Download Lorenzo Livi

Hypo-fractionated RT and ABPI are
recommended but…
Can it be less?
Lorenzo Livi, Full Professor
Clinical Oncologist
Chief Radiation-Oncology Department
Azienda Ospedaliero-Universitaria Careggi
University of Florence, Florence
e-mail: [email protected]
ADVANTAGES
APBI VS WBRT
Decrease of the overall time (1-5 days)
Decrease of the cost and logistical discomfort
BETTER QUALITY OF LIFE
Decrease of the waiting list in the
Radiotherapy Center
OVERVIEW
questions
The question if RT is necessary for all patients to improve
outcome when BCS is performed is a matter of debate
Randomized trials:
Impact of radiotherapy omission on IBTR rate
Impact of radiotherapy omission on OS
Identification of a favorable subgroup of patients
Definition of a very low risk group of patients in whom RT could
be safely avoided
Adjuvant RT omission after BCS
Tamoxifen, Radiation Therapy, or Both for Prevention of
Ipsilateral Breast Tumor Recurrence After Lumpectomy in
Women With Invasive Breast Cancers of One Centimeter or
Less (NSABP-B21)
1009 patients between 1989 and 1998
Primary invasive breast tumor of less than 1 cm
TAM (n:336), RT and placebo (n:336), or RT and TAM (n:337)
Endpoints: IBTR, distant recurrence, and contralateral breast
cancer
Fisher B, et al. JCO, 2002
Adjuvant RT omission after BCS
 The B-21 results demonstrate that TAM administration is less
effective than RT in preventing an IBTR after lumpectomy to
remove invasive tumors of 1 cm
 However, the findings do signify that the use of both RT and TAM
results in a lower rate of IBTR than is observed after the use of
either modality alone in women with ER-positive tumors
 Authors suggested that biologic characteristics, ER status, nuclear
grade, tumor type, and a patient’s clinical status, in conjunction
with tumor size, are likely to be more helpful for making a decision
about the treatment of an individual patient than is tumor size
alone
Fisher B, et al. JCO, 2002
Adjuvant RT omission after BCS
German Breast Cancer Study Group
 Between 1991 and 1998, 361 patients (pT1pN0M0, aged 45–
75 years, receptor positive, grades 1 and 2)
 Radiotherapy (yes/no) and tamoxifen for 2 years (yes/no) in a
2x2-factorial design
 Median follow-up of about 10 years
Winzer KJ, et al. EJC, 2010
Adjuvant RT omission after BCS
 Due to the presence of LRs, the event rate was much higher in the
group with BCS only than in the other three groups
 No significant difference could be established between the four
treatment groups for distant disease-free survival rates
 Even in patients with a favorable prognosis, the avoidance of RT
and tamoxifen after BCS increases the rate of LR substantially
 Because of the limited sample size with corresponding low power
the strength of evidence for such a comparison is weak
Winzer KJ, et al. EJC, 2010
Adjuvant RT omission in the elderly
Breast-conserving surgery with or without
irradiation in women aged 65 years or older with
early breast cancer (PRIME II): a randomised
controlled trial
 2003 - 2009, 1326 women aged 65 years or older early BC
 Hormone receptor-positive, axillary node-negative, T1–T2 up
to 3 cm, grade 3 or LVI, but not both, were permitted
 whole-breast RT (40–50 Gy in 15–25 fr) or NO RT
 Primary endpoint was IBTR
Kunkler IH, et al. Lancet Oncol, 2015
Adjuvant RT omission in the elderly
FINDINGS
 No differences in regional recurrence, distant metastases, contralateral
breast cancers, or new breast cancers
 5-year OS was 93.9% in both groups (p=0·34)
 Postoperative whole-breast RT after BCS and adjuvant endocrine
treatment resulted in a significant but modest reduction in local
recurrence for women aged 65 years or older
 5-year rate of IBTR is probably low enough for omission of RT to be
considered for some patients
Kunkler IH, et al. Lancet Oncol, 2015
Adjuvant RT omission in the elderly
Lumpectomy Plus Tamoxifen With or Without
Irradiation in Women Age 70 Years or Older With
Early Breast Cancer: Long-Term Follow-Up of
CALGB 9343
At 10 years:
 98% of patients receiving TamRT compared with 90% of those receiving
Tam were free from local and regional recurrences
 There were no significant differences in time to mastectomy, time to
distant metastasis, breast cancer–specific survival, or OS
 10-year OS was 67% and 66% in the TamRT and Tam groups, respectively
Hughes KS, et al. JCO, 2013
Adjuvant RT omission in the elderly
TamRT group experienced a significantly longer time to locoregional
recurrence (p<0.001)
No difference in terms of OS (p=0,64)
Hughes KS, et al. JCO, 2013
…and what about endocrine
therapy?
 Tamoxifen
 Letrozole
 Anastrozole
 Exemestane
Aromatase inhibitors vs tamoxifen
overview
Aromatase inhibitors are associated
improvements in DFS but not in OS
with
consistent
 7 trials enrolling 30.023 patients
 Longer duration of AIs use was associated with increased of
developing cardiovascular disease (p<0.001) and bone
fractures (p<0.001) but a decreased of venous thrombosis
(p<0.001) and endometrial carcinoma (p<0.001)
The cumulative toxicity of AIs when used as up-front treatment
may explain the lack of OS benefit
Amir E, et al. JNCI, 2011
Endocrine-therapy – Bone metabolism
Both Anastrozole and Letrozole cause a significant increase in the bone
turnover markers studied, these effects increase over time




Increase on bone fractures risk
Decrease in BMD
Increase in osteoporosis incidence
Increase in bisphosphonates use
McCaig FM, Breast Cancer Res Treat, 2010
Endocrine-therapy
Cognitive complaints
 PURPOSE
To examine cognitive complaints and neuropsychological (NP) testing
outcomes in patients with early-stage BC after the initiation of endocrine
therapy
PATIENTS AND METHODS
173 participants from the Mind Body Study observational cohort
provided data from self-report questionnaires and NP testing obtained at
enrollment (T1), and 6 months later (T2)
Evaluation of demographic and treatment variables, cognitive complaints,
depressive symptoms, quality of life, and NP functioning between those
who received ET versus not
Ganz PA et al, JCO, 2014
Endocrine-therapy
Cognitive complaints
 RESULTS
70% of the 173 MBS participants initiated ET, evenly distributed between
tamoxifen or aromatase inhibitors
ET-treated participants reported significantly increased language and
communication (LC) cognitive complaints at T2 (p=0.003), no significant
differences in NP test
Multivariable regression found higher LC complaints significantly
associated with T1 LC score (p=0.001), and diminished improvement in NP
psychomotor function (p=0.05)
Ganz PA et al, JCO, 2014
Quality of Life and ET - Considerations
 Endocrine-therapy
is
associated
with
consistent
improvements in DFS but not in OS in postmenopausal BC”
 Longer duration of AIs use was associated with increased odds
of developing cardiovascular disease
Amir E, et al. JNCI, 2011
 Increased risk of osteoporosis and/or bone fracture
McCaig FM, Breast Cancer Res Treat, 2010
 Influence on sexual dysfunction
Frechette D, et al. Breast Cancer Res Treat, 2013
 Significant post-treatment cognitive complaints
Ganz PA et al, JCO, 2014
Rugo HS, et al, JCO, 2013 (suppl)
GENES PROFILING
Cancer Res March 15, 2005 65; 2170
GENES PROFILING
“The MINDACT trial results provide level 1A evidence that using
MammaPrint could change clinical practice by substantially
de-escalating the use of adjuvant chemotherapy and sparing
many patients an aggressive treatment they will not benefit
from.”
… can we do it for Radiotherapy as well?
IMMUNOHISTOCHEMISTRY
Intrinsic subtypes of invasive BC (luminal A, luminal B, HER2
positive and triple negative) have different outcomes and may
guide future management strategies
Tamimi RM, et al. Breast Cancer Res Treat, 2012
Goldhirsch A, et al. Ann Oncol, 2011
Luminal A subtype
(ER and/or PgR +, Ki67 low, HER2 -)
FINAL REMARKS
• Even less…
 Radiotherapy?
 Endocrine-therapy?
• Balance efficacy avoiding overtreatment
 Appropriateness
• Waiting for…
 Strength of data
 Role of tumor biology in patients’ selection
• Focusing on new endpoints
 Quality of Life
 Treatment compliance
TAKE HOME MESSAGE
There is the need for investigating if exclusive
irradiation may be a valid alternative to exclusive
endocrine therapy in very low risk breast cancer
patients after BCS
 Evaluating Quality of Life profile
 (Assuming and confirming an equivalent rate of
recurrence)
Partial Breast Irradiation or Endocrine-Therapy for women
age 70 years or older with luminal A breast cancer: a
randomized phase 3 trial
Radiation Oncology Department, University of Florence
Trial Steering Committee:
Lorenzo Livi, Radiation Oncology Department - University of Florence
Icro Meattini, Radiation Oncology Department - University of Florence
Philip Poortmans, Radboud University Medical Center, Nijmegen, The Netherlands
Helen Westenberg, Institute for Radiation Oncology, Arnhem, The Netherlands
Nicola Russell, NKI, Amsterdam, The Netherlands
Orit Kaidar-Person, Division of Oncology, Rambam Health Care Campus, Haifa, Israel
Paulien Westhof, Radboud University Medical Center, Nijmegen, The Netherlands
Isacco Desideri, Radiation Oncology Department – University of Florence
Etienne Brain, Institute Curie, Paris, France
Kim Aalders, EORTC, Bruxelles, Belgium
Vesna Bjielic-Radisic, University of Graz, Austria
Marije Hamaker, Diakonessenhuis, Utrecht, The Netherlands
Sandra Collette, EORTC, Bruxelles, Belgium
STUDY SCHEMA - proposal
Eligible Patient Group
≥70 years
cT1-2, cN0
Unifocal lesion on MRX and/or MRI
WHO performance ≤ 2 and Life expectancy ≥ 5 years
WLE w or w/o SNB
pT1 (≤ 2 cm)
c-pN0 or isolated tumor cells (ITC)
Final surgical margins ≥2 mm
ER+ and PgR+/-, HER2 negative, Ki67<14% @IHC
exclusive aPBI
exclusive ET
STUDY SCHEMA - proposal
Primary Endpoint
Quality of Life
exclusive aPBI versus exclusive ET
Primary endpoint assessment
Global Health Status (GHS) for sample size
EORTC QLQ-C30/BR-23
Secondary endpoints
IBTR, LRR, DM, OS, overall grade 3-4 AEs,
contralateral BC, treatment adherence
STUDY SCHEMA – statistical assumptions
low risk adjuvant BC 3-year GHS score: 60 (SD 15-24)
Null Hypothesis: 5-points difference between ET and PBI
GHS score
King MT. Quality of Life research, 1996
Power=90%, a=0,05
Superiority trial
Clinically relevant 5-pts difference at 3 years
SD 18 n per arm: 273; total 546
(680 if 25% drop out)
STUDY SCHEMA – Patients’ assessments
•EORTC QLQ C-30 (plus BR-23)
•Anxiety and depression
 Hospital Anxiety and Depression Scale (HADS)
•Neurocognitive complaints
 Patient’s Assessment of Own Functioning (PAOF) Inventory
•RT side effects and cosmesis assessment
 RTOG/EORTC Acute and Late Radiation Morbidity Scoring
Criteria
 Harvard Breast Cancer Cosmesis Scale
•Endocrine therapy adverse events
 CTCAE v4.0 (i.e. cardiac disorders, arthralgia, hot flashes,
bone densitometry)
For trial information contact at [email protected]