The power of phase II end-points for different possible mechanisms of action of an experimental treatment.

BACKGROUND: The high failure rate in phase III oncology trials is partly because the signal obtained from phase II trials is often weak. Several papers have considered the appropriateness of various phase II end-points for individual trials, but there has not been a systematic comparison using simulated data to determine which end-point should be used in which situation. METHODS: In this paper we carry out simulation studies to compare the power of several Response Evaluation Criteria in Solid Tumours (RECIST) response-based end-points for one-arm and two-arm trials, together with progression-free survival (PFS) and testing the tumour-shrinkage directly for two-arm trials. We consider six scenarios: (1) short-term cytotoxic therapy; (2) continuous cytotoxic therapy; (3+4) cytostatic therapy; (5+6) delayed tumour-shrinkage effect (seen in some immunotherapies). We also consider measurement error in the assessment of tumour size. RESULTS: Measurement error affects the type-I error rate and power of single-arm trials, and the power of two-arm trials. Generally no single end-point performed well in all scenarios. Best observed response rate, PFS and directly testing the tumour-shrinkages performed best for a number of scenarios. PFS performed very poorly when the effect of the treatment was short-lived. In scenario 6, where the delay in effect was long, no end-point performed well. CONCLUSIONS: A clinician setting up a phase II trial should consider the likely mechanism of action the drug will have and choose an end-point that provides high power for that scenario. Testing the difference in tumour-shrinkage is often powerful. Alternative end-points are required for therapies with a long delayed effect.

Treatment costs associated with interventional cancer clinical trials conducted at a single UK institution over 2 years (2009-2010).

BACKGROUND: The conduct of clinical trials should be an integral part of routine patient care. Treating patients in trials incurs additional costs over and above standard of care (SOC), but the extent of the cost burden is not known. We undertook a retrospective cost attribution analysis to quantitate the treatment costs associated with cancer clinical trial protocols conducted over a 2 year period. METHODS: All patients entered into oncology (non-haematology) clinical trials involving investigational medicinal products in 2009 and 2010 in a single UK institution were identified. The trial protocols on which they were treated were analysed to identify the treatment costs for the experimental arm(s) of the trial and the equivalent SOC had the patient not been entered in the trial. The treatment cost difference was calculated by subtracting the experimental treatment cost from SOC cost. For randomised trials, an average treatment cost was estimated by taking into account the number of arms and randomisation ratio. An estimate of the annual treatment costs was calculated. RESULTS: A total of 357 adult oncology patients were treated on 53 different trial protocols: 40 phase III, 2 randomised II/III and 11 phase II design. A total of 27 trials were academic, non-commercial sponsored trials and 26 were commercial sponsored trials. When compared with SOC, the average treatment cost per patient was an excess of £431 for a non-commercial trial (range £6393 excess to £6005 saving) and a saving of £9294 for a commercial trial (range £0 to £71,480). There was an overall treatment cost saving of £388,719 in 2009 and £496,556 in 2010, largely attributable to pharmaceutical company provision of free drug supplies. CONCLUSION: On an average, non-commercial trial protocols were associated with a small per patient excess treatment cost, whereas commercial trials were associated with a substantially higher cost saving. Taking into account the total number of patients recruited annually, treatment of patients on clinical trial protocols was associated with considerable cost savings across both the non-commercial and commercial portfolio.

A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma.

Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m(-2) days 1-5 every 28 days and lomustine 60 mg m(-2) on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted.

Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group.

PURPOSE: This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS: Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS: Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION: In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.

A prognostic index that predicts outcome following palliative whole brain radiotherapy for patients with metastatic malignant melanoma.

To determine the outcome of patients with metastatic malignant melanoma (MMM) treated with palliative whole brain radiotherapy (WBRT) and to identify factors that predict treatment outcome to assist future trial design, a retrospective study was performed on patients with MMM who received WBRT at the Royal Marsden Hospital between 1998 and 2003. Data regarding patient factors, tumour factors and survival were collected. A total of 112 patients were identified and full data were available for 102 patients. The median age was 53 years (range 25-81 years), 66.7% were male and 33.3% female. The median dose prescribed was 20 Gy in five fractions as a mid-plane dose. The median survival after WBRT for the whole group was 51 days (range 3-1386). In an attempt to define prognostic groups, we used the validated RTOG recursive partitioning analysis (RPA) classification for brain metastasis (class 1: Karnofsky Performance Score (KPS) >/=70%, age <65 years with no extracranial metastasis; class 3: KPS <70%; class 2: all others). The median survivals were 151, 71 and 21 days for RPA class 1, 2 and 3, respectively (P<0.001). Multivariate analysis showed that RPA class, leptomeningeal involvement, presence and number of extracranial metastatic sites and progressive disease in the brain on imaging before WBRT are important independent predictive factors. A prognostic index was derived from these factors that allowed identification of patients unlikely to benefit from WBRT. In conclusion, the RTOG RPA classification is valid when applied to patients with MMM. Patients in RPA class 1 and good prognosis class 2 are likely to benefit from palliative WBRT and should be considered for entry into trials that aim to improve duration of response. We identified that patients with RPA class 3, leptomeningeal involvement or RPA class 2 with poor prognostic index are unlikely to benefit from palliative WBRT.

Differentiation of human melanoma cells through p38 MAP kinase is associated with decreased retinoblastoma protein phosphorylation and cell cycle arrest.

The retinoblastoma protein (pRB), the product of the retinoblastoma gene, is a key regulator of the cell cycle, affecting apoptosis, proliferation and differentiation. Dysregulation of pRB is implicated in the pathogenesis of many cancers, including malignant melanoma. Recently we demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH)-induced activation of p38 mitogen-activated protein (MAP) kinase leads to differentiation of B16 murine melanoma cells. The current study assesses the ability of alpha-MSH to activate p38 MAP kinase in COLO 853 human melanoma cells and determines whether this is linked to modulation of pRB activity. Treatment of COLO 853 cells with alpha-MSH induced time- and concentration-dependent increases in the phosphorylation of p38 MAP kinase, which corresponded with its ability to induce melanogenesis and inhibit cell growth. SB 203580, a selective inhibitor of p38 MAP kinase, blocked both the alpha-MSH-induced melanogenic response and inhibition of cell growth. Cell cycle analysis using flow cytometry revealed that treatment of COLO 853 cells with alpha-MSH for 72 h led to an increase in the proportion of cells in the G(1) phase and a marked reduction in the amount of phosphorylated pRB. Both of these effects were reversed by pre-treatment of cells with SB 203580. In summary, we have demonstrated for the first time that the alpha-MSH-induced differentiation of COLO 853 human melanoma cells proceeds via a p38 MAP kinase-mediated pathway and is associated with decreased pRB phosphorylation and accumulation of cells in the G(1) phase.

A randomised phase II study of conventional versus accelerated infusional chemotherapy with granulocyte colony-stimulating factor support in advanced breast cancer.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) allows cycles of conventional bolus chemotherapy to be accelerated with reduction in treatment time and a boost in dose intensity. Theoretically, this approach could be hazardous with infusional 5-fluorouracil (5-FU) chemotherapy, since G-CSF-stimulated neutrophil proliferation would be occurring in the face of continuous S-phase active 5-FU. We performed this phase II randomised study to compare the safety, tolerability and efficacy of conventional 3-weekly epirubicin, cyclophosphamide and continuous infusional 5-FU (infusional ECF) to an accelerated 2-weekly schedule with G-CSF support, in patients with advanced breast cancer. PATIENTS AND METHODS: Twenty-seven patients were randomised. with 14 in the accelerated arm. Patients received bolus epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks (conventional arm) or every 2 weeks (accelerated arm) and 5-FU 200 mg/m2/day continuous infusion throughout. G-CSF 300 microg/day s.c. on days 10-12 was given each accelerated cycle. RESULTS: There were no treatment delays secondary to inadequate neutrophil or platelet recovery in either arm, with higher median day 1 neutrophil counts for each cycle in the accelerated arm compared with the conventional arm. Eighty-six per cent of the planned conventional chemotherapy cycles and 82% of the planned accelerated cycles were given. There were no major differences in toxicity between the arms, with the most common grade 3 toxicities being alopecia and stomatitis. Eight patients developed neutropenic sepsis (five in the accelerated arm and three in the conventional arm). Ten patients (77%) responded in the conventional arm and nine (64%) in the accelerated arm. CONCLUSIONS: Accelerated infusional ECF with limited G-CSF support is a feasible and well-tolerated regimen with rapid haematological recovery. A 50% increase in relative dose intensity of epirubicin and cyclophosphamide is achieved, while overall treatment time is reduced by 33%.

Thalidomide in solid tumors: the London experience.

Investigators at the Royal Marsden Hospital and University College in London have studied thalidomide (Thalomid) as both low-dose (100 mg orally, every night) and high-dose (600 mg, given as 300 mg twice per day) therapy for patients with a variety of solid tumors. In the phase II low-dose study, responses were disappointing in patients with melanoma, ovarian cancer, and breast cancer. Results for patients with renal-cell carcinoma were more encouraging. A case study of a patient with metastatic renal-cell carcinoma in the lung and lymph nodes in the low-dose thalidomide study illustrates that (1) responses may be very slow; (2) the palliative response is separate from the overall response, occurs much earlier, and is not consistent with an antiangiogenic action; and (3) peripheral neuropathy is a manageable side effect. Besides peripheral neuropathy, patients can experience severe constipation (even on low doses) as well as headache, edema, and skin rash for which treatment recommendations can be made. Anecdotal benefits of thalidomide include enhanced or maintained appetite, improved sleeping, and reduced sweating. The high-dose study has been submitted for publication.

The control of gene expression in melanocytes and melanomas.

Powerful evidence exists that deregulation of cell type-specific gene expression is a major feature of the genesis of several cancers, with many oncogenic proteins known to possess transcription regulation properties. As a consequence of this deregulation, melanomas may ectopically express HLA-DR and also fall to express enzymes required for melanin synthesis, resulting in amelanotic melanoma. Recent work has demonstrated that these phenomena may be accounted for by the expression of a transcription factor called Brn-2, now known to be involved with the development of neural crest-derived tissues. Brn-2 is normally expressed at high levels in melanoblasts and melanomas but only at low levels in normal melanocytes. Brn-2 may act by competing with another transcription factor, ml, necessary for normal melanocyte development.