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Annals of Oncology, 28 (8), 2018
Annals of Oncology, 28 (8), 2018
doi:10.1093/annonc/mdy192
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
Following the effort to standardise definitions and homogenise
Continued
the use of certain medical terms, ABC 4 provides three additional
Guideline statement LoE/GoR Consensus definitions.
Adequate ovarian function suppression (OFS) or ablation
the same organ), potentially amenable (OFA) is a somewhat controversial but crucial issue in the treat-
for local treatment, aimed at achieving a
ment of pre-menopausal patients with oestrogen receptor
complete remission status.
(ER)-positive ABC. As already extensively discussed in previous
Patients with multiple chronic condi- Expert opinion/ 100%
editions, the main recommendation for these patients is the induc-
tions are defined as patients with add- n/a
tion of OFS/OFA, to which an additional endocrine agent should
itional comorbidities (e.g. cardiovascular,
impaired renal or liver function, auto-
be added [1, 11]. The method for inducing OFS or OFA may vary
immune disease) making it difficult to
due to patient’s preferences, logistical and financial issues. Bilateral
account for all of the possible extrapola- salpingo-oophorectomy by a minimal invasive approach is a rea-
tions to develop specific recommenda- sonable option and should be discussed with patients. The con-
tions for care. firmation that ovarian function is adequately suppressed when
Adequate OFS in the context of ABC: chemically induced [i.e. luteinising hormone-releasing hormone
Adequate OFS for ABC pre-menopausal I/A 85% (LHRH) agonist] is not always straightforward but it is indispens-
patients can be obtained through bilat- able if an aromatase inhibitor (AI) is given concomitantly, in view
eral ovariectomy, continuous use of of the oestrogen-inducing effect of these agents in the absence of
LHRH agonists or OFA through pelvic RT OFS. The best way to obtain this confirmation [i.e. testing oestra-
(this latter is not always effective and diol levels with or without levels of luteinising hormone (LH) and
therefore is the least preferred option). follicle-stimulating hormone (FSH)] and the timing and frequency
If a LHRH agonist is used in this age group, II/B 85% of confirmation tests are not well established and there was sub-
it should usually be given on a q4w stantial discussion among panel members. It was decided, as a
basis to guarantee optimal OFS. compromise, to recommend serial measures of serum oestradiol
Efficacy of OFS must be initially confirmed Expert opinion/ 85% during the initial months of treatment with an AI þ LHRH agonist.
analytically through serial evaluations of B When a LHRH agonist is used, the majority of the panel recom-
serum oestradiol, even in the presence mends the use of the q4w (every 4 weeks) regimen. There are,
of amenorrhoea, especially if an AI is
however, some recent data regarding the use of the 3-monthly
administered.
regimen with concurrent tamoxifen that yielded similar results in
As all endocrine interventions for pre- Expert opinion/ 85%
terms of pharmacodynamic and safety profiles [12, 13] in two
menopausal patients with endocrine-re- B
randomised trials of 222 and 170 patients, respectively, and may,
sponsive ABC require indefinite OFS,
choosing one method over the other
therefore, be considered a valid option when combined with
requires balance of patient’s wish for po-
tamoxifen for selected patients.
tentially preserving fertility, compliance
with frequent injections over a long
period of time and cost. Section II: General guidelines
Maintenance therapy: in the context of Expert opinion/ 100%
ABC Guidelines, maintenance therapy n/a
refers to the continuation of anti-HER2
therapy and/or ET after discontinuation Guideline statement LoE/GoR Consensus
of ChT.
Integrative medicine: complementary Expert opinion/ 100% The management of ABC is complex and, Expert opinion/ 100%
and integrative medicine (CIM) repre- n/a therefore, involvement of all appropriate A
sents the use of complementary treat- specialties in a multidisciplinary team
ments side by side with conventional (including but not restricted to medical,
approaches in a proper therapeutic radiation, surgical oncologists, imaging
environment. experts, pathologists, gynaecologists,
psycho-oncologists, social workers,
In green, NEW ABC 4 statements. nurses and palliative care specialists), is
ABC, advanced breast cancer; AI, aromatase inhibitor; Consensus, per- crucial.
centage of panel members in agreement with the statement; ChT, From the time of diagnosis of ABC, Expert opinion/ 100%
chemotherapy; ET, endocrine therapy; GoR, grade of recommendation; patients should be offered appropriate A
HER2, human epidermal growth factor 2; LHRH, luteinising hormone- psychosocial care, supportive care and
releasing hormone; LoE, available level of evidence; OFA, ovarian function symptom-related interventions as a rou-
ablation; OFS, ovarian function suppression; PD, disease progression; tine part of their care. The approach
q4w, every 4 weeks; RT, radiotherapy. must be personalised to meet the needs
of the individual patient.
Continued
doi:10.1093/annonc/mdy192 | 3
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Special Article Annals of Oncology
Continued 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
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Annals of Oncology Special Article
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
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Special Article Annals of Oncology
heterogeneous between different countries and within each coun- Organisation for Research and Treatment of Cancer (EORTC)
try, depending largely on financial, reimbursement and coverage and Functional Assessment of Cancer Therapy (FACT) systems
issues. All guidelines that are related to a certain treatment de- have site and treatment specific modules or subscales that should
pend, obviously, on the availability of that treatment. In all ABC be incorporated with more generic HRQoL measures.
guidelines, when ‘preferred option’ or ‘standard of care’ terms Additionally, attention needs to be paid to collection methods,
are used, they assume availability of the agent(s) discussed. timing of assessments and handling of missing data. More sophis-
Currently, some efforts are being made to adapt the ABC ticated statistics should also be employed to ensure that clinicians
Guidelines to different environments, such as Africa, South have better, reliable data to help patients when choosing between
America and Asia, but these are separate projects, outside the treatment options. In addition, specific tools developed for
scope of the main guidelines and this manuscript. HRQoL assessment in ABC patients are needed and are the goal
One possible way to minimise the issue of cost is the use of bio- of an ongoing collaborative project between the EORTC Quality
similars. In line with the ESMO position [14], the ABC commu- of Life and Breast Cancer Groups.
nity strongly supports the use of biosimilars both for treatment of
breast cancer (i.e. trastuzumab) and for supportive care (i.e.
growth factors). Importantly, only those biosimilars that pass the
stringent development and validation processes required by the Section III: Assessment and treatment
EMA or the Food and Drug Administration (FDA) or other simi-
general guidelines
larly strict authority should be used. Additionally, in order to
lead to a significant economic impact and making treatment
available to more patients with breast cancer, the price of biosimi-
lars should be substantially lower than the original compounds.
Guideline statement LoE/GoR Consensus
Accessibility to multidisciplinary care is also very uneven
throughout the world, for all cancer patients but particularly for Image and disease assessment
advanced cancer patients, who usually continue to be managed by guidelines
a single isolated physician. In Europe, the fight for the establish- Minimal staging work-up for ABC includes II/A 67%
ment of Specialised Breast Units/Centres/Services (SBUs) has been a history and physical examination,
long and slow, with scattered implementation despite recommen- haematology and biochemistry tests,
dations from the European Parliament for the last decade [15]. and imaging of chest, abdomen and
Fortunately, some ABC patients can now live several years, espe- bone.
cially those who achieve long-lasting complete remissions. This is Brain imaging should not be routinely car- II/D 94%
more frequent in situations of oligometastatic disease or with ried out in asymptomatic patients. This
HER2-positive disease. Survivorship issues have therefore started approach is applicable to all patients
to be discussed also for ABC patients. A highly sensitive issue is fer- with ABC including those with HER2-
tility preservation and motherhood in ABC patients. Every patient positive and/or metastatic TNBC.
has the right to be informed about the potential negative impact The clinical value of tumour markers is not II/C 89%
on fertility of anticancer therapies. This is particularly complex for well established for diagnosis or follow-
up after adjuvant therapy, but their use
luminal ABC where induction of OFS or OFA is the mainstay of
(if elevated) as an aid to evaluate re-
therapy. If a desire for pregnancy exists or if pregnancy inadvert-
sponse to treatment, particularly in
ently occurs, a delicate and thorough discussion should occur with
patients with non-measurable metastat-
the patient and partner regarding the long-term prognosis of the
ic disease, is reasonable. A change in
disease and the potential consequences of stopping any ongoing tumour markers alone should not be
therapy. However, after full information, the final decision lays used to initiate a change in treatment.
with the patient and should be respected [16–19]. Evaluation of response to therapy should Expert opinion/ 81%
Discussions about the risk/benefits of different further active generally occur every 2–4 months for ET B
anticancer treatments in ABC can be challenging, especially if the or after two to four cycles for ChT,
drugs offered might not reduce symptom burden or prolong sur- depending on the dynamics of the
vival but do have significant toxicities. Patients need good infor- disease, the location and extent of meta-
mation, collected systematically with reliable tools, about likely static involvement and type of treat-
harms and benefits to enable balanced decision making. ment. Imaging of target lesions may be
Although more trials of novel therapies do now build in health- sufficient in many patients. In certain
related QoL (HRQoL) assessment, many publications still give patients, such as those with
precedence to physician recorded side effects grades using indolent disease, less frequent monitor-
Common Terminology Criteria for Adverse Events (CTCAE) cri- ing is acceptable. Additional testing
teria rather than patient-reported outcomes (PROs). Studies should be carried out in a timely
show that for many common toxicities, there is poor concord- manner, irrespective of the planned
ance between physician reported and patient-reported side effects intervals, if PD is suspected or new
in terms of both frequency and severity. Even when trials do em- symptoms appear. Thorough history
ploy standardised PROs, they are often inappropriate measures, and physical examination must always
be carried out.
more suitable for use in early-stage disease. Both the European
Continued
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Continued Continued
Continued Continued
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Continued
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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
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Special Article Annals of Oncology
proof for endocrine resistance (both defined in Section I). progression (PD) is associated with degradation of HRQoL,
Unfortunately, this recommendation continues to be very often both in the palbociclib arm and the placebo arm [32]. For the
ignored in current clinical practice, mainly due to financial rea- reasons described, the use of a CDK inhibitor in the first-line
sons and reimbursement rules that are not patient-focused, that setting reaches an ESMO-MCBS score of 3. In the second-line
pressure for the use of i.v. therapies (discussed in [20]). setting, their use has been associated with a 6–7 months
Two conceptual changes were introduced at ABC 4 regarding progression-free survival (PFS) benefit [33, 34] and an HRQoL
pre-menopausal patients and lines of therapy. As previously dis- improvement [35, 36], and hence their ESMO-MCBS score is
cussed, the optimal management of pre-menopausal patients 4. There are some differences in the safety profile among the
with luminal ABC consists of the induction of OFS or OFA, in three CDK inhibitors, with less neutropaenia and more diar-
combination with another endocrine agent [21]. Since the first rhoea associated with abemaciclib, less hepatotoxicity with pal-
step is to render the patient post-menopausal, we believe that all bociclib and potential for QT interval prolongation with
other recommendations should be common to both post-meno- ribociclib. Abemaciclib has shown important single-agent ac-
pausal and initially pre- or peri-menopausal patients. tivity [37, 38] as well as potential for crossing the blood-brain
Furthermore, resources should not be wasted running duplicate barrier [39].
and separate trials for pre- and post-menopausal patients, but ra- Combination of an endocrine agent (AI, tamoxifen or fulves-
ther pre-menopausal patients should be eligible for trials if OFS trant) with everolimus has shown a PFS benefit, albeit without a
or OFA is carried out. The definition of optimal OFS/OFA in the statistically significant OS benefit [40, 41] in the second-line set-
context of ABC is described in Section I. Furthermore, the ABC ting and, more recently, also in the first-line setting [42], and is
panel strongly advocates against unrealistic, unnecessary and an available option for patients previously exposed to ET. Its use
sometimes expensive clinical trial requirements on contracep- is associated with substantial toxicity, which downgrades its
tion, with clear negative impact on QoL, for pre-menopausal ESMO-MCBS score to 2. However, as more experience is gained
women who do not undergo OFS/OFA, such as multiple contra- regarding the use of everolimus and the management of its toxic-
ceptive methods [e.g. intrauterine device (IUD) plus condoms ities, its clinical use becomes easier, in particular regarding man-
plus spermicide] or complete abstinence, which are sometimes agement of mucositis, as described in Section XII. Adequate
required to be continued for 6 months after the completion of prevention, close monitoring and proactive treatment of adverse
study drug. events is needed, particularly in older patients treated with evero-
The choice among different available agents as well as their se- limus due to the increased incidence of toxic deaths reported in
quence depends largely on which agents were previously adminis- the BOLERO-2 trial [43].
tered and the response obtained, due to the link with endocrine Areas where research efforts must continue are predictive bio-
resistance. For this reason, previous exposure, and not only line markers, optimal sequence and best management for patients
of treatment, should guide the recommendations. who progressed during or less than 1 year after adjuvant AIs, since
With the publication of the Falcon study [22], available these patients have been consistently and unfortunately excluded
options for initial single-agent ET include an AI, fulvestrant and from most first-line therapy trials.
tamoxifen. The choice will be largely determined by previous ex-
posure in the adjuvant setting.
The last 2 years saw the approval of three cyclin-dependent kin- Section V: HER2-positive ABC
ase (CDK) inhibitors—palbociclib, ribociclib and abemaciclib—
by the FDA and the first two by the EMA (it is foreseen that
abemaciclib will soon be approved by EMA as well). Currently,
several open questions remain regarding the optimal integration Guideline statement LoE/GoR Consensus
of these agents in clinical practice, such as: (i) accurate identifica-
tion, if possible by biomarkers, of the patients who need the com- Anti-HER2 therapy should be offered early I/A 98%
bination of ET and a CDK inhibitor, those who need to be treated (as first line) to all patients with HER2-
with chemotherapy (ChT) and those who can be adequately positive ABC, except in the presence of
treated with endocrine agents alone; (ii) optimal sequence for the contraindications to the use of such
individual patient and (iii) optimal treatment after progression therapy.
on CDK inhibitors. Patients progressing on an anti-HER2 ther- I/A 91%
When applying the ESMO-MCBS version 1.1 [9] to each drug apy combined with a cytotoxic or endo-
in each setting, both efficacy and toxicity/QoL must be taken into crine agent should be offered additional
account. Unfortunately, and as discussed above, some trials do anti-HER2 therapy with subsequent
not assess HRQoL and others do not use the most adequate tools treatment, except in the presence of
to assess it. The use of CDK inhibitors in the first-line setting has contraindications, since it is beneficial to
continue suppression of the HER2 path-
been associated with a substantial (about 10 months) benefit in
way. The choice of the anti-HER2 agent
PFS [23–29], while OS results are still awaited. They have a fa-
will depend on country-specific avail-
vourable safety profile, with neutropaenia not associated with
ability, the specific anti-HER2 therapy
infections being the most common side effect. However, in this
previously administered and the re-
setting their use has not been associated with an improvement in
lapse-free interval. The optimal
HRQoL [30, 31], except perhaps in MONALEESA-7 [27]. A
more recent evaluation in PALOMA-2 indicates that disease Continued
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Annals of Oncology Special Article
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
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Special Article Annals of Oncology
a non-data-driven protocol amendment was made to change the
Continued
primary endpoint to PFS, in agreement with the regulatory
Guideline statement LoE/GoR Consensus authorities. For the primary comparison, ALTERNATIVE has
shown a PFS benefit of 5.3 months for ET þ dual blockade versus
and discussed with the patient in mak- ET þ trastuzumab [11.0 versus 5.7 months; hazard ratio (HR):
ing a final decision. Other ChT agents
0.62 (0.45, 0.88), P ¼ 0.0064]. As a secondary endpoint, PFS was
can be administered with trastuzumab
compared between the three arms showing a PFS of 8.1 months
but are not as well studied and are not
for ET þ lapatinib. OS was not statistically significantly different
preferred.
in the three arms: 46 versus 40 versus 45 months for the dual
For later lines of therapy, trastuzumab can II/A 91%
be administered with several ChT
blockade, trastuzumab and lapatinib arms, respectively.
agents, including but not limited to,
After considering all available data on both ET and ChT com-
vinorelbine (if not given in first line), binations with anti-HER2 agents, a small update was made to the
taxanes (if not given in first line), guideline but retaining its main message, i.e. in the absence of
capecitabine, eribulin, liposomal valuable biomarkers, the approach of ET þ anti-HER2 agents
anthracyclines, platinum, gemcitabine should be reserved for highly selected patients, including those
or metronomic CM. The decision should with contraindications to ChT, patients with a strong preference
be individualised and take into account against ChT or those with a long disease-free interval (DFI), min-
different toxicity profiles, previous imal disease burden (in particular in terms of visceral involve-
exposure, patient preferences and ment) and/or strong ER/progesterone receptor (PgR) expression
country availability. [11]. Trials directly comparing ChT plus anti-HER2 therapy ver-
ChT agents to combine with a dual block- See in 86% sus ET plus anti-HER2 therapy or assessing ET þ anti-HER2
ade of trastuzumab þ pertuzumab are statement therapy as maintenance are currently ongoing [Detect V/
docetaxel [I/A] or paclitaxel [I/B]. Also CHEVENDO (NCT02344472), SYSUCC-002 (NCT01950182)
possible are vinorelbine [II/A], nab- and PERNETTA trials], and their results will allow for better
paclitaxel [II/B] and capecitabine [II/A]. recommendations.
a Furthermore, in several countries, anti-HER2 therapy, namely
See definition in text.
trastuzumab, can only be used once in the metastatic setting since
In green, NEW ABC 4 statements.
its use beyond progression is either not approved or not reim-
ABC, advanced breast cancer; ChT, chemotherapy; CM, low-dose oral
cyclophosphamide and methotrexate; Consensus, percentage of panel
bursed; in those cases, preference should be given to a combin-
members in agreement with the statement; DFI, disease-free interval; ER, ation of ChT plus anti-HER2 therapy in view of the OS benefit
oestrogen receptor; ET, endocrine therapy; GoR, grade of recommenda- observed.
tion; HER2, human epidermal growth factor 2; LoE, available level of evi- The use of a combination of ET plus anti-HER2 therapy as
dence; OS, overall survival; PFS, progression-free survival; T-DM1, maintenance therapy for ER-positive/HER2-positive ABC, after
trastuzumab emtansine. initial cycles of ChT plus anti-HER2 therapy, is a reasonable op-
tion, most probably delaying PD and the consequent need for a
change in therapy. Duration of maintenance therapy should be
until progression, unacceptable toxicity or patient request and
In ABC 3, almost all guidelines for the management of HER2- needs to be evaluated in clinical trials since no randomised trials
positive ABC were reviewed, and few new data were presented/ exist. Of note, in the CLEOPATRA trial, maintenance therapy
published in the last 2 years. The exception is related to the sub- was carried out with anti-HER2 agents alone, which is also an
group of ER-positive/HER2-positive disease for which the option.
ALTERNATIVE trial results were presented at ASCO 2017 [44].
This trial evaluated the role of ET þ anti-HER2 therapy (trastu-
zumab alone, lapatinib alone or dual blockade with
trastuzumab þ lapatinib) in 355 patients with ABC progressing
during or following prior trastuzumab þ ChT in the neo(adju- Guideline statement LoE/GoR Consensus
vant) and/or first-line metastatic setting. Initially, the study was
designed to evaluate the OS benefit of ET þ trastuzumab þ lapa- For non-BRCA-associated advanced TNBC, I/A 98%
tinib, and it had been a request from the regulatory agencies for there are no data supporting different or
the development of lapatinib. With the publication of the specific ChT recommendations.
CLEOPATRA trial [45] results showing a substantial OS benefit, Continued
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Annals of Oncology Special Article
Continued Section VII: Hereditary ABC
Guideline statement LoE/GoR Consensus
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With the approval of olaparib, results from genetic testing in the of PARP inhibitors in platinum-resistant disease, as well as their
setting of ABC may have immediate therapeutic implications and value when compared with platinum compounds.
should therefore be carried out as early as possible. Genetic test-
ing should be guided by international/national guidelines [49]
and may also be considered for all patients with triple-negative
disease. Genes to be tested for depend on personal and family his- Section VIII: Precision medicine
tory, however at present only germline mutations in BRCA1/2
have any clinical utility and therapeutic impact.
Although BRCA1/2 are the most frequently mutated genes,
testing for other additional moderate- to high-penetrance genes Guideline statement LoE/GoR Consensus
may be considered, if deemed appropriate by the geneticist/gen-
Multigene panels, such as those I/D 83%
etic counsellor; however, it must be clarified to the patient that at
obtained using NGS or other tech-
present a mutation in another moderate- to high-penetrance
nology on tumour DNA have not
gene has no direct clinical implications in the setting of ABC. yet proven beneficial in clinical trials
When a hereditary cancer syndrome is suspected in ABC and a for ABC, their impact on outcome
mutation in BRCA1/2 has not been identified, and the patient still remains undefined and should not
seeks information, multi-gene panel testing may be considered. be used in routine clinical practice.
Practice should be guided by high-quality international/national For patients who are suitable to par-
guidelines. As commercially available multi-gene panels include ticipate in clinical trials of novel
different genes, the choices of the specific panel and quality- therapies and are readily able/moti-
controlled laboratory are crucial. Development of quality- vated to attend a centre with rele-
controlled genetic counselling services is strongly encouraged vant clinical trials, NGS testing may
[50, 51]. be used in the context of prospect-
The OlympiAD trial [52] evaluated the role of the poly adeno- ive molecular triage programmes to
sine diphosphate ribose polymerase (PARP) inhibitor olaparib select patients for therapeutic trials.
monotherapy in 302 patients with germline BRCA mutation and Specific tests (as distinguished from
advanced ER-positive/HER2-negative or TNBC, who had broad mutation profiles) may play a
received no more than two previous ChT regimens for metastatic role in the future as the medicines
disease. If prior platinum was used, no evidence of progression they are linked with achieve regula-
during treatment in the advanced setting or 12 months since tory approval.
(neo)adjuvant platinum treatment was required. The comparator ctDNA assessment is not ready for rou- I/D 74%
tine clinical practice use and is not
was standard monoChT per physician’s choice (capecitabine, eri-
recommended, either for demon-
bulin or vinorelbine). Median PFS was longer in the olaparib
stration of PD or selection of tar-
group [7.0 versus 4.2 months; HR: 0.58; 95% confidence interval
geted therapies.
(CI): 0.43–0.80; P < 0.001]. At this follow-up time, there were no
In case an ABC patient was tested in Expert opinion/ Yes: 41%
differences in OS. Toxicity and rate of treatment discontinuation the context of a clinical trial and the C Abstain: 10%
due to side effects were higher in the ChT arm, while QoL was sig- information is available: Insufficient
nificantly better in the olaparib arm. data: 49%
In the San Antonio Breast Cancer Symposium 2017, the first If an ABC patient presents with a Expert opinion/ Yes: 29%
results of the EMBRACA trial were presented [53]. With a similar tumour with MSI-H/MMR defi- C Abstain: 24%
design to OlympiAD, this trial evaluated the role of talazaparib in ciency, treatment with an anti-PD-1 Insufficient
431 ABC patients with a BRCA mutation, when compared with agent is a possible consideration. data: 47%
monoChT per physician’s choice (capecitabine, eribulin, vinorel- If an ABC patient presents with a
bine or gemcitabine). Most patients had not received prior tumour with an NTRK fusion,
platinum-based therapy. At a median follow-up time of treatment with a TRKi is a possible
11.2 months, PFS was longer in the talazaparib arm (8.6 versus consideration.
5.6 months; HR: 0.54; 95% CI: 0.41–0.71; P < 0.0001); no differ- Patients must be informed about
ence was seen, at this time, in OS and QoL was significantly better the amount of data available for ABC
in the talazaparib arm. specifically. Research on the best
While these trials are positive and met their primary endpoint, companion diagnosis tools and
the benefit seen was less than anticipated. Nevertheless, the toler- techniques is needed. Prospective
ability of these agents when given as monotherapy, the ChT-free registries should be created to col-
approach with improved QoL makes it an attractive option for lect data from all patients treated
with these innovative approaches,
BRCA-related ABC. Further studies are needed to clarify the value
after proper consent.
Continued
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Annals of Oncology Special Article
includes the relevant markers, and direct patients toward the use
Continued
of pembrolizumab in the USA.
Guideline statement LoE/GoR Consensus It is important to note that almost half of the panel considered
that there is insufficient data to issue guidelines regarding what to
Immunotherapy, with a checkpoint III/D 85% do in the presence of an MSI-high (MSI)/MMR deficiency or
inhibitor, for any biological subtype
NTRK fusion. In conclusion, multigene assays should not be used
of ABC should not be used in rou-
in routine clinical practice for breast cancer patients (with possible
tine clinical practice, outside clinical
exception of MMR/MSI in the USA only). These assays should be
trials. Several ongoing trials are eval-
used in context of molecular triage programmes where patients
uating the role of this type of treat-
ment in all ABC subtypes.
are potential candidates for appropriately targeted clinical trials.
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Special Article Annals of Oncology
Continued Continued
Continued
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Annals of Oncology Special Article
Continued Section X: Specific populations
Guideline statement LoE/GoR Consensus
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Special Article Annals of Oncology
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
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Annals of Oncology Special Article
Section XII: Supportive and palliative care 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
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Special Article Annals of Oncology
Continued Continued
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Annals of Oncology Special Article
maintain therapy for as long as needed. In order to monitor and
Continued
recognise adverse events adequately, some key points should be
addressed: (i) educate the patient before treatment about the ad- Guideline statement LoE/GoR Consensus
verse events which may appear and about prophylactic measures;
(ii) communication with the patient and their support system is physical performance and fatigue, and
it may also improve DFS and OS.
essential to avoid dose modifications and maintain QoL; tell
MBSR programmes, hypnosis and yoga
patients why, who, when and how they can contact their health-
may improve QoL and fatigue, and
care professionals; (iii) monitor the patient more frequently for
help reduce anxiety, distress and some
the first 12 weeks on every new treatment; from week 13 on, ac-
side effects of anticancer therapies.
tively monitor every one or two cycles, depending on the treat- Acupuncture may help against ChT-
ment schedule and the adverse events that may have developed; induced nausea and vomiting, fatigue
(iv) grade adverse events accurately with an appropriate tool; (v) and hot flashes.
treat symptoms early as this may prevent them from getting Methods with no or unfavourable II/E 100%
worse; (vi) adjust management strategies based on the opinion of effects
the patient regarding tolerability; (vii) consider dose modifica- The following methods of alternative
tions (reductions, delays); and (viii) continue systemic treatment medicine are not recommended in
whenever possible. ABC since available evidence shows
no effect at best, or even association
with worse outcome:
antioxidant supplements;
drugs outside the approved indication
Section XIII: Integrative medicine (e.g. methadone);
herbs including Chinese herbal
medicine;
orthomolecular substances (selenium,
Guideline statement LoE/GoR Consensus zinc etc.)
oxygen and ozone therapy
Alternative therapies (i.e. therapies used in- n/a/E 100% proteolytic enzymes, thymic peptides
stead of scientifically-based medicines) phytoestrogens (soy food, isoflavones)
are not recommended in any phase or high-dose vitamins (vitamin C, D, E, car-
stage of cancer treatment. otenoids etc.)
Breast Cancer Centres/Units/Departments Expert opinion/ 100% L-carnitine, laetrile.
should be aware that the majority of C
their patients would like to be informed In green, NEW ABC 4 statements.
about complementary and integrative ABC, advanced breast cancer; ChT, chemotherapy; Consensus, percent-
medicine and that many of them are age of panel members in agreement with the statement; DFS, disease-
using it. free survival; GoR, grade of recommendation; LoE, available level of evi-
Physicians should actively ask for infor- dence; MBSR, mindfulness-based stress reduction; OS, overall survival;
mation about its use, in view of the QoL, quality of life.
potential deleterious interactions with
specific anticancer therapies.
If complementary therapies are not avail- Complementary and integrative medicine (CIM) represents the
able at the centre, certified contacts use of complementary treatments side by side with conventional
should be available to promote refer- approaches in a proper therapeutic environment [70].
ral to practitioners qualified in the Alternative therapies (i.e. therapies used instead of scientifically
therapies people are interested in
based medicines) are not recommended in any phase or stage of
receiving.
cancer treatment. For that reason, the acronym CAM—
Some complementary therapies have the Expert opinion/ 100%
complementary and alternative medicine—has been replaced by
potential to reduce disease symptom C
CIM excluding the alternative word from current use [70]. The
burden and/or side effects of anticancer
therapies, and, therefore, improve the
term ‘integrative oncology’ represents the application of CIM to
QoL of ABC patients.
cancer patients. However, even in settings in which the term inte-
Evidence suggests beneficial effects of the I/B 100% grative oncology has been used to refer to the combination of
following methods, which can therefore complementary medicine therapies with conventional cancer
be used: treatments the term has been defined in many different ways.
Physical exercise/sport (equivalent to Because of this lack of consensus, it has been difficult to commu-
3–5 h of moderate walking per week) nicate what is meant by integrative oncology to oncologists and
improves QoL, cardiorespiratory fitness, other health professionals, as well as to key stakeholders such as
patients. The current definition of the term integrative oncology
Continued
is a patient-centred, evidence-informed field of cancer care that
utilises mind and body practices, natural products, and/or
doi:10.1093/annonc/mdy192 | 21
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Special Article Annals of Oncology
lifestyle modifications from different traditions alongside con- under the umbrella of the ABC Global Alliance (https://www.abc
ventional cancer treatments. Integrative oncology aims to opti- globalalliance.org).
mise health, QoL and clinical outcomes across the cancer care Efforts must continue not only in research dedicated to ABC,
continuum, to empower people to prevent cancer and to become but also ensuring that ABC patients worldwide have access to the
active participants before, during and beyond cancer treatment best available therapies, including multidisciplinary care as well
[71]. as early and adequate access to supportive and palliative care.
Some complementary therapies have the potential to reduce Reimbursement rules in all countries should be patient-centred
disease symptom burden and/or side effects of anticancer thera- and be an incentive, not work against, the clinical implementa-
pies, and, therefore, improve the QoL of breast cancer patients. tion of high-quality international guidelines. Only united and
The research and evidence of the effects of complementary treat- with common projects and goals, the ABC community will be
ments specifically for ABC patients is very limited and applica- able to achieve success. This was the main objective of the cre-
tions are usually extrapolated from indications in early breast ation of the ABC Global Alliance, which is a multi-stakeholder
cancer patients. platform for all those (advocacy groups, pharma, cooperative
Evidence suggests beneficial effects of the following methods, groups, societies, individuals) interested in collaborating in com-
which can, therefore, be used: (i) physical exercise/sport (equiva- mon projects relating to ABC around the world and is a continu-
lent to 3–5 hours of moderate walking per week) improves ation of the work developed through the ABC International
cardiorespiratory fitness, physical performance and fatigue, and Consensus Conference and Guidelines. Its mission and vision are
it may also improve DFS and OS in breast cancer patients; add- to improve and extend the lives of women and men living with
itionally, a supervised and individualised exercise results in an ABC in all countries worldwide, to fight for a cure for ABC, to
improvement in functional ability and QoL functions in women raise awareness of ABC and to lobby worldwide for improvement
with ABC [72] [IV/B]; (ii) mindfulness-based stress reduction in the lives of ABC patients. As a first step, the Global Alliance has
(MBSR) programmes, hypnosis and yoga may improve QoL and developed an ABC Global Charter, defining 10 achievable and
fatigue, improve sleep and help reduce anxiety, distress and some measurable goals for a period of 10 years (till 2025) [74]. These
side effects of anticancer therapies; and (iii) acupuncture may goals include doubling the median survival of patients by 2025,
help against ChT-induced nausea and vomiting, fatigue and hot improving QoL in clinical practice, increasing availability and ac-
flashes [70, 73]. cess to multidisciplinary care, offering communication skills
Evidence suggests that the following complementary therapies training, improving availability of robust epidemiology and out-
should not be recommended in ABC patients since available evi- comes data, improving access to non-clinical supportive services,
dence shows no effect at best, or even association with worse out- protecting workforce rights for ABC patients and increasing pub-
come: (i) antioxidant supplements; (ii) drugs outside the lic understanding about ABC to fight the still existent stigma.
approved indication (e.g. methadone); (iii) herbs including
Chinese herbal medicine; (iv) orthomolecular substances (selen-
ium, zinc etc.); (v) oxygen and ozone therapy; (vi) proteolytic
enzymes, thymic peptides; phytoestrogens (soy food, isofla- Funding
vones); (vii) high-dose vitamins (vitamin C, D, E, carotenoids,
L-carnitine, laetrile etc.) [70, 73].
No funding to declare.
Discussion Disclosure
The authors’ conflicts of interest are detailed in Supplementary
Conclusions and future directions Table S2, available at Annals of Oncology online.
22 | Cardoso et al.
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Annals of Oncology Special Article
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