Fractionated stereotactic radiotherapy for 136 patients with locally residual nasopharyngeal carcinoma

From January 2000 to December 2009, FSRT was administered to 136 NPC patients who had local residual lesions after the first course of external beam radiotherapy (EBRT). Pretreatment evaluation for all the patients included a complete history and physical examination, flexible fiberoptic nasopharyngolaryngoscopy, initial pathologic diagnosis, and multidisciplinary tumor board discussion. Staging evaluations included chest radiographs, complete blood count, complete metabolic panel, and MRI with gadolinium and/or CT with contrast from the base of skull to 2 cm below the clavicles. In selected patients with T3-T4 tumor or N2-N3 neck nodal disease, bone scans and chest and abdominal CT scans were also obtained.

Inclusion criteria for this study were as follows: pathological confirmation for all primary tumors prior to EBRT; existence of local residual tumor after EBRT and absence of distant metastasis. Residual tumor was defined as residual disease by fibroendoscopy or MRI within one week after completion of definitive EBRT. The criteria for residual disease on MRI were persistent tumor mass, thickened nasopharyngeal walls with enhancement at the primary site, or persistent enhancing retropharyngeal lymph nodes that were present before EBRT. If persistent lesion was observed by fibroendoscopy, tissue biopsy was not always necessary due to the risks of complications. If a superficial lesion in nasopharynx or adjacent area did not meet the diagnostic criteria of residual tumor on imaging studies, tissue biopsy is required within one week after imaging studies. Contraindications for biopsy were as follows: deep lesions that were located in parapharyngeal space, skull base, cavernous sinus or any areas that were not easily accessible; lesions abutting neurovascular tissues, evidence of infection or ulcer in nasopharynx, hemorrhagic tendency, or age older than 60 years or diabetes mellitus that cause healing delays. For the patients with suspicious residual lesions on imaging studies but tissue biopsy was contraindicated, we would repeat imaging studies at one month from completion of EBRT, using the same criteria for persistent disease described above. Residual Sites in this study included nasopharyngeal cavity, parapharyngeal space, retropharyngeal lymph nodes or intracranial residual lesions, while cervical nodes were not included. The patients with local residual tumor of NPC were evaluated jointly by a team of head-and-neck surgeons and clinical oncologists for possible salvage treatment. FSRT was recommended to these patients if it was considered the best available and acceptable treatment option. All patients were staged according to the 2002 International Union against Cancer (UICC) staging system. The twenty-five patients treated before 2002 were re-staged according to 2002 UICC staging system for the purpose of this study. Seventy-six patients (55.9%) had a single residual lesion, whereas 60 patients (44.1%) had multiple lesions, thus, a total of 196 lesions were treated by FSRT. All residual lesions were persistent in the high dose regions of EBRT. The main sites of local residual lesions were the pharyngonasal cavity, and the parapharyngeal space. Thirty-two (29%) patients also had skull base destruction. The details of the patient characteristics are shown in Table 1.

In 85 patients, conventional EBRT was delivered at 2 Gy daily fractions, 5 fractions per week, to a median total dose of 70 Gy. The beam arrangements consisted predominantly of opposed parallel lateral ports, and all fields were treated with 6 MV beam photon. The lower neck was treated with an appositional anterior cervical field to 50 Gy. A block was used to protect the spinal cord at the field junctions for all patients. Fifty-one patients received intensity-modulated radiotherapy (IMRT) as the primary treatment of NPC. The gross tumor vo lume (GTV) with margin for daily positioning uncertainty was treated with 2.12-2.24 Gy fractions to a median total of 73.92 Gy (range, 69.96-78.0 Gy). The clinical target volume (CTV) at high risk for microscopic tumor involvement received 60.06 Gy in 30 fractions, and the low-risk CTV received 50.96 Gy in 30 fractions. All EBRT doses were limited to ≤40 Gy to the spinal cord dose, ≤54 Gy to the optic apparatus, and ≤54 Gy to the surface of the brainstem. The median overall time for EBRT was 50 days (range, 46–68). Seventy-five (71.4%) out of 105 patients with stage III/IV received cisplatin-based concurrent chemoradiotherapy. Thirty patients with stage III/IV cancer did not receive chemotherapy because of poor tolerance (such as severe comorbidities, low Karnofsky performance score) or being treated with RT alone on an institutionally randomized clinical trial.

FSRT was performed using a collimator-based system (Creat Stereotactic treatment system, China) with a 6-MV linear accelerator (Varian, USA) before July 2006, and multileaf collimator (MLC)-based FSRT system (BrainLAB, Germany) since August 2006. Patients were immobilized using a relocatable-type head ring with a wrapping head-band and stereotactic frame. Contrast-enhanced CT scan with a slice thickness of 3 mm was performed for treatment planning. If needed, MRI images were used to aid target delineation. The target volume was defined as abnormal soft-tissue mass or/and contrast-enhanced areas as shown in axial images plus a 2–3 mm margin. Adjacent mucosal and soft tissues were included if residual lesions were seen on flexible nasopharyngoscopy exam. Critical structures including brainstem, spinal cord, optic chiasm, optic nerves, eyeballs, and lenses were contoured.

The fractional dose of FSRT was 2.0-10.0 Gy (median, 4.0 Gy) per fraction. The number of isocenters ranged from 1 to 3 (median, 1). Thirty-three patients received FSRT with fractionated dose>5 Gy, including 16-20Gy/8-10Gy/2f for 3 patients, 20-26Gy/6-8Gy/3-4f for 5 patients, 18-26Gy/5.2-7Gy/3-5f for 25 patients; and 103 patients received FSRT with fractionated dose≤5 Gy, including 12-32Gy/4-5Gy/3-8f for 49 patients, 8-23Gy/2-3.5Gy/3-7f for 54 patients. An example of isodose distribution is shown in Figure 1. To compare various fractionation schemes, the biologically effective dose (BED) was calculated using the equation BED=total dose×(1+d/α/β), where d=dose per fraction and α/β=10, no correction was made for tumor proliferation since all the treatment was finished within 2 weeks[17, 18]. The median BED on FSRT was 28 Gy (range, 10.1-44.8 Gy). Table 2 summarizes the FSRT treatment parameters.

All patients were followed in our clinic every 3 months for the first 2 years, every 6 months for 3–5 years, and annually thereafter. MRI of nasopharynx and neck, and flexible nasopharyngoscopy were routinely performed during follow-up visits, and suspected lesion was subject to a biopsy. Blood chemistry panels, serum chemistries, chest radiographs, ultrasounds of abdomen, and bone scans were performed annually or if clinically indicated.

The following endpoints were examined: response to FSRT, local failure-free survival (LFFS), overall survival, disease free survival (DFS), and freedom from distant metastasis (FFDM). Treatment response was evaluated by fibroendoscopy and MRI scans at six months after completion of FSRT. Treatment response was evaluated by imaging studies in most patients. If imaging studies were nondiagnostic, tissue biopsy would be mandatory if it was feasible. Complete response (CR) was defined as complete regression of tumor assessed on MRI and nasopharyngoscopy or a negative biopsy in patients with suspected lesions on imaging studies. Partial response (PR) was defined as tumor regression more than 50% of bi-dimensional diameters compared to lesions on baseline images, and no response if neither PR nor CR was achieved. In-field recurrence was defined as tumor relapse within the volume encompassed by FSRT prescription isodose line, and out-of-field recurrence as tumor relapse outside FSRT target volume but within the primary EBRT fields. Time was measured from the date when FSRT completed until time of event occurrence, or most recent follow-up for censored observations. Actual incidences of LFFS, OS, DFS and FFDM were calculated using the Kaplan-Meier method, and the differences between survival curves were compared using the log–rank test. Log-rank analysis was used to compare prognostic factors for LFFS, OS, DFS and FFDM, and factors found to influence prognosis on univariate analysis were subjected to multivariate analysis using Cox’s proportional hazard regression model, in order to determine if these factors acted independently. According to previous literature[19‐22], gender, age(≤45 years vs. >45 years), interval between primary radiotherapy and FSRT(≤2 months vs. >2 months), T stage (T1–2 vs. T3–4) and N stage (N0–1 vs. N2–3) at diagnosis, tumor volume(≤10mL vs. >10 mL), BED(≤30 Gy vs. >30 Gy) and concurrent chemotherapy use during primary RT were analyzed as covariates in univariate and multivariate analyses. All statistical analysis was performed using the commercial software package SPSS 15.0 (SPSS Institute Inc., Chicago, USA). All acute and late complications were scored according to the Common Terminology Criteria (CTC) for Adverse Events v3.0 criteria and Radiation Therapy Oncology Group (RTOG) criteria.

The median follow-up for all patients was 66.5 months (range, 10–139). The median follow-up for patients who were alive was 69 months (range, 20–139). At six months after completion of FSRT, the actuarial CR rate was 72.1% and PR rate was 23.5%, with an overall response rate of 95.6%.

Three- and 5-year LFFS and FFDM rates for all patients were 94.5 %, 92.5%, and 84.3 %, 77.0%, respectively (Figure 2). Three- and 5-year OS and DFS rates for all patients were 85.7 %, 76.2%, and 79.0 %, 73.6%, respectively. During follow-up, local relapse developed in 12 patients: 4 were in-field that occurred in 16–28 months, and 8 were out-field that occurred in 42–102 months after FSRT. Five patients developed cervical nodal recurrences, and they were salvaged by neck dissection and were nodal disease free since after. The median local relapse time after FSRT was 35 months (range, 16–102). Distant metastases (DM) were observed in 36 patients (26.5%) with a median time of 9 months (range, 1–110 months). The most common sites were the bones (24 patients), lungs (14 patients), and liver (8 patients). Ten patients developed more than one metastatic site. Of the patients who developed distant metastases, 6 had initial Stage IIb, 18 had Stage III, and 12 had Stage IV disease. Four patients had N0, 12 had N1, 15 had N2, and 5 had N3 disease. One patient had T1, 11 had T2, 15 had T3, 9 had T4 disease. For stage I/II and stage III/IV patients, 5-year LFFS, OS and DFS rates were 89.9% and 93.3% (p=0.577), 86.3% and 70.7% (p=0.0.097), 83.2% and 70.8% (p= 0.455), respectively (Figure 3). The cause of death was distant metastases in 22 patients, local recurrence with dyscrasia in 6 patients, postoperative severe dysphagia and dyscrasia in 1 patient, massive nasopharyngeal hemorrhage in 5 patients, other causes in 12 patients (including dyscrasia, cerebral hemorrhage and non-radiation induced pneumonia).

Univariate analyses revealed that age (80.5% for patients ≤45 years vs. 70.7% for patients >45 years, p = 0.042) was a significant prognostic factor to predict 5-year actuarial overall survival, and T stage at diagnosis was significant for 5-year actuarial overall survival (83.9% for T1–2 vs. 70.1% for T3–4, p = 0.039) and disease free survival (86.2% for T1–2 vs. 63.6% for T3–4, p =0.039). No other variables were found to be significant prognostic factors for OS, DFS, LFFS and FFDM. The results of univariate analyses of OS and DFS are summarized on Table 3. Multivariate analyses showed that age and T stage at diagnosis were the significant independent prognostic factors for 5-year overall survival (p = 0.034 and p = 0.033, respectively), and T stage at diagnosis was significant independent prognostic factors for 5-year disease free survival (p = 0.043). The results of multivariate analysis are summarized on Table 4.

There were no severe acute toxicities secondary to FSRT. All 136 patients completed the full course of FSRT as planned and treatment was well tolerated. Late toxicities included cranial nerve injury (IX-XII, grade 1–2) in 8, massive nasopharyngeal hemorrhage in 5, and asymptomatic temporal lobe necrosis in 6 patients. The diagnosis of temporal necrosis was all made according to magnetic resonance spectroscopy. Temporal lobe necrosis did not affect their job performance or daily life in these patients.