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Purpose: To assess the healthcare resources’ consumption and integrated costs of patients with renal cancer and new metastasis (mRCC), in the perspective of the Italian National Health System (NHS). Methods: From the ReS database, through the administrative data record linkage, adults with a primary/secondary hospital (ordinary/daily admissions) diagnosis (ICD9-CM code) of renal cancer and lymph node and/or distant metastases in the same hospital discharge (index date) were selected in 2015. Metastases were defined new if they were absent in the 2 previous years. Patients were described in terms of gender, age (mean ± SD) and comorbidities of interest. The 2-year survival and annual pharmacological treatments, hospitalization, outpatient specialist services and costs were analysed. Results: Out of >6 million adults in the 2015 ReS database, 133 (2.1 × 100,000) were hospitalized with a diagnosis of RCC and metastasis. Patients with new metastases were 63.2% (1.4 × 100,000; 73.8% males; mean age 68 ± 13). Hypertension was the most common comorbidity (70.2% of mRCC patients). The 2-year survival of mRCC patients was 26.2%. During 1-year follow-up, at least a drug was prescribed to 88.1% of mRCC patients (on average € 12,095/patient), 91.7% were hospitalized (€ 8,897/patient) and 82.1% entrusted the outpatient specialist care (€ 1,075/patient). The mean overall expenditure for the NHS was € 22,067 per capita. Conclusions: This study shows the mRCC burden on the Italian real clinical practice and its economic impact in the perspective of the NHS. Real-world analyses prove to be useful to concretely estimate the overall healthcare responsibility on patients affected by mRCC.

Breast cancer is the second leading cause of cancer death worldwide. The economic burden of breast cancer is crucial for the sustainability of healthcare systems. The objective of this study was to estimate the burden of HR+/HER2− metastatic breast cancer (MBC) in Italy, in terms of incidence, prescription patterns, healthcare resource utilisation and costs for the National Health System (NHS). A cohort study based on healthcare administrative data (ReS database), covering > 10 million Italians, was performed. Incident cases of HR+/HER2− MBC were identified among adult women in 2013. The cohort was followed-up for 2 years to describe healthcare utilisation and integrated costs (pharmaceuticals, hospitalisations and outpatient services) for NHS. Prescription patterns were described as first-line choice and therapeutic changes. Specific therapeutic changes were used as proxies of disease progression. A survival analysis was performed to estimate the time from diagnosis to first disease progression. Of 5174,723 women, 355 cases of de novo HR+/HER2− MBC were selected (incidence: 6.9 per 100,000). During the 1st follow-up year, they generated an average cost of €7543, whereas €4834 in the 2nd year. The 85.9% received a monotherapy, while the 14.1% received a combination therapy. The most used monotherapy was nonsteroidal-aromatase-inhibitors (45.9%), while the most prescribed combination was tamoxifen + luteinizing hormone releasing hormone (LHRH) analogues (6.2%). Therapeutic changes occurred in 45.4% of patients, especially from chemotherapy to nonsteroidal-aromatase-inhibitors, after an average of 276.8 days from the first treatment. Disease progression was identified in 22.5% of patients occurring after a mean 13 ± 6 months from diagnosis. This detailed picture of HR+/HER2− MBC, based on real-world data, could be helpful in health technology assessment and expenditure forecasts of future therapeutic strategies for this condition in Italy.

The approval of clinical pathways (CPWs) represents a key step to focus the care management on the patient. The PDTA Net project, by ReS Foundation and CINECA, aims to create a reference tool to study how the local organizational models influence healthcare and clinical outcomes. The article shows the analysis of all CPWs approved by Italian Regions and Autonomous Provinces until 31/12/2018. The search for documents was performed on the institutional websites through specific keywords. CPWs were filled into a database, according to the Region, publication year, disease of interest (distinguishing between chronic diseases with high epidemiological impact and rare diseases) and relevant clinical area. All documents were analyzed by geographical and temporal distribution, the latter also according to ministerial measures. From 2005 to 2018, 536 Regional CPWs were approved (316 for chronic diseases with a high epidemiological impact and 220 for rare diseases). The Regions with the highest number of CPWs of chronic diseases were Umbria (34 CPWs) and Piemonte (33). The most addressed clinical areas were: oncology (72), neurology (60), cardiology (34) and metabolic disorders (22). The most issued diseases were: diabetes (17), trauma/polytrauma (15), chronic obstructive pulmonary disease and multiple sclerosis (12 each), stroke (11), rheumatoid arthritis, breast cancer and colorectal neoplasms (10 each). The publication of the documents was affected by ministerial measures (Balduzzi Law, National Chronicity Plan, Diabetic Disease Plan and National Dementia Plan). The majority of CPWs on rare diseases was retrieved in Regions with activated Rare Disease Networks: Lombardia (110 CPWs), Lazio (64) and Toscana (17). This study showed that, to date, in Italy there are several CPWs published at Regional level, nevertheless their structure and application are heterogeneous and strongly influenced by the National Plans. All analyzed documents are available through the web platform of the project https://fondazioneres.it/pdta/. This project could be useful for health system stakeholders, in order to encourage the transition to new health governance and making CPWs effective governance tools.

Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third-line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists. Keywords Advanced NSCLC; Observational study; Chemotherapy; Platin-based chemotherapy; Pemetrexed; Docetaxel; Targeted therapy; Erlotinib

We have previously shown that acute psychological stress alerts the adaptive immune response causing an increase in antigen-experienced effector T cells in the peripheral blood. T regulatory cells (Tregs) play a central role in maintaining self-tolerance and controlling autoimmune responses. Here, we analyzed for the first time the behaviour of Tregs in the context of a stress-induced activation of the adaptive immune response. 31 healthy young males underwent a brief laboratory stressor and, in a crossover design, served as their own unstressed controls. We quantified effects of acute stress on CD4(+)FOXP3(+) T regulatory cells and other T cell subpopulations using flow cytometry. In addition, the expression of Treg-related effector molecules and stress hormone receptors were analyzed in the subjects' peripheral T cells. We confirmed our previous observation of a stress-induced decrease in CD45RA(+)CCR7(+) "naïve" and CD45RA(-)CCR7+ "central memory" T cells while CD45RA(-)-CCR7(-) "memory effector" and CD45RA(+)CCR7(-) "terminally differentiated" effector T cells remained stable or increased. Importantly, we found acute psychological stress to cause a concomitant decrease in CD4(+)FOXP3(+) Tregs and in CD4(+) T cells expressing Treg-related effector molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4) and latency associated peptide (LAP). Finally, we observed beta(1)-adrenergic and glucorticoid alpha receptors to be overexpressed in Tregs, suggesting that these molecules might mediate stress-related effects on Tregs. In conclusion, inhibiting components of the adaptive immune response, like Tregs, are down-regulated during a stress-induced activation of the adaptive immune response. In situations of chronic stress, this scenario might result in an exacerbation of inflammatory conditions such as autoimmune diseases.

Purpose, patients and methods This retrospective analysis of the BRAVE study evaluated the impact of baseline risk factors and antithrombotic therapy on the risk of thrombovascular events (TVEs) in patients receiving epoetin compared to patients not receiving epoetin. Results Baseline risk factors have a significant impact on TVE risk under epoetin therapy. More than 2 risk factors increased the risk of TVEs in patients receiving epoetin (hazard ratio [HR] 2.89, confidence interval [CI] 1.04–8.02, p value [ p ] = 0.04). In patients on epoetin without antithrombotic therapy, the risk for TVEs was higher (HR 4.11, CI 1.37–12.4, p = 0.01) compared to those who received antithrombotics (HR 1.37, CI 0.59–3.18, p = 0.45). Conclusions Our analysis has identified several risk factors which may impact the risk of TVEs under epoetin therapy. These data suggest that antithrombotic therapy may have the potential to reduce the risk of TVEs under epoetin therapy. These findings are hypothesis-generating and need to be confirmed in a prospective, randomised study.

Purpose The Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC). Patients and Methods BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia–free survival, Hb response, safety, and quality of life (QoL). Results After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia–free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value. Conclusion In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.

We report the experience of the EBMT Solid Tumours Working Party (STWP) using high-dose chemotherapy (HDCT) with PBPC support in patients with non-small cell lung cancer (NSCLC). Between 1989 and 2004, 36 NSCLC patients (27 men and 9 women), median age 53.5 years (range: 24-62) were treated with 63 HDCT courses. A high-dose carboplatin-based regimen was used in 53% of the cases. Thirty-two patients had relapsed/metastatic disease, while four classified as stage IIIB received HDCT followed by radiotherapy. No treatment-related death occurred. Of 25 patients who were planned to receive multi-cycle HDCT, 4 cases (16%) interrupted the treatment early due to prolonged severe toxicities and 4 (16%) due to progressive disease. Of 36 evaluable patients, 3 (8%) achieved a complete remission and 13 (36%) had a partial remission at an overall response rate of 44%. Of these, one patient with stage IIIB and one with stage IV are alive disease free at 71+ and 149+ months, respectively. After a median follow-up of 48 months (range: 6-149), median survival was 7 months (range: 1-149). Despite one anecdotal case, HDCT did not show significant activity, but induced relevant morbidity in NSCLC patients.

We verified the feasibility of a multi-cycle peripheral blood progenitor cell (PBPC)-supported high-dose chemotherapy (HDC) regimen in patients with non-small cell lung cancer (NSCLC). The HDC regimen consisted of a single course of high-dose epirubicin given in combination with cisplatin plus filgrastim, followed by three courses of high doses of carboplatin and paclitaxel with PBPC reinfusion and filgrastim. Of the 16 enrolled patients, 13 provided an adequate number of PBPCs by a single leukapheresis, while in the three needed two procedures, with a median number of CD34+, CD34+/CD33- and CD34+/CD38- cells collected per patient was 13.5 x 10(6), 10.9 x 10(6) and 0.9 x 10(6)/kg, respectively. No toxic death occurred, and the collected PBPCs supported a rapid hematopoietic reconstitution after HDC; however, seven patients early interrupted the treatment early due to early progressive disease (n=4) or prolonged grade 3 peripheral neurotoxicity (n=3). Despite an overall response rate of 42%, the median survival for stage IV patients has been 5 months (range: 1-25+). Of two patients with stage IIIB NSCLC, one is continuously disease-free at 71+ months, while of 14 with stage IV disease, one is currently alive with disease at 25+ months. In conclusion, the combination of high-dose epirubicin with cisplatin plus filgrastim is an effective regimen in releasing large amounts of PBPCs, which can then be safely employed to support multiple courses of HDC. Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel are ineffective in treating patients with advanced NSCLC.

The randomized multicenter study on rapidly proliferating breast cancer, assessed according to thymidine labelling index (TLI), was activated at the end of the 1980s. The present work investigated whether and to what degree the short-term advantages observed from adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) were maintained at a longer follow-up. Two hundred and eighty-one patients with node-negative and high TLI tumors were randomized to receive six cycles of CMF or no further treatment. At a median follow-up of 12 years, CMF produced a 25% and 20% relative reduction in relapse and death cumulative incidence, respectively. A breakdown analysis identified a subgroup of patients with intermediate proliferating tumors for whom a 70% and 73% reduction in relapse and death was observed in the intention-to-treat population. An even higher reduction of 80% and 84% in relapse and death was seen for the patients who had received the full CMF dose. We identified a subgroup of patients with intermediate proliferating tumors in whom the high benefit obtained from adjuvant CMF was maintained at a long-term follow up.

We conducted a prospective randomized clinical trial to assess the mobilizing efficacy of filgrastim, lenograstim and molgramostim following a disease-specific chemotherapy regimen. Mobilization consisted of high-dose cyclophosphamide in 45 cases (44%), and cisplatin/ifosfamide/etoposide or vinblastine in 22 (21%), followed by randomization to either filgrastim or lenograstim or molgramostim at 5 microg/kg/day. One hundred and three patients were randomized, and 82 (79%) performed apheresis. Forty-four (43%) patients were chemonaive, whereas 59 (57%) were pretreated. A median number of one apheresis per patient (range, 1-3) was performed. The median number of CD34+ cells obtained after mobilization was 8.4 x 10(6)/kg in the filgrastim arm versus 5.8 x 10(6)/kg in the lenograstim arm versus 4.0 x 10(6)/kg in the molgramostim arm (P=0.1). A statistically significant difference was observed for the median number of days of growth factor administration in favor of lenograstim (12 days) versus filgrastim (13 days) and molgramostim (14 days) (P

Purpose: To verify the feasibility of, and quantify the risk of, pneumonitis from locoregional radiotherapy (RT) after high-dose dense chemotherapy with epirubicin and paclitaxel with peripheral blood progenitor cell support in patients with high-risk Stage II-III breast cancer. Methods and Materials: Treatment consisted of a mobilizing course of epirubicin 150 mg/m 2 , preceded by dexrazoxane (Day 1), paclitaxel 175 mg/m 2 (Day 2), and filgrastim; followed by three courses of epirubicin 150 mg/m 2 , preceded by dexrazoxane (Day 1), paclitaxel 400 mg/m 2 (Day 2), and peripheral blood progenitor cell support and filgrastim, every 16–19 days. After chemotherapy, patients were treated with locoregional RT, which included the whole breast or the chest wall, axilla, and supraclavicular area. Results: Overall, 64 of 69 patients were evaluable. The interval between the end of chemotherapy and the initiation of RT was at least 1.5–2 months (mean 2). No treatment-related death was reported. After a median follow-up of 27 months from RT (range 5–77 months), neither clinically relevant radiation pneumonitis nor congestive heart failure had been reported. Minor and transitory lung and cardiac toxicities were observed. Conclusion: Sequential high doses of epirubicin, preceded by dexrazoxane, and paclitaxel did not adversely affect the tolerability of locoregional RT in breast cancer patients. The risk of pneumonitis was not affected by the use of sequential paclitaxel with an interval of at least 1.5–2 months between the end of chemotherapy and the initiation of RT. Long-term follow-up is needed to define the risk of cardiotoxicity in these patients.

Purpose: Gastrointestinal stromal tumor (GIST) metastases are typically intra-abdominal and hypervascular. We assessed the effect of angiosonography with a second-generation contrast agent to monitor response during imatinib treatment in patients with metastatic KIT+ GIST. Experimental Design: Ten consecutive patients with known advanced KIT+ GIST were investigated with angiosonography and computerized tomography (CT). We also monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor. Results: Angiosonography showed a reduction in tumor vascularization of liver metastases during imatinib treatment in all cases. We observed a reduction in tumor vascularization before a reduction in tumor size. The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients, but progressive disease was documented in four patients following imatinib treatment. CT documented tumor response according to standardized criteria in six patients, stable disease in four, and progressive disease according to angiosonography. The reduction of tumor perfusion at angiosonography correlated with the pseudocystic appearance at CT. The “nodule(s) within a mass” pattern of recurrence occurred in two patients with no difference observed between angiosonography and CT. Early decreasing serum vascular endothelial growth factor levels were observed in the two cases with higher pretreatment levels. Conclusions: Imatinib could induce antiangiogenic and/or antivascular effects in GIST, and this effect could be easily monitored with angiosonography. Angiosonography might be a useful complement for monitoring the therapeutic effect of imatinib in these patients.

About 40% of patients with advanced cancer develop metastases in the central nervous system (CNS), mainly from primary tumors of lung, breast and melanoma. In most of cases there are multiple CNS metastases, making surgery or localized radiosurgery not feasible. The current standard of care for these patients is radiation therapy, which can improve neurologic symptoms but does not have any impact on the patient's overall survival. Temozolomide, capecitabine and gefitinib are safe and active in the treatment of CNS metastases from melanoma/recurrent gliomas, breast carcinoma and lung cancer, respectively. New, orally administered drugs hold a great potential for patients with CNS metastases.

Although the overall cure rate for advanced germ cell tumor (GCT) is high, the prognosis for patients with cisplatin-refractory GCT remains poor. Gemcitabine, paclitaxel, and oxaliplatin have shown significant activity as single agents in these patients. We investigated the activity and tolerance of a weekly gemcitabine, paclitaxel, oxaliplatin chemotherapy regimen. From September 2000 to February 2002, 9 patients with cisplatin-refractory GCT were treated with gemcitabine 800 mg/m2, paclitaxel 70 mg/m2, and oxaliplatin 50 mg/m2, days 1, 8, and 15, every 4 weeks. Only 1 patient stayed on schedule. In 7 patients, chemotherapy treatment was modified due to grade 3-4 hematological toxicity, whereas in another patient, who received high-dose chemotherapy 2 months before, chemotherapy was administered biweekly. In total, 21 cycles were administered with a median of 2 cycles for each patient. One patient achieved a partial remission lasting 5 months, 1 had disease stabilization for 5 months, whereas 7 had progressive disease. This chemotherapy regimen was not feasible in our patient population. Recently, oxaliplatin at full doses, but not as weekly administration, has appeared to possess activity in cisplatin-refractory GCT. Thus, we plan a phase II study protocol of the oxaliplatin and gemcitabine combination at full doses every 3 weeks.

The 5-year overall survival rate of patients with germ cell tumor (GCT) with poor prognosis, according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification, is 48% after standard-dose chemotherapy and surgery, if necessary. Two recent studies have showed that early high-dose chemotherapy (HDCT) with hematopoietic progenitor cell support (HPCS) may induce a 2-year overall survival rate of 78% in these patients. We report the long-term results of the experience at the Department of Oncology in Ravenna with early HDCT and HPCS in GCT patients with poor prognosis (IGCCCG criteria). Between 1987 and 2002, 18 poor prognosis GCT patients (17 M, one F), median age 24.5 years (range, 17-52), were treated with early HDCT with HPCS. In total, (67%) patients achieved a complete remission and they are continuously disease-free at a median follow-up of 9.2 years (range, 1.7-16.2). One treatment-related death occurred. No patient developed myelodysplasia or a secondary leukemia. This is notably the longest follow-up reported in patients having received HDCT in this setting. No patient achieving a complete remission relapsed. The role of HDCT in poor prognosis GCT will be defined from the ongoing phase III randomized trials.

We investigated the changes in sexual function in male patients with germ cell tumor continuously disease free after one or two courses of high-dose chemotherapy with hematopoietic stem cell support. A questionnaire was mailed to 35 patients, and 30 patients sent it back. Sexuality was considered a problem by 10 patients (33%), but no patients considered sexuality a major problem. Erection was more difficult to achieve in seven patients (23%) and 10 patients (33%) experienced increased difficulty in maintaining an erection. Eight patients (27%) had the experience of less intensive and less frequent orgasm. In all, 13 patients (43%) thought that both the disease and treatment had worsened their sexual capacity, but 20 patients (67%) were satisfied with their sex life. Most of the patients (63%) considered that insufficient information and counselling had been given by their physicians about the sexual sequelae of therapy. However, the amount of information about the disease and treatment was considered good by 77 and 80% of the patients, respectively. This study shows that 27% of patients were not content with their ability to attain sexual satisfaction due to the illness or its treatment. Communication is an important issue and better information tools could lead to improved compliance in these patients.

Standard chemotherapy in elderly patients is still nowadays a difficult issue, due to the fact that marrow reserve decrease with age and the results might lead to higher toxicity of otherwise well tolerated regimen and schedule. In the literature, very few data exist of myelosuppression in patients with solid tumors, while more data have been published on non-Hodgkin's lymphoma. The burden of toxicity increase with age, leading to the fact that some patients with curable or sensitive disease do not receive appropriate treatment. One of the ways to try to circumvent neutropenia is the prophylactic use of haematopoietic growth factors with the double aim of maintaining dose-intensity and reducing toxicity. This paper will describe the patterns of marrow toxicity in treating elderly patients with cancer and the role of haematopoietic growth factors.

Background: There is now much data that suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is a multistep process resulting from an ordered set of events and regulated by positive and negative modulators of microvessels growth and by the expression of various proteolytic enzymes. Materials and methods: We prospectively evaluated VEGF and microvessels density on tumor specimen and cytosolic levels of uPA and PAI-1. Results: We enrolled 81 primary breast cancer patients. The median follow-up was 38 months. Using the median value as cutoff for the statistical analysis, we found significant correlation between cytosolic levels of uPA and PAI-1(r=0.61;p

The European Group for Blood and Marrow Transplantation (EBMT), formerly known as European Group for Bone Marrow Transplantation, was established in 1974 in the Netherlands to share experiences, to promote research and clinical studies and to set up registries in the field of hematopoietic tissue transplantation. At the present time more 400 European and non-European centers are members of the EBMT group. In 1984 a new Working Party was created (Solid Tumors) with the aim to investigate the role of high-dose chemotherapy and stem cell support in the fields of adult and pediatric solid tumors. By January 2000 more than 14 000 patients were registered, and at the present time this Registry is the world largest database on this subject. Several phase III randomized clinical trials have recently started on behalf of the Group in different diseases (breast carcinoma, small cell lung cancer, ovarian carcinoma, germ cell tumors and Ewing's family sarcoma). Hundreds of randomized patients will finally produce clearer information on this still experimental therapeutic modality. This paper will describe the EBMT Solid Tumors Working Party Registry updated results as well as the main ongoing studies.

Lessons Learned Difficulties in translating in vitro results into clinical practice are inevitable. Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged. Background We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial. Methods Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days. Results Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3–4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9–7.1) and 2.1 months (95% CI: 1.7–2.8), respectively. Conclusion The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic.

PURPOSE: According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials, we investigated whether node-negative breast cancer patients, defined as high-risk cases on the basis of tumor cell proliferation, could benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant therapy. PATIENTS AND METHODS: Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors, defined according to thymidine labeling index (TLI), were randomized to receive six cycles of CMF or no further treatment after surgery ± radiotherapy. RESULTS: The 5-year disease-free survival (DFS) was 83% for patients treated with CMF compared with 72% in the control group (P = .028). Adjuvant treatment reduced both locoregional and distant metastases. When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria, compared with patients in the control arm, 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second (78% v 88%, respectively; P = .037) and third tertiles (58% v 78%, respectively; P = .024). CONCLUSION: The results from this randomized clinical study indicate that patients with node-negative, rapidly proliferating tumors significantly benefit from adjuvant CMF.

The aim of the study was to evaluate peripheral blood progenitor cell mobilization by disease-specific chemotherapy in heavily pretreated patients with germ cell tumor (GCT), scheduled for high-dose chemotherapy. Thirty-four consecutive patients, 29 males and five females, with advanced GCT referred to our department for high-dose chemotherapy were evaluated retrospectively. Sixteen patients were mobilized by vinblastine 0.11 mg/kg on days 1 and 2, ifosfamide 1200 mg/m2 days 1-5 and cisplatin 20 mg/m2 days 1-5 (VeIP). In 10 patients, etoposide 75 mg/m2 days 1-5 was used instead of vinblastine (VIP), while in eight patients the mobilization was attempted by administering 7 g/m2 of cyclophosphamide. The choice of either etoposide or vinblastine was predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. Cyclophosphamide was selected in patients refractory to previous cisplatin-based salvage chemotherapy. Twenty-five out of 34 patients underwent a successful PBPC collection. In 17 of them one leukapheresis procedure was sufficient to collect the target number of CD34+ cells, while in eight patients a double procedure was necessary. Altogether 33 aphereses were performed in 25 patients. In nine patients leukapheresis was not attempted. This was due to the fact that the chemotherapy failed to mobilize the target number of CD34+ cells in eight of them, treated with the VeIP mobilizing regimen, while one patient treated with high-dose cyclophosphamide rapidly progressed during therapy and for this reason leukapheresis was not undertaken. In conclusion, in heavily pretreated patients with GCT, PBPC mobilization is feasible by a further course of salvage chemotherapy. The choice of either etoposide (VIP) or vinblastine (VeIP) can be predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. In our hands, VeIP seems to be less satisfactory as mobilizing treatment than VIP, possibly due to a superior number of premobilization courses of chemo therapy in some patients. Moreover, high-dose cyclophosphamide remains a good alternative for mobilizing patients refractory to salvage chemotherapy.

Pancreatic cancer is a leading cause of cancer death. Despite improvement in diagnosis and treatment in the last 15 years, mortality rates essentially equal the incidence of the disease. Combination treatment with chemoradiation yields up to now better results than chemotherapy or radiotherapy given alone in consideration of substantial radio and chemoresistance of the cancer cells. This study will review the most important literature data about combination adjuvant treatment and preoperative (primary) chemoradiation in pancreatic cancer. Some other reports will be given on locoregional chemotherapy and finally a brief view on a possible perspective for promising future treatments coming from data of molecular pathology.Adjuvant chemoradiation after surgery has been shown to be superior to operation alone in potentially resectable pancreatic cancer in many studies, in terms both of local control and median overall survival. Unfortunately, a consistent percentage of patients cannot receive adjuvant treatment since late recovery after surgery or postoperative morbidity. Owing to this last reason, many authors prefer primary chemoradiation in potentially resectable pancreatic cancer; neoadjuvant treatment find out its background in other relevant biological and clinical evaluations.Some studies report encouraging results with primary chemoradiation using 5-fluorouracil. Other experiences with relatively new drugs, with potent radiosensiting effect, such as gemcitabine or taxol are going on; many of these are phase I studies. Clinical research in the field of preoperative treatment is up to now emerging in some importants Oncological Institutions. The principal actual aim seems to be that of forsee periods of treatment which will be brief and use the dose of chemotherapy that is active, giving acceptable toxicity.Ongoing trials will give, in the next years, the answer about the improvement of efficacy of treatments largely expected by all researchers.

Doxifluridine (dFUR) is a fluoropyrimidine derivative that has shown activity on a variety of solid tumours. The purpose of this study was to compare its therapeutic effect with a standard fluorouracil (FU) regimen in patients with locally advanced or metastatic colorectal cancer. 222 previously untreated patients were randomised to receive dFUR (4000 mg/m 2 ) or FU (500 mg/m 2 ) daily for 5 days every 28 days. The primary tumour originated in the colon in two-thirds of the cases in both groups; approximately 90% of patients had metastatic extension, and liver involvement was present in 69% of the patients in the dFUR and FU groups. A good performance status (ECOG 0–1) was recorded in 90% of cases in both arms. A median of five cycles was administered to the patients (range 1–12). Only one partial response among 110 patients in the FU arm and one complete response and five partial responses out of 112 evaluable patients in the dFUR group were observed. Time to progression was significantly longer in the dFUR group ( P = 0.02); overall survival, while longer in the dFUR arm (48 weeks vs. 39 weeks), was not significantly so ( P = 0.08). Toxicity was acceptable in both arms, although grade 3–4 neurological side-effects and leukopenia were more common after dFUR infusion. Despite the low response rate, our results indicate that dFUR may be a superior alternative to FU. The possibility of enhancing significantly the activity of dFUR with biochemical modulators should be further investigated.

In this paper an Italian cooperative trial investigates the role of a high-dose regimen with carboplatin, etoposide and ifosfamide in germ cell tumours. Twenty-eight patients underwent one or two transplants. Seventeen with progressive disease. Nine in sensitive relapse and two with stable disease after salvage therapy. Toxicity was generally moderate: two deaths occurred at day 15 from ABMT (one from VOD and one from tumour growth). Five patients are alive and disease free at least 10 months follow-up. In highly pre-treated patients this high-dose combination seems to give an option of cure for relapsed patients. Early transplantation is suggested.

Objective High-dose chemotherapy (HDCT) represents an option as salvage treatment for patients with resistant/refractory germ cell tumor (GCT). The objective of this retrospective analysis was to evaluate the long-term results of a single-center experience with salvage HDCT for GCT patients, and to validate the prognostic model proposed by Einhorn and colleagues [9] . Materials and methods Between 1986 and 2003, 100 GCT patients received salvage HDCT consisting of high-doses of carboplatin, etoposide ± cyclophosphamide, or ifosfamide. Twenty-four patients underwent a second HDCT cycle, and in 1 case, a third cycle was given with a median interval time of 6 weeks (range, 5–10). Results With a median follow-up of 8 years (range, 3–17); 6 of 32 (19%) patients with resistant GCT and 1 of 19 (5%) patients with cisplatin-refractory disease have been continuously disease-free, while none of the 16 patients with absolutely cisplatin-refractory GCT were alive at 1 year from HDCT treatment. In the PBPC era, HDCT appeared to be inapplicable in 32% of patients, mainly due to progressive disease during the induction/mobilizing phase. The prognostic model by Einhorn et al. for tandem HDCT did categorize our patients treated with a single HDCT cycle or low-dose intensity regimens in a very similar manner, but with inferior overall results. Conclusions Long-term results with a single HDCT cycle or a low dose-intensity multicycle HDCT regimen remained poor in patients with adverse prognostic features. The tandem HDCT regimen represents a major option for refractory GCTs and relapsed tumors in third-line or later therapy, while a single course of HDCT should be abandoned for these patients.

Lipoplatin is a liposome encapsulated form of cisplatin. Phase I studies on Lipoplatin showed an excellent toxicity profile of the compound. Therefore we performed a phase II trial in heavily pre-treated patients with advanced non–small cell lung cancer (NSCLC).

Aim of the study To investigate the incidence and clinical implications of venous thromboembolism (VTE) in advanced colorectal cancer (ACC) patients treated and followed-up through a prospective randomised trial, comparing FOLFIRI chemotherapy given as an intermittent or as a continuous schedule. Patients, materials and methods A total of 266 patients were randomised by 15 experimental centres: 168 (63.2%) were males, median age: 64.6 years, age range: 37–76 years. Almost all (95.5%) patients had metastatic disease, while the remainder were classified with locally advanced irresectable disease. For 138 (51.9%) of the patients, the chemotherapy treatment was intermittent FOLFIRI and the remaining patients received continuous treatment. All toxicities, including VTE, were prospectively collected. Results During the study protocol, the central data management gathered two cases of VTE. Our analysis retrieved 27 (10.2%) patients who developed a VTE, almost all (89%) during the course of chemotherapy treatment: 20 out of 27 during FOLFIRI, the remaining 7 during following lines or follow-up. VTE was the most frequent grade 3/4 toxicity. The incidence of VTE was significantly increased in the patients receiving continuous rather than intermittent treatment (HR 2.67, 95% CI 1.17–6.10; p Conclusion VTE is a common complication among advanced colorectal cancer patients and yet this type of toxicity is widely underestimated. In this randomised trial, VTE was the most frequent grade 3/4 toxicity. Use of an intermittent schedule is associated with a reduced risk of developing VTE.

The efficacy of the serotonin antagonist ondansetron (GR 38032F) was evaluated in the prevention of nausea and vomiting induced by CMF chemotherapy in 29 breast cancer patients. At their first treatment course of CMF, all given IV on day 1 q 21 days, patients were given oral antiemetic treatment as follows: ondansetron 8 mg, 2 h prior to CMF, repeated after 5 and 10 h the day of chemotherapy and then 8 mg tds for a minimum of 3 days to a maximum of 5 days following chemotherapy. At first course of CMF, complete protection from emesis and nausea was observed in 86.2% and 62% of patients, respectively. At subsequent CMF courses with ondansetron, complete control of emesis was observed in 80% of patients. Side effects were mild and no dystonic reactions were observed. Ondansetron represents an effective, safe, and easily administered outpatient regimen. The addition of a corticosteroid to ondansetron could further improve control of CMF-induced emesis.

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m(-2) and carboplatin AUC 5 mg ml(-1) min(-1) intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as thoseor=70 years old. A total of 178 patients with an ECOG performance status ofor=2 were included. Median age was 65 years (range 38-79), with 48 patientsor=70 years (27%). Grade 3-4 haematological toxicity was slightly worse inor=70 vs70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.

Patients with primary mediastinal nonseminomatous germ cell tumors have a poor prognosis, with a 5-year overall survival of nearly 50%. We investigated the feasibility and activity of early high-dose chemotherapy (HDCT) in these patients. After conventional induction chemotherapy, patients underwent a single shot of HDCT consisting of carboplatin, etoposide, and cyclophosphamide, followed by peripheral blood progenitor cell support. Twenty-one patients were considered for treatment with HDCT. Median age was 29 years (range, 19-55 years). Eight (38%) patients had lung metastases. After primary chemotherapy, 7 patients achieved complete remission, 4 achieved partial remission with negative marker, 1 achieved partial remission with positive marker, 2 had stable disease, and 7 progressive disease. Twelve patients were not treated with HDCT due to progressive disease and poor physical conditions. No HDCT-related deaths or irreversible organ toxicities were observed. Residual surgery after HDCT was performed in 4 patients and resulted in 3 pathologic complete remissions. With a median follow-up of 52 months (range, 15-71 months) in 9 patients treated with HDCT, 8 have been continuously free of disease. Of 12 patients who did not receive HDCT, 0 was alive at 2 years from diagnosis. A single course of HDCT after induction chemotherapy appeared to be inapplicable in most of our patients, mainly due to early progressive disease. These data should be considered in the analysis of retrospective series and in the design of new prospective trials with HDCT in these patients. Earlier HDCT administration followed by residual surgery should be considered for further investigation.

PurposeThis multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM).Patients and MethodsChemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12supplementation. Pemetrexed was provided within the Expanded Access Program.ResultsA total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible.ConclusionTreatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

Objective Cisplatin-refractory germ cell tumors (GCTs) represent a subset of germinal neoplasms with a poor prognosis. Conventional-dose chemotherapy induces objective response in 10–20% of these patients with rare durable complete remissions. We investigated the activity and tolerance of a chemotherapeutic regimen with oxaliplatin and gemcitabine. Patients and methods Treatment consisted of oxaliplatin 130mg/m 2 day 1, and gemcitabine 1250mg/m 2 , days 1 and 8, every three weeks. Results Eighteen patients were enrolled and were assessable for response and toxicity. Primary site was testis in twelve cases, retroperitoneum in four, and mediastinum in two. Seven patients (39%) were cisplatin-refractory, while eleven (61%) absolutely cisplatin-refractory. A median of three cycles (range, 1–6) per patient were given. One patient achieved a clinical complete remission, one a partial remission with negative marker in whom complete surgical resection of residual masses yielded mature teratoma only, and one a partial remission with positive marker in whom complete surgical resection of residual masses yielded viable tumor cells. These three cases were characterized by testicular primary embryonal carcinoma. They remained disease-free at 44+, 20+, and 18+ months of follow-up. Conclusion The oxaliplatin–gemcitabine combination is a safe and active standard-dose regimen for patients with cisplatin-refractory testicular primary GCT.

A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours Background: Incomplete remission or relapse from first-line chemotherapy has poor prognosis in male germ cell tumour patients. This phase III randomised trial compares conventional salvage to high-dose-intensification chemotherapy. Patients and methods: Between February 1994 and September 2001, 280 patients from 43 institutions in 11 countries, were randomly assigned to receive either four cycles of cisplatin, ifosfamide and etoposide (or vinblastine) (arm A), or three such cycles followed by high-dose carboplatin, etoposide and cyclophosphamide (CarboPEC) with haematopoietic stem cell support (arm B). Results: Similar complete and partial response rates were observed in both treatment arms (56%; 95% CI 50% to 62%). There were 3% and 7% toxic deaths in arms A and B, respectively. No significant improvements with CarboPEC were observed in either 3-year event-free survival (35% versus 42%, P=0.16) or overall survival (53%; 95% CI 46% to 59%). Complete responders with CarboPEC had a significant improvement in disease-free survival (55% versus 75% at 3 years, P < 0.04). Conclusions: The single cycle of high-dose salvage chemotherapy after three cycles of standard dose chemotherapy had no effect on treatment outcomes. These results suggest that data from uncontrolled studies should not be used to justify routine use of a toxic and expensive treatment without confirmation in a randomised trial.

Cancer of the testis is a relatively rare disease, accounting for about 1% of all cancers in men. Cryptorchidism is the only confirmed risk factor for testicular germ cell tumour. The majority of GCT are clinically detectable at initial presentation. Any nodular, hard, or fixed area discovered in the testis, must be considered neoplastic until proved otherwise. The appropriate surgical procedure to make the diagnosis is a radical orchidectomy through an inguinal incision. Many GCT produce tumoural markers (AFP, HCG, LDH), who are useful in the diagnosis and staging of disease; to monitor the therapeutic response and to detect tumour recurrence. In 1997 a prognostic factor-based classification for the metastatic germ cell tumours was developed by the IGCCCG: good, intermediate and poor prognosis, with 5-year survival of 91, 79 and 48%, respectively. GCT of the testis is a highly table, often curable, cancer. Germ cell testicular cancers are divided into seminoma and non-seminoma types for treatment planning because seminomatous testicular cancers are more sensitive to radiotherapy. Seminoma (all stages combined) has a cure rate of greater than 90%. For patients with low-stage disease, the cure approaches 100%. For patients with non-seminoma tumours, the cure rate is >95% in stages I and II; it is ∼70% with standard chemotherapy and resection of residual disease, if necessary, in stages III and IV. Minimum guidelines for clinical, biochemical, and radiological follow-up have been reported by ESMO in 2001.

Summary Background In an attempt to mobilise peripheral blood progenitor cells (PBPC) from patients with breast cancer, Epirubicin supported with G-CSF was tested. Another aim of the study was also to optimize the procedure so that the number of leukapheresis procedures could be reduced. These cells were subsequently reinfused as hematologic rescue after high-dose chemotherapy programs. Patients and methods Twenty-nine patients received Epirubicin 150 mg/sqm + G-CSF at the dose of 5 μg/kg/bw s.c. daily, starting 24 hours after chemotherapy. Twelve had metastatic, eight inflammatory or locally advanced disease, and nine were treated in an adjuvant setting. Results The median numbers of CD34+ cells and CFU-GM collected were 12.9 × 10Vkg/bw and 111.7 × 104/kg/bw, respectively. The mean number of leukapheresis procedures per patient was 1.8 ±0.3 (range 1–3), and the mean day of the first procedure was the tenth ± 1 (range 8–13) after Epirubicin. The minimum required target for one high-dose procedure was collected in a single leukapheresis in 13 patients. Moreover, in 9 cases one procedure was adequate for two high-dose courses (i.e. >10 × 10Vkg/bw CD34+ cells). Response to Epirubicin was evaluable in 14/20 cases, with a response rate of 50%. Conclusions Epirubicin delivered at 150 mg/sqm is a very effective mobilising agent for breast cancer patients; to ameliorate the response rate other active drug(s) should be added.

The aim of this study was to identify trends in high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (ASCT) and to assess survival in a large cohort of breast cancer (BC) patients receiving this therapy in Europe from 1990 to 1999. A total of 7471 patients who received HDC with ASCT between January 1, 1990 and December 31, 1999 were reported to the European Group for Blood and Marrow Transplantation Registry. Data required for demographics and survival analysis were available for 2679 patients with high-risk primary BC; 921 patients with inflammatory BC (IBC), and 2295 patients with metastatic disease. The main evaluation parameters were progression-free survival (PFS) and overall survival (OS). Between 1990 and 1998, autotransplants for BC increased 30-fold. Significant trends included use of blood-derived rather than marrow-derived stem cells, increment of reporting centers and decrease of mortality within 100 days from transplantation. The 5-year PFS and OS probabilities were 53 and 68% for high-risk disease and 42 and 53% for IBC, respectively. For metastatic disease 5-year PFS and OS probabilities in the whole cohort were 18 and 27%, respectively, while for women transplanted in complete remission the 5-year PFS was 29%. In conclusion, HDC with ASCT has been increasingly used until 1998 and the 100-day mortality rate has been constantly less than 2% from 1995 to date. The 5-year survival of high-risk BC is related to the number of axillary nodes involved at surgery. Outcome of patients with IBC is encouraging, suggesting the need for randomized trials. Patients with metastatic disease responding to pretransplant chemotherapy and harboring ER+ tumors have a better outcome.

We verified the possibility of collecting large amounts of peripheral blood stem cells (PBSCs) to support three courses of adjuvant high-dose dense chemotherapy (HDDC) with high-dose epirubicin, preceded by dexrazoxane, and high-dose paclitaxel, in patients with high-risk breast cancer (/=9 positive nodes). The mobilizing regimen consisted of high-dose epirubicin 150 mg/m(2), preceded by dexrazoxane 1000 mg/m(2) (day 1), given in combination with paclitaxel 175 mg/m(2) (day 2), plus filgrastim. Of the 25 patients enrolled, one went off study due to a severe hypersensitivity reaction to paclitaxel, another did not undergo leukapheresis due to fever persistent after hematological recovery, while in 23 patients an adequate number of PBSCs was collected by a single leukapheresis. The median number of CD34+, CD34+/CD33-, and CD34+/CD38- cells collected per patient was 17 x 10(6)/kg, 13.4 x 10(6)/kg, and 1.5 x 10(6)/kg, respectively. Neutropenia was the only grade 4 toxicity and lasted a median of 3 days. High-dose epirubicin, preceded by dexrazoxane for the first time used in mobilizing regimen, and paclitaxel plus filgrastim are effective in releasing large amounts of PBSCs, which can then be safely employed to support multiple courses of HDDC.

Sertoli-Leydig cell tumors (SLCTs) are rare neoplasms, accounting for less than 0.2% of ovarian tumors. The endometrioid-like variant of yolk sac tumor (YST) is very rare, and the most extensive series reported only 8 cases. We present a case of ovarian SLCT with endometrioid-like YST in a patient with a 46,XX karyotype with Y-chromosomal material. A 26-year-old woman had undergone a right salpingo-oophorectomy for SLCT with endometrioid-like YST. Chromosomal analysis revealed a 46,XX karyotype with Y-chromosomal material insertion into chromosome 1. The patient’s father and sister, and 7 other paternal relatives (4 male and 3 female) presented the same chromosome variant without evidence of cancer. The YST component relapsed to the right side of the uterine wall and then metastasized to the peritoneum and liver, while SLCT was eradicated with primary surgery. Several chemotherapeutic regimens were totally ineffective to control tumor progression. She died of disease progression 54 months after the diagnosis. We adopted the policy of a close surveillance for ovarian neoplasms for the 22-year-old sister of the patient, who presented the same Y-chromosomal material in her karyotype. In very rare tumors, new methods, based on molecular and cytogenetic models, are requested to define recommended management.

There is now much data that suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is a multistep process resulting from an ordered set of events and regulated by positive and negative modulators of microvessels growth and by the expression of various proteolytic enzymes.We prospectively evaluated VEGF and microvessels density on tumor specimen and cytosolic levels of uPA and PAI-1.We enrolled 81 primary breast cancer patients. The median follow-up was 38 months. Using the median value as cutoff for the statistical analysis, we found significant correlation between cytosolic levels of uPA and PAI-1 (r = 0.61; p.0001), between VEGF and steroid hormone receptor status (p = .01), between PAI-1 and tumor grading (p = .009), and between uPA and tumor size greater than 1 cm (p = .04). With respect to the prognosis, we observed a significant correlation between low uPA levels and RFS and an unforeseen, direct correlation between high VEGF values and better RFS.Our preliminary results indicate that the cytosolic level of uPA at diagnosis may be predictive of early relapse in primary breast cancer.

Background The aim of this study was to evaluate the effectiveness of granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwashes in the prevention of severe mucositis induced by high doses of chemotherapy. Patients and methods Ninety consecutive patients affected by solid tumors and undergoing high-dose chemotherapy with autologous peripheral blood stem cell transplantation rescue were randomized to receive placebo versus GM-CSF mouthwash 150 micro g/day. Patients were stratified on the basis of the conditioning treatment and the consequent different risk of severe oral mucositis. Treatment was administered from the day after the end of chemotherapy until the resolution of stomatitis and/or neutrophil recovery. Results The statistical analyses were intention-to-treat and involved all patients who entered the study. The severity of stomatitis was evaluated daily by the physicians according to National Cancer Institute Common Toxicity Criteria. Both study and control groups were compared with respect to the frequency [30% versus 36%, chi(2) exact test, not significant (NS)] and mean duration (4.8 +/- 4.7 versus 4.4 +/- 2.7 days, t-test, NS) of severe stomatitis (grade > or =3). Oral pain was evaluated daily by patients themselves by means of a 10 cm analog visual scale: the mean (+/- standard error of the mean) maximum mucositis scores were 4.8 +/- 3.5 versus 4.2 +/- 3.5 cm (t-test, NS). Furthermore, 15/46 patients in the study group (33%) and 19/44 patients in the control group experienced pain requiring opioids (chi(2) exact test, NS). Conclusion We did not find any evidence to indicate that prophylaxis with GM-CSF mouthwash can help to reduce the severity of mucositis in the setting of the patients we studied.

Background Approximately 80% of patients with advanced germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. Patients with poor-prognosis disease have a cure rate of only 50%, whereas patients with first relapse have only a 25% chance of prolonged survival and potential cure following standard therapy. High-dose chemotherapy (HDC) is being investigated in patients with GCTs to improve the results of salvage treatment and in first-line setting for poor prognosis disease. Methods The authors review the results of the clinical trials that have evaluated the role of HDC in GCT patients. Data were obtained using a computer-assisted MEDLINE search, and meeting abstracts with clinical relevance in this field were hand-searched. Open randomized phase III studies are described and examined. Results Several phase II studies have shown a possible benefit for patients with recurrent disease, but the preliminary results of a phase III randomized trial did not demonstrate a survival advantage for HDC after three courses of standard-dose chemotherapy in the salvage therapy of patients in whom first-line treatment has failed. Three prospective, randomized trials are evaluating the role of HDC in a first-line setting. Conclusions New HDC strategies are emerging, involving new drugs (eg, paclitaxel), intensive induction regimens, and upfront and/or multiple courses of HDC. The evaluation of mature data of randomized trials will better define the role of HDC in this disease.

BACKGROUND High-dose chemotherapy (HDCT) followed by hematopoietic stem cell support (HSCS) potentially may be curative in patients with germ cell tumor (GCT) who develop recurrent tumors or who have an inadequate response after receiving standard-dose chemotherapy. The authors report their experience with HDCT as salvage therapy for patients with GCT. METHODS Between 1986 and 2000, 84 patients with GCT, with a median age 29 years (range, 15–50 years), were treated with 105 courses of HDCT with HSCS. Patients were stratified into good, intermediate, and poor risk categories according to a validated prognostic index. RESULTS Overall, 28 patients (33%) have been continuously disease free. In the good risk group, 24 patients (69%) have been continuously disease free compared with 4 patients (13%) in the intermediate risk group (P < 0.001) and 0 patients in the poor risk group (P < 0.001). Treatment-related mortality occurred only among patients in the poor risk (n = 6 patients) and the intermediate risk groups (n = 4 patients). CONCLUSIONS In the authors' experience, HDCT induced impressive long-term remissions as salvage treatment among patients in the good risk group. Moreover, the use of validated prognostic classifications may contribute to a better definition of the role of HDCT other than improving the outcome of patients with GCT. The definitive statement on the possible role of HDCT in patients with GCT will derive from the ongoing Phase III randomized studies. Cancer 2002;95:309–15. © 2002 American Cancer Society. DOI 10.1002/cncr.10672

PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer. PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m2 on the first day of each course and 5-FU and LV 350 mg/m2 and 20 mg/m2, respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses. RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m2. Reversible neurologic toxicity occurred in 44.4% of patients. CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m2 dosage offered improved dose-intensity compared with the initial dosage.

Germ cell tumors (GCTs) are very chemosensitive cancers, in which high-dose chemotherapy (HDCT) has been investigated as salvage therapy or as first-line treatment in poor prognosis patients. This paper presents an update of available information in order to define the status of HDCT in GCT patients.The authors have been working in this field, contributing to international clinical trials and to peer-reviewed journals with original papers. The material examined in this review includes articles published in journals covered by MedLine, reviews from journals with high impact factor, and unpublished data from the European Group for Blood and Marrow Transplantation (EBMT) registry.The delineation of prognostic factors associated with a poor probability of survival after HDCT contributed to the selection of patients who are likely to get an advantage from HDCT and those who should be spared from dose-intensive treatment. HDCT as first-line therapy for poor prognosis GCT (IGCCCG classification), and in a salvage setting in good risk GCT (prognostic index from Beyer et al.77), has been associated with a very high rate of complete remissions and long-term disease-free survivors. However, it is important to wait for the results of ongoing randomized trials for the validation of these findings. Other strategies are required for patients with refractory GCTs. Several new treatment options are currently emerging for this subset of patients.