Hudson, Melissa M.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment, with the goal of helping healthcare professionals who work with survivors, including those in primary care. The guidelines also provide recommendations to help clinicians promote physical activity, weight management, and proper immunizations in survivors and facilitate care coordination to ensure that all of the survivors’ needs are addressed. These NCCN Guidelines Insights summarize additions and changes made to the guidelines in 2020 regarding cardiovascular disease risk assessment and screening for subsequent primary malignancies.

Background: Lymphoma patients exposed to chest RT during adolescence/young adulthood are at increased risk for BC; the cumulative incidence exceeds 20% by age 45 and the BC risk is comparable to that in women with BRCA1 mutations. These findings present an urgent yet unmet need to reduce the risk of BC in RT-exposed lymphoma survivors. The risk of BC is 50% lower in chest RT-exposed survivors who also receive ovarian radiation, suggesting a critical role of endogenous estrogens in RT-related breast carcinogenesis, making tamoxifen (a selective estrogen receptor modulator) an attractive risk-reducing option. Tamoxifen administered at 20 mg/d is effective in BC prevention in other high risk populations, but severe adverse events (SAE: venous thromboembolism, endometrial cancer) have limited its broad use. Previous biomarker trials in the general population have shown that LDTam (5mg/d) is not inferior to tamoxifen at 20 mg/d in reducing BC risk, and is associated with a safer AE profile. Mammographic breast density (MBD) is an established biomarker of BC risk; high MBD is associated with a 4-fold higher risk of BC. We hypothesized that LDTam would be effective in reducing BC risk (using MBD as a primary endpoint) in chest RT-exposed lymphoma survivors. We used an investigator-initiated, multi-institutional, randomized phase IIb, double blind, placebo controlled trial (FDA IND 107367) to test this hypothesis. Methods: Female patients from 13 sites were ≥25y at enrollment, with a history of exposure to chest RT at ≥12 Gy by age 40 for their primary cancer, and were off therapy for ≥6 mo. Subjects with a prior history of BC/DCIS, B/L mastectomy, or baseline MBD <25% in both breasts were excluded. Tamoxifen 5mg or identical placebo tablets were provided by Sharp Clinical Services (Allentown, PA) under good manufacturing practice. Subjects were randomized 1:1 in a double-blinded fashion by a Web-based system to receive LDTam or placebo daily for 2y. MBD (in both breasts) was measured centrally on digital scans independently by 3 radiologists at baseline, 1y and 2y. Using an intention-to-treat analysis, the efficacy of LDTam in reducing MBD was compared between the LDTam and placebo arms by applying a linear mixed effects model for bivariate normally distributed data with random intercept and time*treatment arm effects. Correlations between the left and right breasts and within radiologists were accounted for in the model. Treating clinicians and all research staff were blinded to the treatment arm. Results: A total of 72 patients (LDTam: n=34; placebo: n=38) participated in the trial; primary diagnosis: Hodgkin lymphoma (86%); non-Hodgkin lymphoma (10%); other (3%); median age at diagnosis of primary cancer: 21.5y (IQR, 16-28), and at trial enrollment: 43.8y (35-49); median time from diagnosis of primary cancer to study: 17.0y (12-26). Median chest RT dose: 30.3 Gy (21-37.3); 11% had received pelvic radiation; 39% were post-menopausal at study. Participant characteristics were comparable between the two treatment arms, as was the mean baseline MBD (LDTam: 52.6% vs. placebo: 50.4%, p=0.6). The time*treatment arm effect was statistically significant (LDTam vs. placebo: estimate = -1.7, SE = 0.5, p = 0.001), indicating a significantly lower mean fitted MBD for LDTam (43.9%) vs. placebo (47.3%) at 2y (Figure). This represented a 16.5% relative reduction in MBD on the LDTam arm, corresponding to an estimated 33% lower risk of BC (assuming that reductions in MBD have the same benefit in lymphoma survivors as they do in the general population). There were no grade 3 or 4 AEs related to LDTam. Grade 2 AEs did not differ between treatment arms (LDTam: 44.1% vs. placebo: 36.8%, p=0.6). There was no difference in the prevalence of moderate-to-severe patient-reported outcomes between the treatment arms (Table). Conclusion: Low-dose tamoxifen was associated with a significantly steeper decline in MBD in chest RT-exposed lymphoma survivors, when compared with placebo, and was safe and well-tolerated. This is the first trial demonstrating efficacy of a pharmacologic intervention in reducing a biomarker strongly associated with breast cancer risk in lymphoma survivors with a past history of chest radiation. Disclosures Palomares: Covance: Other: Medical monitoring. Henderson:Seattle Genetics: Research Funding. OffLabel Disclosure: The drug is a low-dose tamoxifen, a selective estrogen receptor modulator. Tamoxifen in standard doses is used to reduce the risk of breast cancer in high risk populations. Tamoxifen in standard or low doses have not been tested before for chest-irradiated cancer survivors to reduce the risk of radiation-related breast cancer.

Abstract Abstract 664 Background: Survivors of childhood acute lymphoblastic leukemia (ALL) who received prophylactic cranial radiation therapy (CRT) are at increased risk for deficits in neurocognitive skills, including attention, working memory and processing speed. As survivors age, global brain injury from CRT may reduce cognitive reserve, placing them at risk for early onset dementia or long-term memory deficits. The prevalence of dementia and memory abnormalities in adult survivors of childhood ALL has not previously been established. Methods: Analyses were conducted on 265 of 445 (60%) eligible survivors of childhood ALL (median age 36 years, range 26–54 years; 52% female) treated with 18Gy (n=127) or 24Gy (n=138) CRT with a median time from CRT of 30 years (range 15–46 years). Participants completed the Wechsler Memory Scale IV, including the Brief Cognitive Status Exam (BSCE), and the Wechsler Abbreviated Scale of Intelligence (WASI). Age-adjusted standard scores were calculated and the BSCE was also adjusted for education level. Prevalence of memory impairment (<1 SD below age-expected mean), stratified by RT dose exposure, is reported and logistic regression used to identify risk factors for impairment. A subset of survivors (n=85) completed brain magnetic resonance imaging (MRI), including assessment of hippocampal volume, cortical thickness, white matter volume, diffusion tensor imaging, and functional MRI (fMRI) during a cued-recall memory task. Results: Survivors who received 24 Gy CRT had increased impairment on global measures of both short-term recall (33%; p<0.001) and long-term recall (30%; p<0.001), while no increase in impairment was seen after 18Gy. Impaired short-term recall was associated with smaller right (p=0.02) and left (p<0.01) temporal lobe volumes, while impaired long-term recall was associated with thinner parietal and frontal cortices. On subtests evaluating narrative memory (i.e. story recall) and design memory, increasing RT dose (24 vs. 18Gy) was associated with an increased prevalence of long-term memory impairment (narrative: 28% vs. 12%, p=0.001; designs: 13% vs. 3.2%, p=0.003). However, no CRT dose response was identified for short term narrative and design memory. Survivors with impaired long-term memory for designs demonstrated a compensatory increase in left hippocampal fMRI activation (p=0.005), and the effect was greater in the higher dose group (p = 0.04). The mean score for long-term narrative memory among survivors who received 24Gy was equivalent to the mean score of a 70–74 year old adult population. Neither young age (0–4 years) at CRT (Odds Ratio [OR] 1.4, 95% confidence interval [CI] 0.8–2.7), time from CRT (OR 1.0, 95% CI 0.9–1.1) nor intrathecal methotrexate exposure (OR 3.9, 95% CI 0.4–36.1) were significantly associated with long-term memory deficits. Reduced cognitive status (by BSCE) was identified after 18Gy (9%, p=0.11) and 24Gy (18%, p<0.001), suggesting a CRT dose-response effect. On diffusion tensor imaging, increased radial diffusivity in the frontal, parietal and temporal regions, an inverse measure of white matter integrity, was associated with reduced BSCE. Current employment rates were equivalent (63%) in both CRT dose groups, suggesting no difference in functional status. Conclusions: Aging adult survivors of ALL who received 24Gy CRT have reduced cognitive status and significant impairment in short-term and long-term memory. There appears to be a dose response effect selective for long-term narrative and design memory, but not for short term narrative and design memory. These patterns are consistent with early onset of age-related (long-term) memory loss, and early stage dementia, yet at a median age of only 36 years. After 24Gy, survivors have the narrative memory equivalent to a 70 year-old in the general population. Survivors with memory impairment demonstrated reduced integrity on structural and functional neuroimaging in anatomical regions established as essential for memory formation and long-term recall. However, these memory impairments do not seem to affect functional status (employment rates) suggesting that, rather than frank dementia, deficits in middle adulthood are consistent with mild cognitive impairment (MCI). Longitudinal evaluation of this population is needed as MCI often progresses into early onset dementia with age. Disclosures: No relevant conflicts of interest to declare.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of cancer and cancer treatment to aid healthcare professionals who work with survivors of adult-onset cancer. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors and to facilitate care coordination to ensure that all needs are addressed. These NCCN Insights summarize some of the topics discussed by the NCCN Survivorship Panel during the 2019 update of the guidelines, including the survivorship population addressed, ways to improve care coordination, and pain management.

AbstractBackgroundSurvivors of childhood non‐Hodgkin lymphoma (NHL) are at increased risk for chronic health conditions. The objective of this study was to characterize health conditions, neurocognitive function, and physical performance among a clinically evaluated cohort of 200 childhood NHL survivors.MethodChronic health and neurocognitive conditions were graded as per a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and impaired physical function defined as performance < 10th percentile of normative data. Multivariable regression was used to investigate associations between sociodemographic characteristics, therapeutic exposures, and outcomes.ResultsSurvivors were a median age of 10 years (range 1–19) at diagnosis and 34 years (range 20–58) at evaluation. Eighty‐eight (44%) received radiation, 46 (23%) cranial radiation, and 69 (35%) high‐dose methotrexate. Most prevalent CTCAE Grades 3–4 (severe life‐threatening) conditions were obesity (35%), hypertension (9%), and impairment of executive function (13%), attention (9%), and memory (4%). Many had impaired strength (48%), flexibility (39%), muscular endurance (36%), and mobility (36%). Demographic and treatment‐related factors were associated with the development of individual chronic diseases and functional deficits.ConclusionsClinical evaluation identified a high prevalence of chronic health conditions, neurocognitive deficits, and performance limitations in childhood NHL survivors.

BACKGROUNDHealth complications related to childhood cancer may be influenced by risky health behaviors (RHBs), particularly when RHBs co‐occur. To the authors' knowledge, only limited information is available describing how RHBs cluster among survivors of childhood cancer and their siblings and the risk factors for co‐occurring RHBs.METHODSLatent class analysis was used to identify RHB clusters using longitudinal survey data regarding smoking, alcohol use, and physical activity from adult survivors (4184 survivors) and siblings (1598 siblings) in the Childhood Cancer Survivor Study. Generalized logistic regression was used to evaluate associations between demographic characteristics, treatment exposures, psychological distress, health conditions, and cluster membership.RESULTSThree RHB clusters were identified: a low‐risk cluster, an insufficiently active cluster, and a high‐risk cluster (tobacco and risky alcohol use and insufficient activity). Compared with siblings, survivors were more likely to be in the insufficiently active cluster (adjusted odds ratio [ORadj], 1.17; 95% confidence interval [95% CI], 1.06‐1.27) and were less likely to be in the high‐risk cluster (ORadj, 0.79; 95% CI, 0.69‐0.88). Risk factors for membership in the high‐risk cluster included psychological distress (ORadj, 2.76; 95% CI, 1.98‐3.86), low educational attainment (ORadj, 7.49; 95% CI, 5.15‐10.88), income <$20,000 (ORadj, 2.62; 95% CI, 1.93‐3.57), being divorced/separated or widowed (ORadj, 1.36; 95% CI, 1.03‐1.79), and limb amputation (ORadj, 1.52; 95% CI, 1.03‐2.24). Risk factors for the insufficiently active cluster included chronic health conditions, psychological distress, low education or income, being obese or overweight, female sex, nonwhite race/ethnicity, single marital status, cranial radiation, and cisplatin exposure.CONCLUSIONSRHBs co‐occur in survivors of childhood cancer and their siblings. Economic and educational disadvantages and psychological distress should be considered in screening and interventions to reduce RHBs. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2747–2756. © 2016 American Cancer Society.