Dose-Finding and Efficacy Confirmation Trial of the Superselective Intra-arterial Infusion of Cisplatin and Concomitant Radiation Therapy for Locally Advanced Maxillary Sinus Cancer (JCOG1212): Results of the Efficacy Confirmation Phase in Patients with T4aN0M0.

PURPOSE: Locally advanced maxillary sinus cancers require radical surgery as a standard treatment, but this often results in significant disfigurement and impairment of function. JCOG1212 seeks to evaluate the safety and efficacy of the superselective intra-arterial infusion of cisplatin and concomitant radiation therapy (RADPLAT) for T4aN0M0 and T4bN0M0 maxillary sinus squamous cell carcinomas. We herein report the results of the efficacy confirmation phase in the T4a cohort. METHODS AND MATERIALS: Patients received 100 mg/m2 cisplatin intra-arterially weekly for 7 weeks with concomitant radiation therapy (total 70 Gy) as determined by the results of the preceding dose-finding phase. The trial aimed to evaluate the primary endpoint of 3-year overall survival (OS), comparing RADPLAT with the historical control for 3-year OS in surgery (80%). RESULTS: From April 2014 to August 2018, 65 patients were registered in the T4a cohort from 18 institutions, consisting of 54 men and 11 women with a median age of 64 years (range, 40-78 years) and Eastern Cooperative Oncology Group performance status 0/1 (58/7). After excluding 1 ineligible patient, 64 patients were included in the primary analysis of efficacy and safety. The median follow-up was 4.5 years in all eligible patients, and the primary endpoint for 3-year OS was 82.8% (90% CI, 73.4%-89.2%). With regard to acute adverse events, mucositis (grade ≥3), neutropenia (grade ≥3), increased creatinine (grade ≥2), hearing impairment (grade ≥2), and stroke (grade ≥2) were observed in 20.3%, 14.1%, 3.1%, 3.1%, and 1.6% of patients, respectively. One treatment-related death due to a thromboembolic event was reported. CONCLUSIONS: We demonstrated that RADPLAT showed favorable results for patients with T4aN0M0 maxillary sinus squamous cell carcinomas compared with the historical control for 3-year OS in surgery, which was from an earlier period, and showed some specific toxicities. Therefore, RADPLAT, as well as surgery, can be regarded as a possible treatment option for these patients.

Impact of Radiation Dose on Treatment of Maxillary Cancer With Superselective Intra-arterial Cisplatin With Radiotherapy.

BACKGROUND/AIM: Maxillary sinus cancer is a relatively rare disease, and treatment is still evolving. We compared the efficacy of superselective intra-arterial infusion of high-dose cisplatin (CDDP) with concomitant radiotherapy (RADPLAT) using three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) and analyzed the relationship between the total radiation dose and the treatment outcome in localized maxillary sinus cancer. PATIENTS AND METHODS: We reviewed the cases of 58 patients with localized maxillary sinus cancer treated with RADPLAT at our institution from March 2004 to November 2020. These 58 patients included 34 who received 3DCRT and 24 who received IMRT. RESULTS: The median follow-up period was 38.4 months. The median prescribed dose to the local lesion was 66 Gy in the 3DCRT group and 70 Gy in the IMRT group. CDDP (100-120 mg/m2) was administered once a week for a median of 6 cycles. The 5-year local control rate and overall survival rate were 69.9% and 72.2%, respectively. The patients treated with 70 Gy had a significantly higher local control rate (87.7%) than those treated with 60 Gy or less (41.0%) (p=0.011). No late grade 3 or higher eye disorders except for cataracts developed in the IMRT group, while grade 4 eye disorders occurred in four patients receiving 3DCRT. CONCLUSION: IMRT can escalate radiation dose safely with acceptable toxicities. The total dose may have an impact on the local control rate in RADPLAT.

Ligation of the ethmoid arteries in superselective intra-arterial infusion of cisplatin for advanced maxillary sinus cancer fed by the ophthalmic artery.

BACKGROUND: Superselective cisplatin (CDDP) infusion via the external carotid artery system and concomitant radiotherapy (RADPLAT) provides favorable oncological and functional outcomes in patients with maxillary sinus cancer. However, targeted lesions are occasionally fed by the branch of the internal carotid artery. METHODS: In RADPLAT for maxillary sinus cancer partly fed by the ophthalmic artery, the ethmoid arteries were ligated in two patients without medial orbital wall involvement. In four patients with that, CDDP was administered via the ophthalmic artery. RESULTS: A complete response was obtained in all six patients. Locoregional recurrence was not observed in any cases. However, visual acuity was lost in four patients who received the ophthalmic artery infusion. CONCLUSIONS: Ligation of the ethmoid arteries is recommended in RADPLAT for maxillary sinus cancer with lesions fed by the ophthalmic artery. CDDP administered via the ophthalmic artery may be considered if a patient accepts the possibility of visual loss.

Invasion of the pterygoid plates: an indicator for regional lymph node failure in maxillary sinus cancer.

BACKGROUND: The aim of this study was to evaluate the long-term treatment results of combined superselective intraarterial chemotherapy and radiation therapy for advanced maxillary sinus cancer (MSC) and the incidence of regional lymph node failure, and to reveal the clinical and anatomical predictive factors for metastasis. METHODS: We retrospectively evaluated 55 consecutive patients with locally advanced squamous cell carcinoma of the maxillary sinus who were treated with external radiotherapy and superselective intraarterial chemotherapy. Elective nodal irradiation (ENI) was performed only in the clinical node-positive (cN+) cases and not in the clinical node-negative (cN0) cases. RESULTS: Thirty-eight patients were cN0, and 17 were cN+ at diagnosis. Regional lymph node metastases occurred in 7 of 38 patients with cN0, and 2 of 17 with cN+ during the median follow-up period of 36 months. There were more cases of high-grade (3 or 4) late adverse events in the ENI group than in the non-ENI group (13% vs. 41%, respectively; p = 0.03). In cN0 cases without ENI, invasion of the pterygoid plates (57% vs. 90%; p < 0.01) and oral cavity (35% vs. 92%, with invasion vs without invasion, respectively; p = 0.02) was significantly correlated with a low 5-year regional recurrence-free rate. CONCLUSIONS: Patients with MCS and invasion of the pterygoid plates and oral cavity can be considered appropriate candidates for ENI.

Dose distribution of intensity-modulated proton therapy with and without a multi-leaf collimator for the treatment of maxillary sinus cancer: a comparative effectiveness study.

BACKGROUND: Severe complications, such as eye damage and dysfunciton of salivary glands, have been reported after radiotherapy among patients with head and neck cancer. Complications such as visual impairment have also been reported after proton therapy with pencil beam scanning (PBS). In the case of PBS, collimation can sharpen the penumbra towards surrounding normal tissue in the low energy region of the proton beam. In the current study, we examined how much the dose to the normal tissue was reduced by when intensity-modulated proton therapy (IMPT) was performed using a multi-leaf collimator (MLC) for patients with maxillary sinus cancer. METHODS: Computed tomography findings of 26 consecutive patients who received photon therapy at Okayama University Hospital were used in this study. We compared D2% of the region of interest (ROI; ROI-D2%) and the mean dose of ROI (ROI-mean) with and without the use of an MLC. The organs at risk (OARs) were the posterior retina, lacrimal gland, eyeball, and parotid gland. IMPT was performed for all patients. The spot size was approximately 5-6 mm at the isocenter. The collimator margin was calculated by enlarging the maximum outline of the target from the beam's eye view and setting the margin to 6 mm. All plans were optimized with the same parameters. RESULTS: The mean of ROI-D2% for the ipsilateral optic nerve was significantly reduced by 0.48 Gy, and the mean of ROI-mean for the ipsilateral optic nerve was significantly reduced by 1.04 Gy. The mean of ROI-mean to the optic chiasm was significantly reduced by 0.70 Gy. The dose to most OARs and the planning at risk volumes were also reduced. CONCLUSIONS: Compared with the plan involving IMPT without an MLC, in the dose plan involving IMPT using an MLC for maxillary sinus cancer, the dose to the optic nerve and optic chiasm were significantly reduced, as measured by the ROI-D2% and the ROI-mean. These findings demonstrate that the use of an MLC during IMPT for maxillary sinus cancer may be useful for preserving vision and preventing complications.

Definitive Radiation Therapy Versus Postoperative Radiation Therapy for Patients With Maxillary Sinus Cancer Invading the Upper Jaw.

Maxillectomy following radiation therapy has the strongest local control over maxillary sinus cancer. However, in the advanced stage, complete resection is difficult with adequate margin and has the risk of functional disabilities after surgeries. The objective of the study was to determine the optimal treatment strategy for patients with maxillary sinus cancer invades the upper jaw. A total of 998 histologically confirmed maxillary sinus cancer invades the upper jaw patients were subjected to simple randomization. Patients were subjected to maxillectomy and received 150 mg/m/wk intra-arterial cisplatin for 4 weeks followed by radiotherapy (PR group, n = 499) or received the same chemotherapy and definitive radiotherapy only (DR group, n = 499). Disease status, overall survival, progression-free survival, and treatment-emergent adverse effects were evaluated in the follow-up period of 5 years. At the end of 5 years of follow-up, both the treatments had the same overall survival (P = 0.066). Demographic characters were independent parameters for the overall survival (P ≥ 0.05 for all). Postoperative radiotherapy had a higher progression-free survival than definitive radiotherapy (P = 0.018). Maxillectomy was useful in the reduction of the evidence of local recurrence of cancer (P = 0.027). Dysphagia, palate fistula, incomprehensible voice, and trismus were reported as treatment-emergent effects in the PR group. Definitive radiation therapy is recommended in maxillary sinus cancer that invades the upper jaw (Level of Evidence: I; research registry 4571 dated November 14, 2012).

Clinical T staging is superior to fluorodeoxyglucose positron emission tomography for predicting local outcomes after intra-arterial infusion chemoradiotherapy for maxillary sinus squamous cell carcinoma.

Concomitant intra-arterial infusion chemoradiotherapy (IA-CRT) has been used to treat locally advanced maxillary sinus squamous cell carcinoma (MSSCC) with positive outcomes. However, an optimal predictive prognostic factor for MSSCC treated with IA-CRT remains elusive. The aim of the present study was to assess the feasibility of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), including volumetric parameters, to predict the prognosis of MSSCC treated with IA-CRT. Twenty-four patients with newly diagnosed MSSCC receiving FDG-PET imaging before IA-CRT treatment were analyzed in this retrospective study. All patients underwent radiotherapy with a total tumor dose of 60-66 Gy in a conventional fractionation schedule, using three-dimensional conformal radiation therapy or intensity-modulated radiation therapy. Radiotherapy was performed concurrently with concurrent intra-arterial infusion chemotherapy (cisplatin). The IA-CRT response rate was 83.33%. The 1- and 3-year survival rates were 81.30% and 64.34%, respectively. The 1- and 3-year local failure-free rates were 57.21% and 40.96%, respectively. Local failure was significantly associated with poor survival (P = 0.0152). Further, clinical T staging clearly stratified local control outcomes among patients with clinical T3 or less, T4a, and T4b (P = 0.0312). Moreover, patients with stage T4b showed a significantly poorer local control compared with T3 or less (P = 0.0103). However, FDG-PET parameters provided no significant predictive information regarding treatment outcome. To conclude, pretreatment T stage predicts local control by IA-CRT, which is associated with survival.

Clinical study of cetuximab combined with radical radiotherapy in the treatment of locally advanced sinonasal squamous cell carcinoma.

PURPOSE: To observe the efficacy and side effects of cetuximab combined with radical radiotherapy in the treatment of sinonasal squamous cell carcinoma (SCC), and to investigate the underlying mechanism of cetuximab. METHODS: 62 patients with locally advanced sinonasal SCC diagnosed in our hospital from January 2013 to January 2014 were enrolled. Cetuximab and radical radiotherapy were simultaneously given to patients in the combination group, while only radical radiotherapy was given to patients in the radiotherapy group. Cetuximab was administered weekly until the end of radiotherapy. Patients intolerant to cetuximab or withdrawn the informed consent were excluded. On first administration, cetuximab was given i.v. at a dose of 400 mg/m2 for more than 120 min, with maximum drop rate of 5 mL/min. Afterwards, cetuximab was given i.v. per week at a dose of 250 mg/m2 for more than 60 min. RESULTS: (1) The objective response rate (ORR) and disease control rate (DCR) in the combination group was 77.42% and 93.54%, respectively, while the ORR and DCR in the radiotherapy group were only 45.61% and 70.97%, respectively (p<0.05). (2) The progression free survival (PFS) and the median overall survival (OS) in the combination group were 19.5 and 26.6 months, respectively, while in the radiotherapy group were only 13.8 and 18.9 months, respectively (p<0.05). (3) The incidence of rash in the combination group was significantly higher than that of the radiotherapy group (p<0.05). However, there were no significant differences in other adverse reactions between the two groups. CONCLUSIONS: Combination of cetuximab with radical radiotherapy is safe and effective for advanced local sinonasal SCC and improves the survival rate and the prognosis of patients with sinonasal SCC.

Definitive Carbon-Ion Radiation Therapy for Locally Advanced Sinonasal Malignant Tumors: Subgroup Analysis of a Multicenter Study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS).

PURPOSE: To evaluate the safety and efficacy of carbon-ion radiation therapy (C-ion RT) for locally advanced sinonasal malignant tumors in a multicenter retrospective study (J-CROS 1402 HN). METHODS AND MATERIALS: Clinical data were collected for patients who had sinonasal malignant tumors of stage N0-1M0 and received C-ion RT at 4 institutions in Japan between November 2003 and December 2014. Of the 458 patients, 393 had naïve tumors and 65 had recurrent tumors. The tumors were located in the nasal cavity (n = 263), maxillary sinus (n = 109), ethmoid sinus (n = 71), and other locations (n = 15). The histologic types were mucosal melanoma (n = 221, 48%), adenoid cystic carcinoma (n = 122, 27%), squamous cell carcinoma (n = 31, 7%), olfactory neuroblastoma (n = 30, 7%), adenocarcinoma (n = 21, 5%), and other types (n = 33, 7%). Of the 458 patients, 300 (66%) had T4 tumors. All patients received definitive C-ion RT. RESULTS: The median follow-up period was 25.2 months for all patients (range, 1.4-132.3 months). The 2-year overall survival and local control rates were 79.6% and 84.1%, respectively. As analyzed according to histology, the 2-year overall survival rate was 68.0% for mucosal melanoma, 96.8% for adenoid cystic carcinoma, 70.0% for squamous cell carcinoma, 96.7% for olfactory neuroblastoma, and 89.7% for adenocarcinoma. Regarding late toxicities, 17% of patients developed grade 3 and 4 toxicities, of which visual impairment was the most common. CONCLUSION: The results of our multicenter study have demonstrated that C-ion RT can provide excellent clinical outcomes with acceptable late toxicities in patients who have locally advanced sinonasal malignant tumors.

Radiotherapy for extranodal classic Hodgkin lymphoma of the maxillary sinus: Case report and literature review.

BACKGROUND: Classic Hodgkin lymphoma is a malignant neoplasm of the lymphatic system that commonly presents with cervical and mediastinal lymphadenopathy. Primary extranodal disease of the head and neck is rare, with only a few cases reported in the literature. In this case report, we describe the presentation, treatment, and clinical outcome of a patient who presented with extranodal Hodgkin lymphoma of the maxillary sinus. METHODS: We report a case of extranodal classic Hodgkin lymphoma of the maxillary sinus treated with 2 cycles of chemotherapy and consolidative radiotherapy (RT). We also reviewed the literature. RESULTS: The patient tolerated treatment without complications and has experienced no evidence of recurrence 2 years after treatment. CONCLUSION: This is one of the few reports of extranodal Hodgkin lymphoma of the maxillary sinus. To our knowledge, this report represents the longest follow-up of any patient with this presentation.

A Patient With Submerged Sinonasal Angiosarcoma After Resection of Underlying Organizing Hematoma.

A 30-year-old female patient with facial pain diagnosed as organizing hematoma of maxillary sinus by biopsy and imaging studies, and subsequently tumor was resected via an endoscope-assisted midfacial degloving approach. The tumor was histopathologically confirmed as organizing hematoma. In 3-week follow-up, asymptomatic emerging mass was observed at the same site, and needed a revision endoscopic resection. On pathologic examination, a low-grade angiosarcoma was identified, not organizing hematoma. After postoperative radiotherapy, she has been a status of no evidence of disease. This report emphasizes that complete and delicate resection of sinonasal tumor should be made to prevent recurrence and submerged malignant potential.

Treatment outcomes of locally advanced squamous cell carcinoma of the maxillary sinus treated with chemoradioselection using superselective intra-arterial cisplatin and concomitant radiation: Implications for prognostic factors.

BACKGROUND: This study clarified the clinical results of locally advanced squamous cell carcinoma of the maxillary sinus (SCC-MS) that was treated with chemoradioselection using superselective intra-arterial cisplatin and concomitant radiation (RADPLAT). Prognostic factors were also investigated. METHODS: We retrospectively analyzed 63 locally advanced SCC-MS patients treated with initial RADPLAT followed by sequential RADPLAT (S-RADPLAT) or surgery. RESULTS: The 5-year progression-free survival (PFS) and overall survival (OS) rates of patients with T3, T4a, or T4b disease were 72.2%, 46.6%, and 33.3% (p = 0.104) and 83.3%, 51.6%, and 33.3% (p = 0.031), respectively. The 5-year PFS and OS rates of the S-RADPLAT or surgery groups with T4 disease were 39.6% and 60.6% (p = 0.199) and 44.7% and 63.3% (p = 0.276), respectively. Tumor extension into the medial and/or lateral pterygoid muscle (p < 0.001) and N classification (p = 0.012) were considered significant factors for PFS. Regarding OS, tumor extension into the medial and/or lateral pterygoid muscle (p = 0.005) was considered a statistically significant risk factor. CONCLUSIONS: It may be better for T4 non-responders to initial RADPLAT to undergo surgery. Patients with high risk factors of positive neck metastasis or pterygoid muscle extension may need adjuvant chemotherapy.

Treatment outcomes of malignant fibrous histiocytoma of the maxillary sinus.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is an uncommon neoplasm of maxillary sinus. This study was designed to investigate the clinical courses and summarize the experience of the treatment outcomes. MATERIALS AND METHODS: This is a retrospective analysis which included patients with MFH of the maxillary sinus from January 1980 to December 2008 treated in our institute. Survival data were analyzed by means of the Kaplan-Meier method using univariate analysis and Cox regression model using multivariate analysis. RESULTS: The study included 31 patients. Of which, one patient received radical radiotherapy, and thirty patients received surgical resection. Of these, thirty patients received preoperative radiotherapy, and 11 patients received postoperative radiotherapy. Radical resection with clear surgical margins was obtained in twelve patients (80%) after preoperative radiotherapy, and in eight patients (53.3%) with postoperative radiotherapy (P = 0.221). The 3-year overall survival rate (OS) and recurrence-free survival rate (RFS) were 59.0% and 43.5%, respectively. Patients treated with a radical resection had significantly better survival than patients with a nonradical resection. Three-year OS was 79.8% and 28.1%, 3-year RFS was 61.9% and 18.5%, respectively (P = 0.001 and 0.029, respectively). Local recurrence rate (LRR) was lower in patients resected with clear surgical margins than patients with unclear or uncertain margins, and the 3 years LRR was 33.3% and 72.2%, respectively (P = 0.052). CONCLUSIONS: Surgical resection is the mainstay of treatment for MFH of the maxillary sinus. A radical resection with clear margins is essential for excellent local control and long-term survival.

Radiation retinopathy secondary to treatment of maxillary sinus carcinoma: a dramatic case. / Retinopatía por radiación secundaria a tratamiento de carcinoma de seno maxilar: un caso dramático.

CLINICAL CASE: A 53-year old male presented with visual impairment in right eye after irradiation of right maxillary sinus carcinoma. Funduscopy shows radiation retinopathy: haemorrhages, exudates, macular oedema, and peripheral retinal ischaemia. A poor outcome was achieved despite laser treatment and intravitreal injections of bevacizumab, resulting in evisceration of the affected eye. DISCUSSION: Radiation retinopathy must be considered in any loss of vision after head and neck irradiation. Ophthalmological long-term follow-up of these patients is essential for an early diagnosis.

Hyperbaric oxygen therapy for maxillary bone radiation-induced injury: A 15-year single-center experience.

BACKGROUND: Although hyperbaric oxygen therapy (HBOT) is used to treat chronic radiation tissue injury, clinical evidence supporting its use in maxillary bone osteoradionecrosis (ORN) is lacking. Therefore, the purpose of this study was to report our results of collected patient outcomes from a single center's large experience using HBOT to treat maxillary bone ORN. METHODS: From 1999 to 2015, 21 patients received treatment for maxillary bone ORN at our center. The medical records were retrospectively reviewed for the following variables: age, sex, comorbidities, tumor stage and site, previous surgery, previous radiotherapy or chemoradiation therapy, HBOT data, response to treatment and further management. RESULTS: A positive clinical outcome from HBOT occurred in 85.7% of patients with ORN and was proven radiologically in 14 of 15 patients (93.3%). In 5 patients, reconstructive surgery was required thereafter. CONCLUSION: Controversy exists regarding the management of ORN of the maxillofacial skeleton. Our large, single-center experience probably supports the efficacy of HBOT for maxillary bone ORN. © 2016 Wiley Periodicals, Inc. Head Neck 39: 275-278, 2017.

[Nasal cavity and paranasal sinus cancer]. / Radiothérapie des cancers des cavités nasosinusiennes.

The nasal cavity and parasinusal cancer are rare (10% of tumors of the head and neck) and are mainly represented by squamous cell carcinoma of the nasal cavity or the maxillary sinus and adenocarcinoma of the ethmoid sinus (occupational disease, wood dust). The most common clinical sign is nasal obstruction, but tumors can also manifest as rhinorrhea and/or epistaxis (usually unilateral signs). A magnetic resonance imaging of the facial structure is systematic for staging before treatment. The treatment consists of a first surgery if the patient is operable with a resectable tumor. If it is not the case, the treatment consists of radiotherapy (RT) associated with chemotherapy (CT) according to the initial data (T3/T4 or N+). After first surgery, RT is indicated (except T1N0 with complete resection) associated with a CT based on postoperative data (capsular effraction or incomplete resection). Lymph node irradiation is considered case by case, but is indicated in any nodal involvement. RT must be an intensity modulated RT (IMRT), static or dynamic, and must be imagery guided (IGRT). According to ICRU 83, doses to organs at risk and target volumes must be carried. Finally, after a post-treatment baseline imaging between 2 and 4 months, monitoring will be alternated with the ENT surgeon every 2 or 3 months for 2 years, then every 4 to 6 months for 5 years.

Comparison of effective radiation doses from X-ray, CT, and PET/CT in pediatric patients with neuroblastoma using a dose monitoring program.

PURPOSE: We aimed to evaluate the use of a dose monitoring program for calculating and comparing the diagnostic radiation doses in pediatric patients with neuroblastoma. METHODS: We retrospectively reviewed diagnostic and therapeutic imaging studies performed on pediatric patients with neuroblastoma from 2003 to 2014. We calculated the mean effective dose per exam for X-ray, conventional computed tomography (CT), and CT of positron emission tomography/computed tomography (PET/CT) from the data collected using a dose monitoring program (DoseTrack group) since October 2012. Using the data, we estimated the cumulative dose per person and the relative dose from each modality in all patients (Total group). The effective dose from PET was manually calculated for all patients. RESULTS: We included 63 patients with a mean age of 3.2±3.5 years; 28 had a history of radiation therapy, with a mean irradiated dose of 31.9±23.2 Gy. The mean effective dose per exam was 0.04±0.19 mSv for X-ray, 1.09±1.11 mSv for CT, and 8.35±7.45 mSv for CT of PET/CT in 31 patients of the DoseTrack group. The mean estimated cumulative dose per patient in the Total group was 3.43±2.86 mSv from X-ray (8.5%), 7.66±6.09 mSv from CT (19.1%), 18.35±13.52 mSv from CT of PET/CT (45.7%), and 10.71±10.05 mSv from PET (26.7%). CONCLUSION: CT of PET/CT contributed nearly half of the total cumulative dose in pediatric patients with neuroblastoma. The radiation dose from X-ray was not negligible because of the large number of X-ray images. A dose monitoring program can be useful for calculating radiation doses in patients with cancer.