Gaetano Lanzetta

Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients.

Objectives The optimal treatment for elderly patients (agexa0>xa070xa0years) with glioblastoma remains controversial. We conducted a prospective trial in 32 consecutive elderly patients with glioblastoma who underwent surgery followed by radiotherapy (RT) plus concomitant and adjuvant temozolomide. Patients and Methods 32 patients 70xa0years of age or older with a newly diagnosed glioblastoma and a Karnofsky performance status (KPS)xa0≥xa070 were treated with RT (daily fractions of 2xa0Gy for a total of 60xa0Gy) plus temozolomide at the dose of 75xa0mg/m2 per day followed by six cycles of adjuvant temozolomide (150–200xa0mg/m2 for 5xa0days during each 28-day cycle). The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and toxicity. Results The median OS was 10.6xa0months and the median PFS was 7xa0months. The 6-month and 12-month survival rates were 91% and 37%, respectively. The 6-month and 12-month PFS rates were 56% and 16%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (Pxa0=xa00.01). Adverse effects were mainly represented by neurotoxicity (40%), which resolved in most cases with the use of steroids, and Grade 3–4 hematologic toxicity in 28% of patients. Chemotherapy was stopped in 2 patients, delayed in 9 patients and reduced in 4 patients. Conclusions Standard RT plus concomitant and adjuvant temozolomide is a feasible treatment for elderly patients with newly diagnosed glioblastoma who present with good prognostic factors.

Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide

Epigenetic silencing of the O6-methylguanine-DNA-methyltransferase (MGMT) gene by promoter methylation is correlated with improved progression-free survival (PFS) and overall survival (OS) in adult patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. The aim of this study is to determine the correlation between MGMT and survival in elderly patients with GBM treated with radiotherapy (RT) and temozolomide (TMZ). Eighty-three patients aged 70xa0years or older with histologically confirmed GBM treated with RT plus TMZ between February 2005 and September 2009 were investigated in this study. The methylation status of the MGMT promoter was determined by polymerase chain reaction analysis. Median PFS and OS were 7.5 and 12.8xa0months, respectively. The MGMT promoter was methylated in 42 patients (50.6%) and unmethylated in 41 patients (49.4%). Median OS was 15.3xa0months in methylated patients and 10.2xa0months in unmethylated patients (Pxa0=xa00.0001). Median PFS was 10.5xa0months in methylated tumors and 5.5xa0months in unmethylated tumors (Pxa0=xa00.0001). On multivariate analysis MGMT methylation status emerged as the strongest independent prognostic factor for OS and PFS (Pxa0=xa00.004 and Pxa0=xa00.005, respectively). The results of the present study suggest that MGMT methylation status might be an important prognostic factor associated with better OS and PFS in elderly patients with GBM treated with RT and TMZ.

Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma

Objectives The optimal treatment for elderly patients (age >70xa0years) with glioblastoma (GBM) remains controversial. We conducted a prospective trial in 43 consecutive elderly patients with GBM treated with hypofractionated radiotherapy (RT) followed by adjuvant temozolomide. Patients and methods Forty-three patients 70xa0years of age or older with a newly diagnosed GBM and a Karnofsky performance status (KPS)xa0≥xa060 were treated with hypofractionated RT (6 fractions of 5xa0Gy each for a total of 30xa0Gy over 2xa0weeks) followed by up to 12 cycles of adjuvant temozolomide (150–200xa0mg/m2 for 5xa0days during each 28xa0day cycle). The HRQOL was assessed with the EORTC Quality of Life Questionnaire C30. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), toxicity and quality of life. Results The median OS was 9.3xa0months and the median PFS was 6.3xa0months. The 6 and 12xa0month survival rates were 86% and 35%, respectively. The 6 and 12xa0month PFS rates were 55% and 12%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (Pxa0=xa00.008). Neurological deterioration occurred during or after RT in 16% of patients and was resolved in most cases with the use of steroids. Grade 3–4 hematologic toxicity occurred in 28% of patients during the adjuvant chemotherapy treatment with temozolomide. The treatment had no negative effect on HRQOL, however, fatigue (Pxa0=xa00.02) and constipation (Pxa0=xa00.01) scales worsened over time. Conclusions Hypofractionated RT followed by temozolomide may provide survival benefit maintaining a good quality of life in elderly patients with GBM. It may represent a reasonable therapeutic approach especially in patients with less favourably prognostic factors.

Transsphenoidal adenomectomy for GH-, PRL- and ACTH-secreting pituitary tumours: outcome analysis in a series of 125 patients

Transsphenoidal surgery (TSS) is a well recognised treatment for secreting pituitary adenomas, however a very wide variation of clinical outcomes and recurrence rates has been reported, depending on the different criteria used to define the cure. We reported the clinical outcome of a large series of patients operated on for a secreting pituitary adenoma according to the most recent stringent criteria of biochemical remission nowadays accepted. One hundred and twenty-five consecutive patients with a secreting pituitary adenoma (42 PRL-, 67 GH- and 16 ACTH-secreting adenomas) who were operated on by the two same neurosurgeons were considered for the study. Biochemical remission of disease was achieved in 56% of patients; 78% for patients with microadenoma and 47% for patients with macroadenomas, respectively. No cases of mortality or major immediate postoperative complications were observed. Tumour size, high hormone levels and dural invasion were significantly correlated to a poor surgical outcome. The recurrence rates ranged between 0 and 24%, being higher for PRL-secreting tumours. In conclusion, TSS is safe and effective in secreting pituitary tumours. It is still the first treatment for GH- and ACTH-secreting adenomas, whereas in patients with prolactinomas, surgery should be reserved for cases of resistance or intolerance to dopamine agonists.

Health-related quality of life in elderly patients with newly diagnosed glioblastoma treated with short-course radiation therapy plus concomitant and adjuvant temozolomide

PURPOSEnTo describe the quality of life (QOL) in elderly patients with glioblastoma (GBM) treated with an abbreviated course of radiation therapy (RT; 40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide (TMZ).nnnMETHODS AND MATERIALSnHealth-related QOL (HRQOL) was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30, version 3) and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20). Changes from baseline in the score of 9 preselected domains (global QLQ, social functioning, cognitive functioning, emotional functioning, physical functioning, motor dysfunction, communication deficit, fatigue, insomnia) were determined 4 weeks after RT and thereafter every 8 weeks during the treatment until disease progression. The proportion of patients with improved HRQOL scores, defined as a change of 10 points or more, and duration of changes were recorded.nnnRESULTSnSixty-five patients completed the questionnaires at baseline. The treatment was consistently associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time; mean score differed by 9.6 points between baseline and 6-month follow-up (P=.03). For social functioning and cognitive functioning, mean scores improved over time, with a maximum difference of 10.4 points and 9.5 points between baseline and 6-month follow-up (P=.01 and P=.02), respectively. By contrast, fatigue worsened over time, with a difference in mean score of 5.6 points between baseline and 4-month follow-up (P=.02).nnnCONCLUSIONSnA short course of RT in combination with TMZ in elderly patients with GBM was associated with survival benefit without a negative effect on HRQOL until the time of disease progression.

Standard (60 Gy) or short-course (40 Gy) irradiation plus concomitant and adjuvant temozolomide for elderly patients with glioblastoma: A propensity-matched analysis

PURPOSEnTo evaluate 2 specific radiation schedules, each combined with temozolomide (TMZ), assessing their efficacy and safety in patients aged ≥65 years with newly diagnosed glioblastoma (GBM).nnnMETHODS AND MATERIALSnPatients aged ≥65 years with Karnofsky performance status (KPS) ≥60 who received either standard (60 Gy) or short-course (40 Gy) radiation therapy (RT) with concomitant and adjuvant TMZ between June 2004 and October 2013 were retrospectively analyzed. A propensity score analysis was executed for a balanced comparison of treatment outcomes.nnnRESULTSnA total of 127 patients received standard RT-TMZ, whereas 116 patients underwent short-course RT-TMZ. Median overall survival and progression-free survival times were similar: 12 months and 5.6 months for the standard RT-TMZ group and 12.5 months and 6.7 months for the short-course RT-TMZ group, respectively. Radiation schedule was associated with similar survival outcomes in either unadjusted or adjusted analysis. O(6)-methylguanine-DNA methyltransferase promoter methylation was the most favorable prognostic factor (P=.0001). Standard RT-TMZ therapy was associated with a significant rise in grade 2 and 3 neurologic toxicity (P=.01), lowering of KPS scores during the study (P=.01), and higher posttreatment dosing of corticosteroid (P=.02).nnnCONCLUSIONSnIn older adults with GBM, survival outcomes of standard and short-course RT-TMZ were similar. An abbreviated course of RT plus TMZ may represent a reasonable therapeutic approach for these patients, without loss of survival benefit and acceptable toxicity.

Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas

To evaluate the efficacy of reirradiation and systemic chemotherapy as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2011, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT) plus systemic therapy at University of Rome Sapienza, Sant’ Andrea Hospital. All patients had Karnofsky performance score ≥60 and were previously treated with standard conformal RT (60xa0Gy) with concomitant and adjuvant temozolomide (TMZ) up to 12 cycles. Thirty-eight patients had a GBM and 16 patients had a grade 3 glioma. The median time interval between primary RT and reirradiation was 15.5xa0months. At the time of recurrence all patients received HSRT (30xa0Gy in 6-Gy fractions) plus concomitant TMZ (75xa0mg/m2/day) followed by continuous TMZ at 50xa0mg/m2 everyday up to 1xa0year or until progression. Median overall survival after HSRT was 12.4xa0months, and the 12- and 24-month survival rates were 53 and 16xa0%, respectively. The median progression-free survival (PFS) was 6xa0months, and the 12- and 24-month PFS rates were 24 and 10xa0%, respectively. KPS >70 (Pxa0=xa00.04) and grade 3 glioma were independent favourable prognostic factors for survival. In general chemoradiation regimen was well tolerated with relatively low treatment-related toxicity. HSRT plus concomitant TMZ followed by continuous dose-intense TMZ is a feasible treatment option associated with survival benefits and low risk of complications in selected patients with recurrent malignant glioma. The potential advantages of combined chemoradiation schedules in patients with recurrent malignant gliomas need to be explored in future studies.

IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy

Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46xa0months (range 12–89xa0months), median and 5-year overall survival rates were 50.5xa0months (95xa0% CI, 37.8–63.2) and 38xa0% (95xa0% CI, 25.7–50.7xa0%), and median and 5-year progression-free survival rates were 36xa0months (95xa0% CI, 28.5–44.0) and 22xa0% (95xa0% CI, 10–34xa0%), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60xa0% of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (Pxa0=xa00.001), MGMT methylation (Pxa0=xa00.01), agexa0<xa050xa0years (Pxa0=xa00.02), and extent of resection (Pxa0=xa00.04) were significantly associated with longer survival. Our study confirms the favorable prognostic value of IDH1 mutation and MGMT methylation in patients with AA treated with RT plus concomitant and adjuvant TMZ. The superiority of combined radiochemotherapy over other treatment modalities remains to be demonstrated.

Brain metastasis from non-seminomatous germ cell tumors of the testis : Indications for aggressive treatment

Brain metastases from non-seminomatous germ cell tumors (NSGCTs) are rare and mainly occur in young men whose clinical condition is unimpaired. The records of 15 patients with brain metastasis from non-seminomatous germ cell tumors of the testis, who had been surgically treated between 1984 and 1998, were retrospectively reviewed. All of the patients had undergone surgery plus whole-brain radiotherapy (WBRT), and chemotherapy based on cisplatin. On admission they had a median age of 33 years and their mean Karnofsky performance scale (KPS) score was >70. Mean survival was 37.7 months. Eight patients had a survival period longer than 5 years. Five patients belonged to radiation therapy oncology group (RTOG) classxa0I; all of them survived. There was a significant difference in survival time between patients in whom the brain metastasis was present at diagnosis (six survivors at 5 years; mean survival 53 months) and patients in whom the brain metastasis occurred during or after chemotherapy (two survivors at 5 years; mean survival 24 months) (P=0.04). The presence of a trophoblastic component at histopathological analysis of the metastasis negatively influenced survival at univariate analysis. Multiple brain metastasis proved to be a significant risk factor at both univariate and multivariate analysis, while a metastatic residue with a diameter less than 2xa0cm after surgery did not negatively affect survival in our series. Prognosis is worst in patients with multiple brain metastases, in whom brain involvement occurred during or after cisplatin-based chemotherapy. Considering that these metastases are often both radiosensitive and chemosensitive, and mainly affect young men that are in very good clinical condition, we advocate aggressive treatment with surgery plus adjuvant radiotherapy and chemotherapy. This is mandatory in patients with large metastases (diameter >3xa0cm).

Stereotactic radiosurgery in elderly patients with brain metastases

Stereotactic radiosurgery (SRS) has been increasingly employed as an alternative to whole brain radiation therapy in patients with brain metastases, with the aim to reduce its potential toxicity. We have evaluated clinical outcomes of SRS as initial treatment for brain metastases in patients 70xa0years and older. Between November 2007 and October 2011, 102 patients of 70xa0years and older with 1–4 metastases were treated with SRS. The primary end point of the study was overall survival. Secondary end points were local control and distant failure rates, cause of death, performance measurements, and toxicity of treatment. At a median follow-up of 11.0xa0months (range 1–48xa0months), median survival and median time to distant failure were 13.2 and 10xa0months, respectively. The 1- and 2-year survival rates were 63 and 28xa0%, and respective distant failure rates were 54 and 78xa0%. Forty-five patients succumbed to their extracranial disease and 14 patients died of progressive intracranial disease. Nine patients recurred locally after SRS. The 1- and 2-year local control rates were 90 and 84xa0%, respectively. Evaluation of neurocognitive function using the Mini-Mental State Examination (MMSE) showed no significant neurocognitive decline after SRS. MMSE score improved in 15xa0% of patients, worsened in 12xa0% of patients, and remained stable in the others. Severe neurological complications were reported in 7 (7xa0%) patients, requiring surgery or medical treatment. Initial treatment with SRS with close monitoring may represent a relatively safe treatment strategy associated with survival benefit, with outcomes similar to those reported in historical series of SRS for younger patients.