New agents in the treatment of small-cell lung cancer: focus on gemcitabine

Small-cell lung cancer (SCLC) accounts for 20%-25% of all new cases of lung cancer and represents the sixth most commonly diagnosed cancer in the United States. Given the tumor's systemic nature and chemoresponsiveness, chemotherapy has become the cornerstone of its management. Chemotherapy significantly prolongs survival; however, most of the patients still die within 2 years of diagnosis. Combination chemotherapy represents the treatment of choice for this disease. In the United States, cisplatin/etoposide is the regimen most frequently used for the first-line therapy of SCLC patients because of its better therapeutic index. Upon recurrence, topotecan is the Food and Drug Administration-approved treatment based on a phase III trial that showed no statistically significant differences in survival or response for topotecan compared with CAV (cyclophosphamide/doxorubicin/vincristine) but a better disease-related symptom improvement compared to baseline favoring the topoisomerase I inhibitor. Newer agents, with novel mechanisms of action, have shown activity against SCLC and are being tested in many different combinations. Among these agents, gemcitabine has attractive mechanisms of action and toxicity profile. Gemcitabine is a pyrimidine nucleoside antimetabolite, analogue to cytosine arabinoside, which through incorporation into the DNA leads to inhibition of DNA synthesis and cytotoxicity. As a single agent, gemcitabine has modest activity against SCLC. However, like with many other drugs, response rates improve when gemcitabine is used in combination regimens. Phase II and III studies of combinations with classic drugs for the management of SCLC patients such as cisplatin and/or etoposide and gemcitabine demonstrate comparable results to those of standard therapies. The gemcitabine/paclitaxel and gemcitabine/topoisomerase I inhibitor combinations are also of great interest, and preliminary results in previously treated patients are promising. The proper role of gemcitabine in the treatment of patients with SCLC awaits future testing in randomized phase III trials.     

Effect of combination chemotherapy of nitrosourea MCNU with various anti-tumor agents

The combination chemotherapy of water-soluble nitrosourea MCNU with various anti-tumor agents was studied using L1210 leukemia, Lewis lung carcinoma and B16 melanoma. The combinations of MCNU with 5-fluorouracil, cytosine arabinoside, adriamycin, mitomycin C, carboquone or cyclophosphamide produced significantly enhanced anti-tumor effects in L1210 leukemia. By combination with antimetabolites such as 5-fluorouracil or cytosine arabinoside, marked anti-tumor effects were observed over a wide range of dosage. It was suggested that 2-drug combination of MCNU plus 5-fluorouracil or 3-drug combination of MCNU plus 5-fluorouracil and adriamycin was useful in Lewis lung carcinoma or B16 melanoma. From these results, it was recognized that the multiple drug combination chemotherapy of MCNU was therapeutically useful, when given with 5-fluorouracil or cytosine arabinoside.     

A two-cohort phase II clinical trial of gemcitabine plus treosulfan in patients with metastatic uveal melanoma

In-vitro synergy of treosulfan and gemcitabine has been observed in chemotherapy-resistant tumours. This trial investigated the efficacy of gemcitabine plus treosulfan in metastatic uveal melanoma. Patients received 1000 mg/m of gemcitabine and treosulfan at a dose of 2500 or 3000 mg/m2 in cohort 1 and 3500 or 4000 mg/m2 in cohort 2. Chemotherapy was administered on days 1 and 8 every 4 weeks. Thirty-three patients were treated, 14 in cohort 1 and 19 in cohort 2. In cohort 1 with a treosulfan dose of or=3500 mg/m2 in cohort 2, one had partial remission (5%), 10 showed disease stabilization and eight progressed. An increased survival was observed in the second cohort with higher treosulfan doses, with median survival times of 6.0 versus 9.0 months (P=0.03) in cohort 1 and 2, respectively, and a 1-year survival of 7.1% versus 47.3%, respectively. Based on the observation of prolonged disease stabilization, we recommend further investigation of the gemcitabine/treosulfan combination with a dose of 3500 mg/m2 of treosulfan in metastatic uveal melanoma.     

Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m(-2), followed by a fixed dose of 5.0 g m(-2) treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m(-2) gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m(-2) gemcitabine combined with 5.0 g m(-2) treosulfan.     

A clinical phase I trial of gemcitabine and treosulfan in uveal melanoma and other solid tumours

This trial was performed to define the maximum tolerated dose (MTD) of treosulfan administered in combination with a fixed dose of gemcitabine in uveal melanoma patients. Preclinical studies suggested synergistic activity against uveal melanoma. Gemcitabine (1 g/m2) and treosulfan (2.5-4 g/m2) were administered on days 1 and 8, and cycles were repeated on day 29 for a maximum of six cycles. For treosulfan, dose escalation cohorts of 2-4 patients were enrolled. An additional 25 patients were entered at treosulfan dose levels II (3 g/m2) and III (3.5 g/m2). Thirty three patients with uveal melanoma and six patients with other histologies were accrued. Side-effects were predominantly haematological. The MTD was 3.5 g/m2 of treosulfan together with 1 g/m2 of gemcitabine. In the uveal melanoma patients, one partial response (PR) and 15 stablisations of disease (SD) were recorded and whether this translates into a survival gain should be explored further.     

Differential chemotherapeutic susceptibility of human T-lymphocytes and B-lymphocytes in culture.

After previous work from this laboratory revealed that asparaginase was 800-2,000 times more inhibitory against human T-lymphocytes in culture than against B-lymphocytes, a similar further study of 13 chemotherapeutic and immunosuppressive agents was done. Cytosine arabinoside and 5-fluorouracil also had differential inhibitory activities on human T- and B-cells in culture. On the basis of the dose producing 50% inhibition of viable cell growth on day 5, cytosine arabinoside had 45-80 times more inhibitory activity against T-cells than against B-cells. In contrast to asparaginase and cytosine arabinoside, 5-fluorouracil had 10-20 times more inhibitory activity against B-cells. The rest of the chemotherapeutic and immunosupressive agents tested had minor or no differential activity. These findings indicated that T-cell response to asparaginase and cytosine arabinoside and B-cell response to 5-fluorouracil may be exploitable for the differential immunosuppressive effects presumed to be active in vivo. In addition, such differential responses may predict differential tumor cell behavior against these chemotherapeutic agents by T- and B-cell neoplasms in vivo.     

Effects of mitoxantrone in combination with other anticancer agents on a human leukemia cell line.

To investigate the effects of mitoxantrone in combination with other anticancer agents, a human T-cell leukemia cell line, MOLT-3, was incubated for 3 days in the presence of two drugs (mitoxantrone and the combined drug) and cell growth inhibition was determined by assay with 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazonium bromide. The effects of drug combinations at doses giving 80% inhibition (ID80) were analyzed by an improved isobologram method. A supra-additive (synergistic) effect was observed for mitoxantrone in combination with amsacrine, cisplatin, or cytosine arabinoside. An additive effect was observed for its combination with bleomycin, doxorubicin, etoposide, 5-fluorouracil, mitomycin C, 6-mercaptopurine, or vincristine. A sub-additive (antagonistic) effect was observed for its combination with methotrexate. These data suggest that mitoxantrone, administered simultaneously with any one of a majority of anticancer agents we studied, is advantageous for cytokilling. Of the anticancer agents tested, amsacrine, cisplatin, and cytosine arabinoside are the most suitable for combination with mitoxantrone, and these combinations are worthy of clinical investigation. Methotrexate in our system is inappropriate for simultaneous administration with mitoxantrone. These data should provide useful information for the establishment of clinical protocols involving mitoxantrone.     

A phase II study of bendamustine chemotherapy as second-line treatment in metastatic uveal melanoma

Uveal melanoma is the most frequent primary malignant neoplasm of the eye and has a poor prognosis in metastatic stage. Fotemustine or a combination of gemcitabine and treosulfan has demonstrated some efficacy in metastatic disease. We conducted a phase II trial to assess the second-line activity and toxicity of bendamustine hydrochloride, a nucleoside analogue with alkylating activity. Inclusion criteria were a Karnofsky performance status of > or = 60% and progressive disease during or after first-line chemotherapy. Bendamustine was administered at a dose of 120 mg/m2 on days 1 and 2. Cycles were repeated on day 22. The primary endpoint of the study was the determination of the number of patients achieving an objective response or stable disease. The secondary endpoint was toxicity. Eleven patients were enrolled into the trial. Grade III and IV toxicity consisted of anaemia, thrombocytopenia and leucocytopenia in two, one and two patients, respectively. No grade III or IV non-haematological toxicity was observed. According to Response Evaluation Criteria in Solid Tumours (RECIST), all patients showed progressive disease. We conclude that bendamustine is ineffective as second-line chemotherapy for metastatic uveal melanoma.     

Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning

The tyrosine kinase activity of the BCR-ABL oncoprotein results in reduced apoptosis and thus prolongs survival of chronic myelogenous leukaemia cells. The tyrosine kinase inhibitor imatinib (formerly STI571) was reported to selectively suppress the proliferation of BCR-ABL-positive cells. Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and gamma-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR-ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines. Further, primary cells of untreated chronic myelogenous leukaemia patients were assayed for colony forming ability under combination therapy with imatinib. Additionally, the cytotoxic effect of these combinations on BCR-ABL-negative cells was investigated. In the cell lines a tetrazolium based MTT assay was used to quantify growth inhibition after exposure to cytotoxic drugs alone or to combinations with imatinib. Irradiation was applied prior to exposure to imatinib. Interaction of drugs was analysed using the median-effect method of Chou and Talalay. The combination index was calculated according to the classic isobologram equation. The combination imatinib + gamma-irradiation proved to be significantly synergistic over a broad range of cell growth inhibition levels in both BCR-ABL-positive cell lines and produced the strongest reduction in primary chronic myelogenous leukaemia colony-forming progenitor cells. Combinations of imatinib + busulfan and imatinib + treosulfan showed merely additive to antagonistic effects. Imatinib did not potentiate the effects of irradiation or cytotoxic agents in BCR-ABL-negative cells. Our data provide the basis to further develop imatinib-containing conditioning therapies for stem cell transplantation in chronic myelogenous leukaemia.     

A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma.

BACKGROUND: Several trials demonstrated efficacy of the gemcitabine/treosulfan (GeT) combination in metastatic uveal melamoma. This randomized phase II trial compared the GeT combination versus treosulfan alone (T) in this rare disease. PATIENTS AND METHODS: Chemotherapy-naive patients with proven metastatic uveal melanoma were randomly assigned to receive 1000 mg/m(2) of gemcitabine plus 3500 mg/m(2) of treosulfan (GeT) or 3500 mg/m(2) of T. Chemotherapy was administered on days 1 and 8 in both arms, cycles were repeated on day 29. Primary end point was rate of responses and disease stabilizations. RESULTS: Forty-eight patients were randomized. Seven confirmed stable diseases (SDs) and one partial remission (PR) were observed in 24 patients treated with the GeT regimen, whereas no PR and only three SDs were observed in the T arm (P = 0.08). Median progression-free survival (PFS) was 3 months (95% CI 1.1-4.9) and 2 months (95% CI 1.7-2.3) in the GeT and T arm (P = 0.008, log-rank). Six and 12 months PFS was 34.8% and 17.9% and 16.7% and 0% always favoring the GeT arm. CONCLUSIONS: This first randomized trial in metastatic uveal melanoma showed a superior PFS and a trend for a higher response/stabilization rate of the GeT combination over T.     

Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines

In an attempt to improve current therapeutic strategies for acute myelogenous leukemia (AML), we studied the effects of a commercially available drug, dexrazoxane (DEX), which protects against anthracycline-induced cardiotoxicity. The rationale was that DEX would permit higher doses of cardiotoxic drugs to be given. The drug itself may have therapeutic potential as well. Finally, there are concerns that the drug may, as a protective agent, diminish the effectiveness of various chemotherapeutics. To help resolve the question about potential drug antagonism, we undertook a series of in vitro analyses of DEX and various combinations with anthracyclines and other agents. Colony-forming assays were used to evaluate stem-cell renewal of myeloid cells in vitro, and median-effect analysis was used to evaluate antagonism, synergism, and additivity. The anthracyclines doxorubicin, daunorubicin, and idarubicin were individually combined with DEX to study in vitro effects in leukemic myeloid cell lines. In the hope, we could extend the findings to non-anthracyclines, etoposide and cytosine arabinoside were also evaluated in combination with DEX using the same in vitro model and method. We found that the effects of DEX in combination with any of the anthracyclines were schedule dependent. The antitumor effect was greater for each combination than for any anthracycline alone except when DEX was administered 24h before doxorubicin or daunorubicin. These data were corroborated through median-effect analysis. Etoposide in combination with DEX was synergistic for all combinations and schedules, and the combination of cytosine arabinoside and DEX was effective depending on the schedule used. DEX appears to be a promising drug in the treatment of AML and warrants further clinical study involving novel drug combinations.     

Microbiologic assay for cytosine arabinoside (NSC-63878): the use of a mutant of streptococcus faecium var. durans resistant to methotrexate (NSC-740) and 6-mercaptopurine (NSC-755).

Cytosine arabinoside has been shown to be effective in the treatment of acute leukemias and lymphomas, especially in combination with other established anticancer agents such as methotrexate, 6-mercaptopurine, and 6-thioguanine. A microbiologic assay capable of detecting cytosine arabinoside in the presence of such anticancer agents in body fluids has been developed using a strain of Streptococcus faecium var. durans resistant to methotrexate and 6-mercaptopurine; the assay can also be used to determine cytosine arabinoside concentrations in the presence of l-thioguanine. In view of the present trend toward drug combinations, including those using tetrahydrouridine, in the chemotherapy for human neoplasms, the proposed assay method will be valuable in cytosine arabinoside distribution studies.     

Phase II trial of cisplatin, gemcitabine and treosulfan in patients with metastatic uveal melanoma

Gemcitabine plus treosulfan (GeT) is under investigation in metastatic uveal melanoma. In this phase II trial, cisplatin was added to a GeT regimen to investigate the efficacy and toxicity of two alkylating agents in combination with gemcitabine. Patients received 30 or 40 mg/m of cisplatin, 1000 mg/m of gemcitabine and 3000 mg/m of treosulfan on days 1 and 8. Therapy was repeated on day 29. A maximum of six cycles was administered. Nineteen patients were included in the trial, of whom 17 were evaluable for response. No objective response was observed; seven patients (41%) had stable disease and 10 (59%) progressed. The median progression-free survival of all 19 patients was 3.0 months [95% confidence interval (CI), 1.8-3.1]; the median overall survival was 7.7 months (95% CI, 1.9-13.8). Grade 3 and 4 thrombopenia and leucopenia occurred in eight and nine of the 19 patients, respectively. The addition of cisplatin to the GeT regimen results in excessive haematological toxicity without improvement in efficacy.     

Effects of amsacrine in combination with other anticancer agents in human acute lymphoblastic leukemia cells in culture

Effects of amsacrine in combination with other anticancer agents at ID80 were evaluated by cell growth assay using a human T-cell leukemia cell line (MOLT-3). The data were analyzed with the aid of an improved isobologram, using the concept of an envelope of additivity. A supra-additive effect was observed for amsacrine in combination with cytosine arabinoside and mitoxantrone. An additive effect was observed in its combinations with bleomycin, CPT-11, cisplatin, daunorubicin, doxorubicin, etoposide, 5-fluorouracil, homoharringtonine, mitomycin C, or vincristine. 6-Mercaptopurine had an additive effect with amsacrine at ID80 but a sub-additive to protective effect at ID90. A sub-additive to protective effect was shown for amsacrine in combination with methotrexate. These data suggest that cytosine arabinoside and mitoxantrone are the best of the anticancer agents we studied for use in combination with amsacrine. Bleomycin, cisplatin, CPT-11, doxorubicin, cytosine arabinoside, homoharringtonine, mitomycin C, and vincristine also yielded favorable results when administrated simultaneously with amsacrine. Simultaneous administration of amsacrine with 6-mercaptopurine and methotrexate is not appropriate. If amsacrine is combined with 6-mercaptopurine and methotrexate, other suitable schedules should be explored. These results may provide a rationale for the design of clinical protocols combining amsacrine with other anticancer agents.     

2 chlorodeoxyadenosine activity and cross resistance patterns in primary cultures of human hematologic neoplasms.

2-Chlorodeoxyadenosine (2-CDA) is an adenosine deaminase resistant analogue of deoxyadenosine which has shown clinical activity in human hematologic neoplasms. The exact mode of action of this drug remains the subject of investigation. We applied the Differential Staining Cytotoxicity (DiSC) assay to 50 human tumour specimens obtained from patients with a variety of hematologic malignancies to characterise the activity spectrum of 2-CDA. We evaluated the disease-specific activity of this agent in vitro and compared its relative cytotoxicity with that of other antineoplastic agents in current clinical use. Comparisons were conducted against nitrogen mustard, doxorubicin, vincristine and cytosine arabinoside. Our results indicate that 2-CDA has activity in myeloid and many lymphoid neoplasms but that multiple myeloma specimens reveal significant resistance. Cross resistance studies reveal a correlation between 2-CDA and the alkylator nitrogen mustard but no correlation between 2-CDA and doxorubicin, vincristine nor cytosine arabinoside. The results suggest 2-CDA activity in many human hematologic neoplasms with the clear exception of multiple myeloma and further suggest a relationship between this agent and alkylators of the mustard class. The DiSC assay may provide useful insights in the pre-clinical evaluation of new antineoplastic drugs and may help to elucidate drug activities and mechanisms of action.     

Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients

PURPOSE: The alkylating agent treosulfan exerts a high cytotoxic activity against various malignant cells. Due to limited non-hematological toxicity, treosulfan might be a promising compound in myeloablative therapy for hematopoietic transplantation in children. Since in vitro data regarding the activity of treosulfan against childhood leukemic cells are limited, we compared the effect of treosulfan and busulfan against pediatric leukemic and non-malignant cells. EXPERIMENTAL DESIGN: Both agents were tested alone and in combination with fludarabine by means of the MTT and/or a five color-flow cytometric assay. Moreover, the induction of apoptosis by treosulfan was investigated via regulation of the proteinase caspase 3. RESULTS: Treosulfan was more active against leukemic cells of 20 children as well as against 3 leukemia-derived cell lines than busulfan, with increasing IC(50) values from initial diagnosis to relapse. Overall purified stem cells were most sensitive, followed by CD56(+)CD3(-) NK and CD3(+) T cells. The combination of treosulfan with fludarabine resulted in a synergistic effect against leukemic cells. In malignant cells, treosulfan induced rapid cell apoptosis measured by the activation of the centrally proteinase caspase 3. CONCLUSION: Our results indicate that treosulfan has activity against pediatric leukemic cells, myeloablative potential and immunosuppressive properties suitable for conditioning regimen in childhood malignancies.     

Cisplatin, gemcitabine, and treosulfan in relapsed stage IV cutaneous malignant melanoma patients

To evaluate the efficacy of cisplatin, gemcitabine, and treosulfan (CGT) in 91 patients with pretreated relapsed AJCC stage IV cutaneous malignant melanoma. Patients in relapse after first-, second-, or third-line therapy received 40 mg m(-2) intravenous (i.v.) cisplatin, 1000 mg m(-2) i.v. gemcitabine, and 2500 mg m(-2) i.v. treosulfan on days 1 and 8. Cisplatin, gemcitabine, and treosulfan therapy was repeated every 5 weeks until progression of disease occurred. A maximum of 11 CGT cycles (mean, two cycles) was administered per patient. Four patients (4%) showed a partial response; 15 (17%) patients had stable disease; and 72 (79%) patients progressed upon first re-evaluation. Overall survival of all 91 patients was 6 months (2-year survival rate, 7%). Patients with partial remission or stable disease exhibited a median overall survival of 11 months (2-year survival rate, 36%), while patients with disease progression upon first re-evaluation had a median overall survival of 5 months (2-year survival rate, 0%). Treatment with CGT was efficient in one-fifth of the pretreated relapsed stage IV melanoma patients achieving disease stabilisation or partial remission with prolonged but limited survival.     

The glutathione transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) increases temozolomide efficacy against malignant melanoma

First line treatment of metastatic melanoma includes the methylating agent dacarbazine or its analogue temozolomide (TMZ) with improved pharmacokinetics and tolerability. However, the prognosis of the metastatic disease is poor and several trials are evaluating TMZ in polychemotherapy protocols. The novel glutathione transferase P1-1 (GSTP1-1) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has recently shown activity against melanoma through c-Jun N-terminal kinase activation. In this study we have investigated the in vitro and in vivo efficacy of NBDHEX and TMZ combination against melanoma. The results indicated that NBDHEX and TMZ exerted in vitro synergistic anti-proliferative effects in murine B16 and human A375 melanoma cells. In B16 cells TMZ as single agent caused cell accumulation at the G₂/M phase of cell cycle, whereas NBDHEX induced mainly apoptotic effects. NBDHEX provoked a higher level of p53 phosphorylation with respect to TMZ and the drug combination caused a more than additive increase of p53 activation.The in vivo efficacy of NBDHEX and TMZ has been investigated in an orthotopic B16 model. Treatment with NBDHEX provoked a reduction of tumour growth comparable to that obtained with TMZ, whereas the drug combination significantly increased tumour growth inhibition with respect to the single agents, without worsening TMZ myelotoxicity. Immunohistochemical analysis of tumour grafts revealed a profound reduction of Cyclin D1 and CD31 in all treatment groups; VEGF expression was, instead, markedly decreased only in NBDHEX or NBDHEX and TMZ treated samples. These findings indicate that NBDHEX represents a good candidate for combination therapies including TMZ, offering new perspectives for the treatment of melanoma.     

Gemcitabine and taxanes as a new standard of care in breast cancer

Advances in breast cancer continue to focus on the development of novel agents as well as the development of novel combinations, with the major therapeutic goal of treatment strategies revolving around improving response rates, delaying the time to disease progression, palliating symptoms, and improving quality of life. The taxanes are recognized as some of the most active single agents in breast cancer and demonstrate remarkable activity with manageable toxicity in combination with gemcitabine. Gemcitabine, a novel S-phase specific cytidine nucleoside analogue of deoxycytidine, has broad antitumor activity with significant monotherapy activity in breast cancer, with response rates ranging from 22% to 42% depending on the pretreatment characteristics of the patients. In general, gemcitabine s favorable single-agent activity and novel mechanism of action, in addition to its largely nonoverlapping toxicities, have facilitated its further development in combination with a variety of chemotherapy agents, including the taxanes. Several phase I and II trials have reported impressive activity for the gemcitabine/taxane doublet with the suggestion of clinical synergism between these 2 classes of agents. Given the remarkable and durable activity reported for this doublet, subsequent phase II trials have focused on optimizing doses and schedules. Unmistakably, these trial results are clear improvements over the single-agent activity of the taxanes in metastatic breast cancer, with the recently reported phase III trial comparing gemcitabine plus paclitaxel versus paclitaxel alone clearly reinforcing the superior outcomes demonstrated for the combination. Either as a single agent or in combination with the taxanes, gemcitabine remains a rational choice for the treatment of breast cancer.     

A prospective single arm phase II study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma

Uveal melanoma is relatively uncommon accounting for fewer than 5% of all melanoma cases. Localized tumours are curable by local therapy but a significant percentage of patients go on to have a relapse with metastatic disease. Uncertainty remains concerning the level of activity of dacarbazine in uveal melanoma as opposed to that in the cutaneous form. Recently, a possible role for treosulfan in uveal disease has been reported. A phase II study was therefore undertaken to assess the objective response rate of the combination of dacarbazine and treosulfan in previously untreated patients with metastatic uveal melanoma. All patients received dacarbazine 850 mg/m and treosulfan 8 g/m(2) every 21 days up to a maximum of six cycles. Fifteen patients enrolled in the study. As expected, the major toxicities were haematological (particularly thrombocytopaenia) but the treatment was generally well tolerated. No responses were seen; however, disease stabilization was achieved in two patients. Median progression free survival from the start of chemotherapy was 12 weeks and median overall survival was 30 weeks. This study, using the combination of dacarbazine and treosulfan, while well tolerated, did not confirm earlier reports suggesting treosulfan is active in uveal melanoma.