EMCC News: Radiotherapy between or during chemotherapy cycles reduces risk of

breast cancer recurrence

25.09.11
Category: EMCC 2011
A major UK trial has produced firm evidence that giving radiotherapy between or during
chemotherapy cycles to women with early breast cancer significantly reduces the
risk of the cancer recurring in the breast or chest wall. The treatment, known as
synchronous chemoradiation, has minimal adverse side-effects and no detrimental
effect on the patients’ quality of life.
European Multidisciplinary Cancer Congress 2011: Findings from the SEquencing of Chemotherapy and
Radiotherapy in Adjuvant Breast cancer (SECRAB) study, which was carried out at 48 centres in the UK and is
the largest study to investigate the treatment, have been presented in Stockholm to delegates at the 2011
European Multidisciplinary Cancer Congress [1].
“The results show that synchronous chemoradiation reduces the risk of local cancer recurrence by 35% in
women with early breast cancer. After a follow-up of over eight years, only 41 patients in the synchronous
chemoradiation group had suffered a recurrence compared with 63 patients in the sequential chemoradiation
group,” says Dr Indrajit Fernando, a Consultant Clinical Oncologist at University Hospitals Birmingham NHS
Foundation Trust and Honorary Senior Lecturer at the University of Birmingham, UK.
Radiotherapy and chemotherapy are usually given after breast cancer surgery to destroy any remaining cancer
cells in the breast, chest wall or underarm area, in order to reduce the risk of a local cancer recurrence.
Sequential chemoradiation is the standard treatment schedule where chemotherapy is given first followed by
radiotherapy.
Dr Fernando, the principal investigator of the study: “The five-year local recurrence rates were 2.8% and 5.1%
in the synchronous and sequential chemoradiation groups, respectively. This difference of 2.3% between
treatment groups was statistically significant.”
“According to the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), one breast cancer death can
be avoided for every four local recurrences prevented [2]. Therefore, even a 2.3% reduction in local recurrence
rates will have an impact worldwide when we consider that this is a very common cancer.”
The optimal timing of radiotherapy with chemotherapy has been a subject of debate among cancer experts. The
aim of this trial was to determine the best schedule for giving radiotherapy with
cyclophosphamide/methotrexate/fluorouracil (CMF) or anthracycline–CMF chemotherapy after surgery to
women with early breast cancer.
This randomised Phase III trial enrolled 2,296 women who had undergone breast conserving surgery (1,285
women) or mastectomy (1,011 women) to remove their tumour. All the patients received chemoradiation after
surgery, either sequential (1,146 patients) or synchronous, where the radiotherapy was given in the gaps
between chemotherapy cycles (1,150 patients). More than 60% of patients received 40Gy in 15 fractions over
three weeks.
Dr Fernando also presents results from research into the quality of life of patients in the SECRAB study today.
These focused on skin reactions caused by the radiotherapy, breast and arm symptoms and overall quality of
life.
A total of 565 patients contributed to the quality of life analysis. Overall, the results showed that there were no
observed differences in quality of life between the synchronous and sequential chemoradiation groups.
“Although the results of the main study showed that patients in the synchronous chemoradiation group had a
significantly worse skin reaction, only four percent of patients in the synchronous arm had a severe reaction
which would have taken several weeks to heal and subsequently affect quality of life. The majority of women
 had a moderate skin reaction which would have settled in a very short period of time and this had no detrimental
effect on their quality of life,” he says.
“Our data have shown that the acute skin toxicity of radiotherapy treatment was significantly less in patients
being treated with three weeks of synchronous radiotherapy (40Gy radiation in 15 fractions) compared to those
with schedules of a longer duration (45Gy in 20 fractions over four weeks or 50Gy in 25 fractions over five
weeks). Importantly, the clinical benefit of synchronous chemoradiation treatment was seen in both patient
groups.”
Dr Fernando says that the trial could be important for economic reasons. “Shortening the overall treatment time
may mean that when patients have finished their last chemotherapy course they can return to their normal life
without having to then complete their radiotherapy. This may also have economic benefits in terms of when
patients can return to work.”
“Clinical practice needs to be reviewed for patients who are being treated with a CMF or an anthracycline/CMF
chemotherapy schedule. The data will be forwarded to the National Institute of Clinical Excellence (NICE) in
the UK but the results have implications worldwide,” adds Dr Fernando.
Professor Michael Baumann, president of ECCO said: “This trial raises the important issue of how radiotherapy
and chemotherapy after surgery should be sequenced or integrated to obtain the best outcome in breast cancer.
In today’s modern multidisciplinary oncology, not only each single component of treatment needs to be
optimised, but also the combination thereof. This requires close interaction of specialists from different
specialties in clinical research, as well as in everyday patient care. The SECRAB trial suggests that the risk of
loco-regional recurrences could be reduced by applying radiotherapy simultaneously with chemotherapy. Long
term follow-up will still be necessary to assess potential late side-effects and the benefits versus the risks of this
approach, but I am convinced that this trial will spur a lot of discussion on optimising adjuvant treatment in this
common disease.”
Abstract no: 2 LBA, Presidential session II, 12.20 hrs CEST, Sunday 25 September, Hall A1; and abstract no:
5122, Poster session Breast cancer – early disease, 14:00 – 16:30 hrs CEST, Sunday 25 September.
1. [1] The 2011 European Multidisciplinary Cancer Congress is the 16th congress of the European CanCer
Organisation (ECCO), the 36th congress of the European Society for Medical Oncology (ESMO) and the 30th
congress of European Society for Therapeutic Radiology and Oncology (ESTRO).
2. [2] “Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local
recurrence and 15-year survival: an overview of the randomised trials”. The Lancet 2005:366:9503:2087-2106.
3. [3] The study was funded by Cancer Research UK, and Pharmacia (now Pfizer) provided a small
educational grant.

Intraoperative Radiotherapy Less Costly Than

Whole Breast Irradiation
Mar 06, 2013
By Will Boggs, MD
NEW YORK (Reuters Health) Mar 06 - Intraoperative radiotherapy for breast cancer offers good outcomes and
costs less than conventional whole breast radiation therapy, according to results from the University of Florida.
"We offer single fraction, intraoperative radiation to selected patients with early stage breast cancer at the time
of initial lumpectomy as an alternative to postoperative, whole breast radiotherapy based on our published
results and the results of the international TARGIT trial," Dr. Stephen R. Grobmyer, now at the Cleveland Clinic
in Ohio, told Reuters Health.
Dr. Grobmyer and colleagues analyzed their experience with intraoperative radiation therapy using data from 78
patients in the University of Florida's prospectively collected breast cancer database.
Most women required no additional surgery after the initial procedure and intraoperative radiation therapy. Four
underwent mastectomy and eight required margin re-excision.
Most complications were grade 1 or 2. There were no grade 3 complications and only one grade 4 complication
(skin ulceration three weeks after lumpectomy and intraoperative brachytherapy).
Several women developed seromas, but most were asymptomatic and resolved within four to six weeks, the
authors reported February 15 online in the Journal of the American College of Surgeons.
During a median follow-up of 12.5 months, there have been no local or regional recurrences. One patient
developed bone metastases within a year of diagnosis. This patient is currently alive; all the others are alive, too,
with no evidence of disease.
Most patients had good to excellent cosmesis at all time points. The addition of whole breast radiotherapy was
the only factor associated with an increased risk of having fair or poor cosmesis.
Estimated direct costs of intraoperative radiotherapy ($1,857) were substantially less than those of conventional
whole breast irradiation ($9,653) or interstitial balloon brachytherapy ($18,895), the authors reported.
"Single fraction intra-operative radiation therapy is an excellent option for treating some patients with early
stage breast cancer," Dr. Grobmyer said. "This treatment allows many patients to complete all of their surgery
and radiation in one day, with fewer side effects and a more rapid return to their normal activities."
"We discuss the potential benefits, side effects, and limitations of both single fraction intra-operative radiation
and whole breast radiation therapy in helping patients make choices regarding their treatment plan for early
stage breast cancer," Dr. Grobmyer said. "Treatment decisions can then be individualized based on a patient's
age, tumor type, tumor size, tumor stage, and patient's overall health status to best meet the needs of a patient."
Dr. Grobmyer added that results of the originally published TARGIT-A trial were updated recently in a
presentation at the 2012 San Antonio Breast Cancer Symposium. "This update demonstrated the importance of
giving the single dose radiation therapy at the time of the initial lumpectomy as we have done and continue to
do," he said. "Further, it demonstrated that the best results following lumpectomy and single fraction intra-
operative radiation therapy are seen in patients with hormone sensitive breast cancers."
Dr. Jayant S. Vaidya from University College London, London, UK, who participated in the TARGIT trial, told
Reuters Health by email, "The TARGIT approach is the only type of partial breast irradiation that has level 1
randomized evidence in the form of a large international randomized trial to support it."
This new study, Dr. Vaidya added, "shows that what we found in the large randomized trial can be translated
into routine clinical practice when it is cautiously and meticulously applied to suitable breast cancer patients."
"It is important to remember to select cases for TARGIT properly (e.g., unifocal invasive duct carcinoma, ER
and PR positive, at least 45 years of age), and if postoperatively adverse factors are found whole breast
radiotherapy should be added (in about 15-20% of cases)," Dr. Vaidya said. "It has been estimated that if
TARGIT is used routinely, it would save (the) US economy 1.4 billion dollars over five years."
SOURCE: http://bit.ly/XWYGdM
J Am Coll Surg 2013.

Practice-Changing Radiation Study in Early Breast

Cancer?
Focus on 1-3 Positive Nodes
June 4, 2011 (Chicago, Illinois) — Women with early breast cancer and as few as 1 to 3 positive nodes should
be offered radiation treatment to their regional lymph nodes, in addition to standard whole-breast radiation
(WBI), according to a study presented here at the American Society of Clinical Oncology (ASCO®) 2011
Annual Meeting.
In a phase 3 clinical trial of women with either node-positive or high-risk node-negative breast cancer, regional
nodal irradiation (RNI) significantly improved disease-free survival at 5 years (hazard ratio [HR], 0.67; P = .
003), said lead author Timothy J. Whelan, BM, BCh, from McMaster University in Hamilton, Ontario, Canada.
This constituted a 33% improvement in disease-free survival in the group receiving WBI plus RNI, compared
with the group receiving the WBI alone.
This is a "potentially practice-changing" clinical trial, Dr. Whelan told Medscape Medical News at an ASCO
press conference where the study was highlighted.
However, these are interim, 5-year results, said Dr. Whelan. The study's primary outcome of overall survival has
not yet seen a statistically significant improvement, but there is a trend present, he said.
Overall mortality was reduced by 24% in the group receiving WBI plus RNI, compared with WBI alone group
(HR, 0.76; 5-year risk, 7.7% and 9.3%, respectively; P = .07).
Dr. Whelan presented the results on behalf of the National Cancer Institute of Canada Clinical Trials Group and
American and Australian clinical trials groups, all of which conducted the study, known as MA.20.
Notably, 85% of the 1832 study participants had 1 to 3 positive nodes; the benefit of adding RNI in such women
has been unclear, he said.
At the press conference, Dr. Whelan explained that, in general, women with node-positive breast cancer are
treated with breast-conserving surgery plus axillary lymph node dissection, followed by WBI.
However, if a woman's cancer has high-risk features, such as a tumor larger than 5 cm or more than 3 positive
axillary nodes, she often also receives RNI, which is defined as radiation to the internal mammary,
supraclavicular, and axillary lymph nodes; this is the course of treatment recommended in the ASCO guidelines.
Women with 1 to 3 positive nodes have constituted a gray zone of uncertainty and have been in need of further
study, Dr. Whelan summarized.
Practice Changing: 2 Votes
Some clinicians have already adopted RNI as part of their standard of care for all node-positive women,
including those with 1 to 3 positive nodes.
"As an institutional policy, we have routinely done RNI in these patients for some years," said David E. Wazer,
MD, from Rhode Island Hospital and Brown University in Providence.
Dr. Wazer told Medscape Medical News that all node-positive women should receive RNI and that the study
should be practice changing.
Another radiation oncologist called the study "intriguing," but suggested that clinicians make RNI decisions in
patients with 1 to 3 positive nodes on a case-by-case basis.
"This has been an area of controversy, with data to both support and not support the addition of regional nodal
radiation in this subset of patients," Sandy Anderson, MD, from Fox Chase Cancer Center in Philadelphia
Pennsylvania, told Medscape Medical News.
The MA.20 data are important, said Dr. Anderson, in the context of another study of women with 1 to 3 positive
axillary lymph nodes, the Z0011 trial from the American College of Surgeons, which was presented last year at
the ASCO annual meeting. That study found that "whole-breast radiation is adequate treatment after positive
sentinel lymph node biopsy" in women with 1 to 3 positive nodes, and was not inferior to completion axillary
dissection, said Dr. Anderson.
Just how much treatment a patient with 1 to 3 positive nodes needs is a complex calculation, according to Dr.
Anderson. "Clinicians need to weigh the toxicity of regional nodal radiation against the toxicity of further
axillary dissection, along with the clinical and pathologic factors for each individual patient," she said.
Findings
The women in the MA.20 study, who averaged 53 years in age, had all been treated with breast-conserving
surgery and adjuvant systemic therapy — either chemotherapy (91%) or endocrine therapy (71%). As noted
above, most had 1 to 3 positive nodes, but a small proportion of the women had either more than 4 positive
nodes (5%) or high-risk node-negative breast cancer (10%).
The study design randomized the women to receive either WBI alone (n = 916) or WBI plus RNI (n = 916).
The WBI consisted of 50 Gy in 25 fractions plus boost irradiation. The RNI consisted of 45 Gy in 25 fractions.
There is now a median follow-up of 62 months. Dr. Whelan explained that the study had a protocol-specified
interim analysis of relapse patterns, survival, and toxicity at 5 years. After review of the data, the Data Safety
Monitoring Committee recommended the release of the results.
In addition to the overall disease-free survival benefit, there were other statistically significant benefits for the
group receiving the RNI therapy, said Dr. Whelan.
WBI plus RNI, compared with WBI alone, was associated with a statistically significant 42% improvement in
isolated locoregional disease-free survival (HR, 0.58; 5-year risk, 3.2% and 5.5%, respectively; P = .02), and a
36% improvement in distant disease-free survival (HR, 0.64; 5-year risk, 7.6% and 13.0%, respectively; P = .
002).
On the downside of the data, WBI plus RNI, compared with WBI alone, was associated with a statistically
significant increase in dermatitis (50% and 40%, respectively; P < .001), grade 2 or greater pneumonitis (1.3%
and 0.2%, respectively; P = .01), and lymphedema (7.3% and 4.1%, respectively; P = .004).
The rate of lymphedema with RNI seems low, said Dr. Wazer. "Community experience may see a higher rate,"
he added.
The authors have disclosed no relevant financial relationships.
American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract LBA1003. To be presented
June 6, 2011.

Intraoperative RT Misses 'TARGIT' But Emerges

Strong
Neil Osterweil
Dec 07, 2012
SAN ANTONIO, Texas — Targeted intraoperative radiotherapy (TARGIT) for early breast cancer was
associated with slightly more same-breast recurrences but fewer deaths not related to breast cancer than
standard external-beam radiotherapy (EBRT). This finding comes from the TARGIT-A trial.
Jayant Sharad Vaidya, MD, a consultant surgeon at University College London, United Kingdom, presented the
trial results here at the 35th Annual San Antonio Breast Cancer Symposium.
There were 2.01% more same-breast recurrences, the primary end point, in patients treated with TARGIT than
in those treated with EBRT ( P = .042).
For the secondary end point of mortality, TARGIT was associated with a trend toward lower overall mortality
(absolute difference, –1.4%; P = .01) and there were significantly fewer deaths from causes other than breast
cancer (absolute difference, –2.1%; P = .009).
There were 88 deaths during the 5 years of follow-up — 36 related to breast cancer and 52 not related to breast
cancer. With TARGIT, there was no significant difference in overall mortality (hazard ratio [HR], 0.70; P = .
099) or breast cancer deaths (HR, 0.96; P = .56). However, the 5-year risk for death from causes other than
breast cancer was lower with TARGIT than with EBRT (1.4% vs 3.5%; HR, 0.47; P = .009).
"We believe that these data will significantly improve the...individualization of local treatment for breast
cancer," Dr. Vaidya said.
The documented adverse effects of ionizing radiation might have led to the excess deaths with EBRT,
Matthew P. Goetz, MD, associate professor of oncology and pharmacology at the Mayo Clinic in Rochester,
Minnesota, told Medscape Medical News.
"We know from data that radiation can increase the risk of nonbreast-cancer-related deaths, and clearly there are
data [related to] cardiac deaths. It was not surprising to see that; what was surprising was to see it in a relatively
small study, and relatively early on," Dr. Goetz said.
The study demonstrates that it is possible to treat relatively low-risk patients without significantly increasing
their risk for death from cardiovascular or other noncancer causes, he explained.
Dr. Goetz moderated the session at which the data were presented, but was not involved in the study.
The TARGIT technique involves a mobile electron generator and accelerator that can be wheeled into an
operating room. The radiation is delivered by a spherical-tip applicator that is inserted into the surgical wound.
It delivers 20 Gy to the tumor bed and 5 Gy at a distance of 5 mm to give a uniform dose to the tissues at
highest risk.
Risk-Adapted Strategy
Investigators from 33 centers in Australia, Europe, and the United States enrolled 3451 women older than 45
years with unifocal invasive ductal carcinoma (most tumors were smaller than 3.5 cm). The women were
randomized to receive either standard fractionated EBRT or risk-adapted radiotherapy with a single dose of
TARGIT.
With the risk-adapted strategy, women who received TARGIT and were found postoperatively to have high-risk
factors were strongly encouraged to receive additional EBRT. About 15% of women received both forms of
radiation.
There were 34 cases of ipsilateral breast recurrence; these occurred slightly but significantly more often in the
TARGIT group. Nonetheless, the absolute difference of 2.01% fell within the prespecified boundary for
noninferiority of TARGIT (2.5%), Dr. Vaidya said.
Prespecified subgroups consisted of patients randomized to TARGIT before lumpectomy who received radiation
and surgery in a single session, and those randomized after lumpectomy who received TARGIT in a separate
procedure (delayed TARGIT). The investigators looked at progesterone-receptor (PgR) status as a surrogate for
hormone sensitivity.
Most of the difference in ipsilateral breast recurrence was accounted for by PgR-negative patients (studies have
suggested they are less sensitive to radiation) and by patients in the delayed TARGIT group.
An independent assessor determined that the decrease in deaths not related to breast cancer with TARGIT was
driven by the few cardiovascular events and the few deaths from other cancers.
Dr. Vaidya said that the preferred option is to use TARGIT concurrently with lumpectomy in PgR-positive
patients, with the subsequent addition of EBRT if prognostic factors not detected before surgery are present.
Those factors include previously undetected lobular cancers, positive tumor margins, and the presence of
extensive intraductal components.
The study was supported by the UK National Health Service. Dr. Vaidya and Dr. Goetz have disclosed no
relevant financial relationships.
35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S4-2. Presented December 6, 2012.

START Spreading the News About

Hypofractionated RT to Breast
Neil Osterweil Dec 06, 2012
SAN ANTONIO, Texas — Radiation to the breast at a dose of 40 Gy delivered over 3 weeks is as effective as a
dose of 50 Gy delivered over 5 weeks, according to a new study.
In addition to being more convenient for patients, the hypofractionated regimen of 40 Gy delivered in 15
fractions was associated with fewer adverse events over 10 years than the regimen of 50 Gy delivered in 25
fractions, which is the standard in the United States and elsewhere in the world, said John Yarnold, MD,
professor of clinical oncology at the Institute of Cancer Research in London, United Kingdom.
He presented data from the START (Standardization of Breast Radiotherapy) A and B trials here at the 35th
Annual San Antonio Breast Cancer Symposium.
The shorter regimen was not inferior in efficacy, he emphasized.
"We can say that breast cancer and the dose-limiting normal tissues respond similarly to fraction size, that there
is no advantage...in continuing the practice of 2 Gy fractions over 5 to 6 and a half weeks, and that the 15-
fraction regimen over just 3 weeks is gentler on normal tissue and noninferior in terms of locoregional control
of the cancer at 10 years, Dr. Yarnold said at a press briefing. "This schedule has been the standard of care in the
United Kingdom since 2009 for all patients with invasive breast cancer," he explained.
A German clinician suggested that the trial results would not immediately change practice there. "Our standard
is still 50 Gy, with 1.8 Gy per session over 5 to 6 weeks," said Sibylle Loibl, MD, associate professor at the
University of Frankfurt in Germany, when she was asked about START by Medscape Medical News.
Dr. Loibl, who was not involved in the study, noted that 50 Gy in 25 to 30 fractions is standard treatment for
patients undergoing breast-conserving procedures and for those who have undergone mastectomy but have
residual locally invasive disease.
German oncologists will hold their annual guidelines meeting in January, but "I doubt very much that these data
will make a difference," she said.
Two Trials, 1 Result
START A enrolled 2236 patients from 35 centers in the United Kingdom with T1 to 3, N0 to 1 breast cancer
with no distant metastases. They were randomly assigned to receive 50 Gy in 25 fractions of 2 Gy delivered
over 5 weeks, 39 Gy in 13 fractions of 3 Gy delivered over 5 weeks, or 41.6 Gy in 13 fractions of 3.2 Gy
delivered over 5 weeks.
In START B, 2215 women were randomly assigned to 50 Gy in 25 fractions of 2 Gy delivered over 5 weeks or
40 Gy in 15 fractions of 2.67 Gy delivered over 3 weeks.
In START A, over a median follow-up of 9.3 years, the adverse-event profile of the 41.6 Gy regimen was
similar to that of the 50 Gy regimen (hazard ratio [HR], 0.94, 95% confidence interval [CI, 0.79 - 1.11). The
rates of locoregional tumor relapse for the 2 regimens were also comparable (HR, 0.91; CI, 0.59 - 1.38).
However, the 39 Gy dose was associated with fewer adverse events than the 50 Gy dose (HR, 0.80; 95% CI,
0.67 - 0.96); there were more relapses numerically, but not significantly (HR, 1.18; 95% CI, 0.79 - 1.76).
In START B, over a median follow-up of 9.9 years, the 40 Gy regimen was associated with significantly fewer
adverse events than the 50 Gy regimen (HR, 0.77; 95% CI, 0.66 - 0.89). The efficacy of the 2 regimens was
comparable, with a nonsignificant trend toward modest superiority for the 40 Gy regimen (HR, 0.77; 95% CI,
0.51 - 1.16), Dr. Yarnold said.
The study was supported by Cancer Research UK, the Medical Research Council, and the National Cancer
Research Institute. Dr. Yarnold and Dr. Loibl have disclosed no relevant financial relationships.
35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S4-1. Presented December 6, 2012.

Breasts Look Worse With Accelerated Irradiation

Nick Mulcahy Nov 09, 2012
BOSTON, Massachusetts — For some women with early breast cancer, the convenience of accelerated partial-
breast irradiation (APBI) comes at a cost — a poorer cosmetic outcome, according to a major international
randomized clinical trial.
The APBI used in the study was 3D external-beam radiation therapy (3D-CRT).
The study is ongoing, but at 3 years, 32% of the women with early breast cancer treated with APBI had an
"adverse cosmetic outcome," compared with 19% of women treated with whole-breast irradiation (WBI) (P < .
0001); the appearance of the breast was evaluated by trained study nurses. All of the participants undergone a
lumpectomy.
The interim results of the phase 3 trial, known as RAPID (Randomized Trial of Accelerated Partial Breast
Irradiation Using 3D Conformal External Beam Radiation Therapy), were presented here at the American
Society for Radiation Oncology 54th Annual Meeting.
Radiation can cause fibrosis or thickening of breast tissue and can adversely affect cosmetic results, explained
lead author Timothy J. Whelan, MD, from Juravinski Cancer Centre in Hamilton, Ontario, Canada, during a
meeting press conference.
The short time between fractions with APBI is one possible explanation for its increased toxicity and the related
adverse cosmetic effects, he said.
Cosmetic outcome is a secondary outcome in the study but is a significant one, he told Medscape Medical
News.
Cosmetic outcomes are very important. Dr. Timothy Whelan
"Cosmetic outcomes are very important because breast-conserving therapy was created to preserve the breasts,"
Dr. Whelan explained. There are aesthetic and emotional dimensions to the preservation, he added.
The results are "very solid" and provide "high-level evidence," said Bruce Haffty, MD, from the Cancer
Institute of New Jersey and the Robert Wood Johnson Medical School in New Brunswick, who acted as
discussant for the trial.
"These are the most objective, robust data that we have seen," Dr. Haffty said. Mixed results have come from a
number of phase 2 trials that looked at toxic effects from APBI and WBI, but they were inferior studies, he told
meeting attendees.
"We are pushing the envelope of the normal toxicity curve," he said about the study's APBI schedule, which
consisted of 38.5 Gy in 10 fractions twice daily. In contrast, the WBI consisted of 50 Gy in 25 fractions or
42.5 Gy in 16 fractions once daily.
Dr. Whelan pointed out that WBI has been proven to reduce local recurrence, prevent mastectomy, and improve
overall survival, but it is not used in up to 30% of women, in part because of "inconvenience." APBI was
developed to speed up the delivery of treatment. "Women have a lot of interest in getting shorter radiation
treatments," he said.
Although all of the women in the trial had the option of receiving extra boost irradiation, it was used
infrequently in the WBI group. This is another possible explanation for the difference in cosmesis between the 2
methods, said Dr. Whelan.
The results are not necessarily applicable to interstitial or balloon-based therapy. Dr. Bruce Haffty
Dr. Haffty was quick to clarify that the study results are limited to 3D CRT. "The results are not necessarily
applicable to interstitial or balloon-based therapy, which typically radiate a lower volume of breast tissue," he
said.
Patients and Oncologists Also Rated Appearance
The 2135 study participants, from 33 centers in Australia, Canada, and New Zealand, were at least 40 years of
age. They had either invasive breast cancer or ductal carcinoma in situ less than 3 cm in size, and were treated
with lumpectomy from February 2006 to July 2011. The women were lymph node negative.
The primary study outcome is the rate of ipsilateral breast tumor recurrence, but data are not mature enough for
interim results to be reported, said Dr. Whelan.
Adverse cosmetic outcome (a fair or poor rating, as opposed to an excellent or good rating) was assessed by a
trained study nurse at baseline and 3 and 5 years after treatment.
At baseline (n = 1995 participants), 17% of the WBI patients and 19% of the APBI had an adverse cosmetic
outcome (P = .35).
At 3 years (n = 850 participants), the adverse outcome remained fairly steady in the WBI patients (19%);
however, adverse cosmesis had "deteriorated" in the APBI patients (32%), Dr. Haffty observed.
In addition to the nurses, cosmetic outcome was evaluated by 2 more assessors: the patients themselves and a
panel of radiation oncologists who reviewed unlabeled digital photographs.
Both rated APBI results worse. The patients found that adverse cosmesis was significantly worse in the APBI
group than in the WBI group at 3 years (26.2% vs 18.4%; P = .004), as did the radiation oncologists (35.1% vs
16.6%; P < .0001).
Radiation toxicity is one of the other secondary study outcomes. Dr. Whelan indicated that most of the toxic
effects in both groups were moderate.
Grade 1 and 2 late radiation toxicities, such as breast induration, were higher with APBI (53.0% and 12.0%,
respectively) than with WBI (43.0% and 3.4%, respectively). Grade 3 and 4 toxicities were rare in both groups.
"Our study...found that APBI using 3D external-beam radiation therapy can increase the risk of moderate
radiation side effects, which may affect cosmetic outcome for some patients. 3D CRT APBI treatment needs
additional research," said Dr. Whelan in a press statement.
The study was sponsored by the Ontario Clinical Oncology Group, the Canadian Institutes of Health Research,
and the Canadian Breast Cancer Research Alliance. The study authors have disclosed no relevant financial
relationships.
American Society for Radiation Oncology (ASTRO) 54th Annual Meeting: Abstract 30. Presented October 28,
2012.

25-Year Data: Cardiac Toxicity From Breast

Radiation
Nick Mulcahy Nov 02, 2012
BOSTON, Massachusetts — For women with early breast cancer, radiation to the whole breast does not
increase the risk for long-term cardiac toxicity, compared with mastectomy, according to a study with 25-year
data, presented here at the American Society for Radiation Oncology (ASTRO) 54th Annual Meeting.
In addition, at 25 years, survival outcomes were similar in women treated with mastectomy and those treated
with breast-conserving treatment (BCT), which consisted of radiation and lumpectomy, lead author Charles
Simone II, MD, reported at a meeting press conference. He is from the Abramson Cancer Center at the
University of Pennsylvania in Philadelphia.
These data will "give some comfort to our patients" who receive radiation, said Bruce Haffty, MD, from the
Cancer Institute of New Jersey and the Robert Wood Johnson Medical School in New Brunswick, who
moderated the press conference.
After 25 years, the survival curves for the 2 treatment groups have begun to separate, and patients treated with
BCT have worse outcomes. However, "cardiac toxicity does not seem to be responsible for the slight decrease
in patient survival in the BCT arm," Dr. Simone explained.
This study provides a detailed picture of the participants' cardiac anatomy and function. The cardiac results
were gathered from 50 of the trial's 102 surviving patients, all of whom are now elderly, when they returned to
the National Cancer Institute (NCI) in Bethesda, Maryland for testing 25 years after the trial began. The NCI
sponsored the trial.
Of the 50 surviving patients, 26 were from the BCT group and 24 from the modified radical mastectomy group.
"There was absolutely no difference...whatsoever" in toxicity between these 2 study groups, Dr. Simone noted.
Among patients who died after the study started, there was also no difference in cardiac-related causes of death
between the 2 groups, according to a review of available death certificates, he added.
The data collection in the study included a detailed cardiac history, exam, and cardiac labs; 3T cardiac magnetic
resonance imaging (MRI) to assess anatomic and functional abnormalities; and computed tomography (CT)
angiography to evaluate any stenotic coronary disease and to determine the coronary arterial calcium score (a
high score is indicative of atherosclerosis).
Dr. Simone pointed out that any would-be cardiac morbidity in the patients had been attenuated with "modern
treatment planning." Treating clinicians used CT simulation and 3D planning, he said. A similar trial conducted
today would have even better results, he explained, because "newer radiotherapy techniques are even safer for
the heart."
This is the first study comparing BCT and modified radical mastectomy to have 25-year data, said Dr. Simone.
Long-term data are valuable because "if you are going to see cardiac toxicity, it will take 10 years," he added.
Original Study
In the original NCI study, 247 patients with stage I to II breast cancer were randomized to modified radical
mastectomy or BCT (45.0 to 50.4 Gy whole breast with or without regional nodes, 15.0 to 20.0 Gy boost), and
treated from 1979 to 1986 at the NCI.
In addition, node-positive patients (40% of group) received axillary dissection and chemotherapy (doxorubicin
and cyclophosphamide for 6 to 11 cycles). After 1985, these patients also received tamoxifen.
The 25-year follow-up study was the brainchild of Nicole Simone, MD, from the Kimmel Cancer Center at
Thomas Jefferson University in Philadelphia. She is the sister of Dr. Charles Simone and got to know some of
the study participants while working as a resident and rotating through the federal healthcare institutions in
Washington, DC (Walter Reed Hospital, Navy Hospital, and NCI).
Dr. Nicole Simone and her colleagues wondered if late pulmonary and cardiac toxicities related to radiotherapy
might explain the separation of the survival curves at 25 years.
This led to the launch of the follow-up study. At the ASTRO meeting last year, Dr. Nicole Simone presented the
data on pulmonary toxicity. The 2 treatment approaches for early breast cancer have "largely equivalent
pulmonary toxicity," she said at the time, as reported by Medscape Medical News.
Now it is Dr. Charles Simone's turn with the cardiac data.
Cardiac Data in Detail
CT angiograms showed that, in BCT patients, there was no difference in atherosclerosis between those whose
left breast received radiation therapy and those whose right breast did, Dr. Charles Simone reported. These
atherosclerosis data included the left anterior descending coronary artery, which is in close proximity to the
chest wall and receives the highest radiation dose.
There was a trend for atherosclerosis in patients from either group who received chemotherapy (hazard ratio,
2.4; P = .07).
Diastolic function, including peak filling rate and diastolic volume recovery, was similar in both groups, as were
peak mid-wall strain, chamber mass, volume, and function.
The median coronary arterial calcium score was similar in both groups. No patients exhibited myocardial
fibrosis, and 1 patient in each group experienced pericardial thickening.
Among BCT patients, cardiac structure and function were similar for right- or left-breast tumors.
The authors have disclosed no relevant financial relationships.
American Society for Radiation Oncology (ASTRO) 54th Annual Meeting: Abstract 87. Presented October 29,
2012.

Postop RT Study 'Very Likely' to Change Breast Cancer Practice

Kate JohnsonDecember 16, 2013
SAN ANTONIO — The majority of older breast cancer patients treated with breast-conserving surgery
and adjuvant endocrine therapy can safely skip radiotherapy (RT) with no compromise to their survival
or local control of the disease, according to results from the Postoperative Radiotherapy in Minimum-Risk
Elderly (PRIME II) trial.
The mean age of the 1326 study participants was just over 70 years. "Older patients now represent an
increasing proportion of patients we see in the clinic — over 50%," lead investigator Ian Kunkler, MD, said
during a press conference here at the 36th Annual San Antonio Breast Cancer Symposium (SABCS).
"They often have a relatively benign natural history, and radiotherapy may represent overtreatment," said Dr.
Kunkler, who is professor of clinical oncology at the Edinburgh Cancer Research Center, University of
Edinburgh, Scotland.
Although current guidelines from the National Comprehensive Cancer Network allow omission of RT in
women 70 years and older, "postoperative RT remains the standard of care in older women after wide local
excision and endocrine therapy," Dr. Kunkler told Medscape Medical News.
Another major trial also found that the addition of RT provided negligible benefits but failed to change practice,
he noted.
The CALGB 9343 trial randomized women 70 years and older with T1 estrogen-receptor (ER)-positive
breast cancer to RT or no RT (N Engl J Med. 2004;351:971-977). The 5-year local or regional recurrence risk
was lower in the RT group than in the non-RT group (1% vs 4%), but there was no difference in overall
survival, he reported.
"However, a subsequent survey of 12,925 women in Medicare who fulfilled the criteria of the CALGB trial
showed only a 3.0% to 3.7% reduction in the receipt of RT, suggesting the trial had not changed practice," he
said (J Clin Oncol. 2012;30:1601-1607).
Dr. Kunkler predicted that PRIME II is "very likely" to change practice because it shows that the absolute
benefit RT is even smaller.
The PRIME II results strengthen the data from the CALGB trial, said Kent Osborne, MD, codirector of SABCS
and director of the Dan L. Duncan Cancer Center and Lester Sue Smith Breast Center at Baylor College of
Medicine in Houston. He was not involved in the study.
"This is the second study that addresses this question, and it included a slightly younger age group," he told
Medscape Medical News.
"When I was in training 40 years ago, we were in the era of more is better. Everybody thought that more
treatment, more surgery, more radiation, high-dose chemotherapy, and bone marrow transplant would be better.
That's turning out, as we've evolved over the last 3 decades, not to be the case," Dr. Osborne explained.
Recurrence Difference But No Impact on Survival
In PRIME II, all the patients with early-stage disease were treated with breast-conserving surgery and endocrine
therapy (9% in the neoadjuvant setting), and were considered "low risk" for recurrence.
"Around 85% [of tumors] were T1, and a smaller proportion were T2 (11% to 12%), up to 3 cm, " said Dr.
Kunkler. "Forty percent of tumors were grade 1, the majority (55%) were grade 2, and a very small proportion
(between 3% and 4%) of patients had grade 3 histology."
The 5-year local recurrence rate was lower in the 658 patients randomized to whole-breast irradiation than in
the 668 randomized to no RT (1.3% vs 4.1%; P = .002), and there was no difference in overall survival (93.2%
vs 94.8%; P = .24).
The higher recurrence rate in the non-RT population in PRIME II "does not translate into a survival
detriment, so even if a few more patients have a breast recurrence, they can be salvaged at that time with
another lumpectomy and radiation or with mastectomy," Dr. Osborne explained.
Table. Outcomes in the RT and Non-RT Groups
Outcomes RT Group, %Non-RT Group, %
Regional recurrence 0.5 1.5
Distant recurrence 0.5 1.0
Contralateral breast cancer rates0.7 1.5
New nonbreast cancer rates 3.7 4.8

On multivariate analysis of factors that might predict risk for local recurrence — such as tumor size, margin
status, use of RT, age, grade, presence of lymphovascular invasion, and ER status — only use of radiotherapy
(P = .001) and ER status (P = .02) were statistically significant.
ER Status Is Key to Treatment Consideration
For the 1196 ER-positive patients, "the absolute benefits of radiotherapy are relatively small," although
statistically significant (P = .003). The reduction from 3.2% to 0.8% suggests that omission of RT in this group
"appears a reasonable option," noted Dr. Kunkler. "It's a matter of discussion between the physician and the
patient as to whether that very modest benefit is worth the potential risks of complications of radiotherapy and
the burden of undergoing treatment."
However, in the 117 ER-negative patients, "more than 20% of the events occurred in the nonirradiated
group (0.0% vs 11.1%; P = 0.015), suggesting that radiotherapy should not be omitted in this group," he
said.
The implications of this study "have broad generalizability to a large and growing number of patients," Dr.
Kunkler added.
"Probably 60% to 70% of women older than 65 fall into this category," he explained. More than 50% of patients
presenting with early breast cancer are elderly women, and increasing proportions are presenting through breast
screening programs, meaning their tumors are "quite small," with a relatively small proportion in the ER-
negative category, he said.
The study was funded by the Chief Scientist Office. Dr. Kunkler has disclosed no relevant financial
relationships.
36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S2-01. Presented December 11, 2013.

Forgo Radiation in Patients With Luminal A Breast Cancer?

Roxanne Nelson April 2, 2012 (Chicago, Illinois) — Postmenopausal women with early-stage luminal A–
subtype breast cancer might not require radiation therapy, according to preliminary data presented here at the
annual meeting of the American Association for Cancer Research (AACR).
The study showed that this was particularly the case for women aged 60 years and older. Patients in this age
group, with subtype luminal A and grade I/II tumors, demonstrated the lowest risk for breast relapse, and local
breast radiation therapy appeared to have a minimal effect. Thus, the data suggest that this subgroup of patients
could be managed with tamoxifen alone, the researchers conclude.
"Standard therapy today remains lumpectomy followed by breast radiation therapy," said Fei-Fei Liu, MD, staff
radiation oncologist at Princess Margaret Hospital and a senior scientist at the Ontario Cancer Institute, Toronto,
Ontario, Canada. She noted that for other breast cancer subtypes, radiation therapy is beneficial in preventing
recurrence.
"But in our analysis for women with luminal A breast cancer, the 10-year local relapse rate is at 8%, even if we
left out radiation therapy and gave tamoxifen alone," she said during a press briefing. "And when we added
radiation, that risk was reduced slightly to 4.6%."
"This is in contrast to the other types, where the 10-year local relapse rate is quite high at 22.6% versus 6.3% in
favor of the administration of radiation therapy," Dr. Liu added.
Study Results
To determine the predictive value for ipsilateral breast tumor recurrence, between December 1992 and June
2000 Dr. Liu and colleagues randomly assigned 769 women aged 50 years and older with T1 and T2 node-
negative breast cancer to undergo whole-breast radiation therapy and receive 20 mg of tamoxifen daily (n =
386) for 5 years or to receive tamoxifen alone (n = 383). The median age was 68 years, and 639 women (83%)
had pT1 tumors.
The researchers performed molecular subtyping using 6 immunohistochemical biomarkers (estrogen receptor
[ER], progesterone receptor [PR], Ki-67, HER2, epidermal growth factor receptor, and cytokeratin 5/6) on 304
tumor blocks that were available from the patients in the study.
On the basis of the immunohistochemistry results, Dr. Liu and her team classified the cohort into 6 categories:
luminal A, luminal B, luminal-HER2, HER2-enriched, basal-like, or triple-negative phenotype-nonbasal. They
followed the patients for a median of 10 years.
Best Rates for Older Women
Overall, the rate of ipsilateral breast tumor recurrence at 10 years was 13.8% for women who received
tamoxifen only compared with 5.0% for those who received radiation therapy and tamoxifen (P < .0001).
Significant factors for the risk for recurrence included tumor size (hazard ratio [HR], 1.54; P = .001), ER-
positive status (HR, 0.35; P = .006), age (HR, 0.96; P = .014), and treatment with tamoxifen and radiation
therapy (HR, 0.28; P < .0001).
Of the 304 patients who had tissue available for molecular testing, 145 were treated with tamoxifen alone and
159 received both tamoxifen and radiation therapy.
The luminal A subgroup, defined as women who were ER or PR positive and HER2 negative and had low Ki-67
( < 14%), had the best outcome in the cohort: a 10-year risk for local relapse of 8% with tamoxifen alone
compared with 4.6% with both tamoxifen and breast radiation therapy.
Among women in this subgroup aged 60 years and older, the local breast relapse rate was even lower: 4.3%
with tamoxifen alone vs 6% for those who received both therapies.
In contrast, patients with luminal B tumors (Ki-67 > 14%; n = 82) had a recurrence rate of 16.1% with
tamoxifen alone compared with 3.9% with combination therapy (P = .05), thus indicating the benefit of
radiation therapy in this group, explained Dr. Liu. In the other subtypes, such as luminal HER2 (n = 11), HER2-
enriched (n = 11), and basal-like (n = 16), risks for ipsilateral breast tumor recurrence were higher.
Saving Cost and Personalizing Medicine
"Radiation is of definite benefit for women with luminal B, luminal-HER2, HER2-enriched, and basal-like
breast cancer," concluded Dr. Liu. "On the other hand, for women with luminal A breast cancer, radiation
therapy may not be required, particularly if they are over the age of 60 and have grade 1 or II tumors. It is
important to note that these data apply only to node-negative breast cancer."
The potential impact of these data, if they can be corroborated, is significant, she added. "Luminal A node-
negative breast cancer is estimated to account for 25% of all newly diagnosed cases in North America every
year. This proportion of patients could potentially avoid an unnecessary treatment of radiation therapy."
The savings to the healthcare system are substantial, Dr. Liu emphasized. "In Ontario we have about 9000 new
breast cancer patients diagnosed every year, and each course of radiation therapy is about $8000. So this could
save about $20 million a year."
Extrapolating these costs for the United States, Dr. Liu estimates a savings of about $400 million if unnecessary
radiation treatment can be avoided.
"These studies help us achieve our goal of personalized cancer therapy," she said.
Approached for an outside comment, Worta McCaskill-Stevens, MD, MS director of breast cancer prevention at
the National Cancer Institute, Bethesda, Maryland, agreed that this study is a step in the direction of
individualizing therapy. "This is a very interesting and a very provocative study because we are looking to
personalize medicine," she commented to Medscape Medical News.
"We are also looking to reduce toxicities, and if we can eliminate one of the modalities to prevent recurrence in
a low risk group — that would be an excellent move," she added.
American Association for Cancer Research (AACR) Annual Meeting. Abstract #1032. Presented April 1, 2012.

Radiotherapy At Same Time As Chemo Better in Breast Cancer

September 25, 2011 (Stockholm, Sweden) — Traditionally after surgery, breast cancer patients undergo
chemotherapy first and radiotherapy second, but a new large trial from the United Kingdom shows that
synchronous administration of the 2 modalities results in better local control of the disease.
The results come from the Sequencing of Chemotherapy and Radiotherapy in Adjuvant Breast Cancer
(SECRAB) study, the largest to date to address this issue, with 2296 patients and a median follow-up of 8.8
years. They were reported here at the 2011 European Multidisciplinary Cancer Congress.
Are These Practice-Changing Results?
The results from this trial should change clinical practice, said principal investigator Indrajit Fernando, MD,
consultant clinical oncologist at the University Hospitals Birmingham NHS Foundation Trust in the United
Kingdom. At a press briefing, he said that his team has already changed the way they deliver the 2 modalities.
Patients are really happy to have the radiotherapy sandwiched between the chemotherapy, he said, because it
means that when they finish the last cycle of chemo, they have finished with the whole treatment, and can get
on with their lives.
He also noted that the improvement in outcome is achieved at no extra cost; the treatments remain the same, it
is just the timing of how they are delivered that is changed.
However, although the trial showed a significant reduction in local recurrences in patients who were treated
synchronously, compared with those who were treated sequentially, there was no difference in overall survival
between the 2 groups. That point made discussant Lori Pierce, MD, radiation oncologist from the University of
Michigan Comprehensive Cancer Center in Ann Arbor, hesitate over whether the results are practice changing.
"Perhaps," she said.
If longer follow-up shows a survival advantage, then "absolutely" these results should change practice, she said.
If there is a subgroup of patients that can be identified as particularly benefiting, then "most likely" practice
should be changed. But for the time being, she suggested, the results need to be discussed with individual
patients, who should be informed of the benefit of reduced local relapses, but also about the increase in acute
skin toxicity that was seen with synchronous administration.
Dr. Pierce offered congratulations to Dr. Fernando and his team for having designed and completed "this very
important trial."
Radiotherapy Between Chemotherapy
In the trial, the standard approach of administering radiotherapy after completion of chemotherapy (sequential
approach) was compared with synchronous administration, which was divided into 2 groups, Dr. Fernando
explained. More than 60% of patients received radiotherapy (40 Gy in 15 fractions) delivered over 3 weeks,
which is the most common approach used in the United Kingdom and Canada. The 3 weeks of radiotherapy was
sandwiched between cycles 2 and 3 of chemotherapy.
However, some patients had radiotherapy administered over longer periods, as is common in the United States
and much of Europe, he said. For instance, some women received 45 Gy in 20 fractions over 4 weeks or 50 Gy
in 25 fractions over 5 weeks. In these cases, the radiotherapy was started in the gap between chemotherapy
cycles and then continued and was administered concomitantly.
The trial was started in 1983, and the standard chemotherapy used at that time in the United Kingdom was
cyclophosphamide, methotrexate, and fluorouracil (CMF); later an anthracycline, usually epirubicin, was added
to this regimen, he said.
After a median follow-up of 8.8 years, only 41 women had local recurrences in the synchronous group,
compared with 63 women in the sequential group. The 5-year local recurrence rate was 2.8% vs 5.1% (hazard
ratio, 0.65; P = .03) — it was reduced significantly by 35%, Dr. Fernando noted.
The benefit was seen across all treatments (various chemotherapy and radiotherapy regimens) and across all
biological subgroups (e.g., grade, lymph node status), he noted.
There was an increase in acute skin toxicity with synchronous administration, compared with sequential
administration (24% vs 15%; P < .001), but Dr. Fernando noted that most of these events were "modest and had
healed within 4 weeks."
There was also an increase in modest/severe telangiectasia, seen in 2.5% of patients in the synchronous group
and 1.3% in the sequential group (P = .05).
Dr. Pierce pointed out that there was no difference between the 2 treatment groups in overall survival or in
disease-fee survival.
Both Dr. Pierce and Dr. Fernando referred to a study carried out by the Early Breast Cancer Clinical Trialists'
Collaborative Group, which found that 1 breast cancer death can be avoided for every 4 local recurrences that
are prevented (Lancet. 2005:366:2087-2106).
Clinical practice needs to be reviewed.
Dr. Fernando concluded that for breast cancer patients being treated with CMF or an anthracycline/CMF
chemotherapy schedule, "clinical practice needs to be reviewed." He added that the results could probably be
extended to patients being treated with a taxane as well as anthracycline and CMF.
However, Dr. Pierce cautioned that the results cannot be extrapolated to other chemotherapy regimens. She also
noted that CMF is seldom used in the United States, and that a recent survey of community oncologists revealed
that most treat breast cancer with a combination of anthracycline and taxane, or one or the other of these used
alone.
"This trial raises the important issue of how radiotherapy and chemotherapy after surgery should be sequenced
or integrated to obtain the best outcome in breast cancer," said the president of the European CanCer
Organisation, Michael Baumann, MD, radiation oncologist at the University of Technology in Dresden,
Germany.
"The SECRAB trial suggests that the risk of loco-regional recurrences could be reduced by applying
radiotherapy simultaneously with chemotherapy," he said in a statement. "Long-term follow-up will still be
necessary to assess potential late side effects and the benefits versus the risks of this approach, but I am
convinced that this trial will spur a lot of discussion on optimizing adjuvant treatment in this common disease."
The SECRAB trial was funded by Cancer Research UK.
2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 2BA. Presented September 25, 2011.

Worse Cosmetic Results and Radiation Toxicity

With Accelerated Partial Breast Irradiation
Jul 16, 2013 By Will Boggs, MD
NEW YORK (Reuters Health) Jul 16 - Accelerated partial breast irradiation (APBI) yields worse cosmesis and
more late radiation toxicity than standard whole breast irradiation (WBI), interim results from the RAPID trial
suggest.
Different methods of APBI have been studied, all supported by the hypothesis that larger radiation doses can be
delivered to a smaller volume of tissue over shorter durations, with no loss of local control and with limited
morbidity.
The RAPID trial compared 3-dimensional conformal radiation therapy (3D-CRT) APBI with standard WBI in
women with invasive ductal carcinoma or ductal carcinoma in situ treated with breast-conserving surgery.
3D-CRT is noninvasive and uses the same linear accelerators and treatment planning as WBI, Dr. Ivo A.
Olivotto from BC Cancer Agency, Victoria, British Columbia, Canada and colleagues say in their report,
published July 8th online in the Journal of Clinical Oncology.
Their paper includes an interim analysis of the impact of 3D-CRT APBI on cosmesis and normal tissue toxicity
in the RAPID study.
Similar numbers of women were randomly assigned to APBI (1,070) or WBI (1,065), and the median follow-up
was 36 months.
Significantly more women treated with APBI had adverse cosmesis as assessed by trial nurses at three months
(29.0% vs 16.5%; p<0.001) and at five years (32.8% vs 13.4%; p<0.001).
Results were similar when patients and physician panels assessed cosmesis.
When late radiation toxicities (telangiectasia, breast induration, fat necrosis, breast pain) were assessed three
years after radiotherapy, 1.4% of APBI patients had a grade 3 adverse event, whereas there were no such events
in the WBI group. Grade 1 and 2 adverse events were also significantly more common among women treated
with APBI than among those treated with WBI.
The magnitudes of differences in toxicity between treatment arms remained similar at five years.
The investigators propose several explanations for the higher toxicity of APBI: the 3D-CRT approach may not
have been sufficiently conformal; the radiation dose (38.5 Gy in 10 fractions) may have been too high; the
interfraction interval of six hours may have been too short to allow normal tissues to repair; or the symmetric
nature of the breasts may more readily demonstrate distortion and other changes with APBI compared with
WBI.
Regardless of the reason, the researchers conclude, "Clinicians and patients are cautioned against the use of 3D-
CRT APBI outside the context of a controlled trial."
They also point out, "The NSABP B-39/RTOG 0413 trial has completed accrual of 4,300 participants randomly
assigned to WBI or APBI using 3D-CRT or balloon-catheter or interstitial brachytherapy. An abstract from that
trial, with a mean follow-up of 43 months, reported no significant toxicity-related issues among those treated
with APBI, but cosmetic data were not available."
Dr. Olivotto did not respond to a request for comments on this report.
Dr. Benjamin Smith from the University of Texas MD Anderson Cancer Center in Houston, who contributed to
a 2011 American Society for Radiation Oncology evidence-based guideline on fractionation for WBI
(http://bit.ly/18lZ5RA) and a 2009 consensus statement on APBI (http://bit.ly/18lZ5RA) told Reuters Health by
email, "I use this form of APBI in my practice and outcomes generally seem to be quite good, so I was surprised
that outcomes in the RAPID trial were not as good as I would have expected."
"New technologies in breast radiotherapy need to be examined prospectively in carefully controlled studies,
preferably randomized controlled trials," Dr. Smith said. "The results of these trials can sometimes be
surprising. Although tempting, it is generally best to use these new technologies within the context of a trial
until they are fully vetted and we have a sophisticated understanding of how they can be safely implemented."
"Before we can fully understand external beam APBI, we will also need to see local control results from the
RAPID trial and local control and toxicity results from NSABP B-39/RTOG 0413 trial," Dr. Smith added.
"Until these data are available, it's hard to know what should be considered for future trials."
"My sense is that modestly lowering the radiation dose for external beam APBI, as compared to the dose used in
the RAPID trial, might significantly improve the toxicity profile and cosmetic outcome," Dr. Smith said.
"However, I don't think we understand whether lowering the dose might negatively impact tumor control."
SOURCE: http://bit.ly/14WZHYW
J Clin Oncol 2013.

Analysis Confirms Benefit of Radiation Therapy in Early Breast Cancer

November 3, 2010 (San Diego, California) — Further evidence that radiation therapy after breast-conserving
surgery reduces the risk for recurrence or death from breast cancer comes from a new meta-analysis, presented
here at the American Society for Radiation Oncology 52nd Annual Meeting. The new data also show a
reduction in all-cause mortality.
The results of the analysis of a combined cohort of almost 11,000 women show that adding radiation to breast-
conserving therapy lowers the risk for recurrence within 10 years by nearly 15%.
"The effect of radiotherapy on breast cancer mortality is very little in the first 5 years after randomization, but
by 15 years, there is a very clear effect on breast cancer mortality, with a 3.8% reduction," said study author
Sarah Darby, PhD, professor of medical statistics at the Clinical Trial Service Unit and Epidemiological Studies
Unit at Oxford University, United Kingdom.
"Most important," she added, "radiotherapy not only reduces breast cancer mortality, but also all-cause
mortality — by 3% at 15 years after randomization."
Although this confirms what we already know about radiation therapy in early breast cancer, this study provides
further evidence of a larger magnitude, she told Medscape Medical News.
"This study also shows that there is a real survival benefit, not just a benefit for local recurrence," said Dr.
Wilson, professor of therapeutic radiology and dermatology at Yale University School of Medicine, New
Haven, Connecticut, who was not involved with the study. "It definitely adds to the evidence."
Impact Greater in Certain Subgroups
 Although there is much evidence to support the use of radiation therapy after breast-conserving therapy, it might
be more effective for certain types of breast cancer than for other types. To examine the evidence of any such
differences, and to quantify them when appropriate, collaborative meta-analyses were undertaken.
Dr. Darby and colleagues reviewed data from studies that had begun by 2000 (and were initiated between 1976
and 1999). A total of 10,906 women from 17 randomized trials were included in the analysis, which had a
median follow-up period of 9.5 years.
In addition to reducing overall risk for recurrence, the authors found that the impact of radiation varied among
the different subtypes of breast cancer. Most notably, radiation therapy conferred a substantial benefit on women
with node-positive disease and on women with higher-risk node-negative disease in terms of the 10-year risk for
any recurrence of breast cancer and the 15-year risk for breast-cancer-related mortality.
For the 7334 patients with pathologically node-negative breast cancer, radiation therapy decreased the 10-year
risk for isolated loco-regional recurrence by 15.4% (7.1% vs 22.5%) and the 10-year risk for any recurrence by
14.5% (18.9% vs 33.4%).
Among this subgroup, the reduction in risk varied according to confounders, such as age, grade, estrogen-
receptor (ER) status in combination with tamoxifen use, and extent of surgery.
As an example, note the authors, women with ER-positive tumors participating in trials where breast-conserving
surgery was performed and tamoxifen was planned, the 10-year reduction in the risk for recurrence in women
younger than 40 years with high-grade tumors was 35%. In contrast, for women 70 years and older with low-
grade tumors, it was only 5%.
Among the 1108 women with pathologically node-positive disease, radiation therapy reduced the 10-year risk
for isolated loco-regional recurrence by 30.8% (42.7% vs 11.9%), but the impact was lower for the risk for any
recurrence (17.7%; 46.8% vs 64.5%; P < .00001). This difference is due to the higher percentage of women in
this group with distant recurrence or a contralateral breast cancer as their first event by the 10th year, the authors
explain.
Also, within this subgroup, radiotherapy reduced the 15-year risk for breast-cancer-related mortality by 7.8%
(43.4% vs 51.2%; P = .04).
American Society for Radiation Oncology (ASTRO) 52nd Annual Meeting: Abstract LB2. Presented
November 1, 2010.

Impact of Radiation Therapy on Risk of

Lymphedema After Treatment for Breast Cancer
Int. J. Radiat. Oncol. Biol. Phys 2014 Jan 07;[EPub Ahead of Print], LEG Warren, CL Miller, N Horick, MN
Skolny, L SJammallo, BT Sadek, MN Shenouda, JA O'Toole, SM MacDonald, MC Specht, AG Taghian
Research · January 16, 2014

TAKE-HOME MESSAGE
 In this prospective cohort study of > 1000 women with locally advanced breast cancer who underwent
surgical resection and subsequent radiation therapy, regional lymph node radiation was associated with a
statistically significant increase risk of lymphedema compared with breast/chest wall radiation alone.
 Other risk factors for lymphedema included higher BMI, axillary lymph node dissection, and number of
lymph nodes removed.
- Chris Tully, MD
ABSTRACT
Purpose/Objective
Lymphedema after breast cancer treatment can be an irreversible condition with a negative impact on quality of
life. The goal of this study was to identify radiation therapy-related risk factors for lymphedema.
Methods and Materials
From 2005 to 2012, we prospectively performed arm volume measurements on 1476 breast cancer patients at
our institution using a Perometer. Treating each breast individually, 1099 of 1501 patients (73%) received
radiation therapy. Arm measurements were performed preoperatively and postoperatively. Lymphedema was
defined as ≥10% arm volume increase occurring >3 months postoperatively. Univariate and multivariate Cox
proportional hazard models were used to evaluate risk factors for lymphedema.
Results
At a median follow-up time of 25.4 months (range, 3.4-82.6 months), the 2-year cumulative incidence of
lymphedema was 6.8%. Cumulative incidence by radiation therapy type was as follows: 3.0% no radiation
therapy, 3.1% breast or chest wall alone, 21.9% supraclavicular (SC), and 21.1% SC and posterior axillary boost
(PAB). On multivariate analysis, the hazard ratio for regional lymph node radiation (RLNR) (SC ± PAB) was
1.7 (P=.025) compared with breast/chest wall radiation alone. There was no difference in lymphedema risk
between SC and SC + PAB (P=.96). Other independent risk factors included early postoperative swelling
(P<.0001), higher body mass index (P<.0001), greater number of lymph nodes dissected (P=.018), and axillary
lymph node dissection (P=.0001).
Conclusions
In a large cohort of breast cancer patients prospectively screened for lymphedema, RLNR significantly
increased the risk of lymphedema compared with breast/chest wall radiation alone. When considering use of
RLNR, clinicians should weigh the potential benefit of RLNR for control of disease against the increased risk of
lymphedema.

International Journal of Radiation Oncology, Biology, Physics

The Impact of Radiation Therapy on the Risk of Lymphedema After Treatment for Breast Cancer: A Prospective
Cohort Study
Int. J. Radiat. Oncol. Biol. Phys 2014 Jan 07;[EPub Ahead of Print], LEG Warren, CL Miller, N Horick, MN
Skolny, L SJammallo, BT Sadek, MN Shenouda, JA O'Toole, SM MacDonald, MC Specht, AG Taghian

Adoption of Intensity-modulated Radiation Therapy

for Breast Cancer in the United States
Benjamin D. Smith; I-Wen Pan; Ya-Chen T. Shih; Grace L. Smith; Jay R. Harris; Rinaa Punglia; Lori J. Pierce;
Reshma Jagsi; James A. Hayman; Sharon H. Giordano; Thomas A. Buchholz
Posted: 08/08/2011; Journal of the National Cancer Institute. 2011;103(10):798-809. © 2011 Oxford University
Press
Abstract
Background Although intensity modulation of the radiation beam has been shown to lower toxic effects for
patients receiving whole-breast irradiation, relatively simple techniques may suffice. It is thus controversial
whether such treatment justifies billing for intensity-modulated radiation therapy (IMRT).
Methods We used the claims data to determine billing for IMRT from Surveillance, Epidemiology, and End
Results–Medicare records from 2001 to 2005 for 26 163 women aged 66 years or older with nonmetastatic
breast cancer treated with surgery and radiotherapy. The impact of individual covariates (demographic, health
services, tumor, and treatment factors) on cost of treatment was assessed using the Wilcoxon two-sample test.
Two-sided multivariable logistic regression was used to identify predictors for IMRT use. Cost of radiation was
calculated in 2005 dollars. All statistical tests were two-sided.
Results The number of patients with IMRT billing claims increased from 0.9% (49 of 5196) of patients
diagnosed in 2001 to 11.2% (564 of 5020) in 2005. In multivariable analysis, IMRT billing was more likely for
patients with left-sided tumors (odds ratio [OR] = 1.30, 95% confidence interval [CI] = 1.16 to 1.45), for those
residing in a health service area with high radiation oncologist density (OR = 2.32, 95% CI = 1.47 to 3.68), for
those treated at freestanding radiation centers (OR = 1.36, 95% CI = 1.20 to 1.53), or for those residing in
regions where the Medicare intermediary allowed breast IMRT (OR = 10.87, 95% CI = 9.26 to 12.76, all P < .
001). The mean cost of radiation was $7179 without IMRT and $15 230 with IMRT. IMRT adoption contributed
to an increase in the mean cost of breast radiation from $6334 in 2001 to $8473 in 2005.
Conclusions IMRT billing increased 10-fold from 2001 through 2005, contributing to a 33% increase in the
cost of breast radiation. These findings suggest that reimbursement policy and practice setting strongly
influenced adoption of IMRT billing for breast cancer.
Introduction
Breast cancer is the most common cancer treated with radiation therapy in the United States, with
approximately 120 000 women treated annually.[1] For women with breast cancer, multiple high-quality
randomized trials have demonstrated that radiation therapy plays an important role in enabling breast
conservation, optimizing local-regional control, and improving survival.[2] Although generally well tolerated,
radiotherapy to the breast or chest wall may be associated with acute toxic effects such as dermatitis and late
toxic effects such as soft tissue fibrosis and cardiovascular sequelae.[3–5] The historic limitations of conventional
radiotherapy delivered with two-dimensional planning may have contributed to the severity of these toxic
effects. Specific limitations of two-dimensional radiotherapy include the inability to accurately calculate
volumetric dose distributions and to account for dose inhomogeneity in off-axis planes and reliance on static
wedge compensators of fixed dimensions, which often do not optimally account for irregular tissue separations.
To reduce the risk of radiation toxicity, three-dimensional treatment planning and dynamic multileaf collimators
have been used to modulate the radiotherapy dose in three dimensions across the breast and chest wall, thereby
improving the homogeneity of the dose deposited. A growing body of evidence now suggests that such three-
dimensional modulation of the radiation beam profile improves dose homogeneity within the treated breast[6]
and lowers dose to the contralateral breast[7] and, potentially, the heart.[8,9] In addition, recently published
randomized trials have demonstrated that this dosimetric gain translates into a lower risk of acute skin
toxicity[10] and improved long-term cosmetic outcome for patients receiving whole-breast irradiation following
conservative surgery.[11,12]
These clinically beneficial techniques that involve three-dimensional modulation of the radiation beam profile
can be achieved using intensity-modulated radiation therapy (IMRT) or with other techniques that do not
require IMRT.[10,13–19] Prior research has indicated that treatment with IMRT is associated with increased cost,[20]
but to date, it is not known to what extent IMRT is used in the treatment of breast cancer and what factors may
have affected its adoption. Identifying factors that promote the use of a more costly therapy is critically
important, given the imperative to promote cost-effective value-oriented practice in today's health-care
environment.[21] Accordingly, we used population-based data to characterize adoption of IMRT billing for
patients diagnosed with breast cancer between 2001 and 2005, to identify demographic, health services, tumor,
and treatment factors associated with the use of IMRT billing, and to compare the cost of care between radiation
therapy with and without IMRT billing.
Discussion
In this population-based study of older women with primary non-metastatic breast cancer treated with radiation
therapy between 2001 and 2005, we found that billing for IMRT treatment delivery increased more than 10-
fold. This sharp increase suggests that during this time more patients gained access to the potential benefits of
IMRT with respect to its ability to minimize acute dermatitis and optimize long-term cosmetic outcome.[10,11]
Our findings also help to identify factors that appear to have either promoted or discouraged adoption of billing
for IMRT. Specifically, the Medicare Carrier LCDs powerfully influenced adoption, with use of IMRT billing
more than fivefold higher in regions with coverage favorable toward breast IMRT as compared with regions
with coverage unfavorable toward breast IMRT. Furthermore, use of IMRT billing was 36% higher for patients
treated in freestanding radiation centers as compared with patients treated in hospital-based outpatient clinics.
These findings suggest that reimbursement policy and practice setting strongly influenced adoption of IMRT
billing for breast cancer.
Our cost analysis indicates that, after adjusting for medical inflation, the mean per patient cost of radiation
therapy for breast cancer increased by 33% between 2001 and 2005; among non-IMRT patients, the cost
increase was 21%. Adoption of the IMRT billing code appears to have accelerated growth in the cost of
radiation therapy both because IMRT is reimbursed more favorably than non-IMRT and because the cost of
IMRT is growing faster than the cost of non-IMRT. Looking to years subsequent to 2005, continued increases in
utilization of the IMRT billing code could lead to a further escalation in the cost of radiation therapy. For
example, our data suggest that if 50% of patients were treated with IMRT, then the average cost of radiation per
patient would be 80% higher than the baseline per patient cost of radiation in 2001 (assuming the cost of IMRT
remained at 2005 levels). Furthermore, our data indicate that Medicare LCDs can exert a strong influence over
cost because the mean cost of radiation per patient within the first year of diagnosis was 28% higher in regions
with coverage favorable toward breast IMRT as compared with regions with coverage unfavorable toward
breast IMRT. Finally, our data illuminate a nearly twofold differential in reimbursement for IMRT between
freestanding centers and hospital-based outpatient clinics, indicating that certain variation in cost is endogenous
to the current Medicare reimbursement structure and may have contributed to the differential adoption rates of
IMRT in freestanding vs hospital-based outpatient centers.
In general, three-dimensional modulation of the radiation beam profile in the treatment of breast cancer can be
achieved using two different approaches. The first, referred to herein as "field-in-field (FiF) forward planning,"
is relatively straightforward to implement and entails creation of one or more subfields within the initial
radiation field to improve homogeneity of the delivered radiation dose. The second, referred to herein as
"inverse planning," generally requires a greater degree of physician and treatment planning time to contour
target volumes and critical structures, implement an intensity modulation beam optimization algorithm,
iteratively evaluate and modify the plan, and perform quality assurance to verify the dose delivered. For most
Medicare Carriers, inverse planning is a prerequisite for IMRT billing. In the pivotal randomized trial[10] that
compared intensity-modulated whole-breast irradiation to standard two-dimensional whole-breast irradiation,
both forward-planned FiF intensity modulation and inverse-planned IMRT were used depending on the center at
which the patient was treated.[10] This trial was conducted in Canada, where the distinction between the two
techniques had no reimbursement implications. With respect to the primary endpoint of acute radiation-induced
dermatitis, both techniques appear to have yielded a similar benefit. The investigators also conducted a
dosimetric study[16] comparing forward planning to inverse planning and concluded that although inverse-
planned IMRT conferred a marginal improvement in the volume of breast tissue receiving greater than 110% of
the prescription dose, the dose to the inframammary fold was similar for the two techniques. The authors
concluded that it is unlikely that inverse planning would confer a meaningful clinical benefit over forward
planning with respect to the endpoint of acute radiation-induced dermatitis.[16] Despite the apparent similarity in
clinical outcomes with forward vs inverse planning noted in this trial, it nevertheless remains possible that
inverse-planned IMRT may improve certain outcomes by reducing the dose to the heart and lung, and
prospective investigations along these lines are ongoing.
Despite the proven benefits of FiF forward planning, there is currently lack of consensus regarding whether
such treatment should be considered IMRT for the purposes of billing and reimbursement. Notably, some
treatment centers that use FiF forward planning do not bill for IMRT delivery, and the majority of Medicare
Carriers do not allow billing for IMRT delivery for FiF forward planning.[24] As a result, for many centers the
cost of a course of FiF forward-planned intensity-modulated whole-breast irradiation would be only slightly
higher than the mean cost of non-IMRT ($7179) reported in this study (FiF forward planning may entail some
extra charges because of the need for three-dimensional planning and dosimetric calculations for multiple
subfields.). In contrast, in regions where FiF forward planning meets billing criteria for IMRT, the cost of FiF
forward planning would be approximately $11 496 at hospital-based outpatient centers and $21 487 at
freestanding centers. This type of geographic variation in Medicare payments has been previously cited, both in
the lay press and in health policy circles,[21,38] as a potential source of waste within the Medicare system. Our
data suggest that with respect to breast radiation therapy much of the variation in cost can be directly attributed
to inconsistent treatment definitions and reimbursement rates authorized by Medicare and its intermediaries.
Promotion of value, which is defined as the ratio of quality to cost, has received greater attention as the recently
passed Patient Protection and Affordable Care Act (PPACA) called for study of new reimbursement models that
reward efficiency and value in medical care.[21] When applied to breast radiation therapy, our data illustrate that
the current reimbursement system is structured to either control cost, as in the regions with unfavorable
coverage for breast IMRT, or to promote quality, as in the regions that allow billing IMRT charges for patients
with breast cancer. Although current reimbursement policy does not prohibit the use of FiF forward planning in
regions where such treatment is not billed as IMRT, its use is currently not incentivized or even reported. There
is a need for novel reimbursement strategies that simultaneously incentivize the implementation of clinically
important methods that improve three-dimensional dose distributions and reduce toxicity while promoting use
of the most cost-effective method. The inherently regional nature of LCDs offers the opportunity to enact, study,
and compare different policies in different regions in an effort to identify optimal policy solutions. Specific
policies that could promote value may include creation of quality measures that encourage use of FiF forward-
planned whole-breast irradiation, akin to the Practice Quality Reporting Initiative (PQRI),[39] or tying
reimbursement more closely to achieving the goals of radiation treatment planning.
Regarding other factors predictive of use of the billing code for IMRT, our finding that IMRT was used more
frequently for patients treated with breast-conserving surgery than mastectomy is consistent with the published
literature that primarily evaluated IMRT in the setting of breast-conserving surgery.[10,11] Outside a clinical trial,
caution may be needed in the application of IMRT to the postmastectomy setting because the relatively thin
nature of the chest wall could preclude accurate inverse planning and dose-volume analysis. Our finding that
IMRT was used more frequently for left- than right-sided breast cancers may reflect the potential benefits
suggested in the dosimetric literature of decreased cardiac irradiation with IMRT,[8,9] although other non-IMRT
strategies may offer superior cardiac protection.[40,41] Finally, our finding of an association between density of
radiation oncologists and increased use of IMRT may reflect competitive pressures that spur adoption of new
technologies or possible financial pressures associated with practicing in a relatively saturated market.
Our study has several limitations. First, because FiF forward-planned intensity modulation does not have a
unique CPT code, we were unable to determine to what extent patients were treated with FiF forward planning
as compared with inverse planning techniques. This shortcoming of current CPT coding limits the ability of
subsequent population-based studies to determine if actual use of IMRT is associated with improved clinical
outcomes. Second, our cohort was limited to older women who were Medicare beneficiaries, and it remains
possible that younger women may receive IMRT more frequently because of concerns regarding late toxic
effects or because of insurance coverage issues. Third, our definition of IMRT was exclusively determined by a
claim for delivery of an IMRT fraction, and this approach has not been previously validated when compared
with the gold standard of chart review, although Medicare claims are generally thought to be accurate because
they are tied to physician payment.[42] Finally, our cost analysis was conducted from a payer's perspective and
thus does not consider patient co-payments or coinsurance and also may not accurately reflect cost of radiation
therapy for patients with private insurance. Furthermore, the payer's (Medicare) cost determined in this study
may not reflect the actual cost of providing radiation therapy. This limitation is particularly relevant, given our
finding that radiation therapy delivered with FiF forward planning was reimbursed at much higher rates in
regions with favorable LCDs as compared with regions with unfavorable LCDs, despite the fact that the cost of
providing this treatment should be similar in all regions regardless of LCD status.
In summary, the development of three-dimensional modulation of the radiation beam profile has led to a major
advance in the treatment of breast cancer with respect to lowering risks of both acute and late toxic effects
associated with radiation therapy.[10,11] For patients treated at freestanding centers or residing in regions with a
favorable LCD, Medicare reimbursement policy has helped to improve the quality of breast radiation by
incentivizing adoption of three-dimensional dose modulation in the form of IMRT. However, for patients treated
in regions with unfavorable LCDs, Medicare reimbursement policy has generally served to control cost, and it is
not known to what extent physicians in these regions sought out less expensive yet comparable alternatives to
IMRT such as FiF forward planning to achieve three-dimensional modulation of the radiation dose. Given our
finding that current Medicare policy serves to promote quality in some regions while controlling cost in others,
more research is needed to develop reimbursement models that reward value in the delivery of radiation therapy
by promoting quality while controlling cost.

Accelerated Partial-Breast Irradiation Effective in Subtypes

September 16, 2011 — Five-year outcomes after accelerated partial-breast irradiation (APBI) were "excellent"
in a number of breast cancer subtypes that tend to have poorer prognoses, according to presenters at the 2011
Breast Cancer Symposium (BCS) in San Francisco, California.
Frank J.B. Wilkinson, MD, and colleagues from the Beaumont Cancer Institute in Royal Oak, Michigan,
evaluated 516 consecutive patients with early breast cancer who received APBI. The mean age of the
participants was 66 years and median follow-up was 4.9 years.
The patients received APBI via interstitial brachytherapy (n = 221), balloon-based brachytherapy (n = 201), or
3-dimensional conformal radiation therapy (n = 106).
Tumors were classified according to estrogen-receptor (ER) status, progesterone-receptor (PR) status, and
human epidermal growth-factor (HER-2/neu)-receptor status. Patients lacking test results for all 3 receptors
were excluded.
Of the 278 eligible patients, 164 had the luminal A subtype (ER positive, PR positive/negative, and HER-2
negative; 81 had the luminal B subtype (ER positive, PR positive/negative, and HER-2 positive); 5 had the
HER-2 subtype; and 28 had the basal subtype (ER negative, PR negative, and HER-2 negative). The researchers
estimated ipsilateral breast tumor recurrence, regional node failure, distant metastasis, disease-free survival,
cause-specific survival, and overall survival. All of the subgroups had similar margin and nodal status.
The basal and HER-2 subtype patients had higher histologic grades, larger tumors, and were more likely to have
received chemotherapy. Basal subtype patients were more likely to have been African American (18% vs 4%
luminal A/luminal B; P = .002).
At 5 years, ipsilateral breast tumor recurrence rates ranged from 0.0% to 4.8%, but were not significantly
different among the subtypes. Distant metastasis was seen only in the luminal A (2.5%) and luminal B (1.4%)
subtypes (P = .87).
Disease-free survival (95% to 100%), cause-specific survival (97% to 100%), and overall survival (80% to
100%) were not statistically different among the breast cancer subtypes.
The researchers concluded that "5-year local control rates after treatment with APBI are excellent for luminal,
HER2, and triple-negative phenotypes of early-stage breast cancer. Further study of breast cancer subtypes is
important and may be useful when counseling patients on adjuvant treatment options following breast-
conserving surgery."
H. Joseph Barthold, MD, from Commonwealth Hematology Oncology in Boston, Massachusetts, and who is a
member of the BCS news planning team, noted that "while awaiting the completion and publication of the
randomized trial, the group at Beaumont — who have long been leaders in this field — have shown that this
approach is equally appropriate in various subsets of breast cancer patients.... Partial-breast radiation will
continue to be offered as an alternative therapy/option approach to selected low-risk groups. Published data now
show it to be equivalent to more protracted radiation schedules."
Dr. Wilkinson and Dr. Barthold have disclosed no relevant financial relationships.
2011 Breast Cancer Symposium (BCS): Abstract 83. Presented September 8, 2011.

Brachytherapy Reduces Breast Cancer Recurrence

in Tumor Bed
Nancy A. MelvilleMay 4, 2012 (Phoenix, Arizona) — Accelerated partial-breast irradiation (APBI), or
brachytherapy, is more effective than whole-breast irradiation (WBI) at preventing breast cancer recurrence
after lumpectomy, according to research presented here at the American Society of Breast Surgeons 13th Annual
Meeting.
Lumpectomy with WBI is associated with a rate of survival no worse than with mastectomy; however, the
therapy has not been shown to affect "elsewhere" cancers that are not in the primary tumor quadrant.
Recurrence rates with WBI are known to be higher in the tumor bed than in ipsilateral elsewhere areas. A new
study suggests that the focused APBI technology offers better control of tumor-bed breast cancer recurrence.
Although it is common sense that "APBI offers better rates of local control than WBI, since the radiation
therapy with APBI is delivered directly to the tumor site, this is the first study to have actually proven this
hypothesis," lead author Peter Beitsch, MD, a surgical oncologist at the Dallas Surgical Group in Texas, told
Medscape Medical News.
"WBI has been held as the gold standard for postlumpectomy radiation therapy. Our data may change that line
of thought," said Dr. Beitsch.
Dr. Beitsch and his colleagues evaluated 1444 patients with early-stage breast cancer who had been treated with
APBI after lumpectomy.
They found that, after a mean follow-up of 60 months, there were 50 cases (3.5%) of ipsilateral breast tumor
recurrences among patients treated with APBI (34 Gy in 3.4 Gy fractions). The 5-year actuarial rate for
ipsilateral recurrences was 3.61% (3.65% for invasive breast cancer and 3.36% for ductal carcinoma in situ
[DCIS]).
Just 14 of the ipsilateral breast tumor recurrences (1.0%) were associated with tumor-bed failures, compared
with 36 (2.5%) elsewhere failures (72% of all ipsilateral recurrences).
There were 1255 (87%) patients with invasive breast cancer (median size, 10 mm) and 194 (13%) with DCIS
(median size, 8 mm).
The only variable associated with ipsilateral breast tumor recurrences was estrogen-receptor negativity (P = .
0004).
In the DCIS group, however, age younger than 50 (P = .0431) and close/positive margins (P = .0551) were
associated with increased ipsilateral recurrences.
Dr. Beitsch explained that results are likely explained by the precision of APBI in targeting the site of the
original tumor, which is the site most at risk for tumor recurrence.
"The 'bioequivalent' dose of radiation therapy to the breast is similar between APBI and WBI, but the radiation
therapy is not 'diluted' by applying it to the entire breast," he said.
"The targeted radiation is delivered from within the lumpectomy bed to the cavity walls. The entire reason for
radiation after lumpectomy for early-stage breast cancer is to kill the residual cancer cells," he explained.
He described WBI as "a cannon" and APBI as a "sniper rifle."
"APBI therapy targets the tissue at risk and avoids normal tissue — ribs, lung, heart, pectoralis muscle."
A larger study of nearly 93,000 women (JAMA. 2012;307:1827-1837) had contradictory findings. It found APBI
to be associated with a higher risk for infection and complications and a lower risk for long-term breast
preservation in older women with invasive breast cancer, compared with WBI.
In contrast to the study by Dr. Beitsch and colleagues, which involved a registry in which patients were treated
and reported in "real time, the JAMA study was a retrospective review of a Medicare billing claims database.
"One of the main conclusions of the [JAMA] study is that patients undergoing APBI subsequently had a
mastectomy at twice the rate of patients undergoing WBI," Dr. Beitsch explained.
"However, it is impossible from a claims database to know why those patients underwent mastectomy. Was it
due to a local recurrence, a new cancer somewhere else in the breast, even a new cancer in the other breast?
Neither 'elsewhere' failures nor new breast cancers in the other breast are prevented by WBI," he explained.
Dr. Beitsch added that the study lacked clinical data on where in the body the increased infections were, and it
fails to address the death rate associated with WBI.
"There was actually a higher death rate with WBI that was dismissed on multivariate analysis, which
mastectomy rate was not subjected to," he said. "I find this interesting in light of the pejorative way APBI is
described as 'harming patients.' Isn't the worst possible harm death?"
Benjamin Smith, MD, lead author of the JAMA study, agrees that the claims data were a limitation of his study;
however, he noted that the study has strengths that help address limitations in the study by Dr. Beitsch's team.
"It is an important limitation of the JAMA study that the indication for mastectomy cannot be definitely
determined from claims, although mastectomy in and of itself is obviously a clinically relevant outcome," said
Dr. Smith, assistant professor in the Department of Radiation Oncology at the University of Texas M.D.
Anderson Cancer Center in Houston.
Dr. Beitsch and colleagues do not have data on "the treatment of in-breast tumor recurrence for 24% of the
recurrences [12 of 50 cases]. Our data can provide a nice complement to their data, since we have complete data
on subsequent surgeries performed on patients after treatment with brachytherapy," Dr. Smith told Medscape
Medical News.
He suggested that various factors could explain why there were proportionally fewer tumor-bed recurrences
with brachytherapy than elsewhere recurrences in the study by Dr. Beitsch's team.
"If it is true that the proportion of tumor-bed recurrences to elsewhere recurrences is lower for patients treated
with brachytherapy than with whole-breast irradiation, this could be due to either a lower risk of tumor-bed
recurrences in patients treated with brachytherapy or, conversely, a higher risk of elsewhere recurrences," Dr.
Smith said.
"It is almost certain that patients treated with brachytherapy will have a higher risk of elsewhere tumor
recurrences, as 'elsewhere' is not irradiated," he explained.
"It is probably more important to evaluate absolute risks of tumor-bed recurrences and elsewhere recurrences in
matched patients treated with brachytherapy or whole-breast irradiation, instead of comparing the proportion of
these 2 events."
Dr. Beitsch has disclosed no relevant financial relationships. Dr. Smith reports receiving research funding from
Varian Medical Systems, which makes radiation equipment for both whole-breast irradiation and
brachytherapy; however, the research funding was not used for any portion of this study.
American Society of Breast Surgeons (ASBS) 13th Annual Meeting: Abstract 0058. Presented May 4, 2012.