Andrea L. Cheville

Weight Lifting in Women with Breast-Cancer–Related Lymphedema

BACKGROUND Weight lifting has generally been proscribed for women with breast-cancer-related lymphedema, preventing them from obtaining the well-established health benefits of weight lifting, including increases in bone density. METHODS We performed a randomized, controlled trial of twice-weekly progressive weight lifting involving 141 breast-cancer survivors with stable lymphedema of the arm. The primary outcome was the change in arm and hand swelling at 1 year, as measured through displaced water volume of the affected and unaffected limbs. Secondary outcomes included the incidence of exacerbations of lymphedema, number and severity of lymphedema symptoms, and muscle strength. Participants were required to wear a well-fitted compression garment while weight lifting. RESULTS The proportion of women who had an increase of 5% or more in limb swelling was similar in the weight-lifting group (11%) and the control group (12%) (cumulative incidence ratio, 1.00; 95% confidence interval, 0.88 to 1.13). As compared with the control group, the weight-lifting group had greater improvements in self-reported severity of lymphedema symptoms (P=0.03) and upper- and lower-body strength (P<0.001 for both comparisons) and a lower incidence of lymphedema exacerbations as assessed by a certified lymphedema specialist (14% vs. 29%, P=0.04). There were no serious adverse events related to the intervention. CONCLUSIONS In breast-cancer survivors with lymphedema, slowly progressive weight lifting had no significant effect on limb swelling and resulted in a decreased incidence of exacerbations of lymphedema, reduced symptoms, and increased strength. (ClinicalTrials.gov number, NCT00194363.)

Weight Lifting for Women at Risk for Breast Cancer–Related Lymphedema: A Randomized Trial

CONTEXT Clinical guidelines for breast cancer survivors without lymphedema advise against upper body exercise, preventing them from obtaining established health benefits of weight lifting. OBJECTIVE To evaluate lymphedema onset after a 1-year weight lifting intervention vs no exercise (control) among survivors at risk for breast cancer-related lymphedema (BCRL). DESIGN, SETTING, AND PARTICIPANTS A randomized controlled equivalence trial (Physical Activity and Lymphedema trial) in the Philadelphia metropolitan area of 154 breast cancer survivors 1 to 5 years postunilateral breast cancer, with at least 2 lymph nodes removed and without clinical signs of BCRL at study entry. Participants were recruited between October 1, 2005, and February 2007, with data collection ending in August 2008. INTERVENTION Weight lifting intervention included a gym membership and 13 weeks of supervised instruction, with the remaining 9 months unsupervised, vs no exercise. MAIN OUTCOME MEASURES Incident BCRL determined by increased arm swelling during 12 months (≥5% increase in interlimb difference). Clinician-defined BCRL onset was also evaluated. Equivalence margin was defined as doubling of lymphedema incidence. RESULTS A total of 134 participants completed follow-up measures at 1 year. The proportion of women who experienced incident BCRL onset was 11% (8 of 72) in the weight lifting intervention group and 17% (13 of 75) in the control group (cumulative incidence difference [CID], -6.0%; 95% confidence interval [CI], -17.2% to 5.2%; P for equivalence = .04). Among women with 5 or more lymph nodes removed, the proportion who experienced incident BCRL onset was 7% (3 of 45) in the weight lifting intervention group and 22% (11 of 49) in the control group (CID, -15.0%; 95% CI, -18.6% to -11.4%; P for equivalence = .003). Clinician-defined BCRL onset occurred in 1 woman in the weight lifting intervention group and 3 women in the control group (1.5% vs 4.4%, P for equivalence = .12). CONCLUSION In breast cancer survivors at risk for lymphedema, a program of slowly progressive weight lifting compared with no exercise did not result in increased incidence of lymphedema. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00194363.

Adverse Health Outcomes in Women Exposed In Utero to Diethylstilbestrol

BACKGROUND Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. METHODS We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. RESULTS Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. CONCLUSIONS In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

The Myelofibrosis Symptom Assessment Form (MFSAF): An evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis

Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international Internet-based survey of 458 patients with MF we created a 20-item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials.

The grading of lymphedema in oncology clinical trials

Lymphedema is a common late toxicity of cancer therapy. This article describes the rationale and process utilized by the Lymphedema Working Group for the revision and expansion of the Common Toxicity Criteria version 2 (CTC v2.0) lymphedema criteria to produce the CTC v3.0 lymphedema criteria. Established clinician-based rating scales and quantitative instruments are reviewed in this article. None of the extant rating scales have been formally validated, nor has their reliability been assessed. Drawbacks of current scales were considered in formulating CTC v3.0 criteria. Most rely exclusively on volume to diagnose and grade lymphedema. This imposes significant clinical limitations, particularly in the assessment of toxicity in oncology clinical trials. Volume-based rating scales are of little value in rating the severity of bilateral limb and nonlimb edema. Problems with nonvolumetric staging systems (eg, CTC v2.0) include insufficient detail to permit useful discrimination of severity among the majority of lymphedema patients. Technologies for objectively quantifying lymphedema have been developed and validated. Although these are briefly reviewed, it is recognized that cost and access issues limit their widespread clinical utility and, as such, were not considered in developing the CTC v3.0 criteria. The CTC v3.0 lymphedema criteria adopted several innovations. Principle among these was the decision to generate separate criteria for volumetric increase, dermal changes, and subcutaneous fibrosis. We anticipate the use of the new CTC v3.0 lymphedema criteria to begin in mid-2003 for grading the key clinical features of this disorder in oncology clinical trials. The purpose of this article is to familiarize the reader with (1) background on the clinical features of lymphedema, (2) information on established lymphedema rating systems, (3) the consensus process and rationale of the Lymphedema Working Group, (4) the new CTC v3.0, and (5) quantitative techniques for assessment of lymphedema.

Prevalence and treatment patterns of physical impairments in patients with metastatic breast cancer.

PURPOSE Physical impairments cause profound functional declines in patients with cancer. Although common rehabilitation measures can address many impairments, the extent of their delivery is unknown. We studied these issues by quantifying physical impairments in patients with metastatic breast cancer and by assessing how they are addressed. PATIENTS AND METHODS A consecutive sample of 163 community-dwelling patients with metastatic breast cancer was stratified by Karnofsky performance score and administered the Medical Outcomes Study Physical Function Subscale and the Older Americans Resource Study Activities of Daily Living subscales. Cancer-related physical impairments were identified through a physical examination, the 6-Minute Walk Test, and the Functional Independence Measure Mobility Subscale. Patients were questioned regarding the nature, type, and setting of treatments for impairments. Physical rehabilitation needs were determined through a consensus process involving physiatrists and physical/occupational therapists specializing in cancer. RESULTS Ninety-two percent of patients (150 of 163) had at least one physical impairment. Among 530 identified impairments, 484 (92%) required a physical rehabilitation intervention and 469 (88%) required physical therapy (PT) and/or occupational therapy (OT). Only 30% of impairments requiring rehabilitation services and 21% of those requiring PT/OT received treatment. Impairments detected during hospitalization were overwhelmingly more likely to receive a rehabilitation intervention (odds ratio [OR] = 87.9; 95% CI, 28.5 to 271.4), and PT/OT (OR = 558.8; 95% CI, 187.0 to 1,669.6). Low socioeconomic and minority status were significantly associated with nontreatment. CONCLUSION Remediable physical impairments were prevalent and poorly addressed among patients with metastatic breast cancer, drastically so in the outpatient setting. Undertreatment was particularly prominent among minority and socioeconomically disadvantaged groups.

Physical activity and lymphedema (the PAL trial): Assessing the safety of progressive strength training in breast cancer survivors☆

Lymphedema is a chronic and progressive long-term adverse effect of breast cancer treatment commonly defined by swelling of the affected arm. Current clinical guidelines indicate that women with and at risk for lymphedema should protect the affected arm from overuse. In clinical practice, this often translates into risk aversive guidance to avoid using the arm. This could lead to a disuse pattern that may increase the likelihood of injury from common activities of daily living. Further, such guidance poses an additional barrier to staying physically active, potentially translating to weight gain, which has been shown to be associated with worse clinical course for women with lymphedema. We hypothesize that a program of slowly progressive strength training with no upper limit on the amount of weight that may be lifted would gradually increase the physiologic capacity of the arm so that common activities represent a decreasing percentage of maximal capacity. Theoretically, this increased capacity should decrease the risk that daily activities put stress on the lymphatic system of the affected side. The Physical Activity and Lymphedema (PAL) Trial is a recently completed randomized controlled exercise intervention trial that recruited 295 breast cancer survivors (141 with lymphedema at study entry, 154 at risk for lymphedema at study entry). The purpose of this report is to provide detail regarding the study design, statistical design, and protocol of the PAL trial.

Lymphedema after surgery for endometrial cancer: Prevalence, risk factors, and quality of life

OBJECTIVE: To estimate lower extremity lymphedema prevalence in patients surgically treated for endometrial cancer, identify predictors of lymphedema, and evaluate the effects of lymphedema on quality of life. METHODS: One thousand forty-eight consecutive patients who were operated on between 1999 and 2008 at the Mayo Clinic were mailed a survey, which included our validated 13-item lymphedema screening questionnaire and two validated quality-of-life measures. Logistic regression models were fit to identify factors associated with prevalent lymphedema; a multivariable model was obtained using stepwise and backward variable selection methods. The relationship between lymphedema and obesity with each quality-of-life score was evaluated separate multivariable linear models. RESULTS: There were 591 responders (56%) after exclusions. Our questionnaire revealed a previous self-reported lymphedema diagnosis in 103 (17%) patients and identified undiagnosed lymphedema in 175 (30%) (overall prevalence 47.0%, median 6.2 years follow-up). Lymphedema prevalence in patients treated with hysterectomy alone compared with lymphadenectomy was 36.1% and 52.3%, respectively (attributable risk 23%). Lymphedema risk was not associated with the number of nodes removed or the extent of lymphadenectomy after adjusting for other factors. On multivariable analysis, higher body mass index, congestive heart failure, performance of lymphadenectomy, and radiation therapy were associated with prevalent lymphedema. Multiple quality-of-life scores were worse in women with lymphedema. CONCLUSION: The attributable risk of developing lower extremity lymphedema was 23% for patients with endometrial cancer who underwent lymphadenectomy compared with hysterectomy alone with an overall prevalence of 47%. Lymphedema was associated with reductions in multiple quality-of-life domains. LEVEL OF EVIDENCE: II

Management of Chronic Pain in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide evidence-based guidance on the optimum management of chronic pain in adult cancer survivors. METHODS An ASCO-convened expert panel conducted a systematic literature search of studies investigating chronic pain management in cancer survivors. Outcomes of interest included symptom relief, pain intensity, quality of life, functional outcomes, adverse events, misuse or diversion, and risk assessment or mitigation. RESULTS A total of 63 studies met eligibility criteria and compose the evidentiary basis for the recommendations. Studies tended to be heterogeneous in terms of quality, size, and populations. Primary outcomes also varied across the studies, and in most cases, were not directly comparable because of different outcomes, measurements, and instruments used at different time points. Because of a paucity of high-quality evidence, many recommendations are based on expert consensus. RECOMMENDATIONS Clinicians should screen for pain at each encounter. Recurrent disease, second malignancy, or late-onset treatment effects in any patient who reports new-onset pain should be evaluated, treated, and monitored. Clinicians should determine the need for other health professionals to provide comprehensive pain management care in patients with complex needs. Systemic nonopioid analgesics and adjuvant analgesics may be prescribed to relieve chronic pain and/or to improve function. Clinicians may prescribe a trial of opioids in carefully selected patients with cancer who do not respond to more conservative management and who continue to experience distress or functional impairment. Risks of adverse effects of opioids should be assessed. Clinicians should clearly understand terminology such as tolerance, dependence, abuse, and addiction as it relates to the use of opioids and should incorporate universal precautions to minimize abuse, addiction, and adverse consequences. Additional information is available at www.asco.org/chronic-pain-guideline and www.asco.org/guidelineswiki.

Time course of mild arm lymphedema after breast conservation treatment for early-stage breast cancer.

PURPOSE Arm lymphedema is a potential consequence of the treatment for breast carcinoma. The objective of this retrospective study was to characterize the progression of mild arm lymphedema after breast conservation treatment for breast cancer. METHODS AND MATERIALS The study cohort was drawn from 1,713 consecutive Stage I or II breast cancer patients who underwent breast conservation therapy, including axillary staging followed by radiation. Arm lymphedema was documented in 266 (16%) of 1,713 patients. One hundred nine patients, 6% of the overall group and 40% of the patients with arm lymphedema, presented with mild arm lymphedema, defined as a difference of 2 cm or less between the measured circumferences of the affected and unaffected arms. RESULTS Among the 109 patients with mild arm lymphedema at the time of arm lymphedema diagnosis, the rate of freedom from progression to more severe lymphedema was 79% at 1 year, 66% at 3 years, and 52% at 5 years. The patients who were morbidly obese, had positive axillary lymph nodes, or received supraclavicular irradiation at the time of breast cancer treatment were at higher risk of progression from mild arm lymphedema to more severe edema. CONCLUSIONS Mild arm lymphedema, generally considered to be a minor complication after breast conservation treatment for breast cancer, was associated with a risk of progression to a more severe grade of arm lymphedema in a substantial fraction of patients.