1. Study Design
In this study, PASS software 2021 version was used to calculate the sample size.
In this single-arm, single-center clinical trial, we included eligible patients into the study, followed up their adverse reactions and complications 1, 3, 6, 9, 12, 18 and 24 months after receiving IORT therapy, and assessed the safety of IORT. The results of regular postoperative imaging and
laryngoscopy were recorded, and the efficacy of IORT was analyzed and determined.
2. Subjects
The subjects in this study were all LAL patients diagnosed histopathologically in Tianjin First Central Hospital who received radical surgery (total laryngectomy/hemilaryngectomy) combined with IORT and received local external irradiation within 6 weeks after surgery. The subjects were enrolled from January1, 2019 to September30, 2021, and had signed the informed consent form. See Fig. 1 for study design.
Inclusion criteria
1) Subjects at age of ≥ 18 years; 2) Subjects who were pathologically diagnosed as locally advanced laryngeal squamous cell carcinoma with staging of T2N1-3/T3N0-3/T4N0-3; 3) Subjects who had indication of radical surgery (total laryngectomy / hemilaryngectomy) and agreed to receive surgery; 4) Subjects with estimated survival time of ≥ 3 months.
Exclusion criteria
1) Subjects who received EBRT before surgery; 2) Subjects with distant metastasis; 3) Subjects who had previous history of other malignant tumors; 4) Subjects whose Postoperative tumor bed was not suitable for IORT; 5) Subjects who had contraindications of follow-up CT/MRI examination; 6) Subjects who refused to accept follow-up or loss of follow-up; 7) Subjects with previous serious diseases of other systems; 8) Subjects who were pregnant or planned to be pregnant; 9) Subjects who participated in other clinical trials.
3. Treatment method
1) IORT treatment method: All the patients enrolled were treated with the INTRABEAM system for IORT during radical surgery (total laryngectomy/hemilaryngectomy). The IORT system was calibrated and verified in terms of the probe of the IORT control system, dynamic deviation of the electron beam, isotropy and dose delivery, etc. Then the simulated dose distribution of IORT was verified using GMV Radiance ver 3.0. After tumor resection, a treatment probe of the appropriate diameter (1.5 to 5.0 cm, with increment of 0.5 cm) was selected based on the exposed surgical area volume. The treatment probe was connected to the probe of the mobile 50KV X-ray source intraoperative radiotherapy equipment (INTRABEAM, Carl Zeiss, Oberkochen, Germany), and the radiotherapy site was jointly determined by the otolaryngology surgeon and radiation oncologist together. The choice of applicator type is directly related to the operation method. The flat applicator was used in total laryngectomy and the spherical applicator was used in hemilaryngectomy to fit the tumor bed. In addition, the edge of the skin incision was evaginated to avoid excessive radiation exposure. After preparation, the tumor bed area with high risk of tumor recurrence was subjected to a single high-dose irradiation according to the treatment plan. The prescribed dose of 100% volume X-ray was 8-15Gy, and the radiotherapy time was 7–20 minutes. The surgery was completed by suturing the wound after intraoperative radiotherapy. For the specific condition, see Figs. 2.
Postoperative external irradiation treatment method: All patients were required to begin EBRT within 4–6 weeks after IORT, and the median of time is 5 weeks(35 days). The range of target area delineated is as follows: GTVtb includes tumor bed, surgical bed, and the whole area invaded by the primary tumor, none of them subject to radiotherapy boost; if the metastatic lymph nodes invaded into extrapulmonary sites, muscles or blood vessels, the primary region of the metastatic lymph node should be delineated as GTVnd-tb. CTV (clinical target volume) includes GTVtb, GTVnd-tb, other areas of larynx, hypopharynx, tongue vallecula epiglottitis, paraglottic space, preepiglottic space and the whole thyroid cartilage, sub-area of dissected lymph nodes and high-risk lymph node drainage area. For supraglottic laryngeal carcinoma, CTV should include lymphatic drainage areas of upper and middle neck (zones Ⅱ and Ⅲ). If the upper and middle cervical lymph nodes are positive, CTV should include the whole bilateral neck. Tracheostomy fistula should also be included in the target area sketching in cases of subglottic region invasion, emergency tracheostomy performed before surgery, cervical soft tissue invasion, positive tracheal incision margin or insufficient safety boundary, and surgical incision marks passing through thefistula. The planning target volume (PTV)was generated by expanding the CTV by 0.3 cm isotropically in all dimensions. All the patients received EBRT at a total therapeutic dose of 54-60Gy to PTV within 6 weeks after surgery, 5 times per week, 1.8-2Gy per time, 30 times in total.
4. Subject follow-up
1) The subjects should receive regular follow-up within 2 years after IORT. One month after surgery, the subjects started to receive follow-up every 3 months in the first year, and every 6 months in the second year.
2) The following contents were recorded during follow-up: postoperative complications (occurrence, duration and outcome); adverse reactions after treatment (classified according to RTOG for acute radiation injury); regularly reexamine CT, MRI, laryngoscope and other relevant examination results; and whether there are other anti-tumor treatments.
5. Study endpoints
1) Primary endpoint: ① Safety issues after receiving IORT. ② Local control after receiving IORT. The safety indicators were assessed, including postoperative local tissue necrosis and fibrosis; wound healing time; wound infection; pharyngeal fistula; radiation-induced pain; skin and mucous injury; chondronecrosis; salivary gland injury; loss of taste; dyspnea, etc. 2) Secondary endpoint: 2-year survival rate.
6. Statistical Analysis
PASS software 2022 version was used to calculate the sample size, with a statistical power of 80%. SPSS software 27.0 version (IBM, USA) was used for statistical analysis. The counting data is expressed in percentage (%). χ2 test was adopted for comparison between the two groups, which showed statistical significance (p < 0.05). Kapalan Meier method and log rank test were adopted to analyze and determine local control and survival.