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4th ESO-ESMO International Consensus Guidelines For Advanced Breast Cancer (ABC 4)
4th ESO-ESMO International Consensus Guidelines For Advanced Breast Cancer (ABC 4)
doi:10.1093/annonc/mdy192
Published online 19 July 2018
SPECIAL ARTICLE
*Correspondence to: Dr Fatima Cardoso, MD, Breast Unit, Champalimaud Clinical Center, Av. De Brası́lia s/n, 1400-038 Lisbon, Portugal.
E-mail: fatimacardoso@fundacaochampalimaud.pt
†
These guidelines were developed by the European School of Oncology (ESO) and the European Society for Medical Oncology (ESMO).
Advanced Breast Cancer (ABC) comprises both locally advanced OS, mostly due to advances in human epidermal growth factor
breast cancer (LABC) and metastatic breast cancer (MBC) [1]. receptor 2 (HER2)-positive ABC [4–6]. The better survival is
Although treatable, MBC remains virtually an incurable disease seen in an environment with access to the best available care and
with a median overall survival (OS) of 3 years and a 5-year sur- particularly in de novo ABC, while recurrent ABC seems to be-
vival of only 25% [2, 3]. The MBC Decade Report [2] shows come harder to manage [7, 8].
that progress has been slow in terms of improved outcomes, qual- The last decade has seen an improvement in the levels of evi-
ity of life (QoL), awareness and information regarding ABC. dence (LoEs) used for many of the ABC recommendations, how-
More recently, some studies seem to indicate an improvement in ever, still far from the LoEs existing for the majority of early
C The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
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Annals of Oncology Special article
breast cancer guidelines. More and better, more innovatively highlighting an area where research is needed. Additional changes
designed trials are urgently needed, in particular to address clinic- in the wording of statements were made during the session.
ally important questions, not necessarily related to a specific The statements related to management of side effects and diffi-
therapeutic agent. The use of real world evidence and the applica- cult symptoms, included under the Supportive and Palliative Care
tion of big data analysis to oncology may soon become important section, were not voted on during the consensus session, but dis-
additional pathways to acquire the necessary LoEs. cussed and unanimously agreed by email, and are considered to
At the research level, efforts continue to better understand the have 100% agreement. Previous ABC recommendations that did
biology and heterogeneity of ABC, as well as mechanisms of tu- not require update or only minor changes were not re-voted but
mour resistance and biomarkers predictive of response to the dif- were reviewed by all panel members by email and remain valid. To
ferent therapeutic options. However, the majority of the recent provide a full overview of all ABC guidelines currently approved,
research highlights are not yet ready for routine clinical practice the authors have listed all recommendations per subject, high-
implementation. lighting those that were discussed, voted and approved in ABC 4.
The 4th International Consensus Conference for ABC (ABC 4) Supplementary Table S1, available at Annals of Oncology on-
took place in Lisbon, Portugal on 2–4 November 2017, bringing line, describes the new grading system used, as per ESMO guide-
together 1300 participants from 88 countries, including health lines methodology, adapted from [10]; see http://www.esmo.org/
professionals, patient advocates and journalists. Its primary aim Guidelines/ESMO-Guidelines-Methodology.
is the development of international consensus guidelines for the Supplementary Table S2, available at Annals of Oncology on-
management of ABC patients. These guidelines are based on the line, lists all members of the ABC 4 consensus panel and their dis-
most up-to-date evidence and can be used to guide treatment de- closures of any relationships with the pharmaceutical industry
cision making in many different healthcare settings globally, with that could be perceived as a potential conflict of interest.
the necessary adaptations due to different access to care. Supplementary Figures, available at Annals of Oncology online,
The ABC guidelines are developed as a joint effort from ESO features updated ABC diagnostic and treatment algorithms.
and ESMO and are endorsed by EUSOMA (European Society of Slides with all ABC guidelines statements are available online at
Breast Cancer Specialists), ESTRO (European Society of http://www.abc-lisbon.org/ and http://oncologypro.esmo.org/
Radiation Oncology), UICC (Union for International Cancer Guidelines/ESMO-Consensus-Conferences/Breast-Cancer.
Control), SIS (Senologic International Society) and Flam
(FederatiónLatinoAmericana de Mastologia). There was also offi-
cial representation of ASCO (American Society of Clinical Section I: ABC definitions
Oncology) in the consensus panel. The ABC 4 Conference was also
organised under the auspices of OECI (Organization of European
Cancer Institutes) and with the support of the BCRF (Breast Cancer
Research Foundation) and the Susan G Komen for the Cure. Guideline statement LoE/GoR Consensus
The present manuscript summarises the guidelines developed at
ABC 4 and is supported with the LoEs, grades of recommendation Visceral crisis is defined as severe organ Expert opinion/ 95%
(GoRs), percentages of consensus reached at the Conference and dysfunction as assessed by signs and n/a
supporting references. In addition, the ESMO Magnitude of Clinical symptoms, laboratory studies and rapid
Benefit Scale (ESMO-MCBS) was applied to new European progression of disease. Visceral crisis is
Medicines Agency (EMA)-approved drugs [9], and ESMO-MCBS not the mere presence of visceral meta-
scores for new therapies/indications are included. ESMO-MCBS stases but implies important visceral
version 1.1 (v1.1) [9] was used to calculate scores for new therapies/ compromise leading to a clinical indica-
indications approved by the EMA since 1 January 2016. tion for a more rapidly efficacious ther-
apy, particularly since another treatment
option at progression will probably not
be possible.
Methodology Primary endocrine resistance is defined Expert opinion/ 67%
as relapse while on the first 2 years of n/a
Before the ABC 4 Conference, a set of preliminary recommenda-
adjuvant ET, or PD within first 6 months
tion statements on the management of ABC were prepared, based
of first-line ET for ABC, while on ET.
on available published data and following the ESMO guidelines Secondary endocrine resistance is Expert opinion/ 67%
methodology. These recommendations were circulated to all 42 defined as relapse while on adjuvant ET n/a
panel members by email for comments and corrections on con- but after the first 2 years, or relapse with-
tent and wording. A final set of recommendations was presented, in 12 months of completing adjuvant
discussed and voted upon during the consensus session of ABC 4. ET, or PD 6 months after initiating ET
All panel members were instructed to vote on all questions, with for ABC, while on ET.
members with a potential conflict of interest or who did not feel Oligometastatic disease is defined as Expert opinion/ 78%
comfortable answering the question (e.g. due to lack of expertise low volume metastatic disease with lim- n/a
in a particular field) instructed to vote ‘abstain’. A new possible ited number and size of metastatic
answer was included in the Precision Medicine statements: lesions (up to 5 and not necessarily in
‘Insufficient data’, which should be selected if the panel member Continued
believes the existent data were not enough to vote ‘yes’ or ‘no’,
Continued
Following a thorough assessment and con- Expert opinion/ 97% Survivorship issues and palliative care Expert opinion/
firmation of ABC, the potential treatment A should be addressed and offered at A
goals of care should be discussed. Patients an early stage.
should be told that ABC is incurable but A quality assurance programme cov- Expert opinion/
treatable, and that some patients can live ering the entire breast cancer path- B
with ABC for extended periods of time way from screening and diagnosis to
(many years in some circumstances). treatment, rehabilitation, follow-up
This conversation should be conducted in Expert opinion/ 97% and palliative care including services
the accessible language, respecting pa- A and support for ABC patients and
tient privacy and cultural differences, their caregivers, should be imple-
and whenever possible, written informa- mented by SBUs.
tion should be provided. General: QoL
All ABC patients should be offered compre- I/A 97% Strong consideration should be given to I/C 87%
hensive, culturally sensitive, up-to-date and the use of validated PROMs for patients
easy-to-understand information about to record the symptoms of disease and
their disease and its management. side effects of treatment experienced as
Patients (and their families, caregivers or Expert opinion/ 100% a regular part of clinical care. These
support network, if the patient agrees) A PROMs should be simple and user-
should be invited to participate in the friendly to facilitate their use in clinical
decision-making process at all times. practice, and thought needs to be given
When possible, patients should be to the easiest collection platform, e.g.
encouraged to be accompanied by per- tablets or smartphones. Systematic
sons who can support them and share monitoring would facilitate communica-
treatment decisions (e.g. family mem- tion between patients and their treat-
bers, caregivers, support network). ment teams by better characterising the
Every ABC patient must have access to op- Expert opinion/ 100% toxicities of all anticancer therapies. This
timal cancer treatment and supportive A would permit early intervention of sup-
care according to the highest standards portive care services enhancing QoL.
of patient-centred care, as defined by: Specific tools for evaluation of QoL in ABC Expert opinion/ 100%
• Open communication between patients should be developed. A
patients and their cancer care teams Until then, trials evaluating QoL in this set- Expert opinion/ 100%
as a primary goal. ting should use standardised PROs (in- A
• Educating patients about treatment stead of focusing exclusively on CTCAEs)
options and supportive care, through and incorporate specific site and treat-
development and dissemination of ment specific modules or subscales that
evidence-based information in a clear, exist both in the EORTC and FACT
culturally appropriate form. systems.
• Encouraging patients to be proactive in Additionally, attention needs to be paid to Expert opinion/ 100%
their care and to share decision making collection methods, timing of assess- A
with their healthcare providers. ments and handling of missing data.
• Empowering patients to develop the More sophisticated statistics should also
capability of improving their own QoL be employed to ensure that clinicians
within their cancer experience. have better, reliable data to help
• Always taking into account patient patients when choosing between treat-
preferences, values and needs as es- ment options.
sential to optimal cancer care. General: clinical trials
Every ABC patient should: There are few proven standards of care in Expert opinion/ 100%
Have access to the most up-to-date Expert opinion/ 100% ABC management. After appropriate A
treatments and to innovative therapies A informed consent, inclusion of patients
at accessible Breast Units/Centres. in well-designed, prospective, independ-
Be treated in Specialist Breast Units/ I/A ent trials must be a priority whenever
Centres/Services (SBUs) by a special- such trials are available, and the patient
ised multidisciplinary team including is willing to participate.
specialised side effects management The ABC community strongly calls for clin- Expert opinion/ 100%
and a nurse experienced in the treat- ical trials addressing important un- A
ment of ABC. answered clinical questions in this
Continued Continued
Continued Continued
setting, and not just for regulatory pur- have the option to undergo breast re-
poses. Clinical trials should continue to construction if clinically appropriate.
be carried out, even after approval of a In ABC patients with long-standing stable Expert opinion/ Yes: 53%
new treatment, providing real world disease, screening breast imaging C No: 47%
data on its performance, efficacy and should be an option.
toxicity. Breast imaging should also be carried out I/A 100%
General: affordability/cost- when there is a suspicion of locore-
effectiveness gional progression.
The medical community is aware of the Expert opinion/ 100% Fertility preservation: the impact of the Expert opinion/ 100%
problems raised by the cost of ABC A anticancer therapies on fertility should B
treatment. Balanced decisions should be be discussed with all women with ABC
made in all instances; patients’ well- of childbearing age and their partners,
being, length of life and preferences before the start of treatment. The discus-
should always guide decisions. sion must also include appropriate infor-
We strongly recommend the use of object- Expert opinion/ 88% mation about the prognosis of the
ive scales, such as the ESMO-MCBS or A disease and the potential consequences
the ASCO Value Framework, to evaluate of pregnancy (e.g. stopping ongoing
the real magnitude of benefit provided treatment).
by a new treatment and help prioritise General: other
funding, particularly in countries with Specialised oncology nurses (if possible Expert opinion/ 92%
limited resources. specialised breast nurses) should be part A
The ABC community strongly supports the I/A 90% of the multidisciplinary team managing
use of BIOSIMILARS both for treatment ABC patients. In some countries, this role
of breast cancer (i.e. trastuzumab) and may be played by a physician assistant
for supportive care (i.e. growth factors). or another trained and specialised
To be used, the biosimilar must be healthcare practitioner.
approved after passing the stringent de- The use of TELEMEDICINE in oncology to Expert opinion/ 93%
velopment and validation processes help management of patients with ABC B
required by the EMA or the FDA or other living in remote places is an important
similarly strict authority. option to consider when geographic
General: survivorship distances are a problem and provided
As survival is improving in many patients Expert opinion/ 95% that issues of connectivity are solved.
with ABC, consideration of survivorship A
issues should be part of the routine care In green, NEW ABC 4 statements.
of these patients. Health professionals ABC, advanced breast cancer; ASCO, American Society of Clinical
should therefore be ready to change Oncology; Consensus, percentage of panel members in agreement with
and adapt treatment strategies to dis- the statement; CTCAE, Common Terminology Criteria for Adverse Events;
ease status, treatment adverse effects EMA, European Medicines Agency; EORTC, European Organisation for
and QoL, patients’ priorities and life Research and Treatment of Cancer; ESMO-MCBS, European Society for
plans. Attention to chronic needs for Medical Oncology Magnitude of Clinical Benefit Scale; FACT, Functional
home and family care, job and social Assessment of Cancer Therapy; FDA, Food and Drug Administration; GoR,
requirements should be incorporated in grade of recommendation; LoE, available level of evidence; PRO, patient-
the treatment planning and periodically reported outcome; PROM, patient-reported outcome measure; QoL, qual-
updated. ity of life.
ABC patients who desire to work or need Expert opinion/ 100%
to work for financial reasons should A
have the opportunity to do so, with
needed and reasonable flexibility in their
working schedules to accommodate The majority of general recommendations from previous ABC
continuous treatment and hospital conferences still stand as all available new data reinforces the
visits. guidelines and, in some cases, increases the LoE and/or GoR.
ABC patients with stable disease, being Expert opinion/ 82%
Access to the best available therapies as well as treatment by a
treated as a ‘chronic condition’, should B
specialised and multidisciplinary team are crucial to achieve the
Continued best outcomes. However, access to treatments is very
Continued Continued
Continued Continued
Continued
Continued Continued
were not included in the published It is currently unknown how the different
studies and may not be suitable for this combinations of endocrine þ targeted
combination. OS results are still awaited. agents compare with each other, and
QoL was comparable to that with ET with single-agent ChT. Trials are
alone. ongoing.
ESMO-MCBS v1.1 score: 3 Everolimus and CDK 4/6 inhibitors should n/a/E 74%
The addition of a CDK 4/6 inhibitor to ful- I/A 90% not be used after PD on that specific
vestrant, in patients previously exposed agent (i.e. beyond progression).
to ET, provided significant improvement At present, no validated predictive I/E 95%
in median PFS (6–7 months) as well biomarkers other than HR status exist to
as improvement in QoL, and is one of identify patients who will/will not
the preferred treatment options, if a benefit from the addition of a targeted
CDK 4/6 inhibitor was not previously agent (i.e. CDK 4/6 inhibitor, mTOR
used, for pre- and peri-menopausal inhibitor) to ET and none of the
women with OFS/OFA and post- studied biomarkers is ready for use in
menopausal women and men. clinical practice. Research efforts must
OS results are awaited. continue.
ESMO-MCBS v1.1 score: 4 The combination of a non-steroidal AI and II/C Yes: 33%
The addition of everolimus to an AI is a I/B 88% fulvestrant as first-line therapy for post- No: 53%
valid option for some patients [for pre- menopausal patients resulted in signifi- Abstain: 14%
and peri-menopausal women with OFS/ cant improvement in both PFS and OS
OFA, men (preferably with LHRH agon- compared with AI alone in one phase III
ist) and post-menopausal women] previ- trial and no benefit in a second trial with
ously exposed to ET, since it significantly a similar design. Subset analysis sug-
prolongs PFS, albeit without evidence of gested that the benefit was limited to
OS benefit. The decision to treat must patients without prior exposure to adju-
take into account the toxicities associ- vant ET (tamoxifen). Based on these
ated with this combination, lack of stat- data, combination ET may be offered to
istical significant OS benefit, cost and some patients with ABC without prior
availability. exposure to adjuvant ET.
ESMO-MCBS v1.1 score: 2 Concomitant ChT and ET has not shown a II/D 100%
Tamoxifen or fulvestrant can also be com- II/B 80% survival benefit and should not be car-
bined with everolimus. ried out outside a clinical trial.
Adequate prevention, close monitoring I/B 97% Endocrine treatment after ChT (mainten- III/B 88%
and proactive treatment of adverse ance ET) to maintain benefit is a reason-
events is needed, particularly in older able option, though it has not been
patients treated with everolimus due to assessed in randomised trials.
the increased incidence of toxic deaths
reported in the BOLERO-2 trial. In green, NEW ABC 4 statements.
The optimal sequence of endocrine-based I/A 95% ABC, advanced breast cancer; AI, aromatase inhibitor; CDK, cyclin-
therapy is uncertain. It depends on dependent kinase; ChT, chemotherapy; Consensus, percentage of panel
which agents were previously used [in members in agreement with the statement; ER, oestrogen receptor;
the (neo)adjuvant or advanced settings], ESMO-MBCS, European Society for Medical Oncology Magnitude of
the burden of the disease, patients’ pref- Clinical Benefit Scale; ET, endocrine therapy; GoR, grade of recommenda-
erence, costs and availability. Available tion; HER2, human epidermal growth factor 2; HR, hormone receptor;
options [for pre- and peri-menopausal LHRH, luteinising hormone-releasing hormone; LoE, available level of evi-
women with OFS/OFA, men (preferably dence; mTOR, mechanistic target of rapamycin; OFA, ovarian function ab-
with LHRH agonist) and post-meno- lation; OFS, ovarian function suppression; OS, overall survival; PD, disease
pausal women] include AI, tamoxifen, progression; PFS, progression-free survival; QoL, quality of life.
fulvestrant, AI/fulvestrant þ CDK 4/6 in-
hibitor, AI/tamoxifen/fulvestrant þ ever-
olimus. In later lines, also megestrol
Most of the revised guidelines at ABC 4 relate to ER-positive/
acetate and oestradiol, as well as repeti-
HER2-negative or luminal ABC, in which most of the recent
tion of previously used agents, may be
advances in the field occurred. As in previous ABC guidelines and
used.
in accordance with all national guidelines, the preferred treat-
ment for luminal ABC is endocrine therapy (ET) in the majority
Continued of cases, excluding only those with visceral crisis or concern or
Continued Continued
sequence of all available anti-HER2 The standard first-line therapy for patients I/A 86%
therapies is currently unknown. previously untreated with anti-HER2
The optimal duration of anti-HER2 ther- therapy is the combination of ChT þ
apy for ABC (i.e. when to stop these trastuzumab and pertuzumab, because
agents) is currently unknown. it has proven to be superior to ChT þ
In patients achieving a complete remission, Expert opinion/ 93% trastuzumab in terms of OS in this
the optimal duration of maintenance C population.
anti-HER2 therapy is unknown and For patients previously treated [in the I/A 76%
needs to be balanced against treatment (neo)adjuvant setting] with anti-HER2
toxicity, logistical burden and cost. therapy, the combination of ChT þ
Stopping anti-HER2 therapy after several trastuzumab and pertuzumab is an
years of sustained complete remission important option for first-line therapy.
may be considered in some patients, Few (88) of these patients were treated
particularly if treatment rechallenge is in the CLEOPATRA trial and all with tras-
available in case of progression. tuzumab-free interval >12 months.
Patients who have received any type of I/B 100% There are currently no data supporting the Expert opinion/ 86%
(neo)adjuvant anti-HER2 therapy should use of dual blockade with trastuzumab E
not be excluded from clinical trials for þ pertuzumab and ChT beyond pro-
HER2-positive ABC. These patients re- gression (i.e. continuing dual blockade
main candidates for anti-HER2 therapies. beyond progression) and therefore this
For the highly selected patientsa with ER- I/B 80% three-drug regimen should not be given
positive/HER2-positive ABC, for whom beyond progression outside clinical
ET þ anti-HER2 therapy was chosen as trials.
first-line therapy, dual anti-HER2 block- In a HER2-positive ABC patient, previously II/B 76%
ade (with either pertuzumab þ trastuzu- untreated with the combination of ChT
mab or lapatinib þ trastuzumab) can be þ trastuzumab þ pertuzumab, it is ac-
used since it provides a benefit in PFS. ceptable to use this treatment after first
This decision must be balanced against line.
the higher side effects, higher costs and After first-line, trastuzumab-based therapy, I/A 88%
lack of OS benefit so far, when com- T-DM1 provides superior efficacy relative
pared with ET þ anti-HER2 to other HER2-based therapies in the se-
monotherapy. cond line (versus lapatinib þ capecita-
For patients with ER-positive/HER2-positive n/a/B 80% bine) ‘and beyond’ (versus treatment of
ABC, for whom ChT þ anti-HER2 therapy physician’s choice). T-DM1 should be
was chosen as first-line therapy and pro- preferred in patients who have pro-
vided a benefit, it is reasonable to use ET gressed through at least one line of tras-
þ anti-HER2 therapy as maintenance tuzumab-based therapy, because it
therapy, after stopping ChT, although provides an OS benefit. However, there
this strategy has not been studied in are no data on the use of T-DM1 after
randomised trials. Duration of mainten- dual blockade with trastuzumab þ
ance therapy should be until progres- pertuzumab.
sion, unacceptable toxicity or patient In case of progression on trastuzumab- I/B 84%
request and needs to be evaluated in based therapy, the combination trastu-
clinical trials. There are no data to decide zumab þ lapatinib is a reasonable
between single-agent anti-HER2 or dual treatment option for some patients.
blockade, to combine with maintenance There are however, no data on the use
ET after stopping ChT, in ER-positive/ of this combination after progression on
HER2-positive ABC. pertuzumab or T-DM1.
In the first-line setting, for HER2-positive I/A 95% Regarding the ChT component of I/A 88%
ABC previously treated (in the adjuvant HER2 positive ABC treatment:
setting with DFI >12 months) or un- When pertuzumab is not given, first-line
treated with trastuzumab, combinations regimens for HER2 ABC can include tras-
of ChT þ trastuzumab are superior to tuzumab combined with vinorelbine or
combinations of ChT þ lapatinib in a taxane. Differences in toxicity between
terms of PFS and OS. these regimens should be considered
Continued Continued
Continued
Continued
If LABC remains inoperable after systemic Expert opinion/ 100% node after primary systemic treatment
therapy and eventual RT, ‘palliative’ D are followed (i.e. dual tracer, clipping/
mastectomy should not be done, unless marking positive nodes, minimum of
the surgery is likely to result in an overall three sentinel nodes).
improvement in QoL. Inflammatory LABC
A combined treatment modality based on I/A 100% For inflammatory LABC, overall treatment I/A 93%
a multidisciplinary approach (systemic recommendations are similar to those
therapy, surgery and RT) is strongly indi- for non-inflammatory LABC, with sys-
cated in the majority of cases. temic therapy as first treatment.
Options for HR-positive LABC include an I/A 85% Mastectomy with axillary dissection is rec- I/A 95%
anthracycline- and taxane-based ChT ommended in almost all cases, even
regimen, or ET. when there is good response to primary
The choice of ChT versus ET, as initial treat- Expert opinion/ 85% systemic therapy.
ment, will depend on tumour (grade, A Immediate reconstruction is generally not IV/E 95%
biomarker expression) and patient recommended in patients with inflam-
(menopausal status, PS, comorbidities, matory LABC.
preference) considerations. Locoregional RT (chest wall and lymph I/A 98%
For triple-negative LABC, anthracycline- I/A 85% nodes) is required, even when a pCR is
and taxane-based ChT is recommended achieved with systemic therapy.
as initial treatment.
For HER2-positive LABC, concurrent tax- I/A 92% In green, NEW ABC 4 statements.
a
ane and anti-HER2 therapy is recom- For the purpose of these recommendations, LABC means inoper-
mended since it increases the rate of able, non-metastatic locally advanced breast cancer.
pCR. ABC, advanced breast cancer; BCS, breast-conserving surgery; ChT,
For HER2-positive LABC, anthracycline- I/A 72% chemotherapy; Consensus, percentage of panel members in agreement
based ChT should be incorporated in with the statement; CT, computed tomography; ER, oestrogen receptor;
the treatment regimen. ET, endocrine therapy; GoR, grade of recommendation; HER2, human epi-
When an anthracycline is given, it should I/A 87% dermal growth factor 2; HR, hormone receptor; LABC, locally advanced
be administered sequentially with the breast cancer; LoE, available level of evidence; pCR, pathological com-
anti-HER2 therapy. plete response; PET, positron emission tomography; PgR, progesterone
For patients with HER2-positive LABC I/A 85% receptor; PS, performance status; QoL, quality of life; RT, radiotherapy.
(inflammatory or non-inflammatory),
without distant metastases, who are in
complete remission after appropriate
neoadjuvant systemic therapy and ap-
propriate locoregional therapy, and The majority of patients who present with unresectable non-
being treated with a potential curative metastatic disease should first be treated with primary systemic
intent, the approved adjuvant duration
therapy. If rendered resectable, this should be followed by surgery
of 1 year of anti-HER2 therapy should be
and RT. If the disease remains unresectable, RT should be consid-
used.
ered to treat all sites of the original tumour extension, with a
Following effective neoadjuvant systemic II/A 98%
boost to residual disease. Most durable remissions can be
therapy with or without RT, surgery will
be possible in many patients. This will
expected with an elective dose up to an equivalent of 50 Gy to
consist of mastectomy with axillary dis-
regions with a high likelihood of bearing subclinical disease and a
section in the majority of cases, but in boost up to 60–76 Gy (depending on the dose to the organs at
selected patients with a good response, risk) to all sites of macroscopic disease. Regular evaluation during
BCS may be possible. the course of RT is advised, to select patients that might become
In patients with axillary low burden of dis- III/B 62% amenable for resection after 45–50 Gy. Interesting reports are
ease at presentation (previously cN0- published on combined RT and ChT like 5-FU, docetaxel or
cN1) with complete response after sys- vinorelbine [62]. Further evaluation of the influence of combin-
temic treatment (ycN0), sentinel lymph ing RT with systemic treatment using a PARP inhibitor is on-
node biopsy can be an option, provided going in a prospective trial in patients with LABC or metastatic
all the recommendations for sentinel TNBC cancer and in non-responders to primary ChT [63].
Continued
Management of non-infectious
Guideline statement LoE/GoR Consensus
pneumonitis
NIP is an uncommon complication of II/A 100%
Supportive care allowing safer and more I/A 100%
mTOR inhibition. Patient education is
tolerable delivery of appropriate treat-
critical to ensure early reporting of re-
ments should always be part of the
spiratory symptoms. Treatment interrup-
treatment plan.
tion and dose reduction are generally
Early introduction of expert palliative care, I/A 100%
effective for grade 2 symptomatic NIP
including effective control of pain and
with use of systemic steroids and
other symptoms, should be a priority.
treatment discontinuation for grade 3
Access to effective pain treatment (includ- I/A 100%
or greater toxicity.
ing morphine, which is inexpensive) is
Management of dyspnoea
necessary for all patients in need of pain
Treatable causes like pleural effusion, pul- – 100%
relief.
monary emboli, cardiac insufficiency, an-
Optimally, discussions about patient pref- Expert opinion/ 96%
aemia or drug toxicity must be ruled
erences at the end of life should begin A
out. Patient support is essential. Oxygen
early in the course of metastatic disease.
is of no use in non-hypoxic patients.
However, when active treatment no lon-
Opioids are the drugs of choice in the palli- I/A 100%
ger is able to control widespread and
ation of dyspnoea.
life-threatening disease, and the toxic-
Benzodiazepines can be used in patients II/A 100%
ities of remaining options outweigh
experiencing anxiety.
benefits, physicians and other members
Steroids can be effective in dyspnoea Expert opinion/ 100%
of the healthcare team should initiate
caused by lymphangitis carcinomatosis, B
discussions with the patient (and family
RT or drug-induced pneumonitis, super-
members/friends, if the patient agrees)
ior vena cava syndrome, an inflamma-
about end-of-life care.
tory component or in (cancer-induced)
Management of cancer-related fatigue
obstruction of the airways (in which
Cancer-related fatigue is frequently experi- – 100%
case laser/stent is to be considered).
enced by patients with ABC, exerts a
Management of nausea and vomiting
deleterious impact on QoL and limits
ESMO/MASCC guidelines [64] are available n/a 100%
physical, functional, psychological and
for management of ChT-induced and
social well-being. The aetiology of this
morphine-induced nausea and vomit-
fatigue is complex; therefore, effective
ing, and these are endorsed by the ABC
management needs to be
community.
multidimensional.
There is a need to study nausea and vomit- Expert opinion/ 100%
It is important to assess cancer-related fa- See in 100%
ing related to chronic use of anticancer A
tigue using appropriate PROMs before statement
drugs.
implementing various non-pharmaco-
Management of endocrine toxicities
logical approaches, such as exercise [I,
of mTOR inhibition
A], and, if needed, pharmacological
Hyperglycaemia and hyperlipidaemia are II/A 100%
interventions [II, B].
common sub-acute complications of
Management of CDK inhibitor-
mTOR inhibition. Evaluation of pre-exist-
induced neutropaenia
ing diabetes or hyperglycaemia at base-
Neutropaenia is the most common toxicity II/A 100%
line is essential. Regular careful
associated with CDK 4/6 inhibition and
monitoring of glycaemia and lipid panel
is not generally associated with febrile
is needed to identify these toxicities.
neutropaenia, although an increase in
Management of grade 1 and 2 hypergly-
infections has been reported. Treatment
caemia includes treatment with oral
should be delayed until neutrophils
antidiabetics and basal insulin, in ac-
have recovered to at least 1000/lL; dose
cordance with international
reduction can also be considered.
Continued
Continued
Discussion Disclosure
The authors’ conflicts of interest are detailed in Supplementary
Conclusions and future directions Table S2, available at Annals of Oncology online.