Intraoperative Radiation Therapy in Breast Cancer: Still Not Ready for Prime Time
Ann Surg Oncol
Intraoperative Radiation Therapy in Breast Cancer: Still Not Ready for Prime Time
Chirag Shah 2
Jessica Wobb 1
Atif Khan 0
0 Department of Radiation Oncology, Robert Wood Johnson University Hospital/Cancer Institute of New Jersey , New Brunswick, NJ , USA
1 Department of Radiation Oncology, Ohio State University , Columbus, OH , USA
2 Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic , Cleveland, OH , USA
Over the past two decades, radiation therapy techniques and strategies have continued to evolve beyond standard fractionation (1.8-2.0 Gy per fraction) whole breast irradiation (WBI), which delivers treatment over 5-6 weeks. These include hypofractionated (increased dose per fraction) whole breast irradiation (AWBI), which allows for the whole breast to be treated in 3 weeks and partial breast techniques, including accelerated partial breast irradiation (APBI) and intraoperative radiation therapy (IORT), which target only the tumor bed and a rim or normal tissue surrounding it. Approximately 2 years ago, we presented an editorial evaluating the data supporting IORT and felt that based on the data available at that time that IORT was investigational and not appropriate for off-trial utilization.1 This editorial was met with resistance by some groups who felt the data available supported adoption of IORT.2 Since that time, data have continued to evolve and controversy still exists regarding the role of IORT in the management of women with early-stage breast cancer. The strongest evidence regarding IORT comes from two randomized trials that compared IORT and standard WBI. The TARGIT-A (Targeted Intraoperative Radiotherapy) Trial was a randomized, ''noninferiority'' study that enrolled 3451 women older than age 45 years with unifocal invasive ductal carcinoma following wide local excision. IORT was delivered at a dose of 20 Gy using 50-kv photons, whereas WBI was delivered to a dose of 40-56 Gy with or without boost. Of note, IORT could be delivered at
-
the time of lumpectomy (pre-pathology cohort, 2/3
patients) or after lumpectomy (post-pathology cohort, 1/3
patients). WBI was given to IORT patients with close
surgical margins, extensive DCIS, lobular carcinomas, and
positive lymph nodes (21.6 % pre-pathology, 3.6 %
postpathology, 15.2 % overall). Of note, while 5-year outcomes
were published, median follow-up was only 29 months and
at that time IORT was associated with a statistically
significant increase in local recurrence (3.3 vs. 1.3 %,
p = 0.04); further, in the post-pathology group, the
increase exceeded the 2.5 % noninferiority threshold (5.4
vs. 1.7 %, p = 0.07).3 The updated results have sparked
significant controversy in the surgical and radiation
oncology communities with concern raised regarding the
statistical methodology of the trial including ‘‘misuse of the
noninferiority criterion,’’ a focus on the pre-pathology
cohort rather than all patients, and significant numbers of
patients lost to follow-up with an already shortened
followup.4 Based on these findings, several authors have stated
that IORT is not appropriate therapy off-protocol at this
time while others disagree.4–7
The second randomized IORT trial was the ELIOT trial,
which utilized intraoperative electrons; 1305 patients were
randomized to WBI (50 Gy with 10 Gy boost) or IORT
(21 Gy with 6–9 MeV electrons) with no supplementary
WBI utilized. With a median follow-up of 5.8 years, IORT
was associated with an increase in ipsilateral breast tumor
recurrences (4.4 vs. 0.4 %, p \ 0.0001).8 Taken together,
both randomized trials have demonstrated higher rates of
local recurrence compared with standard WBI. In light of
these findings, a question that emerges is whether IORT is
better than endocrine therapy alone following
breast-conserving surgery. For example, the CALGB 9343 trial had a
4 % rate of local recurrence at 5 years (95 % confidence
interval [CI] 2–7 %), whereas the TARGIT trial had a
Intraoperative Radiation Therapy in Breast Cancer: Still Not Ready for Prime Time
3.3 % rate of local recurrence at 5 years (95 % CI 2.1–
5.1 %, follow-up 28 months), with 15 % of patients
receiving WBI.3,9 Similarly, the 5-year local recurrence
rate with ELIOT was 4.4 % (95 % CI 2.7–6.1 %) with a
hazard ratio of 9.3 compared with standard WBI.8 In light
of a continuing rise in the rate of local recurrence and
difference in local control compared with WBI in the
CALGB trial with excision alone, concern exists regarding
a similar increase in local recurrences and increasing
difference with WBI in the IORT cohort in years 5–10
following treatment.
As noted above, IORT is not the only partial breast
technique available to patients, with APBI representing a
technique with multiple randomized trials and longer
follow-up. While there are some who look to minimize the
difference in recurrence rates seen in the IORT trials and
consider them low overall, it should be noted that none of
the four randomized APB (...truncated)