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Efficacy and safety of CT-guided 125I seed implantation as a salvage treatment for locally recurrent head and neck soft tissue sarcoma after surgery and external beam radiotherapy: A 12-year study at a single institution

Published:October 22, 2019DOI:https://doi.org/10.1016/j.brachy.2019.09.006

      Abstract

      Objectives

      The objective of this study was to evaluate the efficacy and safety of CT-guided radioactive 125I seed implantation as a salvage treatment for locally recurrent head and neck soft tissue sarcoma (HNSTS) after surgery and external beam radiotherapy.

      Methods and Materials

      From December 2006 to February 2018, 25 patients with locally recurrent HNSTS after surgery and external beam radiotherapy were enrolled. All the patients successfully underwent CT-guided 125I seed implantation. The primary end points included the objective response rate (ORR) and local progression-free survival (LPFS). The secondary end points were survival (OS) and safety profiles.

      Results

      After 125I seed implantation, the ORR was 76.0%. The 1-, 3-, and 5-year LPFS rates were 65.6%, 34.4%, and 22.9%, respectively, with the median LPFS of 16.0 months. The 1-, 3-, and 5-year OS rates were 70.8%, 46.6%, and 34.0%, respectively, with the median OS of 28.0 months. Furthermore, univariate analyses showed that the recurrent T stage and histological grade were prognostic factors of LPFS, whereas only the histological grade was a predictor of OS. The major adverse events were skin/mucosal toxicities, which were generally of lower grade (≤Grade 2) and were well tolerated.

      Conclusions

      Radioactive 125I seed implantation could be an effective and safe alternative treatment for locally recurrent HNSTS after failure of surgery and radiotherapy. Recurrent T stage and histological grade were the main factors influencing the efficacy.

      Keywords

      Introduction

      Soft tissue sarcoma (STS) is a type of rare cancer with a morbidity of approximately 5 per 100,000 individuals (
      • Stiller C.A.
      • Trama A.
      • Serraino D.
      • et al.
      Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.
      ,
      • Casali P.G.
      • Blay J.Y.
      Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ). Head and neck soft tissue sarcoma (HNSTS) is the rarest type of STS, accounting for approximately 5–15% of all sarcomas and approximately 1% of malignant head and neck tumors (
      • Stiller C.A.
      • Trama A.
      • Serraino D.
      • et al.
      Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.
      ,
      • Eeles R.A.
      • Fisher C.
      • Ahern R.P.
      • et al.
      Head and neck sarcomas - prognostic factors and implications for treatment.
      ). Owing to its rarity, HNSTSs have been regarded as an infrequent and heterogeneous group of tumors. Although most STSs have a similar natural disease course, the prognosis of HNSTS is usually worse than non-HNSTS cases (STS in the trunk and extremity), with markedly lower local control rates and disease-free survival rates (
      • Zagars G.K.
      • Ballo M.T.
      • Pisters P.W.
      • et al.
      Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients.
      ).
      Currently, the classical treatment modalities for HNSTS are as follows: surgery, radiotherapy, and/or chemotherapy (
      • von Mehren M.
      • Randall R.L.
      • Benjamin R.S.
      Soft Tissue Sarcoma V2.2018, NCCN Clinical Practice Guidelines in Oncology.
      ). Despite combined modality treatment, approximately 22–53% of patients will locally recur within 5 years (
      • Galy-Bernadoy C.
      • Garrel R.
      Head and neck soft-tissue sarcoma in adults.
      ). The treatment for locally recurrent HNSTS after failure of previous surgery and external beam radiotherapy (EBRT) remains a problematic challenge, to our knowledge, without consistent guidelines or widely accepted recommendations. Considering the anatomic constraints, functional preservation, cosmesis, and patients' refusal after several prior surgeries, the use of reoperation is limited for most cases. Even trickier, delivering enough doses to the recurrent disease is very difficult by re-EBRT because of the dose limitations and high risk of sequelae of the adjacent normal tissues. The role of chemotherapy for locally recurrent HNSTS remains unclear, and additional evidences are needed to confirm its effectiveness.
      Bracingly, radioactive 125I seed (RIS) implantation brachytherapy, recently a standard of care in early very low to favorable intermediate-risk prostate cancer, may address this puzzle. There is an increasing number of studies recently demonstrating that RIS implantation, a type of low-dose-rate brachytherapy, characterized by delivering high radiation dose to tumor target while safely sparing the adjacent normal tissue, is an effective salvage treatment for most recurrent cancers, including prostate cancer, lung cancer, pancreatic cancer, rectal cancer, cervical cancer, head and neck cancer, and so on (
      • Wang J.
      • Chai S.
      • Zheng G.
      • et al.
      Expert consensus statement on computed tomography-guided (125)I radioactive seeds permanent interstitial brachytherapy.
      ). Our previous work has showed its good efficacy as a salvage treatment for recurrent cervical cancer (
      • Qu A.
      • Jiang P.
      • Sun H.
      • et al.
      Efficacy and dosimetry analysis of image-guided radioactive 125I seed implantation as salvage treatment for pelvic recurrent cervical cancer after external beam radiotherapy.
      ); head and neck cancer (
      • Ji Z.
      • Jiang Y.
      • Tian S.
      • et al.
      The effectiveness and prognostic factors of CT-guided radioactive I-125 seed implantation for the treatment of recurrent head and neck cancer after external beam radiation therapy.
      ); and rectal cancer (
      • Wang J.J.
      • Yuan H.S.
      • Li J.N.
      • et al.
      CT-guided radioactive seed implantation for recurrent rectal carcinoma after multiple therapy.
      ); which therefore has been referenced by NCCN Guidelines of Rectal Cancer 2015.v2 as a recommendation for locally recurrent rectal carcinoma (
      • Benson A.R.
      • Venook A.P.
      • Bekaii-Saab T.
      • et al.
      Rectal cancer, version 2.2015.
      ). To some extent, RIS implantation is similar to single dose of stereotactic ablative radiotherapy and also can be called "stereotactic ablative brachytherapy". Accordingly, in the present study, we aimed to explore the efficacy and safety of RIS implantation as salvage treatment for locally recurrent HNSTS after surgery and EBRT to provide more advices for the treatment of locally recurrent HNSTS.

      Patients and methods

      Patients

      Our study on patients with locally recurrent HNSTS was approved by the Ethics Committee of our hospital (Ethical No. IRB00006761-M2019226). The cases of 25 patients pathologically diagnosed with locally recurrent HNSTS after surgery and EBRT between December 2006 and February 2018 were reviewed retrospectively. We restaged the recurrent tumors according to the American Joint Committee on Cancer System for soft tissue sarcoma of the head and neck sarcoma (8th ed., 2017) when analyzing the data. For all patients, RIS implantation was performed under CT guidance. Written informed consent was provided by each patient before treatment.

      Inclusion and exclusion criteria

      The inclusion criteria were as follows: pathologically diagnosed locally recurrent HNSTS after initial surgery and EBRT; unresectable due to surgeon consultation and/or individual refusal; tumor size ≤7 cm; Karnofsky performance status score ≥ 70; suitable puncture access; no tendency for bleeding; expected survival > 3 months. The exclusion criteria were as follows: any active concomitant cancer, and any mental disorder or somatic comorbidities of clinical concern.

      Treatment

      The 125I implantation procedure mainly included preoperative treatment planning, intraoperative implantation, and postoperative evaluation (Fig 1).
      Figure thumbnail gr1
      Fig. 1The CT images of preoperation, intraoperation, and postoperation. Fig. (a-c) showed the preoperative treatment planning including the planned locations of needles, distribution of seeds, doses in target volume, and organs at risk. The green or red needles and seeds were simulated needles and seeds in the B-TPS, respectively. Fig. (d-f) showed the actual locations of needles before seed implantation during surgery. Fig. (g-i) showed the actual distribution of seeds and doses in target volume and organs at risk after seed implantation. Fig. (j) showed the 3D-PNCT template model with guide holes on it in the B-TPS including the information of needle distribution, needle-path direction, needle depth, and the characteristics of the surface of the therapeutic area. B-TPS = brachytherapy treatment planning system; 3D-PNCT = 3D-printed non-coplanar template. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

      Preoperative treatment planning

      Patients underwent contrast-enhanced CT simulation with 2.5-mm or 5-mm (rarely, for large tumors only) 2–3 days before RIS implantation to obtain three-dimensional information regarding tumor volume and organs at risk. CT images were then loaded into the brachytherapy treatment planning system (B-TPS; Beijing Feitian Industries Inc. and Beijing University of Aeronautics and Astronautics, Beijing, China) to evaluate the feasibility of seeding. If seeding was feasible, the pretreatment plan was immediately made including the delineation of gross tumor volume (GTV) and adjacent organs at risk (OARs), determination of the prescribed dose (According to international standards for prostate cancer (
      • Davis B.J.
      • Horwitz E.M.
      • Lee W.R.
      • et al.
      American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy.
      ); expert consensus on RIS brachytherapy (
      • Wang J.
      • Chai S.
      • Zheng G.
      • et al.
      Expert consensus statement on computed tomography-guided (125)I radioactive seeds permanent interstitial brachytherapy.
      ); previous literatures (
      • Qu A.
      • Jiang P.
      • Sun H.
      • et al.
      Efficacy and dosimetry analysis of image-guided radioactive 125I seed implantation as salvage treatment for pelvic recurrent cervical cancer after external beam radiotherapy.
      ,
      • Ji Z.
      • Jiang Y.
      • Tian S.
      • et al.
      The effectiveness and prognostic factors of CT-guided radioactive I-125 seed implantation for the treatment of recurrent head and neck cancer after external beam radiation therapy.
      ,
      • Wang J.J.
      • Yuan H.S.
      • Li J.N.
      • et al.
      CT-guided radioactive seed implantation for recurrent rectal carcinoma after multiple therapy.
      ,
      • Wu C.
      • Li B.
      • Sun G.
      • et al.
      Efficacy and safety of iodine-125 brachytherapy combined with chemotherapy in the treatment of advanced NSCLC in the elderly.
      ,
      • He C.
      • Liu Y.
      • Li Y.
      • et al.
      Efficacy and safety of computed tomography-guided (125)I brachytherapy for lymph node metastatic from hepatocellular carcinoma.
      ,
      • Gai B.
      • Zhang F.
      Chinese expert consensus on radioactive (125)I seeds interstitial implantation brachytherapy for pancreatic cancer.
      ,
      • Yu Y.H.
      • Wei C.Y.
      • Qin Q.H.
      • et al.
      Efficacy of iodine-125 seed implantation in locoregionally recurrent and unresectable breast cancer: a retrospective study.
      ,
      • Yao L.
      • Wang J.
      • Jiang Y.
      • et al.
      Permanent interstitial 125I seed implantation as a salvage therapy for pediatric recurrent or metastatic soft tissue sarcoma after multidisciplinary treatment.
      ,
      • Li J.
      • Wang J.
      • Meng N.
      • et al.
      Image-guided percutaneous 125 I seed implantation as a salvage treatment for recurrent soft tissue sarcomas after surgery and radiotherapy.
      ); and clinical experiences gained at our center, 110 to 160 Gy was the dose range usually eliciting a good therapeutic effect with a high safety and commonly used in our center.) and radioactivity of seeds, design of the accesses of the needles for seeding (direction, distribution, and depth) in accordance with Paris system as far as possible, calculation of the RIS number, simulation of the spatial distribution of RIS, and calculation of the dose distribution of the target volume and OARs performed by Monte Carlo Simulation Method (Figs. 1a–1c). The dosimetric goal was that the dose received by 90% of the GTV (GTV D90) could reach the prescription dose as much as possible. The doses delivered to the OARs were as low as possible through optimization.

      Intraoperative implantation

      There were two different methods for intraoperative implantation. The method A was used for the patients treated before 2015 and the method B was used for the patients after 2015 when the 3D-printed non-coplanar template (3D-PNCT) was invented by our center (Patent No. ZL 2016 2 0414011.9).
      Method A: Implantation guided by CT without assistance of the template. After skin preparation, draping, and local anesthesia, disposable needles (Mick Radio Nuclear Instruments, Mount Vernon, NY) were inserted into the target volume under CT guidance along the markers on the surface of the patients marking the puncture sites according to the preoperative treatment plan (Figs. 1d–1f). The Mick applicator (Mick Radio-Nuclear Instruments Inc., Mount Vernon, NY) was used for RIS implantation (CIAE-6711; Chinese Atomic Energy Science Institution, Beijing, China) in a retrusive manner, with a 0.5 cm or 1.0 cm interval. Puncturing and seeding were performed according to the Paris system as far as possible, unless necessitated by a better dose distribution or due to the constraints of anatomical structures.
      Method B: Implantation guided by CT with assistance of the 3D-PNCT. After design of the brachytherapy treatment plans, a digital personal template model was then designed in the B-TPS including the information of needle distribution, needle-path direction, and the characteristics of the surface of the therapeutic area (Fig. 1j). The 3D-PNCT was then printed by the 3D light-cured rapid-forming printer. Then after skin preparation, draping, and local anesthesia, the 3D-PNCT was aligned to the surface of the therapeutic region by means of the outline characteristics of the patient, positioning line on the patient, alignment reference line on the 3D-PNCT, and positioning laser. Before puncture, the CT was performed to make sure the 3D-PNCT was aligned exactly and the position of the template was the same as the model template in the B-TPS. Any error between the actual image and positioning image was adjusted in real time. Then the implantation needles were punctured to the predetermined depth percutaneously through the guide holes on the 3D-PNCT (Fig. 1j). “Fine-tuning” was carried out if necessary. After accomplishment of the puncturing, the 125I seeds were implanted with the Mick applicator in a retrusive manner with a 0.5 cm or 1.0 cm interval.

      Postoperative evaluation

      After the completion of seed implantation, CT scan was immediately conducted to validate the actual postoperative distribution of seeds. Then the images were loaded to B-TPS to achieve actual dose distribution (Figs. 1g–1i). Dosimetric parameters including D90, D100, V100, V150, V200 were used to evaluate the dosimetry. D90 and D100 means the dose delivered to the 90% or 100% of GTV, respectively. V100, V150, and V200 means the percentage of GTV receiving 100% or 150% or 200% of prescription dose, respectively.
      All physicians participating in the procedure of seed implantation are well trained and legally qualified. All procedures were performed in accordance with relevant guidelines and regulations.

      Followup

      Patients were followed up by head and neck CT or MRI by 3-month intervals for the first 2 years, then followed up by 6-month intervals from 2 to 5 years and then followed up annually thereafter.

      Definition of end points

      The primary end points included the objective response rate (ORR) and local progression-free survival (LPFS). ORR was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 classified as complete response (CR), partial response (PR), stable disease, and progressive disease. ORR was confirmed in cases with CR and/or PR. LPFS was defined as the interval from the date of implantation to the date of local progression. The secondary end points included overall survival (OS) and safety. OS was defined as the interval from the date of implantation to the date of death from any cause. The safety end point was assessed as per RTOG Common Toxicity Criteria.

      Statistical analysis

      The patients' characteristics were expressed as continuous variables and/or categorical variables. Continuous variables were compared using the t-test or rank-sum test, whereas the categorical variables were compared using the chi-square or Fisher's exact test. ORR is expressed based on the number and percentage of patients. The LPFS and OS were estimated using the Kaplan–Meier method, compared using log-rank tests. Univariate of LPFS and OS were performed using a Cox proportional hazard regression model. p < 0.05 was considered as statistically significant. SPSS 21.0 software (SPSS, Chicago, IL) was used for statistical analysis.

      Results

      Patient characteristics

      A total of 29 patients were considered for RIS implantation from December 2006 to February 2018, while 4 patients were finally excluded: three with a poor performance and one with a high tendency of bleeding. Finally, 25 patients were enrolled and successfully underwent RIS implantation after at least one failure of surgery and EBRT. Out of the 25 patients, the implantation was done with free hand guided by CT for 16 patients and with assistance of 3D-PNCT guided by CT for 9 patients. A total of 17 patients were staged as recurrent T4: 7 patients with orbital invasion, 8 with invasion of facial skeleton, and 2 with invasion of skull base. The clinical and dosimetric features of the cohort were shown in Table 1.
      Table 1General information of the patients
      Clinical featureVariableAll patients n = 25 (%)
      AgeMedian (IQR)53 (22–57)
      SexMale21 (77.3)
      Female4 (22.7)
      KPS707 (28.0)
      8010 (40.0)
      90–1008 (32.0)
      PathologySpindle cell sarcoma1 (4.0)
      Leiomyosarcoma6 (24.0)
      Chondrosarcoma1 (4.0)
      Adult fibrosarcoma2 (8.0)
      Synovial sarcoma1 (4.0)
      Embryonal rhabdomyosarcoma3 (12.0)
      Malignant peripheral nerve sheath tumor1 (4.0)
      Angiosarcoma5 (20.0)
      Other5 (20.0)
      Histological grade≤G216 (64.0)
      G39 (36.0)
      Recurrent T stage≤T38 (32.0)
      T417 (68.0)
      Times of prior surgery117 (68.0)
      22 (8.0)
      36 (24.0)
      ChemotherapyYes16 (64.0)
      No9 (36.0)
      Times of prior EBRT118 (72.0)
      27 (28.0)
      Prior EBRT dose (Gy)Median (range)68 (50–115)
      GTV (cm³)Median (range)60 (5–164)
      No. of needlesMedian (range)16 (4–33)
      No. of seedsMedian (range)55 (11–158)
      Activity of seeds (mCi
      1 Ci = 3.7 × 1010Bq.
      )
      Median (range)0.68 (0.45–0.96)
      Prescription dose (Gy)Median (range)150 (110–160)
      D90 (Gy)Median (range)152 (106–179)
      D100 (Gy)Median (range)81 (51–111)
      V100 (%)Median (range)95 (81–100)
      V150 (%)Median (range)76 (43–98)
      V200 (%)Median (range)55 (22–93)
      IQR = interquartile range; KPS = Karnofsky Performance Score; EBRT = external beam radiotherapy; GTV = gross tumor volume.
      a 1 Ci = 3.7 × 1010Bq.

      Patient outcomes

      The median followup period was 23 months (range, 6–82 months). The ORR was 76.0% in 10 patients (40.0%) with CR (Fig. 2) and 9 (36.0%) with PR. The clinical and dosimetric characteristics of the patients who achieved a CR were analyzed. Results showed that better T stage and smaller GTV were significantly associated with CR (Table 2). Moreover, higher therapeutic dose (D90) also seemed correlated with CR, though the difference was not significant (Table 2). In addition, the average of D90 of patients with CR (153 Gy) was significantly higher than that of patients without CR (138 Gy), p = 0.005.
      Figure thumbnail gr2
      Fig. 2The therapeutic effect of 125I seed implantation in a case of the patients in this study. The patient in the pictures was diagnosed with locally recurrent embryonal rhabdomyosarcoma of the orbit after surgery and EBRT. Fig. (a-c) showed the tumors of preoperation, 3-month postoperation, and 6-month postoperation by gross photos. Fig. (d-f) showed the tumors of preoperation, 3-month postoperation, and 6-month postoperation by CT or PET-CT images. Encouragingly, 6 months after 125I seeding, PET-CT showed no residual tumor with metabolic activity in Fig (f). EBRT = external beam radiotherapy.
      Table 2The clinical and dosimetric characteristics of the patients with a CR
      VariablesCategoriesCR (n = 10)No CR (n = 15)p-value
      Age (y)>58790.691
      ≤5836
      SexFemale820.532
      Male132
      KPS>80550.075
      ≤80213
      Recurrent T stageT4640.028
      ≤T3213
      Pathological gradeG3730.678
      ≤G287
      Times of prior surgery>1820.402
      196
      Times of prior EBRT>1820.402
      196
      Prior EBRT dose (Gy)>68730.226
      ≤6869
      GTV (cm³)>60820.041
      ≤60510
      D90 (Gy)>152370.111
      ≤152105
      D100 (Gy)>81460.688
      ≤8187
      V100 (%)>95550.697
      ≤9596
      V150 (%)>76640.688
      ≤7678
      V200 (%)>55550.697
      ≤5569
      IQR = interquartile range; KPS = Karnofsky Performance Score; EBRT = external beam radiotherapy; GTV = gross tumor volume; CR = complete response.
      During the followup, 14 patients developed local recurrence. The median LPFS was 16.0 months with the 1-, 3-, and 5-year LPFS rates of 65.6%, 34.4%, and 22.9%, respectively. Subgroup analyses showed that the patient with lower histological grade (≤G2) had favorable LPFS than those with higher histological grade (G3) (34 months vs. 9 months, p = 0.026, Fig. 3a). In addition, the patients with lower recurrent T stage (≤T3) had better LPFS vs. patients with higher T stage (T4) (48 months vs. 12 months, p = 0.021, Fig. 3b).
      Figure thumbnail gr3
      Fig. 3LPFS and OS rates of patients with different histological grades and recurrent T stages. Fig. (a-b) showed the LPFS rates of patients with different histological grades and recurrent T stages, respectively. Fig. (c-d) showed the OS rates of patients with different histological grades and recurrent T stages, respectively. LPFS = local progression-free survival; OS = overall survival.
      Of 25 patients, 15 died, including one as a result of respiratory failure, two as a result of metastasis and other as a result of local progression. There was no treatment-related death. The median OS was 28.0 months with the 1-, 3-, and 5-year OS rates of 70.8%, 46.6%, and 34.0%, respectively. Moreover, subgroup analyses indicated that the OS was significantly better in patients with lower histological grade than those with higher grade (51 months vs. 22 months, p = 0.029, Fig. 3c). Moreover, it was found that the patients with lower T stage had a trend toward better OS compared with patients with higher T stage, although the difference was not significant (51 months vs. 15 months, p = 0.081, Fig. 3d).

      Univariate analyses of LPFS and OS

      LPFS and OS were considered as important indices representing clinical efficacy; therefore, different parameters possibly influencing these two outcomes were analyzed. Univariate analyses for LPFS showed that the recurrent T stage (T4 vs. ≤ T3;hazard ratio [HR] = 4.034; 95% confidence interval [CI] = 1.146–14.203; p = 0.030) and histological grade (G3 vs. ≤ G2;HR = 3.254; 95% CI = 1.066–9.932; p = 0.038) were independent prognostic factors for LPFS (Table 3). Similarly, we found that the histological grade (G3 vs. ≤ G2;HR = 3.230; 95% CI = 1.061–9.834; p = 0.039) was an independent predictor of OS (Table 4). Multivariate analyses were not performed due to a low event rate.
      Table 3Univariate analyses for LPFS
      VariablesCategoriesUnivariate analyses
      HR95% CIp-value
      Age (y)>581.6280.567–4.6750.365
      ≤58
      SexFemale0.3060.040–2.3590.256
      Male
      KPS>800.6390.185–2.2050.478
      ≤80
      Recurrent T stageT44.0341.146–14.2030.030
      ≤T3
      Pathological gradeG33.2541.066–9.9320.038
      ≤G2
      Times of prior Surgery>11.3320.446–3.9810.608
      1
      Times of prior EBRT>11.1400.376–3.4510.817
      1
      Prior EBRT dose (Gy)>681.2490.436–3.5780.679
      ≤68
      GTV (cm³)>601.2470.434–3.5830.682
      ≤60
      D90 (Gy)>1520.8100.267–2.4610.710
      ≤152
      D100 (Gy)>811.1600.382–3.5220.793
      ≤81
      V100 (%).951.1120.379–3.2580.847
      ≤95
      V150 (%)>761.1040.384–3.1780.854
      ≤76
      V200 (%)>550.3870.131–1.1420.085
      ≤55
      LPFS = local progression-free survival; KPS = Karnofsky Performance Score; EBRT = external beam radiotherapy; GTV = gross tumor volume; HR = hazard ratio; CI = confidence interval.
      Table 4Univariate analyses for OS
      VariablesCategoriesUnivariate analyses
      HR95% CIp-value
      Age (y)>581.7550.614–5.0140.293
      ≤58
      SexFemale0.2670.032–2.2580.226
      Male
      KPS>800.3930.117–1.3240.132
      ≤80
      Recurrent T stageT42.7450.842–8.9500.094
      ≤T3
      Pathological gradeG33.2301.061–9.8340.039
      ≤G2
      Times of prior surgery>11.4980.518–4.3320.456
      1
      Times of prior EBRT>11.1050.366–3.3610.859
      1
      Prior EBRT dose (Gy)>682.4310.790–7.4750.121
      ≤68
      GTV (cm³)>602.1870.729–6.5580.162
      ≤60
      D90 (Gy)>1520.8740.315–2.4260.796
      ≤152
      D100 (Gy)>810.5250.187–1.4780.222
      ≤81
      V100 (%)>950.7940.282–2.2350.663
      ≤95
      V150 (%)>760.9910.366–2.7740.802
      ≤76
      V200 (%)>550.4100.137–1.2250.110
      ≤55
      OS = overall survival; KPS = Karnofsky Performance Score; EBRT = external beam radiotherapy; GTV = gross tumor volume; HR = hazard ratio; CI = confidence interval.

      Adverse events

      Adverse events (AEs) associated with needle puncture and seed irradiation were observed in the cohort. Two patients (8%) developed severe pain during seed implantation, and 1 patient (4%) developed a hematoma in the neck. Three patients (12%) developed Grade 1 skin reaction and 2 (8%) developed Grade 2 skin reaction. Two (8%) developed Grade 1 mucosal reaction and 1 (4%) developed Grade 2 mucosal reaction. In addition, 1 (4%) exhibited Grade 1 xerostomia. No other puncture and irradiation-related AEs were observed.

      Discussion

      In this study, 68% of the patients enrolled received one excision and the left 32% received at least two excisions; 72% of the patients underwent one EBRT and the remaining 28% received two EBRTs. Furthermore, 68% of the patients were staged as T4 due to invasion of orbit, facial skeleton, and skull base. For these patients, management of the local recurrence is really a challenging therapeutic problem. In the light of surgeon's consultation and personal refusal, this cohort of patients was deemed unresectable. Considering the dose limitation and high risk of injuries of normal structures, no more EBRT could be performed. As for this group of patients, low-dose-rate brachytherapy, theoretically, is a preferred radiotherapeutic option available because high radiation dose can be delivered and localized to the tumor target and thus the adjacent normal tissues are spared (
      • Rosenblatt E.
      • Meushar N.
      • Eidelman M.
      • et al.
      Low dose-rate interstitial brachytherapy in soft tissue sarcomas.
      ). Administering enough high doses of radiation to the recurrent lesion is of especial importance for these patients whose recurrent lesions generally have regional hypoxia by reason of the scarring from prior surgical excisions and EBRT. This theoretical conjecture is being gradually empirically certificated by clinical evidences from various cancers (
      • Qu A.
      • Jiang P.
      • Sun H.
      • et al.
      Efficacy and dosimetry analysis of image-guided radioactive 125I seed implantation as salvage treatment for pelvic recurrent cervical cancer after external beam radiotherapy.
      ,
      • Ji Z.
      • Jiang Y.
      • Tian S.
      • et al.
      The effectiveness and prognostic factors of CT-guided radioactive I-125 seed implantation for the treatment of recurrent head and neck cancer after external beam radiation therapy.
      ,
      • Wang J.J.
      • Yuan H.S.
      • Li J.N.
      • et al.
      CT-guided radioactive seed implantation for recurrent rectal carcinoma after multiple therapy.
      ,
      • Wu C.
      • Li B.
      • Sun G.
      • et al.
      Efficacy and safety of iodine-125 brachytherapy combined with chemotherapy in the treatment of advanced NSCLC in the elderly.
      ,
      • He C.
      • Liu Y.
      • Li Y.
      • et al.
      Efficacy and safety of computed tomography-guided (125)I brachytherapy for lymph node metastatic from hepatocellular carcinoma.
      ,
      • Gai B.
      • Zhang F.
      Chinese expert consensus on radioactive (125)I seeds interstitial implantation brachytherapy for pancreatic cancer.
      ,
      • Yu Y.H.
      • Wei C.Y.
      • Qin Q.H.
      • et al.
      Efficacy of iodine-125 seed implantation in locoregionally recurrent and unresectable breast cancer: a retrospective study.
      ,
      • Yao L.
      • Wang J.
      • Jiang Y.
      • et al.
      Permanent interstitial 125I seed implantation as a salvage therapy for pediatric recurrent or metastatic soft tissue sarcoma after multidisciplinary treatment.
      ,
      • Li J.
      • Wang J.
      • Meng N.
      • et al.
      Image-guided percutaneous 125 I seed implantation as a salvage treatment for recurrent soft tissue sarcomas after surgery and radiotherapy.
      ). However, to our knowledge, owing to the lack of available literature, whether RIS implantation can be applied to effectively treat the locally recurrent HNSTS is not clear. This study, as far as we know, may be the first one specifically to explore the efficacy and safety of the RIS brachytherapy for locally recurrent HNSTS.
      In this study, the ORR, short-term efficacy, was 72.0%, of which the CR rate was 40%. We further analyzed the clinical and dosimetric features of these patients who achieved a CR. Results showed that the patients with better T stage and smaller tumor size (GTV) were significantly more likely to achieve a CR. Moreover, the patients receiving higher therapeutic dose (D90) were more likely to get a CR, though the difference was not significant. In addition, results showed that the patients with CR had significantly higher mean D90 (153 Gy) compared with the patients without CR (138 Gy), p = 0.005. This underscored that higher dose may contribute to a better elimination of local disease.
      Despite local recurrence in 14 patients at last, the other 11 patients got a long-term local control thereafter. The 1-, 3-, and 5-year LPFS rates were 65.6%, 34.4%, and 22.9%, respectively, and the 1-, 3-, and 5-year OS rates were 70.8%, 46.6%, and 34.0%, respectively. A study exploring the feasibility of RIS implantation brachytherapy as a treatment for recurrent STS (including 3 patients with STS in the head and neck and 15 with STS in the trunk and extremities) reported that the 1-, 2-, 3-, 4-, and 5-year local control rates were 78.8%, 78.8%, 78.8%, 26.3%, and 0% and the 1-, 2-, 3-, 4-, and 5-year survival rates were 76.6%, 61.3%, 39.4%, 39.4%, and 39.4%, respectively(
      • Li J.
      • Wang J.
      • Meng N.
      • et al.
      Image-guided percutaneous 125 I seed implantation as a salvage treatment for recurrent soft tissue sarcomas after surgery and radiotherapy.
      ). Another study, conducted by Pearlstone et al. (
      • Pearlstone D.B.
      • Janjan N.A.
      • Feig B.W.
      • et al.
      Re-resection with brachytherapy for locally recurrent soft tissue sarcoma arising in a previously radiated field.
      ); involving 26 patients with locally recurrent STS (including 2 cases of HNSTS) showed that the 5-year local control rate and overall survival rate were both 52% after brachytherapy with 192Ir wire in conjunction with re-excision. The results from previous studies demonstrated a favorable efficacy of brachytherapy for locally recurrent lesion in STS. However, previous publications on this topic included only a few patients with locally recurrent HNSTS (three in the study by Li et al. (
      • Li J.
      • Wang J.
      • Meng N.
      • et al.
      Image-guided percutaneous 125 I seed implantation as a salvage treatment for recurrent soft tissue sarcomas after surgery and radiotherapy.
      ) and two in the study by Pearlstone et al. (
      • Pearlstone D.B.
      • Janjan N.A.
      • Feig B.W.
      • et al.
      Re-resection with brachytherapy for locally recurrent soft tissue sarcoma arising in a previously radiated field.
      ). In other words, the conclusions of previous studies were mainly based on the outcomes of non-HNSTS patients and hence may not be completely applicable to HNSTS patients. Our study confirmed a good therapeutic effect of RIS implantation in locally recurrent HNSTS, which echoed the aforementioned studies and extended the evidence in favor of applying RIS implantation to HNSTS patients for effective control of locally recurrent lesion.
      As information on the management of locally recurrent HNSTS after initial surgery and radiation is scarce, relevant prognostic data remain unclear. In the present study, univariate analyses showed that histological grade were prognostic factors for LPFS and OS. These results suggested that patients with lower histological grade had significantly lower risk of local recurrence and death. In cases with primary HNSTS, similar results were observed. Zagars et al. (
      • Zagars G.K.
      • Ballo M.T.
      • Pisters P.W.
      • et al.
      Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients.
      ) reported that histological grades were significantly independent prognostic factors for local control and OS in a study involving 1225 patients with primary HNSTS. Gonzalez-Gonzalez et al. (
      • Gonzalez-Gonzalez R.
      • Bologna-Molina R.
      • Molina-Frechero N.
      • et al.
      Prognostic factors and treatment strategies for adult head and neck soft tissue sarcoma.
      ); Mattavelli et al. (
      • Mattavelli D.
      • Miceli R.
      • Radaelli S.
      • et al.
      Head and neck soft tissue sarcomas: prognostic factors and outcome in a series of patients treated at a single institution.
      ); and Penel et al. (
      • Penel N.
      • Mallet Y.
      • Robin Y.M.
      • et al.
      Prognostic factors for adult sarcomas of head and neck.
      ) reconfirmed these results. Moreover, previous studies regarding locally recurrent STS mostly in extremities and trunk also identified high grade as a factor predisposing patients to local recurrence after retreatment (
      • Torres M.A.
      • Ballo M.T.
      • Butler C.E.
      • et al.
      Management of locally recurrent soft-tissue sarcoma after prior surgery and radiation therapy.
      ,
      • Moureau-Zabotto L.
      • Thomas L.
      • Bui B.N.
      • et al.
      Management of soft tissue sarcomas (STS) in first isolated local recurrence: a retrospective study of 83 cases.
      ,
      • Ramanathan R.C.
      • A'Hern R.
      • Fisher C.
      • et al.
      Prognostic index for extremity soft tissue sarcomas with isolated local recurrence.
      ). According to American Joint Committee on Cancer stage system for soft tissue sarcoma of the head and neck sarcoma (8th ed., 2017), T4 refers to tumors with invasion of adjoining structures in spite of any size and T1-T3 include tumors with different size but without invasion of nearby structures. It was found that recurrent T stage (T4 vs. ≤ T3;HR = 4.020; 95% confidence interval [CI] = 1.117–14.466; p = 0.033) was another independent prognostic factor of LPFS in this study. In other words, the patients with Stage T4 had higher risk to develop local recurrence than those with stage lower than T4, which indicated that invasion of adjoining structures was more likely to affect the LPFS than tumor size. Previous studies showed that the radiation dose was a significantly independent prognostic factor of the efficacy in most cancers including head and neck squamous carcinoma, cervical cancer, and so on (
      • Qu A.
      • Jiang P.
      • Sun H.
      • et al.
      Efficacy and dosimetry analysis of image-guided radioactive 125I seed implantation as salvage treatment for pelvic recurrent cervical cancer after external beam radiotherapy.
      ,
      • Ji Z.
      • Jiang Y.
      • Tian S.
      • et al.
      The effectiveness and prognostic factors of CT-guided radioactive I-125 seed implantation for the treatment of recurrent head and neck cancer after external beam radiation therapy.
      ). Similar results were not observed in our work, which may be due to the limited sample size. Our study explored the prognostic factors of locally recurrent HNSTS, filling a research gap in this field and the results may help physicians to predict the outcome of patients.
      As to AEs, mucosal/skin toxicities were the most frequent. Grade 1/2 skin reaction occurred in 5 patients (20%) and Grade 1/2 mucositis in 3 (12%). No patients developed Grade 3/4 side effects. Previous studies also observed low toxicities of RIS implantation as a salvage treatment for recurrent head and neck cancer. Ji et al. (
      • Ji Z.
      • Jiang Y.
      • Tian S.
      • et al.
      The effectiveness and prognostic factors of CT-guided radioactive I-125 seed implantation for the treatment of recurrent head and neck cancer after external beam radiation therapy.
      ) reported that Grade 3 skin/mucosal toxicities were 7.9% and Grade 4 were 2%. A study by Jiang et al. (
      • Jiang Y.
      • Ji Z.
      • Guo F.
      • et al.
      Side effects of CT-guided implantation of 125I seeds for recurrent malignant tumors of the head and neck assisted by 3D printing non co-planar template.
      ) specifically explored the side effects of RIS implantation in the treatment of recurrent head and neck cancer showing that 14.4% of patients had Grade 1/2 skin/mucosal toxicities and no patients suffered from Grade 3/4 skin/mucosal side effects. Conversely, the toxicities of re-EBRT to head and neck cancers seemed much more severe than RIS brachytherapy. De Crevoisier et al. (
      • De Crevoisier R.
      • Bourhis J.
      • Domenge C.
      • et al.
      Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients.
      ) reported mucositis Grade 3 was 32% and Grade 4 was 14% in patients with head and neck carcinomas treated with full-dose re-EBRT. RTOG 9610, a multiinstitutional trial reported that Grade 3 skin/mucosal toxicities were 34.2% and Grade 4 skin/mucosal toxicities were 8% after re-EBRT with chemotherapy (
      • Spencer S.A.
      • Harris J.
      • Wheeler R.H.
      • et al.
      Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck.
      ). Generally, the AEs were of lower grade and well tolerated, indicating the safe nature of RIS implantation.
      As to limitations, this work was a single-center retrospective study and the sample size was limited partly due to the rare morbidity. Even so, it provided preliminary evidences for the application of RIS implantation to the locally recurrent HNSTS after surgery and EBRT. Evidences in the future are needed to further confirm the role of RIS implantation in locally recurrent HNSTS after surgery and EBRT.

      Conclusion

      For patients with locally recurrent HNSTS after failure of surgery and EBRT, RIS implantation produced good short-term therapeutic effects, favorable local control, and survival in accompany with moderate toxicities, which suggested that RIS implantation could be an effective and safe alternative treatment. Recurrent T stage and histological grade were the main factors influencing the efficacy.

      Acknowledgments

      The authors are grateful to Mr. Edwin Leong for his help with editing and improvements of this manuscript.

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