Endpoint For Treatment Efficacy Research Articles

MR Imaging Volumetric Response after Yttrium-90 Radioembolization for Colorectal Liver Metastases: Predictability at Baseline and Correlation with Survival

PurposeTo prove the utility of magnetic resonance (MR) imaging response as a surrogate end point of treatment efficacy and survival after yttrium-90 transarterial radioembolization (TARE) for colorectal liver metastases (CRLMs), and to investigate whether outcomes can be predicted at baseline using MR imaging or clinical variables. Materials and MethodsA total of 50 (135) patients with TARE for CRLMs between August 2008 and January 2020 and peri-interventional MR imaging within defined timeframes were included for tumor segmentation. Pretreatment and posttreatment target tumor volumes were measured according to the volumetric Response Evaluation Criteria In Solid Tumors (vRECIST) and the quantitative European Association for the Study of the Liver (qEASL) criteria. Cox regression models were used to analyze the impact of MR morphologic response, vascularity at baseline, and clinical variables on patient survival. Logistic regression analyses were used to evaluate the predictors of MR morphologic response at baseline. ResultsThe median survival was 337 days (95% confidence interval [CI], 243–431). As opposed to the vRECIST, the application of the qEASL criteria 3 months after the treatment allowed for a significant (P < .05) separation of the survival curves for partial response, stable disease, and progressive disease with a median survival of 412 days (95% CI, 57–767) in responders. High tumor burden and technetium-99m lung shunt significantly decreased the probability of survival. MR morphologic response was not predictable at baseline using imaging or clinical data. ConclusionsMR response according to the qEASL criteria outperformed the vRECIST in measuring the biologic impact of TARE and predicting patient survival. Baseline contrast enhancement did not predict MR response to treatment, which may reflect elevated dose requirements in tumors with a high proportion of viable tumor volume.

The validity of progression-free survival (PFS) 2 as a surrogate endpoint for overall survival (OS) in randomized controlled trials (RCTs) of advanced solid tumors.

1516 Background: OS is the gold-standard endpoint for treatment efficacy in oncology RCTs. However, prolonged follow-up is required to obtain mature data, which impedes regulatory approval of potentially beneficial therapies. Furthermore, increasing therapeutic options including cross over to investigational agents at disease progression often confound OS findings. PFS-2, defined as time from randomization to progression on second-line therapy, has been proposed as a potential surrogate endpoint for OS. Using a meta-analytic approach, we aimed to assess the association between OS and PFS-2, and its validity compared with other surrogate endpoints. Methods: We performed an electronic literature search to identify RCTs of systemic therapies that reported PFS-2 as a pre-specified endpoint with defined follow up protocols. Articles were screened for eligibility and outcome data were extracted. Correlations in the relative treatment difference between treatment arms for OS vs PFS-2, PFS-1, and objective response rate (ORR) were assessed as the comparison of hazard ratios (HR) and odds ratio (OR) respectively. Results: 38 eligible RCTs comprising of 44 analysis units, with 19,031 patients across 8 unique tumor types were identified. The majority received targeted therapies (72.2%), followed by immunotherapy (IO; 26.3%). The correlations of HR-OS/HR-PFS-2, HR-OS/HR-PFS-1 and HR-OS/OR-ORR were r = 0.67 (95% CI 0.08-0.69), r = 0.12 (95% CI 0.00-0.13) and r = 0.21 (95% CI 0.00-0.33) respectively. Correlations between OS with surrogates was assessed in different subgroups according to post-progression survival times (SPP), types of treatment agents and rate of subsequent therapy after progression (table). Conclusions: Across diverse tumors and therapies, treatment effect on PFS-2 has modest to strong correlation with OS, but poor correlations were observed between OS-PFS-1 and OS-ORR respectively. Across all subgroups, PFS-2 performs consistently better than traditional surrogates of PFS-1 and ORR, validating and providing support for use in future RCTs.[Table: see text]

Multicenter Experience with FRED Jr Flow Re-Direction Endoluminal Device for Intracranial Aneurysms in Small Arteries.

Flow diverters are emerging as an endovascular treatment alternative for proximally located intracranial aneurysms. However, treatment of aneurysms at and beyond the circle of Willis is not well-established. We assessed the clinical safety and efficacy of the Flow Re-Direction Endoluminal Device Jr (FRED Jr) dedicated to small-vessel diameters between 2.0 and 3.0 mm. This was a multicenter observational clinical study of 42 patients with 47 aneurysms treated by a flow-direction technique with the FRED Jr. The primary end point for clinical safety was the absence of death, major or minor stroke, and TIA. The primary end point for treatment efficacy was complete and near-complete occlusion according to the O'Kelly-Marotta grading scale at follow-up after 1, 6, and 12 months. The FRED Jr deployment was technically successful in all cases. In 39/42 (93%) patients, the primary safety end point was reached; in the 3 remaining patients, 1 disabling ischemic stroke, 1 minor stroke with complete recovery at discharge, and 1 TIA were observed. Two asymptomatic, completely reversible side-branch occlusions occurred. Angiographic (DSA or flat panel CT) and clinical follow-up were available after 1 month in 41/47 (87%), 6 months in 27/47 (57%), and 12 months in 11/47 (23%) aneurysms. The primary efficacy end point was reached at 1 month in 27/41 (66%), at 6 months in 21/27 (78%), and at 12 months in 11/11 (100%) aneurysms. Deployment of the FRED Jr is safe and effective in the treatment of intracranial aneurysms located in small vessels.

Minimal residual disease in mantle cell lymphoma: insights into biology and impact on treatment.

Despite the recent substantial improvement of clinical outcome in mantle cell lymphoma (MCL), resistance to immunochemotherapy and common relapses are challenges for long-term tumor control. The assessment of minimal residual disease (MRD) by real-time quantitative polymerase chain reaction has emerged as a widely feasible and standardized tool for direct assessment of therapy-induced reduction of tumor burden and regrowth after cytotoxic treatment in MCL, with much improved sensitivity compared with conventional staging procedures. Several studies have shown that intensification of initial treatment, which has resulted in improved clinical outcome, is immediately reflected in higher molecular remission rates; they have also shown that high-dose consolidation might not be able to compensate for less intensive induction regimens. Persistence or reappearance of MRD in clinical remission proved to be highly predictive for imminent clinical relapse associated with shorter overall survival. Therefore, the investigation of novel MRD-guided treatment strategies aimed at early eradication of MRD and pre-emptive treatment of molecular relapse seems warranted. Furthermore, the integration of MRD assessment into clinical response criteria could result in a more specific and potentially earlier end point for treatment efficacy. New technical developments such as high-throughput sequencing will further enhance the wide applicability of MRD detection in MCL.

Predictive values of pathologic complete response for patient outcome in different molecular subtypes of breast cancer

Objective: To analyze the predict values of pathologic complete response (pCR) rates for patient outcome according to breast cancer (BC) molecular subtypes. Methods: Four hundred and sixteen patients with confirmed BC who received neoadjuvant chemotherapy (NCT) in The Affiliated Hospital of Military Medical Science Academy of the PLA were enrolled.The clinical and pathological characteristics of patients were collected. The primary endpoint was pCR rate and the secondary endpoint was disease free survival (DFS). We analyzed the predict values of pCR rate for patient outcome, and the predict factors for DFS by univariate and multivariate Analysis. Results: A total of 416 BC patients confirmed by pathology were enrolled and received treatment and assessment in this study. The overall pCR rate was 23.1% (96/416). The pCR rate was 6.9% (14/204) in patients of HR+ /HER2- Subtype, 41.5% (27/65) in HR-/HER2+ Subtype, 30.9% (17/55) in HR+ /HER2+ Subtype, and 41.1% (37/91) in HR-/HER2- Subtype. The correlation of the pathological status and the patient outcome was analyzed in all patients. Compared with no pCR group, pCR group had significant higher DFS rates. In HER2+ Subtype and HR-/HER2- Subtype, DFS rates of patients who achieved pCR was higher than that of who didn't achieved pCR. In HR+ /HER2- Subtype, DFS rates of patients who achieved pCR was higher than that of who didn't achievced pCR, but without statistics difference. The Cox proportional hazards regression analysis revealed that ER status, T stage, pCR affected the patient outcome of BC. Conclusion: So far, pCR was an established prognostic factor: reaching a pCR could predicte improved survival in HER2-enriched BC and triple-negative breast cancer (TNBC) subgroup, while data remain controversial for the luminal subtypes. Our results do not support the use of pCR as a surrogate end point of treatment efficacy in unselected patients with BC submitted to neoadjuvant systemic therapy.

Gemcitabine fixed-dose rate infusion for the treatment of pancreatic carcinoma: a meta-analysis of randomized controlled trials.

BackgroundPre-clinical evidence shows that fixed dose rate (FDR) infusion of gemcitabine could optimize plasma concentration of gemcitabine, while the clinical efficacy and toxicity of FDR infusion of gemcitabine in advanced pancreatic carcinoma has not been systematically investigated. Thus, this meta-analysis was designed to ascertain this issue.MethodsDatabases of EMBASE, PubMed, and Cochrane Library were searched for eligible randomized controlled trials (RCTs). RCTs comparing FDR and standard 30-min infusion of gemcitabine in advanced pancreatic carcinoma were included. The primary endpoints were treatment efficacy (overall response rate, 1-year survival rate, median survival, and time to treatment failure) and toxicities were secondary endpoints (neutropenia, thrombocytopenia, anemia, and vomiting). Relative risks or mean differences and corresponding 95% confidence intervals (CIs) were calculated.ResultAfter careful and rigorous selection, 3 eligible RCTs including 764 patients of advanced pancreatic adenocarcinoma were included in this meta-analysis. For treatment efficacy, FDR gemcitabine provided significantly longer median survival over standard gemcitabine (Mean Difference = 1.24 months, 95% CI: 0.39-2.09), while there was no statistical difference in other endpoints of treatment efficacy. For toxicities, patients with FDR gemcitabine experienced significantly more grade 3/4 hematological toxicities than those received standard gemcitabine (neutropenia, thrombocytopenia, and anemia), while there was no difference for vomiting.ConclusionCompared with standard 30-min infusion, FDR gemcitabine provide longer median survival, but increased the risk of hematological toxicities for patients with advanced pancreatic adenocarcinoma.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_214Electronic supplementary materialThe online version of this article (doi:10.1186/s13000-014-0214-8) contains supplementary material, which is available to authorized users.

Treatment for continuous spikes and waves during sleep (CSWS): survey on treatment choices in North America.

Current literature does not allow an evidence-based approach to the treatment of continuous spikes and waves during sleep (CSWS). The aim of this study was to describe treatment choices made by clinicians caring for patients with CSWS in North America. A 24-question survey on treatment choices for CSWS was distributed to the members of the American Epilepsy Society (AES). The survey presented a clinical vignette of CSWS. The questions addressed treatment choices for that clinical scenario. Surveys were self-administered and collected using an online survey website (www.surveymonkey.com). Two-hundred thirty-two surveys were completed. Prominent sleep-potentiated spiking was considered to warrant treatment by 81% of respondents. The proportion of patients in whom cognitive improvement occurs when sleep-potentiated spiking is effectively treated is in >75% of patients (according to 16% of respondents), in 25-75% of patients (according to 52% of respondents), in <25% of patients (according to 20% of respondents), and no or unclear cognitive changes (according to 12% of respondents). The preferred first choice to reduce sleep-potentiated epileptiform activity was high-dose benzodiazepines (47%), valproate (26%), and corticosteroids (15%). The preferred second-choice was valproate (26%), high-dose benzodiazepines (24%), and corticosteroids (23%). Among high-dose benzodiazepines, the preferred one was diazepam 1 mg/kg for one night followed by 0.5 mg/kg/day. The preferred dose of valproate was 30-49 mg/kg/day. Among corticosteroids the preferred choice was oral prednisone 2 mg/kg/day. The most commonly considered endpoints of treatment efficacy were (in decreasing order): response of epileptiform activity in electroencephalography (EEG), cognitive function, and seizure reduction. Results were consistent among respondents with different levels of training and clinical experience. There were differences in conceptualization and treatment approaches between pediatric and adult neurologists. Most clinicians considered that prominent sleep-potentiated epileptiform activity should be treated. There was no agreement on best treatment, but potential candidates included high-dose benzodiazepines, valproate, levetiracetam, and corticosteroids.

The LVIS Jr. microstent to assist coil embolization of wide-neck intracranial aneurysms: clinical study to assess safety and efficacy

This study was aimed to assess clinical safety and efficacy of the LVIS Jr. microstent in stent-assisted coil embolization of wide-neck intracranial aneurysms. IRB approved single-center interventional clinical study in 22 patients (10 females, 12 males, mean age 55, age range 33-74 years) for the endovascular treatment of wide-neck aneurysms. After obtaining informed consent, patients were included according to the following criteria: aneurysm fundus-to-neck ratio < 2 or neck diameter > 4 mm, and a parent vessel diameter of ≤3.5 mm. Primary end point for clinical safety was absence of death, absence of major or minor stroke, and absence of transient ischemic attack. Primary end point for treatment efficacy was complete angiographic occlusion according to the Raymond-Roy Occlusion Classification (RROC) immediately after the procedure and at follow-up after 3 and 6 months on magnetic resonance imaging (MRI). In 20/22 (91 %) of patients, the primary end point of safety was reached; in the two remaining patients, transient ischemic attack, but no permanent deficit was observed; in 16/22 (73 %), efficient occlusion (RROC1) was reached, and in 6/22 (27 %), a residual neck remained (RROC2). Single [seven with antegrade, two in crossover configuration, and four with "first-balloon-then-stent" (FBTS) technique] or double-stent (eight patients with Y configuration and one patient with X configuration) deployment was technically successful in all cases. Deployment of the LVIS Jr. microstent in various single- or double-stent configurations is safe and effective to assist the treatment of intracranial wide-neck aneurysms.

Abstract P3-14-03: Pathological complete response after primary chemotherapy as a surrogate end point of treatment efficacy in breast cancer patients: A trial-based meta-analysis

Abstract Background: The relationship between pathological complete response (pCR) and improved long-term prognosis was first reported in the landmark NSABP B-18 and B-27 trials and then validated in large cohort studies and in meta-analyses. Whether pCR, as surrogate end point, should capture the full effect of neoadjuvant chemotherapy on survival is still unproven. To assess the role of pCR as surrogate of disease-free survival (DFS) and overall survival (OS) at a trial level, we performed a trial-based meta-regression of randomized studies comparing different neoadjuvant therapies with data on both pCR rates and outcome end points. Methods: The systematic search included electronic databases and proceeding of international meetings. No restriction regarding treatment types was set up except for endocrine therapy trials that were excluded. We did not include studies comparing neoadjuvant versus adjuvant chemotherapy. Relevant data were extracted from each selected trial: patients randomly assigned to treatment and analyzed per arm, tumor stage, type of chemotherapy and targeted therapy, cycles number, additional post-surgical treatments, number of patients achieving pCR and number of outcome events per arm. For each trial, the experimental and the control arm were defined. Treatment effects on DFS and OS were expressed as hazard ratios (HRs) and on pCR as odd ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between the treatment effects on the surrogate outcome and the treatment effects on the clinical outcome. Results: A final set of 28 trials, 57 arms and 29 contrasts for a total of 13,738 patients was included in the analysis. As one trial had 3 arms, it contributed two contrasts to the analysis. The regression of the logHR for DFS on the logOR for pCR, using the complete set of data, demonstrated a weak but significant association between the two effects (R2 = 0.16, p-value = 0.03). Sixteen% of the variability among the effects on DFS can be explained by the observed effects on pCR. The regression of the logHR for OS on the logOR for pCR demonstrated a weak association between the two effects (R2 = 0.15, p-value = 0.04). Conclusions: This trial-based meta-regression showed a possible role of pCR as surrogate end point for DFS and OS in breast cancer patients treated with neoadjuvant chemotherapy. The surrogacy of pCR warrants to be further evaluated in more homogeneous subsets of clinical trials in the neoadjuvant chemotherapy-based setting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-03.

Identification and Characterization of Clinical, Humanistic and Economic Outcomes and Clinical Endpoints in Vaso Occlusive Crisis of Sickle Cell Disease – A Systematic Review

AbstractAbstract 4710 BACKGROUNDHealth outcomes often serve as a measure of treatment efficacy in clinical studies. Although self-reported, observational, & clinical techniques exist for assessing treatment efficacy in Vaso Occlusive Crisis (VOC) of Sickle Cell Disease (SCD) for both pediatric & adult populations; it is necessary to evaluate quality of evidence available in support of these techniques before they can be used with confidence. OBJECTIVESI. To assess quality of evidence available in support of clinical, humanistic & economic outcomes & clinical endpoints of VOC of SCD.II. To identify & characterize clinical, humanistic & economic outcomes & clinical endpoints for assessment of treatment efficacy of VOC of SCD from literature. METHODPotentially relevant articles were searched electronically using terms related to VOC & pain crisis in SCD, across PubMed, COCHRANE & CINAHL databases. Dissertations, guidelines, abstracts, conference proceedings & case reports were excluded for lack of sufficient information. Reference lists of prior literature reviews, as well as reference lists of studies included in this review, served to identify additional articles. Only blinded randomized studies with a control group in treating VOC of SCD were included for further analyses. Qualified studies were searched for relevant clinical, humanistic, economic outcomes & clinical endpoints, which have previously been defined elsewhere. Qualified studies were assessed utilizing AHRQ’s recommended Evidence based Practice Center- Strength of Evidence (EPC-SOE) methodology. EPC-SOE grades evidence across four primary domains: risk of bias, consistency, precision & directness. Evidence was also assessed for publication bias. Consequently, an overall grade of evidence for each outcome category was assigned. RESULT1,917 potentially relevant study abstracts were identified & reviewed. Of these, 39 studies qualified for analyses. On assessment of the quality of evidence employing EPC-SOE methodology (Table 1), Humanistic outcomes were found to have the highest overall strength of evidence, whereas, clinical outcomes & clinical endpoints were found to have moderate overall strength of evidence. Economic outcomes were graded ‘insufficient' due to lack of published studies. Studies were observed to use more than one outcome measure (25 studies) for assessing treatment efficacy, compared to a single measure (14 studies). 23 humanistic outcomes, 7 clinical outcomes, 6 clinical endpoints & 3 economic outcomes are available to assess treatment efficacy in VOC of SCD. Majority of the studies utilize Visual Analogue Scale (VAS) (14 studies) & Facial contours-based pain scales (5 studies) as humanistic outcome measures. Time to resolution (15 studies) & length of stay (13 studies) are preferred clinical outcome measures whereas amount of analgesics required during a VOC event (14 studies) are preferred clinical endpoints. CONCLUSIONEvidence suggests that humanistic outcomes reflect true treatment effect & further research is very unlikely to change our confidence in using these measures as possible treatment efficacy endpoints. Whereas, assessment of our evidence reflects moderate confidence in using clinical outcomes & clinical endpoints as treatment efficacy endpoints & further research may suggest otherwise. A combination of humanistic & clinical outcomes & clinical endpoints rather than a single outcome measure, is a method of choice to assess treatment efficacies. Evidence however, is inconclusive towards using Economic outcomes as a possible endpoint.Table 1Strength of evidence domains for reviewed literatureNumber of Studies; SubjectsDomains pertaining to Strength of EvidenceOverall Strength of EvidenceRisk of BiasConsistencyDirectnessPrecisionPublication biasClinical endpoints21; 1023LowConsistentDirectImpreciseNoModerateClinical outcomes24; 1716LowConsistentDirectImpreciseNoModerateHumanistic outcomes31; 2072LowConsistentDirectPreciseNoHighEconomic outcomes2; 226MediumInconsistentIndirectImpreciseNoInsufficient Disclosures:Thomas:Pfizer: Consultancy, Research Funding. Shafer:Pfizer: Employment. Sivamurthy:Pfizer: Employment. Kollmer:Pfizer: Employment, Equity Ownership. Vendetti:Pfizer: Employment.

Comparison of the efficacy and toxicity of two dose levels of cisplatin/5-fluorouracil as the chemoradiotherapy regimen for the treatment of locally advanced squamous cell carcinoma of the head and neck

Conclusion: The low-dose regimen brought less grade 3–4 neutropenia and mucositis with similar treatment efficacy. It should be further investigated in prospective randomized clinical trials to confirm its effectiveness and tolerability. Objectives: This nonrandomized study compared the efficacy and toxicity profiles of two dose levels of cisplatin/5-fluorouracil (5-FU) as the chemoradiotherapy regimen for the treatment of locally advanced squamous cell carcinoma of the head and neck. Methods: Concurrent chemotherapy consisted of two dose levels: a low dose (cisplatin 12 mg/m2 + 5-FU 600 mg/m2 per day) or a high dose (cisplatin 15 mg/m2 + 5-FU 750 mg/m2 per day). Both were administered as a 5-day continuous infusion in week 1 and week 5 during radiotherapy. Results: With a median follow-up of 44 months, the overall survival and disease-free survival were 35 months and 22 months (n = 67) for the low-dose group and 36 months and 33 months for the high-dose group (n = 96). The 2-year locoregional control rate was 67.2% for the low-dose and 66.8% for the high-dose group. No statistically significant differences were demonstrated in the treatment efficacy end points. The high-dose regimen resulted in significantly more grade 3–4 neutropenia (31.5% vs 10.9%, p = 0.003) and a trend towards more mucositis (62.1% vs 49.3%, p = 0.066).

Ovarian ablation by radiation therapy: Is it still an option for the ablation of ovarian function in endocrine responsive premenopausal breast cancer patients?

Surgical or medical ovarian ablation is likely to be the treatment of choice at the current time, radiation ablation (RA) can be still a reasonable alternative. The efficacy and toxicity of radiation therapy (RT) for ovarian function suppression in 118 premenopausal breast cancer patients were retrospectively evaluated. The median age was 39 years (range 21–52 years). RT was given with either Co-60 or 15MV photons of the linear accelerator. The median total dose was 15Gy in 4 consecutive fractions (range 5Gy single fraction–36Gy in 18 fractions over 3.5 weeks). The endpoint for treatment efficacy was menstrual status. Amenorrhea was noted in 113 of 118 patients (96%) in 6 months following RA. Five patients (4%) who had still normal menstrual functioning after 6 months of RA underwent estradiol and follicle stimulating hormone measurements and were found to have premenopausal levels. No acute Grade 3 or 4 (according to the Radiation Therapy Oncology Group radiation morbidity scoring criteria) toxicities were noted. With a median follow-up of 24.5 months (range: 6–167), no late severe complications that could be attributable to RT were reported. RA should be considered as an option for endocrine responsive premenopausal breast cancer patients and can be easily delivered when postoperative or palliative irradiation is given.

Oncologic Imaging End-Points for the Assessment of Therapy Response

Sophisticated clinical and diagnostic imaging modalities are critical for the detection, staging, treatment, and follow-up surveillance of cancer. Previously, uni- and bi-dimensional measurements of a tumor lesion were considered the "holy grail" of the assessment of tumor growth and provided imaging end-points for cytotoxic chemotherapeutic agents. With increasing understanding of cancer-related pathways and emerging discoveries of targeted signal transduction inhibitors for cancer treatment, novel pharmacodynamic endpoints of treatment efficacy are required. The innovations in medical imaging include computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission tomography (SPECT), ultrasonography (US) and, mostly in the pre-clinical arena, optical imaging. While CT and MRI provide superb anatomic resolution, physiological changes in tumor microenvironment can be assessed by dynamic contrast enhanced MRI (DCE-MRI), metabolic endpoints can be established with PET and MRS protocol, and molecular biomarkers can be non-invasively followed up using PET and MRI-based molecular probes (and optical imaging mostly in pre-clinical setting). Novel protocols for improved spatial resolution, automated quantitative methods for anatomic assessment, and development of physiological, metabolic and molecular imaging probes are currently under investigation. The imaging future promises new avenues for exploration of physiological, metabolic, molecular and genetic events in the human body, performed non-invasively and in real time, using multi-modality imaging platforms. The aim of this article is to represent the available patents on imaging response assessment in oncology.

Quality of life as an endpoint of treatment efficacy in malignant lung tumours – Author's reply

Quality of life as an endpoint of treatment efficacy in malignant lung tumours – Author's reply

Quality of life as an endpoint of treatment efficacy in malignant lung tumours

We read with interest the findings of the RAPTURE study by Lencioni and colleagues,1 published in the July issue of The Lancet Oncology, in which the researchers assessed the efficacy of radiofrequency ablation of malignant lung tumours in patients who were not candidates for surgical resection and showed it to be an acceptable alternative. There are certain issues related to this study, however, which need further clarification.

Cardiac Cell Therapy Trials: Chronic Myocardial Infarction and Congestive Heart Failure

Although most cardiac cell therapy trials have focused on patients with acute myocardial infarction, attempts at "regenerating" chronically failing hearts have also been performed. These studies have entailed use of skeletal myoblasts and bone marrow-derived cells. In the case of skeletal myoblasts, the randomized placebo-controlled MAGIC trial has not achieved its primary end point as 6-month ejection fractions did not significantly differ between patients receiving cells or placebo, but the finding that the highest dose of myoblasts resulted in a significant anti-remodeling effect (a prespecified secondary end point) compared with the placebo group provides an encouraging signal. In the case of bone marrow cells, surgical injections of the mononuclear fraction combined with coronary artery bypass surgery have failed to show any substantial benefit. A catheter-based trial using a cross-over type of design has reported more successful outcomes, but its results will then have to be confirmed. Indeed, the most positive results have been reported with intraoperative epicardial injections of CD133 progenitors, which is probably explained by the angiogenic potential of these cells. There are three possible reasons for these mixed results. The first is the marked heterogeneity of cell functionality (particularly in the case of bone marrow), which would expectedly translate into variable clinical outcomes. The second reason is the low rate of sustained engraftment caused by early mechanical leakage followed by biologically induced cell death. The third possible explanation is a mismatch between the choice of end points and the presumed mechanism of action of the cells. The initial assumption that adult stem cells could affect myocardial tissue regeneration has led to the usual focus on ejection fraction as the major surrogate end point for treatment efficacy. It is now increasingly recognized that adult stem cells, in contrast to their embryonic counterparts, have little if any regenerative capacity and that their presumed beneficial effects more likely involve paracrine signaling and/or limitation of remodeling, in which case infarct size, perfusion, or left ventricular volumes might be more appropriate markers. Altogether, these observations provide a framework for future research the results of which will then have to be integrated into the protocol design of second-generation clinical trials so as to maximize their likelihood of yielding more successful results.

A Single-Nucleotide Polymorphism in the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor Letrozole in Advanced Breast Carcinoma

To evaluate the efficacy of treatment with the aromatase inhibitor letrozole in breast cancer patients segregated with respect to DNA polymorphisms of the aromatase gene CYP19. Postmenopausal patients (n = 67) with hormone receptor-positive metastatic breast cancer were treated with the aromatase inhibitor letrozole. PCR allelic discrimination was used to examine three single-nucleotide polymorphisms (SNP) in DNA obtained from breast carcinoma tissue. Two SNPs analyzed (rs10046 and rs4646) were located in the 3' untranslated region and one (rs727479) was in the intron of the aromatase CYP19 gene. The primary end point of treatment efficacy was time to progression (TTP). Median age was 62 years and median number of metastatic sites was 2. Observed allelic SNP frequencies were rs10046, 71%; rs4646, 46%; and rs727479, 63%. Of the 67 patients, 65 were evaluable for efficacy. Median TTP was 12.1 months. We observed no relationship between TTP and the rs10046 or rs727479 variants. In contrast, we found that TTP was significantly improved in patients with the rs4646 variant, compared with the wild-type gene (17.2 versus 6.4 months; P = 0.02). In patients with hormone receptor-positive metastatic breast cancer treated with the aromatase inhibitor letrozole, the presence of a SNP in the 3' untranslated region of the CYP19 aromatase gene is associated with improved treatment efficacy. Testing for the CYP19 rs4646 SNP as a predictive tool for breast cancer patients on antiaromatase therapy deserves prospective evaluation.

Quality of life studies and genito-urinary tumors

Genitourinary (GU) tumors represent a large proportion of solid cancers (1 of 4) and a wide variety of natural histories, based on various prognostic factors and resulting in different treatment options and end points. In some cases, for the same stage of disease, different treatment strategies do not impact differently on overall survival (OS): surgery vs. radiation, or radical vs. conservative multidisciplinary approach, adjuvant or neoadjuvant, chemotherapy vs. BSC. Quality of life (QoL) is considered a reasonable end point when differences in OS do not seem to be striking. A review of the literature on different disease stages was undertaken to show where and when QoL was used as the end point of treatment efficacy. Very few studies have been performed in prostate, bladder and testicular cancer to show the impact of different treatment approaches on QoL. Although these studies might be considered as non-conclusive, some data may allow a better choice for the patients. QoL as the principal end point has not been used in clinical trials of GU tumors comparing different treatment approaches. This makes the choice between treatments offering similar survival but different toxicity patterns, body and behavioral consequences more difficult. We suggest that future prospective randomized studies should be planned taking into account the QoL as the main end point.