Carbon ion radiotherapy for nasopharyngeal carcinoma

Carbon ion radiotherapy for nasopharyngeal carcinoma

1.Preliminary Results of Carbon Ion Radiotherapy for Locally Recurrent Nasopharyngeal Carcinoma

This study included patients with locally recurrent, poorly differentiated or undifferentiated nasopharyngeal carcinoma (NPC) who received salvage intensity-modulated carbon ion therapy (IMCT) at the Shanghai Proton and Heavy Ion Center from May 2015 to August 2017. The IMCT dose ranged from 50 to 66 (GyE) (2.0 to 3.0 GyE per fraction). The 1-year overall survival, disease-specific survival, progression-free survival (PFS), local recurrence-free survival, regional recurrence-free survival rate, and distant metastasis-free survival were calculated. Univariate and multivariate analyses of PFS were performed to identify potential predictive factors.

Among the 75 patients, 4, 14, 29, and 28 patients had recurrent AJCC stage I, II, III, and IVA/B diseases, respectively. With a median follow-up of 15.4 months (range, 2.6–29.7 months), the 1-year overall survival rate, disease-specific survival rate, PFS, local recurrence-free survival rate, regional recurrence-free survival rate, and distant metastasis-free survival rate were 98.1%, 98.1%, 82.2%, 86.6%, 97.9%, and 96.2%, respectively. In univariate analysis, a higher dose per fraction of 3 GyE (vs. <3 GyE) or a higher biologically effective dose significantly improved the PFS rate, but this was not the case in multivariate analysis. During IMCT, no patients experienced acute toxicity of grade ≥2. Severe (grade 3 or 4) late treatment-related toxicities were not common, but mucosal necrosis (9.3%), xerostomia (1.3%), and temporal lobe necrosis (1.3%) occurred.

2.Application of Photon and Carbon Ion Beam Hybrid Radiotherapy in the Treatment of Non-metastatic Nasopharyngeal Carcinoma

This study included patients with non-metastatic nasopharyngeal carcinoma who received intensity-modulated radiotherapy (IMRT) + carbon ion radiotherapy (CIRT) at the Shanghai Proton and Heavy Ion Center from June 2015 to June 2018. The Kaplan-Meier method was used to calculate overall survival (OS), progression-free survival (PFS), local control, regional control, and distant control. Acute and late toxicities were graded according to CTCAE 4.03.

Methods: PTV1 and PTV2 were treated with IMRT, with doses of 56 Gy/28 fractions and 50.4 Gy/28 fractions, respectively. Carbon ion radiotherapy was used to deliver 15 - 17.5 GyE in five to six fractions (2.5 - 3.5 GyE per fraction).

Results: A total of 69 patients were included in the analysis. Among them, 74% of the patients had locally advanced (stage III/IV) disease, and 92.8% of the patients had cervical lymph node metastasis. With a median follow-up of 31.9 months, the 3-year OS, PFS, local control rate, regional control rate, and distant control rate were 94.9%, 85.2%, 96.9%, 98.4%, and 89.7%, respectively. The combination of IMRT and CIRT was well-tolerated. Severe (defined as grade ≥3) acute radiation-induced toxicity was observed in 2 patients (dermatitis). More common severe acute hematological toxicities related to chemotherapy included neutropenia, thrombocytopenia, leukopenia, and anemia. Grade 1 or 2 late radiation-induced toxicities included dysphonia in 22 patients (31.8%), xerostomia in 59 patients (85.5%), and hearing impairment in 11 patients (15.9%). No severe (grade 3) radiation-induced late toxicities, such as xerostomia, skin fibrosis, temporal lobe necrosis, radiation osteonecrosis, or radiation neuropathy, were observed at the time of analysis.

3. Survival Outcomes and Toxicity Profiles of Non-metastatic Nasopharyngeal Carcinoma Patients Treated with Intensity-Modulated Radiotherapy (IMRT) and IMRT + Carbon Ion Radiotherapy (CIRT): A Propensity Score Matching Analysis

Methods: A retrospective propensity score matching analysis (1:1) was conducted on patients treated with IMRT and IMRT + CIRT. Descriptive statistical methods were used to examine the baseline characteristics of the patients. The Kaplan–Meier method was used to estimate survival rates. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of survival. The chi-square test was used to examine the association between risk factors and adverse events (AEs). Cox models and logistic regression analyses were used for AEs. All patients in the IMRT group received external radiotherapy with a 6-MV photon beam, using 7 - 9 radiation fields. The treatment technique employed the simultaneous integrated boost (SIB) technique. For T1 - 2 tumors, a prescription dose of 66 Gy was delivered in 30 fractions to the primary tumor planning target volume (PTV_G). For T3 - 4 tumors, a prescription dose of 70.4 Gy was delivered in 32 fractions. The radiation doses for PTV_C1 and PTV_C2 were 60 Gy and 54 Gy, respectively, delivered in 30 - 32 fractions.

In the IMRT + CIRT group, PTV_C1 and PTV_C2 were treated with IMRT at doses of 57.2 Gy/26/Fx and 52 Gy/26/Fx, respectively. An incremental dose of CIRT of 11.5 Gy was prescribed for PTV_C1, delivered in 5 fractions (2.3 GyE/Fx per fraction), and an incremental dose of CIRT of 15 GyE was prescribed for GTV_P, delivered in 5 fractions (3 GyE/Fx per fraction). All patients were treated 5 days a week, once daily.

Results: A total of 109 patients treated with IMRT + CIRT were included in the study, with a median follow-up time of 20.6 months (range: 4.6 - 82 months). There were no statistically significant differences in the rates of local-regional recurrence-free survival, distant metastasis-free survival, disease-free survival, or overall survival between the two groups, although the IMRT + CIRT group might have a better outcome (p > 0.05, respectively). Multivariate analysis showed that lymph node boost was the only factor significantly associated with LRFS and DFS. In the IMRT + CIRT group, 37 patients (34.0%) experienced grade 3 acute oral mucositis, and no grade 4 acute oral mucositis was observed. All patients in the IMRT + CIRT group developed grade 1 dermatitis; in the matched group, 76 patients developed grade 1 dermatitis, 27 patients developed grade 2 dermatitis, 5 patients developed grade 3 dermatitis, and 1 patient developed grade 4 dermatitis. IMRT + CIRT treatment was significantly associated with a trend towards lower grades of oral mucositis and dermatitis (p < 0.05, respectively). No severe (i.e., grade 3) chronic AEs, such as xerostomia, skin fibrosis, temporal lobe necrosis, radiation osteonecrosis, or radiation neuropathy, were observed.

4.Meta-analysis of Concurrent Chemoradiotherapy and Radiotherapy Alone in the Treatment of Locally Advanced Nasopharyngeal Carcinoma in the Intensity-Modulated Radiotherapy Era

Objective: In this study, we aimed to compare the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) and radiotherapy (RT) alone for locally advanced nasopharyngeal carcinoma (LANPC) through a meta-analysis.

Materials and Methods: We searched the databases, and all randomized controlled trials that met the inclusion criteria were included in the meta-analysis using RevMan 5.3 based on the Cochrane method.

Results: According to the inclusion criteria, 15 studies were considered appropriate. With RT alone, the 5-year overall survival rate (OS) for stage I was >90%. However, the 5-year OS rate for LANPC treated with RT alone was only 67% - 77%. In the IMRT era, the addition of chemotherapy increased the estimated 5-year OS rate from 73.7% (without concurrent chemotherapy) to 81.8% (with concurrent chemotherapy).

Conclusion: In this meta-analysis, all included studies were prospective randomized controlled studies. The results of the analysis of 15 clinical studies indicated that the prognosis of concurrent chemotherapy plus IMRT was better than that of IMRT alone. CCRT significantly improved the objective response rate (ORR), complete response rate (CRR), and overall survival (OS). Regarding treatment-related toxicity, CCRT led to more tolerable adverse events compared with IMRT alone.

5.Concurrent Chemoradiotherapy for Locally Advanced Nasopharyngeal Carcinoma: Treatment Outcomes and Prognostic Factors.Department of Radiation Oncology, Kyung Hee University Medical Center

Methods: This retrospective study included 32 patients with stage III - IVB nasopharyngeal carcinoma. All patients received concurrent chemoradiotherapy with either 3D conformal radiotherapy or intensity-modulated radiotherapy. The total dose for the high-risk planning target volume (PTV) was 63 - 73.5 Gy, and the total dose for the low-risk PTV was 45 - 54 Gy.

Results: The 2-year and 5-year overall survival rates were 89.9% and 82.6%, respectively. The 2-year and 5-year distant metastasis-free survival rates were 83.2% and 79.4%, respectively. The 2-year and 5-year local-regional recurrence-free survival rates were 83.3% and 79.5%, respectively. The addition of induction chemotherapy to concurrent chemoradiotherapy did not improve survival outcomes. Compared with 3D conformal radiotherapy, intensity-modulated radiotherapy significantly reduced the development of late toxicity. Acute toxicities occurred in almost all patients. The commonly observed acute toxicities were mucositis, dermatitis, dysphagia, and oral dryness. There were no significant differences in acute toxicities among patients receiving 3D conformal radiotherapy.

Conclusion: Concurrent chemoradiotherapy leads to a high survival rate and an acceptable level of toxicity in patients with locally advanced nasopharyngeal carcinoma.

6.Advances in Intensity-Modulated Radiotherapy-Based Treatment for Early Nasopharyngeal Carcinoma

Kwong et al. reported that the 3-year overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) rates of patients with early nasopharyngeal carcinoma (T1N0 - 1M0) treated with intensity-modulated radiotherapy (IMRT) alone were all 100%. At present, there are also many studies indicating that IMRT alone achieves good therapeutic effects in the treatment of early nasopharyngeal carcinoma. Su et al. analyzed the survival status of 198 patients with early nasopharyngeal carcinoma treated with IMRT alone. The 5-year disease-specific survival rate, LC, and DMFS were 97.3%, 97.7%, and 97.8%, respectively. Among them, the 5-year DMFS rates for T1N0M0, T2N0M0, T1N1M0, and T2N1M0 stages were 100%, 98.8%, 100%, and 93.8%, respectively (P = 0.073). The results of Sun et al.'s study showed that for patients with T1N0M0 and T2N0M0 stages, the 5-year OS rates after receiving IMRT alone were 97.8% and 100%, respectively; the 5-year LC rates were 100% and 92.9%, respectively; and the 5-year DMFS rates were 96.6% and 90.9%, respectively.

7. Long-term Survival and Late Complications of Intensity-modulated Radiotherapy for Recurrent Nasopharyngeal Carcinoma

Methods: A retrospective review was conducted of 184 patients with nasopharyngeal carcinoma (NPC) who had previously received radiotherapy, experienced recurrence, and underwent IMRT re-irradiation between February 2005 and May 2013. Among them, 33 patients were restaged as stage I, 27 as stage II, 70 as stage III, and 54 as stage IV. 75% of the patients received chemotherapy based on cisplatin. A treatment plan using 6 MV photon (SIB) technique was employed. The median dose was 66.7 Gy (range, 42 - 77 Gy). The fractionated dose was 1.8 - 2.3 Gy per day (5 days a week). Thirteen patients received brachytherapy.

Results: The median survival time was 33 months. The 3-year actuarial rates of local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were 85.1%, 91.1%, and 46.0%, respectively. Approximately 53% of the patients experienced grade 3 - 4 late toxicity. Severe adverse events (SAEs) (≥grade 3 toxicity) were recorded after intensity-modulated radiotherapy (IMRT). Common late SAEs included mucosal necrosis, headache, cranial nerve paralysis, and trigeminal neuralgia. Forty-four patients (24.9%) died due to massive epistaxis caused by mucosal necrosis, as the necrosis involved the internal carotid artery. The median latency period of mucosal necrosis was 6.0 months (range, 0.5 - 65.5 months). Multivariate analysis indicated that chemotherapy and the time interval between initial radiotherapy and re-irradiation were independent predictive factors for DMFS.

Conclusion: Intensity-modulated radiotherapy is an effective method for treating locally recurrent nasopharyngeal carcinoma. Massive hemorrhage in the nasopharyngeal region is a serious late complication and a major cause of death. Early recurrence is an unfavorable factor for DMFS. Combined chemotherapy can improve DMFS but not OS. An optimal salvage treatment strategy focusing on improving survival rates and minimizing late toxicity is needed.