Radiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National Comprehensive Cancer Network lymphoma outcomes project.

BACKGROUND: The role of consolidation radiotherapy was examined for patients with diffuse large B-cell lymphoma who were treated at institutions of the National Comprehensive Cancer Network during the rituximab era. METHODS: Failure-free survival (FFS) and overall survival (OS) were analyzed in terms of patient and treatment characteristics. Potential associations were investigated with univariate and multivariate survival analysis and matched pair analysis. RESULTS: There were 841 patients, and most (710 or 84%) received 6 to 8 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); 293 (35%) received consolidation radiation therapy (RT). Failure occurred for 181 patients: 126 patients (70%) who did not receive RT and 55 patients (30%) who did. At 5 years, both OS and FFS rates were better for patients who had received RT versus those who did not (OS, 91% vs 83% [P = .01]; FFS, 83% vs 76% [P = .05]). A matched pair analysis (217 pairs matched by age, stage, International Prognostic Index [IPI] score, B symptoms, disease bulk, and response to chemotherapy) showed that the receipt of RT improved OS (hazard ratio [HR], 0.53 [P = .07]) and FFS (HR, 0.77 [P = .34]) for patients with stage III/IV disease, but too few events took place among those with stage I/II disease for meaningful comparisons (HR for OS, 0.94 [P = .89]; HR for FFS, 1.81 [P = .15]). A multivariate analysis suggested that the IPI score and the response to chemotherapy had the greatest influence on outcomes. CONCLUSIONS: There was a trend of higher OS and FFS rates for patients who had received consolidation RT after R-CHOP (especially for patients with stage III/IV disease), but the difference did not reach statistical significance.

Comparison of referring and final pathology for patients with T-cell lymphoma in the National Comprehensive Cancer Network.

BACKGROUND: T-cell lymphomas (TCLs) are uncommon in the United States. The accurate diagnosis of TCL is challenging and requires morphologic interpretation, immunophenotyping, and molecular techniques. The authors compared pathologic diagnoses at referring centers with diagnoses from expert hematopathology review to determine concordance rates and to characterize the usefulness of second-opinion pathology review for TCL. METHODS: Patients in the National Comprehensive Cancer Network non-Hodgkin lymphoma database with peripheral TCL, not otherwise specified (PTCL-NOS), angioimmunoblastic TCL (AITL), and anaplastic lymphoma kinase (ALK)-positive and ALK-negative anaplastic large cell lymphoma (ALCL) were eligible if they had prior tissue specimens examined at a referring institution. Pathologic concordance was evaluated using available pathology and diagnostic testing reports and provider progress notes. The etiology of discordance and the potential impact on treatment were examined. RESULTS: Among 131 eligible patients, 57 (44%) had concordant results, totaling 64% of the 89 patients who were referred with a final diagnosis. Thirty-two patients (24%) had discordant results, representing 36% of those who were referred with a final diagnosis. The rates of discordance among patients with of PTCL-NOS, AITL, ALK-negative ALCL, and ALK-positive ALCL were 19%, 33%, 34%, and 6%, respectively. In 14 patients (44% of discordant results), pathologic reclassification could have resulted in a different therapeutic strategy. Forty-two patients (32%) were referred for classification with a provisional diagnosis. CONCLUSIONS: In a large cohort of patients with TCL who were referred to National Comprehensive Cancer Network centers, the likelihood of a concordant final diagnosis at a referring institution was low. As current and future therapies target TCL subsets, these data suggest that patients with suspected TCLs would benefit from evaluation by an expert hematopathologist.

An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era.

The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with aggressive non-Hodgkin lymphoma (NHL) for the past 20 years. Using raw clinical data from the National Comprehensive Cancer Network (NCCN) database collected during the rituximab era, we built an enhanced IPI with the goal of improving risk stratification. Clinical features from 1650 adults with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed from 2000-2010 at 7 NCCN cancer centers were assessed for their prognostic significance, with statistical efforts to further refine the categorization of age and normalized LDH. Five predictors (age, lactate dehydrogenase (LDH), sites of involvement, Ann Arbor stage, ECOG performance status) were identified and a maximum of 8 points assigned. Four risk groups were formed: low (0-1), low-intermediate (2-3), high-intermediate (4-5), and high (6-8). Compared with the IPI, the NCCN-IPI better discriminated low- and high-risk subgroups (5-year overall survival [OS]: 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n = 1138), it also demonstrated enhanced discrimination for both low- and high-risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era.

Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma outcomes project.

BACKGROUND: Stem cell transplant (SCT)-related outcomes and prognostication for relapsed/refractory follicular lymphoma (FL) are not well-defined in the post-rituximab era. METHODS: Through the National Comprehensive Cancer Network (NCCN) lymphoma outcomes study, 184 patients with relapsed/refractory FL who underwent autologous SCT (autoSCT) or allogenic SCT (alloSCT) following disease relapse after prior rituximab-based therapy were examined. RESULTS: Patients who underwent autoSCT (N=136) were older compared with patients who underwent alloSCT (N=48) (54 versus 51 years, respectively, P=.01) and more frequently had grade 3 FL (35% versus 8%, respectively, P=.006). Patients who underwent alloSCT received more prior therapies (4 versus 3, respectively, P<.0001) and more often had resistant disease at SCT (19% versus 6%, respectively, P=.008). Cumulative 100-day nonrelapse mortality (NRM) for autoSCT and alloSCT were 1% and 6%, respectively (P<.0001), whereas 3-year NRM rates were 3% versus 24%, respectively (P<.0001). For autoSCT and alloSCT, cumulative rates of relapse, progression, and/or transformation were 32% versus 16%, respectively (P=.03), whereas 3-year overall survival rates were 87% versus 61% (P<.0001); there were no differences in failure-free survival. AlloSCT was associated with increased risk of death on multivariate analysis (hazard ratio=2.77, 95% confidence interval=1.46-5.26, P=.002). This finding persisted on propensity scoring/matching. Multivariate analysis for autoSCT patients identified age>60 years and>3 prior therapies as adverse factors. Furthermore, a survival model was created for the autoSCT cohort based on number of factors present (0, 1, 2); 3-year failure-free survival was 72%, 47%, and 20%, respectively (P=.0003), and 3-year overall survival was 96%, 82%, and 62%, respectively (P<.0001). CONCLUSIONS: AutoSCT remains an effective therapy for patients with FL. For alloSCT, continued strategies to reduce NRM are needed.

Patterns of use of 18-fluoro-2-deoxy-D-glucose positron emission tomography for initial staging of grade 1-2 follicular lymphoma and its impact on initial treatment strategy in the National Comprehensive Cancer Network Non-Hodgkin Lymphoma Outcomes database.

We describe the patterns of use of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the initial staging of patients with newly diagnosed grade 1-2 follicular lymphoma (FL) and its potential impact on treatment. Data were obtained from the National Comprehensive Cancer Network Non-Hodgkin Lymphoma Outcomes database. Patients who presented between 1 January 2001 and 30 September 2009 with newly diagnosed grade 1-2 FL, with at least 6 months of follow-up, were included. We identified 953 eligible patients and 532 (56%) underwent FDG-PET as part of initial staging. Among patients who underwent FDG-PET for initial staging, 438 (82%) received early treatment compared to 259 (61.5%) of those staged without FDG-PET (p < 0.0001). Of all patients with stage I FL (n = 100), 47% were treated with radiotherapy (RT) alone, and the choice of initial treatment strategy for stage I FL did not vary significantly by use of FDG-PET (p = 0.22). The use of FDG-PET for staging of FL is widespread and is associated with a greater proportion of patients receiving early therapy. Given the widespread use and high cost of FDG-PET, its clinical utility in stage I FL should be further evaluated.

Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database.

Few randomized trials have compared therapies in mantle cell lymphoma (MCL), and the role of aggressive induction is unclear. The National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma (NHL) Database, a prospective cohort study collecting clinical, treatment, and outcome data at 7 NCCN centers, provides a unique opportunity to compare the effectiveness of initial therapies in MCL. Patients younger than 65 diagnosed between 2000 and 2008 were included if they received RHCVAD (rituximab fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone), RCHOP+HDT/ASCR (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone + high-dose therapy/autologous stem cell rescue), RHCVAD+HDT/ASCR, or RCHOP. Clinical parameters were similar for patients treated with RHCVAD (n = 83, 50%), RCHOP+HDT/ASCR (n = 34, 20%), RCHOP (n = 29, 17%), or RHCVAD+HDT/ASCR (n = 21, 13%). Overall, 70 (42%) of the 167 patients progressed and 25 (15%) expired with a median follow-up of 33 months. There was no difference in progression-free survival (PFS) between aggressive regimens (P > .57), which all demonstrated superior PFS compared with RCHOP (P < .004). There was no difference in overall survival (OS) between the RHCVAD and RCHOP+HDT/ASCR (P = .98). RCHOP was inferior to RHCVAD and RCHOP+HDT/ASCR, which had similar PFS and OS. Despite aggressive regimens, the median PFS was 3 to 4 years. Future trials should focus on novel agents rather than comparing current approaches.

High rates of surveillance imaging for treated diffuse large B-cell lymphoma: findings from a large national database.

We aimed to characterize surveillance imaging and circumstances of relapse for patients with diffuse large B-cell lymphoma (DLBCL) in the National Comprehensive Cancer Network Non-Hodgkin's Lymphoma Outcomes Database, a prospective cohort study collecting clinical and outcome data at seven comprehensive cancer centers. Patients presenting with newly diagnosed DLBCL in remission ≥3 months after initial therapy and who had accrued 2 years of follow-up were eligible for analysis (n = 625). The median number of imaging studies was 2.5/year (institutional range 0.5-3.5, p < 0.0001); 48.4% received only dedicated computed tomography (CT) scans, 14.6% received only positron emission tomography (PET)-inclusive modalities, 32.8% received a combination and 4.2% received no imaging. Among all eligible patients, 50 (8.0%) experienced relapse, and approximately one-quarter of subclinical relapses were detected through routine imaging. Our results suggest that despite limited data regarding its effect on outcomes, surveillance imaging is prevalent in DLBCL, and a majority of patients receive PET scans at some point during follow-up.

Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era: findings from a large national database.

BACKGROUND: Little is known about the utility of central nervous system (CNS) prophylaxis for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. The objective of this study was to characterize patterns of CNS prophylaxis for patients who received combined rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy using the National Comprehensive Cancer Network Non-Hodgkin Lymphoma Outcomes Database, a prospective cohort study that collects clinical and outcomes data for patients at 7 participating centers. METHODS: Patients who were eligible for this analysis presented with newly diagnosed DLBCL between January 2001 and July 2008, had no evidence of baseline CNS disease, and had received R-CHOP within 180 days of diagnosis. The authors assessed incidence and covariates of prophylaxis, prophylaxis modality, and, using propensity score analysis, outcomes such as overall survival. RESULTS: Of 989 eligible patients, 117 received CNS prophylaxis (11.8%), most intrathecally (71.8%). Involvement of bone marrow, other high-risk site, >1 extranodal site, higher International Prognostic Index score, and higher stage were associated individually with the receipt of prophylaxis (all P < .0001). At a median follow-up of 2.5 years, there were 20 CNS recurrences (2% [95% confidence interval, 1.1%-2.9%]) among all patients, and overall survival was not affected by prophylaxis. CONCLUSIONS: Given the overall low rate of CNS recurrence and lack of prophylaxis-associated survival benefit, the current data called into question the practice of CNS prophylaxis in the rituximab era.

Reliability of staging, prognosis, and comorbidity data collection in the National Comprehensive Cancer Network (NCCN) non-Hodgkin lymphoma (NHL) multicenter outcomes database.

BACKGROUND: Clinical trials and outcomes studies often rely on nonphysicians to abstract complex data from medical records, but the reliability of these data are rarely assessed. METHODS: We used standardized charts of patients with non-Hodgkin lymphoma to assess the reliability of key clinical data elements abstracted by 6 clinical research associates (CRAs), 3 project staff, and 3 medical oncologists. We assessed reliability on 5 variables: MD-reported and rater-determined disease stage; International Prognostic Index (IPI; low-low intermediate, intermediate-high, high); Charlson comorbidity index score; and presence of any item from the Charlson index. Intraclass correlation coefficients (ICCs) of 0-0.20 were indicative of "slight", 0.21-0.40 indicated "fair", 0.41-0.60 indicated "moderate", 0.61-0.80 "substantial" and >0.80 "almost perfect" reliability. RESULTS: By outcome, the ICC (95% confidence interval) values for MD-reported stage, rater-determined stage, and IPI were 0.86 (0.67, 0.94), 0.82 (0.59, 0.93), and 0.80 (0.55, 0.92), respectively. In contrast, the ICC (95% confidence interval) of the Charlson score, or presence of any Charlson comorbidity item was 0.47 (0.03, 0.75) and 0.61 (0.23, 0.83), respectively. Reliability varied by rater group; no rater group was consistently more reliable than others. CONCLUSIONS: Trained CRAs abstracted key clinical variables with a very high degree of reliability, and performed at a level similar to study trainers and oncologists. Elements of the Charlson index were less reliable than other data types, possibly because of inherent ambiguity in the index itself.

Comparison of referring and final pathology for patients with non-Hodgkin's lymphoma in the National Comprehensive Cancer Network.

PURPOSE: Before the implementation of the WHO lymphoma classification system, disagreement about pathologic diagnosis was common. We sought to estimate the impact of expert review in the modern era by comparing final pathologic diagnoses at five comprehensive cancer centers with diagnoses assigned at referring centers. PATIENTS AND METHODS: Patients in the National Comprehensive Cancer Network (NCCN) non-Hodgkin's lymphoma (NHL) database with a documented pathologic diagnosis before presentation and a final pathologic diagnosis of any of five common B-cell NHLs were eligible. After central review of discordant cases, we estimated the rate of pathologic concordance, then investigated the etiology of discordance as well its potential impact on prognosis and treatment. RESULTS: The overall pathologic discordance rate was 6% (43 of 731 patients; 95% CI, 4% to 8%). For the majority of cases in which the referring diagnosis was apparently final, no additional studies were conducted at the NCCN center, and the change in diagnosis reflected a different interpretation of existing data. Concordance was highest for diffuse large B-cell lymphoma (95%) and follicular lymphoma (FL; grades 1, 2, and not otherwise specified, 95%) and lowest for grade 3 FL (88%). Of the 43 pathologically discordant cases, 81% (35 patients) might have experienced a change in treatment as a result of the pathologic reclassification. CONCLUSION: In the era of the WHO lymphoma classification system, the majority of common B-cell NHLs diagnosed in the community were unchanged by second opinion review by an expert hematopathologist. However, for one patient in 20, there was a discordance in diagnosis that could have altered therapy.