Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Prediction of dose-volume histograms in nasopharyngeal cancer IMRT using geometric and dosimetric information.

A method using both patient geometric and dosimetric information was proposed to predict dose-volume histograms (DVHs) of organs at risk (OARs) for a nasopharyngeal cancer (NPC) intensity-modulated radiation therapy (IMRT) plan. A total of 106 nine-field IMRT NPC plans were used in this study. Twenty-six plans were randomly selected as testing cases, and the remaining plans were used as the training data. A method employing geometric and dosimetric information was developed for OAR DVH prediction. The dosimetric information was derived from an initial dose calculation using a simple unoptimized conformal plan. The DVHs were also predicted using only the geometric information. The DVH prediction model was a generalized regression neural network (GRNN). Mean absolute error (MAE) and R 2 values were introduced to evaluate DVH prediction accuracy. Significant differences in the DVH prediction accuracy were found between the method employing the geometric and dosimetric information and the method utilizing the geometric information for the brainstem (R 2, 0.98 versus 0.95, p  = 0.007; MAE, 3.52% versus 7.19%, p  = 0.002), spinal cord (R 2, 0.98 versus 0.96, p  < 0.001; MAE, 2.80% versus 4.36%, p  < 0.001), left optic nerve (R 2, 0.90 versus 0.77, p  = 0.014; MAE, 3.07% versus 11.29%, p  = 0.025) and other organs. On average, the R 2 value increased by ~6.7% and the MAE value decreased by ~46.7% after adding the dosimetric information to the DVH prediction. We developed a method for predicting DVHs of OARs in NPC IMRT plans by using geometric and dosimetric information. Adding dosimetric information can help predict the DVHs of OARs in NPC IMRT plans.

Incidence and dosimetric parameters for brainstem necrosis following intensity modulated radiation therapy in nasopharyngeal carcinoma.

OBJECTIVES: To clarify the incidence of brainstem toxicity and perform a dose-volume analysis for the brainstem after long-term follow-up of a large cohort of nasopharyngeal carcinoma (NPC) patients who underwent intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: All patients with NPC treated with IMRT at Sun Yat-sen University Cancer Center between April 2009 and March 2012 were retrospectively reviewed. A total of 1544 patients with follow-up >12months and detailed treatment plan data were included. Radiotherapy was administered using the simultaneous integrated boost technique in 2.0-2.48Gy per fractions/28-33 fractions. Brainstem necrosis was defined as lesions with high signal intensity on T2-weighted images and low signal intensity on T1-weighted images, with or without enhancement after administration of contrast in follow-up MRI. RESULTS: After median follow-up of 79.7months (range, 12.2-85.6months), 2/1544 (0.13%) patients developed brainstem necrosis after intervals of 12.3 and 18.5months. Actuarial incidence of brainstem necrosis was 0.07%, 0.13%, 0.13% and 0.13% after 1, 2, 3 and 5years, respectively. Overall, 384 (24.9%), 153 (9.9%), 67 (4.3%), 39 (2.5%), 78 (5.1%), and 114 (7.4%) patients had excessive doses of Dmax≥64Gy, D1cc>59Gy, D2cc>59Gy, aV50>5.9cc, aV55>2.7cc and aV60>0.9cc respectively, of whom only two developed brainstem necrosis. CONCLUSIONS: Brainstem necrosis is rare in NPC. The definitive criteria based on conventional radiotherapy cannot accurately predict the occurrence of brainstem necrosis after IMRT, thus more flexible definitive criteria with strict restrictions need to be defined.

Gantry angle-dependent correction of dose detection error due to panel position displacement in IMRT dose verification using EPIDs.

PURPOSE: The purpose of this study was to measure the mechanical position displacement of three types of electronic portal image device (EPID) panels at different gantry angles and evaluate the impact of positional displacement on intensity modulated radiation therapy (IMRT) dose verification using an EPID. METHODS: Three types of linear accelerators and EPIDs (aS500, aS1000 and iViewGT) were used. The portal images were taken every 10° within 360° range. The position coordinate difference between the panel center and the portal film center at different gantry angles was measured, then the mechanical position displacement of EPIDs dependent on the gantry angles was analyzed. For the three linear accelerators and EPIDs, five IMRT plans were measured using EPIDs at 0° gantry angel and at the actual treatment angles. The Gamma technique was used to evaluate the resulted dose difference before and after the corrections of the position displacement by a in-house software. RESULTS: For aS500, aS1000 and iViewGT, the maximum mechanical position displacement was 2.9 ± 0.1 mm, 0.2 ± 0.1 mm and 0.1 ± 0.3 mm in the lateral direction and -4.2 ± 0.2 mm, -4.2 ± 0.1 mm and -2.2 ± 0.1 mm in the longitudinal direction, respectively. The position displacement in the longitudinal direction of the three EPIDs can be fitted well with a function. For aS500, aS1000 and iViewGT, the 3%/3 mm gamma pass rates were increased by 6.7%, 2.9% and 0.1% after displacement corrections; and while the 2%/2 mm gamma pass rates were increased by 11.2%, 8.1% and 1.6%. After the displacement correction, there was a slight gamma pass rate difference between the fixed zero degree gantry and the actual treatment angles. CONCLUSION: When the EPIDs were used for IMRT dose verification, there was occasionally large EPID mechanical position displacement, which should be corrected.