Outcomes of re-irradiation for oral cavity squamous cell carcinoma.

BACKGROUND: To predict the outcome of reirradiation (re-RT) for oral cavity squamous cell carcinoma (OSCC). METHODS: Eighty-three patients met the criterion of having previously irradiated OSCC treated via curative intent re-RT for recurrent or new primary OSCC. The exclusion criteria were a suboptimal dose (<45 Gy) for the first RT and palliative intent for the second irradiation. Re-RT was defined as at least 75% volume at second RT after receiving at least 45 Gy at the first RT. RESULTS: The 2-year locoregional progression-free survival (LRPFS) and overall survival (OS) rates were 20% and 28%. For LRPFS, four predictors were noted through univariate analyses: performance status (PS) (p = 0.001), a dose of at least 60 Gy (p = 0.001), stage IVB (p = 0.020), and surgery before re-RT (p = 0.041). In multivariate analyses, only PS (p = 0.005) and a dose of at least 60 Gy (p = 0.001) remained significant. For OS, PS (p = 0.001) and a dose of at least 60 Gy (p = 0.042) were still independently associated predictors, but surgery before re-RT became marginally beneficial (p = 0.053). For patients with a poor PS (ECOG = 2-3), the 2-year OS was only 4.5%. Twenty-nine percent of the patients experienced severe late complications (≥Grade 3), and 18% had new episodes of osteoradionecrosis during their follow-up. CONCLUSION: We identified PS and a re-RT dose ≥60 Gy as predictors for LRPFS and OS. Surgery before re-RT might improve OS. However, the treatment results of re-RT for OSCC were suboptimal. Prospective trials using modern RT techniques, in combination with new therapeutic drugs or radioenhancers, are warranted for improving these dismal outcomes.

Molecular Interplays Between Cell Invasion and Radioresistance That Lead to Poor Prognosis in Head-Neck Cancer.

BACKGROUND: Cancer metastasis and recurrence after radiotherapy are the significant causes of poor prognosis in head-neck cancer (HNC). Clinically, it is commonly found that patients with either condition may accompany the outcome of the other. We hypothesized that HNC cells might exhibit a cross-phenotypic attribute between cell invasion and radioresistance. To discover effective biomarkers for the intervention of aggressive cancer at one time, the potential molecules that interplay between these two phenotypes were investigated. MATERIALS AND METHODS: Three isogenic HNC cell sublines with high invasion or radioresistance properties were established. Transcriptomic and bioinformatic methods were used to globally assess the phenotypic-specific genes, functional pathways, and co-regulatory hub molecules. The associations of gene expressions with patient survival were analyzed by Kaplan-Meier plotter, a web-based tool, using the HNSCC dataset (n=500). The molecular and cellular techniques, including RT-qPCR, flow cytometry, cell invasion assay, and clonogenic survival assay, were applied. RESULTS: The phenotypic crosstalk between cell invasion and radioresistance was validated, as shown by the existence of mutual properties in each HNC subline. A total of 695 genes was identified in associations with these two phenotypes, including 349 upregulated and 346 downregulated in HNC cells. The focal adhesion mechanism showed the most significant pathway to co-regulate these functions. In the analysis of 20 up-regulatory genes, a general portrait of correlative expression was found between these phenotypic cells (r=0.513, p=0.021), and nine molecules exhibited significant associations with poor prognosis in HNC patients (HR>1, p<0.050). Three hub genes were identified (ITGA6, TGFB1, and NDRG1) that represented a signature of interplayed molecules contributing to cell invasion, radioresistance and leading to poor prognosis. The ITGA6 was demonstrated as a prominent biomarker. The expression of ITGA6 correlated with the levels of several extracellular and apoptotic/anti-apoptotic molecules. Functionally, silencing ITGA6 suppressed cell migration, invasion, and attenuated radioresistance in HNC cells. CONCLUSIONS: A panel of interplay molecules was identified that contribute to cell invasion and radioresistance, leading to poor prognosis. These panel molecules, such as ITGA6, may serve as predictive markers of radioresistance, prognostic markers of metastasis, and molecular therapeutic targets for refractory HNC.

Systemic Investigation Identifying Salivary miR-196b as a Promising Biomarker for Early Detection of Head-Neck Cancer and Oral Precancer Lesions.

BACKGROUND: Liquid biopsy is a rapidly growing field, for it may provide a minimally invasive way to acquire pathological data for personalized medicine. This study developed a systemic strategy to discover an effective salivary biomarker for early detection of patients with head-neck squamous carcinoma (HNSC) and oral precancer lesion (OPC). METHODS: A total of 10 miRNAs were examined in parallel with multiple independent cohorts. These included a training set of salivary samples from HNSC patients, the TCGA-HNSC and GSE31277 cohorts to differentiate miRNAs between tumor and normal tissues, and groups of salivary samples from healthy individuals, patients with HNSC and OPC. RESULTS: The combined results from the salivary training set and the TCGA-HNSC cohort showed that four miRNAs (miR-148b, miR-155, miR-196b, and miR-31) consistently increased in HNSC patients. Further integration with the GSE31277 cohort, two miRNAs (miR-31 and miR-196b) maintained at high significances. Further assessment showed that salivary miR-196b was a prominent diagnostic biomarker, as it remarkably discriminated between healthy individuals and patients with HNSC (p < 0.0001, AUC = 0.767, OR = 5.64) or OPC (p < 0.0001, AUC = 0.979, OR = 459). CONCLUSION: Salivary miR-196b could be an excellent biomarker for diagnosing OPC and early detection of HNSC. This molecule may be used for early screening high-risk groups of HNSC.

Efficacy of Postoperative Unilateral Neck Irradiation in Patients with Buccal Mucosa Squamous Carcinoma with Extranodal Extension: A Propensity Score Analysis.

Unilateral radiotherapy (RT) as a postoperative treatment for multiple ipsilateral lymph node (LN) metastases remains controversial. We investigated the efficacy of postoperative unilateral RT for buccal mucosa squamous cell carcinoma (BMSCC) with extranodal extensions (ENEs). We retrospectively reviewed the clinical records of 186 patients with ENE+ BMSCC who received postoperative RT during 1997-2016. Propensity score matching was used to establish comparable cohorts. The endpoints were contralateral nodal control (CLNC), overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), local control (LC), and regional control (RC). After matching, 123 patients were selected for analysis; 45 (36.6%) and 78 (63.4%) patients underwent unilateral and bilateral RT, respectively. The median follow-up was 36.27 months. The survival outcomes in the unilateral and bilateral RT groups were similar: 3-year CLNC (85.6% vs. 89.1%, p = 0.748), OS (53.2% vs. 57.4%, p = 0.229), DFS (46.5% vs. 48.6%, p = 0.515), DMFS (70.7% vs. 72.0%, p = 0.499), LC (78.0% vs. 75.6%, p = 0.692), and RC (79.9% vs. 76.2%, p = 0.465). On multivariable Cox regression analysis, unilateral and bilateral RT showed comparable outcomes; the number of ENEs ≥ 4 was the only significant prognostic factor for all clinical outcomes. Using decision tree analysis, we classified our patients to have a low, intermediate, or high risk of contralateral failure based on three factors: number of ENEs, margin status, and tumor stage. In conclusion, postoperative unilateral RT did not worsen outcomes in patients with ENE+ BMSCC in this cohort. The decision tree model may assist physicians in optimizing and tailoring radiation fields.

Optimal Timing for Postsurgical Adjuvant Therapy in Patients with Gastric Cancer: A Propensity Score Matching Study.

Background: In clinical trials, adjuvant therapy (AT) has been shown to improve the prognosis in patients with gastric adenocarcinoma who undergo curative gastrectomy and adequate lymph node dissection. However, the optimal timing for initiating AT is still unclear. Method: We collected data from 538 patients with stage II-III gastric cancer who underwent curative gastrectomy and AT in two tertiary hospitals from 2006 to 2013. Patients were divided into the early group (≤8 weeks, n=393) and the late group (>8 weeks, n=145), based on the interval between gastrectomy and initiation of AT. Propensity score matching was applied according to baseline characteristics. Results: After 1:1 propensity score matching, an even distribution of characteristics in both groups (143:143) was achieved. The 5-year overall survival (OS) rates were 56.6% and 40.2% in the matched early and late groups, respectively (p=0.062), while the corresponding 5-year recurrence-free survival (RFS) rates were 57.6% and 46.4%, respectively (p=0.028). The time to AT initiation was correlated with RFS and had a positive association with OS. The 5-year distant metastasis-free survival was also significantly better (HR 0.682, 95% CI 0.472-0.985, p=0.040), suggesting an early AT results in a better outcome in patients. Conclusion: We observed that initiation of AT within 8 weeks of curative gastrectomy produces better disease control and may contribute to better overall survival.

Postoperative radiotherapy with or without concurrent chemotherapy for oral squamous cell carcinoma in patients with three or more minor risk factors: a propensity score matching analysis.

BACKGROUND: To investigate the advantage of concurrent chemotherapy with postoperative radiotherapy (RT) of oral squamous cell carcinoma (OSCC) in patients with three or more minor risk factors. METHODS: Minor risk factors included pT4 disease, pN1 disease, margin ≤ 4 mm, poor differentiation, perineural invasion, vessel or lymphatic invasion, and tumor invasion depth ≥ 11 mm. Surgery was the primary treatment, followed by RT or concurrent chemoradiation (CCRT). After propensity score matching, 34 patients in each treatment group were selected for comparison. RESULTS: The median follow-up for living patients was 86.4 months (range: 47-189 months). The 5-year overall survival of the RT and CCRT groups was 35.3% and 67.2% (p = 0.018), respectively. The 5-year recurrence-free survival of the RT group and CCRT group was 42.6% and 75.4% (p < 0.01). CONCLUSION: Postoperative CCRT for patients with three or more minor risk factors increased recurrence-free and overall survival.

Pre-radiotherapy PSA level as a predictor for biochemical control in prostate cancer patients receiving radiotherapy after radical prostatectomy.

BACKGROUND: To report the outcome of patients receiving radiotherapy (RT) after radical prostatectomy (RP). METHODS: Between May 2001 and December 2008, 53 consecutive cases of prostate adenocarcinoma treated with RP and RT were reviewed. RESULTS: A total of 49 patients were eligible for this study. After a median follow-up of 53 months, the 4-year overall survival (OS) and biochemical progression-free survival (bPFS) for all patients were 91.0% and 68.9%, respectively. According to univariate and multivariate analysis, pre-RT prostate-specific antigen (PSA) was the most significant factor for bPFS. Patients with pre-RT PSA levels of < 0.2 ng/ml and ≧ 0.2 ng/ml had a 4-year bPFS of 83.1% and 52.6%, respectively (p = 0.013). The incidence of chronic rectal toxicity was low, with no grade 3 toxicity reported and grade 2 toxicity found in only 6 patients (12.2%). However, long-term urinary toxicity of grade 2 or higher was found in 24 patients (49.0%). CONCLUSION: For patients with increasing PSA levels following RP, local RT should be administered prior to biochemical failure (PSA ≧ 0.2), to ensure good bPFS.

Adjuvant and salvage radiotherapy for urothelial cell carcinoma of the upper urinary tract: experience in a single institution.

BACKGROUND: To investigate the role of radiotherapy (RT) for upper urinary tract urothelial cell carcinoma (UTUC) after surgery. METHODS: Between July 1997 and February 2007, 40 patients who had undergone radical surgery and RT were selected. Twenty patients received RT as adjuvant treatment for advanced disease (PORT). The remainder received RT as salvage treatment (SART). The prescription dose of RT ranged from 32 to 66.6 Gy (median: 50 Gy). Cisplatin-based chemotherapy was given to 34 patients. The median follow-up was 61 months (22-93 months). RESULTS: At the time of analysis, 10 patients were alive, but two of them had tumor recurrence. Twenty-four patients died from disease recurrence, two died from chemotherapy-related complications, and two from non-cancer comorbidities. Two patients were lost to follow-up but one of them had tumor recurrence. The 3-year overall survival (OS) was 45% for the PORT group, and 16% for the SART group (p = 0.03). The 3-year progression-free survival (PFS) was 41% for the PORT group, and 12% for the SART group (p = 0.02). A prescription dose < 50 Gy (p = 0.02) was another poor prognostic factor. The 3-year OS was 38% for a prescription dose ≥ 50 Gy, and 18% for < 50 Gy (p = 0.06). The 3-year PFS improved from 7% to 41% if the prescribed dose was ≥ 50 Gy (p < 0.05). CONCLUSION: According to our analysis, RT combined with chemotherapy is effective in the postoperative treatment of advanced disease and salvage treatment for recurrent UTUC. The prescription dose should be ≥ 50 Gy.

Adjuvant androgen deprivation therapy loses its therapeutic benefit after premature termination: an experience of combined modality treatment on prostate cancer.

BACKGROUND: To investigate the effect of the premature termination of recommended androgen deprivation therapy (ADT) as an adjunct to radiotherapy. METHODS: Between December 2001 and March 2004, 92 patients with non-metastatic prostate cancer underwent primary, curative radiotherapy via an intensity-modulated technique. Four patients (5%) were treated with a dosage of 70.2 Gy, while 74 (80%) and 14 patients (15%) were treated to 72 and 75.6 Gy. Thirty patients (33%) received pelvic irradiation to 45 Gy as a part of their treatment. Seventy-nine patients (86%) also received variable ADT, but only 35 patients (38%) followed a strict protocol when on ADT. Biochemical failure was defined as nadir plus 2 ng/mL or if there was any clinical evidence of tumor recurrence. RESULTS: The median follow-up time was 37.5 months (20.4-57.8 months). The 3-year overall survival rate was 91.8%. The estimated 3 year recurrence-free survival rates were 100%, 88.9%, and 69.7% for the low, intermediate, and high risk groups, respectively. High risk group patients receiving ADT of an inappropriate length was the only significant risk factor correlated to disease recurrence. The 3-year recurrence-free survival rate was extremely poor (28.6%) in high risk group patients who received adjuvant ADT for less than 2 years. This was significantly worse than patients with the same risk who received long-term ADT (88.1%) or no adjuvant ADT (76.4%, p < 0.001). CONCLUSIONS: Long-term adjuvant ADT after radiotherapy on high risk prostate cancer has no benefit if the duration is less than 2 years. Premature termination should be avoided.

High-dose-rate brachytherapy plus external beam radiotherapy for T1 to T3 prostate cancer: an experience in Taiwan.

OBJECTIVES: To report outcomes for localized prostate cancer patients treated with the combination of high-dose-rate (HDR) brachytherapy and external beam radiotherapy (EBRT). METHODS: Eighty-five Stage T1c to T3b prostate cancer patients treated with HDR brachytherapy plus EBRT were included. An HDR dose of 16.5 Gy in 3 fractions over 24 hours was given 2 weeks before EBRT. An EBRT dose of 50.4 Gy was administered to the prostate and seminal vesicles. Younger patients (aged less than 75 years) with greater than 15% risk of nodal metastasis received whole-pelvis RT (45 Gy in 25 fractions) as part of EBRT. RESULTS: Fifty percent of patients belonged to the high-risk (T3a or Gleason score 8-10 or prostate-specific antigen greater than 20 ng/mL) or very-high-risk (T3b) groups. After a median follow-up of 49 months (range, 24 to 70 months), 4-year biochemical control survival (less than nadir + 2) was 86% (100%, 91%, and 81% for patients in the low, intermediate, and high-risk groups, respectively. Three of four T3b patients experienced early biochemical failure. Four patients (5%) had grade 3 implant-related urinary retention. Chronic gastrointestinal toxicities were limited, but four grade 3 chronic genitourinary toxicities (5%) were noted in relation to urethral stricture and severe hematuria. Whole-pelvis EBRT was a major contributing factor to acute but not to chronic gastrointestinal toxicities. Among 60 patients with pretreatment sexual potency, 17 (26%) retained capability after 4 years. Six patients (10%) lost potency merely as a result of salvage hormone therapy. CONCLUSIONS: High-dose-rate brachytherapy plus EBRT can achieve satisfactory biochemical control with acceptable complications for T1c to T3a prostate cancer patients.

Preliminary treatment results of intensity-modulated radiotherapy for prostate cancer.

BACKGROUND: To review the initial treatment results of intensity-modulated radiotherapy (IMRT) for prostate cancer. METHODS: Ninety-two patients treated with IMRT before July 2003 were included in this study. The median follow-up was 32 months. The indications for IMRT included primary, adjuvant, and salvage treatment. Combined treatment with androgen suppression therapy was variable. The primary study endpoints were chronic adverse events which were subjectively reported. Only patients with an adenocarcinoma and who had been treated by primary radiotherapy were included in the analysis of disease relapse. RESULTS: At the time of analysis, 89 patients were still alive, and only 2 patients had died of prostate cancer. In the survival analysis, the 30-month failure-free survival rates were 100%, 89.2%, and 67.3% for the low-, intermediate-, and high-risk groups of patients, respectively. Pretreatment PSA level, Gleason score, risk classification, and adjuvant hormone therapy were significantly associated with relapse according to the univariate analysis, while only risk classification remained significant in the multivariate analysis. During follow-up, 5 (6%) patients developed grade 2 gastrointestinal (GI) adverse events (AE). Sixteen (18%) and 7 (8%) patients developed grade 2 and 3 urinary AE, respectively. Development of severe urinary adverse events was closely related to previous surgical treatment. No factor was identified as being correlated with the GI adverse events. The preservation rate of sexual function was 25.7%. CONCLUSIONS: Seventy-two Grays of irradiation, administered by IMRT, is a safe method as the primary treatment for prostate cancer. However, severe urinary toxicity was related to previous surgical treatment. There is a need for longer follow-up periods to verity the benetit of this dosage level.

Advantages and pitfalls of 18F-fluoro-2-deoxy-D-glucose positron emission tomography in detecting locally residual or recurrent nasopharyngeal carcinoma: comparison with magnetic resonance imaging.

INTRODUCTION: This prospective study was designed to elucidate the advantages and pitfalls of (18)F-FDG PET in detecting locally residual/recurrent nasopharyngeal carcinoma (NPC) in comparison with MRI. METHODS: We recruited NPC patients from two ongoing prospective trials. One is being performed to evaluate suspected local recurrence (group A) and the other to assess local treatment response 3 months after therapy (group B). Both groups received (18)F-FDG PET and head and neck MRI. The gold standard was histopathology or clinical/imaging follow-up. An optimal cut-off standardised uptake value (SUV) was retrospectively determined. RESULTS: From January 2002 to August 2004, 146 patients were eligible. Thirty-four were from group A and 112 from group B. In all, 26 had locally recurrent/residual tumours. Differences in detection rate between (18)F-FDG PET and MRI were not statistically significant in either group. However, (18)F-FDG PET showed significantly higher specificity than MRI in detecting residual tumours among patients with initial T4 disease (p=0.04). In contrast, the specificity of (18)F-FDG PET for patients with an initial T1-2 tumour treated with intracavitary brachytherapy (ICBT) was significantly lower than that for patients not treated by ICBT (72.2% vs 98.1%, p=0.003). At an SUV cut-off of 4.2, PET showed an equal and a higher accuracy compared with MRI in groups A and B, respectively. CONCLUSION: (18)F-FDG PET is superior to MRI in identifying locally residual NPC among patients with initial T4 disease but demonstrates limitations in assessing treatment response in patients with initial T1-2 disease after ICBT. A cut-off SUV is a useful index for aiding in the visual detection of locally residual/recurrent NPC.