Purpose: To evaluate the prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erbB-2 and cathepsin-D in epithelial ovarian cancer (EOC). Methods: We analyzed 100 patients with ovarian carcinoma, FIGO Stage IC-IV who underwent primary cytoreductive surgery and received adjuvant chemotherapy with cyclophosphamide and a platinum analogue (CP) (n = 46) or paclitaxel and a platinum analogue (TP) (n = 54). Immunohistochemical expression was studied on paraffin-embedded tissue from the primary tumor. Results: After a median follow-up of 55 months median progression-free survival (PFS) and overall survival (OS) were 16 and 41 months, respectively. Positive bcl-2 staining and absence of cathepsin-D expression were associated with an increased complete response rate in the CP group (p = 0.011 and p = 0.003) but not in the TP group. PFS and OS were not associated with the expression of any of the markers studied. FIGO stage (p = 0.006) and histology (p = 0.047) were the only independent prognostic factors for survival. Conclusion: Bcl2 and cathepsin D expression are associated with response to CP but not TP chemotherapy. P53, bcl-2, c-erb B-2 and cathepsin D expression was not correlated with PFS and OS in our study.

Thalidomide-based regimens (TBR) are now widely used for the treatment of refractory multiple myeloma and have shown significant activity in newly diagnosed patients. In some patients with secretory disease, we observed discrepancies between the reduction of the monoclonal protein levels and the plasma cell infiltration in the bone marrow and/or extramedullary sites of relapse after treatment with TBR. The purpose of this study was to assess the incidence and analysis of this phenomenon in all myeloma patients treated with TBR in our Institution. Patients and methods: We studied all patients who received TBRs and had a follow up time of at least 6 months. Partial response (PR) was defined as at least 50% reduction of serum myeloma protein and soft tissue plasmacytomas and/or > 90% reduction of Bence Jones protein excretion and minor response as a > 25% reduction of the serum myeloma protein or > 50% reduction of the Bence Jones myeloma protein. Results: Between July 1999 and July 2002 we treated 94 patients with advanced myeloma and 9 patients with newly diagnosed disease with TBR. Sixty-seven patients (66%) achieved either partial or minor response. In 4 patients (3 with advanced and 1 with newly diagnosed myeloma) the bone marrow was heavily infiltrated by plasma cells, despite a decrease of the paraprotein levels ranging from 38% to 68%. This discordance between monoclonal protein levels and bone marrow plasmacytosis was noted in 6% of patients rated as responders and in 11% of responding patients who actually had a repeat bone marrow assessment. Furthermore 6 responding patients, after achieving a PR which lasted between 5 and 9 months, relapsed with bone marrow (all cases), and extramedullary (2 cases) plasmacytosis, without increase of serum and/or urine monoclonal protein. This hyposecretory conversion was noted in 12.5% of relapsing patients. Conclusion: Our data indicate that after treatment with TBR some patients with myeloma show discordant responses of the monoclonal protein levels and the bone marrow or extramedullary plasmacytosis. If our data are confirmed, they may have practical implications for assessment of response and follow up of patients treated with TBR.

Objective. Patients with epithelial ovarian cancer (EOC) who relapse more than 6 months following completion of platinum-based primary chemotherapy are considered platinum-sensitive, and can be effectively retreated with cisplatin or carboplatin. The nucleoside analogue gemcitabine has proven activity in both platinum-sensitive and platinum-resistant disease. We conducted a phase II study using the combination of carboplatin and gemcitabine for the treatment of patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. Methods. Forty-three patients were treated with gemcitabine 1000 mg/m 2, intravenously, over 30 min on days 1 and 8, and carboplatin at AUC 5 on day 1. Courses were administered every 3 weeks on an outpatient basis. Results. Among 37 patients with measurable or evaluable disease, 15 (40.5%) achieved an objective response including 10 complete and 5 partial responses. The median overall survival was 24.5 months, and the median time to progression for all patients was 9 months. The treatment was well tolerated without toxic deaths; the most common toxicities were Grade 3 or 4 neutropenia, anemia, and thrombocytopenia that occurred in 69%, 26%, and 24% of patients, respectively. Conclusions. The combination of carboplatin and gemcitabine is a well-tolerated outpatient regimen with activity in patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. However, a randomized prospective study is justified to define whether the addition of gemcitabine to single-agent carboplatin results in improved efficacy in this subset of patients. © 2003 Elsevier Inc. All rights reserved.

Background: High-dose chemotherapy with autologous stem cell transplantation after initial cytoreductive chemotherapy with the combination vincristine, doxorubicin and dexamethasone (VAD) is considered an effective therapy for many patients with newly diagnosed, symptomatic multiple myeloma. Response to initial cytoreductive chemotherapy is important for the long-term outcome of such patients. Thalidomide has recently shown significant antimyeloma activity. We studied the efficacy and toxicity of the combination of a liposomal doxorubicin-containing VAD regimen with thalidomide, administered on an outpatient basis, as initial cytoreductive treatment in previously untreated patients with symptomatic myeloma. Patients and methods: Thirty-nine myeloma patients were treated with vincristine 2 mg intravenously (i.v.), liposomal doxorubicin 40 mg/m2 i.v. administered as single dose on day 1, and dexamethasone 40 mg per os daily for 4 days. Dexamethasone was also given on days 15-18 of the first cycle of treatment. The regimen was administered every 4 weeks for four courses. Thalidomide was given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after four cycles of treatment. After completion of four cycles, the patients were allowed to proceed to high-dose chemotherapy or to receive two additional cycles of the same treatment. Results: On an intention-to-treat basis, 29 of the 39 patients (74%) responded to treatment. Four patients (10%) achieved complete and 25 (64%) partial response. Three patients (8%) showed minor response and seven (18%) were rated as non-responders. Major grade 3 or 4 toxicities consisted of neutropenia (15%), thrombocytopenia (15%), deep vein thrombosis (10%), constipation (10%), skin rash (5%) and peripheral neuropathy (5%). Two patients (5%) experienced early death due to infection. Conclusions: The combination of vincristine, liposomal doxorubicin, and dexamethasone (VAD doxil) with thalidomide is an effective and relatively well-tolerated initial cytoreductive treatment.Prospective randomized studies are required in order to assess the effect of this regimen on the long-term outcome of patients with multiple myeloma.

Objectives. To evaluate prospectively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer (HRPC) in a randomized Phase II study. HRPC presents a challenging therapeutic problem. Salvage chemotherapy is the usual approach at this stage of the disease. The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC. Methods. Forty patients with HRPC were randomized to receive one of two treatments. Group 1 underwent chemotherapy (estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days) and group 2 the combination of a somatostatin analog (lanreotide 30 mg intramuscularly every 14 days) and dexamethasone (4 mg tapered to 1 mg), in addition to androgen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog (triptorelin 3.75 mg intramuscularly every 28 days). The clinical and prostate-specific antigen (PSA) response, overall survival, time to progression, and toxicity were compared between the two groups. Results. The data of 20 patients in group 1 and 18 in group 2 were analyzed. The demographic and clinical data were similar in the two groups at study entry. A PSA response (decrease of greater than 50%) was observed in 45% of group 1 and 44% of group 2. The difference was not statistically significant. A partial clinical response was observed in 29% and 30% of groups 1 and 2, respectively. Again, the difference was not statistically significant. Changes in performance status and pain score during treatment were not significantly different in the two groups. Hematologic toxicity was more frequent in group 1 (80% of patients), and mild diabetes was more frequent in group 2 (22% of patients). The overall survival was 18.8 months in group 1 and 18 months in group 2 (not statistically significant). The time to progression was 6 versus 4 months and, in the PSA responder subgroup, it was 8 versus 7.7 months in groups 1 and 2, respectively (neither difference was statistically significant). Conclusions. The results of our randomized Phase II study indicated that the new combination treatment (luteinizing hormone-releasing hormone analog, somatostatin analog, and dexamethasone) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response, overall survival, and time to progression. A larger prospective Phase III trial is required to confirm our observations. © 2004 Elsevier Inc.

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1α), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-Sb)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1α and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1α, as well as TRACP-Sb, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1α, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.

Several studies have indicated that age, hemoglobin and serum albumin are among the most important prognostic factors for survival of patients with Waldenstrom's macroglobulinemia (WM). Furthermore, recent data indicate that serum b2-microglobulin may be also significant. The recently proposed International Staging System (ISS) for multiple myeloma is based on serum albumin and b2-microglobulin. We designed a study to assess this model in patients with WM. Our analysis included 83 previously untreated patients with WM who required systemic treatment and in whom pretreatment values for both serum albumin and b2-microglobulin were available. Based on these variables the patients were stratified into three ISS stages. Stage I: albumin ≥ 3.5 g/dl and b2-microglobulin < 3.5 mg/dl, stage II: albumin < 3.5 g/dl and b2-microglobulin < 3.5 mg/gl or b2-microglobulin 3.5 - 5.5 mg/dl and stage III: b2-microglobulin > 5.5 mg/dl. Low albumin (3.5 g/dl) and high b2-microglobulin (≥ 3.5 mg/dl) were recorded in 45% and 52% of patients respectively. The distribution of patients in the three ISS stages was: stage I: 30%, stage II: 43% and stage III: 27%. The median overall survival from the date of treatment initiation was 115 months. The median survival according to ISS was not reached for stage I, 116 months for stage II and 54 months for stage III (P = 0.02). Our analysis indicated that the recently proposed ISS for multiple myeloma could stratify the patients with WM into three distinct subgroups with significantly different survival times. If this model is validated in independent series, it could provide a new staging system for WM based on readily available and reproducible variables. © 2004 Taylor & Francis Ltd.

Objectives To evaluate, in a multicenter Phase II study, the safety and efficacy of the combination of gemcitabine and carboplatin, as first-line treatment in elderly and unfit patients with advanced bladder carcinoma. The toxicity of platinum-based chemotherapy combinations represents a common problem for elderly or unfit patients with advanced bladder carcinoma. Methods Patients with previously untreated inoperable or metastatic bladder carcinoma and an Eastern Cooperative Oncology Group performance status greater than 2, age older than 75 years, or creatinine clearance of less than 50 mL/min were treated with carboplatin area under the curve 4 on day 1 and gemcitabine 1000 mg/m 2 on days 1 and 8, every 21 days for a total of six cycles. Results A total of 56 patients (48 men and 8 women, median age 75 years) were enrolled. Of these patients, 46% had a performance status of 2 to 3, 68% had a creatinine clearance of less than 50 mL/min, and 59% had distant metastases. The overall response rate was 36% (95% confidence interval 23.4% to 49.6%), and an additional 14 patients had disease stabilization (25%, 95% confidence interval 14.4% to 38.4%). The median time to progression was 4.8 months, the median overall survival was 7.2 months, and the 1-year survival rate was 26%. Grade 3 or 4 toxicity included anemia (18%); thrombocytopenia (16%); neutropenia (27%), with two episodes of febrile neutropenia requiring hospitalization; diarrhea (2%); and fatigue (5.5%). Two toxic deaths occurred during the study. Conclusions The combination of gemcitabine and carboplatin has some activity as first-line treatment of advanced bladder carcinoma in the elderly and those unfit for cisplatin-based chemotherapy, with manageable toxicity, and represents a reasonable choice for the treatment of such patients. © 2004 Elsevier Inc.

Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi's sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer. © 2004 European Society for Medical Oncology.

Background: Small series and retrospective studies have suggested that treatment with gemcitabine may be associated with pulmonary toxicity. However, a prospective evaluation of cancer patients treated with gemcitabine-based chemotherapy without neoplastic involvement of the thorax and without administration of radiotherapy has not been performed. Patients and methods: To investigate this issue, 41 consecutive patients receiving gemcitabine and carboplatin underwent prospective evaluation of lung function, which included pulmonary symptoms, pulmonary function tests, arterial blood gases and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with a substantial decline in diffusion capacity for carbon monoxide (DLCO), defined as a drop of ≥20%, were reassessed 2 months later. Results: After chemotherapy, there were no significant changes in forced vital capacity (FVQ, forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, alveolar volume or total lung capacity. In contrast, there was a significant decline in DLCO (73 ± 22 versus 67 ± 24% predicted; P = 0.017) and in carbon monoxide transfer coefficient (KCO) (89 ± 24 versus 80 ± 24% predicted; P = 0.004). Arterial blood gases did not change following treatment. Ten of the 41 patients (24%) exhibited a substantial decline in DLCO, which, however, recovered within 2 months (DLCO at baseline, immediately after therapy and at 2 months after completion of treatment, 84 ± 14, 58 ± 16 and 77 ± 17% predicted, respectively; P < 0.001; baseline DLCO versus DLCO at 2 months, P > 0.05). Four of the 41 patients (10%) experienced dyspnea, which was self-limiting, with the exception of one patient who developed interstitial lung fibrosis. Among the various risk factors examined, older age, female gender and lower baseline DLCO were associated with more profound changes in DLCO post-treatment. Conclusions: This prospective analysis showed that the combination of gemcitabine and carboplatin induces a significant, but reversible, decrease in diffusion capacity, which is mostly asymptomatic. Thus, this regimen is safe as regards clinically significant lung toxicity. © 2004 European Society for Medical Oncology.

Primary mediastinal B-cell lymphoma (PMBCL) is a discrete subset of large B-cell lymphoma with unique clinicopathologic features. The question of optimal treatment emerges because it is an uncommon but not rare occurrence. A retrospective study was therefore conducted in a group of patients in Greece to evaluate the clinical features and treatment outcome in this disease. Twenty patients with PMBCL, with a median age of 42 years, treated at centers participating in the Hellenic Cooperative Oncology Group over the last 20 years, were reviewed. Thirteen (65%) had bulky disease at the time of presentation, 7 (35%) had superior vena cavae obstruction, and 15 (75%) had extranodal involvement. All received doxorubicin-containing chemotherapy, followed in 11 cases by mediastinal radiotherapy. With a median follow-up of 91 months, the median survival is 67.7 months. These data are consistent with those reported from other centers concerning the patient's characteristics, natural history, response pattern to chemoradiation therapy, and prognosis. Response to therapy proved of prognostic significance. A key question that remains is the prompt identification of patients who would benefit from innovative or more intensive therapies.

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCI (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m2 as a 1-h infusion with escalating increments of 5 mg/m2 until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m 2) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m2 (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m2 (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m2 every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration. © 2004 Lippincott Williams & Wilkins.

Objective: We conducted a phase II trial to evaluate the activity of oral letrozole in women with relapsed or recurrent epithelial ovarian cancer. Methods: Twenty-seven patients were treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n = 21) and those with only increasing CA 125 serum levels (n = 6) were eligible. Paraffin-fixed histological sections from tumor specimens resected at the initial laparotomy were assessed for the presence of estrogen, and progesterone receptors. Results: Among the 21 patients with measurable or evaluable disease who were evaluated for response by WHO criteria, we observed one complete and two partial responses for an objective response rate of 15%. Using criteria for CA 125 response we obtained a marker response in 4 of 27 patients (15%), and the marker remained stable in 5 additional patients (18%). Letrozole treatment was generally well tolerated. No correlation was observed between tumor marker response or stabilization and either estrogen or progesterone receptor expression. Conclusion: The results of our study suggest that the aromatase inhibitor letrozole is an agent with some activity and limited toxicity for relapsed ovarian cancer. As we could not find any association between response and hormonal receptor expression, the underlying mechanisms of letrozole action have to be elucidated. Copyright © 2004 S. Karger AG, Basel.

Introduction: Thalidomide is an oral agent with significant activity in one-third of patients with refractory myeloma. However, long-term continuous administration of thalidomide can be associated with significant side effects such as deep-vein thrombosis and peripheral neuropathy. Furthermore, it is not clear whether continuous administration of thalidomide is necessary for its antimyeloma effect. We performed a phase II study with a combination that was based on the intermittent administration of thalidomide. Materials and methods: A total of 53 patients with previously treated myeloma received cyclophosphamide 150 mg/m2 p.o. every 12 h before meals on days 1-5, thalidomide 400 mg p.o. in the evening on days 1-5 and 14-18 and dexamethasone 20 mg/m2 in the morning after breakfast on days 1-5 and 14-18 (CTD). The CTD combination was repeated every 28 days for three courses. Subsequently, responding patients were scheduled to receive maintenance treatment with monthly courses of CTD administered only for the first five days of each month. Results: On an intention-to-treat basis, 32 patients (60%) achieved a partial response with a median time to response of 1.5 months. Among the 43 thalidomide-naïve patients, 67% responded. Toxicities were mild or moderate and the cumulative incidence of deep-vein thrombosis and peripheral neuropathy was 4 and 2%, respectively. The median time to progression for responding patients was 12 months and the median overall survival for all patients was 17.5 months. Conclusion: The oral, outpatient pulsed CTD regimen is associated with significant activity in patients with previously treated multiple myeloma. The incidence of deep-vein thrombosis and peripheral neuropathy appears to be lower than expected when thalidomide is being administered on a continuous basis. © 2004 The European Hematology Association. All rights reserved.

Purpose: Radical cystectomy represents the treatment of choice for muscle infiltrative bladder carcinoma. Adjuvant chemotherapy has been used to improve outcome after cystectomy. We report results in a prospective cohort of patients at high risk for relapse who were treated with the combination of paclitaxel and carboplatin as adjuvant treatment following cystectomy for muscle invasive bladder cancer. Materials and Methods: A total of 92 patients with extravesical tumor extension (pT 3b or greater) or lymph node involvement (N+) were treated with 4 cycles of paclitaxel at 175 mg/m2 and carboplatin (area under the curve 5 according to the Calvert formula) every 3 weeks following radical cystectomy. Patients were followed every 6 months thereafter. Results: Median followup was 36.6 months. Chemotherapy was well tolerated with 62% of patients receiving 100% of the expected chemotherapy doses without delays. Grade 3 or 4 neutropenia was reported in 19% of patients, while neutropenic fever was reported in 7%. Five-year overall, cause specific and disease-free survival was 28.9% (95% CI 14.8 to 43.0), 36.6% (95% CI 24.4 to 49.7) and 29% (95% CI 16.3 to 42.4), respectively. Conclusions: Adjuvant chemotherapy with paclitaxel and carboplatin is feasible and could be used as adjuvant treatment for high risk bladder carcinoma. Its true value should be assessed in prospective, randomized trials.

Ovarian germ cell tumors (OGCT) are highly curable when treated with cytoreductive surgery and platinum-based chemotherapy. We evaluated the safety and activity of a 3-day modified bleomycin, etoposide, and cisplatinum (mBEP) regimen in patients with OGCT. Patients with FIGO stages I-IV OGCT were treated with three (stages I-III complete resection) or four cycles (incomplete resection or stage IV) of bleomycin 15 mg iv, etoposide 120 mg/m 2 iv, and cisplatin 40 mg/m 2 iv for 3 days every 3 weeks. Forty-eight patients (14 with dysgerminoma and 34 with non-dysgerminomatous tumors) were included in our study. Most patients had stage I disease (65%) and complete resection of their tumor (67%). Twenty percent of patients developed grade 3 or 4 neutropenia with 4 episodes of neutropenic fever. During follow-up (median: 5 years), two patients developed progressive disease including one patient who died. All patients with stage I or II disease and all patients with dysgerminoma remain free of disease. However, 20% of patients with non-dysgerminomatous tumors stage III or IV experienced progressive disease. The modified 3-day BEP regimen was safe and effective in patients with OGCT. Further improvements are needed for patients with advanced, suboptimally debulked non-dysgerminomatous tumors. © 2004 Elsevier Inc. All rights reserved.

Purpose: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. Patients and Methods: Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status ≤ 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m2 and cisplatin 75 mg/m 2 every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. Results: Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P = .017), median time to progression (TTP; 9.4 v6.1 months; P = .003) and median survival (14.2 v9.3 months; P = .026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P = .005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P = .089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P = .006), thrombocytopenia (5.7% v 0.9%; P = .046), and neutropenic sepsis (11.6% v 3.8%; P = .001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. Conclusion: MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma. © 2004 by American Society of Clinical Oncology.

Background: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC) in phase II studies, alone or in combination. Its moderate toxicity profile is well tolerated in elderly patients. Patients and methods: Patients with metastatic prostate cancer, progressive after primary hormonal therapy, were randomised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks, and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression. Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy (HT) for all their patients. Randomisation was stratified by centre. Further chemotherapy was allowed after progression. The primary end point was progression-free survival (PFS). The final analysis was performed on a total of 414 patients. Reported results were all based on intention-to-treat analyses. All progressions and responses were reviewed by an independent panel. Results: PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm, according to the statistical hypothesis of the protocol (P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10%). The 6-month PFS rates were 33.2% versus 22.8%, and the median durations of PFS were 3.7 versus 2.8 months. In the multivariate Cox analysis, which included age, Karnofsky performance status (PS), haemoglobin, alkaline phosphatase at study entry and number of prior hormonal treatments, the P value was decreased to 0.005. The prostate-specific antigen (PSA) response rate (≥50% decline sustained for at least 6 weeks) was significantly higher for VRL plus HT compared with HT (30.1% versus 19.2%; P=0.01). Clinical benefit, defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks, and at least stable assessment in the other two, was also more frequently observed in patients who received VRL plus HT versus HT alone (30.6% and 19.2%; P=0.008). There was no statistical difference in overall survival. Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression, compared with 28% of patients in the VRL-based arm. Aminoglutethimide did not seem to result in better efficacy for either arm. VRL plus HT was well tolerated, with a median administered relative dose intensity of 90%; grade 4 neutropenia occurred in 6.5% of patients and non-haematological toxicity was rare. Conclusions: The combination of VRL and hydrocortisone compared with hydrocortisone alone resulted in improved clinical benefit, PFS and PSA response rate. This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids. There was no gain in survival; however, the combination is well tolerated in this elderly group of patients, who often present cardiac co-morbidities, and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer. © 2004 European Society for Medical Oncology.

Patients with soft tissue sarcoma (STS), even after complete local disease control, often relapse locally or with distant metastases. This multicenter phase II study was conducted to evaluate the safety and efficacy of the combination of pegylated liposomal doxorubicin (PLD) and paclitaxel, as first-line treatment in patients with advanced STS. In all, 42 patients with locally advanced or metastatic STS, median age 54 years and median Eastern Cooperative Oncology Group performance status (PS) I were treated with PLD 45 mg m -2 and paclitaxel 150 mg m -2 every 28 days for a total of six cycles. Histological types included mainly leiomyosarcomas (43%), malignant fibrous histiocytomas (14%) and liposarcomas (12%). At study entry, 69% of patients had distant metastases, Overall response rate was 16%, including one complete (CR 2%) and six partial responses (PRs 14%), while an additional 14 patients had disease stabilization (SD 33%). At median follow-up 41.5 months, median time to progression (TTP) was 5.7 months with median overall survival (OS) 13.2 months. Grade 3-4 toxicities included neutropenia (17%), anaemia (15%), neurotoxicity (5%) and palmar-plantar erythrodysesthesia (9%). There were no treatment-related deaths. The combination of PLD and paclitaxel is a safe and well-tolerated regimen demonstrating modest efficacy as first-line treatment in patients with advanced STS.

We evaluated the predictive value of several parameters, including the International Staging System (ISS) for myeloma, in patients with advanced disease treated with thalidomide-based regimens (TBR). We analyzed 119 patients, from 3 phase II studies. Patients with pretreatment β2 microglobulin < 3.5 mg/l and albumin ≥ 3.5 g /dl were scored ISS stage 1, patients with β2 microglobulin < 3.5 mg/1 and albumin < 3.5 g/dl or β2 microglobulin 3.5-5.5 mg/l regardless of albumin levels were scored ISS stage 2, patients with β2 microglobulin > 5.5 mg/l ISS stage 3. ISS stage was 1, 2 and 3 in 45, 32 and 23% of patients respectively. Seventy-four patients (62% achieved at least partial response. Median progression-free and overall survival were 8 months and 19.5 months respectively. ISS stage, serum LDH and performance status were independent predictive factors for survival. Based on these 3 variables a scoring system was developed with survival times of 38.1, 28.8 and 5.8 months for scores 0, 1 and 2 respectively. The ISS staging system was highly predictive for overall survival of patients with advanced myeloma treated with TBR. With the addition of performance status and serum LDH, a simple scoring system was developed which may help select patients likely to benefit from TBR. © 2004 Taylor & Francis Ltd.

Thalidomide, a glutamic acid derivative, was withdrawn from clinical use in 1962 due to its severe teratogenic effects. Its recent reinstitution in clinical practice was related to its benefits in leprosy and multiple myeloma. Moreover, the antiangiogenic and immunomodulatory properties of thalidomide have led to its evaluation in several malignant diseases, including myelofibrosis, renal cell cancer, prostate cancer, and Kaposi sarcoma. However, thalidomide use is associated with several side effects: somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious. A combination of thalidomide with steroids or chemotherapy is being evaluated in several phase 2 studies. While it is not yet clear whether these combinations will enhance efficacy, they appear to increase the toxicity of thalidomide, and thalidomide analogs are being developed to minimize this toxicity. Ongoing studies will clarify the potential advantages of these agents in the treatment of neoplastic diseases. © 2004 by Elsevier Inc.

The aim of this study was to assess the effect of systemic chemotherapy on the monoclonal protein levels of patients with solid tumors who also have a monoclonal gammopathy of undetermined significance (MGUS). All patients with solid tumors who were referred to our department for consideration of systemic chemotherapy were evaluated with serum protein electrophoresis (SPEP) for the presence of MGUS. When MGUS was confirmed with immunofixation, serial SPEP was performed during and after completion of chemotherapy. Over a 6-year period, 21 patients with solid tumors and MGUS were prospectively identified and assessed. At least 50% reduction of serum monoclonal protein was noted in 4 of 11 patients treated with paclitaxel or docetaxel with a platinum analogue and in 5 of 7 patients who received an irinotecan-containing regimen. Our data indicate that in MGUS patients treated with irinotecan-containing chemotherapy regimens, a high incidence of reduction in their monoclonal protein levels is observed. Since topotecan, another topoisomerase I inhibitor, has some activity in multiple myeloma, further evaluation of irinotecan may be warranted. Evaluation of larger numbers of MGUS patients treated with chemotherapy for their underlying malignancy may help identify "in vivo" potentially active agents and regimens for patients with overt myeloma. © Springer-Verlag 2004.

Recent data have suggested that rituximab is an active agent for the treatment of Waldenstrom's macroglobulinemia (WM). However, the patients that are more likely to benefit have not been clearly defined. In order to address this question we evaluated 52 patients who were treated with single-agent rituximab in the context of prospective studies. Several clinical and laboratory variables were assessed for their correlation with response and time to progression. Twenty-three (44%) patients achieved a partial response after treatment with rituximab. Previously untreated and pretreated patients had the same probability for response. Higher response rates were noted in patients with serum monoclonal protein < 40 g/l, with serum albumin ≥ 35 g/l and with kappa light chain. The median time to progression for all patients was 13.8 months. A multivariate analysis indicated that elevated serum monoclonal protein levels and low serum albumin were the dominant variables associated with shorter progression. Presence of two, one or none of these adverse prognostic factors was associated with time to progression of 3.6 months, 11 months and more than 40 months, respectively. We conclude that rituximab is an effective treatment modality for patients with WM. Patients with both low levels of monoclonal protein and normal albumin are the best candidates for treatment with standard dose rituximab. © 2004 Taylor & Francis Ltd.

Background: To compare survival between patients with advanced breast cancer (ABC) treated with epirubicin/paclitaxel (Taxol) or paclitaxel/carboplatin (Cp) chemotherapy. Patients and methods: From January 1999 to April 2002, 327 eligible patients with ABC were randomized to receive either paclitaxel 175 mg/m2 in a 3-h infusion followed by epirubicin (EPI) 80 mg/m2 (group A) or paclitaxel, as in group A, followed by Cp at an AUC of 6 mg × min/ml (group, B) every 3 weeks for six cycles. Results: After a median follow-up of 23.5 months, median survival was not significantly different between the two groups (22.4 months versus 27.8 months, P = 0.25), whereas median time to treatment failure was significantly longer in patients treated with paclitaxel/Cp (8.1 months in group A versus 10.8 months in group B, P=0.04). Both regimens were well tolerated. In total, 39 patients (24%) in group A and 46 (29%) in group B suffered at least one severe side-effect. Quality-of-life assessment and cost analysis did not reveal any significant differences between the two groups. Conclusion: Our study suggests that the paclitaxel/Cp combination is an effective therapeutic alternative for patients with ABC in which anthracycline administration has the potential of being harmful. © 2004 European Society for Medical Oncology.

Objectives: Neoadjuvant chemotherapy has been used to improve outcome after cystectomy or for selection for bladder preservation in patients with bladder cancer. We have shown encouraging results using docetaxel and cisplatin in patients with advanced urothelial cancer. We are reporting the results of a phase II study using this combination as neoadjuvant treatment in patients with muscle invasive bladder cancer. Methods: Fifty patients were treated with docetaxel and cisplatin at 75 mg/m2 every 3 weeks for 3 cycles prior to cystectomy. Median follow-up was 70.2 months. Results: Chemotherapy was well tolerated. 5-year survival and progression-free survival (PFS) were 51.92% (95% confidence intervals [CI]: 37.76-66.08) and 52.47% (95%CI: 37.99-66.95). Multivariate analysis showed that clinical stage (cT) ≤ 3a was associated with improved 5-year survival (86.42% vs. 40.81%, p=0.027). Forty one patients underwent cystectomy. No tumor was found in 15 cases (36.6%). 5-year survival was 60.34% (95%CI: 52.2-68.48) and PFS was 57.11% (95%CI: 41.29-72.93). Absence of residual tumor was associated with improved 5-year survival (93.33% vs. 40.72%, p=0.031). Conclusions: Neoadjuvant chemotherapy with docetaxel and cisplatin is feasible and produced high pathological complete remission rate and excellent outcome in patients with no residual tumor. © 2004 Elsevier B.V. All rights reserved.

Secondary hemophagocytic lymphohistiocytosis has been reported after infections in immunocompromised hosts or in association with several malignancies. We report a case of secondary hemophagocytic syndrome after chemotherapy for multiple myeloma, which responded dramatically to dexamethasone, etoposide, and cyclosporin A.

Purpose: Radical surgery represents the treatment of choice for carcinoma of the upper urinary tract. Nevertheless, approximately 50% of patients with stage T ≥ 3 or lymph node involvement die from their disease, mainly as a result of the development of distant metastases. Therefore, there is a need for effective adjuvant systemic treatment. We prospectively studied a cohort of patients who underwent surgery for high-risk carcinoma of the upper urinary tract to assess the feasibility of the combination of paclitaxel and carboplatin as adjuvant treatment. Patients and Methods: Thirty-six patients with tumor stage ≥ 3 or lymph node involvement were treated with four cycles of paclitaxel at 175 mg/m2 and carboplatin (area under the curve 5, Calvert Formula) every 3 weeks following surgery. Results: Median follow-up was 40.6 months. Chemotherapy was well tolerated with 32 patients (89%) receiving full carboplatin and paclitaxel doses without delays. The most frequent grade 3/4 toxicity was neutropenia (39%), which was complicated with fever in only one case (3%). Nonhematologic grade 3 or 4 toxicities were reported in only one case. Five-year survival was 52% (95% CI, 35% to 69%), while 5-year disease-free survival was 40.2% (95% CI, 15.8% to 64.6%). Local failure rate was 30%, as opposed to 17% of patients who developed distant metastases. No patients with grade 2 tumors relapsed during follow-up, as opposed to 60% of patients with grade 3 tumors. Conclusion: Adjuvant chemotherapy with paclitaxel and carboplatin is feasible and may reduce the risk of distant metastases in high-risk upper urinary tract carcinoma. © 2004 by American Society of Clinical Oncology.