The Development Of Venous Thromboembolism May Increase The Risk Of Osteonecrosis In Children With Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3864-3864
Author(s):  
Badhiwala H. Jetan ◽  
Trishana Nayiager ◽  
Uma H. Athale
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Older Age ◽  
Regression Analyses ◽  
Female Ratio ◽  
Increased Risk ◽  
The Impact

Abstract Background Osteonecrosis (ON) is a severely disabling complication of anti-leukemic therapy, specifically long-term corticosteroid use. A hypercoagulable state is thought to underlie corticosteroid-related ON. Children with acute lymphoblastic leukemia (ALL) are also at increased risk of venous thromboembolism (VTE), indicating underlying hypercoagulability in this disease entity. Hence, we explored the relationship between ON and VTE, along with the association of ON with other variables, including age and asparaginase (ASP) therapy, in children with ALL. Methods Health records of children (< 18 yrs.) with de novo ALL treated at McMaster Children’s Hospital from 1992 to 2010 were reviewed. Patients were treated according to Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols. Data regarding demographics, leukemia diagnosis and therapy, development and characteristics of ON and VTE, and thrombophilia work-up, if any, were collected from computer records and chart review. Osteonecrosis was diagnosed by plain X-ray, computed tomography (CT), magnetic resonance (MR) imaging, and/or technetium-99m (99mTc) bone scan. We included ON diagnosed during therapy and/or at any point during post-treatment follow-up. Standard radiological measures, including venous Doppler ultrasound and/or venography (conventional, CT, MR), confirmed VTE. We included only clinically significant thromboembolic events, defined as symptomatic VTE, or asymptomatic VTE requiring anticoagulation, developing during ALL therapy. Logistic regression analyses were performed to identify possible predictors of ON. Odds ratios (ORs) with 95% confidence intervals (CIs) and corresponding p-values were determined. Results Mean age of the study cohort (n = 208) was 5.4 years and male/female ratio 1.2:1. Seventy-eight (37.5%) patients had high-risk (HR) ALL and 127 (61.1%) received dexamethasone (DEX) as post-induction steroid. One hundred and sixty-two (77.9%) patients received E. coli ASP, 19 (9.1%) Erwinia ASP, and 27 (13.0%) PEG ASP. Twenty-one (10.1%) children developed ON. Joints affected by ON included the ankle in 11 subjects, knee in 10, hip in 8, and heel in one. Fourteen of the 21 patients (66.7%) had involvement of more than one joint. All patients were diagnosed with ON during ALL treatment, with the average being 69.2 weeks following ALL diagnosis. Forty-two (20.2%) subjects had a VTE while receiving therapy at an average of 29.4 weeks after ALL diagnosis. Nine patients had cerebral sinovenous thrombosis, 7 deep vein thrombosis (DVT), and one pulmonary embolism (PE). Twenty-six patients developed a central venous line (CVL)-related VTE. Results of univariate logistic regression analyses for osteonecrosis are presented in Table 1. VTE strongly predicted development of ON – OR 8.85 (95% CI 3.37–23.25, p< 0.001). Thirteen (31.0%) patients with VTE developed ON compared to 8 (4.8%) of 166 subjects without VTE. In 10 of 13 (76.9%) patients who developed both VTE and ON, the diagnosis of VTE preceded that of ON. Given that older age is a known risk factor for both VTE and ON, we conducted a multivariate analysis, which confirmed that age, ASP type, and VTE were independent, significant risk factors for ON (Table 2). Conclusion In addition to the known impact of older age, we identified VTE and type of ASP as independent risk factors for ON in children with ALL. These observations suggest overlap in the etiopathogenesis of ON and VTE. We recommend larger, prospective studies to confirm the association of VTE and PEG ASP with ON and to assess the impact of hypercoagulability on the development of ON. This in turn may help develop preventive strategies (e.g., thromboprophylaxis) for ALL-associated ON. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Risk Factors for Induction Related Mortality in Adults Patients with Acute Lymphoblastic Leukemia: Report from a Hispanic Population

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5162-5162
Author(s):  
Sergio I Inclan-Alarcon ◽  
Christianne Bourlon ◽  
Oscar Manuel Fierro-Angulo ◽  
Jesus A Garcia-Ramos ◽  
Santiago Riviello-Goya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Score ◽  
Univariate Analysis ◽  
Adult Patients ◽  
Hispanic Population ◽  
Increased Risk ◽  
The Impact ◽  
Hispanic Adult

Abstract Introduction Acute lymphoblastic leukemia (ALL) represents 20-30% of acute leukemia in adults. Higher incidence and inferior outcomes in Hispanic population have been described. In Latin Americans induction mortality (IM) is a major cause of death representing 20-50% vs.7-11% in developed countries. Our aim was to determine risk factors (RF) related to IM in ALL Hispanic adult patients. Methods We retrospectively analyzed clinical data of ≥18yo patients with ALL diagnosed and treated at our institution within 2009 and 2016. Results A total of 170 patients were included. Median age was 29 years (16-70), 64% were AYA, 96.8% had B-cell ALL, and 62.3% received Hyper-CVAD. IM rate was 13.4%. In 64.1% IM was related to an infectious cause. The most frequent infection was pneumonia (39.8%). Gram-negative etiology was more prevalent (35.5% vs. 10.2%), however, IM rate was higher in gram-positive infections (26.3% vs .13.6%; p=.028). RF related to IM in univariate analysis were: CNS involvement (OR4.6,95%IC2.8-9.5;p=<.001), tumor lysis syndrome (TLS) (OR 5.6, 95% CI 2.2-14.1; p=<.001), need for dialysis (OR 28.9, 95% CI 5.3-157.1; p=<.001), primary hypertension (OR 3.5, 95% CI 1.0-12.7; p=.052), shock status (OR 10.3, 95% CI 3.9-27.3; p=<.001), ECOG³2 (OR 1.9, 95% IC 1.1-3.4; p=.022), T-ALL (OR 2.2, 95% IC 1.1-4.3; p=.026), Hyper-CVAD (OR 1.9, 95% IC 1.1-3.8; p=0.51), ventilation assistance (OR 7.7, 95% IC 2.8-21; p=<.001), and vasopressor use (OR 7.6, 95% IC 2.8-20.6; p=<.001). In multivariate analysis TLS, need for dialysis and shock, kept statistical significance. Conclusions To our knowledge, this is the largest study that evaluates the impact over IM of biological, social, and economic factors in Hispanic adult patients with ALL. We identified factors not previously described such as hypertension and need for dialysis. Multicenter prospective studies most be urged to asses and validate these RF, and design a bedside prognostic score that can predict an increased risk of IM at ALL diagnosis. Disclosures No relevant conflicts of interest to declare.

Venous Thromboembolism in Children with Acute Lymphoblastic Leukemia in Northern Europe

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3652-3652
Author(s):  
Nadine Gretenkort Andersson ◽  
Susanna Ranta ◽  
Tony Frisk ◽  
Maria Winther Gunnes ◽  
Jon Helgestad ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Risk Treatment ◽  
The Impact ◽  
All Treatment

Abstract Introduction Children with acute lymphoblastic leukemia (ALL) are at high risk for VTE due to several thrombotic risk factors such as the disease itself, central venous line (CVL), immobilization, infections and treatment with asparaginase and steroids, leading to increased morbidity and mortality. Identifying the clinical risk factors and high risk treatment phases for VTE is important and can lead to a better outcome and quality of life for these children. We conducted this prospective study on symptomatic VTE in children with ALL to characterize the prevalence, the clinical characteristics, and potential clinical predictive factors for symptomatic VTE and the impact of thrombosis on treatment delays. Methods All patients (n=1083), age 1-18 years, diagnosed with B-cell precursor or T-cell ALL between June 2008 and July 2013 and enrolled in the NOPHO ALL 2008 treatment protocol in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), Estonia or Lithuania were included in the study. Thrombotic events (TE) were prospectively recorded until the end of December 2013. TE was defined as objectively confirmed symptomatic TE. Main questions were: time of VTE occurrence, impact on treatment delay, type of CVL, dysfunction of the CVL, blood samples including D-dimers and thrombophilia screening, family history of TE, type and duration of antithrombotic therapy, and major bleeding during anticoagulation. Results The cumulative risk of symptomatic VTE was 6.0% (CI 95% 4.7-7.7) for children treated with the NOPHO- ALL 2008 protocol. No arterial TE was found. VTE occurred in median 80 (IQR 43-118) days in the SR and 104 (IQR 39-127) days in the IR protocol and were in majority of cases associated with asparaginase treatment (84.5%, 49/58). See figure 1 for the localization of the VTE. VTE had a high impact on the treatment in the patients. Treatment with asparaginase was shortened in half of patients with VTE and chemotherapy treatment delayed in 25%. Age ≥ 15 years and residual disease ≥ 5% after induction therapy was significantly associated with VTE in the multivariate analysis (Table 1). Conclusions Our findings indicate that Venous Thromboembolism (VTE): - is a major complication of ALL treatment - may lead to reduced intensity of the ALL treatment and subsequently possible long term impact on the EFS - risk is dependent on the patients age and residual disease after leukemia induction The possibility of identifying patients with elevated risk of VTE needs to be studied further and thromboprophylaxis for such patients during high-risk treatment phases can be considered in future ALL protocols. Table 1. Multivariate Cox regression analysis of the risk for VTE Factor HR (95% CI) P value Age category, years 1-7 8-14 15-17 Ref1.9 (1.0-3.7)6.2 (3.4-11.3) <0.000 0.044 0.000 Gender Male 1.6 (0.9-2.8) 0.074 ALL phenotype B-precursor T-cell Bilineage Ref2.3 (1.2-4.2)4.2 (1.0-17.4) 0.019 0.010 0.047 Residual disease ≥ 5% day 29 4.1 (1.9-9.0) 0.001 Figure 1. Localization of VTE Figure 1. Localization of VTE Disclosures No relevant conflicts of interest to declare.

Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2529-2533 ◽  
Author(s):  
Ulrike Nowak-Göttl ◽  
Elvira Ahlke ◽  
Gudrun Fleischhack ◽  
Dirk Schwabe ◽  
Rosmarie Schobess ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Treatment Modalities ◽  
Thromboembolic Events ◽  
Increased Risk ◽  
Significant Difference ◽  
Prothrombotic Risk Factors

Alterations in hemostasis leading to symptomatic thromboembolism have been observed in patients with acute lymphoblastic leukemia (ALL) receiving Escherichia coli asparaginase (CASP) combined with steroids. Moreover, hereditary prothrombotic risk factors are associated with an increased risk for venous thromboembolism in pediatric ALL patients treated according to the BFM 90/95 protocols (including CASP combined with prednisone during induction therapy). To assess whether the thromboembolic risk associated with established prothrombotic risk factors is modified by treatment modalities (prednisone or dexamethasone), the present analysis was performed. Three hundred thirty-six consecutively recruited leukemic children treated according to different BFM protocols (PRED group, n = 280, 60 mg/m2 prednisone; DEXA group, n = 56, 10 mg/m2 dexamethasone during induction therapy) were studied. Study end point was the onset of symptomatic vascular accidents during induction therapy. Cumulative thromboembolism-free survival was significantly reduced in children in the PRED group (thrombosis frequency, 10.4%) compared with children in the DEXA group (thrombosis frequency, 1.8%; P = .028). Although no significant difference was found in the overall prevalence of prothrombotic risk factors, 46.5% of patients in the PRED group who experienced thromboembolic events were carriers of a prothrombotic risk factor, whereas no carrier in the DEXA group had a thromboembolism. At the time of maximum CASP activity, fibrinogen and activities of antithrombin, plasminogen, and protein S were significantly reduced in the PRED group. No significant correlation could be found between CASP activity and levels of coagulation factors. In conclusion, the use of dexamethasone instead of prednisone, administered with CASP, significantly reduced the onset of venous thromboembolism.

scholarly journals Relation between body composition and severe diarrhea in patients treated with preoperative chemoradiation with capecitabine for rectal cancer: a single-centre cohort study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
J. M. van Rees ◽  
W. Hartman ◽  
J. J. M. E. Nuyttens ◽  
E. Oomen-de Hoop ◽  
J. L. A. van Vugt ◽  
...  
Keyword(s):  
Risk Factors ◽  
Rectal Cancer ◽  
Body Composition ◽  
Logistic Regression ◽  
Cohort Study ◽  
Preoperative Chemoradiation ◽  
Regression Analyses ◽  
Single Centre ◽  
Severe Diarrhea ◽  
The Impact

Abstract Background Chemoradiation with capecitabine followed by surgery is standard care for locally advanced rectal cancer (LARC). Severe diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiation therapy. The aim of this study was to describe the risk factors and the impact of body composition on severe diarrhea in patients with LARC during preoperative chemoradiation with capecitabine. Methods A single centre retrospective cohort study was conducted in a tertiary referral centre. All patients treated with preoperative chemoradiation with capecitabine for LARC from 2009 to 2015 were included. Patients with locally recurrent rectal cancer who received chemoradiation for the first time were included as well. Logistic regression analyses were performed to identify risk factors for severe diarrhea. Results A total of 746 patients were included. Median age was 64 years (interquartile range 57–71) and 477 patients (64%) were male. All patients received a radiation dosage of 25 × 2 Gy during a period of five weeks with either concomitant capecitabine administered on radiation days or continuously during radiotherapy. In this cohort 70 patients (9%) developed severe diarrhea. In multivariable logistic regression analyses female sex (OR: 4.42, 95% CI 2.54–7.91) and age ≥ 65 (OR: 3.25, 95% CI 1.85–5.87) were the only risk factors for severe diarrhea. Conclusions Female patients and patients aged sixty-five or older had an increased risk of developing severe diarrhea during preoperative chemoradiation therapy with capecitabine. No relation was found between body composition and severe diarrhea.

ALL-414: Obesity is Not Associated with an Increased Risk of Venous Thromboembolism in AYA Patients with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 21 ◽  
pp. S276
Author(s):  
Sandra Renee Jones ◽  
Roshni Bharati Patel ◽  
Mahvish Qureshi Rahim ◽  
Sandra K. Althouse ◽  
Sandeep Batra
Keyword(s):  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Increased Risk

scholarly journals Characteristics and Outcomes of COVID-19 Patients with Mature B-Cell Non-Hodgkin Lymphomas (mB-Cell NHL): A US Nationwide Electronic Health Record (EHR) Database Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2418-2418
Author(s):  
Xiaomeng Yue ◽  
David Hallett ◽  
Yangyang Liu ◽  
Reethi Iyengar ◽  
Elisa Basa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
B Cell ◽  
Clinical Characteristics ◽  
Index Date ◽  
B Cell Lymphoma ◽  
Male Gender ◽  
Older Age ◽  
Multivariable Logistic Regression ◽  
The Impact

Abstract Introduction COVID-19 poses a serious concern for mB-cell NHL patients given their advanced age, high burden of comorbidities, and immune dysfunction. Limited by smaller sample sizes during the early period of the COVID-19 pandemic, previous studies were unable to thoroughly evaluate the impact of COVID-19 on patients with mB-cell NHL 1,2. We aim to describe demographics and clinical characteristics, outcomes, and risk factors associated with death and other severe outcomes among COVID-19 patients with mB-cell NHL in a large US nationwide database. Methods This retrospective cohort study was conducted using the Optum EHR database, comprising data from an integrated network of ambulatory and hospital care providers across the US. Patients with COVID-19 (diagnosis code of U07.1, U07.2, or a positive result of SARS-Cov-2 virus PCR or antigen tests) between Feb. 1, 2020 and Jan 7, 2021 (index date) and mB-cell NHL diagnosis prior to the COVID-19 diagnosis were included. Patients were excluded if they were under 18 years of age, had missing age or sex, or had &lt;1year continuous eligibility prior to their index date (pre-index period). All baseline characteristics, including demographics and comorbidities, were determined during the one-year pre-index period. Severe outcomes, including death, hospitalization, ICU admission, and acute respiratory insufficiency (ARI), were evaluated within 30 days post-index date. Multivariable logistic regression was conducted to identify variables independently associated with severe outcomes. Results Among 2,767 patients with mB-cell NHL who were infected with SARS-CoV-2 between Feb. 1, 2020 and Jan. 7, 2021 (mean age±SD: 67.9 years±14.7, 53.9% male), majority were white (73.9%), followed by African American (10.9%), Hispanic (6.9%), and Asian (1.2%). The most common subtypes of mB-cell NHL were chronic lymphocytic leukemia/small lymphocytic lymphoma (26.9%), multiple myeloma (22.4%), diffuse large B-cell lymphoma (13.2%), and follicular lymphoma (7.3%). Of these patients, 93.4% have at least one comorbidity. The most common comorbidities were hypertension (58.5%), neurological disease (49.4%), diabetes (28.2%), ischemic heart disease (25.5%), cardiac arrhythmia/conduction disorders (24.4%), chronic kidney disease (CKD, 19.2%), heart failure/cardiomyopathy (18.1%), and COPD (12.3%). Overall, 960 patients (34.7%) developed severe outcomes, among which, 847 patients (30.6%) were hospitalized, 214 patients (7.7%) were admitted to the ICU, 201 patients (7.3%) experienced ARI, and 220 patients (8.0%) died. Multivariable logistic regression showed that increased odds of severe outcomes were independently associated with older age (85+ years vs. &lt;65 years; adjusted odds ratio [OR], 2.0; 95% CI, 1.4-2.7), male gender (OR, 1.4; 95% CI, 1.1-1.6), insurance coverage with Medicaid (OR, 1.8; 95% CI, 1.1-2.9) and/or Medicare (vs. commercial only; OR, 1.9; 95% CI, 1.5-2.5), infected during the first quarter (OR, 5.6; 95% CI, 3.4-9.4) or second quarter of 2020 (vs. fourth quarter of 2020; OR, 1.7; 95% CI, 1.4-2.1), having CKD (OR, 1.3; 95% CI, 1.0-1.6), COPD (OR, 1.4; 95% CI, 1.0-1.8), diabetes (OR, 1.3; 95% CI, 1.1-1.6), and receiving active treatment for NHL (OR, 1.4; 95% CI, 1.0-2.0) within 30 days prior to COVID-19 diagnosis (Figure). Conclusions This study demonstrated key demographic and clinical characteristics associated with severe outcomes among COVID-19 patients with mB-cell NHL using one of the largest nationwide databases. Risk factors for severe outcomes identified in the general population, such as older age, male gender, and having certain underlying medical conditions were also identified in this study. In addition, COVID-19 infection occurring earlier in the pandemic and receiving active NHL treatments were associated with severe outcomes. These latter two observations might reflect the improvement in patient management during the latter period of the pandemic and that active mB-cell NHL disease and treatment rendered an increased risk of severe outcomes in COVID-19 patients with mB-cell NHL. These insights highlight the importance of utilizing demographic, clinical and treatment information to estimate the risk for severe outcomes, whereas prospective studies focusing on optimal COVID-19 management are required to identify specific actions that can be taken to improve outcomes of COVID-19 in patients with mB-cell NHL. Figure 1 Figure 1. Disclosures Yue: Joule: Current Employment. Hallett: AbbVie: Current Employment. Liu: AbbVie: Current Employment. Iyengar: AbbVie: Current Employment. Basa: AbbVie: Current Employment. Yang: AbbVie: Current Employment.

scholarly journals Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3911-3917 ◽  
Author(s):  
Grace H. Ku ◽  
Richard H. White ◽  
Helen K. Chew ◽  
Danielle J. Harvey ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Venous Catheter ◽  
Population Based ◽  
Older Age ◽  
Myelogenous Leukemia ◽  
Vein Thrombosis ◽  
Chronic Comorbidities

Abstract A population-based cohort was used to determine the incidence and risk factors associated with development of venous thromboembolism (VTE) among Californians diagnosed with acute leukemia between 1993 to 1999. Principal outcomes were deep vein thrombosis in both the lower and upper extremities, pulmonary embolism, and mortality. Among 5394 cases with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE was 281 (5.2%). Sixty-four percent of the VTE events occurred within 3 months of AML diagnosis. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Among 2482 cases with acute lymphoblastic leukemia (ALL), the 2-year incidence of VTE in ALL was 4.5%. Risk factors for VTE were presence of a central venous catheter, older age, and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. The incidence of VTE in acute leukemia is appreciable, and is comparable with the incidence in many solid tumors.

Risk of adverse events in children completing treatment for acute lymphoblastic leukemia: St. Jude Total Therapy studies VIII, IX, and X.

1991 ◽  
Vol 9 (8) ◽  
pp. 1341-1347 ◽  
Author(s):  
C H Pui ◽  
R K Dodge ◽  
A T Look ◽  
S L George ◽  
G K Rivera ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Rank Test ◽  
Late Failure ◽  
Increased Risk ◽  
Viii And Ix ◽  
Total Therapy ◽  
Therapy Studies ◽  
The Impact

We studied the frequency, causes, and predictors of adverse events in 624 patients who had completed treatment for acute lymphoblastic leukemia (ALL) in three consecutive total therapy studies (VII, IX, and X, 1972 to 1983). Event-free survival in study X was significantly better overall than that in studies VIII and IX (P less than .0001 by the log-rank test). In study X, 75% of the patients were electively taken off therapy, compared with 54% in studies VIII and IX. However, the risks of having an adverse event during the first 5 years after completion of therapy were remarkably similar: 22% (95% confidence interval, 17% to 29%) in study X versus 24% (20% to 29%) in studies VIII and IX. Bone marrow, testicular, and CNS relapses accounted for the majority of failures in both groups (85% in study X and 92% in studies VIII and IX). Late adverse events consisted largely of hematologic relapses and the development of solid tumors. Black race (P = .001) and leukemia without an anterior mediastinal mass (P = .05) were associated with an increased risk of failure after completion of treatment in the two earlier clinical trials, whereas a lower leukemic cell DNA content (DNA index less than 1.16) was the only predictor of late treatment failure in the more recent trial (P = .019). None of the other presenting features that were examined (eg, age, leukocyte count, and sex) had value as predictors of late failure. Thus, improved treatment altered the impact of specific prognostic factors and the distribution of sites of relapse, but it did not significantly affect the risk of delayed failure.

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