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ORIGINAL ARTICLE
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Robotic stereotactic body radiotherapy for recurrent nasopharyngeal carcinoma


 Prof. Dr. Cemil Tascioglu City Hospital, Department of Radiation Oncology, Sisli, Istanbul, Turkey

Date of Submission07-Jan-2021
Date of Decision19-Jan-2021
Date of Acceptance07-Mar-2021

Correspondence Address:
Emre Uysal,
Prof. Dr. Cemil Tascioglu City Hospital, Department of Radiation Oncology, Sisli, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_1414_20

  Abstract 


Background: We aimed to evaluate the outcomes of patients reirradiated with stereotactic body radiotherapy for recurrent nasopharyngeal carcinoma (r-NPC) in our hospital.
Methods: We retrospectively analyzed 10 patients with r-NPC previously irradiated with definitive radiotherapy. Local recurrences were irradiated with a dose of 25 to 50 Gy (median: 26.25 Gy) in 3 to 5 fractions (fr) (median: 5 fr). The survival outcomes calculated from the time of recurrence diagnosis were obtained using Kaplan–Meier analysis and compared with the log-rank test. Toxicities were assessed by using Common Terminology Criteria for Adverse Events Version 5.0.
Results: The median age was 55 years (37–79 years), and nine patients were men. The median follow-up was 26 months (3–65 months) after reirradiation. The median overall survival (OS) was 40 months, OS in 1 and 3 years were 80% and 57%, respectively. OS rate of rT4 (n = 5, 50%) was worse compared with rT1, rT2, and rT3 (P = 0.040). In addition, those with less than 24 months of interval between first treatment and recurrence had worse OS (P = 0.017). One patient exhibited Grade 3 toxicity. There is no other Grade ≥3 acute or late toxicities.
Conclusion: In r-NPC, reirradiation is inevitable for patients who are not suitable for radical surgical resection. However, serious complications and side effects prevent dose escalation due to the critical structures previously irradiated. Prospective studies with a large number of patients are required to find the optimal acceptable dose.


Keywords: CyberKnife, recurrent nasopharyngeal carcinoma, stereotactic body radiotherapy, stereotactic radiotherapy
Key Message: Optimal treatment for recurrent nasopharyngeal cancer is still controversial. Although surgical resection has good results in early stage relapses, radiotherapy is inevitable in recurrent nasopharyngeal cancer that frequently occurs in the advanced stage. Increased survival results can be obtained with SBRT technique delivered by protecting critical structures in selected patients.



How to cite this URL:
Uysal E, Aksaray F, Dincer S, Altın S. Robotic stereotactic body radiotherapy for recurrent nasopharyngeal carcinoma. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 2]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=358394





  Introduction Top


Development of radiotherapy techniques and the use of concurrent chemotherapy have increased local control and survival in patients with nasopharyngeal carcinoma (NPC). However, local recurrence still remains the leading cause of morbidity and mortality. Because of the deep localization of the nasopharynx and its proximity to critical structures, radical surgical resection is very difficult in recurrent nasopharyngeal carcinoma (r-NPC). An accepted approach in the management of r-NPC is reirradiation for patients not eligible for nasopharyngectomy.[1],[2] Treatment by reirradiation poses additional challenges because the critical organs have received varying degrees of damage from the previous course of high-dose radiotherapy.

In the past decades, various studies have reported about reirradiation in r-NPC with intensity-modulated radiotherapy (IMRT) or stereotactic body radiotherapy (SBRT).[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] These techniques have surpassed brachytherapy, 3D-conformal RT, and other older techniques.[16] IMRT is a conformal technique that enables the delivery of high doses to the target while sparing the critical structures. However, for patients with extensive recurrences, it is impossible to attain adequate therapeutic dose coverage using reirradiation due to the limited tolerance of the underlying critical organs.[17] Other treatment techniques for r-NPC are proton therapy and carbon-ion RT (CIRT) using heavy, charged particles.[18],[19]

CykerKnife® (Accuray, Sunnyvale, CA, USA), a robotic-based SBRT device using a 6-MV linear accelerator, protects organs at risk with rapid dose fall-off at the target periphery even in an irregularly shaped lesion. Thus, it allows the delivery of high-dose radiation to target tissues while sparing adjacent critical structures. There are limited data in the literature on the efficacy and toxicity of SBRT in r-NPC treatment. In this study, we aimed to present the survival and toxicity results of patients with r-NFC who underwent SBRT in our hospital.


  Materials and Methods Top


Patients

We retrospectively analyzed patients with r-NFC who underwent robotic SBRT with CyberKnife in our clinic between November 2013 and January 2019. A total of 10 patients previously irradiated with a curative dose were included in this study. The data were accessed from the hospital automation system and patient files. All patients were restaged according to the American Joint Cancer Committee (AJCC) eighth edition. This study was approved by the institutional review board on 20/10/2020 and informed consent was obtained from the patients. (Approved number: 48670771-514.10/400).

Diagnosis and treatment techniques

All patients were imaged by magnetic resonance imaging (MRI) and positron emission tomography–computed tomography (PET-CT) during relapse. Only 60% of the patients were verified by biopsy. It was accepted as radiological recurrence due to high FDG (fluorodeoxyglucose) uptake in PET-CT in patients who did not undergo biopsy. Local recurrence of one patient who had liver metastasis was reirradiated after distant metastasis regressed with chemotherapy (4 cycle cisplatin and epirubicin before SBRT). Computed tomography (CT) and contrast-enhanced MRI images of the patients in the supine position immobilized with a thermoplastic head and neck mask were obtained with 1 mm slice intervals. After the CT and MRI images were fused, gross tumor volume (GTV) and critical structures were contoured in each consecutive slice. Planning target volume (PTV) was created by adding a median of 2 mm (1–3 mm) to the GTV [Table 1]. Local recurrences were irradiated with a dose of 25 to 50 Gy (median: 26.25 Gy) in 3 to 5 fractions (fr) (median: 5 fr). The median prescribed isodose was 79% (76%–81%), and the median coverage of GTV was 99.92%. The doses of critical structures are given in [Table 2].
Table 1: Treatment characteristics

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Table 2: Doses of critical structures

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Tumor response assessment and follow-up

Nasopharyngoscopy and MRI were performed after 8 weeks of reirradiation. MRI was performed every 3 months in the first 2 years, then every 3 to 6 months. PET scan was performed for suspicious cases to catch locoregional failure or distant metastasis. Tumor response was evaluated using Response Evaluation and Criteria in Solid Tumors.[20] Toxicities were assessed by using Common Terminology Criteria for Adverse Events Version 5.0.[21]

Statistics

Continuous variables were presented as median (range) and categorical variables as number (percentage). The survival of the patients was calculated from the time of recurrence diagnosis and obtained using Kaplan–Meier analysis. Factors affecting survival were analyzed using the log-rank test. An overall P value of less than 0.05 was considered to show a statistically significant result. SPSS Version 22 (IBM, New York, USA) program was used to calculate the statistics.


  Results Top


A total of 10 patients were included in the study, with the median age of 55 years (37–79 years), and nine patients were men. The initial AJCC stage of 40% of patients was Stage II and 60% was Stage III [Table 3]. All patients with primary NPC were treated with concurrent and/or induction chemotherapy. In the patients, recurrence occurred with a median of 39 months (5–235 months) after the primary curative radiotherapy dose of 70 Gy (70–70.2 Gy): local recurrence in 80% of the patients, locoregional recurrence in 10%, and local recurrence and distant metastasis (liver) in 10%. Except for the metastatic patient, no patient received concurrent or sequential chemotherapy. All local failures were in the high-dose zone. In addition, 50% of r-NPC were in T4 stage.
Table 3: Patients characteristics

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The median follow-up was 26 months (3–65 months) after reirradiation. The median overall survival (OS) was 40 months; OS rates in 1 and 3 years were 80% and 57%, respectively. The median progression-free survival (PFS) was 16 months; PFS rates in the first and third years were 60% and 48%, respectively. The local control (LC) rates for 1 and 3 years were 80% and 50%. At the first imaging after reirradiation, the complete response rate was 60%, the partial response rate was 20%, and the stable lesion was 20%. All patients with rT1 (20%) or rT2 (10%) had a complete response and no progression in recurrent tumors.

OS rate of rT4 was worse compared with rT1, rT2, and rT3 (P = 0.040). In addition, those with less than 24 months of interval between first treatment and recurrence had worse OS (P = 0.017).

A total of six patients died and one patient who had liver metastasis died of disease progression 24 months after diagnosis of recurrence. The patient received four cycles of cisplatin and monthly zoledronic acid because of progression. One patient who did not receive chemotherapy died of local progression. Two patients died of newly developed distant metastasis, of which one received four cycles of gemcitabine and the other received three cycles of cisplatin after metastasis. The cause of death of two patients is unknown. Grade 3 toxicity (hearing loss) was observed in one patient. There was no other Grade ≥3 toxicity. Grades 1 and 2 toxicities were not reported.


  Discussion Top


NPC is well-known as a radiosensitive tumor, and dose escalation in NPC has been reported to improve LC.[22],[23],[24] However, approximately 10% to 15% of the patients fail locally.[25] This may be due to the presence of radioresistant cells within the tumor relapsing in high-dose zone. The optimum RT dose for r-NPC remains unclear, and the standard dose regimen has not been defined yet. Also, serious complications and side effects prevent dose escalation because of the adjacent critical structures previously irradiated. There are limited data in the literature on the management of r-NPC, especially for SBRT. In the present study, we have reported our experiences with SBRT delivered in patients with r-NPC.

In a case-matched study by You et al., the authors reported that surgical resection in locally early-stage r-NPC offers better survival and quality of life, fewer complications, and lesser cost compared with reirradiation with IMRT.[26] However, r-NPC is often presented as a locally advanced stage, and it is not suitable for surgical resection. Reirradiation of the locally advanced stage tumor due to its size and invasion of adjacent tissues prevents delivery of high doses to the target and causes serious toxicities. Also, rT score is the most reported prognostic factor, and the results of treatment modalities for advanced tumors are not satisfactory.

Recently, the most commonly used radiotherapy modality in r-NPC treatment is IMRT. In a meta-analysis that included 1,768 patients with r-NPC, the authors reported that the 5-year OS rate was 41% and fatal complications occurred in 33% of the patients after reirradiation with IMRT.[27] Several studies have reported a 5-year OS rate of 28% to 60% in patients treated with IMRT for r-NPC.[4],[7],[28] In these studies, fatal complications occurred between 0% and 35%. Although the dose given in our study is less than what is reported in the literature, survival results are similar and toxicities are at acceptable levels. While escalating the dose, not exceeding critical organ constraints may reduce toxicity without decreasing curability. In an SBRT study conducted on head and neck cancers, although a median dose of 40 Gy (range: 24–44 Gy) was given with a median of 5 fr (range: 3–5 fr), grade 4 and 5 toxicities were not observed in any patient.[29] As a result of this study, it was reported that the toxicity results of SBRT could be better than IMRT; however, the only way to prove this would be a randomized head-to-head study.

CyberKnife, a 6-MV linear accelerator mounted on robotic arms, enables image-guided radiotherapy using a real-time tracking system. It delivers a large number of small beams with an error of 0.49 to 1 mm to a target volume.[30],[31] Additionally, it allows fractionated SBRT; thus it has physical and radiobiological advantages. In the literature, there are limited retrospective studies, including a small number of patients treated with SBRT and with a short follow-up period.

Recent studies on stereotactic reirradiation for r-NPC are summarized in [Table 4].[11],[12],[13],[14],[15],[32] The 5-year OS and LC rates were 40% to 60% and 57% to 79%, respectively. However, it appears that the doses administered varied and the patient characteristics were heterogeneous. Also, all studies were retrospective. Which patient should receive radiotherapy at what dose is still controversial. The serious complication rate ranges from 8% to 33% in these studies.
Table 4: Recent studies on stereotactic radiotherapy for recurrent nasopharyngeal carcinoma

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In CIRT and proton therapy, beams of heavy and charged particles provide a sharp dose increase named the Bragg peak in the tumor and deliver minimal radiation to the surrounding tissue. In dosimetric studies, it has been reported that CIRT and proton therapy can deliver a higher dose to the target by sparing critical organs than IMRT.[18],[33] In a Phase II trial, including 75 patients treated with CIRT for r-NPC, the 1-year OS, disease-specific survival, PFS, local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival rates were 98.1%, 98.1%, 82.2%, 86.6%, 97.9%, and 96.2%, respectively.[19] In addition, there was no acute toxicity of Grade 2 during CIRT. Late severe (Grade 3 or 4) toxicities were mucosal necrosis (9.3%), xerostomia (1.3%), and temporal lobe necrosis (1.3%). In a study including 17 patients reirradiated with proton therapy, the median follow-up was 10 months, and OS and LC rates in 18 months were 54.4% and 66.6%, respectively.[34] Although these results are encouraging for these treatment methods using charged particles, longer follow-up studies are required.

In the present study, the advanced rT stage and the interval of less than 24 months between initial treatment and recurrence were associated with worse survival. The most-reported prognostic factor was the rT stage, and several studies have demonstrated that the prognostic factors are age, rGTV, rTNM stage, and dose of reirradiation for survival.[11],[12],[13],[14],[35] In 2018, Li et al. reported five prognostic factors that include the rT stage, age, rGTV, presence of prior RT-induced Grade ≥3 toxicity, and dose of reirradiation in a prognostic model.[36]

In a published guideline for the treatment of r-NPC, an irradiation dose of 30 to 50 Gy (3–5 fr) with SBRT is recommended.[37] In the present study, patients were irradiated at a lower dose than prescribed in the guideline. This situation may have been caused by the aim not to exceed critical organ limitations. Therefore, toxicity rates can be low. Also, survival rates are consistent with that reported in the literature despite the low dosage.

The majority limitations of the current study were a small number of patients and retrospective design. Despite the small number of patients, the outcomes are consistent with the literature. In addition, patients with regional or distant metastasis were included and the reirradiation dose was heterogeneous in the study. The patients should be followed up for a longer period to see other possible late effects.


  Conclusion Top


In r-NPC, reirradiation is inevitable for patients who are not suitable for radical surgical resection. However, serious complications and side effects prevent dose escalation due to the critical structures being previously irradiated. Using SBRT without exceeding critical organ constraints can provide adequate survival in order not to cause fatal complications. Prospective studies with a large number of patients are required to arrive at the optimal acceptable dose.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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