No Improvement in Lymphedema With Hypofractionated Nodal RT for Breast Cancer

Hypofractionated lymph node irradiation failed to reduce the frequency of lymphedema after treatment for invasive breast cancer, a randomized trial showed.

A 3-week radiation therapy (RT) protocol led to a 29% incidence of perometry-assessed lymphedema as compared with 36% with a standard 5-week protocol (P=0.24). Analyses of lymphedema frequency by body mass index (BMI) and axillary lymph node dissection (ALND) versus sentinel lymph node (SLN) assessment also showed no significant difference between the two RT protocols.

Interestingly, the incidence of physician-reported lymphedema and grade ≥2 toxicity was significantly lower in patients who received hypofractionated RT, said Karen E. Hoffman, MD, of the University of Texas MD Anderson Cancer Center in Houston, at the American Society for Radiation Oncology (ASTRO) meeting in Washington, D.C.

“The shorter regimen also conferred a low risk of loco-regional recurrence,” said Hoffman. “However, additional follow-up on a larger cohort of patients is needed to establish non-operative cancer control after the shorter regional radiation regimen, and we are following a larger cohort of 850 patients to help establish this.”

A single-arm phase II trial of hypofractionated nodal irradiation also failed to meet the primary endpoint of noninferiority versus historical rates of lymphedema with post-mastectomy conventional RT. The rates were similar to those in the randomized trial, and patients who underwent SLN assessment had a numerically lower incidence of lymphedema as compared with those who had ALND, reported Alfredo Urdaneta, MD, of Virginia Commonwealth University and the Massey Comprehensive Cancer Center in Richmond.

Taken together, the trials showed that rates of lymphedema after moderately fractionated regional nodal irradiation (RNI) are acceptable and comparable to historical rates observed with standard fractionation, said ASTRO invited discussant Asal Rahimi, MD, of UT Southwestern Medical Center in Dallas. The findings also offer a prompt to revisit the decade-old AMAROS trial, which consistently showed a higher incidence of lymphedema after ALND versus axillary RT at all time points. However, the difference did not achieve statistical significance until after 5 years of follow-up.

“It’s still very early in follow-up [in these two trials], so it will be very important for us to see what those 5-year lymphedema rates are,” said Rahimi.

Hoffman reported findings from the phase III, randomized SAPHIRe trial to compare standard versus hypofractionated RNI in early breast cancer. RNI has become a standard component of post-mastectomy RT and also for many patients who have whole-breast irradiation for stage II/III breast cancer, she noted in her introduction.

RNI reduces recurrence and improves survival but typically requires 5 to 6 weeks to complete. Additionally, RNI can cause toxicity that includes fatigue, lymphedema, pain, and skin/tissue changes. Lymphedema, in particular, can be debilitating, causing pain and limitation in arm movement, ability to work, and clothing choices.

Two British studies suggested that hypofractionated RNI might reduce the incidence of lymphedema. START A showed a 50% reduction in the lymphedema hazard with a total radiation dose of 39 Gy in 13 fractions versus 50 Gy in 25 fractions. START B showed a 58% reduction in the hazard ratio with a 40 Gy total dose in 15 fractions. Neither difference achieved statistical significance. However, the reduction in arm lymphedema in START B was similar to the reduction in swelling in the breast (HR 0.55), which did achieve statistical significance.

“We postulated that there might have been some under-ascertainment of lymphedema in the START trials because they didn’t have volumetric measurements of arm size,” said Hoffman.

Investigators at five participating centers enrolled patients who had recommendations for RNI as part of treatment for T0-T3, N0-N2a, N3a invasive breast cancer. RNI consisted of 50 Gy to the breast/chest wall and 45 Gy to regional lymph nodes in 25 fractions over 5 weeks or 40 Gy to the breast/chest wall and 37.5 Gy to regional nodes in 15 fractions over 3 weeks. A boost to the tumor bed was optional with both protocols.

The primary objective was lymphedema rates at 24 months after RNI, assessed by perometry measurements before and after surgery and then 6, 12, and 18 months after RT. Lymphedema was defined as ≥10% difference in arm volume, and lymphedema at any of the measurement times counted as an event.

Data analysis included 324 patients, which gave the trial statistical power to detect a lymphedema rate of 15% with hypofractionation versus 30% in the standard RNI group. Investigators stratified the results by chemotherapy (none vs neoadjuvant vs adjuvant), ALND vs SLN, and BMI <30 vs ≥30.

The study population had a median age of 53, 65% of the patients identified as non-Hispanic white, 39% had a BMI ≥30, 57% had T2 disease, and 64% had N1 nodal status. Two-thirds of the patients had ALND, 72% had neoadjuvant systemic therapy (11% had no systemic therapy), 57% had a mastectomy with or without reconstruction, 85% had 3D conformal RT, and 95% received a boost to the tumor bed or chest wall.

The lymphedema data showed a nonsignificant 7% absolute reduction in the incidence with hypofractionation (P=0.24). Results numerically favored hypofractionation among patients with BMI ≥30 (33% vs 39%), BMI <30 (27% vs 35%), ALND (36% vs 44%), and SLN (17% vs 20%), but none of the differences achieved statistical significance.

Rates of physician-reported lymphedema were almost 50% lower in the hypofractionation group (15% vs 27%, P=0.009), and rates of physician-reported grade ≥2 toxicity also were significantly lower with hypofractionation (52% vs 78%, P<0.001). The difference in grade ≥2 toxicity was driven by dermatitis (32% vs 63%, P<0.001).

Rates of locoregional recurrence were low with hypofractionation (3%) and standard RNI (2%) after a median follow-up of 4.75 years.

Urdaneta reported findings from a study to evaluate lymphedema rates with hypofractionated RNI in patients who had nodal evaluation by SLN (N=84) or ALND (N=50). The trial had statistical power to detect a lymphedema rate <5% versus historical rates of 6% with SLN and 10% with ALND, with a 7% margin for non-inferiority.

Patients had follow-up assessments at 1 month and then at 6-month intervals for 5 years. Assessments included lymphedema

The data showed that 11 (13.1%) patients in the SLN group and nine (18%) in the ALND group developed lymphedema. One patient in each group had grade 2 lymphedema, and all other cases were grade 1.

Cosmesis was a secondary outcome of the trial, and results for 105 patients showed that physician-assessed results were excellent/good in 82.8% of the patients overall, including 85.5% in the lumpectomy group and 75.9% in the mastectomy-with-reconstruction group.