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The purpose of this study was to report our experience with administration of plerixafor for the mobilization of hematopoietic stem cells (HSCs) in patients with refractory or recurrent germ cell tumors who were candidates for salvage therapy with high-dose chemotherapy and HSC transplantation and for whom mobilization of HSCs had not been achieved by standard therapies. This retrospective and observational study selected patients who were eligible for autologous HSC transplantation (AHSCT) and received plerixafor after failure of HSC mobilization by granulocyte colony-stimulating factor (G-CSF). A total of 5 patients (4 male and 1 female), aged 19–41 years (mean age, 29.6 years) were initially selected. Four patients (80%) achieved an adequate HSC mobilization with plerixafor and subsequently received high-dose chemotherapy followed by HSC transplantation. In these patients, the number of CD34+ cells collected following plerixafor mobilization was 1.8×106–10.3×106 cells/kg, with a peak CD34+ cell count of 7.0–32.0 cells/μl. Following HSC infusion, these 4 patients achieved a neutrophil count of >0.5×103/mm3 and a platelet count of >20,000/μl between days 10 and 14. Therefore, patients with high-risk germ cell tumors eligible for AHSCT who are refractory to mobilization by G-CSF, may benefit from the use of plerixafor, possibly to the same extent as patients with lymphoma and multiple myeloma.

Although selective estrogen receptor modulators (SERMs), such as tamoxifen, or aromatase inhibitors (AIs), such as anastrozole, are the preferred endocrine treatment approach for most patients with hormone receptor-positive breast cancer, many patients progress despite this therapy or become resistant. Fulvestrant is a selective estrogen receptor down-regulator (SERD) that has demonstrated activity and efficacy in patients with hormone receptor-positive breast cancer previously untreated or treated with hormonal therapy. The efficacy of fulvestrant has been demonstrated in the neoadjuvant and metastatic settings, either alone or in combination with other therapies such as anastrozole or targeted drugs. Additionally, 500 mg of fulvestrant have been shown to be more effective than 250 mg, without significant differences in the toxicity profile. In this review, the unique mode of action of fulvestrant and the clinical data for different dosing regimens both alone or in combination with other drugs is critically assessed.

Approximately 75% of patients with breast cancer present hormone receptor-positive tumors. This subtype of breast cancer initially shows a high overall response rate to hormonal treatments. However, resistance eventually develops, resulting in tumor progression. The PI3K/Akt/mTOR pathway regulates several cellular functions in cancer such as cell growth, survival, and proliferation. In addition, a high activation level of the PI3K/Akt/mTOR pathway is related to resistance to conventional chemotherapy and hormone therapy. The mTOR inhibitor everolimus, in combination with hormonal treatments, has led to excellent results in progression-free survival in patients with metastatic breast cancer resistant to hormone therapies. Therefore, everolimus has entered the National Comprehensive Cancer Network (NCCN) guidelines 2012 and its combination with exemestane was approved recently by the US Food and Drug Administration and the European Medicines Agency. This is the first time that a drug will have been approved for the restoration of hormone sensitivity in breast cancer.

Background Cisplatin is a potent antitumor agent. However, toxicity and primary and secondary resistance are major limitations of cisplatin-based chemotherapy, leading to therapeutic failure. We have previously reported that mono-sulfonamide platinum complexes have good antitumor activity against different tumoral cell lines and with a different and better cytotoxic profile than cisplatin. Besides, N-sulfonamides have been used extensively in medicinal chemistry as bactericides, anticonvulsant, inhibitors of the carbonic anhydrase, inhibitors of histone deacetylases, and inhibitors of microtubule polymerization, among others. Methods We aimed to compare the cytotoxic effects of cisplatin and a trans-sulfonamide-platinum-complex (TSPC), in two human melanoma cell lines that differ in their TP53 status: SK-MEL-5, TP53 wild type, and SK-MEL-28, TP53 mutated. We performed cytotoxicity assays with both drugs, alone and in combination, cell cycle analyses, western blotting and immunoprecipitation, and fluorescence immunocytochemistry. Results TSPC had similar antiproliferative activity than cisplatin against SK-MEL-5 (3.24 ± 1.08 vs 2.89 ± 1.12 μM) and higher against SK-MEL-28 cells (5.83 ± 1.06 vs 10.17 ± 1.29 μM). Combination of both drugs inhibited proliferation in both cell lines, being especially important in SK-MEL-28, and showing a synergistic effect. In contrast to cisplatin, TSPC caused G1 instead G2/M arrest in both cell lines. Our present findings indicate that the G1 arrest is associated with the induction of CDKN1A and CDKN1B proteins, and that this response is also present in melanoma cells containing TP53 mutated. Also, strong accumulation of CDKN1A and CDKN1B in cells nuclei was seen upon TSPC treatment in both cell lines. Conclusions Overall, these findings provide a new promising TSPC compound with in vitro antitumor activity against melanoma cell lines, and with a different mechanism of action from that of cisplatin. Besides, TSPC synergism with cisplatin facilitates its potential use for co-treatment to reduce toxicity and resistance against cisplatin. TSPC remains a promising lead compound for the generation of novel antineoplastic agent and to explore its synergism with other DNA damaging agents.

Metronomic administration of the same chemotherapy agents (lower doses with closer intervals) may optimize their antiangiogenic properties. The aim of our study was to determine the efficacy and safety of a metronomic regimen based in non-pegylated liposomal doxorubicin (NPLD) in advanced breast cancer patients. Clinical records of patients with pretreated advanced breast cancer and who were treated with the Metronomic-Cooper-type regimen consisting of weekly fixed doses of NPLD (30 mg IV) plus 5-Fluorouracil (5-FU) (500 mg IV) plus vincristine (0.25 mg IV) and daily oral cyclophosphamide (50 mg) plus prednisone (20 mg) were reviewed. In 84 pretreated patients, a tumor response was observed in 38 patients (45 %); stable disease was observed in 23 patients (27 %). Median progression-free survival (PFS) time to progression was 8.4 months and median overall survival (OS) was 21 months. The most common grade 2–3 hematologic adverse event was neutropenia, which was observed in 47 patients (56 %). Febrile neutropenia was observed in 10 patients (12 %). The most common non-hematologic adverse events were asthenia and mucositis which were observed in 60 patients (71 %) and 26 patients (31 %), respectively. Three patients (4 %) experienced an asymptomatic decline of the left ventricular ejection fraction. NPLD-based metronomic regimen was effective and safe in pretreated advanced breast cancer patients. It could be considered as an appealing option to treat patients previously exposed to anthracyclines.

Hypersensitivity reaction (HSR) to antineoplastic drugs can force doctors to stop treatment and seek other alternatives. These alternatives may be less effective, not as well tolerated and/or more expensive. Another option is to use desensitization protocols that induce a temporary state of tolerance by gradually administering small quantities of the antineoplastic drug until the therapeutic dosage is reached. The aim of this study is to assess the effectiveness of oxaliplatin desensitization protocols.A retrospective observational study was carried out between January 2006 and May 2011. The inclusion criteria were patients undergoing chemotherapy treatment with oxaliplatin who had developed an HSR to the drug and who were candidates for continuing the treatment using a desensitization protocol. The patients' clinical records were reviewed and variables were gathered relating to the patient, the treatment, the HSR, and the desensitization protocol administered. The data were analysed using version 18.0 of the statistics program SPSS.A total of 53 desensitization protocols were administered to 21 patients. In 89 % of these cases, no new reactions occurred while the drug was being administered. New reactions of mild severity only occurred in 11 % of cases, and none of these reactions were severe enough for treatment to be stopped. All patients were able to complete the desensitization protocol.This study confirms that oxaliplatin desensitization protocols are safe and effective and allow patients to continue with the treatment that initially caused an HSR.

Introduction The aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC). Materials and methods 191 chemotherapy-naïve patients were randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3 months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint. Results 183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3 % (p = 0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2 months; p = 0.475); progression-free survival (7.7 and 8.7 months; p = 0.292), and response duration (6.4 and 7.6 months; p = 0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (p

Background: The prognosis for patients with triple-negative breast cancer (TNBC) is poor and treatment options are limited. Bevacizumab improves the efficacy of standard first-line therapy in locally recurrent/metastatic breast cancer (LR/mBC). The benefit of bevacizumab seen in patients with TNBC appears similar to that observed in the overall population. We conducted an exploratory analysis of patients with TNBC treated in the single-arm routine oncology practice ATHENA study. Methods: Patients with previously untreated LR/mBC received standard first-line chemotherapy combined with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks, until progression, unacceptable toxicity, or patient/physician decision). Results: Of 2,264 patients treated in ATHENA, 585 (26%) had TNBC. Most patients received single-agent taxane with bevacizumab. In the TNBC subgroup, the overall response rate was 49%, including complete responses in 10%; only 16% had primary resistant disease. Median time to progression was 7.2 months (95% CI 6.6–7.8) and median overall survival was 18.3 months (95% CI 16.4–19.7). The 1-year overall survival rate was 60%. The safety profile in TNBC was consistent with results in the overall population. Conclusion: This exploratory subgroup analysis suggests that first-line chemotherapy in combination with bevacizumab is an active regimen in patients with metastatic TNBC.

The ATHENA study expanded on the safety and efficacy data derived from first-line trials of bevacizumab combined with standard chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC). In ATHENA, 2,264 patients received first-line bevacizumab-containing therapy in routine oncology practice. Overall survival (OS) data are now mature; additional analyses from this large data set can provide insights into treatment duration and the effect of prolonged bevacizumab exposure, where data are currently limited. Patients with HER2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We performed subgroup analyses on data from patients treated for ≥12 months and those who continued single-agent bevacizumab after stopping chemotherapy. After median follow-up of 20.1 months, median OS was 25.2 months (95% confidence interval [CI] 24.0-26.3 months) in the entire population. Median OS was 30.0 months (95% CI 28.5-32.7 months) in 1,205 patients who continued bevacizumab after discontinuation of chemotherapy and 18.4 months (95% CI 17.2-19.7 months) in 1,058 patients who discontinued bevacizumab before or at the same time as stopping chemotherapy. Bevacizumab treatment was continued for ≥12 months in 473 patients (21%). In most, bevacizumab was administered as monotherapy for extended periods after stopping chemotherapy. In the subgroup of patients treated for ≥12 months, the median time to onset of grade 3-5 adverse events was 5.0 months. There was no evidence that first onset of adverse events of special interest, except for proteinuria, was more common in later than earlier cycles. No relationship was detected between development of hypertension and OS. Findings from these analyses suggest that patients with LR/mBC can receive bevacizumab for prolonged periods without major toxicity or progression of disease. In the absence of progression, continuation of single-agent bevacizumab appears to be a reasonable approach, with minimal toxicity and the possibility of long-term disease control.

Maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics (PK) were evaluated for trabectedin 3-h every-3-weeks schedule in 33 cancer patients stratified according to liver dysfunction degree as per baseline alkaline phosphatase (AP). Stratification was as follows: stratum I [upper limit of normal (ULN)AP ≤ 1.5 × ULN; n = 16], stratum II [1.5 × ULNAP ≤ 2.5 × ULN; n = 12], and stratum III [AP2.5 × ULN; n = 5] (bilirubin2.5 × ULN for all 3 strata). In each stratum, patients were treated in sequential cohorts at escalating doses. Dose-limiting toxicities (DLTs) were grade 3 transaminase increases not recovering baseline values on day 21, febrile neutropenia/grade 4 neutropenia lasting5 days and AP increase more than twice over baseline. The MTD and RD for stratum I (mild baseline AP) was 1.3 mg/m(2). Recruitment was stopped early in strata II/III (moderate/severe baseline AP) without reaching the MTD due to slow accrual and difficulty in finding patients. Biochemical parameters other than AP (bilirubin, AST or ALT) were similar between strata. No relevant PK differences were found between strata. In conclusion, the MTD and RD (1.3 mg/m(2)) were confirmed only for stratum I. Stratification criteria based on baseline AP apparently did not segregate the patients according to their liver dysfunction degree. Antitumor activity was found in patients with pretreated ovarian cancer.

The bone is a very common site of metastasis in patients with advanced cancer. Skeletal metastases are most common in breast and prostate cancer, but virtually any advanced cancer may disseminate to the bone. On the basis of recent advances in the understanding of bone remodeling processes, denosumab, a fully human monoclonal antibody against RANK-L, has been developed. Phase III clinical trials have demonstrated that denosumab is well tolerated and effective in the treatment of bone loss and prevention of skeletal-related events in patients with bone metastases., The diagnosis of bone metastases is an event with certain consequences for the patient. They often mean pain and can also mean pathological fractures, hypercalcemia, and spinal cord compression, all synonymous with a diminished quality of life and often also hospitalization. Since the advent of the intravenous bisphosphonates, things began to look a bit brighter for patients with bone metastases—bone destruction was kept at bay a little longer. The next generation of bone metastasis treatments is well on its way in clinical development, and among them, the most advanced drug is denosumab. Denosumab is a fully human monoclonal antibody that inhibits osteoclast maturation, activation, and function by binding to receptor activator of nuclear factor kappa B ligand, with the final result being a reduced rate of bone resorption. In this review, we give an overview of relevant preclinical and clinical data regarding the use of denosumab in patients with solid tumors in general and prostate cancer in particular.

Background: First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). ATHENA, a multinational, open-label, single-arm study, further evaluated first-line bevacizumab in combination with standard chemotherapy in patients treated in routine oncology practice. Patients and methods: Eligible patients had HER2-negative LR/mBC, ECOG performance status 0-2, and had received no prior chemotherapy for LR/mBC. They received bevacizumab 10 mg/kg q2w or 15 mg/kg q3w in combination with taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was safety; secondary endpoints included time to progression (TTP) and overall survival (OS). Results: Between September 2006 and March 2009, 2264 patients began therapy with bevacizumab, combined with single-agent paclitaxel (34%), single-agent docetaxel (33%), taxane-based combination therapy (11%), non-taxane-containing therapy (10%), or sequential chemotherapy (switching chemotherapy regimen before disease progression while continuing on bevacizumab; 12%). After final data cut-off in July 2010, the median duration of follow-up was 20.1 months (range 0.1-43.6 months). Bevacizumab therapy was continued for ≥1 year in 473 patients (21%). The safety profile and median TTP were very similar to those previously reported after median follow-up of 12.7 months and are consistent with findings from randomized phase III trials. Final OS results in the overall population and in clinically important subgroups are reported below for the first time. Conclusion: Median OS in the overall population is consistent with OS results reported from three randomized phase III trials in the first-line setting (25.2-30.2 months). OS results in subsets of patients with TN disease or aged ≥70 years suggest that bevacizumab-containing therapy is an effective option for these patients, who typically have fewer treatment options available. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-06.

Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC). Methods: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted. Results: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogen-activated protein kinase (MAPK) and induced p27 expression in the skin. Conclusion: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.

Anthracyclines such as doxorubicin, epirubicin, and daunorubicin are among the most active cytoxic agents for treatment of a wide variety of solid tumors and hematological malignancies. The downside associated with chronic administration of anthracyclines is the induction of cardiomyopathy and congestive heart failure, usually refractory to common treatments. Anthracycline liposomal formulations are currently the best-known alternatives to improve the index and spectrum of anticancer activity of these drugs and decrease their cardiotoxicity. In the current target therapy era in oncology, anthracyclines increase the antitumor effects in more than additive fashion, being excellent partners for other active agents like taxanes and trastuzumab. It is important to note, however, that the enhanced antitumor activity of these combination therapies is often accompanied with increased cardiotoxicity. The issue of anthracycline cardiotoxicity has not been solved so far and it is also important to stress the current lack of proper prevention and treatment strategies.

Purpose. To assess the toxicity and efficacy of biweekly gemcitabine plus vinorelbine in first-line advanced breast cancer, and to establish whether circulating HER2 ECD levels correlate with the efficacy of the combination. Patients and methods. 52 patients were treated with gemcitabine 2500 mg/m(2) plus vinorelbine 30 mg/m(2), both on day 1 of 14-day cycles, for a maximum of 10 cycles. Baseline serum levels of HER2 ECD were assessed with an ELISA. Results. All patients were evaluable for toxicity, and 50 for efficacy. Overall toxicity was moderate. Grade 3 neutropenia occurred in 35% of patients and grade 4 in 19%. Other grade 3 toxicities were observed in less than 6%. There was one episode of febrile neutropenia, and one death after cycle three. Overall response rate was 52% (95% CI: 38% to 66%), with 2 patients achieving a CR (4%). Response rate did not correlate with HER2 ECD, with 50% of HER2 ECD positive patients responding, vs 48.5% of the HER2 ECD negative. Median overall survival was 24.6 months. Conclusion. Gemcitabine plus vinorelbine, given as an every-two-week schedule, is an active regimen in advanced breast carcinoma. This combination can be an option when anthracyclines and taxanes are not preferred. HER2 ECD has no predictive value in this non-taxane combination.

Women with metastatic breast cancer require tailored chemotherapy that improves outcomes without compromising quality of life. Capecitabine, a pro-drug of 5-fluorouracil, is an oral fluoropyrimidine carbamate that is sequentially activated in a three-step process. This results in the preferential production of 5-fluorouracil in tumors rather than in normal surrounding tissue, improving the tolerability and efficacy of 5-fluorouracil. In combination with docetaxel, capecitabine is the first agent that has shown superior activity to single-agent docetaxel, and it is a particularly appropriate option for younger, fitter patients with rapidly progressing disease and/or visceral metastases. However, for older patients and those with comorbidities and/or after progression to taxanes, single-agent capecitabine may be the best option. Its role in earlier disease stages (adjuvant therapy) is being investigated.

Purpose Cisplatin kills tumor cells through DNA cross linking. Alterations in the function of DNA repair genes may affect DNA repair proficiency and influence cancer patients' response to cisplatin. We studied whether single nucleotide polymorphisms (SNPs) of DNA repair genes predict the response to cisplatin or prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). Methods A polymerase chain reaction–restriction fragment length polymorphism (RFLP) approach was used to determine the frequency of the SNPs: XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A, and XRCC1-Arg399Gln in DNA from peripheral lymphocytes of 103 stage IV SCCHN patients. Results The frequencies of the distinct genotypes were, respectively, for the homozygous common allele, heterozygous and homozygous polymorphic variant: 53%, 40%, and 7% for ERCC1; 50%, 42%, and 8% for XPD-312; 35%, 57%, and 8% for XPD751; and 35%, 51%, and 13% for XRCC1. Patients with only common alleles at all the SNPs tested had a median overall survival of 5.1 months (range, 4.3 to 6.0 months) as compared with not reached for patients with at least one polymorphic variant (P < .001). Estimates from Cox's multivariate analysis suggest that the accumulation of each polymorphic variant decreases the probability of dying by a factor of 2.1 (P < .001; the presence of seven polymorphic variants confers a 175-fold protection). The accumulation of polymorphic variants increases by 2.94-fold the probability of achieving a complete response to treatment (P = .041). Conclusion Using a multivariate model, the presence of polymorphic variants in DNA-repair genes are powerful prognosis factors and response to cisplatin predictors among SCCHN patients.

Purpose To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel, cisplatin, and fluorouracil (FU; PCF) versus standard cisplatin and FU (CF), both followed by chemoradiotherapy (CRT), in locally advanced head and neck cancer (HNC). Patients and Methods Eligibility criteria included biopsy-proven, previously untreated, stage III or IV locally advanced HNC. Patients received either CF (cisplatin 100 mg/m2 on day 1 plus FU 1,000 mg/m2 continuous infusion on days 1 through 5) or PCF (paclitaxel 175 mg/m2 on day 1, cisplatin 100 mg/m2 on day 2, and FU 500 mg/m2 continuous infusion on days 2 through 6); both regimens were administered for three cycles every 21 days. Patients with complete response (CR) or partial response of greater than 80% in primary tumor received additional CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 plus 70 Gy). Results A total of 382 eligible patients were randomly assigned to CF (n = 193) or PCF (n = 189). The CR rate was 14% in the CF arm v 33% in the PCF arm (P < .001). Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm (log-rank test, P = .006; Tarone-Ware, P = .003). PCF patients had a trend to longer overall survival (OS; 37 months in CF arm v 43 months in PCF arm; log-rank test, P = .06; Tarone-Ware, P = .03). This difference was more evident in patients with unresectable disease (OS: 26 months in CF arm v 36 months in PCF arm; log-rank test, P = .04; Tarone-Ware, P = .03). CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients (53% v 16%, respectively; P < .001). Conclusion Induction chemotherapy with PCF was better tolerated and resulted in a higher CR rate than CF. However, new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment.

Purpose To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. Results The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash. Conclusion The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.

Background: North American and Japanese non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activation via tyrosine kinase (TK) mutations respond dramatically to gefitinib treatment. To date, however, the frequency and effect of EGFR TK mutations have not been examined in European patients. Patients and methods: Eighty-three Spanish advanced NSCLC patients who had progressed after chemotherapy, were treated with compassionate use of gefitinib. Patients were selected on the basis of available tumor tissue. Tumor genomic DNA was retrieved from paraffin-embedded tissue obtained by laser capture microdissection. EGFR mutations in exons 19 and 21 were examined by direct sequencing. Results: EGFR mutations were found in 10 of 83 (12%) of patients. All mutations were found in adenocarcinomas, more frequently in females (P = 0.007) and non-smokers (P = 0.01). Response was observed in 60% of patients with mutations and 8.8% of patients with wild-type EGFR (P = 0.001). Time to progression for patients with mutations was 12.3 months, compared with 3.6 months for patients with wild-type EGFR (P = 0.002). Median survival was 13 months for patients with mutations and 4.9 months for those with wild-type EGFR (P = 0.02). Conclusions: EGFR TK mutational analysis is a novel predictive test for selecting lung adenocarci

We measured the expression of the p53 nuclear protein and epidermal growth factor receptor (EGFR) in 46 biopsy samples from patients with advanced head and neck cancer treated with induction combination chemotherapy of 5-fluorouracil, cisplatin, and paclitaxel. Tumour expression of p53 protein was analysed with the monoclonal D07 antibody and EGFR with monoclonal H11 antibody. The overall response, defined as complete (CR) and partial response (PR) rates to treatment, was 88%. p53 positive staining was significantly more frequent in patients who did not respond to the induction treatment. EGFR expression failed to show any correlation with the response rate. Multivariate analysis indicated that a tumour location in the oral cavity together with p53 expression combined with moderate-to-high EGFR staining were independent prognostic factors of a shorter disease-free survival (DFS). Location of the tumour in the oral cavity and EGFR expression had independent prognostic value for overall survival (OS). We conclude that the EGFR status and an oral cavity location of the tumour have independent prognostic value in patients with advanced head and neck carcinoma treated with induction chemotherapy. The p53 status appears to be a determinant of the tumour chemo-sensitivity in advanced head and neck squamous cell carcinoma (HNSCC). The presence in the tumour of a p53-positive stain and moderate-to-high staining of EGFR is associated with a shorter DFS and time to treatment failure (TTF) probably reflecting a more aggressive tumour phenotype.

The role of irinotecan-based chemotherapy as induction treatment of non-resectable advanced colorectal cancer (ACRC) is currently being elucidated. The objective of this retrospective study was to determine complete resection (R0), response rate, time to progression (TTP) and overall survival (OS) in patients with non-resectable ACRC after being treated with neoadjuvant irinotecan-based chemotherapy. Thirty-six patients with ACRC were selected, of whom 23 (64%) were treated with irinotecan (250mg/m 2 on day 1), UFT (300mg/m 2 /day for 14 days) plus leucovorin (45 mg/day for 14 days) every 3 weeks. Another 13 (36%) received the FOLFIRI schedule of irinotecan plus 5-fluorouracil/leucovorin. A total of 214 cycles of irinotecan/UFT/LV (median 8, range 1-15) and 97 cycles of the FOLFIRI schedule (median 9, range 1-30) were administered. The overall response rate was 58% (95% confidence interval 42-74), with six complete and 15 partial responses, whereas seven patients (19%) showed stable disease. Laparotomy was performed in 12 patients, of whom eight (22%) achieved R0 and two (6%) a pathological complete response. Median TTP was 10.0 months and median OS was 38.0 months for all patients. After a median follow-up of 20 months (range 1-49), median TTP in patients with R0 was not reached (mean TTP, 33.1 months), whereas median TTP in non-resected patients was 7.5 months (p=0.016). Toxicity was manageable and no toxic deaths occurred. This retrospective study showed a high resectability rate, and a prolonged TTP and OS in patients with ACRC after induction treatment with irinotecan-based chemotherapy. Both toxicity profile and postoperative complications were acceptable. Nevertheless, the definitive role of irinotecan as induction treatment should be confirmed in future clinical trials.

Metastatic melanoma carries a dismal prognosis and there is a need to develop new treatment strategies. Vinca alkaloids have shown consistent activity in melanoma patients, as monotherapy and as part of combination regimens. The current study evaluates the clinical activity and tolerability of vinorelbine as first-line monotherapy in patients with metastatic melanoma. Patients were eligible if they presented metastatic melanoma not amenable to curative resection, had received no prior systemic therapy for advanced disease and had an adequate performance status (ECOG 0-1). Patients received vinorelbine at a dose of 30 mg/m2 on days 1 and 8 of a 21-day cycle, on an outpatient basis. Thirteen patients were accrued into the study and received 64 cycles. All patients were assessable for response, toxicity and survival. No objective responses were documented, for an overall response rate of 0% [95% confidence interval (CI) 0-19%] and the trial was terminated in accordance to the predetermined early discontinuation rule. The median progression-free survival was 3.3 months (95% CI 2.3-4.3 months) and the estimated median overall survival was 8.1 months (95% CI 6.0-10.2 months). No life-threatening toxicities occurred. Neutropenia was the main hematologic toxicity, but none of the three episodes of grade 3-4 neutropenia were complicated by infection. The most common non-hematologic toxicities were asthenia, nausea, neuropathy and myalgia. We conclude that vinorelbine as a single agent on days 1 and 8 of a 21-day cycle has a favorable toxicity profile, but appears to have no relevant clinical activity in patients with metastatic melanoma.

The combination of cisplatin and capecitabine was evaluated in patients with recurrent or unresectable squamous cell carcinoma of the head and neck (HNSCC), and outcome parameters were correlated with the expression of thymidine phosphorylase (TP), thymidilate syntetase (TS), vascular endothelial growth factor receptor (VEGFR) 1-3, and microvessel density (MVD). Patients with recurrent or unresectable HNSCC were eligible if they had received prior neoadjuvant chemotherapy, concurrent chemo-radiotherapy, or no prior systemic therapy. Patients received cisplatin (75 mg m(-2) day 1), and capecitabine (2000 mg m(-2) day 1-14) every 3 weeks. A total of 41 patients received 194 cycles. In all, 16 complete responses (39%) and 12 partial responses (29%) were documented, for an overall response rate of 68% (95% CI, 53-80%). Grade 3-4 uncomplicated neutropenia was documented in five subjects. Asthenia, anorexia, hand-foot syndrome, and constipation were the most frequent nonhaematologic events. Median progression-free and overall survival were 6.4 and 12.6 months. Cytoplasmic TP expression was more prevalent in patients with a laryngeal location vs other, and in patients with a recurrence vs primary disease. Microvessel density count was higher in patients with recurrent vs primary disease. The combination of cisplatin and capecitabine is effective in recurrent or unresectable HNSCC, and shows a manageable toxicity.

BACKGROUND The current study evaluated the feasibility and clinical activity of a combination of paclitaxel, cisplatin, 5-fluorouracil (5-FU), and leucovorin administered on a biweekly schedule to patients with recurrent or unresectable squamous cell carcinoma of the head and neck (HNSCC). METHODS Patients with recurrent or unresectable HNSCC were eligible if they had received a previous regimen of neoadjuvant chemotherapy, concurrent chemoradiotherapy, or no previous systemic therapy. Patients received paclitaxel (175 mg/m2 on Day 1), cisplatin (35 mg/m2 on Days 1 and 2), leucovorin (200 mg/m2 on Day 1), and 5-FU (1000 mg/m2 per day as a 48-hour continuous intravenous infusion on Days 1 and 2) every 2 weeks. Patients received subcutaneous filgrastim (300 μg per day) on Days 3–9 of each cycle. Treatment was administered on an outpatient basis for a maximum of six cycles. RESULTS Thirty-five patients received a combined total of 194 treatment cycles. Eighteen complete responses (51%) and 12 partial responses (34%) were documented, for an overall response rate of 86% (30 of 35 patients). The median progression-free survival duration was 14 months, and the median overall survival duration was 18 months. Two toxicity-related deaths were documented (one due to neutropenic sepsis and the other due to catheter-related pulmonary embolism). Grade 4 neutropenia was observed in one patient. Other severe (Grade 3 or 4) toxic effects included mucositis (14%), anemia (6%), thrombosis (6%), thrombocytopenia (3%), and neuropathy (3%). CONCLUSIONS The current dose-dense, four-agent, taxane-containing biweekly schedule was feasible and effective in patients with recurrent or unresectable HNSCC. However, given the single-center nature of the current study and the highly selected study population, further validation of these findings is recommended. Cancer 2004. © 2004 American Cancer Society.

HER2 overexpression has been associated with anti-estrogen resistance in human breast cancer, and it has been suggested that the combined treatment of an anti-HER2 antibody plus tamoxifen has enhanced anti-cancer efficacy in breast cancer. The detailed anti-proliferative interactions between trastuzumab and tamoxifen were analyzed with the isobologram and Chou and Talalay methods, which assess the presence of synergy, addition or antagonism. We used the breast cancer cell lines that are estrogen receptor (ER)-positive and HER2-positive. We also analyzed the molecular changes on the HER2 and (ER) signaling pathways that are induced by trastuzumab plus tamoxifen. In terms of cancer cell proliferation, the simultaneous combination of trastuzumab and tamoxifen on BT-474 cells was more growth inhibitory (44%) than the treatment with trastuzumab (24%) or tamoxifen (31%) alone. Isobologram analysis of simultaneous trastuzumab plus tamoxifen exposure showed, however, that there were antagonistic interactions at an effect level of 30% (IC30). Using Chou and Talalay analysis we also observed antagonistic interactions at lower levels of cell kill, although there were additive effects at highest levels of cell kill. Trastuzumab followed by tamoxifen showed antagonism at all effects levels. Tamoxifen followed by trastuzumab showed antagonism at lower levels of cell kill, and additivity at higher levels of cell kill. Similar interactions were observed using T47D cells. The molecular effects of the combined treatment with trastuzumab plus tamoxifen on the levels of HER2 and ER signaling showed that, with respect to HER2 protein levels, trastuzumab downregulated HER2 by 27%, tamoxifen upregulated HER2 by 40%, and the combination of trastuzumab plus tamoxifen did not induce changes in HER2 respect to control. With respect to HER2 mRNA, trastuzumab upregulated HER2 mRNA to 367%, tamoxifen to 166%, and the combination to 401%. With respect to HER2 phosphorylation, trastuzumab upregulated HER2 phosphorylation to 352%, tamoxifen to 202% and the combination to 633%. Epidermal growth factor receptor levels were not changed by trastuzumab or tamoxifen alone, and were upregulated to 138% by the combination. The protein levels and activity of extracellular recptor kinase were not modified by trastuzumab, tamoxifen or the combination. Finally, estrogen receptor protein and mRNA levels were downregulated to about 50% by trastuzumab, tamoxifen or the combination. Taken together, our results show that in ER-positive breast cancer cells overexpressing HER2, trastuzumab plus tamoxifen have antagonistic interactions when used in combination, and that this antagonism may be related with an increase in HER2 signaling pathways that occurs when tamoxifen is added to trastuzumab.

Despite therapeutic improvements and ongoing efforts to develop more efficacious therapies, the majority of lung cancer patients face a poor prognosis. Therefore, the primary goal of current treatment is palliation, improvement and maintenance of quality of life (QOL), and (modest) prolongation of survival. Anemia frequently occurs in lung cancer patients and has been associated with decreased QOL, impaired treatment outcomes, and shortened survival time. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of chemotherapy and radiotherapy. Thus, correction of even mild anemia seems to have a beneficial effect on QOL and cancer treatment outcomes. The current article describes the basis and mechanism for the use of recombinant human erythropoietin (rHuEPO, epoetin alfa), a molecular targeted therapy, for the treatment of cancer-related anemia, with a focus on lung cancer. Epoetin alfa has proven efficacy and safety in correcting anemia and improving QOL based on numerous clinical studies and over a decade of clinical practice. In addition, emerging data show that epoetin alfa may offer potential benefits beyond treating anemia, specifically in terms of treatment outcomes and cognitive function. Future research needs to be conducted to explore the potential for epoetin alfa to improve survival time in lung cancer patients.

Background The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose of a combination of vinorelbine plus gemcitabine administered on a biweekly schedule in patients with advanced solid tumors. Patients and methods Patients with advanced or refractory solid tumors included in this phase I study were treated with vinorelbine followed by gemcitabine. Vinorelbine was given intravenously over 10 min, andgemcitabine was given intravenously at an fixed-dose infusion rate of 10 mg/m2/min. Six dose levels of vinorelbine/gemcitabine were explored: 20/2000, 25/2500, 25/3000, 30/3000, 30/3500 and 30/2500 mg/m2. Results Nineteen patients were included in the study. Fourteen patients were pretreated with chemotherapy and/or radiotherapy. A total of 123 cycles of chemotherapy were administered. DLTs were neutropenic fever and grade 3 asthenia at dose level 5 (30/3500 mg/m2); at dose level 4 (30/3000 mg/m2) they were grade 3 asthenia, and a radiation-recall reaction and pneumonitis. Sixteen patients were evaluable for efficacy. Five patients had an objective response (one complete response and four partial responses), for an overall response rate of 31%. Conclusions The recommended dose for phase II study is vinorelbine 30 mg/m2 and gemcitabine 2500 mg/m2 administered once every 2 weeks. This regimen is feasible and well-tolerated at this dose, and shows a good clinical activity in all levels explored.

BACKGROUND The objective of this study was to clarify the prognostic and predictive value of immunoreactivity for the cyclin-dependent kinase inhibitor p27(Kip1) in patients with early-stage breast carcinoma and to investigate its relation with clinicopathologic features and other markers. METHODS Immunoreactivity for p27 protein was analyzed on tumor slides from 461 patients who were enrolled in the International Breast Cancer Study Group (IBCSG) Trial V (median follow-up, 13 years), including 198 patients with lymph node negative disease and 263 patients with lymph node positive disease. Tumors with < 50% immunoreactive neoplastic cells were considered low expressors. Immunoreactivity for p27 was correlated with several clinicopathologic characteristics. Disease free survival (DFS) and overall survival were analyzed according to p27 immunoreactivity and treatment group. RESULTS In the lymph node negative population, decreased p27 immunoreactivity was associated with higher tumor grade (P = 0.001) and HER-2/neu overexpression (P = 0.04). In the lymph node positive population, low p27 expression was associated with higher tumor grade (P = 0.01), low expression of thymidylate synthase (P = 0.001), and higher Ki-67 expression (P = 0.007). DFS was not significantly different according to p27 status in either lymph node negative patients (10-year DFS: low p27 expression, 53% ± 5%; high p27 expression, 55% ± 5%) or in lymph node positive patients (10 year DFS: low p27 expression, 33% ± 4%; high p27 expression, 32% ± 4%). However, in the lymph node negative population, the benefit of one course of perioperative chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil was confined exclusively to patients with tumors that showed reduced p27 immunoreactivity (P = 0.03; test for interaction). CONCLUSIONS This analysis indicates that p27 immunoreactivity has little if any prognostic value in patients with early-stage breast carcinoma. However, these findings suggest that, in patients with breast carcinoma who have negative lymph node status, reduced p27 immunoreactivity is associated with HER-2/neu overexpression and may be predictive of a benefit from the early administration of adjuvant chemotherapy. Cancer 2003;97:1591–600. © 2003 American Cancer Society. DOI 10.1002/cncr.11224

Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B(12) appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies.

BACKGROUND New chemotherapeutic agents, including paclitaxel and gemcitabine, are active in advanced bladder carcinoma, and combination regimens with these agents have shown promising results. Unlike conventional chemotherapy regimens, such as methotrexate, vinblastine, doxorubicin, and cisplatin, there are no data available on key predictive factors for response and survival with these novel agents. Since this information is needed for selection of patients for these new combinations and for stratification purposes in ongoing randomized trials, the authors aimed to study the predictive factors for response and survival to the current regimen containing cisplatin, paclitaxel, and gemcitabine. METHODS The authors studied 56 patients with advanced urothelial tumors treated on a Phase I/II trial of paclitaxel, cisplatin, and gemcitabine (TCG) to identify pretreatment characteristics that were prognostic for survival using this novel combination. The pretreatment characteristics analyzed were age, gender, Eastern Cooperative Oncology Group performance status, histopathology (pure transitional versus other), visceral (liver, lung, or bone) metastasis, number of sites of disease, lactate dehydrogenase, and hemoglobin. RESULTS The factors that were associated with a worse survival in univariate analysis were performance status > 0, presence of visceral metastasis, and more than one site of malignant disease. In a multivariate model, performance status (P = 0.044) and visceral disease (P = 0.008) showed independent statistical significance for decreased survival. Patients were then grouped based on these two independent prognostic factors. Median survival times in the groups of patients with zero, one, or two of these risk factors were 32.8 months, 17 months, and 9.6 months, respectively (P = 0.0005). CONCLUSIONS A pretreatment performance status > 0 and the presence of visceral metastasis have a profound impact on survival when using the TCG regimen. These two variables will be used to stratify patients in the upcoming Phase III randomized trial comparing this TGC regimen with a gemcitabine/cisplatin regimen in advanced urothelial tumors. Cancer 2002;95:751–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10762

BACKGROUND Currently employed high-dose regimens for patients with breast carcinoma consist mainly of single-cycle combinations of alkylating agents. In a previous Phase I trial, the authors developed a tandem high-dose combination of two cycles of mitoxantrone and cyclophosphamide for the treatment of patients with metastatic breast carcinoma (MBC) and high-risk breast carcinoma (HRBC). Treatment was delivered with granulocyte-colony stimulating factor (G-CSF) but without stem cell support to avoid potential tumor cell reinfusion. The objective was to validate the safety and obtain preliminary efficacy assessment of this combination in a Phase II trial. METHODS Fifty-three patients were included: 27 patients with MBC and 26 patients with HRBC. After standard induction treatment, patients received two cycles of mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2 separated by a 4-week interval. Patients received G-CSF and ciprofloxacin until hematologic recovery. Follow-up was performed in an outpatient setting. RESULTS One hundred one of 106 projected cycles (95%) were delivered. The mean dose intensities achieved were mitoxantrone 5.8 mg/m2 per week and cyclophosphamide 933 mg/m2 per week. Infection developed in 46% of the cycles, and platelet transfusions were required in 42%. Nonhematologic toxicity was mainly Grade 3 emesis. There were no toxic deaths. In 17 evaluable patients with MBC, 13 patients (77%) had response improvements, including 7 complete responses (41%). CONCLUSIONS Treatment with two cycles of mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2 with G-CSF but without stem cell support was well tolerated. The dose intensities achieved approach those obtained with conventional high-dose therapy. This combination warrants further investigation as an alternative to conventional high-dose regimens. Cancer 2001;92:2508–16. © 2001 American Cancer Society.

PURPOSE: To determine whether the addition of rifampin to a quinolone-based antibacterial prophylactic regimen in patients undergoing high-dose chemotherapy (HDC) with peripheral-blood stem-cell transplantation (PBSCT) decreases the incidence of neutropenia and fever, Gram-positive bacteremia, and infection-related morbidity. PATIENTS AND METHODS: Patients with solid tumors undergoing HDC with PBSCT were randomized to receive prophylactic antibiotics with either ciprofloxacin 500 mg orally every 8 hours or the same ciprofloxacin regimen with rifampin 300 mg orally every 12 hours. Prophylaxis was started 48 hours before stem-cell reinfusion. Patients were monitored to document the occurrence of neutropenia and fever, incidence and cause of bacterial infection, time to onset and duration of fever, requirement for intravenous antimicrobials, and length of hospital admission. RESULTS: Sixty-five patients were randomized to receive ciprofloxacin and 65 to receive ciprofloxacin plus rifampin, and from these groups, 62 and 61 were assessable, respectively. The proportion of patients who developed neutropenia and fever was 87% in the group treated with ciprofloxacin and 78% in the group treated with ciprofloxacin and rifampin (P = .25). Although there was a trend toward a reduction in the overall incidence of bacteremia (12 v 4 patients), and Gram-positive bacteremia (8 v 2 patients) with the addition of rifampin, none of these comparisons was statistically significant (P = .05 and P = .09, respectively). CONCLUSION: The results of this study, which demonstrate that rifampin does not improve ciprofloxacin antibacterial prophylaxis in cancer patients undergoing HDC with PBSCT support but that it does increase the occurrence of undesirable side effects, do not support the routine use of rifampin in this setting.

The prognosis of breast cancer in very young women is generally considered to be unfavourable. Therefore, the outcome of adjuvant therapy was analysed in a population of young (35 years) premenopausal patients treated in four randomised controlled trials.Between 1978 and 1993 the International Breast Cancer Study Group (IBCSG) treated 3700 premenopausal and perimenopausal patients with various timing and duration of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF with or without low-dose prednisone and oophorectomy). 314 of these women were less than 35 years old at randomisation.Relapse and death occurred earlier and more often in younger (35 years) than in older (or = 35) patients with a 10 year disease-free survival of 35% (SE 3) versus 47% (1) (hazard ratio 1.41 [95% CI 1.22-1.62], p0.001) and overall survival of 49% (3) versus 62% (1) (1.50 [1.28-1.77], p0.001). Younger patients with oestrogen-receptor positive tumours had a significantly worse disease-free survival than younger patients with oestrogen-receptor negative tumours. By contrast, among older patients the disease-free survival was similar irrespective of oestrogen-receptor status.Young premenopausal breast cancer patients treated with adjuvant CMF chemotherapy had higher risk of relapse and death than older premenopausal patients, especially if their tumours expressed oestrogen receptors. The endocrine effects of chemotherapy alone are insufficient for the younger age group and these patients should strongly consider additional endocrine therapies (tamoxifen or ovarian ablation) if their tumours express oestrogen receptors.

BACKGROUND Hospitalization and treatment with broad-spectrum intravenous antibiotics is the standard care for patients with neutropenia and fever. This randomized clinical trial evaluated the feasibility and efficacy of ambulatory care with oral ofloxacin for patients with low risk, chemotherapy-induced neutropenia and fever. METHODS Patients with solid tumors who were treated with conventional dose chemotherapy, presented with fever (axillary temperature >38°C on 2 occasions or >38.5°C on a single occasion) and neutropenia (absolute neutrophil count

Summary Background Oxaliplatin is a new cytotoxic agent from the diaminocyclohexane family with proven antitumor activity against colon cancer cell lines. Activity in patients with colorectal carcinoma previously treated with 5-fluorouracil has been studied in three single-agent phase II trials, showing a reproducible response rate of 10%. Here we report a phase II trial with oxaliplatin as a first-line chemotherapy for metastatic colorectal cancer. Patients and methods Twenty-five patients were entered in the study. All of them had metastatic disease without previous chemotherapy, and at least one lesion had to be measurable by computed tomography (CT). Therapy consisted of a two-hour infusion of oxaliplatin at a dose of 130 mg/m2 every 21 days. Results The overall response rate determined by investigators was 20% (95% CI, 6.8%–40.7%). Eight patients (32%) had stable disease. The median time to disease progression in responders was six months (range four to nine). The median progression-free survival was four months and median overall survival 14.5 months (95% CI, 10–20 months). The main toxic effects were peripheral neuropathy (92%) and laryngopharyngeal dysesthesia (75%). No severe grade 3–4 neurotoxicities (NCI–CTC) were found. Gastrointestinal and hematological toxicities were mild. Conclusions Oxaliplatin is an active agent in first-line chemotherapy for advanced colorectal cancer. It was well tolerated, caused no toxic deaths, had low hematotoxicity, well controlled gastrointestinal toxicity, and frequent but mild peripheral neurological symptoms. Therefore, it is of interest to associate oxaliplatin with other active compounds.

Background Evidence-based definitions of ‘poor-prognosis’ or ‘aggressive’ advanced breast cancer are lacking. Patients and methods We developed a prognostic factor index using data from 2203 patients treated with first-line chemotherapy plus bevacizumab for HER2-negative advanced breast cancer. Results The risk factors most closely associated with worse OS were: disease-free interval ≤24 months; liver metastases or ≥3 involved organ sites; prior anthracycline and/or taxane therapy; triple-negative breast cancer (TNBC); and performance status 2 or prior analgesic/corticosteroid treatment. Risk of death was increased threefold in patients with ≥3 versus ≤1 risk factors (hazard ratio 3.0 [95% CI 2.6–3.4; p Conclusions This prognostic index may enable identification of patients with a poorer prognosis in whom more intensive systemic regimens may be appropriate. The index may also be considered in designing new trials, although it requires validation in other datasets before extrapolation to non-bevacizumab-containing therapy. ClinicalTrials.gov identifier: NCT00448591 .

Emphasis has been put on the intensification of chemotherapy programs through high-dose chemotherapy regimens. While their myelosuppression is managed through the use of colony-stimulating factors and/or infusion of autologous peripheral blood progenitor cell transfusions (PBPCT), extramedullary dose-limiting toxicities, including gastrointestinal mucosal injury, are a treatment-limiting factor and their management is a critical issue in HSD-HDC. Octreotide is effective in the control of diarrhoea induced by fluoropyrimidines. We have studied its effect on hematopoietic support-dependent high-dose chemotherapy (HSD-HDC) related diarrhoea. HSD-HDC-treated patients were included in the study when they hador =4 loose stools per day. Diagnostic work-up included physical examination, stool culture, Clostridium difficile toxin assay, abdominal plain films, complete blood counts, liver and renal function tests. Patients were treated with 0.1 mg octreotide, q 8 h, subcutaneously for 48 h. Responding patients (or =2 loose stools per day) continued treatment at the same dose for an additional 24 h. Lack of response (or =3 loose stools per day), led to dose escalation by 0.1 mg increments, up to a 0.5 mg/dose and the latter dose was maintained for 24 h. Patients not responding at 0.5 mg/8 h were considered failures. A consecutive cohort of 24 HSD-HDC treated patients was studied. Fourteen (n = 14) (58.33%) patients developed severe diarrhoea with a median number of 7.5 loose stools per day (range, 4-11). Diarrhoea started at a median of 8 days (2-18) from day 0 of the infusion of HSD-HDC. Seven patients (50%) had less than 500 ANC/mm3 (grade 4 neutropenia) simultaneously with the diarrhoea. Twelve of 14 patients (86%) had their diarrhoea controlled, seven of them (50%) at the starting dose level of octreotide. In five of the responding patients (35.7%), octreotide had to be increased to 0.2 mg (one patient), 0.3 mg (two patients) and 0.5 mg (two patients). No toxicity was observed, while one patient had a subcutaneous hematoma at the injection site. We have concluded that octreotide appears to be safe and effective in controlling the diarrhoea induced by HSD-HDC. Prospective controlled trials are needed to confirm its value.

Summary Background: The addition of low-dose prednisone (p) to the adjuvant regimen of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) allowed patients to receive a larger dose of cytotoxics when compared with those on CMF alone. However, disease-free survival and overall survival were similar for the two groups. To test the hypothesis that low-dose prednisone might influence the efficacy of the cytotoxic regimen used, the toxicity profiles of the two treatment regimens and the patterns of treatment failure (relapse, second malignancy, or death) were examined. Patients and methods: 491 premenopausal and perimenopausal patients with one to three positive axillary lymph nodes included in International (Ludwig) Breast Cancer Study Group (IBCSG) trial I from 1978 to 1981 and randomized to receive CMFp or CMFp were analyzed for differences in long-term outcome and toxic events. The 250 patients assigned to CMF and prednisone received on the average 12% more cytotoxic drugs than those who received CMF alone. Results: The 13-year DFS for the CMFp group was 49% as compared to 52% for CMF alone, and the respective OS percents were 59% and 65%. Several toxic effects such as leukopenia, alopecia, mucositis and induced amenorrhea were reported at a similar incidence in the two treatment groups. Using cumulative incidence methodology for competing risks, we detected a statistically significant increase in first relapse in the skeleton for the CMFp group at 13 years follow-up with a relative risk (RR) of 2.06 [95% confidence interval (CI), 1.23 to 3.46; P = 0.004]. Patients with larger tumors in the CMFp regimen were especially subject to this increase with a RR for failure in the skeleton of 3.32 (95% CI, 1.57 to 7.02; P = 0.0005). CMFp-treated patients also had a larger proportion of second malignancies (not breast cancer), with RR of 3.34(95% CI, 0.91 to 12.31; P = 0.09). Conclusions: Low-dose continuous prednisone added to adjuvant CMF chemotherapy enabled the use of higher doses of cytotoxics. This increased dose had no beneficial effect on treatment outcome, but was associated with an increased risk for bone relapses and a small, not statistically significant increased incidence of second malignancies. The effects of steroids, which are widely used as antiemetics (oral or pulse injection) together with cytotoxics, should be investigated to identify their influence upon treatment outcome.

Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts. Patients diagnosed with cholangiocarcinoma must be evaluated by a multidisciplinary team and be treated with individualized management. First of all, it is very important to define the potential resectability of the tumor because surgery is the main therapeutic option for these patients. Overall, cholangiocarcinomas have a very poor prognosis. The 5-year survival rate is 5%-10%. In cases with a potentially curative surgery, 5-year survival rates of 25%-30% are reported. Therefore, it is necessary to increase the cure rate from surgery, exploring the survival benefit of any adjuvant strategy. It is difficult to clarify the role of adjuvant treatment in localized and locally advanced cholangiocarcinomas. There are limited data and the role of adjuvant chemotherapy/chemoradiation in patients with resected biliary tract cancer is poorly defined. The most relevant studies in the adjuvant setting are one from Japan, the well known ESPAC-3 and BILCAP from the United Kingdom and a meta-analysis. We show the results of these trials. According to medical oncology guidelines, postoperative adjuvant therapy is widely recommended for all patients with intrahepatic or extrahepatic cholangiocarcinoma who have microscopically positive resection margins, as well as for those with a complete resection but node-positive disease. Clinical trials are ongoing. The locally advanced cholangiocarcinoma setting includes a heterogeneous mix of patients: (1) patients who have had surgery but with macroscopic residual disease; (2) patients with locally recurrent disease after potentially curative treatment; and (3) patients with locally unresectable disease at presentation. In these patients, surgery is not an option and chemoradiation therapy can prolong overall survival and provide control of symptoms due to local tumor effects. Nowadays, no neoadjuvant therapy can be considered a standard approach for the treatment of patients with cholangiocarcinoma. There are promising results and randomized trials are needed in patients with a metastatic cholangiocarcinoma. In systemic therapy, no single drug or combination has consistently increased median survival beyond the expected 8-12 mo. It is always recommended that patients enrol in clinical trials. Clinical trials have shown that the more standard chemotherapy for a first line regimen of gemcitabine plus cisplatin (or oxaliplatin as a potentially better tolerated agent) is superior to gemcitabine alone. Leucovorin-modulated 5-fluorouracil, capecitabine monotherapy or single agent gemcitabine are reasonable options for patients with a borderline performance status. After progression in patients with an adequate performance status, active regimens that could be considered include gemcitabine plus capecitabine, or erlotinib plus bevacizumab, for second line treatment.

Germ cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10-20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatin-based chemotherapy.Paraffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatin-based chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course.The percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival.Tissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.

Purpose: This study assesses the efficacy, toxicity and pharmacokinetic profile of trabectedin with or without prophylactic dexamethasone co-treatment in patients with recurrent advanced soft tissue sarcoma (STS)., Patients and methods: Patients were randomized to receive trabectedin as a 3-h infusion every 3 weeks with dexamethasone or placebo in the first cycle, with the alternate in the second cycle and with the patient's choice subsequently. Due to toxicity, the randomized design was modified to openlabel to make dexamethasone mandatory and the initial dose (1,650 μg/m 2) was reduced to 1,500 μg/m 2 and then to 1,300 μg/m 2., Results: Forty-one patients were enrolled and 35 were evaluable for efficacy. One partial response and 18 disease stabilizations were found. The median PFS and OS were 2.1 and 10.2 months, respectively, with the 3- and 6-month PFS rates indicating activity in pretreated STS. Twenty-three and 27 patients developed transient asymptomatic grade 3/4 AST and ALT elevation, respectively, and 21 patients had grade 3/4 neutropenia. Dose reduction from 1,650 μg/m 2 to 1,300 μg/m 2 decreased the incidence of grade 3/4 thrombocytopenia (26% vs. 0%), neutropenia (51% vs. 25%) and AST increase (76% vs. 25% of patients). Four patients died due to drug-related toxicities (3 with placebo). The total body clearance of trabectedin was 28% higher and half-life was 21% lower with dexamethasone compared to placebo, with no differences in volume of distribution., Conclusions: Trabectedin has confirmed activity in patients with pretreated STS. This study shows that cotreatment with dexamethasone improves the safety of trabectedin by reducing drug-induced hepatotoxicity and myelosuppression. © Springer Science+Business Media, LLC 2010.

Summary Adjuvant systemic treatment for resectable breast cancer changes the natural history of the disease but provides only a small and delayed effect on survival. Evaluation of the types of first relapse avoided by available treatments may explain why effects on mortality are small and appear late during follow-up. In randomised clinical trials done by the International Breast Cancer Study Group (IBCSG) between 1978 and 1985, 2108 patients with node-positive disease received more-effective treatments (6 or more cycles of cyclophosphamide, methotrexate, fluorouracil and prednisone; with or without tamoxifen, or tamoxifen and prednisone alone), and 722 patients received less-effective treatments (no treatment or a single cycle of chemotherapy). 3 main categories of first site of relapse were defined and evaluated by cumulative incidence analysis: local or regional, and distant soft tissue, bone, and viscera. The more-effective treatments reduced the cumulative incidence of first relapse in local or regional and distant soft tissue sites at 10 years from 36% to 18% (p=0·0001); first relapse in bone and viscera was not altered by the more-effective treatments. These results were similar for premenopausal and postmenopausal women, and for patients with oestrogen-receptor-positive or oestrogen-receptor-negative tumours. Adjuvant systemic treatments in current use improve patient outcome mainly by reducing the incidence of first local or regional and distant soft-tissue relapses, while first recurrences in bone or viscera are influenced much less. More intensive treatments at present being tested in clinical trials might affect bone and visceral relapses and have a greater and earlier influence on survival.

Background Evaluate the safety of surgery in relation to bevacizumab in the first-line treatment of metastatic breast cancer (mBC) in two international trials. Patients and methods The incidence, type and timing of post-surgical bleeding events and wound-healing complications were assessed in surgical patients in the AVastin And DOcetaxel (AVADO) (NCT00333775) and Avastin THErapy for advaNced breAst cancer (ATHENA) (NCT00448591) trials. Both study protocols followed recommendations to withhold bevacizumab for at least 6 weeks before elective surgery and to wait 28 days (or until the wound was fully healed) after major surgery before recommencing bevacizumab therapy. Results In AVADO, 221 surgical procedures (55 major, 166 minor) were performed in 155 patients. In ATHENA, 1190 surgical procedures (435 major, 755 minor) were performed in 672 patients. One bevacizumab-treated AVADO patient (0.9%) who underwent surgery experienced a grade 3 bleeding event. In ATHENA, six patients (0.9%) who underwent surgery experienced grade 3 bleeding events and one patient (0.1%) experienced a grade 4 bleeding event. No grade 5 bleeding events in patients undergoing surgery were reported in either study. One grade 3 wound-healing complication was reported in each of the AVADO arms: placebo (n = 46, 2.2%), bevacizumab 7.5 mg/kg (n = 57, 1.8%) and bevacizumab 15 mg/kg (n = 52, 1.9%). Incidence of grade 3–4 wound-healing complications in ATHENA was 2.2% and 1.3% in patients undergoing minor or major surgery, respectively. Conclusions Surgery can be performed on patients with mBC undergoing bevacizumab therapy with a low risk of severe bleeding or wound-healing complications post surgery, if current labelling recommendations are adhered to.

HER2 over-expression and/or amplification are present in 9-38% of gastric or gastroesophageal junction (GEJ) cancers and are correlated to poor outcome. We conducted a multicentre phase II trial to evaluate trastuzumab in combination with cisplatin in patients with untreated HER2-positive advanced gastric or GEJ cancer. Chemo-naive patients with measurable, non-resectable, advanced or metastatic gastric or GEJ adenocarcinoma, with HER2 over-expression and/or amplification (IHC 3+, or IHC 2+ and FISH+), age ≥18 years, ECOG ≤2, left ventricle ejection fraction ≥50% and adequate organ function were eligible. Treatment consisted of trastuzumab (8 mg/kg on cycle 1 day 1 as loading; 6 mg/kg in subsequent cycles) and cisplatin (75 mg/m2), both intravenously on day 1, every 21 days. Twenty-two out of 228 patients (10%) were HER2-positive and were included in this phase II trial. The median age was 66 years and ECOG 0/1 was 41%/59%. The median number of cycles was 4 (range 1–41). The confirmed ORR was 32% and disease control was achieved in 64% of patients. Median time to progression was 5.1 months. Grade 3 adverse events included asthenia (27%), neutropenia (18%), anorexia (14%), diarrhoea (9%) and abdominal pain (9%). There were no grade 4 toxicities or treatment-related deaths. Higher baseline HER extracellular domain (ECD) levels were associated with better outcome in terms of response and survival. Trastuzumab in combination with cisplatin is an active regimen and has a favourable toxicity profile in advanced HER2-positive gastric or gastroesophageal cancers.

Background On the basis of clinical activity of capecitabine and gemcitabine for metastatic breast cancer, we carried out a multicenter phase II clinical trial on the combination of these two agents in advanced anthracycline-pretreated breast cancer patients. Main objectives were to assess its efficacy and safety profile. Patients and methods Seventy-six anthracycline-pretreated breast cancer patients were evaluated and were stratified according to previous treatment of advanced disease (group-1: not previously treated and group-2: previously treated). Study treatment consisted of gemcitabine 1000 mg/m2, i.v., as 30 min-infusion, days 1 and 8 every 21 days, plus oral capecitabine 830 mg/m2 b.i.d., days 1–14 every 21 days. Results Overall response rate was 61% for group-1, 48.5% for group-2 and 55.2% for the whole population. Clinical benefit rate was 73% for group-1, 80% for patients in group-2 and 76% for all patients. Median time to progression was 13.0 months for group-1, 8.2 months for group-2 and 11.1 months for the whole population. Most frequent grade 3–4 observed toxic effects per patient were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%) and hand–foot syndrome (16%). Only one patient presented febrile neutropenia. No treatment-related deaths occurred. Conclusion Combination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients.

Epirubicin 110 mg/m2 was administered intravenously every 3 weeks to 41 elderly and/or unfit, previously untreated patients with small cell lung cancer (SCLC). There were three complete responses, 16 partial responses and 14 treatment failures, with a response rate of 57% in 33 evaluable patients. The main toxicity was haematological, characterised by leukopenia and, less frequently, thrombocytopenia and anaemia. There were three toxic deaths due to infection occurring during leukopenia. Non-haematological side effects were alopecia, nausea, stomatitis and diarrhoea. WHO grade 2 cardiac toxicity was seen in 3 patients after a cumulative dose of more than 740 mg/m2. In conclusion epirubicin is an active agent in untreated SCLC.

The importance of angiogenesis in tumour growth and development is well known. Overexpression of vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, is associated with poor prognosis in cancer. As a result, several therapeutic agents that inhibit the actions of VEGF or its receptors are currently in development for use in advanced solid tumours, such breast, colorectal, lung and renal cancer. Clinical data from trials of anti-VEGF agents in this group of tumours are discussed, with a particular focus on the efficacy and safety of bevacizumab, the anti-VEGF agent at the most advanced stage of development in those tumour types. Future potential uses of bevacizumab in cancer therapy will be discussed.

Circulating epithelial tumor cells (CTCs) in peripheral blood are an ideal source for the detection of disseminated tumor cells of an easy sampling procedure. Their prognostic significance has been demonstrated in metastatic breast carcinoma and has the potential to influence the clinical management of patients with breast cancer. The aims of the present study are the evaluation of the prevalence and kinetics of CTS before and after anti-angiogenic treatment with bevacizumab (Avastin) in patients with metastatic breast cancer.

Neratinib (HKI-272) is a dual inhibitor of the tyrosine kinase receptors, erbB1 (EGFR) and erbB2 (HER2). In a phase I study, neratinib was tolerable and demonstrated antitumor activity in patients with solid tumors, including 8 of 25 evaluable patients with erbB2-positive advanced breast cancer. In an open-label, two-arm phase II study, patients with stage IIIB, IIIC or IV erbB2-positive advanced breast cancer were evaluated to further characterize the safety and efficacy of neratinib. The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 IHC staining intensity of 2+ or 3+. Neratinib has demonstrated a potent activity against trastuzumab-resistant and trastuzumab-naive HER2-positive breast cancer in a phase II study that evaluated the safety and efficacy of a daily 240 mg oral dose on 136 women with locally advanced or metastatic breast cancer (stage IIIB, IIIC or IV). The 16-week progression-free survival (PFS) rate was the primary end point. Secondary end points included safety, objective response rate and clinical benefit rate. Patients were assigned to one of two study arms based on prior treatment with trastuzumab. The efficacy analysis included 127 evaluable patients, 61 in arm A and 66 in arm B. In patients who were previously treated with trastuzumab (arm A), the 16-week PFS rate was 60%, and the median PFS was 23 weeks. The objective response rate was 26%, and the clinical benefit rate was 36%. At the present time, several phase II studies of neratinib in combination with chemotherapy (capacitabine, vinorelbine, paclitaxel and doxorubicin) are ongoing, some of them already finished. The tolerance and efficacy will be presented. A large worldwide randomized phase III study of the combination of trastuzumab versus neratinib plus paclitaxel in chemonaive advanced HER2-positive breast cancer patients will start very soon in order to determine the efficacy of neratinib compared with standard treatment.