Improvement In Disease-specific Survival Research Articles

We aim to evaluate the role of elective neck dissection (END) and adjuvant radiation on survival in N0 high-grade mucoepidermoid carcinoma (MEC). Retrospective cohort study. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. All patients diagnosed with high-grade MEC with node-negative disease (N0) from 2004 to 2018 were included. Demographic, clinicopathologic, treatment, and outcomes were analyzed. Kaplan-Meier survival curves were used to evaluate 5-year disease-specific survival (DSS) and 5-year overall survival (OS). Multivariate Cox regression analysis was used to control for confounders. A total of 310 patients with high-grade MEC and N0 (clinical and pathologic) disease were identified. The parotid was the most common primary site (266, 86%). Of included patients, 133 (42.9%) were T3-T4 tumors and 212 (68%) received adjuvant radiation. END was performed on 223 (71.9%) of cases. END in T3-T4 high-grade MEC led to significant improvements in DSS (74.3% vs 34.0%, P < .01) and OS (55.2% vs 20.5%, P < .01) as compared to no END. Subanalysis shows that in patients who received neck dissections and were pathologic N0, adjuvant radiation had no impact on DSS (84.0% vs 72.1%, P = .45) and OS (52.1% vs 55.8%, P = .91). Benefits persisted when controlling for confounders using multivariate Cox proportional regression. Patients with T3-T4 high-grade MEC who underwent END and found to be pathologically node-negative (pN0) had significantly improved 5-year DSS and 5-year OS than patients who were cN0 and did not undergo END. Importantly, although 68% of patients received adjuvant radiation, we show no benefit of this treatment modality on outcomes in pN0 high-grade MEC.

There is currently an urgent need to identify factors predictive of immunogenicity in colorectal cancer (CRC). Mucinous CRC is a distinct histological subtype of CRC, associated with a poor response to chemotherapy. Recent evidence suggests the commensal facultative anaerobe Fusobacterium may be especially prevalent in mucinous CRC. The objectives of this study were to assess the association of Fusobacterium abundance with immune cell composition and prognosis in mucinous CRC. Our study included two independent colorectal cancer patient cohorts, The Cancer Genome Atlas (TCGA) cohort, and a cohort of rectal cancers from the Beaumont RCSI Cancer Centre (BRCC). Multiplexed immunofluorescence staining of a tumour microarray (TMA) from the BRCC cohort was undertaken using Cell DIVE technology. Our cohorts included 87 cases (13.3%) of mucinous and 565 cases (86.7%) of non-mucinous CRC. Mucinous CRC in the TCGA dataset was associated with an increased proportion of CD8 + lymphocytes (p = 0.018), regulatory T-cells (p = 0.001) and M2 macrophages (p = 0.001). In the BRCC cohort, mucinous RC was associated with enhanced CD8 + lymphocyte (p = 0.022), regulatory T-cell (p = 0.047), and B-cell (p = 0.025) counts. High Fusobacterium abundance was associated with an increased proportion of CD4 + lymphocytes (p = 0.031) and M1 macrophages (p = 0.006), whilst M2 macrophages (p = 0.043) were under-represented in this cohort. Patients with increased Fusobacterium relative abundance in our mucinous CRC TCGA cohort tended to have better clinical outcomes (DSS: likelihood ratio p = 0.04, logrank p = 0.052). Fusobacterium abundance may be associated with improved outcomes in mucinous CRC, possibly due to a modulatory effect on the host immune response.Key messages• Increased Fusobacterium relative abundance was not found to be associated with microsatellite instability in mucinous CRC.• Increased Fusobacterium relative abundance was associated with an M2/M1 macrophage switch, which is especially significant in mucinous CRC, where M2 macrophages are overexpressed.• Increased Fusobacterium relative abundance was associated with a significant improvement in disease specific survival in mucinous CRC.• Our findings were validated at a protein level within our own in house mucinous and non-mucinous rectal cancer cohorts.

Objective: Differentiated thyroid cancer (DTC) is associated with an excellent prognosis, but patients with distant metastatic DTC have a 10-year disease-specific survival (DSS) of just 50%. The incidence of distant metastatic DTC has steadily increased in the United States since the 1980s. The aim of this study was to examine trends in survival and treatment for patients with distant metastatic DTC. Methods: In this population-based, retrospective cohort study, patients with distant metastatic DTC were identified from the Surveillance, Epidemiology, and End Results-13 cancer registry program. Multivariable logistic and Cox regression analyses were used to examine factors associated with DSS and management. Annual percentage changes in treatment patterns were calculated using log-linear regression. Results: During 1992-2018, 1991 patients (69.7% white, 58.0% female, 47.5% aged ≥65 years) were diagnosed with distant metastatic DTC. Papillary thyroid cancer was the most common histological type (74.5%). While the 10-year DSS for overall DTC increased over time (95.4% for patients diagnosed in 1992-1998, 96.6% in 1999-2008, and 97.3% in 2009-2018; p < 0.01), 10-year DSS for DTC with distant metastases did not change (50.2%, 47.3%, and 52.4%, respectively; p = 0.48). Ten-year DSS rates were reduced for patients aged ≥65 years (28.1%), patients undergoing nonsurgical treatment with external beam radiation therapy and/or systemic therapy (6.0%), and patients undergoing no/unknown treatment (32.8%). On multivariable analysis, oncocytic carcinoma, age 65-79 and ≥80 years, male sex, node-positive disease, larger tumor size, nonsurgical treatment, and no/unknown treatment were associated with increased risk of thyroid cancer death. Between 1992 and 2018, the rate of nonsurgical treatment increased, on average, 1.3% per year (1992-1998: 22.9% vs. 2009-2018: 25.6%; p = 0.03), and the rate of patients receiving no/unknown treatment increased 1.9% per year (1992-1998: 11.3% vs. 2009-2018: 15.6%; p = 0.01). Patients aged 65-79 and ≥80 years were more likely than younger patients to receive nonsurgical management or no/unknown treatment. Conclusion: Patients diagnosed with distant metastatic DTC have experienced no improvement in DSS over the past three decades. An increasing proportion of patients diagnosed with distant metastatic DTC are receiving nonsurgical treatment or no/unknown treatment over time; the proportion was highest among the oldest patients.

Breast cancer (BC) is a heterogeneous group of neoplasms originated via epithelial cells, which line the milk ducts. Breast tumor heterogeneity is matter of discussion and research in histology and clinical outcomes for a long span of time, and these differences pave the paths to disease classification. Out of the few tumor types which successfully use the molecular classification for the design of individualized therapies, BC is one of them. These types of tumors lead to significant improvements in disease-specific survival. The classification based on comprehensive gene expression profiling, divides the breast tumors into at least three broad subtypes: luminal, human epidermal growth factor receptor 2+, and basal like. In both developed and under development countries, BC is the most common type of cancer in females. To be precise, one out of ten cancers identified each year in female is BC. Moreover, it’s a worldwide major cause of deaths occurring among women due to cancer. According to the WHO's 2008 GLOBOCAN, BC is the most frequent cancer in women, affecting an estimated 1.38 million people [1]. Among the Asian population, Pakistan reports the highest incidence of BC i.e., 19.33% [2]. The established risk factors of BC are linked to oestrogens. Risks are increased by several factors including early menarche, late menopause, and obesity in postmenopausal women. Increasing concentrations of endogenous oestradiol also increased risk of BC. Childbearing somehow reduces risk, with a greater protection for early first birth and a larger number of births; illustrated as breastfeeding probably has a protective effect. Moreover, the oral contraceptives and hormonal therapy for menopause both tend to cause a little increase in breast-cancer risk, which appears to diminish once use stops. Alcohol also increases risk, whereas physical activity probably declines. Mutations in certain genes like BRCA1 and BRCA2 also massively enhance the risk to BC, but these certainly account for a minority of cases. Of all the key challenges that occur during BC research, mapping of pathways that give rise to metastasis is one of them. Recent studies have done analysis of gene expression profiles to identify markers which correlate with metastasis. Clinical and pathological risk factors, such as patient age, tumor size, and steroid receptor status, are commonly used to assess the likelihood of metastasis development. In Pakistan socioeconomic factors are to blame for the poor health of women especially in rural communities. One in nine Pakistani women have had BC at some point in their lives. There are no screening facilities for the diagnosis of different types of cancer, and a lot of women lose their lives to BC each year. Most Pakistani women are impoverished and unable to pay for costly screening exams. Talking about BC is considered a taboo and women don’t talk about it due to shyness. Campaigns on awareness of BC are needed country wide specially targeting rural areas. Women who are above 40 should be suggested to get mammogram time to time. Women should be advised to do Breast self-examination (BSE) once a month for detection of cancer at an early stage.

Abstract Background: Murine tumor models show that cold stress increases tumor growth rate by norepinephrine release, altering the tumor microenvironment (TME). Tumor-bearing mice when housed at standard temperature of 22°Celsius (°C) exhibited a pro-tumorigenic TME (with fewer CD8+ T Cells and an increase in immunosuppressive cells) than mice housed at 30°C. The incidence of cancer has been shown to be higher in colder climates. Achievement of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early stage breast cancer (BC) is associated with improved overall survival (OS) and disease specific survival (DSS). Based on these findings, we hypothesized that pCR would be increased while mortality would be decreased in BC patients (pts) living in warmer climates. Methods: A retrospective, population-based analysis was conducted utilizing the Surveillance, Epidemiology and End Results (SEER) from 1996-2017 and National Cancer Database (NCDB) from 2004-2018, and average annual temperature (AAT) data from the National Centers for Environmental Information. Cut-offs for AAT were obtained using the Youden’s index (for pCR) and maximum log-rank (for OS and DSS) methods. Associations between AAT and both pCR and OS/DSS were evaluated using logistic and Cox regression models, respectively, adjusting for confounders (age, race, education, insurance, BC subtype, treatment). Results: A total of 1,209,332 and 270,496 stage I-III BC pts in the US were analyzed using NCDB and SEER, respectively. In NCDB, 52.1% were hormone receptor (HR)+/HER2-, 8.6% triple negative (TNBC), 7.2% HR+/HER2+ and 3.1% HR-/HER2+ and 29% unknown. 37.7% received chemotherapy, 62.6% radiation and 94.3% surgery. 10.2% pts received NAC and 19.5% (19,021/97,669) achieved pCR. The AAT ranged from 44.7°Fahrenheit (°F) to 62.3°F with median 50.9°F. When adjusting for covariates, pts in regions with AAT &gt; 60.9°F, had a greater chance of achieving pCR compared to AAT &lt; 60.9°F with odds ratio (OR) 1.12 (95% CI 1.07-1.18), p &lt;0.001. This was consistent in the TNBC and HR-/HER2+ subgroups with OR 1.14 (95% CI 1.07-1.23) and 1.15 (95% CI 1.04-1.27), respectively. There was a 2% improvement in OS with every 5°F increment, HR 0.98 (95% CI 0.97-0.99), p &lt; 0.001. In SEER, 22.4% were HR+/HER2-, 4.4% TNBC, 4.0% HR+/HER2+, 1.8% HR-/HER2+ and 68.5% unknown. 43.4% received chemotherapy, 49.7% radiation and 94.2% surgery. The AAT ranged from 33.6°F to 67.3°F with median 57.4°F. There was a 3% improvement in OS [HR 0.97 (95% CI 0.968-0.977), p &lt; 0.001] and 2.5% improvement in DSS [HR 0.98 (95% CI 0.968-0.982), p&lt;0.001] with every 5°F increment. Conclusions: Higher environmental temperatures are associated with significant improvements in rate of pCR, OS and DSS in Stage I-III BC pts. Research focusing on underlying mechanisms and therapeutic strategies to abrogate this disparity is warranted. Citation Format: Ashish Gupta, Kristopher Attwood, Kush Gupta, Asha Gandhi, Stephen Edge, Kazuaki Takabe, Elizabeth Repasky, Shipra Gandhi. Favorable impact of higher environmental temperature on clinical outcomes in breast cancer - Does residence matter? A NCDB and SEER population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 31.

This study aims to reveal changes in the incidence and prognosis of patients with tonsillar lymphoma on a population level. The incidence, clinicopathological, and prognostic data of tonsillar lymphoma patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The Join-point software and R packages were utilized to analyze the annual percentage changes (APCs) and survival outcomes. The incidence of primary tonsillar lymphoma increased from 0.1204 per 100,000 person-years (95% CI, 0.0680-0.1962) in 1983 to 0.2158 (95% CI, 0.1675-0.2740) in 2015 with an APC of 1.20. When classified by decades, both cancer-specific survival (CSS) and overall survival (OS) improved with time. The 2006-2015 decade showed the highest rate of CSS and OS. Nevertheless, for disease-specific survival (DSS), the difference was not significant between 1996-2005 and 2006-2015 decades. The main cause of mortality among this cohort was heart diseases. Three nomograms were constructed to predict OS, CSS, and DSS for patients with primary tonsillar lymphoma, respectively. Histological subtype made the most contribution to poor prognosis in OS-predicting and CSS-predicting nomograms. While, for DSS, age at diagnosis made the most contribution to poor outcomes. The incidence of primary tonsillar lymphoma has increased in the past decades. The OS and CSS rates of tonsillar lymphoma improved continuously, while there was no significant improvement in DSS in the past decades. These changes indicated an improved management of tonsillar lymphoma with newer therapeutic agents and the need of multi-disciplinary treatments to offset the future burden of noncancer diseases.

Abstract Background: Emerging data from basic research using animal models shows that cold stress increases tumor growth rate by altering the tumor microenvironment (TME). 4T1 tumor-bearing mice (murine breast cancer model) when housed at standard housing temperature of 22oCelsius (°C) exhibited a pro-tumor immune microenvironment with lower CD8+ T-cells and higher immunosuppressive myeloid derived suppressor cells and regulatory T-cells than mice that were kept at thermoneutral temperature of 30oC. Analysis of large genomic databases where cold stress was quantified by a thermogenesis score showed that triple negative breast cancer with high thermogenesis score was associated with worse disease specific survival (DSS) and a pro-tumor immune microenvironment. Additionally, it was observed that females in the United States (US) are susceptible to developing cancers if they live in regions with colder climates versus warmer climates. Based on these findings, we hypothesized that breast cancer mortality increases in patients living in colder versus warmer climates in the US and utilized Surveillance, Epidemiology, and End Results (SEER) database to investigate this hypothesis. Methods: We conducted a retrospective, population-based analysis utilizing the SEER database and analyzed DSS and overall survival (OS) with respect to the average annual temperature (AAT) of the county in which a patient with breast cancer was diagnosed in, from years 1996-2017. Data on AAT was obtained from the National Centers for Environmental Information https://www.ncdc.noaa.gov/cag/county/mapping/110/tavg/202005/1/value. Multivariate (MV) models were conducted to compare the associations between AJCC stages and demographic/tumor characteristics: age, race, marital status, insurance, rural or urban area, receptor status, and type of treatment received. All associations were compared using Fisher’s Exact and Kruskal-Wallis Tests respectively. All analysis was conducted in RStudio v4.02 at a significance level of 0.05. Results: A total of 284,100 (270,496 stage I-III and 13,604 stage IV) breast cancer patients residing in 3,136 counties in the US were analyzed using the SEER database. Of all patients, 77.9% were White, 62.6% were &gt; 55 years old, 54.9% were married, 54.2% were insured and 87.9% patients resided in urban area. Biomarker data was available for 32.5% patients with 22.4% hormone receptor (HR)-positive/HER2-negative, 4.4% triple negative, 4.0% HR-positive/HER2-positive and 1.8% HR-negative/HER2-positive. 43.4% received chemotherapy, 49.7% radiation and 94.2% had surgery. The AAT for all the counties ranged from 33.6° Fahrenheit (F)/0.89°C to 67.3°F/19.6°C with median temperature 57.4°F/14.11°C. 10-year OS rate for stage I-III patients was 71.1% versus 8.8% for stage IV patients (p &lt; 0.001). Similarly, 10-year DSS rate for stage I-III patients was 85.6% versus 12.1% for stage IV patients (p &lt; 0.001). Temperature was analyzed in 5° F increments. When adjusting for the covariates in a MV model, there was a 3% improvement in OS and 2.5% improvement in DSS for every 5°F increment in AAT for stage I-III breast cancer patients in a time dependent model with HR 0.973 (95% CI 0.968-0.977), p &lt; 0.001 and HR 0.975 (95% CI 0.968-0.982), p&lt;0.001, respectively. A similar trend of improvement in OS and DSS was noted for stage IV breast cancer patients with HR 0.982 (95%CI 0.971-0.994), p = 0.003 for OS and HR 0.976 (95% CI 0.964 - 0.988), p &lt; 0.001 for DSS with every 5°F increment in AAT. Conclusions: Higher environmental temperatures are associated with improved clinical outcomes both among stage I-III and stage IV breast cancer patients. These interesting findings should be validated using other databases and further research focusing on therapeutic strategies to abrogate this outcome disparity is warranted. Citation Format: Ashish Gupta, Kristopher Attwood, Kush Gupta, Kayla Catalfamo, Kazuaki Takabe, Shipra Gandhi. Influence of environmental temperature on breast cancer outcomes: A SEER population-based study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-05.

PurposeTo compare the outcomes of patients with gastrointestinal neuroendocrine tumor liver metastases treated with liver-directed therapy (LDT) to those treated with systemic therapy (ST) in a statewide cancer database. Materials and MethodsA retrospective study was performed of patients with metastatic gastrointestinal tract neuroendocrine tumors treated with either LDT or ST alone between the years 2000–2012 in the California Cancer Registry. Overall survival and disease-specific survival were assessed using multivariable Cox proportional hazards analysis and propensity score matching. ResultsA total of 154 patients (ST, n = 87 and LDT, n = 67) were studied. The median overall survival and disease-specific survival for patients that received ST was 29 and 35 months versus 51 and >60 months for patients that received LDT. On multivariate analysis, LDT and the resection of the primary tumor were associated with improved survival (hazard ratio [HR] 0.52, P = .002; HR 0.43, P = .001). Non-white race, Medicaid/uninsured status, and the presence of lung metastases were associated with poor survival (HR 1.76, P = .014; HR 2.29, P = .009; and HR 1.79, P = .031). Propensity score matching demonstrated an improvement in disease-specific survival for LDT compared to ST (HR 0.53, P = .036). The improvement in overall survival on propensity score matching did not achieve statistical significance (HR 0.70, P = .199). ConclusionsLDT is associated with improved overall and disease-specific survival as compared to ST in patients with gastrointestinal neuroendocrine tumor liver metastases. Further investigation is needed to determine whether combination or sequential treatment can improve outcomes in this population.

Abstract Background: Breast cancer survival advancement can be ascribed to various efforts including community screening programs and educational outreach resulting in earlier diagnosis, treatment advances, and more accessible care. However, racial disparities continue to persist. Identification of populations susceptible to adverse health outcomes is substantial to construct health disparities resolutions. The purpose of the study is to identify trends in breast cancer disease specific survival (DSS) in black patients compared to white patients by age at diagnosis, year of diagnosis, and tumor estrogen receptor (ER) status. Methods: The Surveillance, Epidemiology, and End Results database was utilized to identify patients of black or white race diagnosed with stage I-III, ER positive (+) or ER negative (-) breast cancer between 1990 and 2009. The Kaplan-Meier method was used to determine 14-year breast cancer DSS. Changes in DSS were analyzed over the study’s time period and in 3 age groups to evaluate women who were of pre-menopausal age (&lt; 50 years), perimenopausal or postmenopausal and of the average age for breast cancer diagnosis (50-64 years), and elderly (65 + years). Results: The total study sample was 344,142 patients; 309,415 identified as white (89.9%) and 34,727 identified as black (10.1%) women. All patients diagnosed most recently had stable or improving DSS (p&lt;0.05). White patients with ER+ or ER- disease had significantly higher DSS compared to blacks in all age groups and years of diagnosis (p&lt;0.05); more specifically all black patients diagnosed in 2005-2009, had significantly lower disease specific survival (DSS) compared to white patients diagnosed a decade earlier in 1995-1999 (p&lt;0.05). For women 65+ with ER+ cancer, black patients diagnosed between 2005-2009 had a DSS of 86% compared to 91% in white patients diagnosed between 1995-2000. In ER- patients less than 50 years of age, black patients diagnosed between 2005-2009 had 78% DSS compared to white patient DSS of 84% within the same period. Among black patients, young women &lt;50 years of age ER+ and ER- women aged 50-64 years had consistent and most improvement in DSS over the study’s 4 time intervals; for ER+ cancer, DSS was 68% for those diagnosed in 1990-1994, 71% for 1995-1999, 75% for 2000-2005, and 79% for 2006-2009 and for ER- cancer, the DSS was 60% for those diagnosed in 1990-1994, 67% for 1995-1999, and 72% for 2000-2005, and 75% for 2006-2009 (p&lt;0.05). Conclusion: Improvements in breast cancer DSS are evidenced in black and white women, most especially black patients &lt; 50 years of age with ER+ and 50-64 with ER- disease. However, findings demonstrate DSS remain lower in all black patients compared to white patients, independent of year of diagnosis, age, and tumor receptor status. Continued efforts are crucial to identify and address the causes of continued disparities in breast cancer DSS, particularly in subsets of black patients not having survival improvements. Citation Format: Ewune Ewane, M Yi, A Akhtar, A M Brewster, Lorna McNeil-Haughton, Kelly K Hunt, Dalliah M Black. Differences in breast cancer survival by race, age, and tumor estrogen receptor status [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D056.

Abstract Background: Improvements in breast cancer survival can be attributed to screening programs resulting in earlier diagnosis, treatment advances, and more accessible care. However, racial disparities continue to persist. Identifying the most vulnerable populations can help strategize efforts of programs focused on improving disparities. The purpose of this study is to determine trends in breast cancer disease-specific survival (DSS) in black patients compared to white patients by age at diagnosis, year of diagnosis, and tumor estrogen receptor (ER) status. Methods: The Surveillance, Epidemiology, and End Results database was utilized to identify patients of black or white race diagnosed with stage I-III, ER-positive (+) or ER-negative (-) breast cancer between 1990 and 2005. The Kaplan-Meier method was used to determine 10-year breast cancer DSS. Changes in DSS were analyzed over the study's time period and in 4 age groups to evaluate women who were of premenopausal age (&lt; 50 years), perimenopausal or postmenopausal and of the average age for breast cancer diagnosis (50-64 years), elderly (65-79 years), and most elderly (≥80 years). Results: The study included 634,434 white (89.8%) and 72,124 black (10.2%) women. In all age groups and years of diagnosis, white patients with ER+ or ER- disease had significantly higher DSS compared to blacks (p&lt;0.05); in patients 50-64 years old diagnosed in 2000-2005, white patients with ER+ cancer had an 88% DSS compared to 77% DSS for black patients and, for ER- disease, whites had a 76% DSS compared to 67% for blacks. All patients diagnosed most recently had stable or improving DSS, except for black patients age ≥80 years who had a significantly lower DSS of 47% for those diagnosed in 2000-2005 compared to 52% for those diagnosed in 1990-1994 (p&gt;0.05). All black patients diagnosed in 2000-2005, independent of age and tumor receptor status, had significantly lower disease-specific survival (DSS) compared to white patients diagnosed a decade earlier in 1990-1994 (p&lt;0.05). For women &lt;50 years of age with ER+ cancer, black patients diagnosed between 2000-2005 had a DSS of 75% compared to 81% in white patients diagnosed between 1990-1994. Among black patients, only young women &lt;50 years of age with ER+ or ER- cancer had consistent and the most improvement in DSS over the study's 3 time intervals; for ER+ cancer, DSS was 68% for those diagnosed in 1990-1994, 71% for 1995-1999, and 75% for 2000-2005 and for ER- cancer, the DSS was 60% for those diagnosed in 1990-1994, 63% for 1995-1999, and 67% for 2000-2005 (p&lt;0.05). Conclusion: Black and white women have experienced improvements in breast cancer DSS, particularly in young black patients &lt; 50 years of age with ER+ or ER- disease. However, DSS remained lower in all black patients compared to white patients, independent of year of diagnosis, age, and tumor receptor status. Future efforts are needed to identify and address the causes of continued disparities in breast cancer DSS, particularly in subsets of black patients not having survival improvements. Citation Format: Ewune Ewane, Min Yi, A. Akhtar, Abenaa M. Brewster, Lorna McNeil-Haughton, Kelly K. Hunt, Dalliah M. Black. Differences in breast cancer survival by race, age, and tumor estrogen receptor status [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C039.

4022 Background: No large scale randomised data exists evaluating the impact of age and sex in patients (pts) undergoing potentially curative surgery and CTx for OG cancer. However, differences in age and sex may be contributing factors to variability in CTx dose-response and toxicity which could also impact survival. Methods: Data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival data, hazard ratios were calculated for pts <70 and ≥70 years and between males and females. Pts were allocated to receive neoadjuvant platinum and fluoropyrimidine +/- anthracycline and bevacizumab. Mandard tumour regression grade (TRG) and prevalence of ≥G3 toxicities were compared according to the same subgroups using Chi-squared test. Results: 3265 pts were included for survival analysis (2668 (82%) M, 597 (18%) F; 2626 (80%) <70, 639 (20%) ≥70). A significant improvement in disease specific survival (DSS) (HR 0.78; p<0.001) and OS (HR 0.78; p<0.001) was observed in females vs males. Although OS was worse in older vs younger pts (HR 1.15; p=0.01) no significant difference in DSS was observed (HR 1.04; p=0.52). For those pts who underwent resection following neoadjuvant CTx, older patients (19 vs 13%; p=0.01) and female patients (19% vs 13%, p=0.02) were more likely to achieve more favourable Mandard TRG 1&2 scores. Older pts experienced significantly more ≥G3 neutropaenia (30 vs 22%; p=0.004). Females experienced significantly more ≥G3 nausea (12 vs 7%; p=0.006), vomiting (10 vs 5%; p≤0.001) and diarrhoea (9 vs 4%; p=0.001). Conclusions: This study represents the largest pooled analysis of age and sex differences on safety of neoadjuvant CTx and survival in early OG cancer. Females had significantly improved survival while experiencing more GI toxicities. Older pts achieved comparable DSS and thus, dependent on fitness, should be offered the same treatment paradigm as younger pts.

Malignant peripheral nerve sheath tumors (MPNSTs) comprise a rare, aggressive subtype of soft tissue sarcoma. While surgery is the mainstay of therapy for this disease, the role of neoadjuvant therapy remains undefined. This study reviewed patients 16 years of age and older who underwent surgical treatment for MPNST between 1974 and 2012 at the authors' institution. Univariate and multivariate analyses were performed of clinicopathologic and treatment variables predictive of disease-specific survival (DSS) and disease-free survival. Eighty-eight patients with primary localized MPNST underwent surgical treatment between 1974 and 2012 at our institution. Of these, 38 (43%) underwent neoadjuvant chemotherapy and had tissue available for analysis. Neoadjuvant radiation was given to 25 patients (68%). The median follow-up time for survivors was 12.5 years (range, 4 to 27 y). Nine patients (23%) had underlying MPNST. With a cutoff of ≥90% pathologic necrosis and/or fibrosis defining response, we identified 14 responders (36%). On univariate analysis, patient age, tumor size, and pathologic response were significantly associated with DSS (P=0.015, 0.011, and 0.030, respectively). Although the impact of neoadjuvant chemotherapy on the outcome of primary localized MPNST patients continues to be debated, this study shows that a pathologic response to therapy is associated with a significant improvement in DSS. The challenge moving forward is to determine upfront which patients will be "responders" to standard systemic therapy and which patients should be considered for newer investigational agents as part of a clinical trial.

The extent of surgery for low-risk papillary thyroid cancer (PTC) has been the subject of debate among experts for decades. In this paper, we aimed to systematically review whether thyroid lobectomy versus total thyroidectomy for PTC patients with tumors measuring 1.0-4.0cm impacts tumor recurrence and survival. A systematic review of the literature from January 1990 to February 2018 yielded 13 relevant studies, including eight national cancer registry database studies, one multi-institutional thyroid cancer-specific database, three large-scale institutional series, and one meta-analysis. Data from these studies demonstrate that total thyroidectomy for the treatment of PTC measuring 1.0-4.0cm does not confer a clinically significant improvement in disease-specific survival compared with thyroid lobectomy. Four of six studies also reported that total thyroidectomy is associated with a small but statistically significant improvement in disease-free survival, although it is argued whether this difference is clinically significant. While the quality of the data limit the strength of our conclusions, and while tumor characteristics, patient risk factors, and preferences should be considered, most data support that lobectomy and total thyroidectomy yield comparable oncologic outcomes for PTC measuring 1.0-4.0cm.

Recent progress in understanding the genetic basis of breast cancer and widely publicized reports of celebrities undergoing risk-reducing mastectomy (RRM) have increased interest in RRM as a method of preventing breast cancer. This is an update of a Cochrane Review first published in 2004 and previously updated in 2006 and 2010. (i) To determine whether risk-reducing mastectomy reduces death rates from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast, and (ii) to examine the effect of risk-reducing mastectomy on other endpoints, including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. For this Review update, we searched Cochrane Breast Cancer's Specialized Register, MEDLINE, Embase and the WHO International Clinical Trials Registry Platform (ICTRP) on 9 July 2016. We included studies in English. Participants included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer. At least two review authors independently abstracted data from each report. We summarized data descriptively; quantitative meta-analysis was not feasible due to heterogeneity of study designs and insufficient reporting. We analyzed data separately for bilateral risk-reducing mastectomy (BRRM) and contralateral risk-reducing mastectomy (CRRM). Four review authors assessed the methodological quality to determine whether or not the methods used sufficiently minimized selection bias, performance bias, detection bias, and attrition bias. All 61 included studies were observational studies with some methodological limitations; randomized trials were absent. The studies presented data on 15,077 women with a wide range of risk factors for breast cancer, who underwent RRM.Twenty-one BRRM studies looking at the incidence of breast cancer or disease-specific mortality, or both, reported reductions after BRRM, particularly for those women with BRCA1/2 mutations. Twenty-six CRRM studies consistently reported reductions in incidence of contralateral breast cancer but were inconsistent about improvements in disease-specific survival. Seven studies attempted to control for multiple differences between intervention groups and showed no overall survival advantage for CRRM. Another study showed significantly improved survival following CRRM, but after adjusting for bilateral risk-reducing salpingo-oophorectomy (BRRSO), the CRRM effect on all-cause mortality was no longer significant.Twenty studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have RRM but greater variation in satisfaction with cosmetic results. Worry over breast cancer was significantly reduced after BRRM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BRRM, but there was diminished satisfaction with body image and sexual feelings.Seventeen case series reporting on adverse events from RRM with or without reconstruction reported rates of unanticipated reoperations from 4% in those without reconstruction to 64% in participants with reconstruction.In women who have had cancer in one breast, removing the other breast may reduce the incidence of cancer in that other breast, but there is insufficient evidence that this improves survival because of the continuing risk of recurrence or metastases from the original cancer. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention, when considering RRM. While published observational studies demonstrated that BRRM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies are suggested. BRRM should be considered only among those at high risk of disease, for example, BRCA1/2 carriers. CRRM was shown to reduce the incidence of contralateral breast cancer, but there is insufficient evidence that CRRM improves survival, and studies that control for multiple confounding variables are recommended. It is possible that selection bias in terms of healthier, younger women being recommended for or choosing CRRM produces better overall survival numbers for CRRM. Given the number of women who may be over-treated with BRRM/CRRM, it is critical that women and clinicians understand the true risk for each individual woman before considering surgery. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention when considering RRM.

Abstract Background: Disparity in demographic characteristics as it relates to breast cancer outcomes is well-studied. However, studies evaluating racial differences exclusively among young patients are more limited. We sought to examine socioeconomic and clinical factors and their impact on outcomes in young patients, as well as to determine whether variation in outcomes changed over the 22-year study period. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified female patients aged 20-35 with invasive breast cancer diagnosed from 1990-2012. We performed univariate, multivariate and survival analysis. Variables included patient age, race, stage, receptor status, surgery type and year of diagnosis Results: A total of 18,999 women were identified and analyzed. Mean age was 31.7 years. 31.2% were diagnosed between 1990-2000 while 68.7% were diagnosed between 2001-2012. 80.8% (15,364) of patients were white and 19.1% (3,635) were black. A higher percentage of blacks had stage III/IV disease (34% v 27%) and ≥ 4 positive nodes (19% v 16%) compared to whites. 54% of whites were ER receptor positive while 46% of blacks were ER receptor positive (p&lt;0.0001). White patents were more likely to live in counties where ≤15% of households were below the poverty line (64% v 45%) and where ≤15% of the population had less than a high school education (35% v 28%) compared to blacks. The overall 5-year disease specific survival (DSS) for the entire cohort was 82.5%. 5-year DSS was 84.4% for all white patients and 74.2% for all black patients (p&lt;0.0001). 5-year DSS was 79.1% among all patients diagnosed from 1990-2000 and 84.2% among patients diagnosed from 2001-2012 (p&lt;0.0001). While the 5-year DSS for white patients improved from 80.9% in 1990-2000 to 86.3% in 2001-2012 (p&lt;0.0001), the 5-year DSS improvement for black patients from 1990-2000 to 2001-2012 did not reach statistical significance (71.3% vs 75.7 %, p=0.24). Discussion: Racial disparity among breast cancer patients is also an issue in young females, as young white patients have superior disease-specific survival compared to African-Americans collectively and in each time-period studied. Absolute disease-specific survival has improved from 1990-2000 to 2001-2012 for both races. However, the statistically significant difference in improvement of disease-specific survival seen among white patients was not demonstrated in African-American patients. Continued attention to racial disparity in breast cancer outcomes is needed with additional studies examining potential differences in treatment, disease characteristics and biology, and accessibility to health care, with a particular focus on young cancer patients. With continued research, hopefully new treatment approaches will be developed to reduce this disparity. 5-Year Disease Specific SurvivalTime Period5 year DSSp value WhiteBlack 1990-200080.9%71.3%0.00012001-201286.3%75.7%0.0001p value0.00010.24 Survival by stage 5 yr DSS WhiteBlackp valueStage I96.2%94.9%&lt;0.001Stage II89.0%83.5%&lt;0.0001Stage III69.4%57.4%&lt;0.0001Stage IV34.6%16.9%&lt;0.0001 Citation Format: McClain JT, Mosquera C, Muzaffar M. Racial differences in the characteristics and outcomes of young breast cancer patients: A national population-based study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-10-06.

To analyze the impact of adjuvant radiation therapy (RT) on overall survival (OS) and disease-specific survival (DSS) in patients with verrucous carcinoma (VC) as compared to squamous cell carcinoma (SCC) of the oral cavity. Cross-sectional population analysis. Cases of nonmetastatic VC/SCC of the oral cavity were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (1988-2013). Kaplan-Meier survivals, stratified according to T stage, were compared between VC and SCC for treatment with or without adjuvant RT. A total of 18,819 VC/SCC cases were identified. There were 581 (3.1%) VC (mean age 69.6 years, 48.9% female) versus 18,238 (97.0%) SCC (mean age, 65.3, 37.1% female) patients. Verrucous carcinoma patients receiving surgery alone (N = 539) demonstrated a trend toward improved OS versus VC patients receiving surgery and RT (N = 40) (117.0 vs. 71.4 months, respectively, P = 0.119). There was a statistically significant improvement in DSS in VC patients receiving surgery alone (217.2 vs. 110.9 months, P = 0.05). Verrucous carcinoma patients treated with adjuvant RT demonstrated a trend toward a worse OS (71.4 vs. 93.0 months, P = 0.992) and DSS (110.9 vs. 162.3 months, P = 0.275) compared to SCC treated with adjuvant RT, suggesting a different biology and radiosensitivity between VC and SCC. Verrucous carcinoma treated with adjuvant RT had a worse OS and DSS compared to both VC treated with surgery alone and SCC treated with surgery and adjuvant RT. Consideration should be given to surgical re-section rather than adjuvant RT in patients with positive margins or local recurrence. 2C. Laryngoscope, 127:1334-1338, 2017.

Introduction:Although the spleen is involved in about a third of patients with Diffuse Large B-cell Lymphoma (DLBCL), stage I splenic DLBCL is rare and there is little data to guide management. Potential treatment modalities include combinations of splenectomy, radiation and immuno-chemotherapy, but there is no consensus on the optimal approach. Using multiple publically available and propriety databases, we sought to further define the prognosis and outcomes for stage I splenic DLBCL.Methods:We utilized the Surveillance Epidemiology and End Results (SEER) 18 registry to identify patients with stage I splenic DLBCL diagnosed during the years 1973-2013. Appropriate cases were identified using a combination of International Classification of Diseases for Oncology, 3rd edition code DLBCL (9680/3) and location code for spleen (C42.2). These patients were divided into two cohorts based on the year of diagnosis (1983-2005; 2006-2013) as rituximab (R) was approved by the FDA in 2006 for use in the first line treatment of DLBCL. Patient characteristics and survival outcomes were analyzed by GraphPad Prism 6 and Microsoft Excel. Disease specific survival (DSS) and Overall survival (OS) comparisons were made using the Gehan-Breslow-Wilcoxon test. All p-values were 2-sided and results ≤0.05 were considered significant.We queried the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer to identify patients with stage I splenic lymphoma during the years 1973-2013. We also searched the Caris Life Sciences database for patients profiled by Caris Molecular Intelligence using the keywords "splenic lymphoma " in the clinical history and diagnosis fields for cases of stage I splenic DLBCL from 2007-2015. All database searches were conducted with IRB approval.Results:107,550 patients with known stage and histologically confirmed DLBCL were identified within the SEER database. 30,455 patients had stage I disease with 470 of them diagnosed as stage I splenic DLBCL. The mean age was 66 years (range, 17-93 years) and the majority were Caucasian (89%). There was equal distribution of patients in the pre-rituximab (pre-R) era and post rituximab (R) era (53% vs 47%). 42% (470/1116) of splenic DLBCL were diagnosed as stage I compared to 28% (29,985/106,434) of all other types of DLBCL (p<0.01). Stage I splenic DLBCL treated in the R-era has better OS than all other stage I DLBCLs treated during the same period (HR = 0.62, 95% CI 0.53-0.86, p<0.01)The rate of splenectomy was lower after the approval of rituximab (82% in pre-R vs 72% in R era, p=0.03). Splenectomy was associated with an improvement in DSS (HR = 0.57, 0.28 - 0.96, p=0.04), but when stratified by pre-R and R era, improved DSS with splenectomy was only seen in the pre-R (HR = 0.51, 0.17-1.08, p =0.04), but not in the R-era (HR =0.62, 0.25 - 1.38 p=0.53). OS advantage with splenectomy was also seen only in the pre-R era (HR = 0.66, 0.32 - 1.14, 106m vs 137m, p=0.03) but splenectomy had no impact on OS in the R-era (HR = 0.74, 0.37 - 1.43, p=0.45). There was a trend toward improved OS with the introduction of rituximab (HR = 0.75, 0.48 - 1.14, p=0.054). There was no difference in the utilization of radiation between these cohorts (6% in pre-R vs 3% in R era, p=0.13).Our search of the Mitelman database found 1413 patients with DLBCL, but none of them had stage I splenic DLBCL. We also identified 20 patients with Non-Hodgkin lymphoma profiled by Caris Life Sciences, of which only one had primary splenic DLBCL. This patient was a 35 year old male who on immunohistochemistry was found to be positive for MGMT, MRP1, PTEN, TOP2A, TOPO1, and TS.Conclusion:The utilization of splenectomy for stage I splenic DLBCL has decreased with the introduction of rituximab without compromise of outcomes. Radiation is rarely used and does not appear to influence outcomes. Splenic DLBCL is more likely to present as stage I disease compared to other types of DLBCLs and Stage I splenic DLBCL appears to have a favorable prognosis relative to other stage I DLBCLs. Alternative databases added little to the understanding of the biology of stage I splenic DLBCL. DisclosuresNo relevant conflicts of interest to declare.

BackgroundWaldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades.MethodsThe medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method.ResultsYounger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003).Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1).In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001].ConclusionStriking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. [Display omitted] DisclosuresAnsell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

BackgroundThe role of local therapy for the management of oligometastatic prostate cancer at diagnosis still remains poorly defined. We did a systematic review and meta-analysis evaluating local therapy of the primary tumour for patients with oligometastatic prostate cancer at diagnosis as well as the patients who can benefit the most. MethodsFor this systematic review, we searched PubMed, EMBASE, Medline, and the Cochrane Library for studies from database inception until March, 2016, for local therapy of the primary tumour in patients with oligometastatic prostate cancer. No language restrictions were applied. We estimated the risk of bias for the individual research studies using the Newcastle-Ottawa Scale (NOS). We assessed the publication bias using both the Egger's linear regression approach and funnel plots. The baseline characteristics on trial, patient, and treatment level were extracted. The primary outcomes were overall survival and disease-specific survival. All statistical analyses were performed using Stata v.12.0 software (StataCorp, College Station, TX, USA). FindingsSeven retrospective studies were selected for inclusion, including a total of 24 203 patients who were recruited from 1989 to 2010 form Sweden, USA, and Germany. For overall survival, the pooled hazard ratio (HR) in patients treated with local therapy compared with no local therapy was 0·53 (95% CI 0·40–0·71; p <0·01). Local therapy was also associated with a 49% improvement of disease-specific survival (HR 0·51, 95% CI 0·37–0·69, p<0·01). This significant increase in disease-specific survival was better pronounced in patients younger (HR 0·34, 0·23–0·52, p<0·01) than 65 years than in those 65 years or older (HR 0·44, 0·28–0·68, p <0·01). The tumour-specific factor was associated with the improved survival in patients with AJCC (American Joint Committee on Cancer) M1a stage (HR 0·29, 0·18–0·48, p<0·01) than in those with M1b (HR 0·40, 0·24–0·68, p<0·001) and M1c (HR 0·34; 0·24–0·50, p<0·01). InterpretationLocal therapy for a primary tumour conferred a significantly better outcome in fit patients with oligometastatic prostate cancer at diagnosis. The evidence also suggests that radical prostatectomy is a preferable local therapy procedure for patients aged 65 years or younger or for those who have an AJCC stage M1a tumour. We believe that important local therapy factors should be systematically assessed to develop a personalised approach to improve patient survival FundingThis study was supported by the Prostate Cancer Foundation Young Investigator Award 2013, the National Natural Science Foundation of China (81300627 and 81370855) and Programs from Science and Technology Department of Sichuan Province (2013SZ0006 and 2014JY0219).

Follicular lymphomas (FLs) are the second most frequent subtype of nodal lymphoid malignancies in Western Europe. The annual incidence of this disease has rapidly increased during recent decades and has risen from 2–3/100 000 during the 1950s to 5/100 000 recently [1.Mounier M. Bossard N. Remontet L. et al.Changes in dynamics of excess mortality rates and net survival after diagnosis of follicular lymphoma or diffuse large B-cell lymphoma: comparison between European population-based data (EUROCARE-5).Lancet Haematol. 2015; 2: e481-e491Google Scholar]. Diagnosis should be based on a surgical specimen/excisional lymph node biopsy. Core biopsies should only be carried out in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the possible heterogeneity of FL grading can be difficult to appreciate on core biopsies and re-biopsy may be required if the material is not adequate. Fine needle aspirations are inappropriate for a reliable diagnosis. The histological report should give the diagnosis according to the World Health Organization (WHO) classification. Grading of lymph node biopsies is carried out according to the number of blasts/high-power field (Table 1). FL grade 3A (with sheets of blasts) is considered an aggressive lymphoma and treated as such [2.Tilly H. Gomes da Silva M. Vitolo U. et al.Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2015; 26: v116-v125Google Scholar], whereas grade 1, 2 and 3A should be treated as indolent disease [3.Ott G. Katzenberger T. Lohr A. et al.Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.Blood. 2002; 99: 3806-3812Google Scholar]. Review, especially of grade 3A or 3B, by an expert haematopathologist is advised if the infiltration pattern is atypical (diffuse areas, even with small cells).Table 1Grading of follicular lymphoma (FL)GradeDescription1≤5 blasts/high-power field26–15 blasts/high-power field3A>15 blasts/high-power field, centroblasts with intermingled centrocytes3B>15 blasts/high-power field, pure sheets of blasts Open table in a new tab Since treatment largely depends on the stage of the disease, initial staging should be thorough, particularly in the small proportion of patients with early stages I and II (10%–15%) (Table 2). Initial work-up should include a computed tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy (Table 3). Positron emission tomography (PET)–CT improves the accuracy of staging for nodal and extranodal sites and thus should be recommended for routine staging in FL [IV, C] [4.Cheson B.D. Fisher R.I. Barrington S.F. et al.Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma—the Lugano Classification.J Clin Oncol. 2014; 32: 3059-3068Google Scholar]. This is particularly important to confirm localised stage I/II before involved-field radiotherapy.Table 2Ann Arbor classificationStageArea of involvementI (IE)One lymph node region or extralymphatic site (IE)II (IIE)Two or more lymph node regions or at least one lymph node region plus a localised extralymphatic site(IIE) on the same side of the diaphragmIII (IIIE, IIIS)Lymph node regions or lymphoid structures (e.g. thymus, Waldeyer's ring) on both sides of the diaphragm with optional localised extranodal site (IIIE) or spleen (IIIS)IVDiffuse or disseminated extralymphatic organ involvementA: no symptoms.B: unexplained fever of >38°C, drenching night sweats; or loss of >10% body weight within 6 months. Open table in a new tab Table 3Diagnostic work-upHistoryB symptomsPhysical examinationPeripheral lymph nodes, liver, spleenLaboratory work-upBlood and differential countOptional: FACS on peripheral blood, PCR for BCL2 rearrangementLDH, uric acidElectrophoresis (optional: immune fixation)&bgr;2 microglobulin (FLIPI 2)SerologyHepatitis B, C and HIV serologyImagingCT neck, chest, abdomen, pelvisRecommended: PET–CTaTo confirm localised disease or in the case of suspected transformation.Optional: abdominal ultrasoundBone marrowbIf clinically indicated.HistologyCytologyOptional: FACS, PCR for BCL2 rearrangementToxicityElectrocardiogram, cardiac ultrasound (before anthracyclines, ASCT)Creatinine clearanceReproductive counselling in young patientsFACS, fluorescence-activated cell sorting; PCR, polymerase chain reaction; LDH, lactate dehydrogenase; FLIPI 2, Follicular Lymphoma International Prognostic Index 2; HIV, human immunodeficiency virus; CT, computed tomography; PET–CT, positron emission tomography–computed tomography; ASCT, autologous stem cell transplantation.a To confirm localised disease or in the case of suspected transformation.b If clinically indicated. Open table in a new tab A: no symptoms. B: unexplained fever of >38°C, drenching night sweats; or loss of >10% body weight within 6 months. FACS, fluorescence-activated cell sorting; PCR, polymerase chain reaction; LDH, lactate dehydrogenase; FLIPI 2, Follicular Lymphoma International Prognostic Index 2; HIV, human immunodeficiency virus; CT, computed tomography; PET–CT, positron emission tomography–computed tomography; ASCT, autologous stem cell transplantation. A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH), &bgr;2 microglobulin and uric acid as well as screening tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C are required. The staging is carried out according to the Ann Arbor classification system (Table 2), with mention of bulky disease (>7 cm) when appropriate. For prognostic purposes, a ‘Follicular Lymphoma-specific International Prognostic Index’ (FLIPI, Table 4) has been established [I, A] [6.Solal-Céligny P. Roy P. Colombat P. et al.Follicular lymphoma international prognostic index.Blood. 2004; 104: 1258-1265Google Scholar]. A revised FLIPI 2 (incorporating &bgr;2 microglobulin, diameter of largest lymph node, bone marrow involvement and haemoglobin level) has been suggested for patients requiring treatment which may be more informative on progression-free survival (PFS) [7.Federico M. Bellei M. Marcheselli L. et al.Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project.J Clin Oncol. 2009; 27: 4555-4562Google Scholar].Table 4‘Follicular Lymphoma-specific International Prognostic Index’ (FLIPI) risk factorsParameterDefinition of risk factorsFLIPI 1FLIPI 2Nodal sites>4 lymph node regions (definition in [5.Dave S.S. Wright G. Tan B. et al.Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.N Engl J Med. 2004; 351: 2159-2169Google Scholar])Long diameter of largest lymph node >6 cmAge>60 years>60 yearsSerum markerElevated LDHElevated &bgr;2 microglobulinStageAdvanced (III–IV according to Ann Arbor classification)Bone marrow involvementHaemoglobin<12 g/dl<12 g/dl0–1 risk factors, low risk; 2 risk factors, intermediate risk; 3–5 risk factors, high risk.LDH, lactate dehydrogenase. Open table in a new tab 0–1 risk factors, low risk; 2 risk factors, intermediate risk; 3–5 risk factors, high risk. LDH, lactate dehydrogenase. Extended gene-expression profiling of tumour biopsy suggests a more favourable clinical course in cases with infiltrating T cells, in comparison with cases with non-specific macrophage bystander cells [5.Dave S.S. Wright G. Tan B. et al.Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.N Engl J Med. 2004; 351: 2159-2169Google Scholar]. Recently, a clinicogenetic risk score (m7-FLIPI) has been proposed based on mutation status of seven candidate genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11) [8.Pastore A. Jurinovic V. Kridel R. et al.Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry.Lancet Oncol. 2015; 16: 1111-1122Google Scholar]; however, none of the techniques are yet established in clinical routine practice. In addition, several recent immunohistochemistry studies have reported conflicting data; hence, biological parameters are still investigational for prognostic assessment and are not yet suitable for clinical decision-making [9.Sander B. de Jong D. Rosenwald A. et al.The reliability of immunohistochemical analysis of the tumor microenvironment in follicular lymphoma: a validation study from the Lunenburg Lymphoma Biomarker Consortium.Haematologica. 2014; 99: 715-725Google Scholar]. If possible, additional biopsy material should be stored fresh frozen to allow for the possible future application of additional molecular analyses. In the small proportion of patients with limited non-bulky stages I–II, radiotherapy (involved field, 24 Gy) is the preferred treatment with a potentially curative potential, whereas the 2 × 2 Gy schedule is inferior and is merely palliative [II, B] [10.Hoskin P.J. Kirkwood A.A. Popova B. et al.4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial.Lancet Oncol. 2014; 15: 457-463Google Scholar]. In selected cases, watchful waiting or rituximab monotherapy may be considered to avoid the side-effects of radiation (e.g. cervical: sicca syndrome, hypothyroidism; abdominal: mucositis, myeloablative suppression) [11.Solal-Céligny P. Bellei M. Marcheselli L. et al.Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: results of an F2-study database.J Clin Oncol. 2012; 30: 3848-3853Google Scholar, 12.Friedberg J.W. Byrtek M. Link B.K. et al.Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study.J Clin Oncol. 2012; 30: 3368-3375Google Scholar]. In stage I–II patients with large tumour burden, adverse clinical or biological prognostic features or when local radiotherapy is not applicable (e.g. lung, liver), systemic therapy as indicated for advanced stages should be applied [IV, B] [12.Friedberg J.W. Byrtek M. Link B.K. et al.Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study.J Clin Oncol. 2012; 30: 3368-3375Google Scholar]. In the majority of patients with advanced stage III and IV disease, no curative therapy is yet established. Since the natural course of the disease is characterised by spontaneous regressions in 10%–20% of cases and varies significantly from case to case, therapy should be initiated only upon the occurrence of symptoms, including B symptoms, haematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion or rapid lymphoma progression (Table 5) [I, A].Table 5High tumour burden criteria in FL [Groupe d'Etude des Lymphomes Folliculaires (GELF)ParameterHigh tumour burden criteriaLymph nodesBulk (>7 cm) or 3 lymph nodes in distinct areas >3 cmSpleenSymptomatic splenic enlargement(Potential) complicationOrgan compression by tumour, pleural or peritoneal effusionSerum markersElevated LDH or elevated &bgr;2-microglobulineClinical presentationB symptoms (see Table 2)LDH, lactate dehydrogenase. Open table in a new tab LDH, lactate dehydrogenase. In three randomised trials before the rituximab era, an early initiation of therapy in asymptomatic patients did not result in any improvement of disease-specific survival or overall survival (OS) [13.Ardeshna K.M. Smith P. Norton A. et al.Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.Lancet. 2003; 362: 516-522Google Scholar]. In a more recent study, early initiation of rituximab resulted in improved PFS (80% versus 48%, P <0.001), but no survival benefit has been determined so far [14.Ardeshna K.M. Qian W. Smith P. et al.Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial.Lancet Oncol. 2014; 15: 424-435Google Scholar], and the benefit of rituximab maintenance in this setting appears doubtful [15.Kahl B.S. Hong F. Williams M.E. et al.Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: Eastern Cooperative Oncology Group protocol e4402.J Clin Oncol. 2014; 32: 3096-3102Google Scholar]. Thus, the current therapeutic approach is based on clinical risk factors, symptoms and patient perspective (Figure 1). Four prospective first-line trials, two salvage trials and a systematic meta-analysis confirmed an improved overall response, PFS and OS if rituximab was added to chemotherapy (Table 6) [16.Marcus R. Imrie K. Solal-Céligny P. et al.Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisolone alone in patients with previously untreated advanced follicular lymphoma.J Clin Oncol. 2008; 26: 4579-4586Google Scholar, 17.Hiddemann W. Kneba M. Dreyling M. et al.Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.Blood. 2005; 106: 3725-3732Google Scholar, 18.Herold M. Haas A. Srock S. et al.Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study.J Clin Oncol. 2007; 25: 1986-1992Google Scholar, 19.Bachy E. Houot R. Morschhauser F. et al.Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma.Haematologica. 2013; 98: 1107-1114Google Scholar, 20.Schulz H. Bohlius J.F. Trelle S. et al.Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis.J Natl Cancer Inst. 2007; 99: 706-714Google Scholar]. If complete remission and long PFS is to be achieved, rituximab in combination with chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or bendamustine should be used [I, B] [17.Hiddemann W. Kneba M. Dreyling M. et al.Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.Blood. 2005; 106: 3725-3732Google Scholar, 21.Rummel M. Niederle N. Maschmeyer G. et al.Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.Lancet. 2013; 381: 1203-1210Google Scholar]. CVP (cyclophosphamide, vincristine and prednisone) is not as effective as these two regimens with respect to PFS but not OS [22.Federico M. Luminari S. Dondi A. et al.R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi.J Clin Oncol. 2013; 31: 1506-1513Google Scholar]. Full courses of purine analogue-based schemes [FC (fludarabine and cyclophosphamide) or FM (fludarabine and mitoxantrone)] are not recommended due to higher haematological toxicities, but a brief course of chemoimmunotherapy with full rituximab course is an alternative in elderly patients, with good efficacy and low toxicity [II, B] [22.Federico M. Luminari S. Dondi A. et al.R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi.J Clin Oncol. 2013; 31: 1506-1513Google Scholar, 23.Vitolo U. Ladetto M. Boccomini C. et al.Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi.J Clin Oncol. 2013; 31: 3351-3359Google Scholar]. If there is evidence (histological grade 3B or clinical signs of transformation) of more aggressive lymphoma, an anthracycline-based regimen [rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)] should be applied.Table 6Combined chemoimmunotherapy in FL (first line)StudyTotal no. of patientsMedian follow-upOverall responseTime to treatment failure (months)Overall survivalMarcus et al. [16.Marcus R. Imrie K. Solal-Céligny P. et al.Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisolone alone in patients with previously untreated advanced follicular lymphoma.J Clin Oncol. 2008; 26: 4579-4586Google Scholar]15953 months81%2783% (4 years) R-CVP(P < 0.0001)(P < 0.0001)(P = 0.029)Hiddemann et al. [17.Hiddemann W. Kneba M. Dreyling M. et al.Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.Blood. 2005; 106: 3725-3732Google Scholar]22358 months96%NR90% (2 years) R-CHOP(P < 0.001)(P = 0.0493)Herold et al. [18.Herold M. Haas A. Srock S. et al.Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study.J Clin Oncol. 2007; 25: 1986-1992Google Scholar]10548 months92%NR87% (4 years) R-MCP(P = 0.0009)(P < 0.0001)(P = 0.0096)Bachy et al. [19.Bachy E. Houot R. Morschhauser F. et al.Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma.Haematologica. 2013; 98: 1107-1114Google Scholar]17599 months81%6679% (8 years) R-CHVP-IFN(P = 0.035)(P = 0.0004)(P = 0.076)Rummel et al. [21.Rummel M. Niederle N. Maschmeyer G. et al.Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.Lancet. 2013; 381: 1203-1210Google Scholar]13934 months93%NR84% (4 years) BRFederico et al. [22.Federico M. Luminari S. Dondi A. et al.R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi.J Clin Oncol. 2013; 31: 1506-1513Google Scholar]34 months95% (3 years) R-CVP17888%46% (3 years) R-CHOP17893%62% (3 years) R-FM17891%59% (3 years) + R maintenanceVitolo et al. [23.Vitolo U. Ladetto M. Boccomini C. et al.Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi.J Clin Oncol. 2013; 31: 3351-3359Google Scholar]23442 months86%NR89% (3 years) 4× R-FND + 4× R ± R maintenanceP, significance levels in comparison with chemotherapy only.FL, follicular lymphoma; R-CVP, cyclophosphamide, vincristine and prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-MCP: mitoxantrone, chlorambucil, prednisone; R-CHVP-IFN, rituximab, cyclophosphamide, doxorubicin, etoposide, prednisone, interferon; BR, bendamustine–rituximab; R-FM, rituximab, fludarabine and mitoxantrone; R-FND, cyclophosphamide, vincristine and prednisolone; NR, not reached. Open table in a new tab P, significance levels in comparison with chemotherapy only. FL, follicular lymphoma; R-CVP, cyclophosphamide, vincristine and prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-MCP: mitoxantrone, chlorambucil, prednisone; R-CHVP-IFN, rituximab, cyclophosphamide, doxorubicin, etoposide, prednisone, interferon; BR, bendamustine–rituximab; R-FM, rituximab, fludarabine and mitoxantrone; R-FND, cyclophosphamide, vincristine and prednisolone; NR, not reached. Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab remain alternatives for patients with a low-risk profile or when conventional chemotherapy is contraindicated [III, B] [24.Martinelli G. Schmitz S.F. Utiger U. et al.Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98.J Clin Oncol. 2010; 28: 4480-4484Google Scholar, 25.Scholz C.W. Pinto A. Linkesch W. et al.(90)Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial.J Clin Oncol. 2013; 31: 308-313Google Scholar]. In patients with positive hepatitis B serology including occult carrier (HBS Ag negative and anti-core positive), prophylactic antiviral medication and regular monitoring of HBV DNA are strongly recommended [I, A] [26.Huang Y.H. Hsiao L.T. Hong Y.C. et al.Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B.J Clin Oncol. 2013; 31: 2765-2772Google Scholar]. Rituximab maintenance for 2 years improves PFS (59% versus 43% after 6 years, P < 0.0001) [I, B] [27.Salles G. Seymour J.F. Feugier P. et al.Updated 6 year follow-up of the PRIMA study confirms the benefit of 2-year rituximab maintenance in follicular lymphoma patients responding to frontline immunochemotherapy.Blood. 2013; 122 (abstr. 509)Google Scholar], whereas a shorter maintenance period results in inferior benefit [28.Taverna C.J. Martinell G. Hitz F. et al.Rituximab maintenance treatment for a maximum of 5 years in follicular lymphoma: results of the randomized phase III trial SAKK 35/03.Blood. 2013; 122 (abstr. 508)Google Scholar]. Radioimmunotherapy consolidation also prolongs PFS after chemotherapy, but its benefit seems to be inferior in comparison with rituximab maintenance for 2 years [II, B] [29.Morschhauser F. Radford J. Van Hoof A. et al.90Yttrium-ibritumomab-tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the international, randomized, phase III first-line indolent trial.J Clin Oncol. 2013; 31: 1977-1983Google Scholar, 30.Lopez-Guillermo A. Canales M.A. Dlouhy I. et al.A randomized phase II study comparing consolidation with a single dose of 90y ibritumomab tiuxetan (Zevalin®) (Z) vs. maintenance with rituximab (R) for two years in patients with newly diagnosed follicular lymphoma (FL) responding to R-CHOP. Preliminary results at 36 months from randomization.Blood. 2013; 122 (abstr. 369)Google Scholar]. Myeloablative consolidation followed by autologous stem cell transplantation (ASCT) prolongs PFS after chemotherapy, but its benefit after a rituximab-containing induction is minor and no OS has been observed [31.Hiddemann W. Dreyling M.H. Metzner B. et al.Evaluation of myeloablative therapy followed by autologous stem cell transplantation in first remission in patients with advanced stage follicular lymphoma after initial immuno-chemotherapy (R-CHOP) or chemotherapy alone: analysis of 940 patients treated in prospective randomized trials of the German Low Grade Lymphoma Study Group (GLSG).Blood. 2013; 122 (abstr. 419)Google Scholar]. Therefore, such an approach is not recommended in first-line therapy of responding patients [I, D]. At relapse, it is strongly recommended to obtain a new biopsy in order to exclude transformation into an aggressive lymphoma. It may be useful to target the biopsy based on PET scanning. As at first presentation, observation is an accepted approach in asymptomatic patients with low tumour burden. Selection of salvage treatment depends on efficacy of prior regimens. In early relapses (<12–24 months), a non-cross-resistant scheme should be preferred (e.g. bendamustine after CHOP or vice versa). Other options, including fludarabine-based, platinum salts-based or alkylating agents-based regimens, could also be useful. Rituximab should be added if the previous antibody-containing scheme achieved >6- to 12-month duration of remission [IV, B]. On the other hand, obinutuzumab has recently received a positive recommendation for approval by the European Medicines Agency for rituximab-refractory cases based on an improved PFS in comparison with bendamustine only [I, B] [32.Sehn L.H. Chua N. Mayer J. et al.Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial.Lancet Oncol. 2016; 17: 1081-1093Google Scholar]. In symptomatic cases with low tumour burden, rituximab monotherapy may be applied. Radioimmunotherapy (90yttrium–ibritumomab–tiuxetan) may represent an effective therapeutic approach in elderly patients with comorbidities not appropriate for chemotherapy [IV, B]. Rituximab maintenance for up to 2 years has a favourable side-effect profile and, based on a systematic meta-analysis, substantially prolongs PFS and OS in relapsed disease, even after antibody-containing induction in patients who have not received antibody as first-line therapy [I, A] [33.Vidal L. Gafter-Gvili A. Salles G. et al.Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials.J Natl Cancer Inst. 2011; 103: 1799-1806Google Scholar]. A second-line maintenance treatment has not been investigated in the setting of maintenance use in first line and probably should not be used for those patients who had relapsed during their first maintenance period [IV, D]. High-dose chemotherapy with ASCT prolongs PFS and OS and should be considered, especially in patients who experience short-lived first remissions (<2–3 years) after rituximab-containing regimens, which usually have a much worse long-term outcome, but its general role in the rituximab era has to be redefined [I, B] [34.Schouten H.C. Qian W. Kvaloy S. et al.High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial.J Clin Oncol. 2003; 21: 3918-3927Google Scholar, 35.Le Gouill S. De Guibert S. Planche L. et al.Impact of the use of autologous stem cell transplantation at first relapse both in naive and previously rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study.Haematologica. 2011; 96: 1128-1135Google Scholar, 36.Montoto S. Corradini P. Dreyling M. et al.Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party.Haematologica. 2013; 98: 1014-1021Google Scholar, 37.Casulo C. Byrtek M. Dawson K.L. et al.Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study.J Clin Oncol. 2015; 33: 2516-2522Google Scholar]. A subsequent rituximab maintenance may achieve some improvement in PFS [II, B] [38.Pettengell R. Schmitz N. Gisselbrecht C. et al.Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.J Clin Oncol. 2013; 31: 1624-1630Google Scholar]. In later relapses, monotherapy is an established option with palliative intent [II, B]. The PI3K inhibitor idelalisib has been registered in double-refractory FL, based on a phase II study [39.Gopal A.K. Kahl B.S. de Vos S. et al.PI3K&dgr; inhibition by idelalisib in patients with relapsed indolent lymphoma.N Engl J Med. 2014; 370: 1008-1018Google Scholar]. Recent analyses suggest an increased mortality risk as a consequence of pulmonary morbidity (atypical pneumonias/pneumonitis), so appropriate prophylaxis (cotrimoxazole/acyclovir) is strongly recommended. Cytomegalovirus monitoring may be also advised. In selected younger patients with later relapses of high-risk profile or relapse after ASCT, a potentially curative allogeneic stem cell transplantation (preferably with dose-reduced conditioning) may be considered, especially in patients with early relapse and refractory disease [IV, B] [36.Montoto S. Corradini P. Dreyling M. et al.Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party.Haematologica. 2013; 98: 1014-1021Google Scholar]. In recent years, new approaches, including lenalidomide–rituximab and additional inhibitors of the B-cell signalling pathway, have proved active in phase II studies, but to date their benefit has yet to be confirmed in randomised phase III studies. The combination of bortezomib–rituximab has shown only a minor benefit compared with antibody monotherapy [I, D]. Appropriate imaging evaluation should be carried out midterm and after completion of chemotherapy. Patients with an inadequate response [less than partial response (PR)] should be evaluated for early salvage regimens. PR patients may convert to complete response (CR) under rituximab maintenance. PET–CT after completion of chemotherapy induction has been recommended for prognostic reasons as persistent PET-positivity (using appropriate Deauville scales) identifies a small group (20%–25%) of patients with a worse prognosis [40.Trotman J. Luminari S. Boussetta S. et al.Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies.Lancet Haematol. 2014; 1: e17-e27Google Scholar], but therapeutic consequences remain undefined [II, B]. Minimal residual disease (MRD) analysis by polymerase chain reaction at the end of the treatment is an independent predictor of long-term outcome, but should not guide therapeutic strategies outside of clinical studies. As various therapeutic approaches may achieve durable responses in the vast majority of patients, the selection of optimal treatment is mainly based on clinical risk factors, symptoms and patient perspective (Figure 1). PET- and MRD-based tailored treatments are currently evaluated in studies but are not yet routine clinical practice. Paediatric FL is an FL variant originally described in children, but occurs in adults as well. It is characterised by a localised disease, the absence of bcl-2 aberrations, lack of t(14;18), grade III and a high proliferation rate. It shows a much more indolent course and should be managed with local therapy only, despite displaying histologically more aggressive features [41.Louissaint Jr, A. Ackerman A.M. Dias-Santagata D. et al.Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement.Blood. 2012; 120: 2395-2404Google Scholar]. The following minimal recommendations are based on consensus rather than on evidence (Table 7):•After local radiotherapy: history and physical examination every 6 months for 2 years, subsequently once a year if clinically indicated.•After (during continuous) systemic treatment: history and physical examination every 3–4 months for 2 years, every 6 months for 3 additional years, and subsequently once a year [V, D].•Blood count and routine chemistry every 6 months for 2 years, then only as needed for evaluation of suspicious symptoms.•Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and 5 years.•Minimal adequate radiological or ultrasound examinations every 6 months for 2 years and optionally annually up to 5 years. Regular CT scans are not mandatory outside of clinical trials, especially if abdominal ultrasound is applicable. PET–CT should be not used for surveillance.•MRD screening may be carried out in clinical studies but should not guide therapeutic strategies.Table 7Recommended follow-up after end of therapyExaminationDetailsYear 1–2Year 3–5Year >5HistoryB symptomsEvery 3–4 monthsTwice annuallyAnnuallyPhysical examinationParticular: peripheral lymph nodes, liver, spleenEvery 3–4 monthsTwice annuallyAnnuallyLaboratory work-upBlood and differential countEvery 3–4 monthsTwice annuallyAnnuallyLDHEvery 3–4 monthsTwice annuallyIf progress suspectedImagingAbdominal ultrasoundTwice annuallyEvery 12 monthsIf progress suspectedCT neck, chest, abdomen, pelvisOptional: 6–12 monthsOptional: 12–24 monthsIf progress suspectedLDH, lactate dehydrogenase; CT, computed tomography. Open table in a new tab LDH, lactate dehydrogenase; CT, computed tomography. These clinical practice guidelines were developed in accordance with the ESMO standard operating procedures for clinical practice guidelines development, http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology. The relevant literature has been selected by the expert authors. A summary of recommended treatment strategies outside of clinical studies is provided in Figures 2 and 3, and a summary of recommendations is provided in Table 8. Levels of evidence and grades of recommendation have been applied using the system shown in Table 9. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty. This manuscript has been subjected to an anonymous peer review process.Figure 3Consensus-driven recommendations outside of clinical studies—high tumour burden. R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-CVP, cyclophosphamide, vincristine and prednisolone; BR, bendamustine–rituximab; CR, complete response; PR, partial response; ASCT, autologous stem cell transplantation. aAccording to biological age; bespecially if transformation is suspected; c70–90 mg/m2, 4–6 cycles [42.Cheson B.D. Brugger W. Damaj G. et al.Optimal use of bendamustine in hematologic disorders: treatment recommendations from an international consensus panel—an update.Leuk Lymphoma. 2016; 57: 766-782Google Scholar].View Large Image Figure ViewerDownload (PPT)Table 8Summary of recommendationsIn localised stages: radiation (24 Gy)In advanced stages: treatment depends on clinical risk factors, symptoms and patient perspectiveStandard approach in asymptomatic advanced cases: watch and waitIn advanced symptomatic cases Combined chemoimmunotherapy for long-term remissions Recommend rituximab maintenance for consolidationRelapse is frequently sensitive to conventional approachesAutologous (and allogeneic) transplantation should be only discussed in relapseMonotherapy (antibodies, idelalisib) is appropriate, especially in later relapses Open table in a new tab Table 9Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading SystemaBy permission of the Infectious Diseases Society of America [43].)Levels of evidence IEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity IISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity IIIProspective cohort studies IVRetrospective cohort studies or case–control studies VStudies without control group, case reports, experts opinionsGrades of recommendation AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended CInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …), optional DModerate evidence against efficacy or for adverse outcome, generally not recommended EStrong evidence against efficacy or for adverse outcome, never recommendeda By permission of the Infectious Diseases Society of America [43.Dykewicz C.A. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients.Clin Infect Dis. 2001; 33: 139-144Google Scholar]. Open table in a new tab MD has reported institutional research support from Celgene, Janssen, Mundipharma, Pfizer and Roche; speaker's honoraria from Bayer, Celgene, Gilead, Janssen and Roche; advisory boards for Bayer, Celgene, Gilead, Janssen, Pfizer and Roche. MG has reported honoraria from Roche, Mundipharma, Gilead and Janssen. SR has reported research support from Janssen, Roche and Celgene; advisory boards for Janssen, Gilead, Roche, AstraZeneca and Celgene; speaker's honoraria from Janssen, Celgene and Roche. GS has reported personal fees for advisory boards or participation in meetings from Amgen, Celgene, Gilead, Janssen, Mundipharma, Novartis and Roche; grant support from Roche. UV has reported advisory boards for Roche and Janssen; honoraria for lectures from Roche, Janssen, Celgene, Takeda; conducting research as a global PI in multicentre studies sponsored by Roche and Celgene. ML has reported institutional research support from Celgene, Janssen, Mundipharma, Pfizer and Roche; speaker's honoraria from Bayer, Celgene, Gilead, Janssen and Roche; advisory boards for Bayer, Celgene, Gilead, Janssen, Pfizer and Roche. Correction to: Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-upAnnals of OncologyVol. 28Issue 12PreviewAnn Oncol 2016; 27(Suppl 5): v83–v90 (doi: ) Full-Text PDF Open Archive

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Abstract D056: Differences in breast cancer survival by race, age, and tumor estrogen receptor status

Abstract C039: Differences in breast cancer survival by race, age, and tumor estrogen receptor status

Impact of age and sex on chemotherapy (CTx) efficacy, toxicity and survival in early oesophagogastric (OG) cancer: A pooled analysis of 3265 patients from four large randomised trials (OE02, OE05, MAGIC &amp; ST03).

Pathologic Response to Neoadjuvant Therapy is Associated With Improved Long-term Survival in High-risk Primary Localized Malignant Peripheral Nerve Sheath Tumors.

Impact of Extent of Surgery on Tumor Recurrence and Survival for Papillary Thyroid Cancer Patients.

Risk-reducing mastectomy for the prevention of primary breast cancer.

Abstract P6-10-06: Racial differences in the characteristics and outcomes of young breast cancer patients: A national population-based study

Adjuvant radiotherapy is not supported in patients with verrucous carcinoma of the oral cavity

Multi-Database Description of Primary Splenic Diffuse Large B-Cell Lymphoma

Survival Trends in Young Patients with Waldenstrom Macroglobulinemia: Over 5 Decades of Experience

Efficacy and safety of prostate-targeted local therapy in patients with newly diagnosed oligometastatic prostate cancer: a systematic review and meta-analysis

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Impact of age and sex on chemotherapy (CTx) efficacy, toxicity and survival in early oesophagogastric (OG) cancer: A pooled analysis of 3265 patients from four large randomised trials (OE02, OE05, MAGIC & ST03).