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Andrew Kramar

Publications and source records attributed to Andrew Kramar.

At least 19 recordsLinked to original sources
PubMed2007

Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis.

Progestins increase the risk of breast cancer in the hormone therapy of menopause, and progesterone receptor-induced fatty acid synthase (FAS) is a potential therapeutical target of breast cancer. In a first attempt to specify in which lesions at risk of breast cancer progestins might be acting, we have compared the progesterone receptor (PR) and FAS expression in preinvasive breast lesions and in adjacent "normal" mammary glands. We used archive paraffin-embedded tissues from 116 patients, with 164 lesions of increasing histological risk from nonproliferative "benign" breast disease (BBD) to in situ breast carcinomas. Immunostaining using our FAS antibody and a PR antibody from Dako was quantified as continuous variables by computer-assisted image analysis. FAS level increased (p < 10(-3) by the Kruskall-Wallis test) in all lesions, starting from nonproliferative BBD, and was maximal in in situ carcinoma. The % of PR-positive cells increased from nonproliferative BBD and was higher in proliferative atypia (p < 10(-3)). It was very low in high-grade DCIS corresponding to a likely different carcinogenesis pathway. There was a trend for a positive correlation between FAS and PR in normal glands. However, the 2 markers increased independently in BBD and were negatively correlated in in situ carcinomas. FAS and PR were positively correlated with Ki67 in BBD. The increased PR level in premalignant steps of mammary carcinogenesis suggests an early increased responsiveness to progestins. The increased FAS expression, in lesions parallel to their increased breast cancer risk, suggests further studies to develop new markers of high-risk lesions and to prevent breast cancer.

Adult↗
PubMed2006

Failure of high-dose cyclophosphamide and etoposide combined with double-dose cisplatin and bone marrow support in patients with high-volume metastatic nonseminomatous germ-cell tumours: mature results of a randomised trial.

OBJECTIVES: To assess the impact on survival of high-dose chemotherapy with haematopoietic support in patients with high-volume, metastatic nonseminomatous germ cell tumours. METHODS: One hundred fifteen patients were randomised to receive either four cycles every 21 d of vinblastine (0.2 mg/kg on day 1), etoposide (100 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and bleomycin (30 mg on days 1, 8, and 15) (arm A), or a slightly modified regimen followed by a high-dose chemotherapy including etoposide (350 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and cyclophosphamide (1600 mg/m2/d on days 2 through 5) (arm B). RESULTS: In an intent-to-treat analysis, there were 32 (56%) and 24 (42%) complete responses in arms A and B, respectively (p=0.099). After a median follow-up of 9.7 yr, 31 and 27 patients have continuously shown no evidence of disease in arms A and B, respectively. There was no significant difference between the overall survival curves (p=0.167). According to the International Germ Cell Cancer Collaborative Group prognostic classification, the 5-yr survival rates were 88% and 82% in the intermediate group and 69% and 44% in the poor group (p=0.045) in arms A and B, respectively. CONCLUSIONS: This trial failed to demonstrate an impact on response and survival of high-dose chemotherapy with haematopoietic support in first-line treatment of patients with high-volume, metastatic nonseminomatous germ cell tumours.

Adult↗
PubMed2006

Impact of RNA degradation on gene expression profiles: assessment of different methods to reliably determine RNA quality.

DNA microarray technology enables investigators to measure the expression of several 1000 mRNA species simultaneously in a biological specimen. However, the reliability of the microarray technology to detect transcriptional differences representative of the original samples is affected by the quality of the extracted RNA. Thus, it is of critical importance to standardize sample-handling protocols and to perform a quality assessment of RNA preparations. In this report, 59 human tissue samples were used to evaluate the relationships between RNA quality and gene expression. From Affymetrix GeneChip array data analysis of these samples, we compared the performance of the 28S/18S ratio, two computer methods (RIN and degradometer) and our in-house RNA quality scale (RQS) in assessing RNA quality. The optimal RNA reliability threshold was determined for each method using statistical discrimination measures. We showed that RQS, RIN and degradometer have a similar capacity to detect reliable RNA samples whereas the 28S/18S ratio leads to a misleading categorization. Furthermore, we developed a new approach, based on clustering analyses of full chip expression, to control RNA quality after hybridization experiments. The combination of these methods, allowing monitoring of RNA quality prior to and after the hybridization experiments, ensured reliable and reproducible microarray data.

Cluster Analysis↗
PubMed2005

Delayed rectal and urinary symptomatology in patients treated for prostate cancer by radiotherapy with or without short term neo-adjuvant androgen deprivation.

BACKGROUND AND PURPOSE: To identify contributing factors to delayed rectal and urinary symptoms in a randomised trial comparing different durations of maximal androgen deprivation (MAD), given prior to radiotherapy, for locally advanced prostate cancer. PATIENTS AND METHODS: Between 1996 and 2000, 818 patients with stages T2b,c, 3 and 4 prostate cancer were entered into a trial comparing 0, 3 and 6 months of MAD prior to and during radiotherapy. Their delayed normal tissue effects were recorded by their treating doctors using standardised scales and by the patients using a self-assessment questionnaire regularly. Time to occurrence and prevalence data were analysed. RESULTS: Rectal and urinary symptom levels were observed to vary markedly over time in at least 80% of patients, with some indicating lasting resolution of symptoms. Prevalence rates were found to be substantially lower than actuarial probability rates. Baseline symptom levels and greatest acute symptom levels were both very powerful predictors. Obstructive lower urinary tract symptoms were noted to improve during the first 4 years after radiotherapy in approximately 60% of cases in each treatment arm. However, the treatment arm itself was not shown to influence these improvements in other univariate or multivariate analyses. MAD was shown to reduce both time to occurrence and prevalence of delayed proctopathic symptoms, but this effect was confirmed statistically in the 3 month treatment arm only. Multivariate models indicated that higher levels of haemoglobin prior to any treatment may in some way protect against delayed proctopathic symptoms. CONCLUSIONS: Prevalence data provide more clinically meaningful estimates of risk of delayed effects in normal tissues where assessment relies substantially on reported symptom levels. In these tissues consideration of the impact of baseline symptom levels and pathologies, and greatest acute symptom levels in analyses of delayed effects appears mandatory. Obstructive lower urinary symptoms improve over several years in the majority of patients treated for locally advanced prostate cancer by radiotherapy. Future research could address whether rectal toxicity is affected by initial haemoglobin levels and declines in it due to MAD.

Age Factors↗
PubMed2005

Optimization of follow-up timing from study of patterns of first failure after primary treatment. An example from patients with NSCLC: a study of the REACT working group of ESTRO.

BACKGROUND AND PURPOSE: The European Society for Therapeutic Radiology and Oncology was funded by the EU for a project on Recording providing Education, and Ameliorating the Consequences of Treatment (REACT). An important aim of follow-up (FU) after treatment for cancer is to detect various events associated with disease recurrence or metastatic spread or severe treatment-related complications as early as possible. Each tumour type may show a specific pattern and timing of these events related to different prognostic factors. The aim of this study was to propose a way of defining an optimal timing schedule for follow-up after treatment based on the analysis of failure patterns determined from follow-up data from prospective clinical trials. MATERIAL AND METHODS: Cox proportional hazards model was used to identify prognostic factors associated with each failure type (loco-regional recurrence (LR), distant metastasis (DM) or side effects (SE)). Competing risks methods were applied to estimate the cumulative incidence functions (CIF), adjusted on the significant prognostic factors. Equally spaced quantiles of the CIF were then used to estimate the corresponding optimised follow-up times depending on a pre-specified total number of visits. Follow-up data from the CHART bronchus clinical trial were used to analyse the pattern of time to first failure. RESULTS: A significantly higher risk of failure was observed for males (SE), stage III (DM) and conventional treatment (LR). Overall, patients treated with CHART needed 1 fewer visit in each category of patients compared to the Conventional group. For example, stage III male patients treated with CHART would need 8 visits during the first two years at 7, 11, 16, 24, 37, 52, 64 and 104 weeks rather than the 9 follow-up visits planned in the protocol. Similar patients treated with Conventional radiotherapy would need 8 visits at 3, 5, 7, 11, 15, 24, 52 and 104 weeks. CONCLUSIONS: Use of these methods would allow timing of follow-up visits to be adapted according to tumour site and prognostic factors determined previously from audit or clinical trials. Application of this approach could optimize the timing of follow-up visits by placing them closer to the times when failures are expected to occur. It does not address the wider issues of follow-up such as who should do it or what should be done for which further studies are required.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

CD4 and CD8 T-lymphocyte apoptosis can predict radiation-induced late toxicity: a prospective study in 399 patients.

PURPOSE: Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment. EXPERIMENTAL DESIGN: In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence. RESULTS: No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiation-induced T-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Gray's test, P < 0.0001). CD8 (area under the curve = 0.83) was more sensitive and specific than CD4. No grade 3 late toxicity was observed for patients with CD4 and CD8 values greater than 15% and 24%, respectively. The 2-year cumulative incidence for grade 2 or 3 late toxicity was 70%, 32%, and 12% for patients with absolute change in CD8 T-lymphocyte apoptosis of < or =16, 16 to 24, and >24, respectively. CONCLUSIONS: Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.

Adolescent↗
PubMed2005

Increased estrogen receptor betacx expression during mammary carcinogenesis.

Identification of proteins that markedly vary during early steps of mammary carcinogenesis may help to understand its pathophysiology and to develop a prevention strategy. The expression of total estrogen receptor beta (ERbeta) protein and of its COOH-terminally spliced variant ERbetacx (or ERbeta2) was compared in 43 invasive breast cancers and in 39 adjacent normal mammary glands and 26 ductal carcinoma in situ (DCIS). Thirty-six breast cancers were ER positive by radioligand binding assay. The analysis was done by immunohistochemistry on adjacent sections of formalin-fixed, paraffin-embedded tumors using polyclonal anti-ERbeta 503 IgY and sheep polyclonal ERbetacx antibodies that were previously validated. Nuclear staining was quantified using a computerized image analyzer in selected areas of normal and cancer epithelial cells. Total ERbeta expression was high in normal glands, decreased in DCIS (P = 0.0004), and increased from DCIS to invasive tumors (P = 0.029). In contrast, the ERbetacx expression was low in normal glands, increased significantly in DCIS (P = 0.0014), and continued to increase in invasive carcinomas (P = 0.0027) in both ERalpha-positive and ERalpha-negative tumors. This is the first study showing a significant increase of the ERbetacx variant protein in DCIS and invasive breast cancer compared with adjacent normal glands. This contrasts with the decrease of the total ERbeta level in the same patients and indicates different mechanisms to explain these variations during mammary carcinogenesis. It also suggests a role of the ERbetacx variant in carcinogenesis opposite to the protective effect of the wild-type ERbeta1.

Alternative Splicing↗
PubMed2005

Neoadjuvant percutaneous 4-hydroxytamoxifen decreases breast tumoral cell proliferation: a prospective controlled randomized study comparing three doses of 4-hydroxytamoxifen gel to oral tamoxifen.

PURPOSE: Two chemoprevention randomized studies using tamoxifen showed drug efficacy; however, adverse effects such as hot flushes, endometrial cancer, and above all, thromboembolism, remain a problem. 4 hydroxytamoxifen (4-OHT) is a very active metabolite of tamoxifen. This randomized study was designed to analyze if 4-OHT gel, administered percutaneously on the breast skin, can inhibit the proliferation of malignant breast cells to the same extent as orally administered tamoxifen. PATIENTS AND METHODS: Fifty-five postmenopausal women with an invasive estrogen receptor-positive breast cancer were randomly assigned to receive (for 2 to 3 weeks) either 4-OHT gel (0.5, 1, or 2 mg/d) or oral tamoxifen (20 mg/d) or no treatment. Response was evaluated using proliferation markers (Ki-67, proliferating cell nuclear antigen) and apoptosis markers in tissue samples obtained by Tru-cut biopsy before treatment, and at surgery after treatment. RESULTS: Administration of 4-OHT gel resulted in reductions in tumor tissue proliferation indexes (Ki-67 and PCNA), with approximate equivalence between the 1.0 mg/d or 2.0 mg/d 4-OHT dose, and oral tamoxifen, but had no effect on apoptotic markers. Plasma levels of 4-OHT were consistently higher in the oral tamoxifen group than in the gel groups. No dose-related pattern was shown for estrogen or progesterone receptor levels, and topical 4-OHT gel appeared to be generally well tolerated. Hot flushes are as common in the two higher gel doses as with tamoxifen. CONCLUSION: Percutaneous 4-OHT gel has a local impact on tumor proliferation. It could be tested in future prospective trials of chemoprevention or ductal carcinoma in situ adjuvant hormonotherapy.

Administration, Cutaneous↗
PubMed2005

A nonparametric comparison of the effectiveness of treatments: a multivariate toxicity-penalized approach.

In cancer clinical trials, the amount of treatment dose actually received by a patient may be limited by severe toxicity or lack of efficacy. A nonparametric approach is proposed for comparing the effectiveness of treatments based on the bivariate relationship defined by the doses at which efficacy and toxicity are observed to occur. Simulation studies are used to contrast the performance of the new procedure with the usual method of comparing percentages of patients who have effective results. Data from a randomized clinical trial of patients with metastatic nonseminomatous germ cell tumors are used to illustrate the method.

Antineoplastic Agents↗
PubMed2004

Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer.

The antiestrogen tamoxifen, a major endocrine therapy of estrogen receptor (ER)-positive breast cancer, is nevertheless inefficient in 30 to 40% of cases for unknown reasons. We retrospectively studied 50 ER-positive primary breast carcinomas. All of the patients had received tamoxifen as the only adjuvant therapy. They were divided into two groups depending on whether they relapsed within 5 years (16 tamoxifen-resistant cases) or did not relapse within 5 years (34 tamoxifen-sensitive cases). The expression of total ER beta protein, and of ER beta cx protein, was estimated anonymously in formalin-fixed, paraffin-embedded tumor sections, by using specific antibodies and quantifiying nuclear immunostaining with a computer image analyzer. All of the tumors were found to be HER-2/neu-negative by immunohistochemistry. Univariate analysis showed that Scarff-Bloom-Richardsson grade modified by Elston (SBR grade; P < 0.001), tumor size (P = 0.042), and MIB-1 proliferation index (P = 0.02) were significantly higher in tamoxifen-resistant tumors. A low level of total ER beta, whether in percentage of positive cells or in quantitative immunocytochemical (QIC) score, was also associated with tamoxifen resistance (P = 0.004). ER beta cx expression and lymph node status were similar between the two groups. The expression of ER beta in the total population was positively correlated with ER beta cx (r = 0.63, P < 0.001), and was independent of the other parameters. In a multivariate analysis, ER beta expression was the most important variable (P = 0.001), followed by SBR grade (I+II versus III; P = 0.008), and MIB-1 (P = 0.016). To conclude, tamoxifen resistance is associated with classical variables of aggressive tumors (high SBR grade, proliferation index, and tumor size) but not with node invasiveness. Low ER beta level is an additional independent marker, better than ER alpha level, to predict tamoxifen resistance.

Adult↗
PubMed2004

Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors.

PURPOSE: The prognostic relevance of the rate of decline of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) during the first 3 weeks of chemotherapy for nonseminomatous germ cell tumors (NSGCT) was studied in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. PATIENTS AND METHODS: Data from 653 patients prospectively recruited in clinical trials were studied. Tumor markers were obtained before chemotherapy and 3 weeks later. Decline rates were calculated using a logarithmic formula and expressed as a predicted time to normalization (TTN). A favorable TTN was defined when both AFP and HCG had a favorable decline rate, including cases with normal values. RESULTS: The median follow-up was 50 months (range, 2 to 151 months). Tumor decline rate expressed as a predicted TTN was associated with both progression-free survival (PFS; P <.0001) and overall survival (OS; P <.0001). The 4-year PFS rates were 64% and 38% in patients from the poor-prognosis group who had a favorable and an unfavorable TTN, respectively. The 4-year OS rates were 83% and 58%, respectively. This effect was independent from the initial tumor marker values, the primary tumor site, and the presence of nonpulmonary visceral metastases: tumor marker decline rate remained a strong predictor for both PFS (hazard ratio = 2.5; P =.01) and OS (hazard ratio = 4.6; P =.002) in patients from the IGCCCG poor-prognosis group in multivariate analysis. CONCLUSION: Early predicted time to tumor marker normalization is an independent prognostic factor in patients with poor-prognosis NSGCT and may be a useful tool in the therapeutic management of these patients.

Biomarkers, Tumor↗
PubMed2004

Immunohistochemical assessment of the peripheral benzodiazepine receptor in breast cancer and its relationship with survival.

PURPOSE: The peripheral benzodiazepine receptor (PBR) expression has been shown dramatically increased in neoplastic tissues and tumor cell lines originated from ovary, liver, colon, breast, or brain relative to untransformed tissues. Its expression has been also associated with tumor progression and aggressiveness. To explore whether PBR expression level could be of prognostic value in invasive breast cancer, we studied a series of 117 patients who underwent surgery for primary breast carcinomas and were followed-up for 8 years. EXPERIMENTAL DESIGN: Using an immunohistochemical approach, we first compared PBR expression in normal and tumoral tissues, then we studied PBR expression together with clinicopathological variables (histological type, histological grade, lymph node, estrogen and progesterone receptor status), and biological markers such as BclII, Ki-67, and HER2/Neu. RESULTS: Our results revealed a significant increase of PBR expression in tumoral versus normal breast cells. We found a negative correlation between PBR expression and estrogen receptor status (P = 0.03) as well as a positive correlation between PBR and Ki-67 (P = 0.044). Although the disease-free survival was not affected by PBR in the whole population, high PBR expression level was significantly correlated with a shorter disease-free survival in the lymph node-negative patients, P = 0.038. CONCLUSIONS: As the axillary lymph node-negative status is generally considered as a good prognosis factor, the high expression of PBR in this patient subgroup may be used to identify a new high risk population, for which a more specific therapy would be beneficial.

Adult↗
PubMed2004

Audit of effectiveness of routine follow-up clinics after radiotherapy for cancer: a report of the REACT working group of ESTRO.

BACKGROUND AND PURPOSE: The European Society for Therapeutic Radiology and Oncology was funded by the EU for a project on recording providing education, and ameliorating the consequences of treatment (REACT). An European audit was carried out as part of which to assess the usefulness of current follow-up practices. PATIENTS AND METHODS: Over a 4-month period in 15 cancer centres in 10 countries, patients attending for routine follow-up completed a questionnaire covering their expectations of and satisfaction with the visit. This was matched with a questionnaire completed by the physician about the content and usefulness of the consultation. The feasibility of a short toxicity scale developed by Dische and Saunders was also investigated. RESULTS: In total, 2303 matched questionnaires were analysed. Forty percent of the patients had symptoms or medical problems related to their disease. In 18% there was a positive finding on clinical examination. In 28% investigations were undertaken part of departmental routine practice. Ten percent of the investigations showed an abnormal result. Ninety nine percent of physicians and 85% of the patients expressed satisfaction. Using the short toxicity scale rates of recording toxicity could be increased from 28 to 93%. CONCLUSIONS: There is wide variation in follow-up practices among European centres. There was a low incidence of positive findings clinically or with routine investigations. A simple scale for recording morbidity has proved easy to use by departments, which have not routinely used one of the standard measures. Further work will attempt to produce an European guideline for effective routine follow-up after radiotherapy.

Ambulatory Care Facilities↗
PubMed2003

Identification and pharmacological characterization of SRBP-2: a novel SR31747A-binding protein.

SR31747A is a sigma ligand with potent antiproliferative activity against tumor cells and for which three binding proteins have been identified to date: (a) SRBP-1 (also called sigma 1); (b) HIS; and (c) sigma 2. In this study, we characterized an additional SR31747A binding site, i.e., SRBP-2 (SR31747A-binding protein 2). Using an in silico screening approach, we identified this novel sequence, which exhibits 41% homology with HSI. The 1142-bp cDNA was found to encode a 206 amino acid protein not related to SRBP-1. Northern blot analysis of SRBP-2 mRNA expression revealed a single 1.1-kb transcript that was widely expressed in organs; the liver was particularly enriched, and the brain showed the lowest abundance. A murine homologue that exhibited a similar expression pattern was also characterized. Subcellular localization analysis using specific polyclonal antibodies revealed that SRBP-2 had the same nuclear membrane and endoplasmic reticulum localization as other members of the SR31747A-binding protein family. Considering SRBP-2-binding properties, pharmacological analysis clearly highlighted that SRBP-2 was distinct from sigma 2. Scatchard plot analysis revealed K(d) values of 10 and 3 nM for SR31747A and Tamoxifen, respectively. In contrast with HSI, the protein also did not exhibit detectable isomerase activity. When analyzing SRBP-2 expression in human breast cancer biopsies, we obtained evidence that SRBP-2 expression, together with SRBP-1 and HSI, may be of interest as a prognostic marker. These findings demonstrated that SRBP-2 represents an additional molecular target for SR31747A, which could help to understand the immunosuppressive and antiproliferative effects of the molecule.

Amino Acid Sequence↗
PubMed2003

Individual 5-FU dose adaptation in metastatic colorectal cancer: results of a phase II study using a bimonthly pharmacokinetically intensified LV5FU2 regimen.

AIM: The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers. METHODS: A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m2 per day followed by a 5-FU bolus 400 mg/m2 per day and a 22-h 5-FU continuous infusion 600 mg/m2 per day for two consecutive days every 2 weeks), and the AUC in mg.h/l.m2 was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC < or =5, by 100% for AUC >5-10, by 50% for AUC >10-15, and by 25% for AUC >15-20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program. RESULTS: Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5-1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23-50%) in the intention-to-treat population and 47% (95% CI 29-65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient). CONCLUSIONS: This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.

Adenocarcinoma↗
PubMed2003

Two-treatment comparison based on joint toxicity and efficacy ordered alternatives in cancer trials.

The primary goal of anticancer treatments is to attain efficacy, however toxicity could affect the course of the therapy. Methods have been proposed for comparing two treatments on the basis of the joint distribution for safety and efficacy outcomes, but they do not take into account the cumulative doses of drugs (chemotherapy) or radiation (radiotherapy) received by each patient. Moreover, these methods assume a parametric form for the joint distribution. In this paper we define a multi-dimensional parameter including toxicity and efficacy outcomes and the dose at which one, none or both occur. Each patient is classified into an ordered category depending on the order of occurrence of these two criteria: the sooner the patient benefits from efficacy and/or the later he/she experiences toxicity, the better is the treatment. We then apply likelihood ratio tests with ordered alternatives. This procedure requires constrained maximum likelihood estimation via isotonic regression. A large set of simulations compares the proposed tests to other more usual tests and the results show a good power and a satisfactory type I error control. Our approach is illustrated with a multi-centre randomized clinical trial involving patients with metastatic non-seminomatous germ cell tumours.

Antineoplastic Agents↗