Phase I/II trial evaluating concurrent carbon-ion radiotherapy plus chemotherapy for salvage treatment of locally recurrent nasopharyngeal carcinoma

Abstract

BackgroundAfter definitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma (NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present significant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can benefit from these treatments. Re-irradiation with X-ray—based intensity-modulated radiotherapy (IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radio-resistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy (CIRT). In addition, CIRT is a high linear energy transfer (LET) radiation and provides an increased relative biological effectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 GyE (gray equivalent), at 2.5 GyE per daily fraction, was well tolerated in patients who were previously treated for NPC with a definitive dose of IMXT. The short-term response rates at 3–6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can benefit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the benefits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results.Methods and designThe maximal tolerated dose (MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 GyE (2.5 GyE × 21–26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Efficacy in terms of overall survival (OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%.ConclusionsRe-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate efficacy but causes potentially severe toxicities. Improved outcomes in terms of efficacy and toxicity profile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is n...

Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results

“…To our knowledge, the question of whether the addition of concurrent chemotherapy to salvage IMCT can improve disease control further in patients with LR‐NPC after they fail definitive RT is unknown. This is the subject of one of the dose escalating trials that currently is ongoing at SPHIC …”

“…This is the subject of one of the dose escalating trials that currently is ongoing at SPHIC. 17 The use of Epstein-Barr virus (EBV) DNA as a prognosticator and to guide treatment has been a focus of investigation for patients with NPC. In a pivotal study published by Lin et al, 32 a higher pretreatment plasma EBV (pEBV) DNA concentration was found to be a significant predictor of worse outcome.…”

“…All patients diagnosed with LR-NPC who were previously treated with and reirradiated with IMCT >6 months after the completion of definitive photon-based RT were treated prospectively with IMCT (raster scanning technology) using either a standardized treatment protocol or 1 of the 3 dose-escalating phase 1/2 clinical trial protocols at the Shanghai Proton and Heavy Ion Center (SPHIC). 17,18 All protocols were registered to the institutional review board (IRB) of the SPHIC. IRB approvals were obtained for the 3 projects as well as the treatment protocol involved herein.…”

Induction Chemotherapy Has No Prognostic Value in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Chronic Hepatitis B Infection in the IMRT Era

“…The National Comprehensive Cancer Network currently recommended CCRT as the standard treatment for locoregionally advanced NPC and its survival benefits are well-demonstrated [7] , [9] , [10] , [20] , [21] , [22] , [23] , [24] . Over the last decade, much attention has been paid to assessment of the prognostic value of adding IC to CCRT in locoregionally advanced NPC [11] , [12] , [13] , [14] , [15] , [16] , [25] , [26] , as it may improve LRRFS, DMFS and OS. Though the results obtained are controversial, a meta-analysis of these trials conducted by Ouyang et al [16] indicated IC could effectively enhance OS and reduce distant metastasis in locoregionally advanced NPC.…”

Prognosis of nasopharyngeal carcinoma with insufficient radical dose to the primary site in the intensity‐modulated radiotherapy era

“…Although some studies have been demonstrated the feasibility of reduced-dose radiotherapy based on IC, 11,18,26 reduced-dose radiation for newly diagnosed patients without metastasis may be overaggressive. 27 Therefore, reduced-dose radiotherapy for NPC should be approached with caution. 27 Therefore, reduced-dose radiotherapy for NPC should be approached with caution.…”