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Robotic stereotactic body radiotherapy for recurrent nasopharyngeal carcinoma
Emre Uysal, Ferdi Aksaray, Selvi Dincer, Suleyman Altın
Prof. Dr. Cemil Tascioglu City Hospital, Department of Radiation Oncology, Sisli, Istanbul, Turkey
|Date of Submission||07-Jan-2021|
|Date of Decision||19-Jan-2021|
|Date of Acceptance||07-Mar-2021|
Prof. Dr. Cemil Tascioglu City Hospital, Department of Radiation Oncology, Sisli, Istanbul
Source of Support: None, Conflict of Interest: None
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
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.
| » Introduction|| |
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., 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).,,,,,,,,,,,, These techniques have surpassed brachytherapy, 3D-conformal RT, and other older techniques. 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. Other treatment techniques for r-NPC are proton therapy and carbon-ion RT (CIRT) using heavy, charged particles.,
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|| |
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].
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. Toxicities were assessed by using Common Terminology Criteria for Adverse Events Version 5.0.
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|| |
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.
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|| |
NPC is well-known as a radiosensitive tumor, and dose escalation in NPC has been reported to improve LC.,, However, approximately 10% to 15% of the patients fail locally. 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. 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. Several studies have reported a 5-year OS rate of 28% to 60% in patients treated with IMRT for r-NPC.,, 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. 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., 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].,,,,, 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., 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. 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. 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.,,,, 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.
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. 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|| |
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
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Wong E, Hung J, Ng W-T. Re-irradiation for recurrent NPC: Is treatment merited at all? Ann Nasopharynx Cancer 2018;2:9.
Kong L, Lu JJ. Reirradiation of locally recurrent nasopharyngeal cancer: History, advances, and promises for the future. Chin Clin Oncol 2016;5:26.
Qiu S, Lin S, Tham IW, Pan J, Lu J, Lu JJ. Intensity-modulated radiation therapy in the salvage of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2012;83:676-83.
Han F, Zhao C, Huang SM, Lu LX, Huang Y, Deng XW, et al
. Long-term outcomes and prognostic factors of re-irradiation for locally recurrent nasopharyngeal carcinoma using intensity-modulated radiotherapy. Clin Oncol (R Coll Radiol) 2012;24:569-76.
Hua YJ, Han F, Lu LX, Mai HQ, Guo X, Hong MH, et al
. Long-term treatment outcome of recurrent nasopharyngeal carcinoma treated with salvage intensity modulated radiotherapy. Eur J Cancer 2012;48:3422-8.
Tian YM, Zhao C, Guo Y, Huang Y, Huang SM, Deng XW, et al
. Effect of total dose and fraction size on survival of patients with locally recurrent nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: A phase 2, single-center, randomized controlled trial. Cancer 2014;120:3502-9.
Tian YM, Huang WZ, Yuan X, Bai L, Zhao C, Han F. The challenge in treating locally recurrent T3-4 nasopharyngeal carcinoma: The survival benefit and severe late toxicities of re-irradiation with intensity-modulated radiotherapy. Oncotarget 2017;8:43450-7.
Chan OS, Sze HC, Lee MC, Chan LL, Chang AT, Lee SW, et al
. Reirradiation with intensity-modulated radiotherapy for locally recurrent T3 to T4 nasopharyngeal carcinoma. Head Neck 2017;39:533-40.
Kong F, Zhou J, Du C, He X, Kong L, Hu C, et al
. Long-term survival and late complications of intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma. BMC Cancer 2018;18:1139.
Ng WT, Ngan RKC, Kwong DLW, Tung SY, Yuen KT, Kam MKM, et al
. Prospective, multicenter, phase 2 trial of induction chemotherapy followed by bio-chemoradiotherapy for locally advanced recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2018;100:630-8.
Dizman A, Coskun-Breuneval M, Altinisik-Inan G, Olcay GK, Cetindag MF, Guney Y. Reirradiation with robotic stereotactic body radiotherapy for recurrent nasopharyngeal carcinoma. Asian Pac J Cancer Prev 2014;15:3561-6.
Ozyigit G, Cengiz M, Yazici G, Yildiz F, Gurkaynak M, Zorlu F, et al
. A retrospective comparison of robotic stereotactic body radiotherapy and three-dimensional conformal radiotherapy for the reirradiation of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e263-8.
Seo Y, Yoo H, Yoo S, Cho C, Yang K, Kim MS, et al
. Robotic system-based fractionated stereotactic radiotherapy in locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2009;93:570-4.
Leung TW, Wong VY, Tung SY. Stereotactic radiotherapy for locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2009;75:734-41.
Chua DT, Wu SX, Lee V, Tsang J. Comparison of single versus fractionated dose of stereotactic radiotherapy for salvaging local failures of nasopharyngeal carcinoma: A matched-cohort analysis. Head Neck Oncol 2009;1:13.
Suarez C, Rodrigo JP, Rinaldo A, Langendijk JA, Shaha AR, Ferlito A. Current treatment options for recurrent nasopharyngeal cancer. Eur Arch Otorhinolaryngol 2010;267:1811-24.
Lee AWM, Ng WT, Chan JYW, Corry J, Mäkitie A, Mendenhall WM, et al
. Management of locally recurrent nasopharyngeal carcinoma. Cancer Treat Rev 2019;79:101890.
Lin R, Slater JD, Yonemoto LT, Grove RI, Teichman SL, Watt DK, et al
. Nasopharyngeal carcinoma: Repeat treatment with conformal proton therapy-dose-volume histogram analysis. Radiology 1999;213:489-94.
Hu J, Bao C, Gao J, Guan X, Hu W, Yang J, et al
. Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results. Cancer 2018;124:2427-37.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al
. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16.
Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al
. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81.
Teo PML, Leung SF, Lee WY, Zee B. Intracavitary brachytherapy significantly enhances local control of early T-stage nasopharyngeal carcinoma: The existence of a dose-tumour-control relationship above conventional tumoricidal dose. Int J Radiat Oncol Biol Phys 2000;46:445-58.
Tate DJ, Adler JR Jr, Chang SD, Marquez S, Eulau SM, Fee WE, et al
. Stereotactic radiosurgical boost following radiotherapy in primary nasopharyngeal carcinoma: Impact on local control. Int J Radiat Oncol Biol Phys 1999;45:915-21.
Kam MKM, Teo PML, Chau RMC, Cheung KY, Choi PHK, Kwan WH, et al
. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: The Hong Kong experience. Int J Radiat Oncol Biol Phys 2004;60:1440-50.
Zhang MX, Li J, Shen GP, Zou X, Xu JJ, Jiang R, et al
. Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: A 10-year experience with a large cohort and long follow-up. Eur J Cancer 2015;51:2587-95.
You R, Zou X, Hua YJ, Han F, Li L, Zhao C, et al
. Salvage endoscopic nasopharyngectomy is superior to intensity-modulated radiation therapy for local recurrence of selected T1-T3 nasopharyngeal carcinoma-A case-matched comparison. Radiother Oncol 2015;115:399-406.
Leong YH, Soon YY, Lee KM, Wong LC, Tham IWK, Ho FCH. Long-term outcomes after reirradiation in nasopharyngeal carcinoma with intensity-modulated radiotherapy: A meta-analysis. Head Neck 2018;40:622-31.
Koutcher L, Lee N, Zelefsky M, Chan K, Cohen G, Pfister D, et al
. Reirradiation of locally recurrent nasopharynx cancer with external beam radiotherapy with or without brachytherapy. Int J Radiat Oncol Biol Phys 2010;76:130-7.
Stanisce L, Koshkareva Y, Xu Q, Patel A, Squillante C, Ahmad N, et al
. Stereotactic body radiotherapy treatment for recurrent, previously irradiated head and neck cancer. Technol Cancer Res Treat 2018;17:1533033818780086.
Ho AK, Fu D, Cotrutz C, Hancock SL, Chang SD, Gibbs IC, et al
. A study of the accuracy of cyberknife spinal radiosurgery using skeletal structure tracking. Neurosurgery 2007;60:147-56.
Chang SD, Main W, Martin DP, Gibbs IC, Heilbrun MP. An analysis of the accuracy of the CyberKnife: A robotic frameless stereotactic radiosurgical system. Neurosurgery 2003;52:140-6.
Wu SX, Chua DT, Deng ML, Deng ML, Zhao C, Li FY, et al
. Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69:761-9.
Feehan PE, Castro JR, Phillips TL, Petti P, Collier JM, Daftari I, et al
. Recurrent locally advanced nasopharyngeal carcinoma treated with heavy charged particle irradiation. Int J Radiat Oncol Biol Phys 1992;23:881-4.
Dionisia F, Crocib S, Giacomellia I, Cianchetti M, Caldara A, Bertolin M, et al
. Clinical results of proton therapy reirradiation for recurrent nasopharyngeal carcinoma. Acta Oncol 2019;58:1238-45.
Oksuz DC¸, Meral G, Uzel O, Cagatay P, Turkan S. Reirradiation for locally recurrent nasopharyngeal carcinoma: Treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 2004;60:388-94.
Li YQ, Tian YM, Tan SH, Liu MZ, Kusumawidjaja G, Ong EHW, et al
. Prognostic model for stratification of radioresistant nasopharynx carcinoma to curative salvage radiotherapy. J Clin Oncol 2018;36:891-9.
Parikh P, Patil V, Agarwal JP, Chaturvedi P, Vaidya A, Rathod S, et al
. Guidelines for treatment of recurrent or metastatic head and neck cancer. Indian J Cancer 2014;51:89-94.
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[Table 1], [Table 2], [Table 3], [Table 4]