Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study.

BACKGROUND: Topical imiquimod is sometimes used for lentigo maligna (LM) in situ melanoma instead of surgery, but frequency of cure is uncertain. Pathological complete regression (pCR) is a logical surrogate marker for cure after imiquimod, although residual LM and atypical melanocytic hyperplasia may not be reliably distinguished. A trial comparing imiquimod vs. surgery might be justified by a high imiquimod pCR rate. OBJECTIVES: Primary: to estimate the pCR rate for LM following imiquimod. Secondary: to assess the accuracy of prediction of pCR, using clinical complete regression (cCR) plus negative post-treatment biopsies, tolerability, resource use, patients' preferences and induced melanoma immunity. METHODS: This was a single-arm phase II trial of 60 imiquimod applications over 12 weeks for LM then radical resection. A pCR rate ≥ 25 out of 33 would reliably discriminate between pCR rates < 60% and ≥ 85%. Clinical response was assessed and biopsies taken after imiquimod. Patients recorded adverse events in diaries. Patient preference was measured after surgery using a standard gamble tool. RESULTS: The pCR rate was 10 of 27 (37%, 95% confidence interval 19-58%). The rate of cCR plus negative biopsies was 12 of 28, of whom seven of 11 had pCR on subsequent surgery. The median dose intensity was 86·7%. Of the 16 surveyed patients, eight preferred primary imiquimod over surgery if the cure rate for imiquimod was 80%, and four of 16 if it was ≤ 40%. CONCLUSIONS: The pCR rate was insufficient to justify phase III investigation of imiquimod vs. SURGERY: Clinical complete response and negative targeted biopsies left uncertainty regarding pathological clearance. Some patients would trade less aggressive treatment of LM against efficacy.

The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer.

BACKGROUND: The management of NSCLC has been transformed by stratified medicine. The National Lung Matrix Trial (NLMT) is a UK-wide study exploring the activity of rationally selected biomarker/targeted therapy combinations. PATIENTS AND METHODS: The Cancer Research UK (CRUK) Stratified Medicine Programme 2 is undertaking the large volume national molecular pre-screening which integrates with the NLMT. At study initiation, there are eight drugs being used to target 18 molecular cohorts. The aim is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation. A Bayesian adaptive design that gives a more realistic approach to decision making and flexibility to make conclusions without fixing the sample size was chosen. The screening platform is an adaptable 28-gene Nextera next-generation sequencing platform designed by Illumina, covering the range of molecular abnormalities being targeted. The adaptive design allows new biomarker-drug combination cohorts to be incorporated by substantial amendment. The pre-clinical justification for each biomarker-drug combination has been rigorously assessed creating molecular exclusion rules and a trumping strategy in patients harbouring concomitant actionable genetic abnormalities. Discrete routes of pathway activation or inactivation determined by cancer genome aberrations are treated as separate cohorts. Key translational analyses include the deep genomic analysis of pre- and post-treatment biopsies, the establishment of patient-derived xenograft models and longitudinal ctDNA collection, in order to define predictive biomarkers, mechanisms of resistance and early markers of response and relapse. CONCLUSION: The SMP2 platform will provide large scale genetic screening to inform entry into the NLMT, a trial explicitly aimed at discovering novel actionable cohorts in NSCLC. CLINICAL TRIAL ISRCTN: 38344105.

Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma.

This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-γ ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I- and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses.

Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life.

PURPOSE: Chemotherapy for non-small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease. PATIENTS AND METHODS: Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses. RESULTS: Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P =.14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4. 8 months (PC alone) (P =.03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P =.01) and after adjusting for prognostic factors (P =.01). CONCLUSION: MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.

Patterns, costs and cost-effectiveness of care in a trial of chemotherapy for advanced non-small cell lung cancer.

In a recently published randomised trial of chemotherapy versus palliative care in advanced non-small cell lung cancer (the MIC2 trial), chemotherapy was shown to prolong survival without compromising quality of life. The study presented here examines patterns of care and their associated costs within a representative subgroup of patients from the MIC2 trial. The study consisted of 116 patients from the South Birmingham Health Authority area. The total health service cost for each patient from entry to trial to death or last follow-up was calculated by combining the resources used with their associated unit costs. The mean cost for patients with complete data on the chemotherapy arm was 6999 pounds sterling (standard deviation (S.D.) 4194 pounds sterling) compared to 4076 pounds sterling (S.D. 3078 pounds sterling) for those with complete data on the palliative care arm. Non-parametric bootstrapping gave a difference between treatment arms in mean cost of 2924 pounds sterling(95% CI 1234 pounds sterling - 4323 pounds sterling). With a difference in mean survival of 2.4 months, this translates to an incremental cost-effectiveness ratio of 14,620 pounds sterling per life year gained. Chemotherapy was found to be more costly than standard palliative care, mainly due to the increased number of hospital in-patient days.

Quality assurance of CD34+ cell estimation in leucapheresis products.

In order to examine the feasibility of an external quality assurance (QA) scheme for CD34+ cell enumeration and to identify causes of the differences between laboratories for CD34 counts, we carried out a pilot QA exercise in two parts. There were eight participating laboratories in the initial study and each performed CD34 counts using their in-house method. A series of 12 samples of cryopreserved peripheral blood progenitor cells (PBPC) were analysed by each of the eight laboratories. A very wide range of values for all the samples was found for the different in-house methods. For the second part of the study, 12 laboratories analysed a different set of 12 PBPC samples and each used the same anti-CD34 antibody (HPCA-2 PE), anti-CD45 antibodies to identify leucocytes, and counted a minimum of 50,000 events. These measures have reduced the interlaboratory variation in results but this variation is still too high to allow us to realistically compare values between centres. Overall, most centres performed comparably, but there was one centre in part one of the study which gave results that were significantly different from the other centres.

High lactate dehydrogenase level is associated with an adverse outlook in autografting for Hodgkin's disease.

Forty-two patients with relapsed or refractory Hodgkin's disease (HD) were treated with high-dose chemotherapy (BEAM regimen) followed by autologous bone marrow and/or peripheral blood progenitor cell (PBPC) rescue. There was one procedure-related death and the overall response rate at 6 months was 88% (95% confidence interval 78-98%). The 2 year overall and event-free survival was 81% (95% confidence interval 65-96%) and 74% (95% confidence interval 58-89%) respectively. Median follow-up was 33 months. The use of PBPC instead of marrow resulted in a significant shortening of the time to engraftment (P < 0.01). Multivariate analysis identified the pre-transplant LDH level as a highly significant factor in predicting overall survival (P = 0.007). The BEAM regimen is an effective conditioning schedule that is well tolerated but patients with a raised LDH at the time of transplant remain at high risk of early relapse and death due to disease.

Expression of E-cadherin in oesophageal carcinomas from the UK and China: disparities in prognostic significance.

AIMS: To study the expression and prognostic significance of the cell adhesion molecule E-cadherin in oesophageal tumours from the UK (low risk area) and China (high risk area). METHODS: E-cadherin expression was measured immunohistochemically in resected tumours from 17 patients in the UK with adenocarcinoma, 23 patients from the UK with squamous carcinoma, and 30 patients from China with squamous carcinomas who survived for five years postoperatively and compared with similar tumours from patients in the same regions who did not survive (140 tumours in all). RESULTS: Normal squamous epithelial cells and well differentiated areas of tumours showed membranous staining for E-cadherin expression. Cytoplasmic staining, heterogeneous staining, or an absence of staining was seen in dysplastic epithelium and in less well differentiated areas of tumours. Only one of 140 primary tumours had homogeneous membranous expression. In tumours from UK patients with adenocarcinoma (p = 1.00) and from Chinese patients with squamous carcinomas (p = 0.06) there was no correlation between E-cadherin absence and non-survival. In tumours from UK patients with squamous carcinomas there was a significant correlation between absence of E-cadherin and non-survival (p = 0.009). Tumours from UK patients with squamous carcinoma who survived were significantly less likely to be E-cadherin absent than those from Chinese patients with squamous carcinomas who survived (p = 0.007). Multivariate analysis (n = 37 UK, paired data) showed that absence of E-cadherin in the primary tumour was a weak independent prognostic factor for non-survival (30% significance level; p = 0.26; odds ratio = 3.56). In UK nodal metastases there was no correlation between E-cadherin expression and survival. CONCLUSIONS: Squamous carcinomas from UK patients differed from both adenocarcinomas from UK patients and carcinomas from Chinese patients with respect to E-cadherin expression and prognostic significance. In tumours from UK patients, E-cadherin absence in the primary carcinoma (a weak independent prognostic factor) but not metastases correlated with non-survival.

Simultaneous analysis of quality of life and survival data.

In many phase III clinical trials, particularly in the field of cancer, the comparison of treatments is based on both length of survival and quality of life. Subjects are followed over time until death and during this period, quality of life is assessed on a number of occasions. Simultaneous analysis of these two outcomes supplements the comparison of treatments in terms of each outcome independently with an assessment of the net effect. In addition, it provides a means of accounting for the informative dropout due to death of patients within the time frame of the quality of life study. The methods also have the potential to be extended to allow for informative dropout from the quality of life study prior to death. There are a number of broad approaches for the simultaneous analysis of quality of life and survival data. The most widely used approach in clinical research is quality-adjusted survival analysis, where treatments are compared in terms of a composite measure of quality and quantity of life. The paper reviews the different techniques for quality-adjusted survival analysis, illustrating the methodology by application to data from a phase III clinical trial in pancreatic cancer. In addition, alternative approaches using multistate survival analysis and joint modelling methods are also discussed.

Modelling prognostic factors in advanced pancreatic cancer.

Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA 19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA 19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer.

Follow up after Primary Treatment of Soft Tissue Sarcoma: A Survey of Current Practice in the United Kingdom.

Despite the clinical and financial implications, there is little evidence about how patients who have been treated for soft tissue sarcoma should be followed up. The purpose of this study was to determine current practice in the United Kingdom. 192 clinicians treating patients with soft tissue sarcoma were surveyed with a postal questionnaire enquiring about frequency and method of follow up and how patients would be followed up in each of 3 clinical scenarios: a patient with a trunk or extremity tumour at low risk of relapse; a patient with a trunk or extremity tumour at high risk of relapse; and a patient with a retroperitoneal or abdominal tumour. 155 (81%) clinicians responded. Clinic visits and X-rays were the most frequently used methods of follow up. Chest CT scans, local site imaging, and blood tests were used infrequently. The intensity and methods of follow up varied with each of the clinical scenarios. There was a seven-to-twenty fold variation in cost between the least and the most expensive regimes. Respondents were generally supportive of the development of the clinical trial in this area.

Changes in the serum proteome associated with the development of hepatocellular carcinoma in hepatitis C-related cirrhosis.

Early diagnosis of hepatocellular carcinoma (HCC) is the key to the delivery of effective therapies. The conventional serological diagnostic test, estimation of serum alpha-fetoprotein (AFP) lacks both sensitivity and specificity as a screening tool and improved tests are needed to complement ultrasound scanning, the major modality for surveillance of groups at high risk of HCC. We have analysed the serum proteome of 182 patients with hepatitis C-induced liver cirrhosis (77 with HCC) by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI). The patients were split into a training set (84 non-HCC, 60 HCC) and a 'blind' test set (21 non-HCC, 17 HCC). Neural networks developed on the training set were able to classify the blind test set with 94% sensitivity (95% CI 73-99%) and 86% specificity (95% CI 65-95%). Two of the SELDI peaks (23/23.5 kDa) were elevated by an average of 50% in the serum of HCC patients (P<0.001) and were identified as kappa and lambda immunoglobulin light chains. This approach may permit identification of several individual proteins, which, in combination, may offer a novel way to diagnose HCC.

Identification of serum biomarkers for colon cancer by proteomic analysis.

Colorectal cancer (CRC) is often diagnosed at a late stage with concomitant poor prognosis. Early detection greatly improves prognosis; however, the invasive, unpleasant and inconvenient nature of current diagnostic procedures limits their applicability. No serum-based test is currently of sufficient sensitivity or specificity for widespread use. In the best currently available blood test, carcinoembryonic antigen exhibits low sensitivity and specificity particularly in the setting of early disease. Hence, there is great need for new biomarkers for early detection of CRC. We have used surface-enhanced laser desorbtion/ionisation (SELDI) to investigate the serum proteome of 62 CRC patients and 31 noncancer subjects. We have identified proteins (complement C3a des-arg, alpha1-antitrypsin and transferrin) with diagnostic potential. Artificial neural networks trained using only the intensities of the SELDI peaks corresponding to identified proteins were able to classify the patients used in this study with 95% sensitivity and 91% specificity.

The benefits of chemotherapy in patient subgroups with unresectable non-small-cell lung cancer.

BACKGROUND: Cisplatin-based chemotherapy improves survival in advanced non-small-cell lung cancer. Using data from phase III trials of mitomycin, ifosfamide and cisplatin, this paper investigates whether the beneficial effect of chemotherapy on survival and quality of life seen overall is limited to certain patient subgroups. PATIENTS AND METHODS: The survival benefit of chemotherapy was compared with standard treatment using hazard ratios for subgroups specified by stage, sex, age, histology and performance status (PS). The effect on quality of life was investigated for three subgroups defined by performance status. RESULTS: The overall unstratified hazard ratio for all 797 eligible patients shows a 16% reduction in the risk of death with chemotherapy (P = 0.02). This benefit was seen for both locally advanced and extensive stage disease (significantly in extensive disease). Subgroups defined by sex, age and histology consistently benefitted from chemotherapy. The hazard ratios for the three levels of performance status suggest that PS2 patients gain no survival benefit from chemotherapy. In contrast, these patients experienced the greatest improvement in quality of life during the first six weeks of chemotherapy. CONCLUSIONS: Subgroup analysis suggests that the prolongation of life from cisplatin-based chemotherapy is confined to PS0/1 patients. Palliation is greater in PS2 patients.

Palliative chemotherapy: no longer a contradiction in terms.

Palliative chemotherapy is defined as treatment in circumstances where the impact of intervention is insufficient to result in major survival advantage, but does affect improvement in terms of tumor-related symptoms, and where the palliation/toxicity trade-off from treatment clearly favors symptom relief. The role of chemotherapy in circumstances where little or no survival benefit is anticipated remains controversial. This is despite the mounting body of evidence in favor of its use for symptom palliation. The notion persists that outcomes other than significant survival benefit are not valid, because of firmly held perceptions of toxicity. Studies of chemotherapeutic palliation using valid measures of quality of life, show that patients may be willing to accept some side effects of treatment, as long as they gain relief from tumor-related symptoms. The aims of this review are to present the case for palliative chemotherapy, to highlight the areas of progress which have made this feasible, and to provide guidance with regard to its appropriate use.

Colony counting is a major source of variation in CFU-GM results between centres.

The results for colony forming unit granulocyte-macrophage (CFU-GM) assays vary substantially between centres. It is possible that colony counting is largely responsible for this discrepancy. In order to examine this exclusively from the many factors that make up the CFU-GM assay, we performed a colony counting exercise involving 11 laboratories. Two-way analysis of variance showed a highly significant difference (P = 0.0001) in the counts obtained from the centres. One centre was found to score consistently high and two others scored consistently low numbers of colonies. This suggests that identification of colonies is a major source of variation between centres.