Sloan, Jeffrey A.

Background Lymphedema is an adverse effect of breast cancer treatment that causes swelling and pain in the arm and hand. We tested 2 lymphedema prevention interventions and their impact on health‐related quality of life (HRQOL) in a group‐randomized trial at 38 cooperative group sites within the United States. Methods Patients were recruited before breast surgery. Sites were randomly assigned to education‐only (EO) lymphedema prevention or education plus exercise and physical therapy (LEAP). Lymphedema was defined as a ≥10% difference in arm volume at any time from baseline to 18 months postsurgery. HRQOL was assessed using the Functional Assessment of Cancer Therapy–Breast plus 4 lymphedema items (FACT‐B+4). Longitudinal mixed model regression analysis, adjusting for key demographic and clinical variables, examined participants' HRQOL by intervention group and lymphedema status. Results A total of 547 patients (56% LEAP) were enrolled and completed HRQOL assessments. The results revealed no differences between the interventions in preventing lymphedema ( P = .37) or HRQOL (FACT‐B+4 total score; P = .8777). At 18 months, the presence of lymphedema was associated with HRQOL at borderline significance ( P = .0825). However, African American patients reported greater lymphedema symptoms ( P = .0002) and better emotional functioning ( P = .0335) than patients of other races or ethnicities. Lower HRQOL during the intervention was associated with younger age ( P ≤ .0001), Eastern Cooperative Oncology Group performance status >0 ( P = .0002), ≥1 positive lymph nodes ( P = .0009), having no education beyond high school ( P < .0001), having undergone chemotherapy ( P = .0242), and having had only axillary node dissection or sentinel node biopsy versus both ( P = .0007). Conclusion The tested interventions did not differ in preventing lymphedema or in HRQOL outcomes. African American women reported greater HRQOL impacts due to lymphedema symptoms than women of other races or ethnicities.

Background Lymphedema affects many women who are treated for breast cancer. We examined the effectiveness of an education‐only (EO) versus education plus sleeve compression/exercise intervention (lymphedema education and prevention [LEAP]) on lymphedema incidence and range of motion (ROM) in a group‐randomized trial across 38 cooperative group sites. Methods The treating institution was randomly assigned to either EO or LEAP by a study statistician. All patients at a treating institution participated in the same intervention (EO or LEAP) to minimize contamination bias. Participants completed surveys, arm volume measurements, and self‐reported ROM assessments before surgery and at 12 and 18 months after surgery. Lymphedema was defined as a ≥10% difference in limb volume at any time post‐surgery up to 18 months after surgery or diagnosis by a health provider. Cochran‐Mantel‐Haenszel tests were used to compare lymphedema‐free rates between groups, stratified by lymph node surgery type. Self‐reported ROM differences were compared between groups. Results A total of 554 participants (56% LEAP) were included in the analyses. At 18 months, lymphedema‐free rates were 58% (EO) versus 55% (LEAP) ( P = .37). ROM for both arms was greater in LEAP versus EO at 12 months; by 18 months, most women reported full ROM, regardless of group. In LEAP, only one‐third wore a sleeve ≥75% of the time; 50% performed lymphedema exercises at least weekly. Conclusion Lymphedema incidence did not differ by intervention group at 18 months. Poor adherence in the LEAP group may have contributed. However, physical therapy may speed recovery of ROM. Further research is needed to effectively reduce the incidence and severity of lymphedema in patients who have breast cancer.

9599 Background: We have previously identified overall a single-item measure for baseline quality of life (QOL) as a strong prognostic factor for survival (Tan, ASCO 2008), and that fatigue was an important component of patient QOL (Sloan, 2007). To explore whether patient-reported fatigue was supplemental or redundant to the prognostic information of overall QOL, we performed a patient-level pooled analysis of 43 NCCTG and MCCC oncology clinical trials of the effect of baseline fatigue on OS. Methods: 3,915 patients participating in 43 trials provided data at baseline for fatigue on a single-item 0–100 point scale. OS was tested for association with clinically deficient fatigue (CDF, score 0–50, n=1,497) vs not clinically deficient fatigue (nCDF, score 51–100, n=2,418). Cox proportional hazards models adjusted for the effects of overall QOL, performance score, race, disease site, age and gender. Results: Baseline fatigue was a strong predictor of OS for the entire patient cohort (CDF vs. nCDF: 31.5 mos vs >83.9 mos, p<0.0001). The effect sizes were consistent across different disease sites (GI, esophageal, head and neck, prostate, lung, breast and others). After controlling for covariates, including performance status and overall QOL, baseline fatigue remained a strong prognostic factor in multivariate models (CDF vs. nCDF: HR=1.23, p=0.02). Conclusions: Fatigue is a strong prognostic factor for OS independent of overall QOL and PS in a wide variety of oncology patient populations. Single-item measures of overall QOL and fatigue can help to identify vulnerable subpopulations among cancer patients. No significant financial relationships to disclose.

6518 Background: Several studies have demonstrated the importance of pessimism in cardiovascular disease. However, this construct has not been well explored in oncology. Methods: This study examined the survival time of 534 adult who were diagnosed with lung cancer. These patients had completed the Minnesota Multiphasic Personality Inventory (MMPI) approximately 18.2 years prior to their lung cancer diagnosis. MMPI Optimism-Pessimism (PSM) scores were divided into high (60 or more) and low scores (less than 60), and log-rank tests and Kaplan-Meier curves were used to determine survival differences. Multivariate Cox models were used for assessing prognostic values of pessimism along with other known predictors for survival outcome. Results: At the time of diagnosis, patients were on average 67 years old, 48% were female, 85% had non-small cell lung cancer (NSCLC), 15% had small cell lung cancer (SCLC), 30% were stage I, 4% were stage II, 31% were stage III/Limited, and 35% were stage IV/Extensive. Patients who exhibited a non-pessimistic explanatory style survived approximately six months longer than patients classified as pessimists. Pessimists have significantly worse survival rates even after adjusting for other known prognostic variables. Conclusions: Among lung cancer patients, having a pessimistic explanatory style was related to surviving on average six months less compared to patients with a non-pessimistic explanatory style. [Table: see text] No significant financial relationships to disclose.

Abstract Background: Debate continues as to the clinical relevance of subclassifying patients with the myeloproliferative disorder (MPD) MMM into the subgroups of agnogenic myeloid metaplasia (AMM), post-polycythemic myeloid metaplasia (PPMM), and post-thrombocythemic myeloid metaplasia (PTMM). We looked to validate previously described phenotypic variability amongst subtypes, and explore relevant and differences in constitutional symptoms. Methods: An detailed analysis of patients with MMM whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, complete blood counts, co-morbidities (Charlson Co-morbidity index), symptoms, and fatigue (Fact-An and Brief Fatigue Inventory (BFI)). Results: A total of 456 patients self described as MMM responded of which 32.3% had AMM (n = 148), 38.0% % had PPMM (n = 174), and 29.7% had PTMM (n = 136). Detailed breakdown of differences in demographics, clinical course, current laboratory studies, treatment history, and current symptoms are outlined in the table below. Phenotypic Variability Amongst 458 MMM Patients Category AMM (N=148; 32.3%) PPMM (N=174; 38.0%) PTMM (N=136; 29.7%) MMM Total (N=458) Δ between groups (p = ) Hb = Hemoglobin; SCT = Stem Cell Transplant Age (Median) 61 57 57 58 0.09 Sex (% Males) 60% 49% 30% 47% &lt;0.01 Yrs from MPD Dx 5 6 8 6 &lt;0.01 Labs/ Prior History Hb (g/dL) 11.0 13.7 11.6 12.1 &lt;0.01 % with RBC Tx 43% 6% 11% 20% &lt;0.01 Leukocytes (×10(9)/L) 8.0 7.6 7.2 7.7 0.64 Platelets (×10(9))/L) 200 352 396 321 &lt;0.01 % with Splenomegaly 76% 49% 41% 54% &lt;0.01 % with Prior Thrombosis 10% 22% 31% 21% &lt;0.01 % with Prior Bleed 16% 20% 31% 22% 0.01 Treatment History for the MMM % with Prior Tx for MPD 64% 88% 77% 77% &lt;0.01 % Medical Therapy 57% 70% 75% 67% &lt;0.01 # Meds (Median (Range)) 1 (0–8) 2 (0–6) 2 (0–6) 2 (0–8) &lt;0.01 % with Splenectomy 8% 5% 6% 6% 0.48 % with SCT 6% 1% 1% 3% &lt;0.01 MMM Associated Constitutional Symptoms % with Fatigue 85% 81% 85% 84% 0.56 % with Bone Pain 51% 46% 44% 47% 0.51 % with Fevers 19% 17% 18% 18% 0.87 % with Pruritus 39% 69% 39% 50% &lt;0.01 % with Night Sweats 55% 58% 53% 56% 0.67 % with Weight Loss 30% 15% 16% 20% &lt;0.01 Overall the data suggests patients with AMM are more likely male, with greater burdens of anemia, splenomegaly, and weight loss. However they are less likely to have experienced thrombohemorrhagic complications and have received fewer MPD medications. In contrast PPMM patients (not unsurprisingly) have little trouble from anemia, but have the most pruritus. Patients with PTMM are most likely female, with the highest platelet counts, and the greatest likelihood of thrombohemorrhagic complications. Additionally, all three subgroups of MMM had significant fatigue compared to published controls for both fatigue instruments (P&lt;0.0001) yet there was no difference between MMM subtypes for the severity of fatigue. Conclusions: A large unselected series of MMM patients supports that although constitutional symptoms are significant and similar amongst MMM subgroups, these patients have variable burdens of other MPD manifestations.

Abstract Background: Scant data exists regarding the burden of fatigue and constitutional symptoms in patients with myeloproliferative disorders (MPDs) (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis with myeloid metaplasia (MMM)). Methods: An Internet based survey of MPD patients regarding clinical course, blood counts, constitutional symptoms, and fatigue (FACT-AN and Brief Fatigue Inventory (BFI)). Results: Patient Demographics: A total of 1179 MPD patients (median age 56; 41.4% male) internationally (76% USA: 50 states, 30 countries, 6 continents) responded to the survey. Self reported diagnoses were PV (35%), ET (26%), or MMM (39%). Clinical History: 1025 patients (87%) had undergone MPD therapy (drugs 70.5%, phlebotomy 44.1%, other 16%). Thrombosis (n=261, 22%), hemorrhage (N=272; 23%), and splenomegaly (N=478 (43%) were frequently reported. Blood tests (available in 917) showed 39% were anemic, 7% transfusion dependent. Symptoms: Fatigue, pruritus, night sweats and bone pain were present across the majority of MPD patients (see table). Additionally it was observed that these symptoms appeared with nearly equal frequency in PV as in MMM patients. However MMM patients displayed more advanced features (fevers, night sweats and weight loss). MPD Associated Constitutional Symptoms in 1179 Patients SYMPTOM PV (N=405) ET (N=304) MMM (N=456) MISSING (N=14) TOTAL (N=1179) P VALUE Fatigue 344 (84.9%) 220 (72.4%) 381 (83.6%) 7 945 (81.1%) &lt;0.0001 Pruritus 265 (65.4%) 120 (39.5%) 228 (50.0%) 3 613 (52.6%) &lt;0.0001 Night Sweats 199 (49.1%) 123 (40.5%) 254 (55.7%) 4 576 (49.4%) 0.0002 Bone Pain 174 (43.0%) 125 (41.1%) 214 (46.9%) 4 513 (44%) 0.2480 Fevers 53 (13.1%) 26 (8.6%) 81 (17.8%) 2 160 (13.7%) 0.0013 Weight Loss 39 (9.6%) 22 (7.2%) 93 (20.4%) 0 154 (13.2%) &lt;0.0001 Spleen Pain 17 (4.2%) 27 (8.9%) 30 (6.6%) 4 74 (6.3%) &lt;0.0001 Fatigue (82% MPD linked) was significantly increased across all MPD subtypes compared to published controls for both the BFI (P&lt;0.0001) and Fact-An (P&lt;0.0001). Additionally 69% curtail social activity because of fatigue, 35% need assistance with activities of daily living, and 11% reported MPD associated medical disability. Fatigue strongly correlated with multiple MPD disease features including: anemia, bone pain, constitutional symptoms, pruritus, splenic pain, smoking, thrombosis, and hemorrhagic events (all p&lt;0.0001). Interestingly, even in “asymptomatic” MPD patients (those without anemia, splenomegaly, or thrombohemorrhagic complications) (n=279)) 24% (41% PV, 31% ET, 28% MMM) described significant fatigue worse than published controls. Conclusions: Fatigue and other constitutional symptoms are a significant burden to MPD patients, despite current therapies employed. Additionally fatigue is also a significant problem even in MPD patients lacking other advanced disease features. Clearly, direct attempts to improve fatigue (through pharmacologic and non-pharmacologic interventions) are necessary.

Abstract Background: Little objective data exists regarding the impact that myeloproliferative disorders (MPDs) (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis with myeloid metaplasia (MMM)) have on quality of life. Methods: An Internet based survey of MPD patients regarding clinical course, co-morbidities (through the Charlson Co-Morbidity Index), fatigue (through two validated fatigue instruments (FACT-AN and Brief Fatigue Inventory (BFI)), and exercise tolerance (Godin Leisure-Time Questionnaire). Results: Patient Demographics: A total of 830 MPD patients (median age 56; 60.8% male) from a broad geographic distribution (77% USA: 50 states, 30 countries, 5 continents) responded to the survey. Self reported diagnoses were PV (N=272; 33%), ET (N=221; 27%), or MMM (N=329; 40%) for a median of 5 years (range (0–53). Clinical History: 708 patients (87%) had undergone treatment for their MPD (drugs 84.6%, phlebotomy 49.5%, other 16%). A history of thrombotic (n=195, 24%) or hemorrhagic events (N=214; 26%) were frequently reported. Blood tests (available in 597 a median 1.65 months prior to survey) showed 37% were anemic (7% transfusion dependent). Additionally, 347 (44%) had splenomegaly, painful in 21%. Symptoms: Frequent symptoms reported included fatigue (90%), pruritus (57%), night sweats (54%), bone pain (48%), undesired weight loss (15%), and/or fevers (15%). 41% felt restricted in their activities, and 89 (11%) were medically disabled secondary directly to their MPD. 82% of patients felt their fatigue was linked to their MPD. Additionally 69% curtail social activity because of fatigue, and 41% need some degree of assistance with activities of daily living. Charlson co-morbidity index demonstrated 722 (87%) had minimal co-morbidities strengthening the association between fatigue and their MPD. The burden of fatigue decreased from MMM to PV to ET respectively (p=0.0002). Results from both fatigue assessment tools (FACT-AN and BFI) were highly correlated. Fatigue (FACT-AN fatigue subscale) strongly correlated with multiple MPD disease features including: anemia, bone pain, constitutional symptoms, pruritus, splenic pain, hemorrhagic events (all p&lt;0.0001) and thrombosis(p=0.01). Additionally, currently smoking (as opposed to being a prior smoker) was highly associated with increased fatigue (p&lt;0.0001). Interestingly, even in “asymptomatic” patients (those without anemia, splenomegaly, or thrombohemorrhagic complications (n=187)) 73% (n=128; 40% PV, 32% ET, 27% MMM; p=N.S.) described moderate to severe MPD associated fatigue. Reported physical activity was diminished (Godin Leisure Score) between MPD patients and published norms, with 38% describing minimal to no exercise. Overall, 86% stated fatigue was the major obstacle to exercise. Conclusions: Fatigue is an extremely common problem in patients with MPDs despite current therapies, and a minimal burden of co-morbidities in the majority of patients. Fatigue is also common in patients lacking advanced MPD disease features, or thrombohemorrhagic complications. Clearly, direct attempts to improve fatigue (through pharmacologic and non-pharmacologic interventions) are necessary.

Abstract Background: Myelofibrosis (MF) shortens survival but also compromises quality of life from disease associated splenomegaly and constitutional symptoms (fatigue, weight loss, night sweats, and bone pain). No current validated instrument of patient reported outcomes (PRO) captures the spectrum of MF associated symptoms. In an era of rapid development and testing of therapeutic agents which may impact the natural history and symptoms associated with MF (such as JAK2 inhibitors) a uniform and validated instrument for capturing the presence, severity (and potentially improvement) of MF symptoms is needed. We sought to develop and validate such an instrument, the myelofibrosis symptom assessment form (MFSAF). Methods: Based upon the results in our MF QOL survey (Cancer2007;109(1):68–76), we developed the MFSAF to assess fatigue (via the brief fatigue inventory (BFI-Cancer1999;85:1186)), additional symptoms were independently assessed for presence and severity on a scale from 0 (absent) to 10 (worst possible) for splenomegaly associated symptoms (early satiety, pain, inactivity, cough) night sweats, itching, bone pain, fever, unintentional weight loss as well as an estimate of overall quality of life. Additionally, patients provided feedback on the quality and nature of the MFSAF, and also completed for comparison validated instruments including the Memorial Symptom Assessment Scale (MSAS), the Insomnia Severity Index (ISI), and the Brief Pain Index. Physician input was included including their assessment of patient’s fatigue, spleen symptoms, and quality of life (blinded to patient’s responses) as well as clinical history, lab and exam findings. Results: MFSAF Results 34 MPD patients were enrolled (24 MF, 10 in the comparison group (4 polycythemia vera (PV), 6 essential thrombocythemia (ET)). the MFSAF was rated by patients as easy to understand (median score 1, range 0–6), and “addressed most of my symptoms” (median score 1, range 0–6) both on a scale of 0 (as good as possible to 10 as bad as possible). When asked if a symptom was not addressed (open ended response) no single symptom was named more than once. As we have previously reported fatigue was common with BFI scores (median 3.6 (0–10) for MF and 2.5 (range 0.2–3.8) for the ET/PV group (increasing BFI score associated with worsening fatigue) worse than median score of published “healthy” controls 2.2. Additional MF associated symptoms were captured well by the MFSAF with splenic, constitutional symptoms, and QOL (median 3 (range 0–7) MF, median 2 (0–3) ET/PV) documented easily and worse than ET/PV controls. Physicians estimation of QOL was excellent (median 3 (0–8) for MF, median 2 (0–4) for ET/PV). MFSAF Comparison to other Instruments: The MSAS demonstrated more adverse values for MF (than ET/PV) in the PSYCH (psychologic stress; mean-1.27 (STD DEV 0.80), PHYS (physical symptoms; mean 0.90 (STD DEV 0.53)), GDI (Global Distress Index mean-1.29 (STD DEV 0.77)) and a total MSAS symptom score (mean 0.85 (std dev (0.49)) comparable with advanced renal disease (PSYCH 0.99, PHYS 0.99, GDI 1.27, and MSAS of 0.81; J of Pall Med2007;10(6):1266), as well as advanced lung disease, AIDS, and various advanced malignancies. Individual, previously validated MSAS questions were all highly correlated (all p&lt;0.01) with MFSAF (in italic) counterparts including lack of energy (fatigue), cough (same), pain (both abdominal pain and bone pain), sweats (night sweats), itching (same), and weight loss (same). Further validation of pain measurements in the MFSAF came from comparison to the BPI where both individually the presence, and intensity of pain (both abdominal and bone) were highly correlated (all p&lt;0.01). Insomnia, not yet included in the MFSAF, was present in 68% and 63% of patients (MSAS and ISI, respectively). Additionally, problems with sexual interest, or activity, was noted in 35% of patients to the MSAS. Conclusions: Currently available instruments of PRO and symptoms are lengthy, and individually incomplete for assessing the presence and severity of the diverse nature of symptoms associated with MF. The proposed MFSAF, was comprehensive and well understood by patients and the results for the individual symptoms assessed were highly correlated with previously validated instruments for other conditions as well as with physicians perceptions of fatigue and QOL. The MFSAF, with the addition of questions regarding insomnia and sexuality, should be utilized in all trials of therapeutic agents in MF patients in which symptomatic improvements are an endpoint.

8530 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose limiting complication of chemotherapy. Lamotrigine (an anti-convulsant drug) appears to have some benefit when used to treat pain from neuropathy due to various etiologies. Based on these data, we conducted a phase III randomized placebo controlled study to determine the efficacy of lamotrigine in treating symptoms from CIPN. Methods: Patients with CIPN for 1 month or more were randomly assigned to lamotrigine (target dose 300 mg/day, increased by 50 mg/2 weeks) or placebo for 10 weeks. The co-primary endpoints were differences in average CIPN symptoms assessed by pro-rated area under the curve (AUC) of a numerical pain rating scale (NRS) and the Eastern Cooperative Oncology Group sensory neuropathy (ESN) scale. Accrual of 60 patients per group provided t-tests with 80% power to detect a difference of 0.57 standard deviation for each co-primary endpoint (moderate effect size) with a type I error of 0.025. Results: 131patients were enrolled, with complete data available for analysis in 93 (72%). Analyses were limited to this cohort but will be updated. Chemotherapy drugs considered to be causative of the CIPN were vinca alkaloids (30%), taxanes (25%), platinum-agents (7%), combinations (34%), and others (3%). Patients were equally matched with regards to baseline characteristics. Patients who enrolled had severe symptoms, with a baseline median ESN at enrollment of 3 (out of 3) in both groups. Toxicities were similar in both groups, however, more patients discontinued lamotrigine due to toxicities/refusals than those on placebo (32% vs 13% resp; p=0.04) and were therefore less likely to complete the 10 weeks therapy (60% vs. 78% resp, p=0.08). Average AUC of NRS score for patients on lamotrigine and placebo was 30.5 and 33.7 resp (p=0.48). The corresponding average AUC of the ESN scores were 12.4 and 14.5 (p=0.23). The proportions of patients with a 10 point (of 100) improvement in worst pain score (39% vs 36%) and a 1 point change in ESN (25% vs 27%) were similar between the lamotrigine and placebo arms, resp. Conclusions: These results suggest that lamotrigine is not effective for managing pain and symptoms due to CIPN. No significant financial relationships to disclose.

AbstractBackgroundThe addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum.Subjects, Materials, and MethodsPatients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles.ResultsE5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3–4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue.ConclusionAt 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer.Implications for PracticeAt 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.