Sex-Related Differences in Impact on Safety of Pharmacogenetic Profile for Colon Cancer Patients Treated with FOLFOX-4 or XELOX Adjuvant Chemotherapy.

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. MATERIALS AND METHODS: This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. RESULTS: Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48-4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69-3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. CONCLUSIONS: Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. IMPLICATIONS FOR PRACTICE: The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial.

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Position paper on management of iron deficiency in adult cancer patients.

INTRODUCTION: Disorders of iron metabolism are commonly seen in onco-hematological clinical practice. Iron-deficiency anemia and cancer-associated anemia are usually treated with supportive therapies. Optimal management of these conditions are discussed in this perspective paper. Areas covered: A position paper discussing a number of hot topics on anemia in cancer patients is presented. The main areas covered by experts in the field are: definitions, prevalence and consequences of anemia and iron deficiency, incidence of anemia resulting from targeted therapies, importance of anemia diagnosis and monitoring, evaluation of iron status before and during treatment, role of transfusions and erythropoiesis-stimulating agents, management of iron deficiency with or without anemia, parenteral iron supplementation, role of new oral iron formulations, safety and cost issues regarding different iron compounds and administration routes. Expert commentary: Despite the availability of newer therapeutic options for its management, anemia still represents a major complication of treatment in cancer patients (surgery, chemotherapy, radiotherapy, targeted therapies), aggravating physical impairment, and negatively affecting general outcome. The view expressed by the panelists, attendees of the 4th Mediterranean Course on Iron Anemia, summarizes what they consider optimal clinical practice for screening, diagnosis, treatment and monitoring of iron deficiency and anemia in cancer patients.

Dose-dense adjuvant chemotherapy in premenopausal breast cancer patients: A pooled analysis of the MIG1 and GIM2 phase III studies.

BACKGROUND: No evidence exists to recommend a specific chemotherapy regimen in young breast cancer patients. We performed a pooled analysis of two randomised clinical trials to evaluate the efficacy of adjuvant dose-dense chemotherapy in premenopausal breast cancer patients and its impact on the risk of treatment-induced amenorrhoea. PATIENTS AND METHODS: In the MIG1 study, node-positive or high-risk node-negative patients were randomised to 6 cycles of fluorouracil/epirubicin/cyclophosphamide every 2 (dose-dense) or 3 (standard-interval) weeks. In the GIM2 study, node-positive patients were randomised to 4 cycles of dose-dense or standard-interval EC or FEC followed by 4 cycles of dose-dense or standard-interval paclitaxel. Using individual patient data, the hazard ratio (HR) for overall survival by means of a Cox proportional hazards model and the odds ratio for treatment-induced amenorrhoea through a logistic regression model were calculated for each study. A meta-analysis of the two studies was performed using the random effect model to compute the parameter estimates. RESULTS: A total of 1,549 patients were included. Dose-dense chemotherapy was associated with a significant improved overall survival as compared to standard-interval chemotherapy (HR, 0.71; 95% confidence intervals [CI], 0.54-0.95; p = 0.021). The pooled HRs were 0.78 (95% CI, 0.54-1.12) and 0.65 (95% CI, 0.40-1.06) for patients with hormone receptor-positive and -negative tumours, respectively (interaction p = 0.330). No increased risk of treatment-induced amenorrhoea was observed with dose-dense chemotherapy (odds ratio, 1.00; 95% CI, 0.80-1.25; p = 0.989). CONCLUSION: Dose-dense adjuvant chemotherapy may be considered the preferred treatment option in high-risk premenopausal breast cancer patients.

The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib.

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

That tumor you're going to get tomorrow maybe: making an informed decision.

With the recent progress in predictive medicine several problems have emerged regarding the ethical aspects of genetic testing. The role of the doctor in communicating the consequences of such testing to the patient has become more important than ever in allowing the potential patient to make an informed decision.

[Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy]. / Scelte terapeutiche e trattamento con sorafenib nell'epatocarcinoma: analisi finale dello studio GIDEON in Italia.

INTRODUCTION: Sorafenib, an oral multikinase inhibitor, is the only targeted agent approved for the treatment of patients with hepatocellular carcinoma (HCC) after demonstration to increase overall survival compared to placebo in two randomized phase III study. GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) is the largest, global, non-interventional, prospective study of patients with uHCC (n>3200) treated with sorafenib in real-life clinical practice conditions. Here we report the final analysis of safety and efficacy in the Italian cohort of patients. METHODS: Patients with unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Patients demographics disease characteristics and treatment history were recorded at baseline visit. Sorafenib dose, concomitant medications, performance status, liver function, adverse events and efficacy (survival and response rate) were collected throughout the study. RESULTS: In the Italian cohort of the GIDEON study 278 patients were included in 36 centers. The global rate of adverse events was 81%. Drug-related events accounted for 67%, mostly of grade 1 and 2, and only 8% were classified as serious. The most common were diarrhea (24%), fatigue (23%), dermatological (14%), rash/exfoliation (10%), hypertension (9%), hemorrage/bleeding of gastrointestinal tract (6%). Overall survival was 14.4 months and time to progression 6.2 months. Objective responses were observed in 14 patients (5%) with 3 complete responses (1%). Stable diseases of at least 6 weeks were observed in 113 patients (41%) with a 30% of disease control rate. DISCUSSION: The safety profile of sorafenib in terms of rate and type of adverse events is similar to that emerged in the global international GIDEON study as well as in the pivotal registration studies.

FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies.

OBJECTIVE: The use of neoadjuvant chemotherapy can enable surgical resection of borderline resectable or unresectable pancreatic cancer (PC). The aim of this study was to evaluate the effectiveness of the multiagent 5-fluorouracil + oxaliplatin + irinotecan + leucovorin (FOLFIRINOX) regimen as a neoadjuvant treatment for PC. METHODS: Studies in which FOLFIRINOX with or without radiotherapy was given before surgery to patients with borderline resectable or unresectable PC were analyzed using a meta-analytical approach. The primary outcomes were resection rate and radical (R0) resection rate. Data were expressed as weighted pooled proportions with 95% confidence intervals (CIs). RESULTS: Thirteen studies, with a total of 253 patients, were included in this meta-analysis. After undergoing the treatment, 43% (95% CI, 32.8-53.8) of patients were resected and 39.4% (95% CI, 32.4-46.9) underwent R0 resection (85% of surgical specimens). In particular, among borderline resectable PCs, R0 resection was possible in 63.5% (95% CI, 49%-76%) of the cases. The rate of R0 resection in unresectable PCs was 22.5% (95% CI, 13.3-35.4). CONCLUSIONS: This meta-analysis shows that down-staging after neoadjuvant FOLFIRINOX-based therapy is noticeable in patients with borderline resectable/unresectable PC, with a total R0 resection rate of 40%.

Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial.

BACKGROUND: Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. METHODS: In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. FINDINGS: Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p<0·0001). Addition of fluorouracil led to increased rates of grade 3-4 neutropenia (354 [34·5%] of 1025 patients on FEC-P vs 250 [24·2%] of 1032 patients on EC-P; p<0·0001), fever (nine [0·9%] vs two [0·2%]), nausea (47 [4·6%] vs 28 [2·7%]), and vomiting (32 [3·1%] vs 15 [1·4%]). INTERPRETATION: In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome. FUNDING: Bristol-Myers Squibb, Pharmacia, and Dompè Biotec.

Genetic markers for toxicity of adjuvant oxaliplatin and fluoropyrimidines in the phase III TOSCA trial in high-risk colon cancer patients.

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II-III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3-4 CTCAE toxicity events (grade 2-4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.

Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study.

BACKGROUND: The RAF-MEK-ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations. A phase II randomized trial was designed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer. METHODS: Locally advanced or metastatic pancreatic adenocarcinoma patients were randomized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400mg bid (arm A) or without sorafenib (arm B). RESULTS: One hundred and fourteen patients were enrolled; of these, 43 (74.6%) patients progressed in arm A and 44 (82.4%) in arm B. Median progression-free survival was 4.3 months (95% CI: 2.7-6.5) and 4.5 months (95% CI: 2.5-5.2), respectively (HR=0.92; 95% CI: 0.62-1.35). Median overall survival was 7.5 (95% CI: 5.6-9.7) and 8.3 months (95% CI: 6.2-8.7), respectively (HR=0.95; 95% CI: 0.62-1.48). Response rates were 3.4% in arm A and 3.6% in arm B. CONCLUSIONS: Sorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients, and therefore should not be assessed in phase III trials.

Dose-dense FEC followed by dose-dense ixabepilone as neoadjuvant treatment for breast cancer patients: a feasibility study.

BACKGROUND: Ixabepilone is an effective chemotherapy in metastatic breast cancer that has been pretreated with anthracyclines and is resistant or refractory to taxanes. Adjuvant dose-dense (DD) chemotherapy is more effective than regimens administered every 3 weeks, especially in hormonal receptor (HR)-negative tumors. METHODS: A feasibility study of neoadjuvant DD ixabepilone was conducted in breast cancer patients with tumors measuring at least 2 cm. Patients received 5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2) ("FEC" in combination) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor (filgrastim) followed by ixabepilone 40 mg/m(2) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor. The study's primary endpoint was feasibility, and the secondary endpoint was pathologic complete response. A two-stage Simon's design was adopted. RESULTS: Forty-seven patients were enrolled, and 42 were evaluable. For 10 of 42 patients, DD ixabepilone was not feasible. Six (14%) required ixabepilone interruption, and four (9.5%) required ixabepilone dose reduction of 25%. One toxic death occurred. Hematologic grade 3-4 toxicities included anemia (9.5%), grade 4 neutropenia (2.4%), febrile neutropenia (4.8%), and thrombocytopenia (2.4%). Nonhematologic grade 3-4 toxicities consisted of fatigue (14.3%), mucositis (14.3%), sensory neuropathy (7.1%), onychopathy (7.1%), and liver toxicity (4.8%). Grade 2 sensory neuropathy lasting longer than 7 days was recorded in 11.9% of patients. Pathologic complete response was observed in 16 of 42 patients (38.1%), including 11 of 23 (47.8%) with HR-negative tumors and 5 of 19 (26.3%) with HR-positive tumors. CONCLUSION: Despite high activity, DD ixabepilone after DD FEC is poorly tolerated.

A rare case of metastatic pancreatic hepatoid carcinoma treated with sorafenib.

BACKGROUND: Hepatoid carcinoma (HC) is a rare histopathological tumor type with prominent features of hepatoid differentiation, and while most of the reported cases are of gastric origin, ten cases of pancreatic HC have been reported to date. The majority of HC cases are metastatic at presentation, mainly to the liver, lymph nodes, and lungs. They are aggressive, invading, and proliferating in the venous and lymphatic systems, with a behavior similar to that of hepatocellular carcinoma. Diagnosis is challenging: alpha-Fetoprotein, the most useful marker, is not always positive. METHODS: We present the first case of metastatic pancreatic HC treated with sorafenib, an oral multikinase inhibitor approved for advanced hepatocellular carcinoma that has antiangiogenic, pro-apoptotic, and raf-kinase inhibitory properties. RESULTS: The patient, a 37-year-old male, was diagnosed with hepatoid carcinoma of the pancreas that had metastasized to liver, lungs, and lymph nodes. The cytokeratin (CK) profile was useful for the diagnosis: Both the hepatoid and adenocarcinoma components of the tumors were CK18+, CK19+, and CK20+/-, whereas normal and neoplastic hepatocytes are CK18+, CK19-, and CK20-. Amylase, lipase, and liver enzyme levels were elevated, but bilirubin was normal. Treatment with sorafenib resulted in more than 7 months of progression-free survival. Therapy was discontinued after 8 months when his bilirubin level increased dramatically. Signs of liver failure resolved temporarily with insertion of a biliary stent, but his condition deteriorated and he died 3 months later, 1 year after diagnosis. CONCLUSION: In the absence of evidence-based experience with this rare and aggressive tumor and given its similarities with hepatocellular carcinoma, sorafenib should be considered as a possible treatment.

Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials.

BACKGROUND: Iron supplementation could improve the hematopoietic response of erythropoiesis-stimulating agents (ESAs) used for chemotherapy-induced anemia. METHODS: We performed a meta-analysis of randomized, controlled trials by comparing parenteral or oral iron and no iron, when added to ESAs in anemic cancer patients, in order to calculate the relative risk (RR) of hematopoietic response and transfusions, the time required to reach this response, and toxicity. RESULTS: A total of 1,606 patients out of eight trials were available for meta-analysis. The RR of obtaining an hematopoietic response was 1.29 (P = 0.0001) with parenteral iron and 1.04 for oral iron (P = 0.59). The risk of transfusion was reduced with parenteral iron versus no iron (RR 0.77; P = 0.02) but not with oral iron (RR 0.68; P = 0.08). The time to reach hematopoietic response was 1 month shorter and no increased toxicity appeared with iron supplementation. CONCLUSION: Overall parenteral iron reduces the risk of transfusions by 23% and increases the chance of hematopoietic response by 29% when compared with ESAs alone. On the contrary, oral iron does not increase hematopoietic response nor transfusion rate. The significance of these results is that the proportion of non-responders to ESAs will have strongly improved and quality of life and cost ameliorated.

A patient presenting nasal septum perforation during bevacizumab-containing chemotherapy for advanced breast cancer.

Nasal septum perforation is a rare but described complication of the anti-angiogenetic agent bevacizumab. This is the case of a 48-year-old female breast cancer patient, who developed a nasal septum perforation during treatment with paclitaxel and bevacizumab for advanced disease. After 2 cycles the patient developed nasal irritation and occasional epistaxis; after the 4th cycle with bevacizumab the symptoms worsened to include nasal congestion, major epistaxis and rhinorrhoea. Anterior rhinoscopy revealed a large perforation involving the antero-inferior portion of the cartilaginous nasal septum surrounded by necrotic mucosa. The upper septum and the columellar strut were intact. The patient denied use of cocaine or other intranasal irritants. Bevacizumab was discontinued and with only a topical intranasal vitamin application the symptoms improved. One month later anterior rhinoscopy showed that the lesion healed and normal mucosa surrounded the previous site of perforation. The patient continued successfully with other chemotherapy regimens (gemcitabine and then vinorelbine) until irreversible progressive disease led to her death in February 2010. Thus far 8 other cases of bevacizumab-related nasal septum perforation have been published: 5 patients with colorectal cancer, 2 patients with breast cancer and 1 with ovarian cancer. Nasal septum perforation is an emerging challenge with targeted therapies and in particular with antiangiogenetic or antivascular agents. A rapid diagnosis is important and hence we recommend that patients undergoing treatment with bevacizumab and presenting with nasal symptoms (epistaxis, crusting, rhinorrhoea, nasal congestion and local pain or irritation) should undergo anterior rhinoscopy immediately.

Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials.

The aim of this meta analysis was to evaluate the benefit of adding concomitant trastuzumab to neoadjuvant(anthracycline and taxane-based) chemotherapy, which was assessed based on two published randomized controlled trials. The eligible patients were randomized to receive either neoadjuvant chemotherapy alone or with concurrent administration of trastuzumab. Relative risks(RRs) with 95% confidence intervals of pathologically complete response in breast and nodes, relapse-free survival, overall survival, and cardiotoxicity were calculated.The RR of obtaining a pathologically complete response in breast and nodes was 2.07 in the experimental arms(1.41­3.03; P = 0.0002; P for heterogeneity 0.63; fixed effect model). The RR of being disease free was 0.67 in favor of the experimental arms (0.48­0.94; P = 0.02; P for heterogeneity 0.22; fixed affect model). The RR of being alive was 0.67 in favor of the experimental arms (0.39­1.15;P= 0.15). The RR of a cardiac event was 1.09 in the arms treated with chemotherapy and concomitant trastuzumab, but that is not significant (0.6­1.98; P =0.77). The addition of concomitant trastuzumab to neoadjuvant chemotherapy doubles the risk of obtaining a pathologically complete response in both breast and nodes compared with controls. Trastuzumab significantly reduces the risk of relapse and does not increase the risk of cardiotoxicity,despite being associated with anthracyclines. The largest benefit was observed in a locally advanced patient study.

What else in gemcitabine-pretreated advanced pancreatic cancer? An update of second line therapies.

Advanced pancreatic cancer is usually treated with first-line gemcitabine (GEM) (alone or in combination). More recently, GEM has become an established part of an adjuvant therapy based on two recently-reported randomized trials. There remains unresolved the problem of second-line therapy in patients relapsed during or after adjuvant or first-line GEM-based treatment. As of today, platinum analogues in combination with fluoropyrimidine or with GEM represent the most common schedule in clinical practice with data from single-centre or multicentric phase II studies. In 2008, for the first time, a randomized phase III trial conducted on good performance status GEM-refractory patients (CONKO 003) confirmed their benefit in progression-free and overall survival by adding oxaliplatin to a bolus 5-FU/folinic acid schedule. Other agents (irinotecan, taxanes, antifolates, biological) have been tested, although only dismal results have been achieved, as they turned out to be too toxic in combination and to have too low activity when used as single agents. Which the optimal candidate is for second-line therapies, is debatable. Good performance status and discrete progression-free survival since the beginning of the GEM therapy (more than 6 months?) are likely to be the best indicators of subsequent line benefit. The benefit of biological agents is unknown, also given the poor results achieved in the first-line treatment. In summary, as of today, there is one randomized study that confirms the benefit of second-line chemotherapy for the treatment of GEM-relapsed pancreatic cancer. Current data indicate 5-FU plus a platinum agent (oxaliplatin) as the standard of care for PS 0-1 patients. Ongoing clinical trials will clarify whether there is obviously a place for improvement and for other agents. At present, even though no data on benefits in unfit patients (Karnofsky < 70) are available, a fluopyrimidine agent still remains a reasonable treatment option.

Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomized controlled trial.

BACKGROUND: Promising findings obtained using a weekly regimen of 5-fluorouracil (5-FU), epidoxorubicin, leucovorin (LV), and cisplatin (PELFw) to treat locally advanced and metastatic gastric cancer prompted the Italian Group for the Study of Digestive Tract Cancer (GISCAD) to investigate the efficacy of this regimen as adjuvant treatment for high-risk radically resected gastric cancer patients. METHODS: From January 1998 to January 2003, 400 gastric cancer patients at high risk for recurrence including patients with serosal invasion (stage pT3 N0) and/or lymph node metastasis (stage pT2 or pT3 N1, N2, or N3), were enrolled in a trial of adjuvant chemotherapies; 201 patients were randomly assigned to receive the PELFw regimen, consisting of eight weekly administrations of cisplatin (40 mg/m2), LV (250 mg/m2), epidoxorubicin (35 mg/m2), 5-FU (500 mg/m2), and glutathione (1.5 g/m2) with the support of filgrastim, and 196 patients were assigned to a regimen consisting of six monthly administrations of a 5-day course of 5-FU (375 mg/m2 daily) and LV (20 mg/m2 daily, 5-FU/LV). Disease-free and overall survival were estimated and compared between arms using hazard ratios (HRs) and Kaplan-Meier estimates. All statistical tests were two-sided. RESULTS: The 5-year survival rates were 52% in the PELFw arm and 50% in the 5-FU/LV arm. Compared with the 5-FU/LV regimen, the PELFw regimen did not reduce the risk of death (HR = 0.95, 95% confidence interval [CI] = 0.70 to 1.29) or relapse (HR = 0.98, 95% CI = 0.75 to 1.29). Less than 10% of patients in either arm experienced a grade 3 or 4 toxic episode. Neutropenia (occurring more often in the PELFw arm) and diarrhea and mucositis (more prevalent in the 5-FU/LV arm) were the most common serious side effects. Nevertheless, only 19 patients (9.4%) completed the treatment in the PELFw arm and 85 (43%) patients completed the treatment in the 5-FU/LV arm. CONCLUSIONS: Our study found no benefit from an intensive weekly chemotherapy in gastric cancer. The extent of toxicity experienced by the patients in the adjuvant setting suggests that, in gastric cancer, chemotherapy may be more safely administered preoperatively.

Optimizing use of opiates in the management of cancer pain.

Cancer pain is often suboptimally managed. The underestimation and undertreatment continues to be a problem despite the availability of consensus-based guidelines. Most patients with cancer develop pain. The prevalence and severity of pain among cancer patients varies according to primary and metastatic sites and stage of disease. Opioid therapy is the cornerstone of management of severe chronic pain in the field of cancer patients and in general in palliative care medicine. Since this class of drugs is the cornerstone of the treatment, optimizing its use may be useful in clinical practice. For this purpose we focused on 4 distinct issues: 1) How to implement the use the opioids in cancer patients; 2) How to optimise the use of morphine in cancer patients; 3) The management of side effects and opioid switching; 4) What is the role of other potent opioids. A holistic approach including an appropriate use of opioids may improve pain control in most cancer patients, particularly for those with advanced disease.