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We report the case of a 34-year-old woman affected by breast cancer that had metastasized to the bone. She had been treated with oral cyclophosphamide and methotrexate (metronomic chemotherapy) and achieved 3.5 years of clinical remission. To our knowledge, this is the first description of such a prolonged response to therapy. This case report adds weight to known data on metronomic treatment and supports further investigation of this therapy. [ABSTRACT FROM AUTHOR]

Aim: to appraise the role of volumetric-modulated arc therapy (VMAT) in the neoadjuvant chemoradiotherapy management of advanced medium and distal oesophageal cancer in terms of toxicity and response to treatment., Patients and Methods: Thirty patients were treated according to the neoadjuvant chemoradiation followed by surgery versus surgery-alone trial scheme with VMAT radiation therapy. Patients presented mainly T3-T4 stage (80%) and N1-2 (96.6%) disease. The chemotherapy scheme consisted of 3-5 cycles, while a radiotherapy course of 41.4 Gy in 23 fractions was administered to all patients., Results: The median age of patients was 65 years, and there was a predominance of males (80%), smokers or ex-smokers (90%) and modest alcohol habit (80% negative). Primary tumor localisation was in the medium and distal third of the oesophagus in 57% of the cases, the rest being in the gastro-oesophageal junction. Modest toxicity profiles were observed, with limited incidence of grade 2-3 events. Partial or complete response was observed in more than 90% of the cases (radiological/metabolic) and was confirmed after surgical intervention (67% partial or complete and 27% stable response). Tumor down-staging was recorded in 67% of patients and nodal down-staging in 50%., Conclusion: VMAT was applied in the context of neoadjuvant chemoradiotherapy for the treatment of medium and distal oesophageal carcinoma with satisfactory results in terms of tolerance and toxicity., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Unlabelled: Brain metastases from Non-Small Cell Lung Cancer are usually associated with poor prognosis and up to now chemotherapy has shown a modest activity upon cerebral localizations. We investigated the role of Pemetrexed, a new, well tolerated multi-target antifolate, on brain metastases., Patients and Methods: We collected 39 patients with evidence of cerebral nervous system (CNS) localizations from Non-Small Cell Lung Cancer (NSCLC) before starting treatment with Pemetrexed as second-line or further-line therapy., Results: We confirmed the good tolerability of Pemetrexed even in that setting of patients and we reported a progressive disease (PD) in 12 patients (30.8%), a stable disease (SD) and partial response (PR) in 12 (30.8%) and 15 (38.4%) patients respectively, with an overall clinical benefit obtained in 69% of patients. The cerebral response to Pemetrexed was interesting with a cerebral radiological benefit obtained in 32 patients (82%), while 7 patients only showed brain progressive disease. Overall median survival was 10 months. All irradiation-naïve patients and those with clear radiological evidence of cerebral progression after brain radiotherapy and before Pemetrexed, overall 22 patients, were included in one group, in order to avoid overlapping effects between brain radiotherapy and Pemetrexed over CNS localizations. Within that setting, we demonstrated an overall clinical benefit (SD+PR) and cerebral benefit in 63% and 68%, of patients respectively. Distribution of patients by overall response to Pemetrexed and CNS response was highly suggestive of activity of Pemetrexed on brain metastases., Conclusion: We demonstrated the good tolerability of Pemetrexed even in patients with advanced NSCLC and brain metastases, and we found a very good overall response rate with evidence of activity on brain localizations., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Several drugs have been approved for the treatment of patients affected by advanced non-small cell lung cancer (NSCLC) in progression after first line chemotherapy: Docetaxel, Pemetrexed and Erlotinib. Poor gain of survival has been demonstrated in randomised trials and patient characteristics predicting activity are poorly known yet. We evaluated the activity and toxicity of Pemetrexed, in a post-registration phase, to assess whether clinical benefits justify its employment in a second-line setting in routine clinical practice., Patients and Methods: We collected data on patients with advanced NSCLC treated with Pemetrexed 500mg/m(2) every 21 days, after progression to prior chemotherapy., Results: One hundred and sixty patients from 4 different Italian Institutions, treated with Pemetrexed, mostly as second-line therapy, were analysed. There was a predominance of males versus females, adenocarcinoma versus other histologies; the median age was 63.6 years. The toxicity profile was extremely mild and the response rate (11.2% patients in complete or partial response) was similar to previous reports from the literature. The median overall survival, 12 months, was better than previously reported., Conclusion: Improved efficacy and mild toxicity observed in this clinically relevant patient population confirms Pemetrexed as an interesting choice in second-line treatment of NSCLC. Patient characteristics alone are not able to predict response to Pemetrexed.

Background: Pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM., Methods: From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. Gemcitabine 1000 mg/m(2) and vinorelbine 25 mg/m(2) were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity., Results: A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1-26.5%), and 10 patients (33.3%; 95% CI, 17.3-52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5-62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6-12.1 months), and the median survival was 10.9 months (range, 0.8-25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild., Conclusions: The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors.

Methylation of tumor suppressor genes is among the most frequent alterations in patients with malignant pleural mesothelioma (MPM). The aim of this study was to analyze the promoter methylation status of four tumor suppressor genes, p15(INK4B), p16(INK4A), RASSF1A and NORE1A in MPM. Samples of 79 MPM patients were analyzed using a methylation-specific PCR method. Associations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined. The analysis documented methylation in 30 cases (38%). The methylation frequency for individual genes was 19% for p15(INK4B) (n=15), 11.4% for p16(INK4A) (n=9), 20.2% for RASSF1A (n=16) and 5.1% for Nore1A (n=4). In the whole series methylation was associated to an increased proliferation index (P=0.05). In patients treated with extrapleural pneumonectomy, methylated MPM showed a trend to a poorer OS in comparison to unmethylated cases (median OS 16 months vs. 35 months, P=0.06, HR=2.01, 95% CI 0.95-4.30). In the overall population, methylation did not correlate to patient outcome but a trend to an improved survival was detectable in ummethylated MPM treated with extrapleural pneumonectomy. This result suggests the need to select homogeneously treated and staged patients with MPM to address whether their methylation profile may impact on patient's survival.

Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). Several platinum-based doublets have been tested in phase II/III trials with equivalent results in terms of tumour response and survival. Our study was designed to evaluate activity, tolerability and convenience of alternating intravenous (i.v.) and oral vinorelbine in combination with cisplatin in advanced NSCLC. Forty chemo-naive patients with stage IV or relapsed unresectable disease and good performance status were enrolled to receive i.v. cisplatin 40 mg/m(2) on days 1 and 2 plus i.v. vinorelbine 25 mg/m(2) on day 1, every 3 weeks. Oral vinorelbine 60 mg/m(2) was given at home on day 5, without checking of blood cell count. A total of 175 treatment cycles were delivered. The overall response rate was 30% (one complete, 11 partial responses). Median time to progression and overall survival were 5 and 10 months, respectively. The main toxicity was haematological, with grade 3-4 neutropenia observed in 75% of patients, without febrile neutropenia. Non-haematological toxicity was mild. This schedule of cisplatin and vinorelbine treatment showed a good toxicity profile and an efficacy similar to other standard regimens. Oral vinorelbine could be administered safely at home on day 5.

Intra-arterial chemotherapy in patients with liver metastases from colorectal cancer has some limitations such as hepatic toxicity and extra-hepatic progression. With the aim of overcoming these limitations, a phase II trial was designed to assess the efficacy and tolerability of a hybrid chemotherapy regimen with systemic infusion of oxaliplatin and folinic acid associated with intra-arterial 5-fluorouracil. Thirty-nine patients with colorectal liver metastases were recruited. The median age was 59 years, 30 patients (77%) had synchronous metastases, and half of the patients were chemo-naive. A total of 313 chemotherapy cycles were administered (median number 8). Treatment was well tolerated and hepatic toxicity negligible. Out of 34 evaluable patients an ORR of 41%. was observed. Eight patients (21%) underwent radical liver surgery. The median time to progression (TTP) was 10 months (range 2-63) and the median overall survival (OS) 21 months (range 6-63). Extra-hepatic progression was observed in six patients. Our results suggest that this regimen is active even if technical complications are frequent. Our aim to reduce hepatic toxicity and extra-hepatic progression was reached.

The EGF receptor (EGFR) is one of the most important targets for cancer treatment implicated in the control of cell survival, proliferation and metastasis. In the last few years different EGFR molecular antagonists have been evaluated in the clinical setting and some of these drugs have demonstrated clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Gefitinib or erlotinib are a new class of compounds able to inhibit the tyrosine kinase domain of EGFR (EGFR TKI) and, during recent years, clinical and biologic predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, and EGFR gene mutation or EGFR increased gene copy number represent critical biologic variables associated with an improved outcome for patients exposed to these agents. Unfortunately, cancer cells possess escape mechanisms to overcome inhibition of cell proliferation leading to drug resistance. There are several mechanisms that have been identified as responsible for intrinsic or acquired resistance. The aim of the present review is to analyze available data in order to identify an optimal paradigm for patient selection.

Gemcitabine is a novel pyrimidine nucleoside antimetabolite agent that is active, either as monotherapy or in association with other cytotoxic compounds, in pancreatic, ovarian, breast, bladder and non-small-cell lung cancer. The drug has an acceptable toxicity profile with myelosuppression being the most common adverse event. Pharmacoeconomic assessments have been performed in order to determine whether gemcitabine is a cost effective cancer treatment. Several cost analyses have investigated gemcitabine in association with cisplatin in the treatment of non-small-cell lung cancer, indicating that the combination is cost effective when compared with either old- or new-generation platinum-based treatments. Results in other malignancies are not corroborated by the same quality of evidence, therefore more extensive analyses are warranted. Overall, available data indicate that accurate selection of patients and careful cost analyses should be included in the development of new anticancer drugs for an appropriate use of limited healthcare resources.

Objective: There is little information on Herpes zoster infection in breast cancer patients as a complication during adjuvant chemotherapy. The aim of this study is to evaluate the incidence of Herpes zoster and simplex infections in this patients setting., Methods: We analyzed 623 early-stage breast cancer patients in our Institute over a period of 7 years (1998-2005). Four-hundred and sixty-one patients were treated with anthracycline-based chemotherapy, 116 with CMF and 46 with taxane-containing regimens., Results: Twelve (1.9%) developed herpes zoster; 9 patients, receiving anthracycline-based chemotherapy, two taxane-containing regimens, and one CMF regimen. Herpes zoster infection required treatment delay in 6 patients. Adjuvant chemotherapy was delayed for 1 week in 2 patients, while in 4 patients with more severe symptoms chemotherapy was delayed for 2 weeks. One patient, despite i.v. acyclovir, had severe postherpetic motor neuropathy with a permanent ambulation impairment, and chemotherapy was stopped. In our study, herpes zoster occurred in 55/1,000 cases/year. The reported incidence in the general population varies between 2.2 and 4.1 per 1,000 patients/year; therefore, the risk of developing herpes zoster in these patients may be 13- to 25-fold higher compared to the incidence in the general population. In addition, 13 of 623 patients developed herpes simplex., Conclusion: Our findings suggest that adjuvant chemotherapy can facilitate reactivation of herpes infection.

In this phase II study, 23 patients with metastatic breast cancer were treated with a combination of Caelyx (40 mg/m2 on day 1) and vinorelbine (20 mg/m2 on days 1 and 8) every 4 weeks. According to the statistical design, enrollment was closed after the first stage due to the low response rate observed (four partial remissions, 12 stabilizations). Toxicity was acceptable, however, grade 3-4 neutropenia was not negligible. Our study does not support the development of this combination in advanced breast cancer.

Objective: This study included patients with inoperable primary or recurrent cervical cancer whose treatment plan called for exclusive radiotherapy. The endopoints of the study were to confirm the feasibility of concurrent radiotherapy and paclitaxel in relation to potential acute toxicity and to evaluate if an increase of complete local control might be obtained with the association of paclitaxel to radiotherapy as a radiosensitizer., Methods: Twenty patients (13 new cases, stage IIB-III, and 7 with pelvic recurrences) were enrolled and, with exclusion of one recurrence, 19 were evaluable for acute toxicity and response. In new cases, radiotherapy was conventionally administered: 50.4 Gy/28 fractions by external beam (whole pelvis) followed by intracavitary cesium or reduced transcutaneous field. In recurrences, radiotherapy was performed with external beam only through individualized fields. Paclitaxel was administered weekly at the dose of 40 mg/m2 or 60 mg/m2 during the entire course of external radiotherapy., Results: Complete regression (CR) as defined by clinical and imaging examinations was achieved in eight of the 13 new cases (62%) and in four of the six recurrences (66%), for a total complete response rate equal to 63%. Five patients (3 treated with 40 mg/m2 and 2 with 60 mg/m2) experienced grade 3 small bowel toxicity, one patient treated with 40 mg/m2 grade 3 bladder toxicity and one patient treated with 60 mg/m2 had grade 4 mucositis. Out of 12 CR patients at the end of treatment, ten maintain complete local remission for a median follow-up of 47 months but two have developed distant metastases., Conclusion: The results confirm that this approach is feasible and suggest the use of paclitaxel as radiosensitizer in locally advanced cervical cancer.

After a long period in which the only therapeutic approach for the management of colorectal cancer was the optimization of fluoropyrimidine-based chemotherapy, the last few years have seen the emergence of newly active chemotherapeutic agents endowed with novel mechanisms of action, such as oxaliplatin (OHP), irinotecan (CPT11), raltitrexed and oral 5-fluorouracil (5-FU) pro-drugs which can offer new therapeutic possibilities. The availability of these different classes of cytotoxic agents has introduced the possibility of combination chemotherapy. The most widely studied combinations are 5-FU/folinic acid (FA)/CPT11 and 5-FU/FA/OHP, both of which have been tested in two randomized studies. These trials consistently demonstrated that the addition of CPT11 or OHP to widely accepted infusional/bolus 5-FU/FA regimens is superior to the same 5-FU/FA schedule alone in term of response rate (rate of about > 50%) and time to progression. It's worth nothing that both trials with the combination of 5-FU/FA/CPT11 showed a significant survival benefit. Toxicity profiles were more pronounced with the combination therapies but the quality of life evaluation showed that the combinations had no negative impact on the evolution of the global health status over time. A current ongoing randomized study compares 5-FU/FA/CPT11 with 5-FU/FA/OHP in order to identify the best first-line chemotherapy. Preliminary results in terms of objective response and toxicity are similar for both treatments. Raltitrexed is a thymidilate synthase inhibitor with activity comparable to 5-FU and a convenient administration schedule. In our institution, we performed a phase II single center trial to assess the efficacy of the combination of raltitrexed and CPT11. The principal aim of the study was the overall response rate. We observed a very promising 51% overall response rate. Most relevant side effects were diarrhea in about 20% of patients, asthenia and vomiting. Two recent studies have assessed the efficacy and tolerability of raltitrexed-OHP combination therapy. The results showed that the combination is active (ORR: 46-62%) and tolerable. Promising results have also been obtained in phase I studies with the OHP/CPT11 combination. All these data need to be confirmed in phase II-III clinical trials. In conclusion, combination therapy with CPT11 plus 5-FU/FA produces a 2-3 month survival advantage over 5-FU/FA alone and represents the new reference in the first-line chemotherapy of colorectal cancer. The association of 5-FU/FA and OHP improves response rates and progression-free survival. The increase in toxicity of these combinations is predictable and reversible and does not compromise quality of life. These important data suggest that there is now a limited role for single-agent first-line chemotherapy of metastatic colorectal cancer.