Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma-the ISAC trial protocol

Matthias Uhl, Lutz Edler, Alexandra D Jensen, Gregor Habl, Jan Oelmann, Falk Röder, Oliver Jäckel, Jürgen Debus, Klaus Herfarth, Matthias Uhl, Lutz Edler, Alexandra D Jensen, Gregor Habl, Jan Oelmann, Falk Röder, Oliver Jäckel, Jürgen Debus, Klaus Herfarth

Abstract

Background: Chordomas are relatively rare lesions of the bones. About 30% occur in the sacrococcygeal region. Surgical resection is still the standard treatment. Due to the size, proximity to neurovascular structures and the complex anatomy of the pelvis, a complete resection with adequate safety margin is difficult to perform. A radical resection with safety margins often leads to the loss of bladder and rectal function as well as motoric/sensoric dysfunction. The recurrence rate after surgery alone is comparatively high, such that adjuvant radiation therapy is very important for improving local control rates. Proton therapy is still the international standard in the treatment of chordomas. High-LET beams such as carbon ions theoretically offer biologic advantages in slow-growing tumors. Data of a Japanese study of patients with unresectable sacral chordoma showed comparable high control rates after hypofractionated carbon ion therapy only.

Methods and design: This clinical study is a prospective randomized, monocentric phase II trial. Patients with histologically confirmed sacrococcygeal chordoma will be randomized to either proton or carbon ion radiation therapy stratified regarding the clinical target volume. Target volume delineation will be carried out based on CT and MRI data. In each arm the PTV will receive 64 GyE in 16 fractions. The primary objective of this trial is safety and feasibility of hypofractionated irradiation in patients with sacrococygeal chordoma using protons or carbon ions in raster scan technique for primary or additive treatment after R2 resection. The evaluation is therefore based on the proportion of treatments without Grade 3-5 toxicity (CTCAE, version 4.0) up to 12 months after treatment and/or discontinuation of the treatment for any reason as primary endpoint. Local-progression free survival, overall survival and quality of life will be analyzed as secondary end points.

Discussion: The aim of this study is to confirm the toxicity results of the Japanese data in raster scan technique and to compare it with the toxicity analysis of proton therapy given in the same fractionation. Using this data, a further randomized phase III trial is planned, comparing hypofractionated proton and carbon ion irradiation.

Trial registration: ClinicalTrials.gov Identifier: NCT01811394.

Figures

Figure 1
Figure 1
Workflow.
Figure 2
Figure 2
Dose distribution and DVH of a patient treated with 64GyE carbon ion therapy within the ISAC trial. a) dose distribution and b) dose volume histogram (DVH) of a patient within the trial.
Figure 3
Figure 3
Examinations during the trial in tabular view. RT = radiothrapy.

References

    1. Friedrich T, Scholz U, Elsasser T, Durante M, Scholz M. Calculation of the biological effects of ion beams based on the microscopic spatial damage distribution pattern. Int J Radiat Biol. 2012;88:103–107. doi: 10.3109/09553002.2011.611213.
    1. Kramer M, Weyrather WK, Scholz M. The increased biological effectiveness of heavy charged particles: from radiobiology to treatment planning. Technol Cancer Res Treat. 2003;2:427–436.
    1. Scholz M, Kraft G. Track structure and the calculation of biological effects of heavy charged particles. Adv Space Res. 1996;18:5–14.
    1. Murakami M, Eguchi-Kasai K, Sato K, Minohara S, Yatagai F, Kanai T. Differences in heavy-ion-induced DNA double-strand breaks in a mouse DNA repair-deficient mutant cell line (SL3-147) before and after chromatin proteolysis. J Radiat Res. 1995;36:258–264. doi: 10.1269/jrr.36.258.
    1. Heilmann J, Taucher-Scholz G, Haberer T, Scholz M, Kraft G. Measurement of intracellular dna double-strand break induction and rejoining along the track of carbon and neon particle beams in water. Int J Radiat Oncol Biol Phys. 1996;34:599–608. doi: 10.1016/0360-3016(95)02112-4.
    1. McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM. Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control. 2001;12:1–11. doi: 10.1023/A:1008947301735.
    1. Bjornsson J, Wold LE, Ebersold MJ, Laws ER. Chordoma of the mobile spine. A clinicopathologic analysis of 40 patients. Cancer. 1993;71:735–740. doi: 10.1002/1097-0142(19930201)71:3<735::AID-CNCR2820710314>;2-8.
    1. Rosenberg AE, Brown GA, Bhan AK, Lee JM. Chondroid chordoma–a variant of chordoma. A morphologic and immunohistochemical study. Am J Clin Pathol. 1994;101:36–41.
    1. Chugh R, Tawbi H, Lucas DR, Biermann JS, Schuetze SM, Baker LH. Chordoma: the nonsarcoma primary bone tumor. Oncologist. 2007;12:1344–1350. doi: 10.1634/theoncologist.12-11-1344.
    1. Chen KW, Yang HL, Lu J, Liu JY, Chen XQ. Prognostic factors of sacral chordoma after surgical therapy: a study of 36 patients. Spinal Cord. 2010;48:166–171. doi: 10.1038/sc.2009.95.
    1. Fuchs B, Dickey ID, Yaszemski MJ, Inwards CY, Sim FH. Operative management of sacral chordoma. J Bone Joint Surg Am. 2005;87:2211–2216. doi: 10.2106/JBJS.D.02693.
    1. Osaka S, Kodoh O, Sugita H, Osaka E, Yoshida Y, Ryu J. Clinical significance of a wide excision policy for sacrococcygeal chordoma. J Cancer Res Clin Oncol. 2006;132:213–218. doi: 10.1007/s00432-005-0067-3.
    1. York JE, Kaczaraj A, Abi-Said D, Fuller GN, Skibber JM, Janjan NA, York JE, Kaczaraj A, Abi-Said D, Fuller GN, Skibber JM, Janjan NA, Gokaslan ZL. Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery. 1999;44:74–79. doi: 10.1097/00006123-199901000-00041. discussion 9–80.
    1. Park L, Delaney TF, Liebsch NJ, Hornicek FJ, Goldberg S, Mankin H, Rosenberg AE, Rosenthal DI, Suit HD. Sacral chordomas: Impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor. Int J Radiat Oncol Biol Phys. 2006;65:1514–1521. doi: 10.1016/j.ijrobp.2006.02.059.
    1. Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull base. Strahlenther Onkol. 1999;175(Suppl 2):57–63.
    1. Hug EB, Loredo LN, Slater JD, DeVries A, Grove RI, Schaefer RA, Rosenberg AE, Slater JM. Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg. 1999;91:432–439. doi: 10.3171/jns.1999.91.3.0432.
    1. Ares C, Hug EB, Lomax AJ, Bolsi A, Timmermann B, Rutz HP, Schuller JC, Pedroni E, Goitein G. Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol Biol Phys. 2009;75:1111–1118. doi: 10.1016/j.ijrobp.2008.12.055.
    1. Schulz-Ertner D, Karger CP, Feuerhake A, Nikoghosyan A, Combs SE, Jäkel O, Edler L, Scholz M, Debus J. Effectiveness of carbon ion radiotherapy in the treatment of skull-base chordomas. Int J Radiat Oncol Biol Phys. 2007;68:449–457. doi: 10.1016/j.ijrobp.2006.12.059.
    1. Nikoghosyan AV, Karapanagiotou-Schenkel I, Munter MW, Jensen AD, Combs SE, Debus J. Randomised trial of proton vs. carbon ion radiation therapy in patients with chordoma of the skull base, clinical phase III study HIT-1-Study. BMC Cancer. 2010;10:607. doi: 10.1186/1471-2407-10-607.
    1. Devin C, Chong PY, Holt GE, Feurer I, Gonzalez A, Merchant N, Schwartz HS. Level-adjusted perioperative risk of sacral amputations. J Surg Oncol. 2006;94:203–211. doi: 10.1002/jso.20477.
    1. Cheng EY, Ozerdemoglu RA, Transfeldt EE, Thompson RC Jr. Lumbosacral chordoma. Prognostic factors and treatment. Spine (Phila Pa 1976) 1999;24:1639–1645. doi: 10.1097/00007632-199908150-00004.
    1. Nishida Y, Kamada T, Imai R, Tsukushi S, Yamada Y, Sugiura H, Shido Y, Wasa J, Ishiguro N. Clinical outcome of sacral chordoma with carbon ion radiotherapy compared with surgery. Int J Radiat Oncol Biol Phys. 2011;79:110–116. doi: 10.1016/j.ijrobp.2009.10.051.
    1. Imai R, Kamada T, Tsuji H, Sugawara S, Serizawa I, Tsujii H, Tatezaki S. Working Group for Bone and Soft Tissue Sarcomas. Effect of carbon ion radiotherapy for sacral chordoma: results of Phase I-II and Phase II clinical trials. Int J Radiat Oncol Biol Phys. 2010;77:1470–1476. doi: 10.1016/j.ijrobp.2009.06.048.
    1. Elsasser T, Kramer M, Scholz M. Accuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo. Int J Radiat Oncol Biol Phys. 2008;71:866–872. doi: 10.1016/j.ijrobp.2008.02.037.
    1. Imai R, Kamada T, Sugahara S, Tsuji H, Tsujii H. Carbon ion radiotherapy for sacral chordoma. Br J Radiol. 2011;84(Spec No 1):S48–S54.
    1. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys. 2006;65:1–7. doi: 10.1016/j.ijrobp.2006.01.027.
    1. Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials. 1982;3:345–353. doi: 10.1016/0197-2456(82)90024-1.
    1. DeLaney TF, Liebsch NJ, Pedlow FX, Adams J, Dean S, Yeap BY, McManus P, Rosenberg AE, Nielsen GP, Harmon DC, Spiro IJ, Raskin KA, Suit HD, Yoon SS, Hornicek FJ. Phase II study of high-dose photon/proton radiotherapy in the management of spine sarcomas. Int J Radiat Oncol Biol Phys. 2009;74:732–739. doi: 10.1016/j.ijrobp.2008.08.058.
    1. Yanagi T, Kamada T, Tsuji H, Imai R, Serizawa I, Tsujii H. Dose-volume histogram and dose-surface histogram analysis for skin reactions to carbon ion radiotherapy for bone and soft tissue sarcoma. Radiother Oncol. 2010;95:60–65. doi: 10.1016/j.radonc.2009.08.041.
    1. Davidge KM, Eskicioglu C, Lipa J, Ferguson P, Swallow CJ, Wright FC. Qualitative assessment of patient experiences following sacrectomy. J Surg Oncol. 2010;101:447–450.
    1. Hulen CA, Temple HT, Fox WP, Sama AA, Green BA, Eismont FJ. Oncologic and functional outcome following sacrectomy for sacral chordoma. J Bone Joint Surg Am. 2006;88:1532–1539. doi: 10.2106/JBJS.D.02533.

Source: PubMed

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