In Vivo MR Imaging of Fibrin in a Neuroblastoma Tumor Model by Means of a Targeting Gd-Containing Peptide.

PURPOSE: A magnetic resonance imaging contrast agent based on a tetrameric Gd-DTPA-like system linked to a fibrin-targeting peptide (Gd-F) has been designed for in vivo tumor characterization. PROCEDURES: Gd-F was synthesized following Fmoc-SPPS strategy. Binding was measured using soluble fibrin DD(E) fragment and a dried fibrin assay. Contrast efficiency was tested on human and mouse clots and in vivo on Neuro2A tumor model. An anti-thrombotic drug was used to evaluate Gd-F sensitivity for changes in fibrin availability at the tumor site. RESULTS: The high relaxivity of Gd-F (42 mM(-1) s(-1), per molecule) yielded a strong signal enhancement in human and murine clots. High contrast was also measured in vivo in Neuro2A tumors, with a persistent enhancement in tumor rim and stroma. Upon treatment with an anti-thrombotic drug, the contrast uptake was significantly reduced in the tumor area confirming the specificity of the probe. CONCLUSIONS: Gd-F resulted to be an efficient probe for tumor delineation and for monitoring fibrin deposits during tumor progression and anti-thrombotic therapy.

Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial.

BACKGROUND: We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT). PATIENTS AND METHODS: mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups. RESULTS: Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2-10.3] and 8.4 (95% CI 7.2-9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70-1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. CONCLUSIONS: The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population. CLINICAL TRIAL NUMBER: NCT01878422.

Biophysical stimulation and the periprosthetic bone: is there a rationale in the use of Pulsed Electromagnetic Fields after a hip or knee implant?

The biophysical stimulation of bone and cartilage, using Pulsed ElectroMagnetic Fields (PEMF), covers many different aspects of bone formation and/or cartilage repair, such as healing of delayed or non-union of fracture, bone necrosis, osteocartilagineous defects. To date there are no specific data on the effects of PEMFs in osteointegration of prosthetic implants but there are some papers that denote clinical advantages, in terms of early recovery, in patients treated with these procedures. Considering these clinical applications, PEMF stimulation around hip or knee joint implants could be useful to reduce the bone oedema, pain and to reduce excessive bone reabsorption around the femoral stems.

Non-pegylated liposome-encapsulated doxorubicin citrate plus cyclophosphamide or vinorelbine in metastatic breast cancer not previously treated with chemotherapy:a multicenter phase III study.

We conducted a phase III multicenter randomized trial to compare the efficacy of the combination of liposome encapsulated doxorubicin (Myocet(©)) plus either cyclophosphamide (MC) or vinorelbine (MV). Since July 2006, 233 patients affected with metastatic breast cancer were randomized to receive the combination of Myocet (M) 60 mg/m(2) i.v. plus cyclophosphamide (C) 600 mg/m2 on Day 1 of a 21­day cycle (Arm A) or Myocet (M) at 50 mg/m2 plus vinorelbine (V) 25 mg/m2 i.v. on Day 1 and V 60 mg/m2 orally on Day 8 on a 21­day cycle (Arm B). The primary endpoints of the study was time to progression (TTP); secondary endpoints were RR, toxicity and OS. Response was observed in 53/116 (45.7%) evaluable patients of Arm A vs. 51/112 (45.5%) of Arm B, respectively (P=NS). Median TTP was 41 weeks (95% CI, 32­51) and 34 weeks (95% CI, 26­39), for M/C and M/V, respectively (P=0.0234). The difference in median OS was not statistically significant (131 vs. 122 weeks; P=0.107). With regard to toxicity, patients treated with MV showed a slight increase of neutropenia and constipation, as compared to those treated with MC. No clinical signs of cardiotoxicity were observed. The MC combination remains as an unbeaten 'standard' in first line treatment of MBC.

A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy.

BACKGROUND: Antiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). NEPA is a new oral fixed-dose combination of 300 mg netupitant, a highly selective NK1 receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA, which targets dual antiemetic pathways. PATIENTS AND METHODS: This multinational, randomized, double-blind, parallel group phase III study (NCT01339260) in 1455 chemotherapy-naïve patients receiving moderately emetogenic (anthracycline-cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of NEPA versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on day 1 only (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed (25-120 h) phase in cycle 1. RESULTS: The percentage of patients with CR during the delayed phase was significantly higher in the NEPA group compared with the PALO group (76.9% versus 69.5%; P = 0.001), as were the percentages in the overall (0-120 h) (74.3% versus 66.6%; P = 0.001) and acute (0-24 h) (88.4% versus 85.0%; P = 0.047) phases. NEPA was also superior to PALO during the delayed and overall phases for all secondary efficacy end points of no emesis, no significant nausea and complete protection (CR plus no significant nausea). NEPA was well tolerated with a similar safety profile as PALO. CONCLUSIONS: NEPA plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, NEPA along with a single dose of DEX on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.

Patients attitudes towards sleep disturbances during chemotherapy.

Sleep disturbances are among the most distressing symptoms in cancer: they often co-occur with fatigue, pain and psychological distress. Despite the negative impact on quality of life, patients rarely seek help for managing their sleep disturbances. This paper presents the results of a multicentre observational study on patients' attitudes towards their sleep problems. The study also investigates symptom correlates. Patients responded to a semi-structured interview and completed the following questionnaires: Pittsburgh Sleep Quality Index; Brief Fatigue Inventory; Hospital Anxiety and Depression Scale; and European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life QLQ-C30 Questionnaire (QLQ-C30). Four hundred and three cancer patients were enrolled in the study. Bad sleepers constituted 66% of the sample. Thirty-eight per cent of them had not turned to any professional to solve their sleep disturbances because they had various beliefs about the importance of the problem and the possibility to be treated. The main correlates of sleep disturbances were psychological distress, reduced physical functioning and reduced overall quality of life. In conclusion, there is a need to sensitise patients to actively search for a solution to their sleep disturbances so they can be solved along with other co-occurring symptoms. Doctors could also be encouraged to dedicate more attention to routinely asking cancer patients about eventual sleep disturbances.

A prospective observational study to evaluate G-CSF usage in patients with solid tumors receiving myelosuppressive chemotherapy in Italian clinical oncology practice.

Febrile neutropenia (FN) is a severe dose-limiting side effect of myelosuppressive chemotherapy in patients with solid tumors. Clinical practice guidelines recommend primary prophylaxis with G-CSF in patients with an overall ≥ 20 % risk of FN. AIOM Italian guidelines recommend starting G-CSF within 24-72 h after chemotherapy; for daily G-CSF, administration should continue until the absolute neutrophil count (ANC) is 1 × 10(9)/L post-nadir and should not be terminated after ANC increase in the early days of administration. The aim of this study was to assess guideline adherence in oncology practice in Italy. In this multicenter, prospective, observational study, patients were enrolled at the first G-CSF use in any cycle and were followed for two subsequent cycles (or until the end of chemotherapy if less than two additional cycles). Primary objective was to explore G-CSF use in Italian clinical practice; therefore, data were collected on the G-CSF type, timing of administration, and number of doses. 512 eligible patients were enrolled (median age, 62). The most common tumor types were breast (36 %), lung (18 %), and colorectal (13 %). A total of 1,164 G-CSF cycles (daily G-CSF, 718; pegfilgrastim, 446) were observed. Daily G-CSF was administered later than 72 h after chemotherapy in 42 % of cycles, and the median [range] number of doses was four [1, 10]. Pegfilgrastim was administered later than 72 h in 8 % of cycles. G-CSF prophylaxis in Italy is frequently administered in a manner which is not supported by evidence-based guidelines. As this practice may lead to poor outcomes, educational initiatives are recommended.

Health resource utilization associated with skeletal-related events in patients with bone metastases: Results from a multinational retrospective - prospective observational study - a cohort from 4 European countries.

BACKGROUND: Skeletal-related events (SREs; pathologic fracture, radiation or surgery to bone, spinal cord compression) frequently occur in patients with advanced cancer with bone metastases/lesions. Limited data on the associated patient and economic burden are available to aid in resource planning and evaluating treatment options. METHODS: Patients with bone metastases/lesions secondary to breast, lung or prostate cancer or multiple myeloma; with at least one SRE within 97 days prior to enrollment; life expectancy of at least 6 months; and Eastern Cooperative Oncology Group performance status 0, 1 or 2 were recruited. Information on health resource utilization (HRU; including number/duration of hospitalizations, outpatient visits, procedures), attributed by investigators to be associated with a SRE, was collected retrospectively for up to 97 days prior to enrollment and prospectively for up to 18-21 months. RESULTS: A total of 631 patients contributing 1282 SREs, were enrolled across Germany, Italy, Spain and the United Kingdom. Approximately a third of all SREs required an inpatient stay. Mean duration of inpatient stay for patients with SREs requiring one ranged from 8.4 to 41.1 days across all countries and SRE types. CONCLUSION: All types of SREs are associated with substantial HRU burden. Preventing SREs by using the best therapeutic options available may help to reduce the burden to patients and healthcare systems.

Methodological assessment of HCC literature.

Despite the fact that the hepatocellular carcinoma (HCC) represents a major health problem, very few interventions are available for this disease, and only sorafenib is approved for the treatment of advanced disease. Of note, only very few interventions have been thoroughly evaluated over time for HCC patients compared with several hundreds in other, equally highly lethal, tumours. Additionally, clinical trials in HCC have often been questioned for poor design and methodological issues. As a consequence, a gap between what is measured in clinical trials and what clinicians have to face in daily practice often occurs. As a result of this scenario, even the most recent guidelines for treatment of HCC patients use low strength evidence to make recommendations. In this review, we will discuss some of the potential methodological issues hindering a rational development of new treatments for HCC patients.

Cost of skeletal-related events in European patients with solid tumours and bone metastases: data from a prospective multinational observational study.

OBJECTIVES: Patients with bone metastases often experience skeletal-related events (SREs: radiation or surgery to bone, pathologic fracture, and spinal cord compression). This study examined health resource utilization and costs associated with SREs. METHODS: Data presented are from the European cohort (Germany, Italy, Spain, and the UK) of patients with solid tumours enrolled in a multi-national, prospective, observational study in patients with solid tumours or multiple myeloma. Patients with Eastern Cooperative Oncology Group score 0-2 and life expectancy ≥6 months, who experienced an SRE up to 97 days before enrolment, were eligible. Health resource utilization associated with SREs (including number/length of inpatient stays, numbers of procedures and outpatient visits) were collected through chart review for up to 97 days before enrolment and prospectively during follow-up. Country-specific cost calculations were performed. RESULTS: In total, 478 eligible patients contributed 893 SREs to this analysis. Radiation to bone occurred most frequently (66% of total). Spinal cord compression (7%) and surgery to bone (10%) were the least common events, but most likely to require inpatient stays. The most costly SREs were also spinal cord compression (mean per SRE across countries, €4884-€12,082) and surgery to bone (€3348-€9407). Inpatient stays were the main cost drivers. LIMITATIONS: Health resource utilization used to calculate the costs associated with SREs may have been under-estimated as a result of exclusion of patients with low performance status or life expectancy; unavailable information and exclusion of resource consumption associated with pain. Thus, the estimate of associated costs is likely to be conservative. CONCLUSIONS: SREs result in considerable health resource utilization, imposing a substantial financial burden driven by inpatient stays. Treatments that prevent/delay SREs may help ease this burden, thereby providing cost savings across European healthcare systems.

Sequential use of sorafenib and sunitinib in advanced renal cell carcinoma: does the order of sequencing matter?

To investigate the sequential use of two tyrosine-kinase inhibitors (TKI), sorafenib (SOR) and sunitinib (SUN), in advanced renal carcinoma. We retrospectively analyzed the clinical outcome of 33 patients who had experienced progression or unacceptable toxicity after receiving either sorafenib or sunitinib and then switched to the other reciprocal agent. Progression-free survival (PFS) during the first TKI was similar regardless of drug with a median of 6 months in the SOR-SUN group (n = 15) and 7.5 months in the SUN-SOR group (n = 18). Interestingly, PFS during the second TKI was significantly longer in the SOR-SUN group as compared to the SUN-SOR group with median values of 11 and 3 months, respectively (P = 0.0377; HR 0.46; 95% CI: 0.16-0.95). As a consequence, total PFS (sum of PFS on first and second TKI) was significantly longer in the SOR-SUN group than in the SUN-SOR group with medians of 20 versus 10 months, respectively (P = 0.0393; HR 0.47; 95% CI: 0.18-0.96). Median wash-out period between the two TKI was 3 weeks in both groups. Differences in baseline characteristics, including histology and line of treatment, were not significant, and toxicity was not increased during the second part of the sequence. Here, we show that responses can be achieved when a second TKI is given soon after a TKI failure in renal cancer with apparent more durable disease control when SOR is followed by SUN.

Castration-resistant prostate cancer: targeted therapies.

BACKGROUND: Castration-resistant prostate cancer (CRPC) refers to patients who no longer respond to surgical or medical castration. Standard treatment options are limited. OBJECTIVE: To review the concepts and rationale behind targeted agents currently in late-stage clinical testing for patients with CRPC. METHODS: Novel targeted therapies in clinical trials were identified from registries. The Medline database was searched for all relevant reports published from 1996 to October 2009. Bibliographies of the retrieved articles and major international meeting abstracts were hand-searched to identify additional studies. RESULTS: Advances in our understanding of the molecular mechanisms underlying prostate cancer (PCa) progression have translated into a variety of treatment approaches. Agents targeting androgen receptor activation and local steroidogenesis, angiogenesis, immunotherapy, apoptosis, chaperone proteins, the insulin-like growth factor (IGF) pathway, RANK ligand, endothelin receptors, and the Src family kinases are entering or have recently completed accrual to phase III trials for patients with CRPC. CONCLUSIONS: There has been an increase in the understanding of the mechanisms of progression of CRPC. A number of new agents targeting mechanisms of PCa progression with early promising results are in clinical trials and have the potential to provide novel treatment options for CRPC in the near future.

Vacuum-assisted biopsy diagnosis of atypical ductal hyperplasia and patient management.

PURPOSE: This study sought to evaluate the accuracy of vacuum-assisted biopsy (VAB) in the diagnosis of atypical ductal hyperplasia (ADH) by determining the rate of VAB underestimation compared with definitive histology. In addition, an attempt was made to identify parameters that could help determine the most appropriate patient management. MATERIALS AND METHODS: We retrospectively reviewed 1,776 VAB procedures performed between November 1999 and January 2008 for suspicious subclinical breast lesions visible only at mammography. A total of 177 patients with a VAB diagnosis of pure ADH were studied. Patients with a diagnosis of ADH associated with other lesions (lobular intraepithelial neoplasia, papilloma), atypical lobular hyperplasia, lobular carcinoma in situ and any lesions with a microhistological diagnosis other than ADH were excluded. Mammographic appearance of lesions was as follows: 152 mostly clustered microcalcifications (86%); five opacities with microcalcifications (3%); 12 single opacities (3%); and eight parenchymal distortions (4%), of which five were without and three were with microcalcifications. In cases underestimated by VAB, we evaluated the extent of ADH within ducts and lobules. Based on results, patients were subdivided into two groups: ≤2 ADH foci; >2 ADH foci. Patients were subdivided into two groups: one was referred for surgery and the other for follow-up care. The decision to either perform or not perform surgery was based on combined analysis of the following parameters: patient age; risk factors in the patient's history; mammographic extent of microcalcifications; complete excision of microcalcifications at VAB; and final Breast Imaging Reporting and Data System (BI-RADS) assessment. RESULTS: In the first group (n=98), comparison of microhistology with final histology revealed that 19 cases of ADH had been underestimated by VAB. In the second group (n=79), six cases of ADH showed progression of the mammographic abnormality, which was subsequently confirmed by surgical biopsy. CONCLUSIONS: The most relevant parameters affecting the decision to proceed to surgical excision were lesion diameter >7 mm on mammography, >2 ADH foci, incomplete removal of the calcifications and a family and/or personal history of breast cancer. Although there are no definite mammographic predictors of malignancy, a radiological assessment of suspicious lesion in the presence of an additional equivocal parameter always warrants surgical management.

Update on capecitabine alone and in combination regimens in colorectal cancer patients.

Capecitabine is an orally administered fluoropyrimidine carbamate which has been developed as a prodrug of 5-FU with the goal to improve its tolerability and intratumoral drug concentration. The review aims to provide an evidence-based update of clinical trials investigating the clinical efficacy, adverse-event profile, dosage and administration of this drug, alone or in combination with conventional chemotherapeutics and/or new target-oriented drugs, in the management of colorectal cancer patients.

Lapatinib in breast cancer: clinical experiences and future perspectives.

Lapatinib, an orally available dual inhibitor targeting the tyrosine-kinase domain of both epidermal growth factor receptor-1 and 2, has been introduced for the treatment of advanced/metastatic HER2+ breast cancer in combination with capacitabine after chemotherapy regimens containing anthracycline, taxanes and trastuzumab. Moreover, lapatinib is under investigation in combination with anthracycline and taxanes in neoadjuvant and adjuvant settings. Another potential field of investigation for this drug is related to its ability to restore hormonal sensitivity of HER2-, hormone-receptor positive breast cancer cells. This paper reviews the current use of lapatinib in breast cancer and its future perspectives.

Treatment of triple negative breast cancer (TNBC): current options and future perspectives.

Breast cancer is not considered anymore a unique disease. Microarray gene expression analysis led to the identification of 4 major breast cancer "intrinsic" subtypes, including hormone receptor (HR)-positive luminal A and B, human epidermal growth receptor 2 (HER2)-positive and basal-like breast cancer (BLBC). These subtypes have distinct phenotypes, molecular profiles, clinical behaviour and response to therapy, with the BLBC carrying the worst outcome. Microarray analysis is not feasible in routine practice and therefore oncologists rely on a simpler immunohistochemical (IHC) classification to identify relevant breast cancer subtypes. Triple negative breast cancer (TNBC) is defined by the absence of oestrogen receptor, progesterone receptor and HER2 expression at IHC analysis. TNBC is strictly related to BLBC and, given the lack of common therapeutic targets, represent a major challenge for breast oncologist. In this review we will summarize the updated knowledge on TNBC, with emphasis on its current treatment and on the new therapeutic options under development.

Microsatellite instability (MSI) as genomic markers in endometrial cancer: toward scientific evidences.

Endometrial Cancer is the most frequent tumor in western world nations, with 142,000 new cases each year and 42,000 casualties. This form of cancer typically affects women between 55 and 65 years of age, and ranks fourth among female tumors. Endogenous predisposing conditions to endometrial cancer development are: late menopause, early menarche and hyperestrogenism, while hormone replacement therapy, obesity, alcohol, diabetes, and a diet rich in animal fats as well as chronic liver disease, are the exogenous factors. This tumor may also have an hereditary predisposition, as in the Lynch Syndrome or in HNPCC (Hereditary NonPolyposis Colorectal Cancer), since genetic modifications induced by the "MisMatch Repair" genes lead to a tumoral development susceptibility, not only in the colon. The phenotypical consequences of these genetic modifications may be found in the microsatellite instability (MSI) and in the loss of heterozygosity (LOH), which generate the replication errors in positive phenotypes repeats. These express the incapability to repair short nucleotide insertions or deletions, generated by a wrong DNA replication. Due to such genetic modifications, new allelic variants arise in the endometrial tissue, confirming the high degree of this genetic disorder. Recent studies showed that the MSI and LOH in endometrial cells may be associated with the possible loss in the expression of cellular control and with the possible degeneration of the cell growth phenomenon. There is also a possibility of utilizing these new genetic markers in the endometrial mucosa to study these tissues and to detect any possible neoplastic transformations, thanks to Genomics.

Single dose of palonosetron plus dexamethasone to control nausea, vomiting and to warrant an adequate food intake in patients treated with highly emetogenic chemotherapy (HEC). Preliminary results.

INTRODUCTION: The aim of our study was to evaluate the efficacy of a single-dose palonosetron plus dexamethasone to control emesis in patients (pts) receiving HEC. Moreover, we evaluated the amount of their food intake (FI) in the week following therapy, in order to measure any reduction of calories consumption related to Chemotherapy-induced nausea and vomiting (CINV). METHODS: Patients affected with advanced cancer were treated with palonosetron 250 mcg plus dexamethasone 20 mg before HEC. Nausea, vomiting, and FI were monitored by a 7-day diary. Complete Response (CR: no vomiting and no rescue therapy) was the primary endpoint, Complete Control (CC: CR and no more than mild nausea) and the evaluation of FI were the secondary endpoints. The endpoints were evaluated during the acute (0-24 h), the delayed (25-168 h) and overall (0-168 h) phases. RESULTS: Thirty-five patients were enrolled; 85.7% and 82.9% of patients achieved CR and CC respectively, during the acute phase; 82.9% and 77.1% of patients achieved CR and CC, during the delayed phase; 80% and 77.1% of patients achieved CR and CC, during the overall phase. During the acute phase, patients with a CC without nausea had a median daily FI of 1,575 kcal, whereas patients with CC and presence of mild nausea had a median daily FI of 1,040 kcal (-535 kcal; p < 0.0001). CONCLUSIONS: Our preliminary results confirm the efficacy of a single-dose palonosetron plus dexamethasone to prevent both acute and delayed nausea and vomiting. Moreover, the efficacy of palonosetron in nausea and vomiting control seems to warrant adequate caloric intake in these patients.

A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer.

BACKGROUND: Gefitinib inhibits the epidermal growth factor receptor tyrosine kinase and preclinical studies indicate that it may enhance CPT-11 cytotoxicity. This randomized phase II trial investigates the feasibility and efficacy of gefitinib and 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients were randomized to FOLFIRI +/- gefitinib 250 mg daily p.o. Patients randomized to FOLFIRI + gefitinib without disease progression after 6 months continued to receive gefitinib alone until disease progression. RESULTS: From October 2002 to September 2004, 100 patients were enrolled. Twenty-three patients (47.9%) in the FOLFIRI arm and 23 (45.1%) in the FOLFIRI + gefitinib arm experienced an objective response. The median progression-free survival and overall survival were 8.3 and 18.6 months in the FOLFIRI arm, and 8.3 and 17.1 months in the FOLFIRI + gefitinib arm, respectively. In the combination arm, grades 3-4 adverse events were experienced by 35 (67.3%) patients versus 25 patients (52.1%) in the FOLFIRI arm; 12 patients (23.1%) withdrew for an adverse event in the FOLFIRI + gefitinib arm and 5 (10.4%) in the FOLFIRI arm. CONCLUSIONS: These data show that adding gefitinib to FOLFIRI does not improve the efficacy of FOLFIRI regimen. These disappointing results could be related to the high toxicity observed that led to significant dose reductions and delays.

Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study.

This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) were > or =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs > or =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.