The feasibility and efficacy of new SBRT technique HyperArc for recurrent nasopharyngeal carcinoma: noncoplanar cone-based robotic system vs. noncoplanar high-definition MLC based Linac system.

The purpose of this study was to evaluate the feasibility and efficacy of HyperArc (HA) for recurrent nasopharyngeal cancer (NPC) by comparing it with the CyberKnife system (CK). Fifteen patients with recurrent nasopharyngeal cancer who were treated using the noncoplanar cone-based robotic CK system were enrolled. CK was delivered with a median dose of 37.5 Gy in 5 fractions. The delivered CK treatment plans were the sources for the corresponding homogeneous HA (HA-H) and inhomogeneous HA (HA-IH) plans. The HA-H plans were generated to meet the corresponding treatment plan criteria for the CK plans. The HA-IH plans were designed to emulate the corresponding inhomogeneous CK isodose distributions. These three SBRT treatment plans were compared with target coverage, sparing of organs at risk (OARs), and dose distribution metrics. The HA-H and HA-IH plans consistently exhibited CTV and PTV coverage levels similar or better to those of the CK plans but significantly reduced the dose to OARs. Using the HA techniques (both HA-H and HA-IH plans), the mean maximal doses to the spinal cord, brainstem, optic nerves, and optic chiasm were reduced by approximately 60%, compared to the CK plans. The high dose spillage, conformity, and homogeneity indices of the HA-H plans were significantly better than those of the CK plans. The HA-IH plans showed faster dose falloff and similar conformity of the HA-H plans and dose heterogeneity of the CK plans. Here we demonstrated the HA treatment plan system for recurrent NPC is feasible, either homogeneous or inhomogeneous delivery. Excellent sparing of OARs and dosimetric distribution and very efficient delivery make HA an attractive SBRT technique for recurrent NPC treatment.

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

BACKGROUND: After 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 DESIGN: The 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%. CONCLUSIONS: Re-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 needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.

Phase I/II Trial Evaluating Carbon Ion Radiotherapy for Salvaging Treatment of Locally Recurrent Nasopharyngeal Carcinoma.

BACKGROUND: Radiation therapy is the mainstay strategy for the treatment of nasopharyngeal cancer (NPC). Intensity-modulated X-ray therapy (IMXT) alone is the current standard for stage I and II NPC. For stage III and IV A/B diseases, concurrent chemotherapy should be provided in addition to IMXT. However, optimal treatment for locally recurrent NPC after previous definitive dose of radiotherapy is lacking. Various techniques including brachytherapy, IMXT, stereotactic radiosurgery or radiotherapy (SRS or SBRT) have been used in the management of locally recurrent NPC. Due to the inherent limitation of these techniques, i.e., limited range of irradiation or over-irradiation to surrounding normal tissues, moderate efficacy has been observed at the cost of severe toxicities. Carbon ion radiotherapy (CIRT) offers potential physical and biological advantages over photon and proton radiotherapy. Due to the inverted dose profile of particle beams and their greater energy deposition within the Bragg peak, precise dose delivery to the target volume(s) without exposing the surrounding organs at risk to extra doses is possible. In addition, CIRT provides an increased relative biological effectiveness (RBE) as compared to photon and proton radiotherapy. Such advantages may translate to improved outcomes after irradiation in terms of disease control in radio-resistant and previously treated, recurrent malignancies. It is therefore reasonable to postulate that recurrent NPC after high-dose radiotherapy could be more resistant to re-irradiation using photons. Reports on the treatment of radio-resistant malignancies in the head and neck region such as melanoma, sarcoma, and adenoid cystic carcinoma (ACC) have demonstrated superior local control rates from CIRT as compared to photon irradiation. Thus patients with recurrent NPC are likely to benefit from the enhanced biological effectiveness of carbon ions. As effective retreatment strategy is lacking for locally recurrent NPC, carbon ion radiation therapy offers an ideal alternate to conventional X-ray irradiation. METHODS AND DESIGN: The recommended dose of re-irradiation using CIRT for locally recurrent NPC will be determined in the dose-escalating phase (Phase I) of the study. Efficacy in terms of local progression-free survival (LPFS) and overall survival (OS) will be studied in the second phase of the study. Increasing doses of CIRT using raster scanning technology from 55GyE (22×2.5 GyE) to 65 GyE (26× 2.5 GyE) will be delivered in the Phase I part of the study. The primary endpoint of the Phase I part of the study is acute and sub-acute toxicities; the primary endpoint in the Phase II part is local progression-free survival and overall survival. Using the historical 2-year OS rate of 50% in locally recurrent NPC patients treated with photon or proton, we hypothesize that CIRT can improve the 2-year OS rate to 70%. DISCUSSION: The utilization of conventional radiation techniques including IMXT, brachytherapy, or stereotactic radiation therapy provides moderate efficacy in the treatment of locally recurrent NPC due to the limitations in dose distribution and biological effectiveness. Improved outcome in terms of treatment-induced toxicity, LC, LPFS, and OS are expected using CIRT due to the physical and biological characteristics of carbon ion beam. However, the recommended dose of CIRT used in re-irradiation for the local NPC focus remain to be determined. The recommended dose as well as the efficacy of CIRT in the treatment of locally recurrent NPC will be evaluated in the present trial.

Identification of novel tumor suppressor genes down-regulated in recurrent nasopharyngeal cancer by DNA microarray.

The nasopharyngeal cancer is a common cancer among southern Chinese. In order to better understand molecular mechanism of recurrent nasopharyngeal cancer (rNPC), we used DNA microarray to identify down-regulated tumor suppressed genes (TSGs) in rNPC, and bioinformatics to analyze their chromosomal localizations and molecular functions. Eight non-recurrent nasopharyngeal cancer (nNPC) and six rNPC tissue samples were selected, and Affymetrix Gene1.0 ST chips were used to construct the expression profiling of each tissue sample. Identify the down-regulated TSGs in rNPC by comparing expression profiling data of two type tissue samples. A total of five TSGs were identified to be down-regulated in rNPC. These five TSGs include SERPINF1, TPD52L1, FBLN1, RASSF6, and S100A2, and Signal Log Ratio were -2.2, -2.3, -3.5, -3.9 and -6.9 respectively. Chromosomal localization analysis showed that S100A2, RASSF6, TPD52L1, SERPINF1, and FBLN1 were located on chromosomes 1q, 4q, 6q, 17p and 22q, respectively. Functional analysis showed that SERPINF1 and TPD52L1 belonged to enzyme activity genes, S100A2 and FBLN1 belonged to calcium ion binding genes, RASSF6 belong to protein binding genes. Five TSGs likely to be the candidate TSGs involved in rNPC, and may play important roles in occurrence of rNPC. Chromosomes 1q, 4q, 6q, 17p and 22q may be considered as important region for screening TSGs that may relevant to rNPC. Those genes and chromosomal region need to be further studied.

Lateral palatal flap approach to the nasopharynx and parapharyngeal space for transoral robotic surgery: a cadaveric study.

The da Vinci surgical robot has been used for minimally invasive surgery of the head and neck region including resection of tumors in the nasopharynx. Access to and vision of the nasopharynx with the robot are difficult. A pure transoral approach and midline palatal split approach have been described. The disadvantage of these approaches is the limited lateral access to the parapharyngeal space. The objective of this study was to investigate the feasibility of accessing the nasopharynx and parapharyngeal space with a lateral palatal flap. Two complete nasopharyngectomies with resection of the parapharyngeal space and exposure of the internal carotid artery and branches of the mandibular nerves were performed on two fresh cadavers with the da Vinci surgical robot. The set up of the robot, the surgical procedure of elevating the lateral palatal flap, and robotic resection of the nasopharynx and parapharyngeal space are described.