Metronomic chemotherapy (mCHT) in metastatic triple-negative breast cancer (TNBC) patients: results of the VICTOR-6 study.

PURPOSE: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. METHODS: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). RESULTS: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines. CONCLUSION: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study.

BACKGROUND: The management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC. PATIENTS AND METHODS: Patients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P). Vandetanib (300 mg or 100 mg) or placebo was given in single oral daily doses. Gemcitabine 1000 mg/m(2) was i.v. infused on day 1 and day 8 of each 21-day cycle. The primary end point was progression-free survival (PFS). Secondary end points were: objective response rate (ORR), disease control rate, overall survival, duration of response, performance status and safety outcomes. RESULTS: A total of 173 patients (mean age 63.6 years) were recruited at 19 centers across Italy. Median (95% confidence intervals) PFS (days) were 105 (72-155), 114 (91-193) and 148 (71-225), respectively, for the V, V/G and G/P treatment groups, with no statistical difference among them (P = 0.18). No statistical difference between treatments was observed for secondary end points, except ORR, which slightly favored the V/G combination over other treatments. The proportion of patients reporting adverse events (AEs) was similar for the three groups (96.6% in V arm, 91.4% in the V/G arm and 89.3% in the G/P arm). CONCLUSIONS: Vandetanib treatment did not improve PFS in patients with advanced BTC. The safety profile of vandetanib did not show any additional AEs or worsening of already known AEs. CLINICAL TRIAL NUMBER: NCT00753675.

Nutritional management of the patient with pancreatic cancer: from the diagnostic and therapeutic pathway to an integrated hospital-territory approach.

Abstract: Pancreatic cancer is associated to a high risk of malnutrition and neoplastic cachexia even at first diagnosis. Malnutrition is a negative prognostic factor for the outcome of surgery or medical oncology treatments. Despite the good awareness of the problem and the knowledge of the guidelines, the early recognition of malnutrition and its management are still uneven, mainly due to the lack of implementation of standardized and shared protocols and the shortage of dedicated clinical nutritionists and dieticians. An early and appropriate nutritional intervention is mandatory to improve the outcome of patients with pancreatic cancer at any stage of disease. The Mini Nutritional Assessment is useful tool to screen patients malnourished or at risk of malnutrition. The need for the establishment and implementation of an integrated hospital - territorial assistance as well as a home-delivered nutrition service is discussed.

Final results of the real-life observational VICTOR-6 study on metronomic chemotherapy in elderly metastatic breast cancer (MBC) patients.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75-98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3-4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

Management of Patients with Gastric or Gastroesophageal Junction Cancer: From Theory to Integrated Clinical Path- ways Implementation in the Real World.

Introduction: Best care of esophagogastric junction and gastric cancer (EGC) requires a complex, timely interaction between members of a multi-disciplinary team (MDT). An integrated clinical pathway (ICP) is necessary to achieve this goal as well as the implementation of its use in daily practice. The objective of this study was to elaborate on an integrated clinical pathway for the multi-disciplinary management of ECG. Authors also put in act an implementation program to improve adherence to guidelines thought an ICP. Method: This prospective work carried out by a multi-institutional MDT in Italy identified expert panel extracted relevant recommendations and/or statements from published papers and guidelines obtaining a set of crucial interventions employed the Estimate-Talk-Estimate method. A flow-chart diagram was elaborated to elicit the process at a glance. The primary outcome measure was the elaboration of an ICP with a high consensus rate also reported as a snapshot diagram and its implementation in daily clinical practice. An accredited certification body agency validated results, and an implementation process was started in several hospitals known to treat ECG. Results: A methodologist aggregated a multi-disciplinary panel of experts from different institutions. The panel elaborated a flow-chart diagram with crucial intervention highlight and connecting lines, as well as outcome measures. An accredited certification body agency validated the entire process, representing the basis for empowerment and implementation among patients and oncological professionals in various hospitals. Conclusion: The multi-disciplinary and multi-institutional expert panel successfully elaborated on a validated ICP for all stages ECG. An in-hospital implementation program has been programmed.

Carboplatin and pegylated liposomal doxorubicin for advanced ovarian cancer: preliminary activity results of the MITO-2 phase III trial.

BACKGROUND: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. PATIENTS AND METHODS: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m(2) or PLD 30 mg/m(2) every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). CONCLUSIONS: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.

Metronomic chemotherapy for advanced breast cancer patients in the real world practice: Final results of the VICTOR-6 study.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3-10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8-11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3-15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.

BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33-83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.

Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM).

BACKGROUND: The aim of the study was to test the clinical efficacy and toxicity profile of gemcitabine (GEM) in combination with cisplatin (CDDP) in a series of patients affected by unresectable and/or metastatic biliary tree carcinoma (BTC) previously untreated with chemotherapy. PATIENTS AND METHODS: Overall 38 consecutive patients who satisfied eligibility criteria (10 with gall-bladder carcinoma and 28 with bile duct carcinoma) were included in this phase II study. Median age was 61 years with median PS 1. Treatment included GEM 1000 mg/m(2)/week as 30 min i.v. on days 1 and 8, and CDDP 75-80 mg/m(2) on day 1 with adequate hydration protocol and forced diuresis. Treatment was repeated every 3 weeks for three cycles before first re-evaluation of disease status. RESULTS: According to an intent-to-treat analysis a complete response (CR) was achieved in 1 patient (3%) with duration of 8 months. A partial response (PR) was recorded in 11 cases (29%; 95% CI 6% to 48%) with a median duration of 6.4 months (range 5-11 months) for an overall response rate (ORR) of 32%. Stable disease (SD) was seen in eight cases (21%), while the remaining 18 patients showed progressive disease (PD). Tumor growth control rate was 53%. Objective responses were recorded at loco-regional disease, liver and nodal metastases. Lung and peritoneal metastases did not respond. Time-to-progression was 4 months (range 2-11 months) and median overall survival was 8+ months (range 2-15 months). Side-effects were mild with few cases of grade 4 hematological toxicity. Transient and reversible liver toxicity was recorded in nearly one-quarter of patients. Infection without severe grade 4 neutropenia was observed in three cases. In no case was chemotherapy withdrawn for toxicity. CONCLUSION: The GEM/CDDP regimen is active against advanced and/or metastatic BTC with a favourable toxicity profile. This regimen represents a reasonable therapeutic choice for palliation of advanced BTC. Inferences concerning overall survival are difficult to draw due to the phase II nature of the study.

FOLFIRI with or without celecoxib in advanced colorectal cancer: a randomized phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM).

BACKGROUND: The aim of the study was to verify the efficacy and safety of the addition of celecoxib to FOLFIRI combination therapy in patients affected by advanced colorectal cancer. PATIENTS AND METHODS: Eighty-one chemotherapy-naïve patients entered in this randomized phase II trial of the GOIM (protocol no. 2301). Patients were randomized to receive FOLFIRI regimen (arm A): irinotecan 180 mg/m(2) on day 1 with LV5FU2 regimen (LV at 100 mg/m(2) administered as a 2-h infusion before FU at 400 mg/m(2) as an intravenous bolus injection, and FU at 600 mg/m(2) as a 22-h infusion immediately after 5-FU bolus injection on day 1 and 2); or FOLFIRI plus celecoxib 400 mg twice daily for 14 days (arm B). Both treatments were repeated every 2 weeks. RESULTS: Seventy-seven patients (38 in arm A and 39 in arm B) were evaluable for response. The overall response rate was 41% in arm A (95% CI 27% to 57%) and 35% in arm B (95% CI 20% to 50%). When only assessable patients were analyzed, overall response rate was 45% in arm A (95% CI 29% to 61%) and 36% in arm B (95% CI 21% to 51%). Median time to progression, median duration of response and survival were, respectively, 8 months, 9 months and 16 months in arm A, and 7 months, 9 months and 19 months in arm B. All patients were evaluable for toxicity, which was globally mild in both arms; grade 3-4 toxicity was uncommon, and gastrointestinal disturbances were the most common. CONCLUSIONS: FOLFIRI regimen is effective and well-tolerated as a first-line treatment in patients with advanced colorectal cancer. The addition of celecoxib to FOLFIRI regimen does not improve results.

Raltitrexed plus levofolinic acid and bolus/continuous infusion 5-fluorouracil on a biweekly schedule for elderly patients with advanced colorectal carcinomas.

BACKGROUND: The aim of the study was to evaluate the safety and efficacy of the raltitrexed/5-fluorouracil/levofolinic acid combination regimen as first-line chemotherapy for elderly patients with advanced/metastatic colorectal cancer. PATIENTS AND METHODS: Previously untreated patients with metastatic colorectal cancer received raltitrexed 2 mg/m(2) i.v. plus levofolinic acid and 5-fluorouracil according to the De Gramont' schedule given every 2 weeks as first-line chemotherapy. Patients were re-evaluated after six cycles and chemotherapy was continued up to tolerance or disease progression. RESULTS: Seventy patients aged >/=65 years were accrued from 11 centers between September 2001 and July 2002. According to the intention-to-treat analysis, the overall response rate was 35% (95% CI 29.5% to 40.5%) including one complete response (1%) and 24 partial responses (34%). Twenty patients (31%) showed a stabilization of disease for a tumor growth control rate of 64% (95% CI 57% to 71%). The median overall survival was 12.5 months and the median time to disease progression was 6.5 months. No toxic deaths or allergic reaction were recorded. Grade 4 toxicities were non-existent. The main hematological toxicity was grade 3 neutropenia, which occurred in 9% of patients, and grade 3 anemia in only one case, while no case of graded 3 thrombocytopenia was observed. Grade 3 non-hematological toxicities were asthenia (11%), transient increase of transaminases (10%) and diarrhea (4%). CONCLUSIONS: The results of this study suggest that the raltitrexed/5-fluorouracil/levolofinic acid combination is an effective and well tolerated regimen for the treatment of elderly patients with advanced colorectal cancer. Its ease of administration and patient's tolerance warrant further investigation over 5-fluorouracil/folinic acid regimens.

Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.

PURPOSE: To evaluate the clinical benefits of switching from morphine to oral methadone in patients who experience poor analgesia or adverse effects from morphine. PATIENTS AND METHODS: Fifty-two consecutive cancer patients receiving oral morphine but with uncontrolled pain and/or moderate to severe opioid adverse effects were switched to oral methadone administered every 8 hours using different dose ratios. Intensity of pain and adverse effects were assessed daily, and the symptom distress score (DS) was calculated before and after switching. RESULTS: Data were analyzed for 50 patients. Switching was considered effective in 80% of the patients; results were achieved in an average of 3.65 days. In the 10 patients who switched to methadone because of uncontrolled pain, a significant reduction in pain intensity (P <.005) and an average of a 33% increase in methadone doses necessary (P <.01) were found after an average of 3.5 days. DS significantly decreased from an average of 8.4 to 4.5 (P <.0005). In the 32 patients switching because of uncontrolled pain and morphine-related adverse effects, significant improvement was found in pain intensity (P <.0005), nausea and vomiting (P <.03), constipation (P <.001), and drowsiness (P <.01), but a significant increase in the methadone dose of an average of 20% (P <.004) was required. CONCLUSION: In most patients with cancer pain referred for poor pain control and/or adverse effects, switching to oral methadone is a valid therapeutic option. In the clinical setting of poor pain control, higher doses of methadone are necessary with respect to the equianalgesic calculated dose ratios previously published.

Neoadjuvant chemotherapy for stage IIIA-N2 non-small cell lung cancer.

Neoadjuvant chemotherapy in potentially resectable stage IIIA-N2 non-small cell lung cancer (NSCLC) has become standard of treatment in the last years. Two randomised pioneer phase III trials conducted with second generation platinum combinations had demonstrated an advantage in survival of induction chemotherapy followed by surgery versus surgery alone. Subsequently, a wide number of phase II studies with third generation platinum-based doublets or triplets have increased the evidence of the activity as well as the good tolerability of this approach. Nowadays, the main topics of ongoing clinical research are to assess the role of induction chemotherapy in early stage disease, and the role of induction radiotherapy, as well as definite chemo-radiotherapy in stage IIIA NSCLC. This report review these issues and focuses on current treatment options for resectable stage IIIA-N2 NSCLC.

Italian clinical research in non-small-cell lung cancer.

Lung cancer is the most common cause of cancer deaths in both men and women worldwide and has a poor prognosis. Non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers. Surgery is the only curative treatment of NSCLC but only 15-20% of tumours can be radically resected with a survival of about 40% at 5 years. Considering these disappointing results NSCLC is one of the most frequent subjects of clinical research worldwide. Italy is playing an important role in the clinical research of NSCLC performing phase I, II and III trials, prevalently by cooperative groups, and achieving important results that contributed to define the standard treatment for NSCLC patients. In particular, Italy is leader in the clinical research of the treatment of advanced NSCLC elderly patients. Today, large controlled clinical trials are ongoing. In this paper we analyse and discuss the main trials performed by Italian groups in the fields of NSCLC.

FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dell'Italia Meridionale (GOIM).

PURPOSE: To verify the experience of the GOIM in the treatment of advanced colorectal cancer patients with the FOLFIRI combination therapy. PATIENTS AND METHODS: Patients entered in three consecutive trials of the GOIM (protocols no. 9706, 9901, and 2301) were reported in this analysis. A total of 287 chemotherapy-naive patients were treated with FOLFIRI regimen: Irinotecan 180 mg/m(2) on day 1 with LV5FU2 regimen (LV at 100 mg/m(2) administered as a 2-hour infusion before FU at 400 mg/m(2) as an intravenous bolus injection, and FU at 600 mg/m(2) as a 22-hour infusion immediately after 5FU bolus injection on day 1 and 2); the treatment was repeated every 2 weeks. RESULTS: 287 patients entered in these three trials, and 264 (92%) were evaluable for response. The overall response rate was 34.5% (95% confidence interval [CI]: 29% to 40%). When only assessable patients were analyzed, overall response rate was 37% (95% CI: 31% to 43%). Median time to progression, median duration of response and survival were 7 months, 10.5 months and 14 months, respectively. All but three patients were evaluable for toxicity which was globally mild; grade 3-4 toxicity was uncommon, and gastrointestinal disturbances were the most common. CONCLUSIONS: FOLFIRI regimen is effective and well-tolerated as first-line treatment in patients with advanced colorectal cancer. Further studies needed to evaluate the improvement in results with the addition of new drugs to this combination therapy.

Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.

The purpose of the study was to evaluate the antitumor activity and the safety of paclitaxel combined with gemcitabine and cisplatin in patients affected by advanced transitional cell carcinoma of the urothelium (TCC). Eighty-five patients affected by advanced TCC and measurable disease were randomized to receive either paclitaxel at dosage of 70 mg/m2, gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks (GCP) or gemcitabine 1000 mg/m2 on days 1, 8, 15 and cisplatin 70 mg/m2 on day 2 every 4 weeks (GC). All enrolled patients were considered evaluable for response and toxicity (intention to treat). The observed response rate was 43% for GCP and 44% for GC combination, respectively. Median time to treatment failure was 32 weeks for GCP and 26 weeks for GC and overall survival 61 vs 49 weeks, respectively (p-value not significant). Grade 3-4 neutropenia was observed in 49% of patients treated with GCP vs 35% of those treated with GC (P=0.05) and grade 3-4 thrombocytopenia was observed in 36% of GCP treated patients as compared to 21% of those treated with GC (P=0.01). Seven patients over 70 years old or with poor PS were removed from the study: 6 patients from GCP group (2 toxic deaths, 2 grade 4 myelotoxicity and 2 grade 3 asthenia) and 1 from GC group was lost to follow-up after the first cycle. The combination of paclitaxel, gemcitabine and cisplatin is effective in the treatment of TCC. However, the addition of paclitaxel to the combination of gemcitabine plus cisplatin seems to increase toxicity, therefore it seems not suitable for poor PS patients and those over 70 years old. Larger and more powered studies are needed to exactly define the role of paclitaxel in this combination.

Anaemia in cancer: pathophysiology and treatment.

Anaemia in cancer patients is multifactorial and may occur as a either a direct effect of the cancer, as a result of the cancer treatment itself, or due to chemical factors produced by the cancer. The clinical symptoms of anaemia vary according to the individual's capacity to respond to blood loss or reduced red cell production. The haematological features in anaemic patients depend on the different types of malignant disease. Clinical and laboratory evaluation, and examination of the bone marrow can provide important diagnostic clues in many cases. Decisions are commonly made based on subjective consideration rather than on objective data. Blood transfusion involves many hazards, some of which may be reduced or avoided. Erythropoietin (EPO) treatment has been found to be effective in preventing anaemia and in reducing the need for blood transfusions, although it would be useful to identify high-risk patient subgroups who would benefit most from this expensive treatment. In advanced cancer patients the use of blood transfusion should be evaluated on an individual basis, according to the presence of distressing symptoms and life expectancy. These measures are unlikely to have an effect in irreversible and progressive bleeding states.

An I.T.M.O. group study on second-line treatment in advanced epithelial ovarian cancer: an attempt to identify clinical and biological factors determining prognosis.

The aim of the present study was to determine the activity of a combined regimen of mitoxantrone (DHAD) and ifosfamide (IFO) and identify clinical and biological factors with prognostic importance for the second-line treatment of ovarian cancer. The following factors were investigated for their prognostic importance: age, disease sites, platinum responsiveness, histological grade, the presence of clinically/radiologically detectable versus not detectable disease, residual disease volume after first surgery, p53 protein, c-erbB-2 oncoprotein and laminin receptor. 72 patients entered the trial. DHAD and IFO therapy led to a 15% response rate among the 47 cases with clinically/radiologically detectable disease (1 complete and 6 partial responses), with a median response duration of 4 months. The response rate was significantly different according to platinum responsiveness (4% objective responses in platinum-resistant versus 27% in platinum-sensitive disease). The time to treatment failure (TTF) and overall survival (OS) were affected by the presence of clinically detectable disease at study entry (median TTF 4 months in the presence of clinically/radiologically detectable disease versus 9 months if the disease was not similarly detectable, P = 0.02; median OS 10 months versus 21 months, P = 0.01). Initially overexpressed in only a few tumours, the c-erbB-2 oncoprotein became overexpressed in 36% of platinum-resistant tumours; this modulation did not occur in platinum-sensitive tumours. Furthermore, laminin receptor was expressed in 77% of platinum-sensitive versus 39% of platinum-resistant patients. There were no differences in p53 protein expression according to drug responsiveness.

Subcutaneous recombinant-human-erythropoietin prevents chemotherapy-related anemia in patients with advanced cancer.

Nineteen patients with advanced cancer were randomly allocated to receive: (i) rhEpo 150 UI/kg subcutanously three times/week starting 24 hours after the completion of cisplatin- or carboplatin-based chemotherapy; or (ii) normal saline. There were 17 patients with advanced head and neck carcinoma and 2 patients with small cell lung cancer. Patients were monitored for hemoglobin level, hematocrit, WBC, PLT and reticulocytes. Patients who received rhEpo overall showed a 7.2 +/- 6.3% mean increase in Hb level over their pretreatment values, while control patients had a 26.4 +/- 12% decrease. This difference was statistically significant (p<0.001). No patients in the rhEpo group required transfusion, while 4 patients in the control group received packed red cell transfusion. No significant side-effects attributable to rhEpo were recorded, but 1 patient showed a transitory increase in PLT count. In conclusion, subcutaneous rhEpo may be safely administered to patients with advanced cancer and effectively prevents cisplatin- or carboplatin-related anemia.