In this cohort of 269 breast cancer patients, LVC at ≥ 5.0% occurred in up to 61.3% of patients by 24 months postoperatively, with an incidence that increased over time. The most common signs and symptoms associated with LVC (e.g., tenderness, firmness/tightness, swelling, heaviness, and aching) were detected in 22.2% to 37.0% of patients with mild LVC (5.0–9.9%). In multivariate analyses, other complications and increase in BMI were the most significant factors associated with increasing LVC, while increasing age was associated with a lower risk of LVC. Significant decrements in QOL scores, as measured by the FLIC, were also detected in patients with mild LVC (5.0–9.9%). However, moderate LVC (10.0–14.9%) (p=0.015) and postoperative infections (p=0.003) had the most significant impact on QOL.
The risk factors identified in this study are concordant with findings noted in the existing body of lymphedema literature (7
). Several contemporary studies with 6 to 12 months of follow-up have documented less overall risk for lymphedema (2.2–6.9%) in the current era of breast conservation and sentinel lymph node techniques (20
). However, with a median follow-up of over 24 months, the incidence of maximum LVC at ≥ 5.0% was 23.8% by 12 months and 41.4% at 24 months for patients in this cohort undergoing sentinel lymph node biopsy. This discrepancy may be a result of differing lengths of follow-up. Considering the number of new cases of invasive breast cancer exceeds 175,000 annually (26
), thousands of women remain at risk for LVC despite less extensive lymph node surgery.
BMI varied over time among women enrolled in the current study, ranging from a gain of 27.2% to a loss of 19.8% compared with baseline. An increase in BMI was noted to be significantly associated with an increase in LVC in this study. Weight gain has long been identified as a common issue for many women during breast cancer treatment (27
). In addition to LVC and the psychological impact of weight gain in breast cancer survivors, tumor recurrence, and even increased breast cancer mortality have been associated with weight gain following breast cancer diagnosis (33
Most of the initial studies examining the link between lymphedema and QOL are limited by measurement issues pertaining to lymphedema and QOL (40
). The instruments used in this study, the FLIC and the SF-36, are two of the most widely used cancer-specific and generic QOL instruments available. Both have been used in studies of breast cancer patients, and more specifically in studies pertaining to post-breast cancer treatment lymphedema (44
). Numerous studies have examined the consequences of breast cancer treatment-related lymphedema (12
), but results have varied. Our results corroborate those of Wilson et al (17
), who reported lower QOL scores for breast cancer patients with lymphedema when compared to controls. In our study, multivariate analysis showed that FLIC total scores were significantly associated with moderate LVC (10–14.9%) (OR=3.72, 95% CI=1.28–10.73, p=0.015) (). The literature on the SF-36 supports effect sizes for clinically important differences in the range of 0.3 to 0.5 (18
). At 24 months, the differences in mean SF-36 scores among the four LVC groups consistently exceeded these limits, suggesting that the differences in scores are clinically meaningful. In contrast, Kwan et al reported that women with lymphedema scored lower than women without lymphedema on the SF-36 physical functioning subscale but found no differences with regard to social functioning or mental health (12
). Similarly, Beaulac et al observed lower overall QOL and physical functioning but not mental or social well-being in patients with lymphedema using the Functional Assessment of Cancer Therapy questionnaire (46
In our study, symptom assessment with the LBCQ, a previously validated questionnaire for lymphedema-related signs and symptoms, turned out to be the most sensitive instrument for detecting differences among the LVC groups; the LBCQ symptom scores were 4.2, 5.5, 7.0, and 12.5 for the <5.0%, mild (5.0–9.9%), moderate (10.0–14.9%), and severe (≥15.0%) LVC groups, respectively (p<0.001). Our findings are similar to previous findings by Armer et al (10
), in that patient reports of swelling and heaviness significantly increased as LVC increased, suggesting that changes in reported symptoms may be early signs of lymphedema. In this study, additional symptoms sensitive to changes in LVC were tenderness (p<0.004), firmness/tightness (p=0.028), and aching (p<0.001). Our finding that differences in symptom reporting are detectable at ≥5.0% LVC supports those of Stout Gergich et al (19
), who recently proposed that 5.0–8.0% LVC is an appropriate threshold for mild lymphedema and also suggested that detectable differences in symptom reporting may exist for subclinical lymphedema at >3% LVC. Furthermore, they demonstrated that early intervention with compression garments for patients with >3% LVC may reduce LVC over time and prevent the progression of lymphedema.
The severity of symptoms and their subjective impact on patients with a given disease or undergoing treatment have collectively been defined as symptom burden
). Somewhat distinct from the concept of QOL, which assesses a patient’s subjective evaluation of their well-being on a broader scale, symptom burden is limited to the impact of a disease or treatment on a patient’s daily living (48
). Symptom assessment has become increasingly relevant as an independent study outcome 48, and our findings indicate that the LBCQ is sensitive to changes in LVC over time and is useful in determining clinically meaningful thresholds.
The current study possesses a number of strengths that set it apart from other studies reported in the literature, including (1
) the rigor and accuracy of repeated prospective limb volume measurements made over time using a perometer, (2
) the repeated assessment of signs and symptoms of lymphedema using a previously validated instrument, (3
) the inclusion of sensitive QOL measures, (4
) the size of the cohort, and (5
) and a median follow-up period exceeding two years. There are also several limitations to our study. For the subset of patients who were not enrolled prior to surgical treatment (n=110), baseline limb measurements were defined one month postoperatively in the ipsilateral limb. It is possible that some patients had already developed some degree of LVC associated either with acute postoperative swelling or early lymphedema, leading to an underestimation of maximum LVC for these patients. Also, some of the changes in affected limb volume noted in our analysis may be related to weight gain which was not controlled for in our methodology. Other definitions of lymphedema have been used to account for such changes in patient BMI (49). Given the significant correlation observed over time between differences calculated using the contralateral limb at 24 months (controlling for BMI) and the ipsilateral limb at baseline (controlling for pre-operative limb volume differences) the effects of BMI on the outcomes were likely minimal. Another limitation is that QOL assessments were performed at baseline, 12 months, and 24 months, and that the QOL scores at these time points may not correspond directly with the time of maximum LVC. Indeed, only the group with 10–14% LVC showed statistically significant differences in QOL, and it is likely that the cohort with ≥15% LVC was too small for statistical significance to be reached (OR=1.42, 95% CI 0.5–56.0, p=0.16). Lastly, lymphedema treatment, which is routinely recommended for patients with LVC ≥10%, was not accounted for in the analysis.
This study establishes that the majority of breast cancer survivors are at risk for developing LVC over time. A key finding is that symptoms and decrements in QOL can be detected in patients with LVC as minimal as 5–9.9%, a level that is unlikely to be detected by routine clinical evaluation. Based on our findings, postoperative lymphedema risk reduction practices should emphasize post-treatment weight maintenance. In summary, optimal cancer surveillance programs should include postoperative limb and signs and symptoms monitoring to enable early detection of LVC and the timely referral of patients with ≥ 5% LVC for treatment.