Locoregional Control and Mild Late Toxicity After Reducing Target Volumes and Radiation Doses in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Treated With Induction Chemotherapy (IC) Followed by Concurrent Chemoradiotherapy: 10-Year Results of a Phase 2 Study

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Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Locoregional Control and Mild Late Toxicity After Reducing Target Volumes and Radiation Doses in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Treated With Induction Chemotherapy (IC) Followed by Concurrent Chemoradiotherapy: 10-Year Results of a Phase 2 Study Chong Zhao, MD,*,y Jing-Jing Miao, MD,y Yi-Jun Hua, MD,y Lin Wang, MD,y Fei Han, MD,y Li-Xia Lu, MD,y Wei-Wei Xiao, MD,y Hai-Jun Wu, MM,y Man-Yi Zhu, MM,y Shao-Min Huang, BS,y Cheng-Guang Lin, PhD,y Xiao-Wu Deng, PhD,y and Cong-Hua Xie, MD* *Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China; and yState Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China Received Nov 12, 2018. Accepted for publication Mar 27, 2019.

Summary Delineation of target volumes and determination of their optimal doses present challenges in nasopharyngeal carcinoma after induction chemotherapy (IC). We

Purpose: To evaluate the long-term locoregional control, failure patterns, and late toxicity after reducing the target volume and radiation dose in patients with locoregionally advanced nasopharyngeal carcinoma patients treated with induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT). Methods and Materials: Previously untreated patients with locoregionally advanced nasopharyngeal carcinoma were recruited into this prospective study. All patients received 2 cycles of IC followed by CCRT. The gross tumor volumes of the nasopharynx (GTVnx) and the neck lymph nodes (GTVnd) were delineated according to

Reprint requests to: Cong-Hua Xie, MD, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Donghu Rd, Wuhan, Hubei, P.R. China. Tel: þ86-27-67812565; E-mail: [email protected] Chong Zhao and Jing-Jing Miao and Yi-Jun Hua made equal contributions to this study.

Int J Radiation Oncol Biol Phys, Vol. 104, No. 4, pp. 836e844, 2019 0360-3016/$ - see front matter Ó 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ijrobp.2019.03.043

This study was funded by the Science and Technology Project of Guangdong Province (No. 2014A020212433) and National Natural Science Foundation of China (No. 81872469). Disclosures: none. Supplementary material for this article can be found at https://doi.org/ 10.1016/j.ijrobp.2019.03.043. AcknowledgmentsdThe authors thank the patients and their families for their participation in this study.

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conducted a prospective study in locoregionally advanced nasopharyngeal carcinoma treated with IC plus concurrent chemoradiation therapy. The gross tumor volumes were delineated as the post-IC tumor extension receiving full therapeutic dose; post-IC tumor shrinkage was treated with a reduced dose. Excellent long-term locoregional control was obtained with limited marginal and outfield recurrences and mild late toxicities.

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the post-IC tumor extension and received full therapeutic doses (68 Gy and 62-66 Gy, respectively). The primary tumor shrinkage after IC was included in the high-risk clinical target volume (CTV1) with a reduced dose of 60 Gy. The locoregional recurrencefree survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. The location and extent of locoregional recurrences were transferred to pretreatment planning computed tomography for dosimetry analysis. Results: There were 112 patients enrolled in this study. The average mean dose of post-GTVnx, post-GTVnd (left), post-GTVnd (right), post-CTV1, and post-low-risk clinical target volume (CTV2) was 75.24, 68.97, 69.16, 70.49, and 63.37 Gy, respectively. With a median follow-up of 125.95 months, the 10-year LRRFS, DMFS and OS were 89.0%, 83.3%, and 75.9%, respectively. There were 8 local recurrences and 6 regional recurrences in 12 patients. All 8 of the local recurrences were in-field; among the 6 regional recurrences, 4 were in-field, 1 was marginal, and 1 was out-field. The most common late toxicities were grade 1 to 2 subcutaneous fibrosis, hearing loss, and xerostomia. No grade 4 late toxicities were observed. Conclusions: Reduction of the target volumes according to the post-IC tumor extension and radiation dose to the post-IC tumor shrinkage could yield excellent longterm locoregional control with limited marginal and out-field recurrences and mild late toxicities. Ó 2019 Elsevier Inc. All rights reserved.

Introduction The aim of radiation therapy (RT) is to deliver a precisely measured dose of irradiation to a defined tumor volume with as little damage as possible to the surrounding normal tissue, resulting in eradication of the tumor, favorable survival, and a high quality of life at a reasonable cost.1 Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia,2 and RT is the primary treatment modality for this disease. Because of its characteristics of escalating the tumor dose while sparing the adjacent organs, intensity modulated RT (IMRT) has improved treatment outcomes and become the standard RT technique for NPC since the 21st century. However, because of the anatomic proximity of critical organs at risk (OARs) and the highly infiltrative behavior of NPC, delineation of the target volumes and determination of their corresponding optimal doses often presents challenges, especially in patients with locoregionally advanced NPC (LANPC) whose tumors extend very close to critical OARs such as the brainstem, temporal lobe, optic chiasm, cranial nerves, and pituitary gland. For patients with LANPC, many randomized trials have shown that induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) can improve progression-free survival.3-5 Many trials have also reported that IC can achieve different degrees of tumor shrinkage,3,6 which increases the distance between the gross tumor and OARs. Given these findings, could target volumes be delineated according to the post-IC tumor volume, which may achieve the balance of delivering full therapeutic radiation dose to tumors while not exceeding the maximum tolerance dose to critical OARs? The present guidelines have different ideas.7,8 In head and neck cancer (HNC), it

has been proposed that pre-IC primary site and nodal gross tumor volumes (GTVs) should be used for RT planning. All structures involved in the tumor before IC should be included even if they not grossly involved after IC, and radiation doses should not be modified according to the response to IC even if a complete response is achieved because tumors might not undergo uniform macroscopic or microscopic regression.7 In the latest international guideline for the delineation of clinical target volumes (CTVs) for NPC, experts in general agreed that the pre-IC tumor volume should receive the full therapeutic dose regardless of post-IC shrinkage.8 Recently, Yang et al published a study9 showing that treating the post-IC tumor volume with the full therapeutic dose and ensuring the pre-IC volume receives at least 64 Gy does not appear to compromise the 3-year local, regional, or distant control or overall survival, but it does reduce late toxicities in patients with stage III to IV NPC. However, because of the short follow-up, this method of delineation of target volumes was not adopted by the latest international guideline.8 In 2004, we conducted a prospective clinical study in naive patients with LANPC treated with IC followed by CCRT. In this study, the GTVs of the nasopharynx (GTVnx) and the neck lymph nodes (GTVnd) were delineated according to the post-IC tumor extension and received the full therapeutic dose (68 Gy and 62-66 Gy, respectively), whereas the post-IC primary tumor shrinkage, as a high-risk area, received a reduced dose (60 Gy). With a median follow-up of over 10 years, we summarized the long-term results, including survival, locoregional failure patterns, and late toxicities, and share them to provide more evidence for a reasonable target volume delineation in LANPC treated with IC plus CCRT.

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Methods and Materials Patient eligibility Patients who fulfilled the following criteria were eligible: (1) histologically confirmed NPC (WHO I-III); (2) no previous treatment for NPC; (3) stage III to IVb disease according to the staging system of the 6th American Joint Committee on Cancer/Union for International Cancer Control10; (4) Karnofsky Performance Status scores 80; and (5) adequate organ function. All patients were required to provide written informed consent before entering the study. The study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. This study was registered in ClinicalTrials.gov (NCT03283293).

Sample size The sample size of this study was calculated using the Power and Sample Size Program. We designed this study in 2004, and at that time there were no 5-year survival data for patients with NPC treated by IMRT, so we referred to the data of 2-dimensional conventional-RT. According to previous studies, the 5-year locoregional recurrence-free survival (LRRFS) rate in stage III to IVb NPC treated by 2-dimensional conventional-RT with or without concurrent chemotherapy was approximately 70%.11-13 We assumed that our treatment regimen would increase the LRRFS rate to 85%. With a significance level of 0.05 and power equal to 80%, the minimum sample size requirement was 101 patients. Assuming a loss rate of 10%, the total sample size was estimated to be 112 patients.

Chemotherapy All recruited patients received 2 cycles of IC before CCRT. The IC consisted of 2 regimens: Regimen A, cisplatin 80 mg/m2 intravenously and 5-fluorouracil 3.5 g/m2 by 72-hour infusion; and Regimen B, carboplatin AUC Z 6 and paclitaxel 135 mg/m2 intravenously on day 1. The IC was scheduled every 3 weeks for 2 cycles unless the patient showed intolerance or progressive disease. Concurrent chemotherapy was scheduled 3 weeks after the last cycle of IC. Cisplatin at 80 mg/m2 was given intravenously on days 1 and 22, concomitant with IMRT. The chemotherapy time was postponed if neutrophil was <2.0  109/L or platelets were <100  109/L and was suspended if the creatinine clearance rate became <50 mL/ min.

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Radiation therapy and delineation of the target volumes All patients received radical IMRT, which was delivered 3 weeks after the last cycle of IC. The IMRT technique and process were previously described.14 All patients underwent a second head and neck magnetic resonance imaging (MRI) scan and endoscopy within the second week after the last cycle of IC. Patients also underwent 2 head and neck computed tomography (CT) scans (CT simulation with the same thermoplastic mask for each patient), at 1 week before the first cycle of IC and again the second week after the last cycle of IC. The target volumes were delineated on the 2 sets of CT scans by the same radiologist (Fig. E1; available online at https://doi.org/10.1016/j.ijrobp.2019.03.043). The images of the second CT scan and the target volumes after IC were used for IMRT treatment planning purposes. The GTVs of the primary site and neck lymph nodes before (pre-GTVnx, pre-GTVnd) and after (post-GTVnx, post-GTVnd) IC were defined according to the 2 sets of MRI scans and clinical and endoscopic findings. The bony structures of the skull base, cervical vertebra, pterygoid structures, and paranasal sinus invasion before IC were included in both the preGTVnx and post-GTVnx. If a complete response was achieved in the primary tumor (not including the base of the skull, cervical vertebra, pterygoid structures, or paranasal sinus erosion) or involved neck lymph nodes after IC, postGTVnx and post-GTVnd would not be delineated, and the post-CTVnd would be delineated according to the preGTVnd position. The high-risk CTVs before and after IC (pre-CTV1 and post-CTV1) were defined as the preGTVnx and post-GTVnx plus a 5 to 10 mm margin (2-3 mm margin posteriorly) to encompass the high-risk sites of the microscopic extension and the whole nasopharynx. The post-IC tumor shrinkage must be included in the post-CTV1 as a high-risk area. The low-risk CTVs before and after IC (pre-CTV2 and post-CTV2) were defined as the pre-CTV1 and post-CTV1 plus a 5 to 10 mm margin (2-3 mm margin posteriorly) to encompass the lowrisk sites, the level of the lymph node location before IC, post-CTVnd, and the elective neck area (bilateral levels IIa-b, III, and Va are routinely covered for all N0 patients, whereas ipsilateral levels IV, Vb, or supraclavicular fossae were also included for N1-3 patients). Planning target volumes were generated automatically after delineation of tumor targets by a uniform expansion ranging from 3 mm (1 mm posteriorly), depending on immobilization and localization uncertainties. The prescribed doses were 68 Gy in 30 fractions to the post-GTVnx, 62 to 66 Gy in 30 fractions to the postGTVnd, 60 Gy in 30 fractions to the post-CTVnd and the post-CTV1, and 54 Gy in 30 fractions to the post-CTV2. In addition, the prescribed dose to the lower neck and supraclavicular fossae by irradiation using the conventional RT technique was 50 Gy in 25 fractions for prophylactic intent and 60 to 66 Gy in 30 to 33 fractions for therapeutic intent.

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All of the critical adjacent structures, including the brainstem, spinal cord, temporal lobes, lens, optic nerves and chiasm, parotid glands, temporomandibular joints, and mandibles, were carefully outlined. The doses to these structures were constrained as much as possible without sacrificing coverage of the tumor targets.14

Patient evaluation and follow-up The pretreatment evaluation was performed within 2 weeks before IC and included a complete physical examination, fiberoptic nasopharyngoscopy, MRI of the head and neck, chest radiography, electrocardiogram, ultrasonography of the abdominal region, hematologic/biochemical profiles, and dental assessment. CT scans of the chest and abdomen, bone scans, or positron emission tomography scans were performed as clinically indicated. Patients’ routine physical examinations, blood tests, and biochemical laboratory tests were evaluated at least once per week during IC and CCRT. All patients were followed up every 3 months during the first 3 years, every 6 months during the fourth through fifth years, and then annually thereafter, with the same evaluation as pretreatment. Further investigations were arranged when clinically indicated. Management of the residual disease and tumor relapse, if detected, was determined on a case-by-case basis. The last follow-up date was July 31, 2017.

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Table 1 Patient’s demographic and clinical characteristics (n Z 112) Characteristic Sex Male Female Age, y Pathologic type WHO I WHO II WHO III T classification* T1 T2a-b T3 T4 N classification* N0 N1 N2 N3a-b Clinical stage* III IVa-b Induction chemotherapy Cisplatin þ 5-fluorouracil Paclitaxel þ carboplatin

n

%

84 28 42 (14-68)

75.0 25.0

1 9 102

0.9 8.0 91.1

1 20 62 29

0.9 17.9 55.4 25.9

27 31 46 8

24.1 27.7 41.1 7.1

76 36

67.9 32.1

67 45

59.8 40.2

* The 6th American Joint Committee on Cancer/Union for International Cancer Control Staging System.

Failure pattern analysis The Computational Environment for Radiological Research software (v 4.0 Beta2) was used to evaluate failure patterns. For patients with local or regional failures, the original IMRT plans were transferred to the Computational Environment for Radiological Research software. The recurrent GTVs of the nasopharynx (rGTVnx) or neck lymph nodes (rGTVnd), which were identified on the MRI obtained at the time recurrence was diagnosed, were delineated on the IMRT treatment plan. The exact site and extent of each tumor were then compared to the treatment plan, focusing on the 95% isodose lines. Failures were categorized as occurring inside or outside the high-dose target volume, depending on the location of the rGTVnx or rGTVnd: “infield” if at least 95% of the rGTVnx or rGTVnd was within the 95% isodose; “marginal” if 20% to 95% of the rGTVnx or rGTVnd was within the 95% isodose, or “out-field” if less than 20% of the rGTVnx or rGTVnd was inside the 95% isodose.15

Statistical analysis The primary endpoint was LRRFS. The secondary endpoints included locoregional failure patterns, distant metastasis-free survival (DMFS), overall survival (OS), and late toxicities. Durations were calculated from the date of pathologic diagnosis to the date of disease progression,

death, or last follow-up. The late toxicities, which are defined as occurring 3 months after IMRT, were graded according to the Radiation Therapy Oncology Group radiation morbidity scoring criteria.16 The estimates of LRRFS, DMFS, and OS were calculated using the Kaplan-Meier method. A paired t-test was used to compare the target volumes before IC and 2 weeks after the last cycle of IC. All tests were 2-sided. P values <.05 and a 95% confidence interval (CI) that did not include 1 were considered significant. Statistical analyses were performed using SPSS version 22.0 (SPSS, Chicago, IL).

Results Patient characteristics From April 2004 to April 2008, 112 patients were enrolled in this study. There were 76 patients in stage III and 36 patients in stage IVa-b. The demographic and clinical characteristics are shown in Table 1.

Volumetric changes after IC All patients completed 2 cycles of IC. The post-IC target volumes decreased significantly compared with pre-IC target volumes (all P < .001), especially in GTVnx and

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Table 2

Volumetric changes of target volumes No. of patients

GTVnx GTVnd (left) GTVnd (right) CTV1 CTV2

112 68 69 112 112

Pre-IC (cm3) 60.87 15.78 17.33 75.91 279.98

    

Post-IC (cm3)

42.69 13.76 15.59 36.47 76.55

45.49 10.63 12.07 65.55 268.37

    

35.40 10.44 12.38 33.69 73.84

GTVnd. The mean volume shrinkage of GTVnx, GTVnd (left), GTVnd (right), CTV1, and CTV2 was 15.38, 5.15, 5.26, 10.36, and 11.61 cm3, respectively, and the mean percentage of volume shrinkage was 28.5%, 37.7%, 37.1%, 14.1%, and 4.1%, respectively (Table 2).

15.38 5.15 5.26 10.36 11.61

    

Volume shrinkage (cm3)

P

    

<.001 <.001 <.001 <.001 <.001

10.89 4.48 3.71 5.90 7.08

28.2 37.7 37.1 14.1 4.1

12.0 16.0 16.1 6.5 2.2

lymph nodes, 1 at the parotid lymph node, and 2 at both the primary site and neck lymph nodes. Nineteen patients developed distant metastasis. Thirty-one patients died: 6 died of local recurrence, 17 of distant metastasis, 2 of nasopharynx bleeding after retreatment, 1 of another malignancy, and 5 of nontumor reasons. The LRRFS, DMFS, and OS were 89.0% (95% CI, 83.1%-94.9%), 85.3% (95% CI, 78.6%-92.0%), and 79.5% (95% CI, 72.1%-86.9%) at 5 years and 89.0% (95% CI, 83.1%-94.9%), 83.3% (95% CI, 76.2%-90.4%), and 75.9% (95% CI, 68.1%-83.7%) at 10 years, respectively (Fig. 1). The subgroup analyses concerning different stage and IC regimes is given in Figure E2 (available online at https://doi.org/10.1016/j. ijrobp.2019.03.043).

Dosimetry data of target volumes and critical OARs All patients completed IMRT within 42 to 45 days (median 42 days). The dose-volume histogram (DVH) statistics of the target volumes and critical OARs are shown in Table 3. The average mean dose of post-GTVnx, post-GTVnd (left), post-GTVnd (right), post-CTV1, and post-CTV2 was 75.24, 68.97, 69.16, 70.49, and 63.37 Gy, respectively. The average percent of target volumes receiving 100% of the prescribed dose (V100) was more than 95%. The DVHs also showed significant sparing of the critical OARs (Table 3).

Failure patterns All 12 of the patients with locoregional recurrence underwent dosimetry analyses. The rGTVnx receiving 95% of the prescribed dose (rV95) was over 95% in 8 patients, and they were considered in-field failures. The rGTVnd was well within the applicable 95% isodose lines in 4 patients, and they were considered in-field failures. One rGTVnd was considered to be a marginal failure. One patient with

Treatment outcomes The median follow-up was 125.95 months (range, 6.44169.33 months). Twelve patients experienced locoregional recurrences; 6 occurred at the primary site, 3 at the neck

Table 3

Volume shrinkage (cm3)

Dose and volume statistics for target volumes and critical organs at risk

Target volume/OARs Post-GTVnx Post-GTVnd (left) Post-GTVnd (right) Post-CTV1 Post-CTV2 Brain stem Spinal cord Optic chiasm Optic nerve (left) Optic nerve (right) Temporal lobe (left) Temporal lobe (right) Parotid glands (left) Parotid glands (right) TMJ (left) TMJ (right)

Dmin (Gy) 63.08 62.69 62.79 54.18 39.25 7.61 6.13 14.07 9.29 10.16 4.28 4.57 13.30 13.61 20.45 20.71

               

5.92 2.89 3.08 5.37 5.29 6.20 5.00 12.03 7.03 8.55 6.45 7.23 2.54 2.16 5.41 6.08

Dmean (Gy) 75.24 68.97 69.16 70.49 63.37 25.21 21.06 23.62 21.47 22.60 17.83 18.22 30.33 30.66 30.44 31.54

               

1.58 2.44 2.44 1.60 1.78 6.01 3.39 15.87 11.40 12.61 8.25 7.05 3.25 4.30 6.83 7.33

Dmax (Gy)

D5/D1cc (Gy)

               

e e e e e 46.63  4.24 (D5) 39.60  3.68 (D1ml) 29.60  2.07 (D5) 34.99  1.96 (D5) 34.47  1.98 (D5) e e e e e e

82.12 74.39 74.15 80.67 78.34 56.27 34.16 35.92 41.90 42.63 62.47 65.15 62.21 62.96 49.36 50.85

2.41 3.74 3.58 2.03 2.24 0.89 0.50 2.43 1.75 1.85 1.68 1.33 0.98 0.80 1.13 1.44

D33 (Gy) e e e e e e e e e e 17.00  17.66  36.52  36.81  34.82  35.11 

V100 (%) 98.8 99.8 99.8 99.0 97.5

1.02 1.04 4.50 5.06 6.64 6.72

     e e e e e e e e e e e

1.6 0.6 0.8 1.2 2.5

Abbreviations: Dmax Z the average maximum dose, Dmean Z the average mean dose, Dmin Z the average minimum dose, D1cc Z the dose to 1 cm3 of spinal cord, D5 Z the dose to 5% of brain stem, D33 Z the dose to 33% of the volume, TMJ Z temporomandibular joints, V100 Z the percentage of the target volume covered by the 100% prescribed dose line.

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Reducing target volume and dose in NPC

80 60 40 20 0

100

100

80

80

Probability of OS

Probability of DMFS

Probability of LRRFS

100

60 40 20 0

0

12 24 36 48 60 72 84 96 108 120 132 144

Months after diagnosis No. at risk 112 110 103 93 89 86 84 83 82 79 63 41 13

Fig. 1.

841

60 40 20 0

0

12 24 36 48 60 72 84

96 108 120 132 144

Months after diagnosis

No. at risk 112 102 97 92 91 86 84 81 79 77 61 41 13

0

12 24 36 48 60 72 84 96 108 120 132 144

Months after diagnosis

No. at risk 112 110 107 99 94 89 86 84 83 81 65 42 13

Survival curves of locoregional recurrence-free survival, distant metastasis-free survival, and overall survival.

parotid lymph node relapse was considered as having an out-field regional failure. The details are shown in Table 4.

Acute and late toxicities All patients finished scheduled IC and CCRT. All patients had acute toxicity evaluation. Commonly occurring acute toxicities (grade 1-4) were radiodermatitis (98.2%), mucositis (97.3%), dry mouth (96.4%), and leukopenia (89.3%). The commonest grade 3/4 acute toxicity was mucositis (38.4%); this was followed by leukopenia (12.5%) and neutropenia (10.7%), shown in Table 5. One hundred and eleven patients with more than 3 months of follow-up were evaluated for late toxicities. No patient had grade 4 late toxicity. The most common late toxicities were grade 1 to 2 subcutaneous fibrosis, hearing loss, and xerostomia; the only grade 3 late toxicities were subcutaneous fibrosis, hearing loss, and xerostomia, with a 8% incidence (Table 5). Six patients had neuropathy. One experienced a cranial nerve V and VI injury before treatment that remained after treatment. One experienced V3 palsy before treatment, which reappeared 4 years after treatment. One had a VII injury 1 year after RT. One patient had V3 palsy 3 years after RT. One had an IX-XII injury 4 years after RT. One had a VI injury 5 years after RT. Ten patients developed radiation-induced temporal lobe injuries (3 occurred on the left side, 5 on the right side, and 2 bilaterally), and they all presented cavernous sinus or skull base involvement before treatment. Among them, 7 patients were asymptomatic, 2 had mild symptoms with headache, and 3 presented slight lethargy.

Discussion Recently, IC followed by CCRT has been widely used in treating patients with LANPC, although it remains controversial because of the lack of long-term survival, increasing acute toxicities, reduced subsequent CCRT compliance, and so on. Another important issue faced with IC is that the delineation of target volumes and determination of their corresponding optimal doses for these

patients is still unclear, especially in the precise RT era of IMRT. Because surgery is not the primary treatment for NPC, clinicopathologic data are lacking, and the current recommendations for the delineation of target volumes are based on extrapolations from available data on recurrent NPC and other HNCs.17-22 In a recently published international guideline for the delineation of CTVs of NPC, most experts agreed that the pre-IC volume should be included in the GTV with the full therapeutic dose regardless of tumor shrinkage,8 similar to the guidelines for patients with locoregionally advanced HNC.7 Fletcher23 pointed out that the radiation dose to eradicate an aggregation of cancer cells increases with the number of cells. For squamous cell carcinomas of the upper respiratory and digestive tracts, over 90% of subclinical diseases can be controlled with 45 to 50 Gy and microscopic diseases with 60 to 65 Gy; higher doses should be given to clinically detectable tumors. According to these results, we speculated that the post-IC primary tumor and neck lymph nodes that could be detected by MRI still had a high density of tumor cells and should be delineated as GTVs receiving the full therapeutic dose. However, the post-IC tumor shrinkage, where the number of tumor cells was significantly reduced and undetected by MRI, could be encompassed in the high-risk area and treated with a lower dose, such as 60 Gy. This method could not only be beneficial for RT planning and implementation, ensuring sufficient dose to the residual and disappeared tumor after IC, but also reduce the high-dose region of nearby normal tissue, maintaining organ function and good quality of life, especially for those whose tumors are extremely close to, or even overlapping, critical OARs. Many similar studies of other tumors, such as lymphoma and lung cancers, have confirmed the efficacy of this method.24,25 In this study, patients’ tumors shrank greatly after receiving IC; the median volumes of GTVnx, GTVnd (left), and GTVnd (right) shrinkage were 15.38, 5.15, and 5.26 cm3, respectively, nearly 28% to 38% of pre-IC tumor volumes. With this reduction in tumor volumes, theoretically there would have been a greater and safer distance between the tumor and critical OARs, which was beneficial for RT planning. The DVH statistics showed that all post-GTVs and post-CTVs met the dose

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Table 4

N0.

Details of recurrent patients and their locoregional failures Stage (6th AJCC/ UICC)

5 6 2 1 12 8 3

T2N3 T3N0 T4N0 T3N1 T3N2 T4N1 T4N0

9

T3N1

11 7 4 10

T3N2 T4N3 T3N2 T2N2

DVH statistics to rGTVnx/rGTVnd Site of recurrence

Location of recurrence

Local Local Local Local Local Local Local Regional Local Regional Regional Regional Regional Parotid lymph node

Post-GTVnx Post-GTVnx Post-GTVnx Post-GTVnx Post-GTVnx Post-GTVnx Post-GTVnx Post-CTV2 Post-GTVnx Post-CTV2 Post-CTV2 Post-GTVnd Marginal to GTVnd Outside-CTV2

requirements, with V100 >97%. Meanwhile, the exposure doses of OARs were all within the tolerance ranges. Furthermore, the long-term survival was satisfactory, with the 10-year LRRFS, DMFS, and OS being 89.0%, 83.3%, and 75.9%, respectively. The results are similar to those of

Table 5

Vrecur (ml)

Dmin (Gy)

Dmax (Gy)

Dmean (Gy)

V95 (%)

Type of recurrence

14.4 66.5 89.7 68.3 42.0 81.0 45.2 6.6 56.7 12.4 10.3 15.3 15.8 8.21

68.2 58.0 55.1 40.5 54.8 59.3 64.8 57.1 57.8 55.7 53.7 64.6 50.3 12.3

80.0 83.9 85.0 83.6 85.0 85.0 85.0 64.5 85.0 67.7 66.5 70.7 65.7 34.1

75.8 74.3 74.2 75.4 74.7 75.8 75.7 61.0 76.5 63.8 64.1 68.0 58.6 25.6

100 98.7 97.5 97.1 96.8 96.5 99.3 100 96.9 100 95.9 100 38.9 0

In-field In-field In-field In-field In-field In-field In-field In-field In-field In-field In-field In-field marginal out-field

previous studies,26,27 which shows that this method did not compromise survival. In 2012, Yang et al designed a randomized trial with a target volume delineation method similar to ours, and the radiation dose to the post-IC primary tumor shrinkage

Acute and late toxicities Type

Acute radiation toxicities* Leukopenia Neutropenia Anemia Thrombocytopenia Hepatotoxicity Nephrotoxicity Radiodermatitis Mucositis Dry mouth Gastrointestinal reactions Dysgeusia Ear damage Dysphagia Cardiac damage Late radiation toxicitiesy Subcutaneous fibrosis Hearing loss Xerostomia Skin dystrophy Trismus Temporal lobe necrosis Cranial nerve injury Brainstem injury Spinal cord * 112 patients included. y 111 patients included.

All grades n (%)

Grade 1 n (%)

Grade 2 n (%)

Grade 3 n (%)

Grade 4 n (%)

100 79 52 25 18 0 110 109 108 92 76 53 33 0

(89.3) (70.5) (46.4) (22.3) (16.1) (0) (98.2) (97.3) (96.4) (82.1) (67.8) (47.3) (29.4) (0)

30 33 38 13 16 0 72 11 38 56 51 52 21 0

(26.8) (29.5) (33.9) (11.6) (14.3) (0) (64.3) (9.8) (33.9) (50.0) (45.5) (46.4) (18.8) (0)

56 34 14 9 2 0 34 55 68 33 22 1 11 0

(50.0) (30.4) (12.5) (8.0) (1.8) (0) (30.4) (49.1) (60.7) (29.5) (19.6) (0.9) (9.8) (0)

14 11 0 3 0 0 4 43 2 3 3 0 1 0

(12.5) (9.8) (0) (2.7) (0) (0) (3.6) (38.4) (1.8) (2.7) (2.7) (0) (0.9) (0)

0 1 0 0 0 0 0 0 0 0 0 0 0 0

(0) (0.9) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)

101 96 65 46 6 10 6 0 0

(91.0) (86.5) (58.6) (41.4) (5.4) (9.0) (5.4) (0) (0)

52 54 48 37 4 10 6 0 0

(46.8) (48.6) (43.2) (33.3) (3.6) (9.0) (5.4) (0) (0)

41 40 15 9 2 0 0 0 0

(36.9) (36.0) (13.5) (8.1) (1.8) (0) (0) (0) (0)

8 2 2 0 0 0 0 0 0

(7.2) (1.8) (1.8) (0) (0) (0) (0) (0) (0)

0 0 0 0 0 0 0 0 0

(0) (0) (0) (0) (0) (0) (0) (0) (0)

Volume 104  Number 4  2019

reduced to 64 Gy. Last year, they reported that this method did not compromise 3-year local control or survival but did decreased late toxicities.9 However, the median follow-up time was short and, more importantly, the authors did not analyze the locoregional failure pattern. In our study, we further reduced the radiation dose to the post-IC primary tumor shrinkage (60 Gy) and not only assessed long-term survival over 10 years but also conducted a detailed analysis of the locoregional failure pattern. Among 112 patients, 12 patients had 14 locoregional failures; 12 (85.7%) were considered in-field failures, 1 (7.1%) a marginal failure, and 1 (7.1%) an out-field failure, which is better than in previous studies.28-31 The limited marginal or outfield recurrences also indicated that delineation of the target volumes and reduction of dose to the post-IC primary tumor shrinkage were feasible. In addition to long-term locoregional control, failure pattern, and survival, the acute and late toxicity assessment also showed favorable safety. In this study, the acute toxicity was not serious enough to cause CCRT delay or to affect CCRT compliance, and all patients could finish CCRT as planned; this may be related to the lower dose intensity of IC and concurrent chemotherapy compared with treatment in other studies.4,5 There was no grade 4 late toxicity, and the common toxicities (grade 1-3) included subcutaneous fibrosis, hearing loss, xerostomia, and skin dystrophy. For nerve tissue damage, only 10 patients had grade 1 temporal lobe necrosis (11.4%), 6 patients had a grade 1 cranial nerve injury (6.8%), and no patient had a brainstem injury or spinal cord injury. Based on the Xiao et al study, the occurrence rates of subcutaneous fibrosis hearing loss, xerostomia, skin dystrophy, temporal lobe necrosis, and cranial nerve injury were 94.1%, 91.2%, 61.8%, 35.3%, 16.1%, and 4.4%, respectively, in patients with NPC treated with IMRT plus chemotherapy.14 The incidence rates in the present study were slightly lower than those in previous studies26,27,32 and were thought to be acceptable. Therefore, our results show that OARs can be well protected with this method of reduction of the target volumes according to the post-IC tumor volumes and radiation dose to the post-IC primary tumor shrinkage. In this study, we focus mainly on the target volumes delineation after IC, so the IC regimens were not strictly limited, but 2 regimens were commonly used in our center. Furthermore, the dose intensity of concurrent cisplatin was slightly lower than the dose intensity recommended by the National Comprehensive Cancer Network. This study was a single-arm phase 2 clinical trial without a control group, but the sample size was more than 100 patients and showed satisfactory long-term results and fewer late toxicities compared with other studies in the same period. Therefore, our results can provide reliable evidence for clinical application after IC. In addition, this study was carried out targeting common pathologic types in high-incidence areas; whether it is suitable for patients in nonehigh-incidence areas needs further study.

Reducing target volume and dose in NPC

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Conclusions Delineation of the target volumes according to the shrunken GTVs after IC and reduction of the radiation dose to the post-IC tumor shrinkage was reasonable and could yield excellent long-term locoregional control with fewer marginal and out-field recurrences and milder late toxicities for patients with LANPC.

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