BackgroundIn spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status) do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma.Patients and methodsLong-term survivor group were 40 patients with glioblastoma with survival longer than 30 months. Control group were 40 patients with shorter survival and matched to the long-term survivor group according to the clinical prognostic factors. All patients underwent multimodality treatment with surgery, postoperative conformal radiotherapy and temozolomide during and after radiotherapy. Biopsy samples were tested for the methylation of MGMT promoter (with methylation specific polymerase chain reaction), IDH1 (with immunohistochemistry), IDH2, CDKN2A and CDKN2B (with multiplex ligation-dependent probe amplification), and 1p and 19q mutations (with fluorescent in situ hybridization).ResultsMethylation of MGMT promoter was found in 95% and in 36% in the long-term survivor and control groups, respectively (p < 0.001). IDH1 R132H mutated patients had a non-significant lower risk of dying from glioblastoma (p = 0.437), in comparison to patients without this mutation. Other mutations were rare, with no significant difference between the two groups.ConclusionsMolecular and genetic testing offers additional prognostic and predictive information for patients with glioblastoma. The most important finding of our analysis is that in the absence of MGMT promoter methylation, longterm survival is very rare. For patients without this mutation, alternative treatments should be explored.
After monotherapy with gemcitabine in low dose in long infusion, promising results in a variety of advanced chemoresistant tumors have been reported. In a previous phase I trial on heavily pre-treated patients, maximum tolerated dose (MTD) of gemcitabine in a 6 h infusion was 250 mg/m. The objective of our phase I-II trial was to test the combination of gemcitabine in a 6-h infusion and cisplatin in the treatment of advanced non-small cell lung cancer (NSCLC). Eligible patients were chemonaive, had locally advanced or metastatic NSCLC, Eastern Oncology Cooperative Oncology Group performance status 0-2 and normal organ function. Treatment consisted of gemcitabine in a 6-h infusion on days 1 and 8, and cisplatin at 75 mg/m on day 2 of a 3-week cycle. During phase I of the trial, the dose of gemcitabine was escalated from 130 to 170, 210 and 250 mg/m. After establishing dose-limiting toxicity (DLT) and MTD of the combination, the trial continued as phase II. Altogether, 61 patients were enrolled, of whom 54 had stage IV disease. In phase I of the trial, groups of six, seven, eight and eight patients were treated at the four dose levels of gemcitabine. In phase II, the remaining 32 patients all received gemcitabine at 250 mg/m. Serious toxicity included a patient with grade 5 ventricular arrhythmia and another with grade 4 cerebrovascular ischemia; four patients had grade 3 anemia. Reversible thrombocytosis with platelets over 500 was recorded in 32 patients; 42 patients had grade 2 alopecia. In general, tolerance to this treatment was good. One patient had complete response and 27 had partial responses, for a 28 of 61 (46%) response rate. Median progression-free survival, median survival and 1-year survival were 6 months, 9.5 months and 40%, respectively. We conclude that this treatment has an acceptable, yet distinct, toxicity profile; routine thromboprophylaxis is recommended. In our population of chemonaive patients, no DLT has been encountered. Due to the remarkable response rate, further research is warranted.
After a favorable experience with gemcitabine at a low dose in a prolonged infusion in combination with cisplatin for advanced non-small-cell lung cancer, here, we present the results from a phase II trial for patients with malignant pleural mesothelioma. Eligible patients had biopsy-proven malignant pleural mesothelioma, were chemo-naive, Eastern Cooperative Oncology Group performance status 0-2, had normal hematopoietic liver and renal function, and gave informed consent. Treatment consisted of gemcitabine 250 mg/m in a 6-h infusion on days 1 and 8 and cisplatin at 75 mg/m on day 2 of a 3-week cycle for four cycles, followed by two additional cycles without cisplatin. Seventy-eight patients (58 men, 20 women; age 33-82 years, median 58) were recruited into the trial. The histologic types were as follows: epitheloid 56 (71.8%); four sarcomatoid (5.1%); mixed 15 (19.2%); and mesothelioma, three not otherwise specified (3.8%). Grades 3-4 toxicity included two (2.6%) patients with anemia, 18 (23.1%) with neutropenia, and one with nausea/vomiting. Reversible thrombocytosis with platelets over 1000-10/l was recorded in 10 (12.8%) patients and grade 2 alopecia in 60 (76.9%). Four (5.1%) patients showed a complete response and 35 (44.9%) showed a partial response with a response rate of 39/78 (50%). Minimal response or stable disease was seen in 35 (44.9%), whereas only four (5.1%) patients progressed during treatment. Most patients reported symptomatic improvement with a higher or a stable quality of life score in 70 (89.7%) cases. The median progression-free survival was 8.0 months (confidence interval 6.9-9.0). The median overall survival was 17.0 months (confidence interval 14.7-19.2). One-year, two-year, and three-year survival rates were 67.3, 32.7, and 19.8%, respectively. Epitheloid histological type was the only statistically significant favorable prognostic factor for progression-free survival and overall survival. Because of the acceptable toxicity, remarkable activity, and reasonable cost, this treatment should be further explored.
We present experience from a phase II randomized clinical trial, comparing standard gemcitabine as monotherapy with low-dose gemcitabine in long infusion in a doublet with cisplatin at reduced dose for patients with non-small cell lung cancer (NSCLC) and who are unfit for standard platin-based chemotherapy. Eligible patients had microscopically confirmed NSCLC in stage IIIB (wet) or IV, were chemo-naive, and were in poor performance status or presented with significant comorbidity. Standard treatment with gemcitabine, 1250 mg/m in 20-30 min on days 1 and 8 as monotherapy (arm A) was compared with low-dose gemcitabine in long infusion (200 mg/m in 6 h on day 1) and cisplatin at 60 mg/m on day 2 (arm B). Both treatment schedules were repeated every 3 weeks until disease progression, unacceptable toxicity, or to a maximum of six cycles. A total of 112 patients (83 male, 29 female, median age 66 years) were randomized between arm A (57 patients) and B (55 patients). The two groups were balanced for prognostic factors. Fifty-three patients in arm A and 52 in arm B received at least one application of chemotherapy and were evaluable for toxicity and response. The median number of cycles was four and five for arms A and B, respectively. Except for grade 3 anemia (one patient in arm A and two in arm B), no other major toxicity was seen. Regarding response to treatment, arm B was superior: 1 complete response and 13 partial remissions (response rate 26.9%) as compared with five partial remissions (response rate 9.4%) in arm A (P<0.01). The median time to progression was 3.8 and 5.6 months, and the median survival was 4.3 and 6.8 months for arms A and B, respectively (P<0.05). Treatment with low-dose gemcitabine in long infusion and cisplatin at reduced dose has very low toxicity, is effective, was found to be superior to monotherapy with gemcitabine in standard doses, and is suitable for patients with NSCLC who cannot tolerate a standard platin-based doublet.
Early perfusion changes during concomitant chemoradiation in GBMs can be detected by means of DCE-MRI and have significant prognostic value for the 12-month PFS.
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