Journal of Neuro-Oncology

, Volume 62, Issue 1–2, pp 111–121 | Cite as

A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease

  • Paul M. Busse
  • Otto K. Harling
  • Matthew R. Palmer
  • W. S. Kiger
  • Jody Kaplan
  • Irving Kaplan
  • Cynthia F. Chuang
  • J. Tim Goorley
  • Kent J. Riley
  • Thomas H. Newton
  • Gustavo A. Santa Cruz
  • Xing-Qi Lu
  • Robert G. Zamenhof
Article

Summary

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase 1 trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24–78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The10B carrier,l-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg−1 over 1 h (10 subjects), 300 mg kg−1 over 1.5 h (two subjects), or 350 mg kg−1 over 1.5–2 h (10 subjects). The pharmacokinetic profile of10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

Key words

BNCT glioblastoma melanoma clinical trial boronophenylalanine-fructose (BPA-f) 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Harling OK, Bernard JA, Zamenhof RG: Neutron beam design, development, and performance for neutron capture therapy. In: Bernard JA, Harling OK, Zamenhof RG (eds) Neutron Beam Design, Development, and Performance for Neutron Capture Therapy. Plenum Press, New York and London, pp, 1990Google Scholar
  2. 2.
    Rogus RD, Harling OK, Yanch JC: Mixed field dosimetry of epithermal neutron beams for boron neutron capture therapy at the MITR-II research reactor. Med Phys 21: 1611–1625, 1994PubMedCrossRefGoogle Scholar
  3. 3.
    Riley KJ, Harling OK: An improved prompt gamma neutron activation analysis facility using a focused diffracted neutron beam. Nucl Instru Meth Phys Res B 143: 414–421, 1998CrossRefGoogle Scholar
  4. 4.
    Solares GR, Zamenhof RG: A novel approach to the microdosimetry of neutron capture therapy. Part 1. High-resolution quantitative autoradiography applied to microdosimetry in neutron capture therapy. Radiat Res 144: 50–58, 1995PubMedCrossRefGoogle Scholar
  5. 5.
    Soloway AH, Tjarks W, Barnum BA, Rong F-G, Barth RF, Codogni IM, Wilson JG: The chemistry of neutron capture therapy. Chem Rev 98: 1515–1562, 1998PubMedCrossRefGoogle Scholar
  6. 6.
    Zamenhof R, Redmond E, Solares G, Katz D, Riley K, Kiger S, Harling O: Monte Carlo-based treatment planning for boron neutron capture therapy using custom designed models automatically generated from CT data. Int J Radiat Oncol Biol Phys 35: 383–397, 1996PubMedCrossRefGoogle Scholar
  7. 7.
    Coderre JA, Morris GM: The radiation biology of boron neutron capture therapy. Radiat Res 151: 1–18, 1999PubMedCrossRefGoogle Scholar
  8. 8.
    Busse PM, Zamenhof RG, Madoc-Jones H, Solares G, Kiger WS III, Riley KJ, Chuang CF, Rogers G, Harling OK: Clinical follow-up of patients with melanoma of the extremity treated in a phase I boron neutron capture therapy protocol. In: Larsson B, Crawford J, Weinreich R (eds) Advances in Neutron Capture Therapy. Elsevier, Amsterdam, 1997, pp 60–64Google Scholar
  9. 9.
    Busse PM, Zamenhof RG, Harling OK, Kaplan I, Kaplan J, Chuang CF, Goorley JT, Kiger WS III, Riley KJ, Tang L, Solares GR, Palmer MR: The Harvard-MIT BNCT program: overview of the clinical trials and translational research. In: Hawthorn FM, Shelly K, Wiersema RJ (eds) Frontiers in Neutron Capture Therapy. Kluwer Academic / Plenum Publishers, New York, 2001, pp 37–60Google Scholar
  10. 10.
    Busse PM, Zamenhof RG, Harling OK, Kaplan I, Kaplan J, Chuang C, Goorley J, Kiger WS III, Riley K, Tang L, Solares GR, Palmer M: The Harvard-MIT BNCT Program: overview of the clinical trials and translational research. Eleventh International Congress of Radiation Research. Dublin, Ireland, 1999, pp 702–705Google Scholar
  11. 11.
    Busse PM, Harling OK, Palmer MR, Kaplan I, Newton TH Jr, Kaplan J, Chuang CF, Kiger WS III, Riley KJ, Goorley JT, Zamenhof RG: A phase I clinical trial for cranial BNCT at Harvard-MIT. Ninth International Symposium on ‘Neutron Capture Therapy for Cancer’. Osaka, Japan, 2000, pp 27–28Google Scholar
  12. 12.
    Chanana A, Capala J, Chadha M, Coderre JA, Diaz A, Elowitz E, Iwai J, Joel D, Liu H, Ma R, Pendzick N, Peress N, Shady M, Slatkin D, Tyson G, Wielopolski L: Boron neutron capture therapy for glioblastoma multiforme: interim results from the phase I/II dose-escalation studies. Neurosurgery 44: 1182–1192, 1999PubMedCrossRefGoogle Scholar
  13. 13.
    Diaz AZ, Chanana AD, Capala J, Chadha M, Coderre JA, Elowitz EH, Iwai J, Joel DD, Liu HB, Ma R, Shady M, Slatkin DN, Tyson GW, Wielopolski L: Safety and efficacy of BNCT for glioblastoma multiforme: results from the initial dose escalation studies. In: Hawthorn FM, Shelly K, Wiersema RJ (eds) Frontiers in Neutron Capture Therapy. Kluwer Academic / Plenum Publishers, New York, 2001, pp 61–72Google Scholar
  14. 14.
    Diaz AZ, Chanana AD, Coderre JA, Ma R: Retrospective review of the clinical BNCT trial at Brookhaven National Laboratory. Ninth International Symposium on ‘Neutron Capture Therapy for Cancer’, Osaka, Japan, 2000, pp 13–14Google Scholar
  15. 15.
    Palmer MR, Goorley JT, Kiger WS III, Busse PM, Riley KJ, Harling OK, Zamenhof RG: Treatment planning and dosimetry for the Harvard-MIT phase-I clinical trial of cranial neutron capture therapy. Int J Radiat Oncol Biol Phys 53: 1361–1379, 2002PubMedCrossRefGoogle Scholar
  16. 16.
    Zamenhof RG, Solares GR, Kiger WS III, Redmond EL, Busse PM, Yam CS: MacNCTPLAN: an improved Macintosh-based treatment planning program for boron neutron capture therapy. In: Larsson B, Crawford J, Weinreich R (eds) Advances in Neutron Capture Therapy. Elsevier, Amsterdam, 1997, pp 100–105Google Scholar
  17. 17.
    Zamenhof RG, Solares GR, Kiger WS III, Riley KJ, Busse PM, Fischer E, Norregaard T, Harling OH: Clinical treatment planning of subjects undergoing boron neutron capture therapy. In: Larsson B, Crawford J, Weinreich R (eds) Advances in Neutron Capture Therapy. Elsevier, Amsterdam, 1997, pp 614–620Google Scholar
  18. 18.
    Tishler RB, Loeffler JS, Lunsford LD, Duma C, Alexander E III, Kooy HM, Flickinger JC: Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 27: 215–221, 1993PubMedGoogle Scholar
  19. 19.
    Kiger WS III, Palmer MR, Riley KJ, Zamenhof RG, Busse PM: A pharmacokinetic model for the concentration of boron-10 in blood after boronophenylalanine-fructose administration in humans. Radiat Res 155: 611–618, 2001PubMedCrossRefGoogle Scholar
  20. 20.
    Kiger WS III, Palmer MR, Riley KJ, Zamenhof RG, Busse PM: Pharamacokinetic modeling for boronophenylalanine-fructose mediated neutron capture therapy:10B concentration predictions and dosimetric consequences. J Neuro-Oncol 62: 171–186, 2003CrossRefGoogle Scholar
  21. 21.
    Madoc-Jones H, Zamenhof R, Solares G, Harling OK, Yam C-S, Riley K, Kiger S III, Wazer D, Rogers G, Atkins M: A phase-I dose escalation trial of boron neutron capture therapy for subjects with metastatic subcutaneous melanoma of the extremities. In: Mishima Y (ed) Cancer Neutron Capture Therapy. Plenum Press, New York, 1996, p 707Google Scholar
  22. 22.
    Kiger WS III, Micca PL, Morris GM, Coderre JA: Boron microquantification in oral muscosa and skin following administration of a neutron capture therapy agent. Radiat Protection Dosimetry 99: 409–412, 2002Google Scholar
  23. 23.
    Morris GM, Smith DR, Patel H, Chandra S, Morrison GH, Hopewell JW, Rezvani M, Micca PL, Coderre JA: Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy. Br J Cancer 82: 1764–1771, 2000PubMedCrossRefGoogle Scholar
  24. 24.
    Gavin PR, Kraft SL, DeHaan CE, Swartz CD, Griebenow ML: Large animal normal tissue tolerance with boron neutron capture. Int J Radiat Oncol Biol Phys 28: 1099–1106, 1994PubMedGoogle Scholar
  25. 25.
    Gavin PR, Kraft SL, Huiskamp R, Coderre JA: A review: CNS effects and normal tissue tolerance in dogs. J Neuro-Oncol 33: 71–80, 1997CrossRefGoogle Scholar
  26. 26.
    Mishima Y, Honda C, Ichihashi M, Obara H, Hiratsuka J, Fukada H, Karashima H, Kobayashi T, Kanda K, Yoshino K: Treatment of malignant melanoma by single thermal neutron capture therapy with melanoma-seeking10B-compound. The Lancet August 12: 388–389, 1989CrossRefGoogle Scholar
  27. 27.
    Coderre JA, Chanana AD, Joel DD, Elowitz EH, Micca PL, Nawrocky MM, Chadha M, Gebbers JO, Shady M, Peress NS, Slatkin DN: Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity. Radiat Res 149: 163–170, 1998PubMedCrossRefGoogle Scholar
  28. 28.
    Elowitz EH, Bergland RM, Coderre JA, Joel DD, Chadha M, Chanana AD: Biodistribution of p-boronophenylalanine (BPA) in patients with glioblastoma multiforme for use in boron neutron capture therapy. Neurosurgery 42: 463–469, 1998PubMedCrossRefGoogle Scholar
  29. 29.
    Harling O, Riley K, Newton T, Wilson B, Bernard J, Hu L-W, Fonteneau E, Menadier P, Ali S, Sutharshan B, Kohse G, Ostrovsky Y, Stahle P, Binns P, Kiger W, III, Busse P: The fission converter based epithermal neutron irradiation facility at the MIT reactor. Nucl Sci Eng 140: 223–240, 2002Google Scholar
  30. 30.
    Kiger WS III, Sakamoto S, Harling OK: Neutronic design of a fission converter-based epithermal neutron beam for neutron capture therapy. Nucl Sci Eng 131: 1–22, 1999Google Scholar
  31. 31.
    Sakamoto S, Kiger WS III, Harling OK: Sensitivity studies of beam directionality, beam size and neutron spectrum for a fission converter-based epithermal neutron beam for boron neutron capture therapy. Med Phys 26: 1979–1988, 1999PubMedCrossRefGoogle Scholar
  32. 32.
    Barth RF, Yang W, Rotaru JH, Moeschberger ML, Joel DD, Newrocky MM, Goodman JH, Soloway AH: Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption. Cancer Res 57: 1129–1136, 1997PubMedGoogle Scholar
  33. 33.
    Barth RF, Yang W, Bartus RT, Rotaru JH, Ferketich AK, Moeschberger ML, Nawrocky MM, Coderre JA, Rofstad EK: Neutron capture therapy of intracerebral melanoma: enhanced survival and cure after blood-brain barrier opening to improve delivery of boronophenylalanine. Int J Radiat Oncol Biol Phys 52: 858–868, 2002PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Paul M. Busse
    • 1
  • Otto K. Harling
    • 3
  • Matthew R. Palmer
    • 2
  • W. S. Kiger
    • 1
  • Jody Kaplan
    • 1
  • Irving Kaplan
    • 1
  • Cynthia F. Chuang
    • 3
  • J. Tim Goorley
    • 3
  • Kent J. Riley
    • 3
  • Thomas H. Newton
    • 3
  • Gustavo A. Santa Cruz
    • 4
  • Xing-Qi Lu
    • 1
  • Robert G. Zamenhof
    • 2
  1. 1.Department of Radiation OncologyBeth Israel Deaconess Medical CenterBostonUSA
  2. 2.Department of RadiologyBeth Israel Deaconess Medical Center, Harvard Medical SchoolBoston
  3. 3.Nuclear Reactor LaboratoryMassachusetts Institute of TechnologyCambridgeUSA
  4. 4.Comisión Nacional de Energía AtómicaBuenos AiresArgentina

Personalised recommendations