cDNA microarray analysis of human keratinocytes cells of patients submitted to chemoradiotherapy and oral photobiomodulation therapy: pilot study.

Oral mucositis is an acute toxicity that occurs in patients submitted to chemoradiotherapy to treat head and neck squamous cell carcinoma. In this study, we evaluated differences in gene expression in the keratinocytes of the oral mucosa of patients treated with photobiomodulation therapy and tried to associate the molecular mechanisms with clinical findings. From June 2009 to December 2010, 27 patients were included in a randomized double-blind pilot study. Buccal smears from 13 patients were obtained at days 1 and 10 of chemoradiotherapy, and overall gene expression of samples from both dates were analyzed by complementary DNA (cDNA) microarray. In addition, samples from other 14 patients were also collected at D1 and D10 of chemoradiotherapy for subsequent validation of cDNA microarray findings by qPCR. The expression array analysis identified 105 upregulated and 60 downregulated genes in our post-treatment samples when compared with controls. Among the upregulated genes with the highest fold change, it was interesting to observe the presence of genes related to keratinocyte differentiation. Among downregulated genes were observed genes related to cytotoxicity and immune response. The results indicate that genes known to be induced during differentiation of human epidermal keratinocytes were upregulated while genes associated with cytotoxicity and immune response were downregulated in the laser group. These results support previous clinical findings indicating that the lower incidence of oral mucositis associated with photobiomodulation therapy might be correlated to the activation of genes involved in keratinocyte differentiation.

Long-term survival of a randomized phase III trial of head and neck cancer patients receiving concurrent chemoradiation therapy with or without low-level laser therapy (LLLT) to prevent oral mucositis.

BACKGROUND: The impact of low-level laser therapy (LLLT) to prevent oral mucositis in patients treated with exclusive chemoradiation therapy remains unknown. This study evaluated the overall, disease-free and progression-free survival of these patients. METHODS: Overall, disease-free and progression-free survival of 94 patients diagnosed with oropharynx, nasopharynx, and hypopharynx cancer, who participated on a phase III study, was evaluated from 2007 to 2015. The patients were subjected to conventional radiotherapy plus cisplatin every 3weeks. LLLT was applied with an InGaAlP diode (660nm-100mW-1J-4J/cm2). RESULTS: With a median follow-up of 41.3months (range 0.7-101.9), patients receiving LLLT had a statistically significant better complete response to treatment than those in the placebo group (LG=89.1%; PG=67.4%; p=0.013). Patients subjected to LLLT also displayed increase in progression-free survival than those in the placebo group (61.7% vs. 40.4%; p=0.030; HR:1:93; CI 95%: 1.07-3.5) and had a tendency for better overall survival (57.4% vs. 40.4%; p=0.90; HR:1.64; CI 95%: 0.92-2.91). CONCLUSION: This is the first study to suggest that LLLT may improve survival of head and neck cancer patients treated with chemoradiotherapy. Further studies, with a larger sample, are necessary to confirm our findings.

Cost-effectiveness of low-level laser therapy (LLLT) in head and neck cancer patients receiving concurrent chemoradiation.

BACKGROUND: Oral mucositis is a major event increasing treatment costs of head and neck squamous cell carcinoma (HNSCC) patients treated with chemoradiation (CRT). This study was designed to estimate the cost-effectiveness of low-level laser therapy (LLLT) to prevent oral mucositis in HNSCC patients receiving CRT. METHODS: From June 2007 to December 2010, 94 patients with HNSCC of nasopharynx, oropharynx, and hypopharynx entered a prospective, randomized, double blind, placebo-controlled, phase III trial. CRT consisted of conventional radiotherapy (RT: 70.2 Gy, 1.8 Gy/d, 5 times/wk)+concurrent cisplatin (100mg/m2) every 3 weeks. An InGaAlP (660 nm-100 mW-4J/cm2) laser diode was used for LLLT. RESULTS: From the perspective of Brazil's public health care system (SUS), total costs were higher in Placebo Group (PG) than Laser Group (LG) for opioid use (LG=US$ 9.08, PG=US$ 44.28), gastrostomy feeding (LG=US$ 50.50, PG=US$ 129.86), and hospitalization (PG=US$ 77.03). In LG, the cost was higher for laser therapy only (US$ 1880.57). The total incremental cost associated with the use of LLLT was US$ 1689.00 per patient. The incremental cost-effectiveness ratio (ICER) was US$ 4961.37 per grade 3-4 OM case prevented compared to no treatment. CONCLUSIONS: Our results indicate that morbidity was lower in the Laser Group and that LLLT was more cost-effective than placebo up to a threshold of at least US$ 5000 per mucositis case prevented. CLINICAL TRIAL INFORMATION: NCT01439724.

Phase III trial of low-level laser therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent chemoradiation.

BACKGROUND: Oral mucositis (OM) is a complication of chemoradiotherapy treatment of head and neck squamous cell carcinoma (HNSCC) patients with no effective therapy. This study was designed to assess the efficacy of preventive low-level laser therapy (LLLT) in reducing the incidence of grade 3-4 OM. MATERIAL AND METHODS: From June 2007 to December 2010, 94 HNSCC patients entered a prospective, randomized, double-blind, placebo-controlled phase III trial. Chemoradiotherapy consisted of conventional radiotherapy plus concurrent cisplatin every 3weeks. A diode InGaAlP (660nm-100mW-1J-4J/cm(2)) was used. OM evaluation was performed by WHO and OMAS scales and quality of life by EORTC questionnaires (QLQ). RESULTS: A six-fold decrease in the incidence of grades 3-4 OM was detected in the LLLT group compared to the placebo; (6.4% versus 40.5%). LLLT impacted the incidence of grades 3-4 OM to a relative risk ratio of 0.158 (CI 95% 0.050-0.498). After treatment QLQ-C30 showed, differences favoring LLLT in physical, emotional functioning, fatigue, and pain; while the QLQ-H&N35 showed improvements in LLLT arm for pain, swallowing, and trouble with social eating. CONCLUSION: Preventive LLLT in HNSCC patients receiving chemoradiotherapy is an effective tool for reducing the incidence of grade 3-4 OM. Efficacy data were corroborated by improvements seen in quality of life.

Timing of radiation in children with medulloblastoma/PNET.

BACKGROUND: To evaluate the importance of timing of radiation therapy in children with PNET/medulloblastoma, treated at the Brazilian National Cancer Institute (INCA). PROCEDURE: The records of 101 children with confirmed diagnosis of medulloblastoma were retrospectively reviewed. Patients had a median follow-up of 48 months (0.5-241 months). The age varied from 0.8 to 17.5 years (median: 7.6 years) and 21.7% were 3 years old or younger. RESULTS: According to the data collected from patients that received treatment for medulloblastoma from 1983 to 2001, the overall survival (OS) rate was 53% and the Disease Free Survival (DFS) rate was 40%. Multivariate analysis showed that under age 3 years, presence of neoplasic cells in the cerebrospinal fluid (CSF) at presentation or subtotal tumor resection resulted in a worse OS. The patients that received a biological effective dose (BED) greater than 44 Gy10 had better prognosis. Two-thirds of the patients had complete response after the initial treatment. Among them, 50% (34 patients) recurred, and of those 34 patients, 42% of them (14 patients) had recurrence in the posterior fossa. CONCLUSION: Surgery with total resection of the tumor and absence of neoplasic cells in the CSF are effective predictors of better OS. Radiotherapy was more effective when a BED was greater than 44 Gy10.

Concurrent chemotherapy and hypofractionated twice-daily radiotherapy in cervical cancer patients with stage IIIB disease and bilateral parametrial involvement: a phase I-II study.

PURPOSE: Stage IIIB cervical cancer patients with bilateral parametrial involvement have a poor prognosis with low survival rates. In an effort to improve outcome of these patients, we initiated a prospective, Phase I-II trial of concomitant chemotherapy with cisplatin and 5-fluorouracil and hypofractionated twice-daily radiotherapy. This program was initiated on the basis of the encouraging results obtained in the treatment of bladder cancer using a similar regimen. The purpose of this study was to evaluate the results of treatment (toxicity, survival, and patterns of failure) using this novel approach. METHODS AND MATERIALS: A total of 34 patients with Stage IIIB squamous cell cervical cancer and bilateral parametrial involvement entered the study. After inclusion of the first 14 patients, the study was put on hold for 6 months, and the patients were carefully observed. Once the toxicity level was found acceptable, the remaining 20 patients entered the study. External beam radiotherapy was delivered twice daily on Days 1 and 3, 15 and 17, 45 and 47, and 59 and 61. The whole pelvis was treated each treatment day at a dose of 2.5 Gy b.i.d. Low-dose-rate brachytherapy (35 Gy to Point A) was delivered on Day 29. Chemotherapy was administered on Days 1-3, 15-17, 45-47, and 59-61 and consisted of cisplatin 15 mg/m(2) and 5-fluorouracil 400 mg/m(2). RESULTS: The treatments were well tolerated. None of the patients developed Grade 3-4 acute toxicity. Late Grade 3-4 GI or GU toxicity was seen in 4 (11.7%) and 1 (3%) patient, respectively. At a median follow-up of 60 months, 18 patients were alive. The 3-year and 5-year overall survival rate was 76% and 59%, respectively. CONCLUSION: This protocol, comprising concomitant chemotherapy and twice-daily hypofractionated split-course radiotherapy was associated with moderate toxicity and a survival that exceeds that previously reported for this high-risk population.