Intensive induction chemotherapy with C-BOP/BEP for intermediate- and poor-risk metastatic germ cell tumours (EORTC trial 30948)

New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9–79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7–66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5–91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6–93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m2 and grade 2 in two, one who received a cumulative dose of 960 mg m2 and the other a cumulative dose of 600 mg m2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated

A comparative quantitative study of human myeloid dendritic cell progenitors in cord blood, bone marrow, peripheral blood and their mobilization kinetics in the peripheral blood of cancer patients undergoing leucaphaeresis

Dendritic cell (DC)-based immunotherapy has potential for use in the treatment of cancer, infections and transplantation. Generating large numbers of DC from haemopoietic progenitor cells (HPC) is a key step in this process, often achieved by the aphaeresis of HPC, following their mobilization from the bone marrow into peripheral blood (PB) with chemotherapy and growth factor support (usually, granulocyte-colony stimulating factor, G-CSF). The objective of this work was to identify the optimum time for leucaphaeresis of DC progenitors. An established clonogenic assay specific for colony-forming cell (CFC) DC was used and validated with linearity, dose-response experiments and morphological confirmation. The optimal numbers of mononuclear and CD34+ (or AC133+) cells for plating were 5x104 and l-2xl03 respectively. The optimal concentrations of recombinant cytokines were also determined. Kinetic studies were done in patients with solid tumours, and HPC mobilization was achieved with conventional chemotherapy and G-CSF. The best time for harvesting large numbers of DC progenitors was when the leucocyte count rose rapidly from its nadir at a median 10 days (range 7-13) post chemotherapy. Comparative studies identified mobilized PB as the richest source of CFC-DC (mean, 1,481/ ml PB), with at least, 1.5-fold more progenitors per unit volume than cord blood (CB). These data suggest that venesection alone could provide sufficient CFC-DC to generate mature DC, after ex vivo culture and expansion. This might obviate the need for leucaphaeresis thus making DC-based immunotherapy potentially more widely available. In all the haemopoietic tissues examined the majority of DC and granulo (G)-monocytic (M) progenitors, was found within the CD34+AC133+ cell population. It is concluded that the kinetics of mobilization of CFC-DC are very similar to those of other HPC like CFC- GM and erythroid progenitors. This has important implications for designing immunotherapy protocols to isolate DC precursors from CD34+ HPC for ultimate use in DC-based immunotherapy

Management of endocrine resistant breast cancer

Metastatic breast cancer (MBC) may present de novo but more commonly develops in women initially presenting with early breast cancer despite the widespread use of adjuvant hormonal and cytotoxic chemotherapy. MBC is incurable. Hormone sensitive MBC eventually becomes resistant to endocrine therapy in most women. Anthracyclines are the agents of choice in the treatment of endocrine resistant MBC. With the widespread use of anthracyclines in the adjuvant setting, taxanes have become the agents of choice for many patients. Recently capecitabine has become established as a standard of care for patients pretreated with anthracyclines and taxanes. However, a range of agents have activity as third line treatment. These include gemcitabine, vinorelbine and platinum analogues. The sequential use of non-cross resistant single agents rather than combination therapy is preferable in most women with MBC. Even though combination therapy can improve response rates and increase progression free interval, there is no robust evidence to indicate an advantage in terms of overall survival. Moreover, combination therapy is associated with a higher toxicity rate and poor quality of life. There is no role for dose-intense therapy, high dose therapy or maintenance chemotherapy outside the context of a clinical trial. The introduction of trastuzumab, monoclonal antibody targeting growth factor receptors, has improved the therapeutic options for women with tumours overexpressing HER2/neu. DNA micro-array profiles of tumours can potentially help to individualise therapy in future. Molecular targeted therapy has the potential to revolutionise the management of MBC

Platinum-based chemotherapy in metastatic breast cancer : the Leicester (UK) experience

Aims: After failure of anthracycline- and taxane-based chemotherapy in metastatic breast cancer, treatment options until recently were limited. Until the introduction of capecitabine and vinorelbine, no standard regimen was available. We conducted a retrospective study to determine the efficacy and toxicity of platinum-based chemotherapy in metastatic breast cancer. Materials and methods: Forty-two women with metastatic breast cancer previously treated with anthracyclines (93%) and/or taxanes (36%) received mitomycin-vinblastine-cisplatin (MVP) (n = 23), or cisplatin-etoposide (PE) (n = 19), as first-, second- and third-line treatment at a tertiary referral centre between 1997 and 2002. Chemotherapy was given every 3 weeks as follows: mitomycin-C (8 mg/m 2) (cycles 1, 2, 4, 6), vinblastine (6 mg/m 2), and cisplatin (50 mg/m 2) all on day 1; and cisplatin (75 mg/m 2) and etoposide (100 mg/m 2) on day 1 and (100 mg/m 2) orally twice a day on days 2-3. Results: The response rate for 40 evaluable patients (MVP: n = 23; PE: n = 17) was 18% (95% confidence interval [CI]: 9-32%). The response rate to MVP was 13% (95% CI: 5-32%, one complete and two partial responses) and to PE 24% (10-47%, four partial responses). Disease stabilised in 43% (26-63%) and 47% (26-69%) of women treated with MVP and PE, respectively. After a median follow-up of 18 months, 37 women (MVP: n = 19; PE: n = 18) died from their disease. Median (range) progression-free survival and overall survival were 6 months (0.4-18.7) and 9.9 months (1.3-40.8), respectively. Median progression-free survival for the MVP and PE groups was 5.5 and 6.2 months (Log-rank, P = 0.82), and median overall survival was 10.2 and 9.4 months (Log-rank, P = 0.46), respectively. The main toxicity was myelosuppression. Grades 3-4 neutropenia was more common in women treated with PE than in women treated with MVP (74% vs 30%; P = 0.012), but the incidence of neutropenic sepsis, relative to the number of chemotherapy cycles, was low (7% overall). The toxicity-related hospitalisation rate was 1.2 admissions per six cycles of chemotherapy. No treatment-related deaths occurred. MVP and PE chemotherapy have modest activity and are safe in women with metastatic breast cancer. © 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved

Immune checkpoint inhibitors as first-line and salvage therapy for advanced non-small-cell lung cancer

Advanced non-small-cell lung cancer (NSCLC) has a poor prognosis with few treatment options available for patients after failure of first-line therapy. Nivolumab is the first immune checkpoint inhibitor targeting the PD-1 to be approved in recurrent NSCLC with squamous and nonsquamous histology. More recently, pembrolizumab has also been approved as salvage therapy in PD-L1-positive recurrent NSCLC. The success of immunotherapy in malignant melanoma, previously a disease with no effective treatment, has generated optimism and expectation that some of the checkpoint inhibitors currently in clinical development will soon become available as first-line therapy and hence improve outcomes for the vast majority of patients with advanced NSCLC. This article summarizes the progress accomplished in the field and discusses controversies surrounding the use of immune checkpoint inhibitors

Clinician perspective on molecular profiling of non-small-cell lung cancer [Correspondence]

The article by Meric-Bernstam et al1 that was recently published in Journal of Clinical Oncology raises important questions about the clinical application of large-scale genomic testing. We congratulate the authors for this ambitious study, which successfully profiled 2,000 consecutive patients with advanced cancer. The next-generation sequencing (NGS) platform was used for 1,749 of 2,000 patients (87.5%). Of 789 patients with potentially actionable mutations, 83 (11%, or 4% of screened population) were enrolled in a genomically matched clinical study. As the editorial2 accompanying the article by Meric-Bernstam et al1 pointed out, the 4% figure, albeit disappointing, may be an underestimate because cancers such as lung adenocarcinoma and melanoma, for which ≥ 50% of patients have actionable mutations, were under-represented. ..

Platinum-based chemotherapy in metastatic breast cancer : current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently ∼60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-naïve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer. © 2003 Elsevier Ltd. All rights reserved