Pretreatment Risk Factors Research Articles

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer

Purpose To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). Methods and materials The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log–rank test. Results Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk ( p = 0.04) and high-risk ( p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% ( p = 0.04) in low-risk patients, 70% vs. 75% ( p = 0.72) in intermediate-risk patients, and 29% vs. 53% ( p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level ≥20 ng/mL ( p = 0.01) and Gleason score ≥8 ( p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8–10 ( p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7–10 ( p = 0. 033). Conclusion A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

Metastatic renal carcinoma comprehensive prognostic system.

The purpose of the study was to identify a comprehensive prognostic system of pretreatment clinical parameters in 425 patients (pts) with metastatic renal-cell carcinoma treated with different subcutaneous (s.c.) recombinant cytokine-based home therapies in consecutive trials. Treatment consisted of (A) s.c. interferon-α2a (INF-α), s.c. interleukin-2 (IL-2) (n=102 pts), (B) s.c. IFN-α2a, s.c. IL-2, and i.v. 5-fluorouracil (5-FU) (n=235 pts) or (C) s.c. IFN-α2a, s.c. IL-2, and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (13cRA) (n=88 pts). Kaplan–Meier survival analysis, log-rank statistics, and Cox regression analysis were employed to identify risk factors and to create a multiple risk factor model. The following pretreatment risk factors were identified by univariate analysis: (1) three and more metastatic sites, (2) presence of liver, lymph node or bone metastases, (3) neutrophil count ⩾6500 cells μl−1, (4) serum lactate dehydrogenase level (LDH) ⩾220 U l−1, and (5) serum C-reactive protein level (CRP) ⩾11 mg l−1. Cox regression analysis with forward stepwise variable selection identified neutrophil count as the major prognostic factor (hazard ratio=1.9, P<0.001), while serum levels of LDH and CRP, time between diagnosis of tumour and onset of metastatic disease, number of metastatic sites, and bone metastases were significant but somewhat less important prognostic variables within the multiple risk factor model (hazard ratio ⩽1.5). Patients were assigned to one of the three risk groups according to cumulative risk defined as the sum of simplified risk s.c.ores for six pretreatment variables. Low-, intermediate-, and high-risk patients achieved a median overall survival of 32+ months (95% CI 24, 43; 5-year survival of 27%), 18+ months (95% CI 15, 20; 5-year survival of 11%), and 8+ months (95% CI 6, 10; 5-year survival of 5%), respectively. These prognostic categories are helpful both in individual patient care and in the assessment of patients entering prospective clinical trials.

Clinical pretreatment risk factors and Ga‐67 scintigraphy early during treatment for prediction of outcome of patients with aggressive non‐Hodgkin lymphoma

Clinical pretreatment risk factors indicate the severity of disease in patients with aggressive non-Hodgkin lymphoma (NHL). Ga-67 scintigraphy during treatment is an early indicator of treatment-related features of lymphoma cells. The ability of risk factors and Ga-67 to predict disease outcome was compared in 139 patients with aggressive NHL. Pretreatment clinical risk factors and Ga-67 scintigraphy performed after one cycle and at mid-treatment were evaluated for their correlation with response rate and as predictors of 5-year failure-free survival (FFS). Univariate analysis was performed to determine the ability of pretreatment risk factors and Ga-67 early during treatment to predict FFS. Subsequently, multivariate analysis was performed on the variables with significant univariate results using the Cox proportional hazards method. The predictive value of risk factors and Ga-67 scintigraphy was calculated to determine their suitability in selecting patients with poor outcome. Response rate correlated with stage of disease (P < 0.01) and the international prognostic index (IPI) score (P < 0.05). Five-year FFS was predicted by stage of disease (P < 0.004), performance status (P < 0.02), and the IPI score (P < 0.01). Response rate correlated with results of Ga-67 scintigraphy after one cycle of chemotherapy (P < 0.001) and at mid-treatment (P < 0.001). Five-year FFS was predicted by Ga-67 after one cycle of chemotherapy (P < 0.0004) and at mid-treatment (P < 0.0001). Positive Ga-67 after the first cycle of treatment predicted 64% of patients who had failure of treatment. A positive study at mid-treatment predicted 77% of patients who had treatment failure. Cox analysis showed Ga-67 after one course (P < 0.0012) and at mid-treatment (P < 0.0002) as being the most significant variables in predicting FFS. Ga-67 scintigraphy demonstrates early the effect of treatment in patients with aggressive NHL. It is a better predictor than pretreatment risk factors of both response rate and FFS. Positive Ga-67 early during treatment may be used as an independent test in selecting patients who will not respond favorably to current protocol treatment for early therapeutic modifications.

Clinical pretreatment risk factors and Ga‐67 scintigraphy early during treatment for prediction of outcome of patients with aggressive non‐Hodgkin lymphoma

Clinical pretreatment risk factors and Ga‐67 scintigraphy early during treatment for prediction of outcome of patients with aggressive non‐Hodgkin lymphoma

Sex-Related HIV Risk Reduction Behavior among Adolescents in DATOS-A

This study examines the effect of drug treatment on reducing HIV-related risky sex behavior among 796 adolescents entering drug treatment programs in four cities in the United States. More than half of the adolescents (54%) reported reductions in risky sex behavior after treatment. Conduct-disordered adolescents with abuse history, unmet physical and emotional needs, and low commitment to school were associated with lack of improvement. Furthermore, conduct-disordered adolescents who perceived treatment to be effective were more likely to show posttreatment improvement, with the exceptions that those who scored high on hostility or low in self-perception were not likely to improve. Among adolescents without conduct disorder, receipt of mental health services was associated with improvements in their risky sex behavior. The effect of drug treatment on HIV risk reduction can be increased when attention is focused on adolescents’ pretreatment risk factors, service needs, intreatment responses, and key personality characteristics.

Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: A randomized, double-blind, placebo-controlled pilot study

Objective: Eradication of Chlamydia pneumoniae infection and inhibition of elastolytic matrix metalloproteinases with doxycycline have been suggested to reduce the growth rates of small abdominal aortic aneurysms (AAA). We designed a study to investigate the efficacy of doxycycline in reducing the expansion of small AAAs. Subjects and Methods: This was a prospective, double-blind, randomized, placebo-controlled study that was set in a university referral hospital. The study group consisted of 32 of 34 initially eligible patients who had an AAA diameter perpendicular to the aortic axis of 30 mm or more in size or a ratio of infrarenal to suprarenal aortic diameter of 1.2 or more and a diameter less than 55 mm. Patients were randomly assigned to receive either doxycycline (150 mg daily) or placebo during a 3-month period and underwent ultrasound surveillance during an 18-month period. Outcome measures included aneurysm expansion rates, the number of patients who had AAA rupture or repair, C pneumoniae antibody titers, and serum concentrations of C-reactive protein. Results: The aneurysm expansion rate in the doxycycline group was significantly lower than that in the placebo group during the 6- to 12-month (P =.01) and the 12- to 18-month periods (P =.01). Five patients (41%) in the placebo group and 1 patient (7%) in the doxycycline group had an overall expansion of the aneurysm of 5 mm or more during the 18-month follow-up. Among the placebo group patients, a higher expansion rate was observed in those with enhanced C pneumoniae immunoglobulin G antibody titers (> 128) than in those with lower titers (P =.03). Doxycycline treatment had no clear effect on antibody titers. However, at 6-month follow-up, C-reactive protein levels in the doxycycline group were significantly lower than the baseline levels (P =.01). Conclusions: The results of this small pilot study suggest that doxycycline may favorably alter the outcome of patients with small AAA. However, because of the small size of this randomized study and of the potentially confounding effect of pretreatment risk factors, doxycycline-based treatment cannot be justified only on the ground of the current results. Because of the high prevalence of this disorder and its clinical, social, and economic relevance, a multicenter study should be performed to further investigate whether there is any place for medical treatment of small AAAs. (J Vasc Surg 2001;34:606-10.)

Identification of Risk Factors for Requiring Transfusion during Front-Line Chemotherapy for Ovarian Cancer

Objective. Anemia requiring red blood cell (RBC) transfusion is common in ovarian cancer (OC) patients receiving post-debulking surgery chemotherapy. Erythropoietin use has been shown to decrease transfusion requirements in patients receiving chemotherapy. We sought to identify pretreatment risk factors that could identify patients at increased risk for requiring RBC transfusion during first-line treatment for ovarian cancer.Methods. One hundred seventy-five consecutive patients who received chemotherapy with either carboplatin–paclitaxel or cisplatin–paclitaxel following debulking surgery for epithelial OC from 1993 to 1996 were identified. No patient received erythropoietin. Patient characteristics recorded included: age, stage, prechemotherapy hemoglobin, nadir hemoglobin, number of cycles and doses of chemotherapy received. The outcome was requiring RBC transfusion. Independent predictors of requiring RBC transfusion were identified using multivariate analyses.Results. Median age of the cohort was 62 years (range, 28–86). Seventy-one and four-tenths percent had FIGO stage III/IV disease. Median prechemotherapy hemoglobin was 11 g/dL (range, 7.1–15.4); median nadir hemoglobin was 9.3 g/dL (range, 6.6–11.1). One hundred nineteen (66%) patients received cisplatin–paclitaxel, and 61 (34%) received carboplatin–paclitaxel. Of 175 patients, 31 (18%, 95% CI = 12–23%) required RBC transfusion. Independent risk factors for RBC transfusion were prechemotherapy hemoglobin <10 g/dL (P < 0.01, odds ratio = 3.78, 95% CI = 1.52–9.44) and carboplatin–paclitaxel versus cisplatin–paclitaxel treatment (P = 0.01, odds ratio = 3.14, 95% CI = 1.27–7.76). Of 175 patients, 40 (22.8%) had a prechemotherapy hemoglobin <10 g/dL. Fifty percent of patients with prechemotherapy hemoglobin <10 g/dL who received carboplatin–paclitaxel required RBC transfusion, compared with 7.7% of patients with hemoglobin >10 g/dL who received cisplatin–paclitaxel.Conclusion. Ovarian cancer patients frequently require RBC transfusion during postdebulking platinum–paclitaxel chemotherapy. Patients with prechemotherapy hemoglobin <10 g/dL and those receiving carboplatin–paclitaxel are at increased risk of requiring RBC transfusion. Early initiation of erythropoietin use in such patients may reduce transfusion needs.

Radiotherapy for carcinoma of the bladder: a review.

Carcinoma of the bladder (CaB) is a common and important tumor in North America and Western Europe. There has been a steady increase in the incidence of CaB during the past 25 years in both of these regions with a simultaneous decrease in the mortality rates. The decrease in mortality is primarily due to an earlier diagnosis and the availability of more effective therapeutic interventions resulting from major advances in surgery and a wide use of multimodality bladder preservation therapy.The use of radiotherapy in the management of muscle-invasive CaB has undergone a major evolution. External beam radiotherapy alone is used infrequently in carefully selected patients. The same applies to the use of preoperative irradiation. Brachytherapy alone or combined with external beam radiotherapy has been used successfully in Europe but is used infrequently in North America. External beam radiotherapy is an essential component of a multimodality therapy consisting of cytoreductive surgery via transurethral resection of a bladder tumor followed by a planned combination of radiotherapy and chemotherapy. The outcomes of this bladder preservation therapy are similar to those reported in a like patient population treated with radical cystectomy. The main benefit of conservatively treated patients is functioning bladder in about 50% of those receiving conservative therapy. Radiotherapy alone or in a combination with chemotherapy remains an important and effective palliative therapy for patients with recurrent and/or metastatic CaB. Current research efforts are directed toward a better identification of important pretreatment risk factors predicting failure thus helping in a more optimal selection of patients who would benefit most from radical cystectomy or from the application of bladder preservation therapy.

Prognostic impact of in vivo soluble cell adhesion molecules in metastatic renal cell carcinoma.

The purpose of the study was to determine prognostic significance of pretreatment serum levels of different molecules involved in cell to cell interactions along with other clinical parameters in patients with metastatic renal cell carcinoma. sICAM-1, sVCAM-1 and sELAM-1 serum levels were determined by ELISA assays in sera from 99 patients with histologically confirmed progressive metastatic renal cell carcinoma prior to initiation of systemic therapy. Kaplan–Meier survival analysis, log-rank statistics and two-proportional Cox regression analyses were employed to identify risk factors and to demonstrate statistical independence. In univariate analyses, the following pretreatment risk factors could be identified: serum sICAM-1 level > 360 ng ml−1, erythrocyte sedimentation rate > 70 mm h−1, serum C-reactive protein level > 8 mg l−1, serum lactic dehydrogenase level > 240 U/ l and neutrophil count > 6000 μl−;1. Multivariate analyses demonstrated statistical independence for serum sICAM-1 level, erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) level as pretreatment predictors of overall patient survival. The prognostic significance of sICAM-1 might indicate a role of this molecule for tumour progression, potentially in association with the abrogation of anti-tumour immune responses. The possibility of defining a pretreatment risk model based on sICAM-1 level, ESR and CRP also warrants further investigation, with regard to a possible linkage between acute phase proteins and sICAM-1 levels. © 1999 Cancer Research Campaign

Continuous ambulatory peritoneal dialysis and hemodialysis: Comparison of patient mortality with adjustment for comorbid conditions

A historical prospective national sample of 1,725 diabetic and 2,411 non-diabetic Medicare end-stage renal disease (ESRD) patients incident from 1986 to 1987 was analyzed for the mortality of patients selected to receive continuous ambulatory peritoneal dialysis (CAPD) or hemodialysis (HD) with adjustment for patient characteristics, including the presence of comorbid conditions at onset of ESRD. Cox proportional hazards analyses were used to compare the mortality of CAPD and HD patients. Patients were followed from 30 days following onset of ESRD until two to four years post-onset. No statistically significant difference in relative mortality risk (RR) was found among non-diabetic patients selected for CAPD compared to HD (RR = 0.84 for CAPD versus HD, P = 0.25), while evidence of higher adjusted mortality for CAPD compared to HD was found among diabetic patients (RR = 1.26, P = 0.03). Mortality analyses adjusted for pre-treatment risk factors suggest that CAPD and HD provide incident non-diabetic ESRD patients with similar expected survival outcomes. Evidence that increased mortality was associated with CAPD among diabetic patients, particularly among elderly patients, suggests the need for further controlled studies of mortality among CAPD patients with diabetes.

Fatal Streptokinase-Induced Intracerebral Haemorrhage in Cerebral Amyloid Angiopathy

A fatal intracerebral haemorrhage (ICH) associated with streptokinase (SK) treatment of an acute myocardial infarction is described. Autopsy examination showed a lobar ICH and severe cerebral amyloid angiopathy (CAA). The close temporal relationship between SK administration and intracranial haemorrhage, the absence of pretreatment risk factors for ICH, and the presence of CAA suggests that these are related phenomena. Accordingly: 1. There may be a synergistic relationship between CAA and intracranial haemorrhage induced by fibrinolytic agents; 2. Thrombolytic agents may induce more frequent than expected intracranial haemorrhage in conditions associated with a high incidence of CAA, notably old age and Alzheimer's disease; 3. A regional defect in haemostasis other than vessel fragility may contribute to the intracranial haemorrhagic predisposition of CAA; 4. Autopsy examination of cases of ICH is an essential part of the audit of clinical trials of fibrinolytic agents.

Transient and chronic neurological complications of fast neutron radiation for adenocarcinoma of the prostate

The records of 132 patients participating in clinical trials using fast neutron ( n = 94), mixed neutron and photon ( n = 16), or conventional photon ( n = 22) irradiation for primary management of prostatic cancer were retrospectively reviewed to assess treatment-related neurological complications. With a median follow-up of 14 months (range 1 to 101 months), 31 132 patients (26 neutron, 3 mixed beam, 2 photon) have experienced either sciatica beginning during or shortly after treatment, or diminished bladder or bowel continence that developed at a median time of 6.5 months following treatment. Sciatica responded to oral steroids and was usually self-limited, whereas sphincter dysfunction appears to be permanent. Pre-treatment risk factors for complications included a history of hypertension, diabetes, cigarette smoking or peripheral vascular disease, with 81% of affected patients having one or more risk factors compared with 55% of unaffected patients ( p = 0.01). Seven patients have moderate (5) or severe (2) residual problems, all in the cohorts receiving neutrons ( 6 7 ) or mixed beam therapy ( 1 7 ).

Evaluation of circulating malignant cells provides prognostic information in cutaneous T cell lymphoma

Peripheral blood lymphocyte morphology was evaluated prospectively by light microscopy of blood smears and E rosette preparations in 160 patients with cutaneous T cell lymphoma (CTCL). Blood involvement was related to the type of cutaneous T-stage, being present in 90% of patients with erythroderma (T4), 27% of those with cutaneous tumors (T3), 9% of those with generalized (T2), and 0% of those with limited skin plaques (T1). Untreated patients with blood involvement (38 of 105) had a higher frequency of CTCL in lymph nodes and viscera and survival inferior to that of patients with normal or nondiagnostic lymphocyte morphology (P less than .001). Multivariate analysis showed skin stage and age to be the most important pretreatment risk factors for survival. Although blood involvement was not an independent risk factor for the entire group, it appeared to have some adverse influence in the T2/T3 subsets (P = .051). Both lymphocytosis and size distribution of the circulating CTCL cells at initial diagnosis influenced survival. Patients with “mixed cell” cytology (greater than 20% large [greater than 11 microns] CTCL cells), had a worse survival than those with predominantly small circulating CTCL cells (P = .009). The former were more likely to have aggressive features, including lymph node effacement by tumor (P less than .001) and visceral disease (P = .074), than were “small cell” patients. Our data indicate that detailed review of the blood lymphocyte morphology in patients with diagnosed or suspected CTCL is helpful in predicting extent of disease and prognosis.

Evaluation of Circulating Malignant Cells Provides Prognostic Information in Cutaneous T Cell Lymphoma

Peripheral blood lymphocyte morphology was evaluated prospectively by light microscopy of blood smears and E rosette preparations in 160 patients with cutaneous T cell lymphoma (CTCL). Blood involvement was related to the type of cutaneous T-stage, being present in 90% of patients with erythroderma (T4), 27% of those with cutaneous tumors (T3), 9% of those with generalized (T2), and 0% of those with limited skin plaques (T1). Untreated patients with blood involvement (38 of 105) had a higher frequency of CTCL in lymph nodes and viscera and survival inferior to that of patients with normal or nondiagnostic lymphocyte morphology (P less than .001). Multivariate analysis showed skin stage and age to be the most important pretreatment risk factors for survival. Although blood involvement was not an independent risk factor for the entire group, it appeared to have some adverse influence in the T2/T3 subsets (P = .051). Both lymphocytosis and size distribution of the circulating CTCL cells at initial diagnosis influenced survival. Patients with "mixed cell" cytology (greater than 20% large [greater than 11 microns] CTCL cells), had a worse survival than those with predominantly small circulating CTCL cells (P = .009). The former were more likely to have aggressive features, including lymph node effacement by tumor (P less than .001) and visceral disease (P = .074), than were "small cell" patients. Our data indicate that detailed review of the blood lymphocyte morphology in patients with diagnosed or suspected CTCL is helpful in predicting extent of disease and prognosis.

Acute lymphoblastic leukemia in children: Immunologic, cytochemical, morphologic, and cytogenetic studies in relation to pretreatment risk factors

Thirty children with previously untreated acute lymphoblastic leukemia were studied prior to therapy to determine whether sheep erythrocyte (E)-receptor status correlated with clinical factors, cytochemical staining characteristics, FAB morphologic classification, and karyotype. Five patients (17%) with more than 50% E+ blasts had intense focal acid phosphatase staining and distinct clinical characteristics, including high leukocyte counts, mediastinal masses, and involvement of the central nervous system at diagnosis. Focal acid phosphatase activity was present in blasts of patients with greater than 20% E+ blasts, but this group had fewer poor risk factors. Morphologic and karyotypic features were not related to erythrocyte-receptor status, but the L2 morphologic appearance occurred more frequently in older patients (P less than 0.05). Erythrocyte receptors have both qualitative and quantitative clinical correlations in childhood acute lymphoblastic leukemia; however, E+ and E- groups are heterogeneous and E+ groups must be analyzed for other risk factors and relapse rates determined before firm conclusions can be made about erythrocyte rosetting as an independent risk variable.