PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System

Anouk Corbeau, Remi A Nout, Jan Willem M Mens, Nanda Horeweg, Jérémy Godart, Ellen M Kerkhof, Sander C Kuipers, Mariette I E van Poelgeest, Judith R Kroep, Ingrid A Boere, Helena C van Doorn, Mischa S Hoogeman, Uulke A van der Heide, Hein Putter, Marij J P Welters, Sjoerd H van der Burg, Carien L Creutzberg, Stephanie M de Boer, Anouk Corbeau, Remi A Nout, Jan Willem M Mens, Nanda Horeweg, Jérémy Godart, Ellen M Kerkhof, Sander C Kuipers, Mariette I E van Poelgeest, Judith R Kroep, Ingrid A Boere, Helena C van Doorn, Mischa S Hoogeman, Uulke A van der Heide, Hein Putter, Marij J P Welters, Sjoerd H van der Burg, Carien L Creutzberg, Stephanie M de Boer

Abstract

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

Keywords: bone marrow; bowel; cervical cancer; chemoradiotherapy; dose reduction; proton therapy; quality of life; toxicity.

Conflict of interest statement

R.A.N. reports to have received research grants from Dutch Cancer Society, Dutch Research Council, Elekta, and Accuray, and a research grant for this work by Varian Medical Systems. N.H. reports to have received research grants from the Dutch Cancer Society and Varian Medical Systems. J.G. reports to have received a research grant for this work by Varian Medical Systems. J.R.K. reports to have received research grants from Amgen, Astra Zeneca, Novartis, Philips, and Sanofi, and is on the advisory board for Astra Zeneca, Eisai, Lilly, MSD, Novartis, Roche, Pfizer, and Tesaro/GSK. M.S.H. reports to have received research grants from Varian Medical Systems and clinical advisory membership of Accuray. S.H.v.d.B. reports to be a consultant for CHDR Innovation Services and member of the advisory board for ISA Pharmaceuticals, PCI Biotech, DCprime, and AGLAIA. C.L.C. reports a nonfinancial support (research platform to institution) from Elekta, compensation for IDMC membership (paid to institution) by Merck, and a research grant for this work by Varian Medical Systems. S.M.d.B. reports to have received a research grant for this work by Varian Medical Systems. All other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
A typical dose distribution for the para-aortic region for IMRT (left) and IMPT (right) [24].
Figure 2
Figure 2
Schematic scheme of PROTECT’s study design. IMRT, intensity-modulated radiation therapy; VMAT, volumetric-modulated arc therapy; IMPT, intensity modulated proton therapy.
Figure 3
Figure 3
Sample size calculation to determine power to detect significant differences in pelvic bones Dmean (Gy (left) and bowel mean V15Gy (cc) (right) when comparing IMPT and IMRT/VMAT.
Figure 4
Figure 4
Overview of data collection points per patient enrolled in the PROTECT trial. *, data collection point; EBRT, external beam radiation therapy; W, week; M, month; MRI, magnetic resonance imaging; QoL, quality of life.

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