Aug 15, 2010 - Department of Radiation Oncology, University of Colorado Denver Comprehensive Cancer ... 50th Annual Meet
Original Article
Improved Survival in Patients With Early Stage Low-Grade Follicular Lymphoma Treated With Radiation A Surveillance, Epidemiology, and End Results Database Analysis Thomas J. Pugh, MD; Ari Ballonoff, MD; Francis Newman, MS; and Rachel Rabinovitch, MD
BACKGROUND: External beam radiation therapy (RT) is the standard treatment for stage I-II, grade 1-2 follicular lymphoma. Because of an indolent natural history, some advocate alternative management strategies, including watchful waiting for this disease. The relative improvement in outcomes for patients treated with and without RT has never been tested in randomized trials. METHODS: The Surveillance, Epidemiology, and End Results database was queried for adult patients with stage I-II, grade 1-2 follicular lymphoma diagnosed from 1973 to 2004. Retrievable patient data included age, sex, race, stage, extranodal disease, and treatment with RT within the first year after diagnosis. Actuarial overall survival (OS) and disease-specific survival (DSS) were analyzed. RESULTS: A total of 6568 patients were identified. DSS at 5, 10, 15, and 20 years in the RT group was 90%, 79%, 68%, and 63% versus 81%, 66%, 57%, and 51% in the no RT group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.55-0.68; P < .0001). OS at 5, 10, 15, and 20 years in the RT group was 81%, 62%, 45%, and 35% versus 71%, 48%, 34%, and 23% in patients not receiving RT (HR, 0.68; 95% CI, 0.63-0.73; P < .0001). On multivariate analysis, upfront RT remained independently associated with improved DSS (P < .0001, Cox HR, 0.65; 95% CI, 0.57-0.72) and OS (P < .0001; Cox HR, 0.73; 95% CI, 0.67-0.79). Lymphoma was the most common cause of death (52%). Only 34% of patients received upfront RT. CONCLUSIONS: Upfront RT was associated with improved DSS and OS compared with alternate management approaches, a benefit that persisted over time. This benefit suggests that watchful waiting with administration of salvage therapies on progression/relapse do not compensate for inadequate initial definitive treatment. Although it is the standard of care for this disease, RT for early stage low-grade follicular lymphoma is greatly underused in the US population; increased use of upfront RT could prevent thousands of deaths from lymphoma in these patients. Cancer 2010;116:3843–51. C 2010 American Cancer Society. V KEYWORDS: follicular lymphoma, radiation therapy, indolent non-Hodgkin lymphoma, watchful waiting.
In 2008, an estimated 66,120 new cases of non-Hodgkin lymphoma (NHL) were diagnosed in the United States.1 Follic-
ular B-cell lymphoma represents 30% of these cases, making it the most commonly diagnosed indolent subtype.2 Whereas the majority of patients present with advanced disease (stage III-IV), approximately 30% of newly diagnosed cases of follicular lymphoma are early stage (stage I-II), or approximately 5950 patients annually in the United States.2,3 Unlike advanced follicular lymphoma, for which there is no established curative therapy, early stage disease is potentially curable with regional or involved field radiation therapy (RT), long considered the standard treatment for patients with stage I-II disease. RT results in excellent complete response rates and long-term local control rates of >90%, documented in numerous single institution series.4-10 Out-of-field recurrences are common, however; approximately half of all patients treated with RT alone will relapse within 10 years of treatment.4-8 For the half of patients who remain disease-free
Corresponding author: Rachel Rabinovitch, MD, Department of Radiation Oncology, University of Colorado Health Sciences Center, 1665 Aurora Court, Suite 1032, P.O. Box 6510, Mail Stop F-706, Aurora, CO 80045-0508; Fax: (720) 848-0222;
[email protected] Department of Radiation Oncology, University of Colorado Denver Comprehensive Cancer Center, Aurora, Colorado This article is the original work of the authors and was presented at the 50th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, Boston, Massachusetts, September 22, 2008. We thank Jason Zhang for his assistance in data analysis. DOI: 10.1002/cncr.25149, Received: August 19, 2009; Revised: November 1, 2009; Accepted: November 10, 2009, Published online May 17, 2010 in Wiley InterScience (www.interscience.wiley.com)
Cancer
August 15, 2010
3843
Original Article
for 10 years, first recurrences thereafter are infrequent, demonstrating that treated patients with stage I-II follicular lymphoma, in contrast to those patients presenting with advanced disease, can be cured by definitive RT.4-5,11 Despite the long-documented curative potential of definitive RT for early stage disease, a contrasting approach of no therapy (watchful waiting) has also been proposed as reasonable, given the indolent natural history of the disease and the high likelihood of treatment failure.9,12,13 The relative outcome differences between a watchful waiting approach and initial treatment with RT have never been tested in a prospective randomized trial for patients with early stage follicular lymphoma. We used the Surveillance, Epidemiology, and End Results (SEER) database to determine whether there are differences in disease-specific survival (DSS) or overall survival (OS) in patients treated with upfront RT compared with an alternative approach such as observation in patients with stage I-II, grade 1-2 follicular lymphoma. Patterns of RT utilization over time were also evaluated.
METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results (SEER) Program The SEER Program of the National Cancer Institute (NCI) collects and publishes information from population-based registries covering approximately 26% of the US population.14 SEER routinely collects data regarding patient demographics, morphology, stage at diagnosis, first course of treatment, survival, and cause of death. Data from these registries are deidentified and electronically submitted to the NCI on a biannual basis. The data are subsequently made available to the general public. Study Population The SEER database (SEER 17 November 2006 data submission [1973-2004]) was queried for adult patients (18 years old) with microscopically confirmed stage I, IE, II, or IIE, grade 1 (follicular small cleaved cell) or grade 2 (follicular mixed) lymphoma diagnosed from 1973 to 2004 for whom outcome information was available. SEER*Stat 6.3.5 software was used to perform all queries. Stage designation was based on the SEER Program Coding and Staging Manual 2007,15 which conforms to the Ann Arbor staging system and the American Joint Committee on Cancer sixth edition16 staging for NHL. Patients coded as either receiving external beam
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radiation or not receiving radiation were included. Patients coded as not receiving radiation were defined by the following conditions: 1) there is no information in the patient’s medical record about radiation, 2) multiple treatment options were offered and the patient selected treatment that did not include radiation, 3) the patient elected to pursue no treatment after the discussion of radiation treatment, and 4) a watchful waiting approach was the chosen treatment plan. Patients coded as receiving radiation are defined as patients who received external beam radiation to cancer tissue. The SEER database records first course of therapy data, which is defined as a treatment plan initiated within 12 months of diagnosis. Second-line therapies, including those initiated after a watchful waiting approach, are not recorded. Therefore, patients coded as receiving RT included only those patients who received radiation therapy as initial treatment soon after diagnosis, hereafter referred to as upfront RT. Data regarding patient age, sex, race, stage, grade, and extranodal disease were retrieved for all identified patients. Known prognostic factors for NHL, such as presenting lactate dehydrogenase (LDH), hemoglobin, and total number of involved lymph node regions,17 are not recorded in SEER. Data were retrieved by 3-month intervals for a maximum follow-up of 360 months (30 years). Patients with multiple primary cancers, unknown age, or unknown ethnicity were excluded from analysis. Endpoints and Statistical Analysis DSS was determined from the time of diagnosis to the time of death from NHL. Death from lymphoma of any histology was chosen to account for patients initially diagnosed with early stage follicular lymphoma who experienced pathologic transformation to more aggressive NHL subtypes. OS was determined from the time of diagnosis to the time of death from any cause. Comparisons of characteristics between patients treated with upfront RT and those not receiving RT were made using the chi-square test. Actuarial DSS and OS analyses were illustrated using the Kaplan-Meier method18 and compared using the logrank test.19 Five-, 10-, 15-, and 20-year actuarial rates of DSS and OS are reported. Chi-square analyses between retrievable variables and treatment groups were conducted. Covariates analyzed included age (
