Risk factors associated with breast cancer-related lymphedema in the WHEL Study

Introduction

Lymphedema is a significant health problem faced by a large percentage of breast cancer survivors. The Women’s Healthy Eating and Living (WHEL) Study has a unique dataset collected after the completion of breast cancer treatment, which allowed a focused analysis of risk factors for breast cancer-related lymphedema.

Methods

Participant characteristics, treatment modalities, and health behaviors were examined as potential predictors of lymphedema among breast cancer survivors with univariate analyses and multivariate logistic regression.

Results

Lymphedema status was assessed for 83 % of the study cohort (2,431 of the 2,917 WHEL participants). Among these respondents, 692 (28.5 %) women reported yes to either a physician’s diagnosis of lymphedema or a question on arm/hand swelling. When compared to other participants, women with lymphedema were diagnosed at a younger age, more likely to have a higher body mass index, had a larger tumor size, had more lymph nodes removed, more likely to have a mastectomy with radiation therapy, and more likely to have chemotherapy. In the final multivariate-adjusted model, body mass index greater than 25 kg/m² (p?<?0.01), the removal of 11 or more lymph nodes (p?<?0.01), and breast cancer surgery plus radiation therapy (p?<?0.01) showed a strong independent association with developing breast cancer-related lymphedema.

Conclusions

The results of this study highlight the importance of educating breast cancer survivors about the modifiable risk factors (e.g., body mass index) associated with the development of lymphedema.

Implications for Cancer Survivors

Breast cancer survivors at risk for lymphedema may benefit from interventions aimed at achieving or maintaining a healthy body weight.     

Can axillary reverse mapping avoid lymphedema in node positive breast cancer patients?

Background

Tracing lymphatic drainage of the ipsilateral arm of node positive breast cancer patients, termed “axillary reverse mapping” (ARM), has recently been described in several reports. We analyzed our experience with this new technique in patients scheduled for axillary lymph node dissection (ALND) and evaluated its usefulness for reducing the incidence of lymphedema.

Methods

Blue dye was injected subcutaneously along the intermuscular groove of the upper inner arm; radioisotope was injected subcutaneously in the interdigital webspace of the hand. All blue and radioactive lymph vessels and lymph nodes were recorded. Only unsuspicious “ARM lymph nodes” located in the lateral part of the axillary basin were preserved. All other level I and II axillary lymph nodes were removed. Resected ARM nodes were immediately separated from all other lymph nodes.

Results

ARM was performed in 143 patients subsequently undergoing ALND. ARM lymph nodes were successfully identified in 112 cases (78%). In 55 patients at least one ARM lymph node had to be removed. In 14 of these, tumor involvement was confirmed. In 71 patients one or more ARM nodes were preserved.During a median follow-up time of 19 months no axillary recurrence was noted. 35 of 114 evaluated patients developed lymphedema. Preservation of ARM lymph nodes did not significantly decrease the incidence of lymphedema.

Conclusion

ARM is feasible for patients with node positive breast cancer. However, we found no evidence that it reduces the incidence of lymphedema.     

Radiation therapy of post-mastectomy patients with positive nodes using fixed beam tomotherapy

Purposes

To develop an optimized dosimetric class solution for post-mastectomy irradiation for fixed beam tomotherapy (FBT).

Methods and materials

CT simulation scans from 10 post-mastectomy patients were used to generate plans with planning target volumes (PTVs) that included the chest wall, axillary nodes and supraclavical nodes using FBT and helical tomotherapy (HT) with 3D and IMRT modes and the resultant dosimetry was compared to conventional IMRT. FBT IMRT plans were analyzed with both 4 (4FBT) and 11-field (11FBT) plans. Important organs at risk (OARs) included the heart, ipsilateral and contralateral lungs, esophagus and contralateral breast. In all plans, the spinal cord and contralateral lung were completely blocked while the heart and ipsilateral lung were directionally blocked. Doses to the contralateral breast were minimized. Each plan was evaluated for its delivery time, percentile volume of lung receiving x Gy (V_x) and dose received by x percent volume (D_x). D₁ and D₅ were used to measure the maximum dose to the OAR or PTV, D₉₅ and D₉₉ were used to measure the minimal dose to the PTV.

Results

Compared to the conventional IMRT technique, HT IMRT, 11FBT IMRT and 11FBT 3D significantly reduced the D₁ of the heart in cases of left-sided tumors by 13%, 41% and 36%, and the V₁₀ of ipsilateral lung in all cases by 26%, 49% and 46%, respectively. A close to 90% reduction in the contralateral breast dose was also observed with the 11FBT plans. Target dose homogeneity of 11FBT 3D plans is inferior to that of the HT and conventional IMRT plans but the treatment delivery time, 7.59 min, was significantly shorter by 3 min. 4FBT IMRT resulted in clinically unacceptable heterogeneity with high dose regions in both the PTV and normal tissue.

Conclusions

A class solution based on an 11 beam configuration was established to optimize the dosimetry of fixed beam tomotherapy planning for post-mastectomy patients. The 11FBT plans were deliverable in clinically efficient treatment times.     

The incidence and risk factors of related lymphedema for breast cancer survivors post-operation: a 2-year follow-up prospective cohort study

Purpose

To investigate the incidence rate, severity and risk factors of related lymphedema in breast cancer survivors.

Methods

A 2-year follow-up prospective study of 387 women who had operation from four hospitals from January 1, to December 31, 2014 was conducted. Limb volume was measured by circumference and symptoms were measured using questionnaires pre-treatment and 1, 3, 6, 12, 18, 24 months after surgery separately. The incidence rates and the severity of lymphedema were evaluated, respectively. Risk factors for the development of breast cancer-related lymphedema (BCRL) were analyzed using log-rank test and Cox regression.

Results

The incidences of BCRL were 4.4, 10.1, 15.2, 28.6, 31.2 and 32.5% at 1, 3, 6, 12, 18, 24 months after surgery, respectively, measured by Norman questionnaire. The rates measured by arm circumference were 2.5, 6.7, 13.4, 21.4, 26.3 and 29.4%, respectively. About 114 (29.4% of 387) women were diagnosed with BCRL, and 78 of them got mild lymphedema. Axillary lymph node dissection (ALND) (HR = 5.2, 95% CI 1.6–17.3), radiotherapy (HR = 3.9, 95% CI 2.0–7.5), modified radical mastectomy (MRM) (HR = 2.1, 95% CI 1.3–3.4), the number of positive lymph nodes (HR = 1.1, 95% CI 1.0–1.2) and body mass index (BMI) (HR = 1.1, 95% CI 1.0–1.1) were independent risk factors for BCRL.

Conclusions

BCRL is a common complication for breast cancer patients after surgery. It can be fairly diagnosed only 1 month post-operation and the cumulative incidence of BCRL seems to be increasing over time, especially in the first year after surgery. ALND, radiotherapy, MRM, the number of positive axillary lymph nodes and BMI were found to be independent risk factors in the development of BCRL in this study.

     

First Clinical Report of Proton Beam Therapy for Postoperative Radiotherapy for Non–Small-Cell Lung Cancer

Background and Purpose

The characteristic Bragg peak of proton beam therapy (PBT) allows for sparing normal tissues beyond the tumor volume that may allow for decreased toxicities associated with postoperative radiation therapy (PORT). Here we report the first institutional experience with proton therapy for PORT in patients with non–small-cell lung cancer (NSCLC) and assess early toxicities and outcomes.

Correction to: Secretomes reveal several novel proteins as well as TGF-β1 as the top upstream regulator of metastatic process in breast cancer

Purpose

We studied the lymphatic drainage of the upper limb and mammary region directing to the axilla to investigate whether independent pathways can be observed or whether anastomoses and shared drainage occur between them. This analysis aimed to assess the safety of axillary reverse mapping (ARM) in breast cancer treatment and to understand the development of lymphedema after sentinel lymph node biopsy (SLNB) alone.

Methods

Seven unfixed stillborn fetuses were injected with a modified Gerota mass in the peri-areolar area, palm and dorsum of the hands, formalin fixed, and then submerged in 10% hydrogen peroxide solution. Microsurgical dissection was then performed on the subcutaneous cellular tissue of the upper limb, axillary region, and anterior thorax to expose the lymphatic vessels and lymph nodes.

Results

The dye injected into the upper limb reached either the lateral axillary group, known to be exclusively responsible for upper limb drainage, or the anterior group, which is typically related to breast drainage. There was great proximity among the pathways and lymph nodes. Communicating lymphatic vessels among these groups of lymph nodes were also found in all studied cases.

Discussion

Lymphedema remains a challenging morbidity in breast cancer treatment. ARM and SLNB aim to avoid unnecessary damage to the lymphatic drainage of the upper limb. However, our anatomical study suggests that ARM may have potential oncological risks because preserved lymph nodes may harbor malignant cells due their proximity, overlapping drainage pathways, and connecting lymph vessels among lymph nodes.

     

Time and dose-related changes in lung perfusion after definitive radiotherapy for NSCLC

Background and purpose

To examine radiation-induced changes in regional lung perfusion per dose level in 58 non-small-cell lung cancer (NSCLC) patients treated with intensity-modulated radiotherapy (IMRT).

Superficial doses in breast cancer radiotherapy using conventional and IMRT techniques: A film-based phantom study

Background and purpose

Superficial doses in radiotherapy are affected by the treatment technique. The implications for breast cancer treatments were evaluated.

Material and methods

Four treatment techniques relevant for breast cancer irradiation were evaluated; tangential standard, tangential IMRT, 7-field IMRT (arc-like field arrangement) and hybrid IMRT (an IMRT plan mixed with non-modulated fields). Only 6 MV photons were used. GafChromic EBT film was used for dose measurements at the surface, in the skin (0–5 mm depth) and in the superficial parts of CTV (5–10 mm depth) of an anthropomorphic thorax phantom.

Results

Only small differences in superficial doses were observed between tangential standard and tangential IMRT. Compared to the tangential standard plan, the surface and skin doses were reduced with the 7-field IMRT plan, on average by 20% and 5%, respectively, while hybrid IMRT reduced the surface and skin doses medially (by 44% and 8%, respectively) and increased the surface and skin dose laterally (by 40% and 15%, respectively). Minimum superficial CTV doses varied between regions, but were mainly between 90% and 95% of the target dose for all plans, only the hybrid IMRT plan resulted in a region with minimum dose below 90%.

Conclusions

Compared to tangential irradiation, skin sparing was achieved by the 7-field IMRT plan. The minimum dose in the superficial parts of the CTV was below 95% of the target dose for all plans investigated.     

A pilot study to assess the utility of SPECT/CT-based lymph node imaging to localize lymph nodes that drain the arm in patients undergoing treatment for breast cancer

Image-guided treatment planning that minimizes irradiation of critical lymph nodes (LNs) may reduce the incidence and severity of long term complications following breast cancer treatment. This localization cannot be obtained with conventional imaging techniques and we undertook this proof of concept study to determine whether a coordinated use of SPECT and CT has sufficient precision to inform radiation planning and potentially lessen the incidental exposure of critical LNs. Thirty-two consecutive women with breast cancer were injected in the arm ipsilateral to their breast cancers prior to radiation treatment with 0.5 mCi of filtered ^99mTc-sulfur colloid and underwent scanning with a hybrid device which combined a dual-head SPECT camera and a low-dose, single slice CT scanner. The number of visualized LNs as well as their locations, maximum counts, and total uptake were recorded. Coordinates derived from the SPECT/CT fusion images were used to map LN locations onto the 3D radiation treatment planning system. A mean of 3.4 (SD 2.0) lymph nodes were detected in each subject. Level I and II LNs were detected more often in patients who had sentinel node biopsies, and more supraclavicular nodes were detected in patients who had undergone axillary dissection (P < 0.001). SPECT-CT derived LN coordinates were successfully mapped onto radiation simulation CT scans for all patients. SPECT/CT fusion images localize the LNs draining the arm after breast cancer surgery. These finding suggest that SPECT/CT may be helpful in minimizing incidental LN irradiation and in directing breast cancer therapy to reduce long-term morbidity.     

Comparison of electron IMRT to helical photon IMRT and conventional photon irradiation for treatment of breast and chest wall tumours

Background and purpose

Conventional irradiation of breast and chest wall tumours may cause high doses in underlying organs. Intensity-modulated radiation therapy (IMRT) with photons achieves high conformity between treated and tumour volume but is associated with considerable low-dose effects which may induce secondary malignancies. We compare treatment plans of electron IMRT to helical photon IMRT and conventional irradiation.

Material and methods

Treatment planning for three patients (breast, chest wall plus lymph nodes, sarcoma of medial chest wall/sternum) was performed using XiO 4.3.3 (CMS) for conventional photon irradiation, Hi-Art 2.2.2.05 (TomoTherapy) for helical photon IMRT, and a self-designed programme for electron IMRT.

Results

The techniques resulted in similar mean and maximum target doses. Target coverage by the 95%-isodose was best with tomotherapy. Mean ipsilateral lung doses were similar with all techniques. Electron IMRT achieved best sparing of heart, and contralateral breast. Compared with photon IMRT, electron IMRT allowed better sparing of contralateral lung and total healthy tissue.

Conclusions

Electron IMRT is superior to conventional irradiation, as it allows satisfying target coverage and avoids high doses in underlying organs. Its advantage over photon IMRT is better sparing of most organs at risk (low-dose effects) which reduces the risk of radiation-induced malignancies.     

Diagnostic Methods,Risk Factors,Prevention, and Management of Breast Cancer-Related Lymphedema: Past,Present, and Future Directions

Purpose of Review

Breast cancer-related lymphedema (BCRL) is a chronic, adverse, and much feared complication of breast cancer treatment, which affects approximately 20% of patients following breast cancer treatment. BCRL has a tremendous impact on breast cancer survivors, including physical impairments and significant psychological consequences. The intent of this review is to discuss recent studies and analyses regarding the risk factors, diagnosis, prevention through early screening and intervention, and management of BCRL.

Recent Findings

Highly-evidenced risk factors for BCRL include axillary lymph node dissection, lack of reconstruction, radiation to the lymph nodes, high BMI at diagnosis, weight fluctuations during and after treatment, subclinical edema within and beyond 3 months after surgery, and cellulitis in the at-risk arm. Avoidance of potential risk factors can serve as a method of prevention. Through establishing a screening program by which breast cancer patients are measured pre-operatively and at follow-ups, are objectively assessed through a weight-adjusted analysis, and are clinically assessed for signs and symptoms, BCRL can be tracked accurately and treated effectively. Management of BCRL is done by a trained professional, with research mounting towards the use of compression bandaging as a first line intervention against BCRL. Finally, exercise is safe for breast cancer patients with and without BCRL and does not incite or exacerbate symptoms of BCRL.

Summary

Recent research has shed light on BCRL risk factors, diagnosis, prevention, and management. We hope that education on these aspects of BCRL will promote an informed, consistent approach and encourage additional research in this field to improve patient outcomes and quality of life in breast cancer survivors.

     

Analysis of direct oil contrast lymphography of upper limb lymphatics traversing the axilla – A lesson from the past – Contribution to the concept of axillary reverse mapping

Introduction

Axillary reverse mapping (ARM) is a method to preserve upper extremity (UE) lymphatics during axillary surgery in breast cancer patients. This may reduce the incidence of lymphedema. Very precise method to demonstrate lymphatic drainage is direct X-ray lymphography.

Materials and methods

The evaluation of direct lymphography X-ray images of the axilla and proximal part of the upper extremity was performed in 9 subjects. As contrast was used Lipiodoil injected on the dorsal side of hand.

Results

The lymph from UE is drained by 2–4 main afferent collectors, which in 5 of 9 cases entered into one node in the lateral axilla (ARM node). This node was considered to be the sentinel lymph node for the UE. In 4 cases a cranial collector was shown, which led directly to nodes in the upper part of the axilla. This collector had numerous anastomoses with other collectors before entering the axillary nodes. The most important finding is the demonstration of numerous lymphatic anastomoses that take place between all imaged nodes in the axilla including the caudal nodes, which is the most frequent localization of the breast sentinel lymph node.

Conclusion

The relationship of lymphatic drainage of the UE and breast are closely related and share numerous connections. These connections represent the main problem of the ARM concept because they may pose potencional route for metastatic cancer cells in sentinel node positive breast cancer patients. Further studies are necessary to improve understanding of this method.Axillary reverse mapping – breast cancer – lymphedema – sentinel node biopsy.     

Volumetric modulated arc therapy and breath-hold in image-guided locoregional left-sided breast irradiation

Purpose

To investigate the effects of using volumetric modulated arc therapy (VMAT) and/or voluntary moderate deep inspiration breath-hold (vmDIBH) in the radiation therapy (RT) of left-sided breast cancer including the regional lymph nodes.

Materials and methods

For 13 patients, four treatment combinations were compared; 3D-conformal RT (i.e., forward IMRT) in free-breathing 3D-CRT(FB), 3D-CRT(vmDIBH), 2 partial arcs VMAT(FB), and VMAT(vmDIBH). Prescribed dose was 42.56 Gy in 16 fractions. For 10 additional patients, 3D-CRT and VMAT in vmDIBH only were also compared.

Results

Dose conformity, PTV coverage, ipsilateral and total lung doses were significantly better for VMAT plans compared to 3D-CRT. Mean heart dose (D_mean,heart) reduction in 3D-CRT(vmDIBH) was between 0.9 and 8.6 Gy, depending on initial D_mean,heart (in 3D-CRT(FB) plans). VMAT(vmDIBH) reduced the D_mean,heart further when D_mean,heart was still >3.2 Gy in 3D-CRT(vmDIBH). Mean contralateral breast dose was higher for VMAT plans (2.7 Gy) compared to 3DCRT plans (0.7 Gy).

Conclusions

VMAT and 3D-CRT(vmDIBH) significantly reduced heart dose for patients treated with locoregional RT of left-sided breast cancer. When D_mean,heart exceeded 3.2 Gy in 3D-CRT(vmDIBH) plans, VMAT(vmDIBH) resulted in a cumulative heart dose reduction. VMAT also provided better target coverage and reduced ipsilateral lung dose, at the expense of a small increase in the dose to the contralateral breast.     

Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial

Background and purpose

We conducted a prospective phase II multicentric trial to determine if radical radiation therapy to all metastatic sites might improve the progression-free survival (PFS) in oligometastatic breast cancer patients. Secondary endpoints were local control (LC), overall survival (OS) and toxicity.

High discordance rates between sub-areolar and peri-tumoural breast lymphoscintigraphy

Objective

To test the hypothesis that sub-areolar (SA) lymphoscintigraphy (LSG) identifies the same sentinel node as peri-tumoural (PT) injections.

Background

It is commonly believed that all LSG techniques will identify the same sentinel lymph nodes (SLN) draining the breast. Hybrid imaging technology (SPECT/CT) allows accurate identification of the exact location of SLNs. Using SPECT/CT SA and PT LSG techniques were compared.

Method

In a multi-centre trial 39 patients sequentially underwent LSG (SA followed by PT) separated by 2–7 days. Patients were referred by 4 surgeons to 3 LSG centres, with standardization of isotope (99mTc-antimony sulfide colloid), LSG and SPECT/CT evaluation techniques. LSG were evaluated for SLN concordance and degree of discordance in the axilla and internal mammary nodes (IMN).

Results

39 eligible patients, median age 62 years, were recruited. Successful axillary SLN mapping for SA and PT injection techniques was 87% and 95% respectively. Successful internal mammary SLN mapping occurred with SA and PT LSG in 5% and 36% respectively. Discordance was identified in the IMN (39%) and axilla (21%), with an overall rate of discordance between SA and PT LSG of 56%.

Conclusions

There is a high level of discordance in the localization of SLN by these commonly used LSG injection techniques. This discordance has implications for accuracy of axillary and extra-axillary staging and could impact on patient outcome.     

Time evolution of regional CT density changes in normal lung after IMRT for NSCLC

Purpose

This study investigates the clinical radiobiology of radiation induced lung disease in terms of regional computed tomography (CT) density changes following intensity modulated radiotherapy (IMRT) for non-small-cell lung cancer (NSCLC).

Methods

A total of 387 follow-up CT scans in 131 NSCLC patients receiving IMRT to a prescribed dose of 60 or 66 Gy in 2 Gy fractions were analyzed. The dose-dependent temporal evolution of the density change was analyzed using a two-component model, a superposition of an early, transient component and a late, persistent component.

Results

The CT density of healthy lung tissue was observed to increase significantly (p < 0.0001) for all dose levels after IMRT. The time evolution and the size of the density signal depend on the local delivered dose. The transient component of the density signal was found to peak in the range of 3–4 months, while the density tends to stabilize at times >12 months.

Conclusions

The radiobiology of lung injury may be analyzed in terms of CT density change. The initial transient change in density is consistent with radiation pneumonitis, while the subsequent stabilization of the density is consistent with pulmonary fibrosis.     

乳腺癌保乳术后常规、三维适形及两种调强放疗技术剂量学评估(英文)

Objective: The purpose of this study was to compare the dose distribution and dose volume histogram (DVH) of the planning target volume (PTV) and organs at risk (OARs) among conventional radiation therapy (CR), three-dimensional conformal radiation therapy (3DCRT), two-step intensity-modulated radiation therapy (TS-IMRT) and direct machine parameter optimization intensity-modulated radiation therapy (DMPO-IMRT) after breast-conserving surgery. Methods: For each of 20 randomly chosen patients, 4 plans were designed using 4 irradiation techniques. The prescribed dose was 50 Gy/2 Gy/25 f, 95% of the planning target volume received this dose. The cumulated DVHs and 3D dose distributions of CR, 3DCRT, TS-IMRT and DMPO-IMRT plans were compared. Results: For the homogeneity indices, no statistically significant difference was observed among CR, 3DCRT, TS-IMRT and DMPO-IMRT while the difference of the conformality indices were statistically significant. With regard to the organs at risk, IMRT and 3DCRT showed a significantly fewer exposure dose to the ipsilateral lung than CR in the high-dose area while in the low-dose area, IMRT demonstrated a significant increase of exposure dose to ipsilateral lung, heart and contralateral breast compared with 3DCRT and CR. In addition, the monitor units (MUs) for DMPO-IMRT were approximately 26% more than those of TS-IMRT and the segments of the former were approximately 24% less than those of the latter. Conclusion: Compared with CR, 3DCRT and IMRT improved the homogeneity and conformity of PTV, reduced the irradiated volume of OARs in high dose area but IMRT increased the irradiated volume of OARs in low dose area. DMPO-IMRT plan has fewer delivery time but more MUs than TS-IMRT.     

Changes in arm tissue composition with slowly progressive weight-lifting among women with breast cancer-related lymphedema

Background

Studies in breast cancer-related lymphedema (BRCL) have exclusively examined total arm volume, but not the specific tissue composition that contributes to total volume. We evaluated baseline differences in arm tissue composition [fat mass, lean mass, bone mineral content (BMC), and bone mineral density (BMD)] between the affected and unaffected arms in women with BRCL. We compared changes in arm tissue composition and self-reported lymphedema symptoms after 1 year of weight-lifting versus control.

Methods

We utilized data from physical activity and lymphedema trial that included 141 women with BRCL. Arm tissue composition was quantified using dual-energy X-ray absorptiometry. The severity of lymphedema was quantified using self-report survey. Weight-lifting was performed at community fitness facilities.

Results

At baseline, the affected arm had more fat (? = 89.7 g; P < 0.001) and lean mass (? = 149.1 g; P < 0.001), but less BMC (? = ?3.2 g; P < 0.001) and less BMD (? = ?5.5 mg/cm²; P = 0.04) than the unaffected arm. After 12 months of weight-lifting, composition of the affected arm was improved: lean mass (71.2 g; P = 0.01) and BMD (14.0 mg/cm²; P = 0.02) increased, arm fat percentage decreased (?1.5%; P = 0.003). Composition of the unaffected arm was only improved in lean mass (65.2 g; P = 0·04). Increases in lean mass were associated with less severe BCRL symptoms.

Conclusions

Among women with BRCL, slowly progressive weight-lifting could improve arm tissue composition. Changes in arm tissue composition predict changes in symptom burden. Investigating the combined effects of exercise and weight loss on arm tissue composition and BCRL symptoms may provide additional insight into the benefits of lifestyle modification on lymphedema biology.