Squamous cell carcinoma of the eyelid.

Eyelid squamous cell carcinoma is a major type of rare eyelid cancer, together with basal cell carcinoma and sebaceous gland carcinoma. It is a painless disease that progresses slowly and is often detected by the appearance of nodules or plaques. Risk factors include exposure to ultraviolet light, fair skin, radiation and human papillomavirus infection. The standard treatment is surgical removal, and in cases of orbital invasion, orbital content removal is required. If sentinel node biopsy reveals a high risk of lymph node metastasis, adjuvant radiotherapy may be considered. Local chemotherapy, such as imiquimod and 5-fluorouracil, may be used for eyelid squamous cell carcinoma in situ. When surgery or radiotherapy is not recommended for distant metastases or locally advanced disease, drug therapy is often according to head and neck squamous cell carcinoma in Japan. The treatment often requires a multidisciplinary team to ensure the preservation of function and cosmetic appearance.

Long-Term Follow-up of a Randomized Controlled Trial on Accelerated Radiation Therapy Versus Standard Fractionated Radiation Therapy for Early Glottic Cancer (JCOG0701A3).

PURPOSE: We previously reported the primary results of JCOG0701, a randomized, multicenter, phase 3, noninferiority trial comparing accelerated fractionation (Ax) to standard fractionation (SF) for early glottic cancer. In the primary results, although the similar efficacy of 3-year progression-free survival and toxicity of Ax compared with SF was observed, the noninferiority of Ax was not confirmed statistically. To evaluate the long-term follow-up results of JCOG0701, we conducted JCOG0701A3 as an ancillary study of JCOG0701. METHODS AND MATERIALS: In JCOG0701, 370 patients were randomly assigned to receive SF of 66 to 70 Gy (33-35 fractions; n = 184) or Ax of 60 to 64.8 Gy (25-27 fractions; n = 186). The data cutoff date for this analysis was in June 2020. Overall survival, progression-free survival, and late adverse events including central nervous system ischemia were analyzed. RESULTS: With a median follow-up period of 7.1 years (range, 0.1-12.4), progression-free survival of the SF and Ax arms were 76.2% and 78.2% at 5 years and 72.7% and 74.8% at 7 years (P = .44). OS of the SF and Ax arms were 92.7% and 89.6% at 5 years and 90.8% and 86.5% at 7 years (P = .92). Among 366 patients with a protocol treatment, the cumulative incidence of late adverse events of the SF and Ax arms were 11.9% and 7.4% at 8 years (hazard ratio, 0.53; 95% CI, 0.28-1.01; P = .06). Central nervous system ischemia of grade 2 or higher was observed in 4.1% for the SF arm and 1.1% for the Ax arm (P = .098). CONCLUSIONS: After long-term follow-up, Ax showed comparable efficacy to SF and a tendency for better safety. Ax may be suitable for early glottic cancer because of its convenience in minimizing treatment time, cost, and labor.

The Geriatric Nutritional Risk Index as a prognostic factor in older adult patients with locally advanced head and neck cancer receiving definitive chemoradiotherapy with tri-weekly cisplatin.

INTRODUCTION: Concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. The Geriatric Nutritional Risk Index (GNRI) is a screening tool to predict the risk of morbidity and mortality in the older adult. Nutritional management is key during CCRT but the association between prognosis and initial nutritional status in older adults with LAHNC undergoing CCRT remains unknown. MATERIALS AND METHODS: Patients ≥65 years old with LAHNC who received definitive CCRT with cisplatin (80 mg/m2 or 100 mg/m2, every three weeks, three times) between 2012 and 2018 were included. Patients without completion of radiotherapy were excluded. Patients were stratified into two groups based on the GNRI (≦98 or > 98). Overall survival (OS) and event-free survival (EFS) were analyzed by the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was adopted to identify prognostic factors. GNRI, sex, T and N categories were prespecified as variables for multivariable analysis. RESULTS: The median age of 111 patients (88 male, 79%) was 69 years (interquartile range: 67-71), among which 23 patients had low GNRI (20 male, 87%) and 88 patients had high GNRI (68 male, 77%). Baseline clinical characteristics were not statistically different between the two groups. OS was significantly worse in the low GNRI group than in the high GNRI group (p = 0.048). There was no statistical difference in EFS between the two groups (p = 0.12). Multivariable analysis revealed that low GNRI (hazard ratio [HR]: 3.17, 95% confidence interval [95%CI]: 1.12-8.96, p = 0.029) and higher N category (HR: 4.37, 95% CI: 1.58-12.06, p = 0.004) were associated with worse OS. For EFS, the higher N category was significantly associated with a worse outcome (HR: 2.54, 95% CI: 1.16-5.59, p = 0.02). DISCUSSION: Poorer nutritional status before initiation of CCRT was associated with worse OS in older adults with LAHNC in the definitive setting. The GNRI is a convenient tool for predicting OS in older adult patients with LAHNC treated with CCRT.

Organs-at-risk dose constraints in head and neck intensity-modulated radiation therapy using a dataset from a multi-institutional clinical trial (JCOG1015A1).

BACKGROUND: JCOG1015A1 is an ancillary research study to determine the organ-specific dose constraints in head and neck carcinoma treated with intensity-modulated radiation therapy (IMRT) using data from JCOG1015. METHODS: Individual patient data and dose-volume histograms of organs at risk (OAR) were collected from 74 patients with nasopharyngeal carcinoma treated with IMRT who enrolled in JCOG1015. The incidence of late toxicities was evaluated using the cumulative incidence method or prevalence proportion. ROC analysis was used to estimate the optimal DVH cut-off value that predicted toxicities. RESULTS: The 5-year cumulative incidences of Grade (G) 1 myelitis, ≥ G1 central nervous system (CNS) necrosis, G2 optic nerve disorder, ≥ G2 dysphagia, ≥ G2 laryngeal edema, ≥ G2 hearing impaired, ≥ G2 middle ear inflammation, and ≥ G1 hypothyroidism were 10%, 5%, 2%, 11%, 5%, 26%, 34%, and 34%, respectively. Significant associations between DVH parameters and incidences of toxicities were observed in the brainstem for myelitis (D1cc ≥ 55.8 Gy), in the brain for CNS necrosis (D1cc ≥ 72.1 Gy), in the eyeball for optic nerve disorder (Dmax ≥ 36.6 Gy), and in the ipsilateral inner ear for hearing impaired (Dmean ≥ 44 Gy). The optic nerve, pharyngeal constrictor muscle (PCM), and thyroid showed tendencies between DVH parameters and toxicity incidence. The prevalence proportion of G2 xerostomia at 2 years was 17 versus 6% (contralateral parotid gland Dmean ≥ 25.8 Gy vs less). CONCLUSIONS: The dose constraint criteria were appropriate for most OAR in this study, although more strict dose constraints might be necessary for the inner ear, PCM, and brainstem.

Clinical Impact of Cachexia in Head and Neck Cancer Patients Who Received Chemoradiotherapy.

PURPOSE: There have been few reports on the evaluation of cancer cachexia based on skeletal muscle mass index (SMI) in patients with head and neck cancer. PATIENTS AND METHODS: One hundred and ninety-two head and neck cancer patients were enrolled. In definitive and adjuvant chemoradiotherapy settings, clinical outcomes were compared between cachexia and non-cachexia patients. RESULTS: Forty patients were diagnosed with cachexia (20.8%). In the definitive setting, overall survival (OS) was significantly shorter in the cachexia group (3-year OS: 50.0% vs 88.5%; p < 0.01), and multivariate analysis identified UICC stage IV, baseline albumin of <4 and cachexia as poor prognostic factors. However, cachexia was not significant in the adjuvant setting. CONCLUSION: Cancer cachexia was negatively associated with prognosis in patients with HNC who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients.

Clinicopathological and genomic features in patients with head and neck neuroendocrine carcinoma.

Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

Phase 3 Randomized Trial of Topical Steroid Versus Placebo for Prevention of Radiation Dermatitis in Patients With Head and Neck Cancer Receiving Chemoradiation.

PURPOSE: Radiation dermatitis is one of the most common acute toxicities induced by chemoradiation therapy (CRT) for head and neck cancer (HNC). The benefit of topical steroids in the management of radiation dermatitis is still unclear. This phase 3, multi-institutional, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of topical steroids for radiation dermatitis in patients with locally advanced HNC receiving CRT. METHODS AND MATERIALS: Eligible patients were scheduled to receive bilateral neck irradiation (≥66 Gy) with concurrent cisplatin (≥200 mg/m2) as definitive or postoperative CRT. Patients were randomly assigned to receive either topical steroid or placebo when grade 1radiation dermatitis was observed or the total radiation dose reached 30 Gy. Basic skin care including gentle washing and moistening in the head and neck region was performed in both groups. The primary endpoint was the frequency of grade ≥2 radiation dermatitis, in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Grading of radiation dermatitis was performed by independent central review using photographs taken weekly. RESULTS: A total of 211 patients were enrolled (intention to treat: steroid 101 and placebo 102). The frequency of grade ≥2 radiation dermatitis was not significantly reduced with the steroid (73.3%; 95% confidence interval, 64.6%-81.9%) compared with the placebo (80.4%; 95% confidence interval, 72.7%-88.1%; P = .23), whereas the steroid significantly reduced the frequency of grade ≥3 radiation dermatitis (13.9% vs 25.5%; P = .034). No significant differences in adverse events, including local infection or compliance with CRT, were observed between the groups. CONCLUSIONS: Topical steroid may reduce the severity of radiation dermatitis in patients with HNC and thus may become an important therapeutic tool in the management of radiation dermatitis.

A phase II study of adaptive two-step intensity-modulated radiation therapy (IMRT) with chemotherapy for loco-regionally advanced nasopharyngeal cancer (JCOG1015).

BACKGROUND: A phase II study of adaptive two-step intensity-modulated radiotherapy (IMRT) with chemotherapy for nasopharyngeal cancer (NPC) (JCOG1015) was conducted to evaluate the efficacy and safety. METHODS: Patients aged 20-75 years with stages II-IVB NPC were enrolled. As adaptive two-step IMRT, computed tomography planning was performed twice before IMRT for the initial plan of 46 Gy/23 fractions and during treatment for the boost plan of 24 Gy/12 fractions with a total dose of 70 Gy. Chemotherapy (cisplatin 80 mg/m2/3-weeks × 3 courses) was administered concurrently with IMRT, followed by adjuvant chemotherapy (cisplatin at 70 mg/m2 with 5-FU 700 at mg/m2 for 5 days/4 weeks × 3 courses). RESULTS: Between 2011 and 2014, 75 patients were enrolled from 12 institutions. The 3-year overall survival (OS) for the 75 patients was 88%, and the upper and lower limits of the 95% CI of 78%-94% were higher than the expected 3-year OS of 75% for the target population adjusted by the actual proportion of stage II:III:IV = 21%:44%:35%. The 3-year progression-free survival (PFS) and loco-regional PFS were 71% [59-80%] and 77% [66-85%], respectively. Although no grade 4-5 late toxicities were observed, 15 patients (20%) developed grade 3 late toxicities. Grade 2 xerostomia was noted in 26%, 12%, and 9% at 1, 2, and 3 years after starting IMRT, respectively. CONCLUSIONS: Adaptive two-step IMRT for NPC demonstrated an excellent 3-year OS with acceptable toxicities. This method may be one treatment option for locally advanced NPC.

[Impact of Respiratory Motion on Dose Variation in Radiation Therapy for Glottic Cancer].

In radiation therapy for glottic cancer, respiratory motion of larynx may change the dose variation in the target. The purpose of this study is to measure the respiratory motion of the larynx, and quantify the impact of the motion on the dose variation. This study included 10 patients treated by opposing portal irradiation for glottic cancer. We acquired fluoroscopy and respiratory waveform of the patients simultaneously and formulated the relationship between the displacement of larynx and the respiratory phase. We divided one field into 39 sub-fields on the basis of control points. Dose distributions accounting for the displacement were calculated by shifting isocenter calculated using the formula in every sub-fields. Dose variations of clinical target volume (CTV) were evaluated by subtracting dose distributions with displacement consideration and dose distributions without it. Average amplitude and the maximum amplitude of respiratory motion were 2.5 and 8.7 mm, respectively. Average of mean dose variation in CTV was 0.1% of the prescribed dose, and maximum of local dose variation was 2.0% of the prescribed dose. Hence, it is realized that dose variation in CTV by respiratory motion was slight.

Predictive factors of head and neck squamous cell carcinoma patient tolerance to high-dose cisplatin in concurrent chemoradiotherapy.

Although high-dose cisplatin is the standard regimen of concurrent chemoradiotherapy (CCRT) for locally advanced head and neck squamous cell carcinoma (HNSCC), varying levels of patient tolerance towards cisplatin have been reported, and the predictive factors of cisplatin tolerance remain to be elucidated. The present study retrospectively reviewed newly diagnosed HNSCC patients who received CCRT. Cisplatin (80 mg/m2) was administered every 3 weeks. The proportion of high-dose cisplatin-tolerant patients (cumulative cisplatin dose, ≥200 mg/m2) was determined, and the predictive factors of cisplatin tolerance were analyzed in a logistic regression analysis. Between June 2006 and March 2013, a total of 159 patients were treated with CCRT. The median follow-up time was 36.7 months. A total of 73 patients (46%) tolerated a cumulative cisplatin dose ≥200 mg/m2; male gender [odds ratio (OR), 25.00; P=0.005] and high body surface area (BSA) (>1.80 m2; OR, 2.21; P=0.032) were significantly predictive of high-dose cisplatin tolerance. The high-dose cisplatin-tolerant patients had a significantly higher complete response (CR) rate (82 vs. 67%, P=0.045); however, there were no significant between-group differences in the 3-year OS (79.5 vs. 81.2%, P=0.59) or PFS (70.4 vs. 44.6%, P=0.076) by cisplatin tolerance. In clinical practice, approximately one-half of the patients tolerated high-dose cisplatin in CCRT. Male gender and high BSA could be predictive of cisplatin tolerance.

High-dose-rate interstitial brachytherapy for gynecologic malignancies--dosimetric changes during treatment period.

To overcome cranio-caudal needle displacement in pelvic high-dose-rate interstitial brachytherapy (HDRIB), we have been utilizing a fullystretched elastic tape to thrust the template into the perineum. The purpose of the current study was to evaluate dosimetric changes during the treatment period using this thrusting method, and to explore reproducible planning methods based on the results of the dosimetric changes. Twenty-nine patients with gynecologic malignancies were treated with HDRIB at the Cancer Institute Hospital. Pre-treatment and post-treatment computed tomography (CT) scans were acquired and a virtual plan for post-treatment CT was produced by applying the dwell positions/times of the original plan. For the post-treatment plan, D90 for the clinical target volume (CTV) and D2cc for the rectum and bladder were assessed and compared with that for the original plan. Cranio-caudal needle displacement relative to CTV during treatment period was only 0.7 ± 1.9 mm. The mean D90 values for the CTV in the pre- and post-treatment plans were stable (6.8 Gy vs. 6.8 Gy) and the post-treatment/pre-treatment D90 ratio was 1.00 ± 0.08. The post-/pre-treatment D2cc ratio was 1.14 ± 0.22 and the mean D2cc for the rectum increased for the post-treatment plan (5.4 Gy vs. 6.1 Gy), especially when parametrial infiltration was present. The mean D2cc for the bladder was stable (6.3 Gy vs. 6.6 Gy) and the ratio was 1.06 ± 0.20. Our thrusting method achieved a stable D90 for the CTV, in contrast to previous prostate HDRIB reports displaying reductions of 35-40% for D90 during the treatment period.

Dedifferentiated liposarcoma of the retroperitoneum with osteosarcomatous component: report of two cases.

We describe two cases of ossified soft tissue tumors of the retroperitoneum. Computed tomographic and magnetic resonance imaging both revealed retroperitoneal masses consisting of two components -- densely ossified and lipid-rich components. In one case, a 50-year-old man, a histological diagnosis of dedifferentiated liposarcoma with osteosarcoma was made based on the needle biopsy of the two components. In another case, a 54-year-old man, surgical resection of the complex perirenal mass was performed and the same diagnosis was made. Although an ossified component represent high-grade lesion, the fatty component is an important clue to the diagnosis of dedifferentiated liposarcoma. The imaging features may be similar to those of malignant mesenchymoma, which is not a currently used term.