Results of a randomized trial revealed that patients with early breast cancer had considerably less lymphedema if they were administered axillary radiotherapy in place of surgical lymph node dissection.
The occurrence of clinically significant lymphedema ranged from 21% to 25% over a span of 5 years in patients who received surgical dissection of axillary lymph nodes as opposed to 10% to 15% among patients who underwent radiotherapy.
Patients who had both lymph node dissection and radiotherapy had the highest occurences of lymphedema.
A preliminary analysis of the data revealed that surgery and radiation therapy reached similar 5-year disease control, according to Mila Donker, MD, of Netherlands Cancer Institute in Amsterdam, and reported the findings at the European Cancer Congress.
"Axillary lymph node dissection (ALND), compared to axillary radiotherapy (ART), is associated with a 2.5 times higher baseline surgical complication rate and a two times higher rate of lymphedema at 5 years. Axillary lymph node dissection plus axillary radiotherapy is associated with a lymphedema rate that is five times higher than axillary radiotherapy at 5 years. The type of axillary treatment is the strongest risk factor for both lymphedema and shoulder function,” said Donker
“Sentinel lymph node biopsy has supplanted ALND as the preferred approach to management of patients who have early breast cancer and clinically negative axillary lymph nodes. For patients with positive sentinel lymph nodes, ALND and ART provide similar axillary disease control. ALND carries a well-recognized risk of side effects, including potentially severe lymphedema. In contrast, few studies have examined side effects associated with ART for patients with positive sentinel lymph nodes,” she added.
The randomized AMAROS trial drew comparisons from ALND and sentinel lymph node biopsy (SNB) in patients with early breast cancer. Moreover, patients with positive sentinel nodes were randomized to surgical axillary dissection or radiotherapy. The trial involved 4,800 patients, 1,400 of whom had positive sentinel nodes.
The trial displayed identical low rates of axillary reappearance with the two treatment methods. The 5-year disease-free and overall survival did not vastly differ between the two groups.
The AMAROS results verified those from the ACOSOG Z0011 trial, which also revealed no major difference in recurrence rates with surgical dissection or radiation therapy to the axilla.
Updated AMAROS results with follow-up passed 10 years showed 5-year axillary recurrence rates of 0.43% with surgical dissection and 1.19% with radiation therapy, Donker noted. She also assessed complication rates for patients who underwent upfront ALND as opposed to SNB.
ALND was linked to notably higher rates of hemorrhage (3.1% versus 1.7%, P<0.001), infection (10.7% versus 3.8%, P<0.001), persistent seroma (10.4% versus 1.3%, P<0.001), and early lymphedema (1.6% versus 0.2%, P=0.007). The total complication rates were 22.6% with ALND and 9.0% with SNB (P<0.001).
Lymphedema was evaluated at time period of 1, 3, and 5 years and compared between patients who received ALND, ART, or both forms of treatment. The evaluation included clinical observation and measurement of arm circumference at several points.
By clinical observation, lymphedema rates with ALND were 25.6% at 1 year, 21% at 3 years, and 20.8% at 5 years. That compared with rates of 15%, 13.4%, and 10.3% at the same time periods for ART.
Patients who received both ALND and ART had lymphedema rates of 59.3%, 44.8%, and 58.3% respectively.
Lymphedema was also recognized as an increase in arm circumference ?10%. By that notion, the rates at 1, 3, and 5 years were 7.2%, 9.2%, and 11.7% with ALND, 5.9%, 6.2%, and 5.7% with ART, and 14.8%, 24.1%, and 29.2% with ALND plus ART.
Assessment of shoulder function comprised anteversion/retroversion and abduction/adduction function. Values did not differ significantly between ALND and ART at 1, 3, or 5 years.
Multivariate analysis recognized four elements connected with lymphedema: menopausal status, body mass index, treatment on the dominant side, and type of axillary treatment. Predictors of impaired shoulder function were type of axillary treatment, supraclavicular radiation therapy (in the absence of ART), and level of ALND (I + II versus I + II + III).
“The weight of the evidence supports the conclusion that ART is the recommended treatment in breast cancer patients with positive sentinel nodes,” said Peter Dubsky, MD, of the Medical University of Vienna, as he reviewed the results of AMAROS and other trials.
Yet, Michael Gnant, MD, also from the Medical University of Vienna, doubted whether the response data demonstrated a fair comparison of ALND and ART. He mentioned that two-thirds of the ALND group had level III dissections, while rates in the single digits have become the staple throughout Europe. The infection rate of almost 11% also seemed out of context with modern medical practice.
"If you compare what you said is the 'new preferred treatment' to something that is hampered by these factors, the conclusion might be a little different," said Gnant.
“The high rate of level III dissection reflected contemporary practice when the trial began. However, she argued, the lymphedema is not associated with the extent of dissection. With respect to the infection rate, she said participating centers throughout Europe applied local definitions of infection, which might have confounded calculation of the overall rate,” said Donker.
While surgical oncologist from Magee-Women's Hospital and the University of Pittsburgh, U.S., Kandace McGuire, MD, reviewed the key results of AMAROS and concentrated on the hypothesis that ALND and ART lead to similar disease control. In the presentation of the primary outcome data, AMAROS investigators admitted that the low event rates in both arms left the trial powerless to effectively showcase non-inferiority.
"So the major question remains whether the two treatments are equivalent in terms of cancer outcomes. I believe that they likely are, but this trial had the same pitfalls as ACOSOG Z0011: low event rate of axillary recurrence and use of a non-inferiority test to establish the two treatments to be equivalent,” said McGuire.
“Statisticians tell us that a non-inferiority test is inferior to a superiority test. It requires fewer patients, but can often fail to detect small differences. The data definitely support the theory that radiation is equivalent to surgery in the node- positive patient, but both AMAROS and Z0011 will benefit from longer follow up. For some patients, this will be very important as they may be willing to accept a possibly increased, but still very low risk of recurrence to decrease their risk of lymphedema significantly,” she added.
