The percentage of Epidermal Growth Factor Receptor (EGFR)-mutated neoplastic cells correlates to response to tyrosine kinase inhibitors in lung adenocarcinoma.

BACKGROUND: Epidermal Growth Factor Receptor (EGFR) molecular analysis is performed to assess the responsiveness to Tyrosine Kinase Inhibitors (TKIs) in patients with Non-Small Cell Lung Cancer (NSCLC). The existence of molecular intra-tumoral heterogeneity has been observed in lung cancers. The aim of the present study is to investigate if the percentage of mutated neoplastic cells within the tumor sample might influence the responsiveness to TKIs treatment. MATERIAL AND METHODS: A total of 931 cases of NSCLC were analyzed for EGFR mutational status (exon 18, 19, 20, 21) using Next Generation Sequencer. The percentage of mutated neoplastic cells was calculated after normalizing the percentage of mutated alleles obtained after next generation sequencer analysis with the percentage of neoplastic cells in each tumor. RESULTS: Next generation sequencing revealed an EGFR mutation in 167 samples (17.9%), mainly deletions in exon 19. In 18 patients treated with TKIs and with available follow-up, there was a significant correlation between the percentage of mutated neoplastic cells and the clinical response (P = 0.017). Patients with a percentage of mutated neoplastic cells greater than 56%, have a statistical trend (P = 0.081) for higher Overall Survival (26.3 months) when compared to those with a rate of mutated neoplastic cells lower than 56% (8.2 months). CONCLUSIONS: The percentage of EGFR-mutated neoplastic cells in the tumor is associated with response to TKIs. A "quantitative result" of EGFR mutational status might provide useful information in order to recognize those patients which might have the greatest benefit from TKIs.

New drugs in the treatment of elderly patients with metastatic castration-resistance prostate cancer.

Treatment of prostate cancer is continually evolving and new therapies have become available. However, the management of elderly patients is challenging due to their age and comorbidities. Androgen deprivation therapy remains the mainstay treatment of hormonal-sensitive disease. Nevertheless, when disease becomes resistant to castration, docetaxel-based chemotherapy represents the standard rescue therapy irrespective of patient age. Recently, chemotherapeutic agents such as cabazitaxel and hormonal therapies such as abiraterone acetate and enzalutamide have been shown to improve survival in patients with progression of disease before or following docetaxel. This review focuses on the safety and efficacy results of these new drugs in elderly patients.

A Randomized Controlled Trial of Tong Len Meditation Practice in Cancer Patients: Evaluation of a Distant Psychological Healing Effect.

CONTEXT: Tong Len meditation is an important therapeutic tool in the Tibetan medicine, and it can be used for self-healing and/or to heal others. Currently, in the West, there is no scientific study concerning the efficacy of a Tong Len distant healing effect on psychological disorders in cancer patients. OBJECTIVES: To evaluate a distant healing effect of Tong Len meditation on stress, anxiety, depression, fatigue, and self-perceived quality of life in cancer patients. These psychological objectives were chosen as a consequence of the limited scientific literature of present day. DESIGN: We performed a double-blind randomized controlled trial on 103 cancer patients with tumors. Overall, 12 meditators used Tong Len in aid of 52 patients randomly selected as experimental group, while the remaining 51 patients constituted the control group. Patients and meditators did not know each other. All patients completed profile of mood states (POMS) and European Quality of Life-5 dimensions (EQ-5D) questionnaires before treatment (T0), after two (T1) and three months of treatment (T2), and one month after treatment cessation (T3). RESULTS: With regard to the parameters related to depression, a statistically significant improvement (P = .003) was observed in the treatment group compared to controls. On the other hand, the vigor/activity parameter saw significant improvements in the control group (P = .009). Both groups exhibited significant improvements in the other factors assessed in the POMS and EQ-5D questionnaires. CONCLUSIONS: This study did not provide sufficient evidence supporting an efficacy of Tong Len meditation in distant psychological healing as compared to a control condition. The research highlighted some psychological improvements through Tong Len distant meditation in a group of patients unknown to meditators. Therefore, the enhancement detected in most parameters in both treatment and control groups raises interest on in-depth analysis and evaluation of distant meditation on cancer patients to mitigate psychological problems caused by the disease.

Maintenance therapy in non-small cell lung cancer.

Several randomized trials have investigated the role of maintenance treatment for patients with advanced non-small cell lung cancer (NSCLC) not progressed after completion of first-line chemotherapy, with good performance score (PS) and no persistent chemotherapy-induced toxicity. Two separate strategies have been developed: the immediate use of non-cross-resistant drug (switch maintenance or early second-line therapy) or the continuation of platinum partner alone (continuation maintenance) or in combination with other drug (combination maintenance). Here we discuss how the benefits demonstrated in these studies may change clinical practice (in terms of potential toxicity and costs) and reflect on factors that may identify subgroups of patients who might benefit from maintenance therapy in general, and which maintenance therapy specifically.

Outcomes of Platinum-Sensitive Small-Cell Lung Cancer Patients Treated With Platinum/Etoposide Rechallenge: A Multi-Institutional Retrospective Analysis.

UNLABELLED: Small-cell lung cancer has a high chemotherapeutic sensitivity but with disappointing outcome results. Patients with "sensitive disease" are those who respond to treatment with a long relapse-free interval (RFI): in these cases rechallenge with first-line chemotherapy might represent a therapeutic opportunity. Our largest retrospective experience confirmed that rechallenge is feasible with interesting outcome results; there are no statistical differences between RFI and outcome. INTRODUCTION: Patients with small-cell lung cancer (SCLC) that progresses after first-line (FL) chemotherapy have a poor prognosis and second-line (SL) chemotherapy has limited efficacy. Patients whose disease relapses/progresses > 90 days after FL platinum-based treatment are considered platinum-sensitive and could be rechallenged with a similar regimen. We conducted a multicenter retrospective analysis to evaluate outcomes of SCLC patients rechallenged with platinum/etoposide. PATIENTS AND METHODS: Records of all SCLC patients treated in 7 institutions between January 2007 and December 2011 were reviewed. The primary end point was overall survival from the time of rechallenge (OS-R); secondary end points were progression-free survival (PFS) and overall survival from the time of diagnosis (OS-D). Survival curves were calculated using the Kaplan-Meier method. RESULTS: Of the 2000 SCLC patients identified, 112 (5.6%) had sensitive disease treated with rechallenge platinum/etoposide; 65% were men with a median age of 64 years. At the time of diagnosis, 44% of patients had limited disease, 82% had an Eastern Cooperative Oncology Group performance status of 0 to 1. A median of 4 cycles of rechallenge was administered. Tumor response was 3% for complete response and 42% for partial response, 19% of patients maintained stable disease, 27% progressive disease, and 9% were not evaluable. Median PFS from the time of rechallenge was 5.5 months (95% confidence interval [CI], 4.4-6.3). Median OS-R and OS-D were 7.9 months (95% CI, 6.9-9.7) and 21.4 months (95% CI, 19.8-24.1), respectively. Subgroup analysis according to relapse-free interval (90-119 vs. 120-149 vs. > 150 days) did not show any statistically significant difference in PFS or OS-R. CONCLUSION: The outcome for SL chemotherapy for SCLC is poor. Rechallenge platinum/etoposide is a reasonable option with potentially better outcomes than standard chemotherapy.

A commentary on interstitial pneumonitis induced by docetaxel: clinical cases and systematic review of the literature.

BACKGROUND: Pulmonary toxicity is a well-known complication observed with several anticancer drugs. Docetaxel, a taxane chemotherapy drug widely used in the treatment of many types of solid tumors including non-small cell lung cancer (NSCLC), rarely causes infiltrative pneumonitis. The exact mechanism by which docetaxel develops this side effect is not well understood; probably it is produced by type I and IV hypersensitivity responses. Here we describe 2 cases of infiltrative pneumonitis induced by docetaxel as second-line chemotherapy in advanced NSCLC. MATERIALS AND METHODS: Two patients with advanced NSCLC were treated with weekly docetaxel as second-line chemotherapy. After 3 courses of chemotherapy, restaging computed tomography (CT) of the chest revealed bilateral diffuse ground-glass opacities with a peribronchial distribution possibly indicative of hypersensitivity pneumonitis. No evidence of pulmonary embolus or pleural effusion was found. Fiberoptic bronchoscopy showed normal bronchi without lymphangitis; biopsies showed interstitial fibrosis without tumor cells. Bronchial tissue laboratory tests for fungi or bacilli were negative. No malignant cells were found at bronchoalveolar lavage. The patients were given high-dose corticosteroid therapy with prednisone 0.7 mg per kilogram per day. RESULTS: After 1 month of therapy, contrast-enhanced chest CT showed complete disappearance of the pulmonary changes in both patients. Spirometry and blood gas analysis revealed complete recovery of pulmonary function. The patients continued their oncological follow-up program. CONCLUSIONS: Pulmonary injury is a rare adverse event during docetaxel chemotherapy. Prompt treatment with high-dose corticosteroids is needed to avoid worsening of respiratory performance.

Third- and further-line therapy in advanced non-small-cell lung cancer patients: an overview.

Non-small-cell lung cancer (NSCLC) treatment has led to improved efficacy and compliance due to individual tailoring of the therapeutic options and the use of strategies based on both clinical characteristics and histological and biological features of the disease. In nonsquamous NSCLC, novel agents, such as pemetrexed and bevacizumab, have improved survival in the first-line setting. Maintenance therapy with pemetrexed and erlotinib resulted in improved progression-free survival compared with second-line therapy at disease progression. In the second-line setting, pemetrexed improves survival in nonsquamous NSCLC compared with docetaxel, and erlotinib has shown a survival benefit compared with best supportive care in patients who did not previously receive an EGF receptor inhibitor. Although the benefit of first- and second-line treatment over best supportive care alone has been firmly established, the role of further-line treatment remains controversial. This article summarizes the state-of-the-art treatments in this setting.

Correlations between O6-methylguanine DNA methyltransferase promoter methylation status, 1p and 19q deletions, and response to temozolomide in anaplastic and recurrent oligodendroglioma: a prospective GICNO study.

PURPOSE: To date, no data are available on the relationship between 1p/19q deletions and the response to temozolomide (TMZ) in primary anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) recurrent after surgery and standard radiotherapy. The aim of this study was to evaluate correlations between 1p/19q deletions, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, and response rate to TMZ in this setting. PATIENTS AND METHODS: From June 2000 to February 2005, 67 patients were enrolled; 39 patients (58%) had AO and 28 patients (42%) had AOA. All patients received 150 to 200 mg/m2 of TMZ every 28 days. Chromosome 1p and 19q deletions were detected by fluorescence in situ hybridization and MGMT promoter methylation was analyzed using methylation specific polymerase chain reaction. RESULTS: The overall response rate was 46.3% (17 complete responses and 14 partial responses). The response rate was higher in patients with AO than in those with AOA (61.5% v 25%, P = .003). Combined 1p/19q allelic loss was found in 32 patients (47.8%), while MGMT methylation occurred in 37 (68.5%) of 54 assessable patients. 1p/19q loss was significantly correlated with response rate (P = .04), time-to-progression (P = .003), and overall survival (P = .0001). Despite the significant concordance found between MGMT promoter methylation and 1p/19q deletions (P = .02), MGMT promoter methylation showed only a borderline correlation with overall survival (P = .09). CONCLUSION: TMZ is active in anaplastic oligodendroglial tumors treated at first recurrence. In this setting, 1p/19q allelic loss is an important predictive and prognostic factor. Further studies on MGMT promoter methylation should be performed in randomized trials to test its correlation with survival.

Carboplatin and etoposide (CE) chemotherapy in patients with recurrent or progressive oligodendroglial tumors.

BACKGROUND: Oligodendroglial tumors are rare and chemosensitive diseases; but the overall results with current chemotherapy regimens cannot be considered satisfactory and other active treatments are necessary. We decided to determine the efficacy and toxicity profile of the carboplatin and etoposide (CE) regimen in this setting. METHODS: In this phase II trial we evaluated the response rate of first or second line CE regimen (Carboplatin AUC 5 on day 1 and Etoposide 120 mg/m2 on days 1-3 every 28 days) in patients with recurrent/progressive oligodendroglial tumors. RESULTS: Thirty-two patients were enrolled. Median age was 42 years (range 22-66); median ECOG PS was 0 (range 0-2); 9 patients had oligodendroglioma, 3 patients had oligoastrocytoma, 11 patients had anaplastic oligodendroglioma, 9 patients had anaplastic oligoastrocytoma. CE regimen showed a response rate of 46.9% with 5 complete responses (15.6%) and 10 partial responses (31.3%). Eleven patients (34.4%) had stable disease. Median time to progression was 8 months, progression-free survivals at 6 and 12 months were 80% and 46.9%, respectively. Toxicity was mainly hematological, with grade 3-4 neutropenia in 5 (15.6%) patients. CONCLUSIONS: In this trial CE regimen has shown relevant activity with a favourable safety profile.

Paclitaxel, cisplatin and 5-fluorouracil in recurrent squamous cell carcinoma of the head and neck: a phase II trial from an Italian cooperative group.

The aim of this multicenter trial was to test the feasibility and the activity of a three-drug combination where paclitaxel is added to cisplatin and 5-fluorouracil. Patients with metastatic or relapsed SCC-HN unsuitable for further loco-regional radical treatment, not previously treated with chemotherapy, were eligible to receive paclitaxel 160 mg/m2 (3-hr infusion) day 1, CDDP 25 mg/m2/day and 5-FU 250 mg/m2/day bolus on days 1, 2, 3 every three weeks up to a maximum of five courses. Fourty-seven patients were enrolled by five Institutions in Italy. Main grade III-IV toxicities were: neutropenia (48%), thrombocytopenia (6%), anemia (4%), diarrhea (2%), mucositis (2%). Six patients had a complete response (13.3%) and eight a partial response (17.8%). Median progression free survival and overall survival are 4.1 and 7.9 months. One-year progression free survival and overall survival are 16% and 29%. This three-drug regimen has an excellent safety profile. The activity in the palliation of recurrent SCC-HN, however, does not appear to be improved in comparison with cisplatin and 5-fluorouracil or cisplatin and paclitaxel regimens. Recent studies indicate a more promising role of taxanes including triplets in the induction therapy of previously untreated patients.

Temozolomide-induced partial response in a patient with primary diffuse leptomeningeal gliomatosis.

Herein we describe the case of a patient with primary diffuse leptomeningeal gliomatosis (PDLG). After surgery and ventriculoperitoneal shunt placement, due to poor general conditions, the patient was not eligible for radiotherapy. For this reason we decided to start a systemic chemotherapy treatment with Temozolomide (150 mg/m2 per day for 5 days every 4 weeks). After three cycles a partial response was achieved with a clear improvement of general conditions. In our knowledge, this is the first time that PDLG treatment with Temozolomide has been described.

A multicenter retrospective study of chemotherapy for recurrent intracranial ependymal tumors in adults by the Gruppo Italiano Cooperativo di Neuro-Oncologia.

BACKGROUND: No data on the role of chemotherapy in recurrent ependymal tumors are available in adults. The aim of the current study was to investigate outcomes after salvage chemotherapy in this setting. METHODS: A retrospective review was made of the charts of 28 adults (> or = 18 years) with progressive or recurrent ependymal tumors after surgery and radiotherapy, who received chemotherapy between 1993 and 2003 in 3 institutions of the Gruppo Italiano Cooperativo di Neuro-Oncologia network. RESULTS: Thirteen patients (46.3%) received cisplatin-based chemotherapy (Group A) and 15 (53.7%) received regimens without cisplatin (Group B). Platinum-based chemotherapy yielded 2 complete responses (CR) (15.4%) and 2 (15.4%) partial responses (PR), whereas 7 patients (53.8%) remained stable (SD). After regimens without cisplatin, there were no CR, 2 PR (13.3%), and 11 SD (73.3%). The overall median time to progression was 9.9 months (95% confidence interval [95% CI], 7.5-21.7 months), 9.9 months (5.2-not reached) for Group A and 10.9 months (95% CI, 7.17-23.9 months) for Group B. The overall median survival (OS) was 40.7 months (95% CI, 16-not reached), 31 months (21-not reached) for Group A and 40.7 months (13.4-not reached) for Group B. CONCLUSIONS: Cisplatin-based chemotherapy achieved a higher response rate, but did not prolong disease progression-free survival or OS. More active regimens for the salvage treatment of ependymal tumors have yet to be found.

First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia.

PURPOSE: Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O(6)-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival. PATIENTS AND METHODS: Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days. RESULTS: A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%). CONCLUSION: The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

A multicenter study of the prognosis and treatment of adult brain ependymal tumors.

BACKGROUND: The current analysis of outcomes in a large series of adult patients with intracranial ependymal tumors contributes to the characterization of the primary prognostic factors and to the therapeutic management of this rare disease, for which limited information is available in the literature. METHODS: The authors analyzed data on patient and tumor characteristics, treatment, and survival in a series of 70 patients age > 17 years with pathologic diagnoses of brain ependymal tumors from 4 institutions. RESULTS: The 5- and 10-year overall survival (OS) rates (+/- standard errors) were 67% +/- 6% and 50% +/- 8%, respectively. The 5- and 10-year failure-free survival (FFS) rates were 43% +/- 7% and 24% +/- 6%, respectively. Younger age and infratentorial tumor location were associated with longer survival. Among patients with Grade 2 ependymoma (n = 51), 21 (41%) received no postsurgical treatment. These 21 patients had a 5-year OS rate of 78% +/- 10% and a 10-year OS rate of 68% +/- 13%; the 5- and 10-year FFS rates for these patients were 47% +/- 12% and 12% +/- 11%, respectively. Twenty-six patients with Grade 2 ependymoma (51%) received postoperative radiotherapy (RT). These 26 patients had a 5-year OS rate of 71% +/- 9% and a 10-year OS rate of 59% +/- 11%; the 5- and 10-year FFS rates for these patients were 54% +/- 10% and 34% +/- 10%, respectively. Among patients with Grade 2 ependymoma, neither OS nor FFS differed significantly between those who did not receive postoperative RT and those who did; however, these two groups were heterogeneous with respect to prognostic factors. On multivariate analysis, RT use exhibited a trend toward improved OS and was significantly predictive of improved FFS. CONCLUSIONS: The current analysis does not rule out the possibility that deferral of RT at the time of recurrence could have a detrimental effect on FFS or OS in patients with Grade 2 ependymoma, regardless of the degree of ablation. The role of postoperative RT for patients who undergo imaging-based macroscopic total resection remains to be addressed.