Eugenia Verger

Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Determined by Promoter Hypermethylation and Immunohistochemical Expression in Anaplastic Gliomas

Purpose: Anaplastic gliomas constitute a heterogeneous group of tumors with different therapeutic responses to adjuvant chemotherapy with alkylating agents. O6-Methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, is one of the implicated factors in glioma chemoresistance.The prognostic value of MGMT remains controversial due in part to the fact that previous published studies included heterogeneous groups of patients with different tumor grades. The aim of this study was to evaluate the prognostic significance of MGMT in patients with anaplastic glioma. Experimental Design: Ninety-three patients with anaplastic glioma were analyzed for MGMT protein expression by immunohistochemistry. In addition, for those patients from whom a good yield of DNA was obtained (n = 40), MGMT promoter methylation profile was analyzed by methylation-specific PCR. MGMT prognostic significance was evaluated together with other well-known prognostic factors. Results: Fifty-one tumors (54.8%) showed nuclear staining of MGMT. There was a trend towards longer overall survival for those patients with negative MGMT immunostaining (hazard ratio, 1.66; P = 0.066). In a secondary analysis including those patients who actually received chemotherapy (n = 72), the absence of MGMT expression was independently associated with better survival (hazard ratio, 2.12; P = 0.027). MGMT promoter methylation was observed in 50% of the analyzed tumors. No statistical correlation between MGMT expression and MGMT promoter hypermethylation was observed. Conclusions: Unlike previous studies, we did not find a correlation between MGMT promoter methylation and survival. However, we observed a correlation between MGMT protein expression and survival in those patients who received chemotherapy thus suggesting that the absence of MGMT expression is a positive predictive marker in patients with anaplastic glioma.

Importance of Radiotherapy in the Outcome of Patients With Primary CNS Lymphoma: An Analysis of the CHOD/BVAM Regimen Followed by Two Different Radiotherapy Treatments

PURPOSE To assess the effect of a reduced dose of radiotherapy (RT) in patients with primary CNS lymphoma (PCNSL) responding to the cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) regimen. PATIENTS AND METHODS Patients received one cycle of CHOD and two of BVAM. In the first trial, all 31 patients received 45-Gy whole-brain RT (CHOD/BVAM I). In the second, with 26 patients, RT dose was reduced to 30.6 Gy if there was a complete response (CR) after chemotherapy (CHOD/BVAM II). RESULTS Age, performance status, and chemotherapy received were similar in both protocols. CR rate at the end of all treatment was 68% for CHOD/BVAM I and 77% and for CHOD/BVAM II. Treatment modality was the only predictor of relapse, with 3-year relapse risks of 29% and 70% for CHOD/BVAM I and II, respectively. This was specifically important in the 25 patients less than 60 years old (3-year relapse risk, 25% v 83%; P =.01). The 5-year overall survival (OS) was 36%. Age (< 60 v > or = 60 years) was the only predictor for OS in the multivariate analysis (relative risk, 2.1; 95% confidence interval, 1.4 to 2.8). RT dose was the only predictor of OS in patients younger than 60 years old who achieved CR at the end of all treatment (3-year OS, 92% v 60% for patients receiving 45 or 30.6 Gy, respectively; P =.04). CONCLUSION Reduction of the RT dose from 45 Gy to 30.6 Gy in patients younger than 60 years old with PCNSL who achieved CR resulted in an increased risk of relapse and lower OS.

CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non-Hodgkin's lymphoma.

PURPOSE To assess the efficacy and toxicity, including long-term neurotoxicity, of combined therapy with the CHOD/BVAM regimen given before cranial radiotherapy in the treatment of primary CNS lymphoma (PCNSL). METHODS AND MATERIALS Thirty-one consecutive patients with PCNSL were treated with one cycle of cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD) and two of carmustine (BCNU), vincristine, cytosine arabinoside, and methotrexate (BVAM), followed by cranial radiotherapy (45 Gy whole brain plus a 10-Gy boost for single lesions). The median age was 59 years (range 21-70) and 39% had poor performance status. The median follow-up of patients was 4.1 years (range 2.7-9.0). RESULTS Twenty-one patients had no PCNSL at the end of treatment. The 5-year actuarial probability of survival was 31% (95% confidence interval [CI]: 11%-57%), with a median survival of 38 months. Patients < 60 years had a survival significantly longer than those > or = 60 years (4-year survival: 58% (95% CI: 34-82%) vs. 29% (95% CI: 5-53%), respectively; p = 0.04). Two patients died during chemotherapy from pulmonary embolism and bronchopneumonia, respectively, with no evidence of PCNSL at the autopsy. Dementia probably related to treatment occurred in 5 (62%) of the 8 patients 60 years and older, and 4 of them died without evidence of relapse of PCNSL. Dementia correlated with developing brain atrophy and leuco-encephalopathy on serial CT or MR scans. CONCLUSION This regimen can be given with the planned dose intensity to patients aged less than 70 years, and produces better survival than that reported with radiotherapy alone; however, dementia occurs in the majority of patients aged 60 years of age or more.

Efficacy of radiotherapy for malignant gliomas in elderly patients

PURPOSE Age above 65 years is a strong negative prognostic factor for survival in patients with malignant gliomas (MG) treated with radiotherapy (RT) and its value has been questioned. We analyzed the effect of RT on the survival of elderly patients with malignant gliomas. METHODS AND MATERIALS We examined 85 consecutive elderly patients with a histological diagnosis of MG. Age ranged from 65 to 81 years (median 70 years). Glioblastoma multiforme (GBM) was diagnosed in 64 patients (75.3%). Surgical treatment included needle biopsy in 32 patients (37.6%). Median postoperative Karnofsky Performance Status (KPS) was 60 (range: 30-100). Survival probability was estimated using Kaplan-Meier method and compared with the log-rank test. Crude and adjusted hazard ratios (HR) were calculated using Coxs regression models. RESULTS Median survival time for all patients was 18.1 weeks. In multivariate analysis, RT was the only independent prognostic variable for survival (HR: 9.1 [95% CI: 4.5-18.7]). Forty-two patients did not start RT mostly due to low KPS (<50). The median survival of the 43 patients who started RT was 45 weeks. In these patients, Cox multivariate analysis indicated that age was independently associated with prolonged survival (HR: 2.85 [95% CI 1.31-6.19]). Median survival of patients age 70 years and younger was 55 weeks compared with 34 weeks for patients older than 70 years. CONCLUSIONS The overall survival for elderly patients with MG is poor. RT seems to improve survival in patients up to 70 years, but in older patients treated with RT the survival is significantly shorter.

Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients

Conclusions. Weekly paclitaxel may be an active and well tolerated chemotherapy regimen for patients with platin-resistant advanced head and neck cancer. Objectives. Weekly paclitaxel should be an active and well tolerated regimen for palliative treatment of platin-resistant patients with recurrent or metastatic carcinoma of the head and neck. We analyzed the antitumor activity and toxicity profile. Patients and methods. Sixty consecutive patients with advanced head and neck cancer were treated with 1 h infusion of paclitaxel, 80 mg/m2 weekly, for 6 consecutive weeks. Patients who showed disease response or disease stabilization continued until progression of disease. Results. A total of 719 doses of paclitaxel were administered to the 60 patients. No complete response was observed. Partial response and stable disease were observed in 26 (43.3%) and 9 (15%) patients, respectively. Median time to tumor progression for patients who responded to therapy was 6.2 months (SD=1.3; 95% CI, 3.7–8.6) and the overall median survival in this group of patients was 8.5 months (SD=1.4; 95% CI, 5.7–11.2). The main toxic effects were leukopenia (26.6%), anemia (43.3%), fatigue (37.4%), alopecia (18.7%), rash/desquamation (13.3%), and thrombophlebitis (6.8%).

Multidisciplinary Approach in Advanced Cancer of the Oral Cavity: Outcome with Neoadjuvant Chemotherapy according to Intention-to-Treat Local Therapy

Objectives: To determine outcomes in local-regional control and overall survival in patients with squamous locally advanced cancer of the oral cavity, based on intention-to-treat with neoadjuvant chemotherapy followed by surgery or radiation therapy. Methods: Two hundred and four out of 1,089 patients analyzed met the defined criteria. All had squamous cell carcinomas of the oral cavity in stage III or in nonmetastatic stage IV and were selected for surgery or radiation therapy (if located in the tonsils or in the base of the tongue). Chemotherapy was based on cisplatin 120 mg/m2 i.v. day 1 plus bleomycin 20 mg/m2 days 1–5 in continuous i.v. perfusion or plus 5-fluorouracil 1,000 mg/m2 days 1–5 in continuous i.v. perfusion. A total of 418 cycles were given to 204 patients (mean 2.049 per patient). Definitive surgery (n = 73; plus adjuvant radiation therapy) or definitive radiation therapy (n = 131) was performed. Results: One hundred thirty-five out of 204 (66%) patients were chemotherapy responders, 16% complete and 50% partial. One hundred ninety-four patients (95%) completed 2 courses of chemotherapy. After neoadjuvant chemotherapy, 34 out of 46 patients considered inoperable initially (74%) obtained a disease-free status with surgery. Eighty-three percent of surgical patients obtained a disease-free status (initial tumor control) versus 72% of radiation therapy patients. Disease-free survival rates at 5 years were 26 and 22%, respectively. A better prognosis was observed in stage III over IV (p = 0.02); primary tumor in the retromolar trigone, palate or buccal mucosa over tongue, tonsil or floor of the mouth (p = 0.0085); negative cervical nodes over positive (p = 0.0186); responders to chemotherapy over nonresponders (p = 0.0003); and adjuvant postsurgical radiation therapy (p = 0.0013). Causes of death were relapses in local area (86%), regional nodes (10.5%) or distant metastases (3.5%). Eleven patients (5%) died of a second primary. The main toxic effects were vomiting in 9% of patients and hemolytic-uremic syndrome in 3% of the patients treated with bleomycin. Conclusions: In locally advanced squamous cell carcinoma of the oral cavity, neoadjuvant chemotherapy induces a high response rate that may facilitate definitive surgery or radiotherapy. In this study, patients have an acceptable long-term survival.

Effects of single dose irradiation on pancreatic beta-cell function.

We have irradiated abdominal cavity of 23 rats with 10 Gy irradiation-induced hypoglycemia on the fourth day after intervention. Islets collected at this time showed an impaired insulin secretion without affecting insulin content. This impairment persisted after one month follow-up with reduced number of beta-cells in morphological examination.

Transoral laser microsurgery for locally advanced (T3–T4a) supraglottic squamous cell carcinoma: Sixteen years of experience

Controversy exists regarding treatment of advanced laryngeal cancer. The purpose of this study was to evaluate the oncologic and functional outcomes of T3 to T4a supraglottic squamous carcinomas treated with transoral laser microsurgery (TLM).

Does gender matter in glioblastoma

BackgroundThe clinical outcome of glioblastoma (GBM) patients who receive radiotherapy alone or with chemotherapy is well established. However, little is known about how many patients do not receive this treatment. We consider it is important to investigate why a proportion of operated patients do not receive further treatment after surgery.MethodsWe reviewed all consecutive GBM patients operated on in our hospital between January 2000 and December 2008.ResultsA total of 216 patients with GBM were identified. Fifty-five (25%) did not receive any treatment after surgery. Univariate analysis showed that factors associated with no further treatment after surgery were older than 60 years (p=0.002), of female gender (p=0.03), had a KPS<70 (p<0.001) and had had a biopsy (p<0.001). Multivariate analysis indicated that age ≥60 years and KPS <70 were independent predictors of no further treatment after surgery. Gender was not an independent variable. However, women in the whole series were older than 60 years (p=0.01), and they had a worse KPS (p=0.02) and more biopsies (p=0.04) than men. In the whole group, median survival time was 10.4 months for men (n=125) vs. 7.2 months for women (n=91), log rank p<0.04. This difference was not observed in the group that was treated after surgery.ConclusionsOne out of four patients could not be treated after surgery. Independent predictors were older age and low KPS. These poor risk variables were more frequent in women and their survival was therefore lower than men in our series.

Pseudoprogression as an adverse event of glioblastoma therapy

We explored predictive factors of pseudoprogression (PsP) and its impact on prognosis in a retrospective series of uniformly treated glioblastoma patients. Patients were classified as having PsP, early progression (eP) or neither (nP). We examined potential associations with clinical, molecular, and basal imaging characteristics and compared overall survival (OS), progression‐free survival (PFS), post‐progression survival (PPS) as well as the relationship between PFS and PPS in the three groups. Of the 256 patients studied, 56 (21.9%) were classified as PsP, 70 (27.3%) as eP, and 130 (50.8%) as nP. Only MGMT methylation status was associated to PsP. MGMT methylated patients had a 3.5‐fold greater possibility of having PsP than eP (OR: 3.48; 95% CI: 1.606–7.564; P = 0.002). OS was longer for PsP than eP patients (18.9 vs. 12.3 months; P = 0.0001) but was similar for PsP and nP patients (P = 0.91). OS was shorter–though not significantly so—for PsP than nP patients (OS: 19.5 vs. 27.9 months; P = 0.63) in methylated patients. PPS was similar for patients having PsP, eP or nP (PPS: 7.2 vs. 5.4 vs. 6.7; P = 0.43). Neurological deterioration occurred in 64.3% of cases at the time they were classified as PsP and in 72.8% of cases of eP (P = 0.14). PsP confounds the evaluation of disease and does not confer a survival advantage in glioblastoma.