Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma

Sven van den Bosch, Tim Dijkema, Martina C Kunze-Busch, Chris H J Terhaard, Cornelis P J Raaijmakers, Patricia A H Doornaert, Frank J P Hoebers, Marije R Vergeer, Bas Kreike, Oda B Wijers, Wim J G Oyen, Johannes H A M Kaanders, Sven van den Bosch, Tim Dijkema, Martina C Kunze-Busch, Chris H J Terhaard, Cornelis P J Raaijmakers, Patricia A H Doornaert, Frank J P Hoebers, Marije R Vergeer, Bas Kreike, Oda B Wijers, Wim J G Oyen, Johannes H A M Kaanders

Abstract

Background: In definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called 'elective dose' in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary. Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment.

Methods: UPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial. Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4 N0-2 M0 squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors. In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level. Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5 weeks. The primary endpoint is 'normalcy of diet' at 1 year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment (safety).

Discussion: The objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck.

Trial registration: ClinicalTrials.gov Identifier: NCT02442375 .

Keywords: Accelerated radiation therapy; Dose de-escalation; Dose reduction; Elective nodes; Euality of life; FDG-PET; Head and neck cancer; Squamous cell carcinoma.

Figures

Fig. 1
Fig. 1
Flow chart giving an overview of the study design. *the reported dose is the equivalent dose in 2 Gy fractions (EQD2)
Fig. 2
Fig. 2
Radiation therapy planning FDG-PET/CT-scan of a patient with an laryngeal squamous cell carcinoma (red arrow) with an intermediate risk lymph node in level 3 right (red arrow) (a + b). Comparison of dose planning conform this study protocol for the control-arm (c) and intervention-arm (d) shows the potential of FDG-PET guided gradient dose prescription with dose reduction to the elective neck in order to better spare organs at risk

References

    1. Maccomb WS, Fletcher GH. Planned combination of surgery and radiation in treatment of advanced primary head and neck cancers. Am J Roentgenol Radium Ther Nucl Med. 1957;77(3):397–414.
    1. de Bondt RB, Nelemans PJ, Hofman PA, Casselman JW, Kremer B, van Engelshoven JM, et al. Detection of lymph node metastases in head and neck cancer: a meta-analysis comparing US, USgFNAC, CT and MR imaging. Eur J Radiol. 2007;64(2):266–272. doi: 10.1016/j.ejrad.2007.02.037.
    1. Liao LJ, Lo WC, Hsu WL, Wang CT, Lai MS. Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck-a meta-analysis comparing different imaging modalities. BMC Cancer. 2012;12:236. doi: 10.1186/1471-2407-12-236.
    1. Suwinski R, Maciejewski B, Withers HR. Dose-response relationship for elective neck irradiation of head and neck cancer--facts and controversies. Neoplasma. 1998;45(2):107–112.
    1. Withers HR, Peters LJ, Taylor JM. Dose-response relationship for radiation therapy of subclinical disease. Int J Radiat Oncol Biol Phys. 1995;31(2):353–359. doi: 10.1016/0360-3016(94)00354-N.
    1. Zhou SM, Wong TZ, Marks LB. Using FDG-PET activity as a surrogate for tumor cell density and its effect on equivalent uniform dose calculation. Med Phys. 2004;31(9):2577–2583. doi: 10.1118/1.1779372.
    1. Schinagl DA, Hoffmann AL, Vogel WV, van Dalen JA, Verstappen SM, Oyen WJ, et al. Can FDG-PET assist in radiotherapy target volume definition of metastatic lymph nodes in head-and-neck cancer? Radiother Oncol. 2009;91(1):95–100. doi: 10.1016/j.radonc.2009.02.007.
    1. Al-Mamgani A, van Rooij P, Tans L, Verduijn GM, Sewnaik A. Baatenburg de Jong RJ: A prospective evaluation of patient-reported quality-of-life after (chemo)radiation for oropharyngeal cancer: which patients are at risk of significant quality-of-life deterioration? Radiother Oncol. 2013;106(3):359–363. doi: 10.1016/j.radonc.2012.12.014.
    1. Langendijk JA, Doornaert P, Rietveld DH, Verdonck-de Leeuw IM, Leemans CR, Slotman BJ. A predictive model for swallowing dysfunction after curative radiotherapy in head and neck cancer. Radiother Oncol. 2009;90(2):189–195. doi: 10.1016/j.radonc.2008.12.017.
    1. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, Leemans CR, Aaronson NK, Slotman BJ. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol. 2008;26(22):3770–3776. doi: 10.1200/JCO.2007.14.6647.
    1. Dijkema T, Raaijmakers CP, Ten Haken RK, Roesink JM, Braam PM, Houweling AC, et al. Parotid gland function after radiotherapy: the combined michigan and utrecht experience. Int J Radiat Oncol Biol Phys. 2010;78(2):449–453. doi: 10.1016/j.ijrobp.2009.07.1708.
    1. Terhaard CH, Dijkema T, Braam PM, Roesink JM, Raaijmakers CP. Abstract OC-0078: Sparing the contralateral submandibular gland in oropharyngeal cancer patients; dose-response analysis. Radiother Oncol. 2013;106(Supplement 2):S30. doi: 10.1016/S0167-8140(15)32384-7.
    1. Eisbruch A, Kim HM, Feng FY, Lyden TH, Haxer MJ, Feng M, et al. Chemo-IMRT of oropharyngeal cancer aiming to reduce dysphagia: swallowing organs late complication probabilities and dosimetric correlates. Int J Radiat Oncol Biol Phys. 2011;81(3):e93–e99. doi: 10.1016/j.ijrobp.2010.12.067.
    1. Levendag PC, Teguh DN, Voet P, van der Est H, Noever I, de Kruijf WJ, et al. Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship. Radiother Oncol. 2007;85(1):64–73. doi: 10.1016/j.radonc.2007.07.009.
    1. Bakhshandeh M, Hashemi B, Mahdavi SR, Nikoofar A, Vasheghani M, Kazemnejad A. Normal tissue complication probability modeling of radiation-induced hypothyroidism after head-and-neck radiation therapy. Int J Radiat Oncol Biol Phys. 2013;85(2):514–521. doi: 10.1016/j.ijrobp.2012.03.034.
    1. List MA, Ritter-Sterr C, Lansky SB. A performance status scale for head and neck cancer patients. Cancer. 1990;66(3):564–569. doi: 10.1002/1097-0142(19900801)66:3<564::AID-CNCR2820660326>;2-D.
    1. van den Bosch S, Dijkema T, Verhoef LC, Zwijnenburg EM, Janssens GO, Kaanders JH. Patterns of Recurrence in Electively Irradiated Lymph Node Regions After Definitive Accelerated Intensity Modulated Radiation Therapy for Head and Neck Squamous Cell Carcinoma. Int J Radiat Oncol Biol Phys. 2016;94(4):766–774. doi: 10.1016/j.ijrobp.2015.12.002.
    1. Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2015;42(2):328–354. doi: 10.1007/s00259-014-2961-x.
    1. van den Bosch S, Dijkema T, Hoebers F, Terhaard C, Kaanders J, Oyen W: Tumor to cervical spinal cord standardized uptake ratio improves the reproducibility of 18F-FDG-PET based tumor segmentation in head and neck squamous cell . Submitted to Journal. 2017
    1. Gregoire V, Ang K, Budach W, Grau C, Hamoir M, Langendijk JA, et al. Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol. 2014;110(1):172–181. doi: 10.1016/j.radonc.2013.10.010.
    1. Brouwer CL, Steenbakkers RJ, Bourhis J, Budach W, Grau C, Gregoire V, et al. CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines. Radiother Oncol. 2015;117(1):83–90. doi: 10.1016/j.radonc.2015.07.041.
    1. Santanam L, Hurkmans C, Mutic S, van Vliet-Vroegindeweij C, Brame S, Straube W, et al. Standardizing naming conventions in radiation oncology. Int J Radiat Oncol Biol Phys. 2012;83(4):1344–1349. doi: 10.1016/j.ijrobp.2011.09.054.
    1. Common Toxicity Criteria v2.0 (Revised March 23, 1998).
    1. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) Int J Radiat Oncol Biol Phys. 1995;31(5):1341–1346. doi: 10.1016/0360-3016(95)00060-C.
    1. Dijkema T, Raaijmakers CP, Braam PM, Roesink JM, Monninkhof EM, Terhaard CH. Xerostomia: a day and night difference. Radiother Oncol. 2012;104(2):219–223. doi: 10.1016/j.radonc.2012.06.004.
    1. Roesink JM, Moerland MA, Battermann JJ, Hordijk GJ, Terhaard CH. Quantitative dose-volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region. Int J Radiat Oncol Biol Phys. 2001;51(4):938–946. doi: 10.1016/S0360-3016(01)01717-5.
    1. Patterson JM, McColl E, Carding PN, Kelly C, Wilson JA. Swallowing performance in patients with head and neck cancer: a simple clinical test. Oral Oncol. 2009;45(10):904–907. doi: 10.1016/j.oraloncology.2009.03.012.
    1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–376. doi: 10.1093/jnci/85.5.365.
    1. Bjordal K, Ahlner-Elmqvist M, Tollesson E, Jensen AB, Razavi D, Maher EJ, et al. Development of a European Organization for Research and Treatment of Cancer (EORTC) questionnaire module to be used in quality of life assessments in head and neck cancer patients. EORTC Quality of Life Study Group. Acta Oncol. 1994;33(8):879–885. doi: 10.3109/02841869409098450.
    1. Beetz I, Burlage FR, Bijl HP, Hoegen-Chouvalova O, Christianen ME, Vissink A, et al. The Groningen Radiotherapy-Induced Xerostomia questionnaire: development and validation of a new questionnaire. Radiother Oncol. 2010;97(1):127–131. doi: 10.1016/j.radonc.2010.05.004.
    1. McHorney CA, Robbins J, Lomax K, Rosenbek JC, Chignell K, Kramer AE, et al. The SWAL-QOL and SWAL-CARE outcomes tool for oropharyngeal dysphagia in adults: III. Documentation of reliability and validity. Dysphagia. 2002;17(2):97–114. doi: 10.1007/s00455-001-0109-1.
    1. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139–144. doi: 10.1200/JCO.1998.16.1.139.
    1. Pocock SJ. Group Sequential Methods in Design and Analysis of Clinical-Trials. Biometrika. 1977;64(2):191–200. doi: 10.1093/biomet/64.2.191.
    1. Thames HD, Withers HR, Peters LJ, Fletcher GH. Changes in early and late radiation responses with altered dose fractionation: Implications for dose-survival relationships. Int J Radiation Oncol, Biol, Physics. 1982;8(2):219–26.
    1. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncologica. 1988;27(2):131–46.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere