DNA damage response and potential biomarkers of radiosensitivity in head and neck cancers: clinical implications.

Head and neck cancers include a wide variety of tumor sites that originate in the epithelium of the upper aerodigestive airways. The curative treatment of this group of pathologies most frequently involves multidisciplinary approach in which radiotherapy (RT) plays a central role. Treatment failures are mainly due to recurrences and local or regional evolution and rarely to distant metastases, which emphasizes the importance of ensuring local control. For patients with recurrences, the treatment options are significantly reduced, and prognosis is considerably attenuated. At the cellular level, the main irradiation target is the deoxyribonucleic acid (DNA), its lesions being largely responsible for radiation-induced cell death. However, not all DNA damage will have the same biological significance and a considerable part will be repaired through an intricate network of signaling proteins and repair pathways. Radiobiologically, compared to normal cells, tumor clonogens are defined by malfunction of DNA repair pathways. Tumors with an increased repair capacity, especially DNA double-strand breaks, the most lethal lesions induced by RT, will be radioresistant. The purpose of this review was to elucidate the mechanisms involved in avoiding radiation-induced apoptosis of head and neck cancers mediated by modulating the repair of DNA damage via p53, epidermal growth factor receptor (EGFR) and p16. The role of DNA damage-associated biomarkers in response to irradiation in clinical practice for the selection of personalized treatments and specifying the prognosis and, finally, the bases of immunotherapy association are presented.

Long-term survival following neoadjuvant chemotherapy and concomitant radiochemotherapy in locally advanced cervical cancer: results of the Oncology Institute "Prof. Dr. Ion Chiricuta" experience.

Objective:to analyze the efficiency of (NACT) followed by concurrent radiochemotherapy (RCT) in patients with locally advanced cervical cancer, 5-year overall, specific and disease-free survival and the prognostic factors correlated with the response and survival. Materials and methods:207 patients with cervical carcinoma stages IIB-IIIB, who received 2-4 cycles of neoadjuvant chemotherapy followed by concurrent chemoradiation were retrospectively analyzed for an objective response (OR), overall survival (OS), and disease-specific survival (DSS) rate. All patients received platinum-based NACT followed by concurrent RCT to a total dose (TD) of 46 Gy/pelvis when patients were evaluated for surgery. Patients with favorable parametrial response optionally underwent surgery. The rest of the patients continued radiochemotherapy exclusively. Results:The baseline characteristics were: median age at diagnosis - 52 years; 82% squamous and 12% adenocarcinoma histologies; 67 patients (32.4%) with FIGO stage IIB, 87 (42%) with stage IIIA and 53 (25.6%) with stage IIIB. The OR rate was 56.5% post-NACT and the complete response (CR) after exclusive RCT was 19.7% while pathological complete response (pCR) in patients that underwent surgery was 61.2%. The median follow-up was 58.3 months. Overall and disease-specific survivals at 5 years were 78% and 84%, respectively. The OS for stages IIB and IIIA was 84%, and 61% for stage IIIB while the DSS rates were 90% for stage IIB, 86% for stage IIIA and 72% for stage IIIB. The disease-free intervals (DFS) rates were 88%, 76% and 69% for stages IIB, IIIA and IIIB, respectively. Conclusions:Neoadjuvant chemotherapy followed by concurrent chemoradiation produces higher response rates and improvements in disease-specific survival and disease-free survival rates compared to RCT.

A prospective study of the value of pre- and post-treatment magnetic resonance imaging examinations for advanced cervical cancer.

BACKGROUND AND AIM: Cervical cancer has high incidence and mortality in developing countries. It is the only gynecological malignancy that is clinically staged. Staging at the time of diagnosis is crucial for treatment planning. After radiation therapy, clinical examination is limited because of radiation changes. An imaging method relatively unaffected by radiation changes would be useful for the assessment of therapy results and for management. We sought to demonstrate the value of magnetic resonance imaging (MRI) in the pre- and post-treatment assessment of cervical cancer. METHODS: This was a prospective study, carried out between November 2012 and October 2014 on 18 subjects with advanced-stage cervical cancer diagnosed by colposcopy. The disease stage was determined clinically according to the International Federation of Gynecology and Obstetrics (FIGO) criteria. Only patients with disease stage ≥ IIB or IIA with one of the tumor dimensions > 4 cm were enrolled in the study. All patients underwent abdominal-pelvic contrast-enhanced MRI as part of the workup. Tumor size, local invasion, involved pelvic lymph nodes, and staging according to MRI criteria were evaluated. Clinical and MRI examinations were also performed after chemoradiotherapy. After chemoradiotherapy, 94% of the patients (17 of 18) were treated surgically. RESULTS: Eighteen patients aged 32-67 met the inclusion criteria and were enrolled: 10 stage IIB, 6 stage IIIA, 1 stage IIA and 1 stage IIIB, according to clinical staging. Using histopathological findings as a reference, MRI staging accuracy was 83.3%. The concordance of the clinical stage with MRI stage at the first examination was 56%. Parametrial involvement was assessed on pretreatment and post-treatment MRI, with post-treatment MRI compared with histology. There was no statistically significant difference between the pre- and post-therapy gynecological examinations (GYN) and the corresponding MRI assessments as to tumor size measurements (p>0.05). The post-therapy restoration of the cervical stroma ruled out tumor recurrence. CONCLUSIONS: For a detailed characterization of loco-regional extension, the calculation of tumor volume, and the evaluation of distant metastatic changes, clinical examination is insufficient. Magnetic resonance imaging is helpful aftertherapy.

Neoadjuvant conformal chemoradiation with induction chemotherapy for rectal adenocarcinoma. A prospective observational study.

BACKGROUND & AIMS: The purpose of this prospective observational study was to evaluate the rate and the prognostic factors for down-staging and complete response for rectal adenocarcinoma after induction chemotherapy and neoadjuvant chemoradiation followed by surgery, and to analyze the rate of sphincter-saving surgery. METHODS: We included from March 2011 to October 2013 a number of 88 patients hospitalized with locally advanced rectal adenocarcinoma in the Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj. The treatment schedule included 2-4 cycles of Oxaliplatin plus a fluoropyrimidine followed by concomitant chemoradiation with a dose of 50 Gy in 25 fractions combined with a fluoropyrimidine monotherapy. RESULTS: The rate of T down-staging was 49.4% (40/81 evaluable patients). Independent prognostic factors for T down-staging were: age >57 years (p<0.01), cN0 (p<0.01), distance from anal verge >5 cm (p<0.01), initial CEA <6.2 ng/ml (p<0.01), higher number of chemotherapy cycles with Oxaliplatin (pROC=0.05) and protraction of radiotherapy of >35 days (p<0.01). Nine patients from 81 (11.1%) presented complete response (7 pathological and 2 clinical); the independent prognostic factors were stage cT2 versus cT3-4 (p<0.01), initial tumor size ≤3.5 cm and distance from anal verge >5 cm (p=0.03). Sixty-eight patients (79.1%) underwent radical surgery and among them 35 patients (51.5 %) had a sphincter saving procedure. CONCLUSIONS: Induction chemotherapy with neoadjuvant chemoradiation produced important down-staging in rectal adenocarcinoma. Independent prognostic factors for T down-staging were: age, cN0, distance from anal verge, initial CEA, the number of Oxaliplatin cycles and duration of radiotherapy; for complete response: cT2, initial tumor size and distance from the anal verge.

Randomized phase 3 trial comparing 2 cisplatin dose schedules in 326 patients with locally advanced squamous cell cervical carcinoma: long-term follow-up.

OBJECTIVE: The evaluation of 5-year results obtained through 2 radiochemotherapy (RCT) regimens: cisplatin (CDDP), 20 mg/m × 5 days every 21 days; and CDDP, 40 mg/m per week in locally advanced cervical carcinoma. METHODS/MATERIALS: In this single-institution prospective randomized phase 3 study, 326 patients with stage IIB to IIIB squamous cell cervical carcinoma treated from March 2003 to March 2005 were included. One hundred sixty patients (49%) had stage IIB cervical carcinoma, 103 patients (31.5%) had stage IIIA cervical carcinoma, and 63 patients (19.5%) had stage IIIB cervical carcinoma. The patients were randomly assigned to 2 therapeutic arms: 164 patients in arm A (5 days) concurrent RCT with CDDP, 20 mg/m per day, days 1 to 5 every 21 days; and 162 patients in arm B (weekly), concurrent RCT with CDDP, 40 mg/m per day weekly. All patients were treated with external beam radiotherapy on the abdominopelvic region using 15-MV x-rays and a cervical boost using the x-rays arch technique or medium-dose-rate intracavitary brachytherapy. RESULTS: The 5-year survival rate obtained through the 2 RCT regimens are not statistically different, even if a tendency of superiority can be observed in the 5-day arm as far as overall survival (78% in arm A vs 72% in arm B; p = 0.14) and disease-free survival (73% in arm A and 69% in arm B; p = 0.09) are concerned. Five-year local relapse-free survival was significantly superior in the 5-day CDDP arm (87%) in comparison with the weekly CDDP arm (77%); p < 0.01. In the 5-day arm, local relapse rate was twice lower, 21/164 (13%), compared with the weekly arm, 40/162 (25%); p < 0.01). Distance failures were identical in the 2 therapeutic groups: 22/164 (13%) and 21/162 (13%), respectively, which shows the superiority of arm A regarding local control. CONCLUSIONS: The results of our study demonstrate that RCT with cisplatin, 20 mg/m × 5 days every 21 days, is superior regarding local efficacy and is less toxic compared with the weekly chemotherapy regimen.

Expression of VEGF, VEGFR, EGFR, COX-2 and MVD in cervical carcinoma, in relation with the response to radio-chemotherapy.

INTRODUCTION: Despite the improvement in the treatment results due to modern irradiation techniques and to the association of chemo-radiotherapy, cervical cancer remains an unsolved problem of oncology both due to the increased rate of local failures and of the distant metastasis. Efforts to implement new therapeutic strategies in order to obtain better results in patients with cervical cancer appear justified. Neovascularization is an important step in the tumor progression and the therapeutic targeting of the tumor blood vessels appears to be a good strategy to follow in the anti-cancer treatment. Thus, even in an incipient phase of the clinical research process, the combination between the anti-angiogenic aimed therapies and the current radio-chemotherapy seems to represent a new, feasible and promising approach. The aim of the present study was to determine the prognostic and/or predictive value of some biological markers of tumor angiogenesis and of their implication in increasing the efficacy of current treatments for this cancer. MATERIALS AND METHODS: So far, 54 women were included in a prospective trial: 44 having an advanced cervical carcinoma and 10 healthy women, as controls. A tumor biopsy and a blood sample were obtained from each patient before the start of therapy. The density of microvascularization was assessed using CD34 monoclonal antibody (hot spot technique), the expression of angiogenic factors VEGFR, EGFR and COX-2 were determined in tumor biopsies by specific immunohistochemistry techniques, using primary antibodies anti-EGFR, anti-VEGF and anti-COX-2 respectively. The quantitative polymerase chain reaction (Real Time PCR) was employed for assessing the expression level of the genes involved. Serum VEGF was determined by quantitative ELISA technique. RESULTS: Among the studied clinical and molecular factors, we found to be predictive for the type of response the following factors: tumor size at diagnosis (p=0.01), VEGFR2 expression (p=0.02) and a tendency to significance for patients' age (p=0.06). From the large panel of studied markers it was observed correlation between MVD expression with stromal COX-2 (p=0.01) and a tendency with epithelial COX-2 (p=0.06). Stromal COX-2 has higher correlation with VEGFR2 (p=0.01) and MVD (p=0.01) and also has a lower correlation with tumor size (p=0.08). CONCLUSIONS: Univariate analysis demonstrates that the response to radio-chemotherapy in cervical cancer is related to a set of clinical and molecular factors as: the tumor size, the expression of VEGFR2 as mRNA level and the patients' age. Unfortunately, the multivariate analysis by logistic model selects only VEGFR2 expression for prediction of tumor response. The interrelations between the different biomarkers demonstrate the complexity of the tumor progression process and the necessity of further studies to identify new therapeutic targets.

Updating the management of rectal cancer.

In the last 25 years rectal cancer has changed from a surgically managed disease into a multidisciplinary treatment model. Accurate staging has a critical role in the decision-making process of patients with rectal cancer. The four most commonly used imaging modalities in the pretherapeutical staging include endoscopic ultrasound, computerized tomography, magnetic resonance imaging and positron emission tomography. Locoregional tumor control in rectal cancer surgery has improved significantly over the last 15 years, after the introduction of total mesorectal excision (TME), which leads to the complete removal of the intact mesorectum including the lymphatics, lymph nodes, nerves, and vascular supply. At the present time, given the improved local control, acute and long-term toxicity profile, and sphincter preservation rate, patients who require combined modality therapy should receive concomitant radiochemotherapy preoperatively. Recently, the novel 'targeted' therapies have been incorporated into a multidisciplinary approach for rectal cancer.