRefGoogle Scholar
  26. 26.
    Griffey SM, Verstraete FJM, Kraegel SA, et al. Computer-assisted image analysis of intratumoral vessel density in mammary tumors from dogs. Am J Vet Res 1998; 59:1238–42PubMedGoogle Scholar
  27. 27.
    Kent MS, Griffey SM, Verstraete FJM, et al. Computer-assisted image analysis of neovascularization in thyroid neoplasms from dogs. Am J Vet Res 2002; 63:363–9PubMedCrossRefGoogle Scholar
  28. 28.
    Simpson JF, Han C, Battifora H, Esteban JM. Endothelial area as a prognostic indicator for invasive breast carcinoma. Cancer 1996; 77:2077–85PubMedCrossRefGoogle Scholar
  29. 29.
    Barbareschi M, Weidner N, Gasparini G, et al. Microvessel density quantification in breast carcinomas. Appl Immunohistochem 1995; 3:75–84Google Scholar
  30. 30.
    Fox SB. Tumour angiogenesis and prognosis. Histopathology 1997; 30:294–301PubMedCrossRefGoogle Scholar
  31. 31.
    DiResta GR, Aiken SA, Healey JH. Dog osteogenic sarcoma microvasculature visualized with a Spälteholz technique. Clin Orthop Relat Res 2004; 426:39–43PubMedCrossRefGoogle Scholar
  32. 32.
    Yoshikawa M, Noguchi K, Toda T. Effect of particle sizes in India ink on its use in evaluation of apical seal. J Osaka Dent Univ 1997; 31:67–70PubMedGoogle Scholar
  33. 33.
    Paders TP, Stoll BR, Tooredman JB, et al. Pathology: cancer cells compress intratumour vessels. Nature 2004; 4527:695CrossRefGoogle Scholar
  34. 34.
    Coomber BL, Denton J, Sylvestre A, et al. Blood vessel density in canine osteosarcoma. Can J Vet Res 1998; 62:199–204PubMedGoogle Scholar
  35. 35.
    DiResta GR, Nathan SS, Manoso M, et al. Population dynamics of cultured human cancer cells are affected by the elevated tumor pressures that exist in vivo. Ann Biomed Eng 2005; 33:1270–80PubMedCrossRefGoogle Scholar
  36. 36.
    Nathan SS, DiResta GR, Casas-Ganem JE, et al. Elevated physiological tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma cells. Clin Cancer Res 2005; 11:2389–97PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  • Gene R. DiResta
    • 1
  • Sean W. Aiken
    • 2
  • Holly K. Brown
    • 1
  • Philip J. Bergman
    • 2
  • Ann Hohenhaus
    • 2
  • E. J. Ehrhart
    • 3
  • Keith Baer
    • 2
  • John H. Healey
    • 1
  1. 1.Orthopaedic Surgical ServiceMemorial Sloan Kettering Cancer CenterNew YorkNew York
  2. 2.The Animal Medical Center New YorkNew York
  3. 3.College of Veterinary Medicine and Biomedical ScienceColorado State UniversityFt. CollinsColorado

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