Nrf2 metagene as a prognostic biomarker across all stages of colorectal cancer (CRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 557-557
Author(s):  
Sean Micheal O'Cathail ◽  
Chieh-Hsi Wu ◽  
Annabelle Lewis ◽  
Tim Maughan ◽  
Maria A Hawkins
Keyword(s):  
Colorectal Cancer ◽  
Transcription Factor ◽  
Prognostic Biomarker ◽  
Stage Iv ◽  
Stage I ◽  
Braf V600e ◽  
Candidate Gene Approach ◽  
Metastatic Focus ◽  
Stage Iv Disease ◽  
Nrf2 Expression

557 Background: Keap1/Nrf2 is an important intracellular canonical stress response pathway, with Nrf2 acting as a potent transcription factor. Lung cancer is known to acquire constitutive activation of the pathway thus promoting survival, resisting chemo-radiation and dysregulating metabolism. Mechanisms of pathway activation include methylation of KEAP1, somatic mutation and direct activation by KRAS, BRAF and MYC. Its role in CRC is unknown. Due to its role as a transcription factor, activated in many ways, we hypothesise a metagene of Nrf2 regulated genes would act as a prognostic biomarker in CRC. Methods: Using a candidate gene approach and publicly available data (GSE17536), we derived and trained a 36 gene metagene to aggregate Nrf2 pathway expression, using principal component analysis and cox proportional hazard models. GSE14333 was used for validation in stage I/II/III CRC. The first line metastatic FOCUS trial was used for validation in Stage IV disease. Results: 601 patients are included in the validation analysis. Nrf2 metagene expression is associated with worse DFS outcomes in stage I/II/III disease in Cox PH model comparisons (LRT, p = 0.00175) and worse OS in stage IV disease (LRT, p = 0.00574). On multivariate analysis, Nrf2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and Duke’s stage in stage I/II/III disease (ANOVA, p = 0.03), BRAF V600E and sidedness in stage IV disease (ANOVA, p = 0.00255). Using the median cut point, high expression has a HR 2.36 (C.I 1.27-4.38) in stage I/II/III disease and HR 1.39 (C.I 1.12-1.72) in metastatic disease. Conclusions: Nrf2 expression is a novel, robust prognostic biomarker of poor prognosis across all stages of colorectal cancer. Greater understanding of its mechanistic role could lead to targeted strategies to improve outcomes in CRC. [Table: see text]

scholarly journals A metagene of NRF2 expression is a prognostic biomarker in all stage colorectal cancer

2019 ◽  
Author(s):  
Séan M. O’Cathail ◽  
Chieh-Hsi Wu ◽  
Annabelle Lewis ◽  
Chris Holmes ◽  
Maria A Hawkins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Prognostic Biomarker ◽  
Molecular Taxonomy ◽  
Disease Free Survival ◽  
Stage Iv ◽  
Stage I ◽  
Braf V600e ◽  
Stage Iv Disease ◽  
Nrf2 Expression

ABSTRACTObjectiveNrf2 overexpression confers poor prognosis in some cancers but its role in colorectal cancer (CRC) is unknown. Due to its role as a transcription factor we hypothesise a metagene of NRF2 regulated genes could act as a prognostic biomarker in CRC.DesignUsing known NRF2 regulated genes, we defined an NRF2 metagene to represent the pathway expression using principal component analysis and Cox proportional hazard models. The NRF2 metagene was validated in four independent datasets, including the recently profiled MRC FOCUS randomised controlled trial.Results36 genes comprised the final prognostic metagene in the training set. 1,360 patients were included in the validation analyses. High NRF2 metagene expression is associated with worse disease free survival (DFS) and overall survival (OS) outcomes in stage I/II/III disease and worse OS in stage IV disease. In multivariate analyses, NRF2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and stage in stage I/II/III disease, as well as BRAF V600E mutation and sidedness in stage IV disease. NRF2 metagene expression exhibits variation within each of the Consensus Molecular Subtypes (CMS) but high expression is particularly enriched in CMS 4.ConclusionWe demonstrate in a large scale analysis that NRF2 expression is a novel biomarker of poor prognosis across all stages of colorectal cancer. Higher expression observed in CMS 4 further refines the molecular taxonomy of colorectal cancer.

The impact of colorectal cancer screening on incidence and stage IV disease in the Netherlands.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3531-3531
Author(s):  
Myrtle F Krul ◽  
Marloes AG Elferink ◽  
Niels FM Kok ◽  
Evelien Dekker ◽  
Iris Lansdorp-Vogelaar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
The Netherlands ◽  
Local Treatment ◽  
Stage Iv ◽  
Stage I ◽  
Crc Screening ◽  
Stage Distribution ◽  
Incidence And Mortality ◽  
Stage Iv Disease ◽  
The Impact

3531 Background: Population-based screening for colorectal cancer (CRC) aims to decrease incidence and mortality due to precancerous polyp removal, early detection and early treatment of CRC. In the Netherlands, phased introduction of a biennial fecal immunochemical hemoglobin test started in 2014 for individuals aged 55-75. This evaluation of the national data focuses on the initial effect of CRC screening on incidence and stage distribution and the impact on stage IV disease. Methods: All CRC patients diagnosed in the Netherlands between 2009 and 2018 were selected from the Netherlands Cancer Registry (NCR). Patients were linked to the Dutch national pathology registry (PALGA) to identify screen-detected tumors. Results: The NCR identified 137,717 CRC patients between 2009 and 2018. The incidence within screening age (55-75 yr) of all CRC stages showed an initial peak after introduction of screening in 2014, followed by a continuous decrease for all stages. CRC incidence outside the screening age did not show these explicit changes between 2009 and 2018. In 2018, the incidence of stage IV CRC within screening age was lower than the level at the start of the screening program. Stage distribution within screening age shifted towards earlier stages in the screening period (2014-2018) compared to the period before screening (2009-2012) (stage I: 31% vs. 18%, stage II: 22% vs. 26%, stage III: 29% vs. 31%, Stage IV: 18% vs. 25%, respectively). In the period 2014-2018 and within screening age, the ratio of screen-detected and symptom-detected tumors was highest in stage I (47%:53%) and lowest in stage IV (9%:91%). Screen-detected compared to symptom-detected stage IV patients diagnosed in the period 2014-2018 and within screening age had more frequently single organ metastases (74.5% vs 57.4%, p < 0.001), higher resection rate of the primary tumor (57.5% vs. 41.3%; p < 0.001) and higher local treatment rate of metastases (40.0% vs. 23.4% p < 0.001). The median overall survival of screen-detected stage IV patients was significantly longer than that of symptom-detected stage IV patients (31.0 months (95% CI: 27.7 – 34.3) vs. 15.0 months (95% CI: 14.5 – 15.5), p < 0.001). Conclusions: The initial results of the introduction of CRC screening in the Netherlands showed a favorable trend on CRC incidence and stage distribution. Screen-detected patients with stage IV disease had less extensive disease, resulting in better treatment options and improved survival.

Immunomagnetic Enrichment and Detection of Micrometastases in Colorectal Cancer: Correlation With Established Clinical Parameters

2002 ◽  
Vol 20 (21) ◽  
pp. 4338-4343 ◽  
Author(s):  
Martin R. Weihrauch ◽  
Edmund Skibowski ◽  
Thomas C. Koslowsky ◽  
Wilfried Voiss ◽  
Daniel Re ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Stage Iv ◽  
Stage I ◽  
Clinical Parameters ◽  
Uicc Stage ◽  
Detection Rates ◽  
Stage Iv Disease ◽  
Colorectal Cancer Patients

PURPOSE: Micrometastatic disease in bone marrow is of prognostic significance in colorectal cancer patients. However, detection rates of standard immunocytology are relatively low. We used magnetic activated cell sorting (MACS), a highly sensitive method, to increase detection rates and correlated the presence of cytokeratin (CK)-expressing cells with clinical parameters. PATIENTS AND METHODS: Bone marrow was obtained from 51 consecutive patients with newly diagnosed colorectal adenocarcinoma who underwent primary surgery and 18 control subjects. International Union Against Cancer (UICC) stage I disease was diagnosed in 11 patients, stage II disease was diagnosed in 14 patients, stage III disease was diagnosed in 12 patients, and stage IV disease was diagnosed in 14 patients. CK-positive cells were enriched and stained with magnetically labeled CAM 5.2 antibodies directed to CK 7 and 8. RESULTS: CK-positive cells were found in 33 (65%) patients and were absent in 18 (35%). Four of 11 (36%) patients with UICC stage I disease, nine of 14 (64%) with stage II diease, eight of 12 (67%) with stage III disease, and 12 of 14 (86%) with stage IV disease were CK-positive. Epithelial cells were more frequently found in pT3/4 (72%) than in pT1/2 (36%) tumors (P = .026), but there was no difference for lymph node status. CK-positive patients had a higher chance for elevated carcinoembryonic antigen (85% v 15%, P = NS) and CA 19-9 levels (92% v 8%, P = .019). There were no significant differences in CA 72-4, sex, age, tumor grading, or tumor localization regarding the presence of CK-positive cells. All control subjects were CK-negative. CONCLUSION: In searching for micrometastases in colorectal cancer patients, we have achieved high detection rates by using MACS. The presence of these cells correlated significantly with tumor stage, tumor extension, and the tumor marker CA 19-9.

scholarly journals NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

2019 ◽  
Author(s):  
Séan Micheal O'Cathail ◽  
Chieh-Hsi Wu ◽  
Annabelle Lewis ◽  
Chris Holmes ◽  
Maria A Hawkins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Biomarker ◽  
Molecular Subtype ◽  
Molecular Taxonomy ◽  
Disease Free Survival ◽  
Stage Iv ◽  
Principal Component ◽  
Braf V600e ◽  
Clinical Value ◽  
Consensus Molecular Subtype

Abstract Background NRF2 overexpression confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights.Methods Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway expression using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms.Results 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2–2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086–1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06–1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04–1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 expression was particularly enriched in Consensus Molecular Subtype (CMS) 4.Conclusion For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study.

Results from an institutional universal reflex testing program for MSI/MMR in colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 796-796 ◽  
Author(s):  
Aaron J Franke ◽  
Maira Gaffar ◽  
Michael Feely ◽  
Jason Scott Starr ◽  
Hiral D. Parekh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Impact Analysis ◽  
Early Stage ◽  
Stage Iv ◽  
Stage I ◽  
Braf V600e ◽  
Mismatch Repair Gene ◽  
Protein Loss ◽  
System Solution ◽  
Reflex Testing

796 Background: In colorectal cancer (CRC), clinical guidelines and immunotherapy treatment selection requires knowledge of tumor DNA mismatch repair gene deficiencies (dMMR) or accumulation of microsatellite repeats through genomic errors (MSI-H). Tumors harboring dMMR/MSI-H are found in 15- 20% of early stage CRC while the prevalence is ~5% in metastatic disease. Reflex testing of CRC to identify these important subsets has been proposed as a system-solution to improve identification. We present a large, single-institutional database of CRC reflexively profiled for MSI/MMR status at the University of Florida (UF). Methods: Beginning in 2009, stage IV CRC underwent reflex testing for MSI/MMR status. Earlier stage CRC testing began in subsequent years. For all new CRC diagnosed at UF, concurrent testing for dMMR by IHC (MLH1, PMS2, MSH2, MSH6), MSI by PCR (Promega MSI kit) and NGS is performed with appropriate positive and negative controls. IHC protein loss is confirmed by second GI pathologist. MSI is not performed if inadequate adjacent normal tissue. We conducted a retrospective analysis of all CRC samples analyzed between 2009 and 2017. Clinical data was collected from the EMR. This study was approved by the UF IRB. Results: A total of 388 new CRC cases were reflex tested (16% Stage I, 23% Stage II, 35% Stage III, and 25% Stage IV). Median age at diagnosis was 63 yrs (range: 17-98 yrs), 51% male and 79% white. Both MMR and MSI were performed in 244 (63%) tumors with 100% concordance when concurrently tested. dMMR/MSI-H incidence (20% in overall population) decreased with stage: I/II (31%), III (18%) and IV (~9%) and was associated with BRAF V600E mut in 36/76 cases (47%). Importantly, in pts < 50 yrs, 13% of stage IV patients were dMMR/MSI-H. Conclusions: Reflex testing of MMR/MSI status in CRC is feasible with concordant results. Routine testing results in identification of dMMR/MSI-H at or higher than published rates. Notable findings include the high prevalence in those with sporadic CRC and/or younger than 50 yrs. Continued impact analysis of this approach is warranted to maximize IO therapy offering.

The impact of the COVID-19 pandemic on stage at diagnosis of breast and colorectal cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6501-6501
Author(s):  
Jade Zhou ◽  
Shelly Kane ◽  
Celia Ramsey ◽  
Melody Ann Akhondzadeh ◽  
Ananya Banerjee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Cancer Screening ◽  
Late Stage ◽  
Stage Iv ◽  
Stage I ◽  
Screening Programs ◽  
Stage Distribution ◽  
Number Of Patients ◽  
The Impact

6501 Background: Effective cancer screening leads to a substantial increase in the detection of earlier stages of cancer, while decreasing the incidence of later stage cancer diagnoses. Timely screening programs are critical in reducing cancer-related mortality in both breast and colorectal cancer by detecting tumors at an early, curable stage. The COVID-19 pandemic resulted in the postponement or cancellation of many screening procedures, due to both patient fears of exposures within the healthcare system as well as the cancellation of some elective procedures. We sought to identify how the COVID-19 pandemic has impacted the incidence of early and late stage breast and colorectal cancer diagnoses at our institution. Methods: We examined staging for all patients presenting to UCSD at first presentation for a new diagnosis of malignancy or second opinion in 2019 and 2020. Treating clinicians determined the stage at presentation for all patients using an AJCC staging module (8th edition) in the electronic medical record (Epic). We compared stage distribution at presentation in 2019 vs 2020, both for cancers overall and for colorectal and breast cancer, because these cancers are frequently detected by screening. Results: Total numbers of new patient visits for malignancy were similar in 2019 and 2020 (1894 vs 1915 pts), and stage distribution for all cancer patients was similar (stage I 32% in 2019 vs 29% in 2020; stage IV 26% in both 2019 and 2020). For patients with breast cancer, we saw a lower number of patients presenting with stage I disease (64% in 2019 vs 51% in 2020) and a higher number presenting with stage IV (2% vs 6%). Similar findings were seen in colorectal cancer (stage I: 22% vs 16%; stage IV: 6% vs 18%). Conclusions: Since the COVID-19 pandemic, there has been an increase in incidence of late stage presentation of colorectal and breast cancer, corresponding with a decrease in early stage presentation of these cancers at our institution. Cancer screening is integral to cancer prevention and control, specifically in colorectal and breast cancers which are often detected by screening, and the disruption of screening services has had a significant impact on our patients. We plan to continue following these numbers closely, and will present data from the first half of 2021 as it becomes available.

Impact of BRAF mutations on prognosis and immunotherapy response in microsatellite instability/mismatch repair deficient metastatic colorectal cancer: A systematic review and meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3557-3557
Author(s):  
Robin Park ◽  
Laércio Lopes da Silva ◽  
Sunggon Lee ◽  
Anwaar Saeed
Keyword(s):  
Colorectal Cancer ◽  
Systematic Review ◽  
Braf Mutation ◽  
Meta Analysis ◽  
Stage Iv ◽  
Stage I ◽  
Prognostic Impact ◽  
Braf Mutations ◽  
Mutation Status ◽  
The Impact

3557 Background: Mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC) defines a molecular subtype with distinct clinicopathologic characteristics including an excellent response to immunotherapy. Although BRAF mutations are established as a negative prognostic marker in CRC, whether they retain their negative prognostic impact in or alter the response to immunotherapy in dMMR/MSI-H CRC remains unknown. Herein, we present a systematic review and meta-analysis of the impact of BRAF mutations on the overall survival (OS) and immune checkpoint inhibitor (ICI) response in dMMR/MSI-H CRC. Methods: Studies published from inception to 26 January 2021 were searched in PubMed, Embase, and major conference proceedings (AACR, ASCO, and ESMO). Eligible studies included the following: 1) observational studies reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients and 2) experimental studies of ICI reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients. A summary hazard ratio (HR) was calculated for OS in BRAF mutated ( BRAFmut) vs. BRAF wild type ( BRAFwt) patients (pts) with the random effects meta-analysis (REM). A summary odds ratio (OR) was calculated for objective response rate (ORR) in BRAFmut vs. BRAFwt pts treated with ICI with the REM. Results: Database search conducted according to PRISMA guidelines found 4221 studies in total. Initial screening identified 30 studies and after full-text review, 9 studies (N = 4158 pts) were included for the meta-analysis of prognosis (analysis A) and 3 studies (N = 178 pts) were included for the meta-analysis of ICI response (analysis B). The outcome measures are summarized in the table below. Analysis A showed that in stage I-IV dMMR/MSI-H CRC pts, BRAFmut was associated with worse OS than BRAFwt (HR 1.57, 1.23-1.99). The heterogeneity was low (I2 = 21%). Subgroup analysis showed no significant difference in the prognostic impact of BRAF mutation status between stage IV only and stage I-IV CRC pts. Analysis B showed no difference in ORR (OR 1.04, 0.48-2.25) between BRAFmut vs. BRAFwt dMMR/MSI-H pts who received ICI. The heterogeneity was low (I2 = 0%). Conclusions: BRAF mutations retain their negative prognostic impact in dMMR/MSI-H stage I-IV and stage IV CRC but are not associated with differential ICI response. Limitations include the following: analysis A was based on retrospective studies; also, the impact of BRAF status on the survival outcome of ICI could not be assessed due to limited number of studies.[Table: see text]

Clinical pathways implementation in a community-based oncology practice: Real-world outcomes in patients with non-small cell lung cancer segmented by disease stage at diagnosis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18719-e18719
Author(s):  
Natalie R. Dickson ◽  
Karen Beauchamp ◽  
Toni S. Perry ◽  
Ashley Roush ◽  
Deborah Goldschmidt ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Clinical Pathways ◽  
Stage Iv ◽  
Treatment Patterns ◽  
Stage I ◽  
Stage Iii ◽  
Disease Stage ◽  
Stage At Diagnosis ◽  
Small Cell Lung ◽  
Stage Iv Disease

e18719 Background: Clinical pathways have been introduced as tools to optimize cancer care delivery, but evidence of their value in the real world is limited. This retrospective study was performed to assess treatment patterns and clinical outcomes in patients with non-small cell lung cancer (NSCLC) before and after pathway implementation at Tennessee Oncology (TO). Methods: Chart data were abstracted for patients (≥18 years) diagnosed with Stage I-IV NSCLC who initiated first-line (1L) systemic treatment at a TO clinic and had follow-up for ³6 months or until death. Patients were divided into two cohorts: pre-pathways (treatment initiation 2014–2015) and post-pathways (treatment initiation 2016–2018). Patient characteristics, treatment patterns, and outcomes were described and compared across cohorts. An exploratory study endpoint was the evaluation of outcomes based on disease stage at diagnosis. Results: Among 501 patients (251 pre-pathways and 250 post-pathways), most had advanced or metastatic NSCLC at diagnosis (Stage III: 40%; Stage IV: 42%). Chemotherapy comprised almost all 1L systemic therapy used pre-pathways (Stage I/II: 100%; Stage III: 96%; Stage IV: 83%). Post-pathways, chemotherapy remained the most common 1L therapy in patients with Stage I/II (89%) and Stage III (72%) disease, but among patients with Stage IV disease, use of chemotherapy decreased (47%) and immuno-oncology (IO) therapy alone or in combination became common (45%). Median duration of 1L therapy was longer post-pathways in patients with Stage III (2.1 months vs 1.4 months pre-pathways; P < 0.01) and Stage IV disease (3.3 months vs 2.3 months pre-pathways; P < 0.01) but did not differ among Stage I/II patients. Median progression-free survival was significantly longer post-pathways in patients with Stage IV disease (7.0 months vs 4.2 months pre-pathways; P < 0.05), but not in other disease-stage subgroups. Median overall survival increased non-significantly post-pathways for all disease stage subgroups (Stage I/II: 26 months vs 20 months pre-pathways; Stage III: 26 months vs 20 months; Stage IV: 10 months vs 9 months). For each disease stage, rates of severe adverse events were similar between cohorts. Conclusions: While outcomes for patients diagnosed with Stage III/IV NSCLC were generally improved following the implementation of clinical pathways, this change coincided with a dramatic shift in available treatment options. Improvements post-pathways were mainly observed in patients diagnosed with advanced disease. Thus, differences in outcomes between pre-pathways and post-pathways cohorts in our study are more likely attributable to other evolving practices in cancer care, particularly the availability of newer, more effective treatments such as IO therapy as part of standard practice, than implementation of the clinical pathways.

Follicular lymphoma: prognostic factors for response and survival.

1986 ◽  
Vol 4 (10) ◽  
pp. 1470-1480 ◽  
Author(s):  
C J Gallagher ◽  
W M Gregory ◽  
A E Jones ◽  
A G Stansfeld ◽  
M A Richards ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Poor Prognosis ◽  
Single Agent ◽  
Stage Iv ◽  
Poor Response ◽  
Stage I ◽  
Stage Ii ◽  
Response To Treatment ◽  
Stage Iv Disease ◽  
Short Courses

One hundred forty-eight patients with newly diagnosed follicular lymphoma were treated over a 12-year period. Twenty-two patients received radiotherapy for stage I and II disease, followed by adjuvant chemotherapy in 14 patients. One hundred thirteen were treated at presentation with short courses of chemotherapy, most often with single-agent chlorambucil for bulky stage II and stages III and IV disease. Thirteen patients were managed expectantly until there was evidence of disease progression. The median survival was 9 years. Patients treated with radiotherapy for stage I and II disease had an 83% relapse-free survival, but those with bulky stage II or stages III and IV disease treated with chemotherapy pursued a remitting and relapsing course with a 70% response rate at initial and subsequent retreatments, but a median duration of remission of 4 years in stage III and 1 year in stage IV disease (P = .041). Patients were observed in relapse and retreatment was administered as appropriate, once every 33 months on average. Poor prognosis patients could be identified by a combination of the presentation characteristics: B symptoms, hepatosplenomegaly, anemia, and abnormal liver function. These factors predicted a poor response to treatment and correlated with a short survival. Histologic subgroups were not associated with differences in survival, but transformation to a diffuse high-grade lymphoma was observed in 23 of the 72 patients (32%) at risk, with a median follow-up of 6 years and 6 months, and was associated with a very poor prognosis. The present treatment strategy has proved successful for most patients with localized disease and those older patients with indolent small volume disseminated follicular lymphoma. New approaches are being investigated for the younger poor prognosis patients.

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