Radiotherapy & Oncology
Volume 95, Issue 2 , Pages 135-141 , May 2010

A systematic methodology review of phase I radiation dose escalation trials

  • Madelon Pijls-Johannesma

      Affiliations

    • Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands
    • Corresponding Author InformationCorresponding author. Address: Maastro Clinic, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
    • These authors equally contributed to this work.
    • ,
  • Ghislaine van Mastrigt

      Affiliations

    • Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands
    • These authors equally contributed to this work.
    • ,
  • Steve M. Hahn

      Affiliations

    • Department of Radiotherapy, Hospital of the University of Pennsylvania, Philadelphia, USA
    • ,
  • Dirk De Ruysscher

      Affiliations

    • Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands
    • ,
  • Brigitta G. Baumert

      Affiliations

    • Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands
    • ,
  • Guido Lammering

      Affiliations

    • Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands
    • ,
  • Jeroen Buijsen

      Affiliations

    • Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands
    • ,
  • Soren M. Bentzen

      Affiliations

    • Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, WI, USA
    • ,
  • Yolande Lievens

      Affiliations

    • Department of Radiation Oncology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium
    • ,
  • Andrew Kramar

      Affiliations

    • CRLC Val d’Aurelle – Paul Lamarque, Unité de Biostatistique, Montpellier, France
    • ,
  • Philippe Lambin

      Affiliations

    • Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands

Received 17 September 2009 ,Accepted 8 February 2010.

References 

  1. EORTC guidelines for phase I trials with single agents in adults. EORTC New Drug Development Committee. Eur J Cancer Clin Oncol 1985;21:1005–7.
  2. Bentzen SM, Trotti A. Evaluation of early and late toxicities in chemoradiation trials. J Clin Oncol. 2007;25:4096–4103
  3. Belderbos JS, De Jaeger K, Heemsbergen WD, et al. First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2003;66:119–126
  4. Blackstock AW, Ho C, Butler J, et al. Phase Ia/Ib chemo-radiation trial of gemcitabine and dose-escalated thoracic radiation in patients with stage III A/B non-small cell lung cancer. J Thorac Oncol. 2006;1:434–440
  5. Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2005;61:318–328
  6. Byhardt RW, Pajak TF, Emami B, Herskovic A, Doggett RS, Olsen LA. A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: report of Radiation Therapy Oncology Group 84-07. Int J Radiat Oncol Biol Phys. 1993;26:459–468
  7. Choi NC, Herndon JE, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol Official J Am Soc Clin Oncol. 1998;16:3528–3536
  8. De Ruysscher D, Wanders S, Van Haren E, et al. Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study. Int J Radiat Oncol Biol Phys. 2005;62:988–994
  9. Ernst Stecken A, Lambrecht U, Mueller R, Sauer R, Grabenbauer G. Hypofractionated stereotactic radiotherapy for primary and secondary intrapulmonary tumors: first results of a phase I/II study. Strahlentherapie und Onkologie Organ der Deutschen Rontgengesellschaft [et al.]. 2006;182:696–702
  10. Garces YI, Okuno SH, Schild SE, et al. Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2007;67:995–1001
  11. Hayman JA, Martel MK, Ten Haken RK, et al. Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial. J Clin Oncol Official J Am Soc Clin Oncol. 2001;19:127–136
  12. Holloway CL, Robinson D, Murray B, et al. Results of a phase I study to dose escalate using intensity modulated radiotherapy guided by combined PET/CT imaging with induction chemotherapy for patients with non-small cell lung cancer. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2004;73:285–287
  13. Komaki R, Swann RS, Ettinger DS, et al. Phase I study of thoracic radiation dose escalation with concurrent chem, otherapy for patients with limited small-cell lung cancer. Report of Radiation Therapy Oncology Group (RTOG) protocol 97–12. Int J Radiat Oncol Biol Phys. 2005;62:342–350
  14. Le QT, Loo BW, Ho A, et al. Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors. J Thorac Oncol. 2006;1:802–809
  15. Marks LB, Garst J, Socinski MA, et al. Carboplatin/paclitaxel or carboplatin/vinorelbine followed by accelerated hyperfractionated conformal radiation therapy: report of a prospective phase I dose escalation trial from the Carolina Conformal Therapy Consortium. J Clin Oncol official J Am Soc Clin Oncol. 2004;22:4329–4340
  16. McGarry RC, Papiez L, Williams M, Whitford T, Timmerman RD. Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: phase I study. Int J Radiat Oncol Biol Phys. 2005;63:1010–1015
  17. Narayan S, Henning GT, Ten Haken RK, Sullivan MA, Martel MK, Hayman JA, et al. 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer. Lung Cancer Amsterdam, Netherlands. 2004;44:79–88
  18. Rosenman JG, Halle JS, Socinski MA, et al. High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys. 2002;54:348–356
  19. Rosenzweig KE, Mychalczak B, Fuks Z, et al. Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer. Cancer J Sudbury, Mass. 2000;6:82–87
  20. Schild SE, McGinnis WL, Graham D, et al. Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2006;65:1106–1111
  21. Socinski MA, Morris DE, Halle JS, et al. Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial. J Clin Oncol Official J Am Soc Clin Oncol. 2004;22:4341–4350
  22. Socinski MA, Rosenman JG, Halle J, et al. Dose-escalating conformal thoracic radiation therapy with induction and concurrent carboplatin/paclitaxel in unresectable stage IIIA/B nonsmall cell lung carcinoma: a modified phase I/II trial. Cancer. 2001;92:1213–1223
  23. Socinski MA, Rosenman JG, Schell MJ, et al. Induction carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal thoracic radiation therapy in unresectable stage IIIA/B nonsmall cell lung carcinoma: a modified phase I trial. Cancer. 2000;89:534–542
  24. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest. 2003;124:1946–1955
  25. Wu KL, Jiang GL, Liao Y, et al. Three-dimensional conformal radiation therapy for non-small-cell lung cancer: a phase I/II dose escalation clinical trial. Int J Radiat Oncol Biol Phys. 2003;57:1336–1344
  26. Yee D, Halperin R, Hanson J, et al. Phase I study of hypofractionated dose-escalated thoracic radiotherapy for limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2006;65:466–473
  27. Socinski MA, Marks LB, Garst J, et al. Carboplatin/paclitaxel or carboplatin/vinorelbine followed by accelerated hyperfractionated conformal radiation therapy: a preliminary report of a phase I dose escalation trial from the Carolina Conformal Therapy Consortium. Oncologist. 2001;6(Suppl. 1):20–24
  28. Freeman CR, Krischer JP, Sanford RA, et al. Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys. 1993;27:197–206
  29. Hudes RS, Corn BW, Werner Wasik M, et al. A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys. 1999;43:293–298
  30. Kalapurakal JA, Goldman S, Stellpflug W, et al. Phase I study of intraoperative radiotherapy with photon radiosurgery system in children with recurrent brain tumors: preliminary report of first dose level (10 Gy). Int J Radiat Oncol Biol Phys. 2006;65:800–808
  31. Laing RW, Warrington AP, Graham J, Britton J, Hines F, Brada M, et al. Phase I/II study. Radiother Oncol J Eur Soc Ther Radiol Oncol. 1993;27:22–29
  32. Werner Wasik M, Scott CB, Nelson DF, et al. Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83–02. Cancer. 1996;77:1535–1543
  33. Allen AM, Zalupski MM, Robertson JM, et al. Adjuvant therapy in pancreatic cancer: phase I trial of radiation dose escalation with concurrent full-dose gemcitabine. Int J Radiat Oncol Biol Phys. 2004;59:1461–1467
  34. Brade A, Brierley J, Oza A, et al. Concurrent gemcitabine and radiotherapy with and without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic cancer: a phase I-II study. Int J Radiat Oncol Biol Phys. 2007;67:1027–1036
  35. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;58:1017–1021
  36. Morganti AG, Valentini V, Macchia G, et al. 5-fluorouracil-based chemoradiation in unresectable pancreatic carcinoma: phase I–II dose-escalation study. Int J Radiat Oncol Biol Phys. 2004;59:1454–1460
  37. Regine WF, Hanna N, Garofalo MC, et al. Low-dose radiotherapy as a chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I study exploring a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2007;68:172–177
  38. Tsujie M, Nakamori S, Tanaka E, et al. Phase I/II trial of hyperfractionated accelerated chemoradiotherapy for unresectable advanced pancreatic cancer. Jpn J Clin Oncol. 2006;36:504–510
  39. Ueno H, Okusaka T, Ikeda M, Tokuuye K. Phase I study of hyperfractionated radiation therapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer. Oncology. 2004;67:215–221
  40. Forman JD, Duclos M, Shamsa F, Porter AT, Orton C. Hyperfractionated conformal radiotherapy in locally advanced prostate cancer: results of a dose escalation study. Int J Radiat Oncol Biol Phys. 1996;34:655–662
  41. Kitamura K, Shirato H, Shinohara N, et al. Reduction in acute morbidity using hypofractionated intensity-modulated radiation therapy assisted with a fluoroscopic real-time tumor-tracking system for prostate cancer: preliminary results of a phase I/II study. Cancer J Sudbury, Mass. 2003;9:268–276
  42. Leibel SA, Heimann R, Kutcher GJ, et al. Three-dimensional conformal radiation therapy in locally advanced carcinoma of the prostate: preliminary results of a phase I dose-escalation study. Int J Radiat Oncol Biol Phys. 1994;28:55–65
  43. Michalski JM, Purdy JA, Winter K, et al. Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. Int J Radiat Oncol Biol Phys. 2000;46:391–402
  44. Ryu JK, Winter K, Michalski JM, et al. Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG 9406, level III (79.2Gy). Int J Radiat Oncol Biol Phys. 2002;54:1036–1046
  45. Zelefsky MJ, Fuks Z, Wolfe T, et al. Locally advanced prostatic cancer: long-term toxicity outcome after three-dimensional conformal radiation therapy – a dose-escalation study. Radiology. 1998;209:169–174
  46. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys. 1998;41:491–500
  47. Zelefsky MJ, Leibel SA, Kutcher GJ, Kelson S, Ling CC, Fuks Z. The feasibility of dose escalation with three-dimensional conformal radiotherapy in patients with prostatic carcinoma. Cancer J Sci Am. 1995;1:142–150
  48. Michalski JM, Winter K, Purdy JA, et al. Trade-off to low-grade toxicity with conformal radiation therapy for prostate cancer on Radiation Therapy Oncology Group 9406. Semin Radiat Oncol. 2002;12:75–80
  49. Madani I, Duthoy W, Derie C, et al. Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;68:126–135
  50. Wu Q, Mohan R, Morris M, Lauve A, Schmidt Ullrich R. Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced head-and-neck squamous cell carcinomas. I: dosimetric results. Int J Radiat Oncol Biol Phys. 2003;56:573–585
  51. Harney J, Goodchild K, Phillips H, Glynne Jones R, Hoskin PJ, Saunders MI. A phase I/II study of CHARTWEL with concurrent chemotherapy in locally advanced, inoperable carcinoma of the oesophagus. Clin Oncol R College Radiol Great Br. 2003;15:109–114
  52. Palazzoni G, Nardone L, Cianciulli M, Ciresa M, Ausili Cefaro G. Dose fractionation and biological optimization in breast cancer. Rays. 2004;29:333–338
  53. McAfee SL, Powell SN, Colby C, Spitzer TR. Dose-escalated total body irradiation and autologous stem cell transplantation for refractory hematologic malignancy. Int J Radiat Oncol Biol Phys. 2002;53:151–156
  54. Dawson LA, Saito NG, Ratanatharathorn V, et al. Phase I study of involved-field radiotherapy preceding autologous stem cell transplantation for patients with high-risk lymphoma or Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 2004;59:208–218
  55. Scarantino CW, Caplan R, Rotman M, Coughlin C, Demas W, Delrowe J. A phase I/II study to evaluate the effect of fractionated hemibody irradiation in the treatment of osseous metastases – RTOG 88-22. Int J Radiat Oncol Biol Phys. 1996;36:37–48
  56. Russell AH, Clyde C, Wasserman TH, Turner SS, Rotman M. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol. Int J Radiat Oncol Biol Phys. 1993;27:117–123
  57. Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys. 2005;62:1371–1378
  58. Freedman GM, Meropol NJ, Sigurdson ER, et al. Phase I trial of preoperative hypofractionated intensity-modulated radiotherapy with incorporated boost and oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2007;67:1389–1393
  59. Movsas B, Hanlon AL, Lanciano R, et al. Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 1998;42:43–50
  60. Calkins AR, Harrison CR, Fowler WC. Hyperfractionated radiation therapy plus chemotherapy in locally advanced cervical cancer: results of two phase I dose-escalation Gynecologic Oncology Group trials. Gynecol Oncol. 1999;75:349–355
  61. Epstein BE, Scott CB, Sause WT, et al. Improved survival duration in patients with unresected solitary brain metastasis using accelerated hyperfractionated radiation therapy at total doses of 54.4 gray and greater. Results of Radiation Therapy Oncology Group 85-28. Cancer. 1993;71:1362–1367
  62. Sause WT, Scott C, Krisch R, et al. Phase I/II trial of accelerated fractionation in brain metastases RTOG 85-28. Int J Radiat Oncol Biol Phys. 1993;26:653–657
  63. Lauve A, Morris M, Schmidt Ullrich R, et al. Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced head-and-neck squamous cell carcinomas: II – clinical results. Int J Radiat Oncol Biol Phys. 2004;60:374–387
  64. Dent SF, Eisenhauer EA. Phase I trial design: are new methodologies being put into practice?. Ann Oncol. 1996;7:561–566
  65. Hawkins MJ. Early cancer clinical trials: safety, numbers, and consent. J Natl Cancer Inst. 1993;85:1618–1619
  66. Thall PF, Lee SJ. Practical model-based dose-finding in phase I clinical trials: methods based on toxicity. Int J Gynecol Cancer. 2003;13:251–261
  67. Braun TM. Generalizing the TITE-CRM to adapt for early- and late-onset toxicities. Stat Med. 2006;25:2071–2083
  68. Normolle D, Lawrence T. Designing dose-escalation trials with late-onset toxicities using the time-to-event continual reassessment method. J Clin Oncol. 2006;24:4426–4433
  69. Paoletti X, Baron B, Schoffski P, et al. Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study. Eur J Cancer. 2006;42:1362–1368
  70. Ahn C. An evaluation of phase I cancer clinical trial designs. Stat Med. 1998;17:1537–1549
  71. Trotti A. Toxicity in head and neck cancer: a review of trends and issues. Int J Radiat Oncol Biol Phys. 2000;47:1–12
  72. Arbuck SG. Workshop on phase I study design. Ninth NCI/EORTC New Drug Development Symposium, Amsterdam, March 12, 1996. Ann Oncol. 1996;7:567–573
  73. Denis F, Garaud P, Bardet E, et al. Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys. 2003;55:93–98
  74. Hoeller U, Tribius S, Kuhlmey A, Grader K, Fehlauer F, Alberti W. Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores. Int J Radiat Oncol Biol Phys. 2003;55:1013–1018
  75. Trotti A, Colevas AD, Setser A, Basch E. Patient-reported outcomes and the evolution of adverse event reporting in oncology. J Clin Oncol. 2007;25:5121–5127
  76. Lutgens LC, Deutz NE, Gueulette J, et al. Citrulline: a physiologic marker enabling quantitation and monitoring of epithelial radiation-induced small bowel damage. Int J Radiat Oncol Biol Phys. 2003;57:1067–1074
  77. Barthelemy-Brichant N, Bosquee L, Cataldo D, et al. Increased IL-6 and TGF-beta1 concentrations in bronchoalveolar lavage fluid associated with thoracic radiotherapy. Int J Radiat Oncol Biol Phys. 2004;58:758–767
  78. Hartsell WF, Scott CB, Dundas GS, et al. Can serum markers be used to predict acute and late toxicity in patients with lung cancer? Analysis of RTOG 91-03. Am J Clin Oncol. 2007;30:368–376
  79. Heemsbergen WD, Peeters ST, Koper PC, Hoogeman MS, Lebesque JV. Acute and late gastrointestinal toxicity after radiotherapy in prostate cancer patients: consequential late damage. Int J Radiat Oncol Biol Phys. 2006;66:3–10
  80. Tucker SL, Dong L, Cheung R, et al. Comparison of rectal dose-wall histogram versus dose-volume histogram for modeling the incidence of late rectal bleeding after radiotherapy. Int J Radiat Oncol Biol Phys. 2004;60:1589–1601
  81. Husing J, Sauerwein W, Hideghety K, Jockel KH. A scheme for a dose-escalation study when the event is lagged. Stat Med. 2001;20:3323–3334
  82. Belderbos JS, Heemsbergen WD, De Jaeger K, Baas P, Lebesque JV. Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:126–134
  83. Rosenzweig KE, Fox JL, Yorke E, et al. Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma. Cancer. 2005;103:2118–2127
  84. Leibel SA, Zelefsky MJ, Kutcher GJ, Burman CM, Kelson S, Fuks Z. Three-dimensional conformal radiation therapy in localized carcinoma of the prostate: interim report of a phase 1 dose-escalation study. J Urol. 1994;152:1792–1798

PII: S0167-8140(10)00086-1

doi: 10.1016/j.radonc.2010.02.009

Radiotherapy & Oncology
Volume 95, Issue 2 , Pages 135-141 , May 2010

Article Tools

* Image Usage & Resolution