Lipoplatin monotherapy: A phase II trial of second-line treatment of metastatic non-small-cell lung cancer.

Lipoplatin is a liposome encapsulated form of cisplatin. phase i studies on lipoplatin have demonstrated that the compound has an excellent toxicity profile. therefore we performed a phase ii trial in heavily pre-treated patients with advanced non-small-cell lung cancer (NSClC), performance status 0-2 in which the primary endpoint was response rate and secondary endpoints were safety and overall survival.Nineteen patients, average age 64 years old, with stage iV NSClC, were treated with lipoplatin 100 mg/m(2) every two weeks, as second line chemotherapy.We observed 1 partial remission (5.2%) and 3 stable diseases (15.9%). Time to progression (ttp) was 16 weeks and median overall survival (OS) was 31 weeks (7.2 months). We observed G1-G2 toxicity during chemotherapy, mainly gastrointestinal with nausea and vomiting (4 patients), asthenia (3 patients), mucositis (2 patients) and anemia (4 patients).Our phase ii study does not support a more extensive use of lipoplatin in phase III studies. An increase of dosage and a better selection of patients are mandatory to understand the real therapeutic activity of lipoplatin.

Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials.

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 those >or=70 years old. A total of 178 patients with an ECOG performance status of or=70 years (27%). Grade 3-4 haematological toxicity was slightly worse in >or=70 vs <70-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.

High-dose chemotherapy with peripheral blood progenitor cell support for patients with non-small cell lung cancer: the experience of the European Group for Bone Marrow Transplantation (EBMT) Solid Tumours Working Party.

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.

Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel following mobilization with epirubicin and cisplatin are feasible but ineffective in treating patients with advanced non-small cell lung cancer.

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.

Unilateral retinal detachment as the initial sign of lung adenocarcinoma.

Intraocular metastases, especially to the retina, are uncommon in cancer patients and generally occur in an advanced phase of the disease. In patients with lung cancer, uveal metastases, in particular to the choroid, are the most frequent, and are associated mainly with small cell carcinoma or undifferentiated carcinoma. We report a case of unilateral retinal detachment as first sign of a moderately differentiated lung adenocarcinoma in a 55-year-old non-smoker that was admitted to the hospital for the first time complaining of a sudden visual loss in the superior fields of the left eye. A CT revealed a slight retinal enlargement of the left eye and a solid mass of about 3 centimeters behind the right pulmonary hilus. Bronchoscopic biopsies were performed with diagnosis of adenocarcinoma of the lung. The patient died after 2 months for rapid progression of the disease despite of combined chemotherapy treatment.

A randomized study comparing filgrastim versus lenograstim versus molgramostim plus chemotherapy for peripheral blood progenitor cell mobilization.

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<0.0001) and for the subgroup of chemonaive patients (12 days) versus pretreated patients (14 days) (P<0.001). In conclusion, all three growth factors were efficacious in mobilizing peripheral blood progenitor cells with no statistically significant difference between CD34+ cell yield and the different regimens, and the time to apheresis is likely confounded by the different mobilization regimens.

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma.

Lymphodepletion and infusion of autologous expanded tumour-infiltrating lymphocytes is effective therapy for patients with malignant melanoma. Antitumour responses are likely to be mediated by HLA class I- and II-restricted immune responses directed at tumour antigens. We assessed whether the peripheral blood of normal HLA-matched siblings of patients with melanoma could be used to generate lymphocytes with antimelanoma activity for adoptive immunotherapy after allogeneic blood or marrow transplantation. Melanoma cell lines were derived from two donors and were used to stimulate the mononuclear cells of three HLA-identical siblings. CD4(+) clones dominated cultures. Of these, approximately half were directly cytotoxic towards recipient melanoma cells and secreted interferon-gamma in response to tumour stimulation. More than half of the noncytotoxic clones also secreted interferon-gamma after melanoma stimulation. No CD4(+) clones responded to stimulation with recipient haemopoietic cells. The majority of CD8(+) clones directly lysed recipient melanoma, but did not persist in long-term culture in vitro. No crossreactivity with recipient haemopoietic cells was observed. The antigenic target of one CD4(+) clone was determined to be an HLA-DR11-restricted MAGE-3 epitope. Antigenic targets of the remaining clones were not elucidated, but appeared to be restricted through a non-HLA-DR class II molecule. We conclude that the blood of allogeneic HLA-matched sibling donors contains melanoma-reactive lymphocyte precursors directed at tumour-associated antigens. Adoptive immunotherapy with unselected or ex vivo-stimulated donor lymphocytes after allogeneic stem cell transplantation has a rational basis for the treatment of malignant melanoma.

Pemetrexed and malignant pleural mesothelioma.

Malignant Pleural Mesothelioma (MPM) continues to be a challenging problem; because few patients may be treated with radical surgery and conventional chemotherapy have achieved very dismal results. Pemetrexed is a new drug with multitarget antifolate activity which seems to be particularly active in many solid tumors and also in MPM. The principal clinical experiences of pemetrexed alone or in combination with other compounds, chiefly platinum and its derivative, are reported. The Italian study on 1114 cases of MPM treated over 30 months is discussed and the definitive results will be available after a complete external review of all responsive patients.

Locally advanced ovarian carcinoid.

Primary carcinoid tumor of the ovary is an extremely rare neoplasm, accounting for less than 0.1 % of all ovarian neoplasms. We report a case of a 79-year-old woman with locally advanced ovarian carcinoid presenting as acute abdomen. At laparotomy, a large mass appeared in the pelvis, with maximum size of 18 cm, growing from the left ovary with infiltration of the left Fallopian tube and compression of the small bowel and the sigmoid tract. A bilateral salpingo-oophorectomy was performed, and the tumor mass was completely removed. Post-operative treatments were not considered due to the absence of data in literature to support adjuvant treatments. Ten years after surgery the patient remains well without evidence of recurrence. Older age should not be considered an absolute contraindication for aggressive surgery, if this represents the best chance of cure. An aggressive cytoreductive surgery remains the best treatment for advanced or locally advanced primary ovarian carcinoid.

FDG-PET in the management of germ cell tumor.

Germ cell tumor is the most common malignancy in young men. The cure rate of these patients has tremendously increased in the cisplatin era, and recent results have indicated that the management of patients with GCT is still improving. The use of FDG-PET in the management of patients with GCT has been recently investigated. This report attempts to comprehensively review new advances and delineate the potential applications of FDG-PET in 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.

Long-term follow-up of patients with poor prognosis germ cell tumor treated with early high-dose chemotherapy with hematopoietic progenitor cell support: a single-center experience.

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.

Innovative therapy for patients with brain metastases: oral treatments.

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.

Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology.

Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.

Ifosfamide in small cell lung cancer.

Recent literature about the treatment options of small cell lung cancer stresses the role of ifosfamide both alone and in combination with either cisplatin or carboplatin and etoposide. Its pharmacokinetics and the lower hematological toxicity permit the use of high doses which seem to be more effective in this very sensitive tumor. However, despite the increment in the response rate, in both limited and extended disease, the overall and long-term survival seems to be little influenced by therapy. Newer strategies combining old and new therapeutic approaches have to be explored to overcome the lack of progresses registered in these years.

Sexual functions after high-dose chemotherapy in survivors of germ cell tumors.

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.