Rationale and relevance for patients and the scientific community. In low risk early stage
patients ≥70 years, exclusive Partial Breast Irradiation (PBI) as radiation therapy (RT)
approach might be superior in terms of Health-Related Quality of Life (HRQoL), when compared
to exclusive endocrine therapy (ET) following breast-conserving surgery (BCS). Assuming an
equal rate of disease control, unnecessary long-term toxicity of ET may be avoided.
Study Background. BCS has been established as the preferred treatment option for early stage
breast cancer (BC) or for initially inoperable tumors that respond sufficiently to
preoperative therapy. BCS plus RT obtains at least the same results in terms of survival,
without the huge impact on the patient's body image and HRQoL as that seen after mastectomy.
For decades, standard whole breast irradiation (WBI) consisted of 45-50 Gy delivered at
1.8-2.0 Gy/fraction over 4.5-5 weeks with or without a boost dose to the surgical bed. Large
phase 3 trials evaluating different hypofractionation schedules proved that overall treatment
time could be reduced without compromising local control and safety profile.
PBI has been introduced as an alternative treatment method for selected patients with early
stage BC. Potential advantages of accelerated PBI include shorter treatment time, equivalent
disease control, improved safety profile, and cost reduction as compared to standard WBI. The
role of PBI has been investigated in large-scale prospective phase 3 clinical trials (i.e.,
NSABP-B29/RTOG 0413, IRMA, RAPID, IMPORT-LOW, GEC-ESTRO trials).
5-year results of the IMPORT-LOW trial showed non-inferiority of PBI when compared to WBI in
women with low risk early BC, with a 5-year local recurrence (LR) rate of 0.5%. Ongoing
research explores other modalities of RT that will minimize toxicities without reducing
effectiveness. Intensity-modulated radiotherapy (IMRT) has the theoretical advantage of a
further increase in dose conformity compared with three-dimensional techniques, with
increased normal tissue sparing. To date, only the Florence IMRT-APBI phase 3 trial reported
the outcomes of exclusive IMRT accelerated PBI compared to WBI, demonstrating no significant
difference between the two groups in terms of ipsilateral breast tumor recurrences (IBTR).
The PBI group presented significantly better results considering acute (p=0.0001), late
(p=0.004), and cosmetic outcome (p=0.045). The subgroup analysis evaluating patients aged 70
years or older, showed a 5-year IBTR rate of 1.9% for both groups, and significantly better
results in terms of acute skin toxicity, in favor of the PBI arm. Therefore, a significant
impact on patients' compliance to RT could translate into a consistent improvement of overall
HRQoL.
Heart exposure to ionizing radiation during RT for BC increases subsequent rates of ischemic
heart disease (IHD). The increase is proportional to the mean dose to the heart. Women with
pre-existing cardiac risk factors have greater absolute increases in risk from RT. An age >70
years seems to be one of the most significant factor for IHD occurrence. PBI represents one
of several effective strategies to reduce cardiac radiation dose when compared to WBI.
Postoperative RT in the elderly is a matter of constant debate. RT was shown to benefit these
patients with regards to local control; however, the absolute benefit is small (for low risk
subtypes). Moreover, considering the poor compliance of elderly patients to conventional RT
treatment time (3-6 weeks), conventional RT is often omitted in cases of low-risk BC, at the
expense of reducing the local control rate by less than 4%.
In an unplanned subgroup analysis of the PRIME-II trial by estrogen receptor (ER) score, LR
at 5 years for women in the rich ER subgroup was lower than in the whole population; for
patients assigned no RT, 3% had a LR compared with 1% of women allocated WBI (5-year IBTR was
3.3%, and 1.2%, respectively).
The British Association of Surgical Oncology (BASO)-II trial confirmed that patients treated
with either exclusive adjuvant RT or ET with tamoxifen had an equivalent LR rate per year of
0.8%. These data suggested that RT or ET alone resulted in excellent disease control in older
women with early BC, and that the combination of treatments may have less benefit than
expected. A direct comparison between PBI or ET omission as adjuvant treatment is lacking in
the existing literature.
Conversely, the toxicity profile of ET is well known, and could significantly impact long
term HRQoL of these potentially frail patients. Elderly patients with early BC are a unique
population with regards to good prognosis and potential comorbidities, thus minimizing
treatment to maintain HRQoL without compromising survival is extremely important. In the
decision-making process for adjuvant therapy, estimates of the patient's risk of benefit
and/or harm with treatment should be performed together with an assessment of baseline
comorbidities, life expectancy and care preferences. Many large phase III studies reported on
the detrimental effects of postmenopausal ET on bone density and fractures incidence,
thromboembolic complications, sexual, and cognitive functionality. Moreover, patient's
compliance and oral treatment adherence may be a concern, and some patients would like to
avoid the toxicities associated with ET.
Considering that the potential benefit of PBI alone could be better than that of the RT-only
effect reported in the above WBI-using trials, it may be possible to avoid the long term
toxicity of ET and favorably impact HRQoL in selected patients, such as elderly patients with
a good prognosis.
Importantly, all previously published de-escalation studies were designed and performed in
order to evaluate RT omission, regardless of efficacy and compliance of ET. When expecting a
comparable efficacy among tested treatment modalities, HRQoL might be the factor with the
most influence on the treatment decision-making process and should therefore be the primary
endpoint.
Inclusion Criteria:
- Women aged ≥70 years;
- histologically proven invasive adenocarcinoma of the breast;
- pathological T1 (pT1) stage (clinical T1-2 [cT1-2] stage is allowed);
- clinical and pathological N0 (cN0 and pN0) stage (isolated tumor cells [i+] allowed);
- any tumor grade (if pT ≤10 mm), G1-2 tumor grade (if pT between 11 and 19 mm);
- Luminal-A by immunohistochemistry (IHC)-based on local assessment (consistent with
14th St. Gallen consensus definition):
- ER+ (defined as ≥10% by IHC staining),
- PgR+ (in any case PgR should be at least >20% by IHC staining),
- Human epidermal growth factor receptor 2 (HER2)- (0 or 1+ following IHC staining
and proven negative by in-situ hybridization [ISH] in case of 2+), and
- Ki67 ≤20% by IHC staining;
- surgically treated with BCS with or without sentinel node biopsy (SNB);
- no clinical evidence of distant metastases. Imaging work up is not mandatory to enter
the trial. If there are signs/symptoms suggesting the presence of local relapse or
distant metastasis, an appropriate work up should be performed according to the
treating physician standard practice. A patient with confirmed local relapse or
distant metastasis will no longer be eligible for the trial;
- postoperative final surgical margins negative (no ink on tumor);
- baseline HRQoL questionnaires completion;
- adjuvant bisphosphonates and denosumab are allowed;
- before patient registration/randomization, written informed consent must be given.
Exclusion Criteria:
- Preoperative systemic treatments (i. e., chemotherapy, endocrine therapy);
- current treatment with any hormonal agents such as tamoxifen, raloxifene or other
selective estrogen receptor modulators (SERMs), either for osteoporosis or BC
prevention (patients are eligible if these medications are discontinued prior to
randomization);
- prior breast or thoracic RT;
- known disorders associated with a higher risk for complications following RT such as
collagen vascular disease, dermatomyositis, systemic lupus erythematosis or
scleroderma;
- prior diagnosis, detection, or treatment of any other invasive cancer (except basal or
squamous cell carcinoma of the skin that has been definitely treated);
- any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule; these conditions
should be discussed with the patient before registration;
- patients must not be considered a poor medical risk due to serious, uncontrolled
medical disorder, non-malignant systemic disease, or active uncontrolled infection.
Examples include but are not limited to uncontrolled ventricular arrhythmia, recent
(within 3 months) myocardial infarction or uncontrolled major seizure disorder.
