Accepted Manuscript

Ablative Therapy for Oligometastatic Non-Small-Cell Lung Cancer

Oscar Juan, Sanjay Popat

PII: S1525-7304(17)30079-7
DOI: 10.1016/j.cllc.2017.03.002
Reference: CLLC 617

To appear in: Clinical Lung Cancer

Received Date: 25 December 2016

Revised Date: 22 February 2017
Accepted Date: 6 March 2017

Please cite this article as: Juan O, Popat S, Ablative Therapy for Oligometastatic Non-Small-Cell Lung
Cancer, Clinical Lung Cancer (2017), doi: 10.1016/j.cllc.2017.03.002.

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 ACCEPTED MANUSCRIPT
AblativeTherapy for Oligometastatic Non-Small-Cell Lung Cancer

Oscar Juan1 and Sanjay Popat2,3,4

1. Department of Medical Oncology. University Hospital La Fe, Av. Fernando Abril

Martorell 106, 46026 – Valencia, Spain

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2. Lung Unit, Royal Marsden Hospital, London, SW3 6JJ, UK

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3. National Heart & Lung Institute, Faculty of Medicine, Imperial College London, Guy

Scadding Building, Cale Street, London, SW3 6LY, UK

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4. The Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK
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Correspondence to:
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Oscar Juan

Department of Medical Oncology

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University Hospital La FE

Av. Fernando Abril Martorell 106

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46026 – Valencia. SPAIN

E: ojjuanv@seom.org

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Declaration of conflicting interests

OJ has no conflicts of interest to declare. SP is consultant to Ariad, Pfizer, and

Novartis and has received honoraria and travel expenses from Pfizer.

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Abstract

The oligometastatic state represents a distinct entity amongst those with metastatic
disease and consists of patients with metastases limited in number and location,
representing an intermediate state between locally confined and widely metastatic
cancers. Although similar, “oligorecurence” (limited number of metachronous
metastases under conditions of a controlled primary lesion) and “oligoprogressive” state

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(disease progression at a limited number of sites with disease controlled at other sites of
disease) are distinct entities. In non-small-cell lung cancer, the oligometastatic state is

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relatively common, with 20-50% of patients being oligometastatic at diagnosis. This
subgroup of patients when managed with ablative therapies, such as surgery or

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stereotactic body radiation radiotherapy (SBRT), may obtain markedly long
progression-free survival and overall survival.
The role of radical treatment in intracranial oligometastases is well established.

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However, fewer data exits about the radical treatment of extracranial metastases in lung
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cancer, but retrospective series using surgery or SBRT for extracranial oligometastatic
disease in non-small cell lung cancer (NSCLC) showed an excellent local control and
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suggest an improvement in progression-free survival. Here, we review data on treatment

of brain metastases in oligometastatic NSCLC, as well as the results of ablative
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treatment of extracranial sites. Recently, the first randomized trial comparing ablative
treatment versus control in oligometastatic disease has been reported and this is
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reviewed in context of smaller series. Finally, areas of controversy are discussed and a
therapeutic approach for patients with oligometastatic disease is proposed.
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Keywords: oligometastases; non-small-cell lung cancer; synchronous; surgery;
radiotherapy; SBRT
Introduction

Lung cancer remains the leading cause of cancer death all over the world. According to
EUCAN, in the year 2012, 409,911 new cases of lung cancer were diagnosed in
Europe1, approximately 80% of which are non-small cell lung cancer (NSCLC) subtype.

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Around 70% of NSCLC patients have advanced disease at diagnosis, and are considered
unsuitable for curative treatment. Classically, all metastatic NSCLC patients have been

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grouped in a unique category by TNM classification under the M descriptor (stage IV).
The seventh TNM classification of lung cancer proposed by the UICC was the first time

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that the stage IV grouping and, therefore, the M descriptor was subdivided in two
categories: M1a, grouping cases with malignant pleural/pericardial effusions and cases
with nodules in the contralateral lung; and M1b, for cases with distant metastases 2.

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However, stages I-III were subdivided in 17 categories related to different T and N
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descriptors according to prognosis. It is therefore striking that 70% of NSCLC patients
(about 230,000 in the year 2012) may be classified by only two categories according to
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prognosis.
In the eight edition of TNM classification of lung cancer, the International Association
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for the Study of Lung Cancer (IASLC) proposes that cases with pleural/pericardial
effusions, contralateral/bilateral lung nodules, contralateral/bilateral pleural nodules, or
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a combination of multiple of these parameters should continue to be grouped as M1a

category, but single metastatic lesions in a single distant organ should be newly
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designated to an M1b category, and multiple lesions in a single organ or multiple

lesions in multiple organs should be reclassified in a new M1c category. This is the
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first step to providing a rational definition for an oligometastatic disease stage in

NSCLC for the future 3.
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Definition of oligometastatic state

The concept of the oligometastatic state was initially coined in an editorial by Hellman
and Weichselbaum in 1995 4 and consists of patients with metastases limited in number
and location, representing an intermediate state between locally confined and widely
metastatic cancers. The number of metastases to consider oligometastatic can vary and
has ranged from a single metastatic lesion to a single organ with multiples metastases to

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multiples lesions in multiples organs5. However, the most accepted number of
metastatic lesions to be considered oligometastatic is up to five and these should be
suitable to radical treatment by local therapy (surgical resection, radiotherapy or both)
to achieve long-term survival.
The most important prognostic factor for oligometastatic disease is status of the primary
tumour. In the concept of oligometastases, the status of the primary tumour is

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unrestricted. However patients with an uncontrolled primary site seem to have a worse
prognosis than those with controlled primary lesions. Niibe et al. proposed the concept
of oligo-recurrence to overcome this problem6. Oligo-recurrence is thus defined as 1–5

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distant metachronous metastases that can be treated by local therapy, under conditions

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of a controlled primary lesion. Oligo-recurrence is considered to have a better prognosis
than synchronous oligometastases.
Currently, the oligometastatic disease comprises four different diferent setting:

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1. Patients who have metastatic lesions limited in number and location4.
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Although, a definitive number of metastasis is not established, the most
accepted is up to 5. The aim of the treatment is prolonging PFS or achiving
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cure; all the lesions including the primary tumour should be suitable to radical
therapy.
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2. Patients with multiple metastasis who are transformed into an oligometastatic

disease following systemic treatment due to response, where all lesions can
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now be managed with radical intent 4. This setting reflects the failure of
systemic treatment to destroy one or a limited number of resistant clones and
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becomes more frequent with the use of highly effective targeted therapies.
3. Patients with primary tumour and most areas of metastatic disease remain
controlled, but one or a limited number of metastases progress while systemic
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therapy continues 6. Similarly to the previous group is the presence of resistant

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clones and is observed more commonly with targeted therapies.

4. Oligorecurrence occurs in patients who have been treated with curative intent
to loco-regional disease and metachronously present with 1-5 metastastic
lesions suitable to ablative therapy 6.
The prognosis among these clinical situations is different, as well as each representing a
heterogeneous group contingent on number of metastatic lesions, tumour genotype
(EGFR mutated, ALK rearrangements, etc.) and type of systemic treatment. In this

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review, we shall focus on group 1 patients without actionable mutations (such as EGFR,
ALK or ROS1), although unavoidable references to the other groups will be made.

Incidence of oligometastatic disease

The different clinical settings defining oligometastatic diseases make it difficult to know
the exact incidence of this state. Most studies have employed a numeric definition of

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one to five lesions as cut-off and the number of organs involved (one or more).
Nevertheless, oligometastases seem relatively common. Single metastasis has been

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reported in 7% of cases of metastatic lung cancer7, but improvements in diagnostic
imagining and the introduction of positron emission tomography (PET) may diagnose

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latent metastases in patients who would otherwise have been thought to be localized in
stage. In an analysis of 725 stage IV NSCLC patients, 186 (26%) were identified with

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oligometastatic disease defined as ≤5 lesions at diagnosis. Disease was confined to one
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organ site in 81% of the cases and 51% of the patients had a single metastatic lesion.
Median overall survival (OS) was longer for patients with oligometastatic disease
compared with patients with more lesions (17 vs. 14 months) 5.
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Similarly, in the proposal for M descriptors for the eight edition of TNM classification
of lung cancer, the IASLC found 225 (22%) of the 1025 metastatic patients had a single
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metastatic lesion and observed prognostic differences in subjects with multiple

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metastatic lesions in a single organ and in multiple lesions in multiple organs. The most
frequent site of a single lesion was bone, followed by brain, adrenals and liver3.
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Ablative techniques in oligometastatic disease

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Surgical metastatectomy has been the most common option chosen as definitive therapy
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in oligometastatic state (55%)8. However, in recent years an increasing use of less

invasive ablative techniques such as stereotactic radiosurgery (SRS), first used to treat
brain metastases and consisting of an ablative dose of radiation to the intracranial target
by using multiple beams centred on the same location, minimizing the radiation dose to
any critical surrounding structures, has emerged. The application of this concept to sites
outside the cranium has been called stereotactic ablative radiotherapy (SART) or
stereotactic body radiation radiotherapy (SBRT). There are no direct comparisons
between surgery and radiotherapy as radical treatment for oligometastatic disease.

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Moreover, several studies included patients treated with surgery as well as those
receiving radiotherapy. The other ablative modalities, radiofrequency ablation (RFA)
and cryoablation, have also been utilized but their use is still limited. The main
advantages of RFA is the freedom to perform the procedure regardless of any previous
therapy and the procedure can be repeated whenever is required. However, rare but
serious complications can occur including bronchopleural fistula, pulmonary artery

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pseudoaneurysm, systemic air embolism, injury of the brachial nerve and the phrenic
nerve, pneumonia and needle-tract seeding of cancer9.

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Surgery

Metastasectomy has been used for a long time in metastatic NSCLC patients, mainly

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those with isolated metastases to the contralateral lung, brain and adrenal glands.
Occasionally, patients with isolated metastases in other locations (bone, liver, etc.) have

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been treated with surgery, but the number reported is much smaller. In a retrospective
analysis of 99 NSCLC patients with a synchronous solitary metastasis treated with
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curative surgery (primary tumour and metastasectomy) 5-year OS was 38%. Favourable
prognostic factors for OS were absence of mediastinal nodal involvement (median 40
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vs. 10 months, p=0.015, N2-N3 involved or not, respectively) and pulmonary compared
to extrapulmonary metastases (5-year OS 48.5% vs. 23.6%)10.
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In another retrospective series, 22 synchronous oligometastatic NSCLC patients eligible

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for curative intent (metastasis limited to a single organ and all sites of disease amenable
to curative therapy) underwent invasive mediastinal staging before the treatment. N2-
negative patients showed a 5-year OS of 58%11.
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Radiotherapy
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Technological advances in the field of radiation oncology allow delivery of very high
radiation doses to specific sites. The use of SBRT for oligometastatic disease in the
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lung, liver, spine and multiple sites reported local control rates of 70-90% with grade ≥3
toxicity of less than 10% 12. Hence, this non-operative approach has been preferred for
some oligometastatic patients because of risks of surgical morbidity and mortality, with
increasing numbers of studies in this setting over recent last years.

Treatment of oligometastatic disease by site

Most trials in oligometastatic disease include patients with primary tumours in others

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locations besides NSCLC. Few studies have reported exclusively for NSCLC by
specific sites of metastases.

Oligometastatic in the brain

Lung cancer is the main cause of brain metastases in cancer patients, representing up to
63% of all patients with brain metastases13,14. Such metastases occur in 30-50% of
NSCLC patients15 and are an early event in the natural history. Historically, brain

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metastases have been associated with poor prognosis. However, in recent years efforts
have been made to more accurately categorize these patients by outcome, ranging from

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a median survival of 7.1 months for patients with recursive partitioning analysis (RPA)
class I to 2.3 months in those with RPA class III16. Patients with brain metastases,

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retain several of favourable prognostic factors at diagnosis. For instance, in an analysis
of 1888 patients with NSCLC and brain metastases, 43% were <60 years old, 85% had

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a Karnofsky performance status (KPS) ≥70%, 76% had between one to three brain
lesions and only one third had extracranial metastasis13.
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For years now, in patients with good KPS in whom both sites are amenable to complete
resection or radiotherapy, aggressive curative treatment intent of both the primary and
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the brain metastases has been recommended. ESMO guidelines recommend for patients
with RPA class I (< 65 years old, KPS ≥70%, no other-cranial metastases and controlled
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primary tumour) or class II patients in case of two or three metastases treatment with
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SRS or with either SRS or resections when a single metastasis is diagnosed. Patients
with RPA class III (<70% KPS) should not be treated in view of the dismal prognosis17.
NSCLC patients with synchronous brain metastases who received radical treatment to
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the metastases and the primary tumour have shown a median survival of 5.2-64.9
months and 1-year OS of 22-95%15,18-32. When no radical treatment was administered to
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the primary tumour, survival decrease (table 1).

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We analysed the outcomes of 54 NSCLC patients with brain metastases treated with
radical intent (surgery, SBRT or both) or palliative (WBRT or not treatment)31. Median
OS was 3 months for patients with RPA class III, 16.2 months for RPA class II and was
not reached for RPA class I. Prognostic factors for longer survival were: solitary vs. ≥1
metastasis (20.2 vs. 10 months), radical vs. no treatment to the primary (31.4 vs. 5.9
months), N0-N1 vs. N2-N3 involvement (24.5 vs. 9.7 months) and radical vs. no radical
treatment to the brain metastases (31 vs. 6 months). In the multivariate analysis, radical
treatment to the primary and to the metastases and RPA group remained statistically

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significant.
Arrieta et al15 reviewed 30 patients with NSCLC and brain metastases at diagnosis
without evidence of other metastatic sites who were treated homogenously to the brain
with WBRT and managed with concurrent radiotherapy for primary tumours in the
chest. All patients were RPA class II and 47% presented N2-3 nodal status. Median PFS
and OS were 8.4 and 31.8 months, respectively. The 1- and 2-year OS rates were 71.1%

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and 60.2%. Three-year OS was significantly superior for patients with N0-N1 stage
disease vs. N2-N3 (60 vs. 24%, respectively; p = 0.038).

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In another study, forty-two NSCLC patients diagnosed with synchronous solitary brain
metastases were treated with gamma knife SRS. However, only 26 out of 42 patients
(62%) received definitive thoracic therapy. All patients had a KPS ≥70 and 16 patients

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(38%) had N2-3 nodal status. The median OS was 18 months and the 1-, 2- and 5-year
actuarial OS were 71.3%, 34.1% and 21%, respectively. As expected, definitive thoracic

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therapy and KPS were a significant prognostic factors on multivariate analysis27.
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Similar result were reported in the largest series published, where 84 newly diagnosed
NSCLC patients with a synchronous solitary brain metastases were treated from
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December 1993 through June 2004 with craniotomy (n = 53) or SRS (n = 31). Forty-
four patients received treatment of their primary lung cancer using radiotherapy,
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chemotherapy or both. The 1-, 2-, 3-, and 5-year OS rates from time of lung cancer
diagnosis were 49.8%, 16.3%, 12.7%, and 7.6%, respectively. The median OS for
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patients by thoracic stage excluding brain metastases (I, II, and III) were 25.6, 9.5, and
9.9 months, respectively (p = 0.006). The median OS was different for patients who had
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received treatment for primary tumours compared to those who did not (15.5 vs. 5.9
months, respectively; p=0.046)26.
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In a series from the Dana-Farber Hospital, sixty-six NSCLC patients with synchronous
brain-only metastases treated between 2000-2011 were analysed. Intrathoracic disease
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extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients
received aggressive thoracic therapy, defined as resection of the primary disease or
chemoradiotherapy whose total radiation dose exceeded 45 Gy. Aggressive thoracic
treatment was associated with prolonged median OS (26.4vs. 10.5 months; p < 0.001)
as well as with higher actuarial 2-year OS rates of 54% vs. 26%. The benefit of
aggressive thoracic therapy remained significant for patients with stage III or with
multiple brain lesions30.
A recent review of a series of patients with NSCLC and with brain oligometastatic

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disease who received aggressive treatment with surgery and SRS, with or without
WBRT, and primary thoracic treatment has been published33. Most series where surgery
was the treatment for the primary lung tumour included patients with synchronous and
metachronous brain metastases. For patients treated with surgical resection for the
primary lung tumour, median OS ranged from 19 to 27 months, and the 1- and 2-year
survival reached 56% -69% and 28%-54, respectively. Patients treated with aggressive

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radiotherapy with or without chemotherapy (generally locally advanced stages),
achieved a median OS of 15.5-31.8 months, with 1-year survival of 50%-71% and a 2-

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year OS of 16%-60%.
In conclusion, patients with NSCLC and brain-only oligometastasis represent a

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subgroup of stage IV with better prognosis when aggressive treatment can be delivered
to the primary lung tumour and metastatic site. Although, N2-3 disease is an adverse
prognostic factor, treatment with chemoradiotherapy may obtain median OS over 24

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months and 3-year OS of 40%30, similar to that reported recently in unresectable stage
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IIIA/IIIB34.
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Oligometastatic in adrenal glands

Draining the lung bases, the adrenal gland is a common site of metastatic disease in
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NSCLC. Although adrenal metastases are usually found in patients with other sites of
distant metastases, incidence of solitary metastases has been reported in 4-20% of
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metastatic NSCLC3,35. CT is a poor predictor of adrenal involvement, as adrenal

enlargement is a benign lesion in a considerable proportion of cases. Magnetic
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resonance (MR) and PET can be helpful in differentiating incidental benign adenomas
from adrenal metastases. However, considering that the management and the prognosis
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of the patient may depend on whether the lesion is benign or malignant, a histologic
confirmation is recommended36.
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Traditionally, adrenalectomy (first open and lately laparoscopic) has been the treatment
modality used in the management of adrenal metastases, although in recent years, the
numbers of series reporting SBRT as curative treatment has increased.
Evidence for adrenalectomy comes from case reports or small retrospective series of
cases. Only seven reports included more than 10 patients37-46 (table 2). Tanvetyanon et
al47 performed a systematic review including 10 studies (114 patients) to analyse
outcome of adrenalectomy for isolated adrenal metastases of NSCLC patients in whom

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the primary had been treated with surgery, with an emphasis on survival outcomes
between patients with synchronous (n = 48) and metachronous (n =66) metastases. The
use of PET scanning to exclude other occult metastases was only reported in one study.
Laparoscopic adrenalectomy was used in 40% of patients. No significant difference in
median DFS was observed between synchronous (median 11 months) or metachronous
metastases (9 months). Median OS was shorter for patients with synchronous

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metastases than those with metachronous metastases (12 months vs. 31 months, p =
0.029), but 5-year survival rates were equivalent at 26% and 25%, respectively.

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Recurrence at the adrenal bed or retroperitoneum occurred in 21 of 100 patients (21%).
There were few surgical complications and no mortality reported. Open adrenalectomy

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was associated with greater complications than a laparoscopic approach.
Porte et al.40 included 43 patients (32 synchronous and 11 metachronous metastasis), in
a retrospective review not included in the previous meta-analysis. These results,

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contrary to the meta-analysis, did not show any difference between recurrence rates or
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survival rates of the synchronous and metachronous groups.
One of the most recent series46 including 37 patients with isolated adrenal metastases
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from NSCLC where 20 patients underwent adrenalectomy, reported a 5-year survival of

34% in the surgical group vs. 0% in the non-surgical group. Patients did not undergo
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adrenalectomy owing to suspicion of N2 disease, medical comorbidities, or patient

preference. On multivariate analysis, mediastinal lymph node involvement was
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predictive of worse 5-year survival (52% for patients with mediastinal involvement vs.
0% for those without mediastinal involvement). Ipsilateral adrenal metastasis was also
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predictive of 5-year survival (83% in the ipsilateral group vs 0% in the contralateral

group). It is likely that malignancy is locally draining into the adrenal gland via
lymphatic channels at an early stage in development, thus explaining the ipsilateral
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preponderance and the better prognosis, as contralateral adrenal involvement would

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likely occur through hematogenous pathways48.

Whilst SBRT has been most extensively studied in brain metastases and for primary
lung tumours, in recent years several studies have analysed outcomes of SBRT to
adrenal gland metastases49-53 (table 2). The number of fractions (between three and ten)
and the accumulated doses (10-45Gy) vary between studies.
Chawla et al. reported the first large series of SBRT for adrenal metastases49. Here, 30
patients including 20 adrenal metastases from the lung were analysed. Of these 30, 14
had ≤5 metastatic lesions and were considered oligometastatic being treated with SBRT

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with curative intent. Dosing ranged from 16 Gy in 4 fractions to 50 Gy in 10 fractions,
with a median dose of 40 Gy. Twenty-four patients were evaluable for response: 1
complete response (CR), 15 partial response (PR), 4 stable disease (SD) and 4
progressed locally. Ten patients (30%) eventually developed local failure. The 1-year
local and distant control rates were 55% and 13%, respectively. The actuarial 1- and 2-
year OS rates were 44% and 25%, respectively. No patients developed Radiation

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Therapy Oncology Group (RTOG) grade ≥2 toxicity.
In the largest series published51, 48 patients (24 lung cancer patients) with adrenal

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metastases were treated with SBRT (36 Gy in 3 fractions). Only two lesions progressed
locally whilst all patients had distant failures. The actuarial 1-year disease control rate

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was 9%; the actuarial 1- and 2-year local control rate was 90%. Although the number of
patients is small and precludes definitive conclusions, no significant differences were
observed by primary site, synchronous vs. metachronous and unilateral vs. bilateral.

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Thus, in adrenal oligometastatic disease, SBRT has been effectively and safely used as a
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non-invasive alternative to the gold standard of surgery. Despite heterogeneity of
studies reported and the lack of prospective clinical trials, relatively comparable rates of
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OS and local control have been obtained.

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Oligometastatic in the liver

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Aggressive treatment for liver metastases from colorectal cancer is well established and
has been shown to improve OS, with 5-year survival rate of 30-60%54,55. Liver
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metastases from NSCLC are less common than in other sites, especially as a single
metastatic site, and are associated with worse survival compared with other sites such as
brain or bone metastases56-58. Surgery is contraindicated in the majority of liver
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metastases from NSCLC because of the number, the distribution or the presence of
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extrahepatic disease. Hence, information concerning efficacy of liver resections for

metastases from NSCLC are limited to few cases published, and are therefore likely to
be prone to marked biases. Nevertheless, long-term survival was unexpectedly high,
ranging from ≥21 to ≥60 months59-62 (table 3). These results are likely influenced by
careful patient selection and are unlikely to represent the general NSCLC population
with liver metastases.
SBRT has no strict restrictions regarding lesion location, and offers the possibility of a
high precision non-invasive treatment, using small margins. Several studies have

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demonstrated that SBRT is safe and effective for the treatment of one to three hepatic
lesions63-70 (table 4).
Rusthoven et al.67 in a multi institutional phase I/II trial treated 47 patients with
differing malignancies and one to three hepatic metastases; ten patients (21%) had
diagnosis of lung cancer. The dose was escalated from 36Gy (phase I) to 60Gy (phase
II) in 3 fractions. Most of the patients (69%) had received at least one prior systemic

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therapy for metastatic disease and 45% had extrahepatic disease at study entry.
Actuarial in-field local control rates at two years after SBRT was 92%. Among lesions

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with maximal diameter of 3 cm or less, 2-year local control was 100%. Overall, median
survival was 20.5 months. Only one patient experienced grade ≥3 toxicity. The lung

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cancer patients were included with ovarian and noncolorectal gastrointestinal
malignancies in a group of metastases from unfavourable primary sites. Here, median
OS was 12 months, whilst patients with favourable primary sites (breast, colorectal,

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renal, carcinoid, gastrointestinal stromal tumours and sarcoma) had median OS of 32
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months.
In conclusion, whilst aggressive therapy with surgery or SBRT for oligometastatic liver
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disease with one to three lesions may obtain a high local control and a suggestion of
prolonged survival, outcomes specifically for NSCLC are markedly lacking.
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Oligometastatic in lungs
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In a Japanese study of 76 patients with resected NSCLC pulmonary metastases, 5-year

survival for patients with simultaneous metastases in the same or different lobe was
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79.6% and 41.6%, respectively71. In patients with recurrent pulmonary metastasis 5-

year survival was 34.8%. Multiple pulmonary metastasis and mediastinal node
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metastasis were identified as significant factors affecting survival. No significant

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difference in survival was observed between ipsilateral and contralateral metastases.

Similarly, in a study of surgical resection of synchronous multiple lung cancers, both
ipsilaterally (n = 27) or controlaterally (n =28), the 5-year survival was not significant
different between the two groups (27% vs. 43%)72. Mediastinal nodal involvement was
a negative prognostic factor for survival. The 5-year survival was 57% and 0% for
patients without (n = 25) and with (n = 18) lymph node metastasis.
In another retrospective analysis of 66 patients after complete resection for synchronous
pulmonary malignant lesions, the median OS was 25.4 months and the 5-year survival

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rate of 38%73.
Based on these findings, even patients with contralateral lung oligometastases should
can be considered for surgical resection, provided that there is no evidence of lymph
node involvement and distant metastases after an extensive pre-operative work-up, as
survival is much higher than that of patients assumed to have stage IV disease and
treated with palliative systemic therapy74.

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Similarly, several series of patients with lung metastasis from NSCLC treated with
SBRT showed 2-year OS of 33-84% with local control of 51-96%65,67,75-81 (table 5),

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reinforcing this concept.

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Studies in oligometastatic disease
Several retrospective studies have analysed the impact of aggressive therapy in
oligometastatic disease. In this group of palliative patients, results should be measured

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in terms of efficacy such as improvement in OS and toxicity.
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In a retrospective study published in 200682, 23 oligometastatic NSCLC patients (1 or 2
sites) were treated with aggressive therapy to the primary thoracic tumour (12 received
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chemoradiation, 4 surgery and 7 preoperative chemoradiation followed by surgery) and

distant metastases (15 with radiation or SRS, 1 surgery and 6 resection followed by
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radiotherapy). The majority of these patients had brain-only metastases (14 out of 23)
and stage III disease (18 out of 23). The median survival of the entire group was 20
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months. Median time to any recurrence was 12 months.

In another retrospective study83, 25 patients with oligometastatic NSCLC (1 to 5
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lesions, median 2) were treated to all known sites of active disease with
hypofractionated image-guided radiation therapy (HIGRT). Most patients (92%) had
extracranial oligometastatic lesions, mainly lung, lymph node and adrenal lesions.
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Median OS and PFS were 22.7 and 7.6 months, respectively. Two patients experienced
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grade 3 toxicity (one patients had fatigue and another one radiation pneumonitis). More
than 2 sites treated with HIGRT was one of the negative prognostic factors for PFS,
alongside non-adenocarcinoma histology, prior systemic therapy and progression after
systemic therapy.
One of the largest series comes from the MD Anderson84. Here, 78 patients with
oligometastatic NSCLC (<5 metastases) at diagnosis underwent definitive
chemoradiation therapy (≥45 Gy) to the primary site. Most had only one metastatic site
(61 out of 78) and the most common site of metastatic disease at diagnosis was the brain

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(42% of patients). Definitive local treatment for oligometastases was administrated in
44 (56%) patients. For all patients, the 2-year OS rate was 32%. OS was better for
those patients who received at least 63Gy of radiation to the primary site, received
definitive local treatment for oligometastasis, had a KPS score >80 and had a gross
tumour volume ≤124 cm3. Grade ≥3 pulmonary and oesophageal toxicity were 6.4%
and 19.4%, respectively.

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Griffioen et al. 85 treated 61 patients with 1-3 synchronous metastases with radical intent
in all sites of disease. Besides the primary tumour, 50 patients had a solitary metastasis,

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9 had two metastases, and 2 had three metastases. The principal location of metastases
was the brain (n=36). The majority of patients (62%) had locally advanced (stage III)

SC
intra-thoracic disease. Median OS was 13.5 months, with an actuarial 1 year OS of
54%.
In our experience, 34 patients with unresectable primary NSCLC and 1-3 synchronous

U
metastasis were treated radically with chemo-radiotherapy at the primary tumour with
AN
surgery or SBRT to the metastases 86. Most patients had ECOG performance status 0-1
(96%) and histological subtype adenocarcinoma (65%). All patients had unresectable
M

mediastinal involvement. Oligometastases location was brain (65%), lung (18%), bone
(9%) and other locations (6%). Definitive treatment of the primary lung tumour was
D

sequential chemo-radiotherapy (44%) and concomitant chemo-radiotherapy (52%).

Treatment of metastases was SBRT (58.8%), external beam radiotherapy (23.5%),
TE

surgery (11.7%), radiofrequency ablation (2.9%), and none (2.9%). In this group of
poor prognosis patients, median OS was 19 months and 1-year OS 76%86.
EP

In a French surgical series87, 94 NSCLC patients with extrathoracic synchronous

solitary metastases underwent lung surgery with curative intent. Metastasis mainly
C

involved the brain (n = 57). Sixty-nine metastases were resected. Median OS was 13
months. Metastasis resection was not a prognostic criterion in the multivariate analysis.
AC

According to these data, oligometastatic NSCLC patients treated with curative intent to
their thoracic disease and distant metastases may get a median OS of more than 20
months. Despite the heterogeneous population and treatment approach used in these
studies, a group of stage IV patients may potentially benefit from such aggressive
therapy.

Clinical trials in oligometastatic disease

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Few prospective trials have been conducted in oligometastatic NSCLC patients andmost
have evaluated the safety and efficacy of SBRT67,88,89.
The multi-institutional phase I/II of SBRT for liver metastasis has been commented
above 67. In another dose-escalation trial to determine the maximally tolerated dose of
SBRT, 61 patients with ≤5 metastatic lesions were included, although only 11 patients
had NSCLC88. The 2-year OS for the whole population was 56.7%. For patients with 1

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to 3 metastases, the 2-year OS was 60.3% compared with 21.9% for patients with 4 to 5
metastases.

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A prospective single-arm phase II trial examined the value of SBRT in 39 NSCLC
patients with <5 metastatic lesions amenable to local treatment (surgery or
radiotherapy) 89. Thirty-five (87%) had a single metastatic lesion and most of the

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patients had local stage III (74%). Brain was the most common site of metastasis (44%).
Median OS was 13.5 months and 1-year OS 56.4%. Median PFS was 12.1 months.

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Only two patients (5%) had a local recurrence. The treatment was well tolerated,
AN
transient acute esophagitis was 15% and no toxicity of grade ≥3 was observed with the
treatment of distant metastases.
Recently, the first phase II randomized study of oligometastatic NSCLC was reported90.
M

Seventy-four patients received front-line systemic therapy consisting of chemotherapy,

EGFR-TKIs or ALK inhibitors. Patients with ≤3 metastases after systemic therapy were
D

randomized to receive local consolidation therapy (LCT) with surgery ± radiation to

TE

primary and metastases or physician choice for standard maintenance or surveillance.

Patients were balanced according to: nodal status, EGFR/ALK status, response to front-
EP

line systemic therapy, brain metastases and number of metastases. The study was closed
at the first interim analysis due to observed efficacy in the experimental arm after
C

randomization of 49 patients. The study met the primary objective of 24 patients who
received LCT with a statistically significant higher median PFS (11.9 months)
AC

compared with 24 patients who not received LCT (3.9 months). A different pattern of
failure was observed: distant failure only was more frequent in the LCR arm, whilst
locorregional or both locorregional and metastatic were more common in no-LCT. The
time to new site of failure was 11.9 months in LCT arm vs. 5.7 months in no-LCR arm
(p=0.0497). There were no substantial differences in toxicity between arms. The
principal limitations of the study were the small number of patients (24 in each arm),
the molecular heterogeneity (including EGFR and ALK patients) and the definition of
oligometastatic disease (after front-line systemic therapy).

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Prognostic factors
Several trials have tried to address the question of patient selection through prognostic
factor identification, but since most are heterogenous retrospective series composed of
mixed synchronous and metachronous metastases, different thoracic stage and sites of
metastases, as well as different treatments, and variably reported oncogene status, it is

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difficult to draw definitive conclusions.
In the largest retrospective series from the Dana-Farber Cancer Institute5, ECOG PS ≥

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2, nodal status N2-3, squamous histology and metastases to multiple organs were
associated with shorter OS. However, the number of metastatic lesions and radiologic

SC
size of the primary were not statistically significant. Definitive local therapy to the
primary tumour and to the metastatic sites was associated with prolonged survival.
Ashworth et al91 performed an individual patient data meta-analysis to determine

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prognostic factors in oligometastatic NSCLC. Data were available from 757 NSCLC
AN
patients with 1 to 5 synchronous (75.5%) or metachronous (24.5%) metastases treated
with surgical metastectomy, stereotactic radiotherapy/radiosurgery, or radical external-
M

beam radiotherapy, and curative treatment of the primary lung cancer. Median patient
age was 61.1 years and 98.3% had good performance status. Excluding metastatic
D

disease, 66% of patients had intrathoracic stage I-II. Patients most commonly presented
with a single synchronous metastasis located in the brain (36%) or lung (34%). Only
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3% of patients had multi-organ metastatic disease.

Median OS for the whole population was 26 months. In multivariate analysis, factors
EP

predictive of OS were: synchronous versus metachronous metastases, nodal stage and

adenocarcinoma histology. A recursive partitioning analysis was subsequently
C

performed to stratify patients into risk groups: low-risk, metachronous metastases and
N0 (5-year OS, 47.8%); intermediate risk, synchronous metastases and N0 disease (5-
AC

year OS, 36.2%); and high risk, synchronous metastases and N1/N2 disease (5-year OS,
13.8%). Limitations of the meta-analysis are that 96.5% of patients had 1-2 metastatic
sites and the number of patients with ≥3 metastases is underrepresented.
Several factors have shown impact on survival in different studies. Among the most
prominent are the number of metastases and mediastinal involvement. The number of
metastatic sites may be a potential predictor of survival. In an analysis from Southwest
Oncology Group of 2,531 advanced NSCLC patients 7, median OS was different for
patients with a single lesion, patients with multiple lesions in one site and for those who

17
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had multiple lesions in multiple sites (8.7, 6.2 and 5.1 months, respectively). Similar
results were obtained in preparation for the revision for the IASLC Lung Cancer
Staging Project3, where single metastatic lesion in one organ (M1b) show significant
better survival compared to multiple metastases in either single organ or multiple organs
(M1c). Others studies have shown that patients who have a larger number of metastatic
sites (more than 3 or 5) have shorter survival 5,67. The major number of metastasis is

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expression of a higher tumour burden and, likely, represents a different status than
oligometastatic disease.

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Mediastinal nodal involvement has shown to be an adverse prognostic factor for
survival in patients with oligometastatic disease10,11,15,46,71,72,92,93. Despite heterogeneity

SC
in these studies, findings support that nodal involvement is a prognostic factor. The
value of nodal status in of cancer prognosis is unsurprising as it is a well-established
category for the TNM classification. Recently, a review of 39,731 patients with NSCLC

U
and M1a disease showed that M1a patients without lymph node involvement had the
AN
best survival, followed by patients with N1 disease. No difference in survival was
observed between N2 and N3 disease. Multivariate analysis confirmed that lymph node
involvement was an independent prognostic factor for M1a patients94.
M

In conclusion, patients with good performance status, single metastatic site and without
D

thoracic nodal involvement represent the group of most favourable prognosis in

oligometastatic disease and should be selected for curative ablative therapy.
TE

Future directions
EP

Oligometastasic disease is a unique clinical and, likely, biological entity observed in

some patients with metastatic lung cancer. The main characteristic of the
oligometastatic status is that the solitary or the few metastases can be amenable to
C

localized therapy including SBRT or resection. However, the key question is “What is
AC

the impact of locally ablative therapies in these patients?” The treatment benefit in
oncology should be measured in terms of toxicity and efficacy. Studies using ablative
therapies such as SBRT or surgery have reported acceptable toxicity rates. The
retrospective methodology used in most of the reported series make it difficult to draw
definitive conclusions on the effectiveness of ablative therapies. Moreover, another
major limitation of theses series is their single arm nature. Hence, the question that
remains unanswered is whether the better outcomes are due to the ablative treatment or
the more indolent behaviour of the disease. A retrospective analysis of 90 NSCLC

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 ACCEPTED MANUSCRIPT
patients presenting with ≤3 metastatic lesions at diagnosis addresses the question if
comprehensive local therapy (chemotherapy plus surgery or radiotherapy or both) with
curative intent improves outcomes compared with less aggressive therapy mostly with
palliative intent. An improved OS (27.1 vs. 13.1 months) and PFS (11.3 vs. 8 months)
were observed in patients treated with comprehensive local therapy95. In another
retrospective analysis, 78 patients with oligometastatic disease received definitive

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chemoradiation to the primary site and the majority (44 out of 78) also underwent
localized radiotherapy to sites of oligometastases. Radiotherapy dose of at least 63 Gy

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to the primary site and localized radiotherapy to all sites of oligometastases were
associated with a significant prolonged OS84.

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These findings suggest that the aggressive management of local disease and limited
synchronous metastases may provide improved PFS and OS. More light to this question
comes from the unique randomized phase II trial in oligometastatic disease90. LCT to

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the primary and metastases (surgery ± radiation) in patients with ≤3 lesions prolonged
AN
median PFS in 8 months compared to no local therapy (median PFS 3.9 months in
patients without LCT vs. 11.9 months for the LCT group).
M

Another important question that remains unanswered is “Which oligometastatic patients

should be treated?” Good performance status, single metastatic site and N0-1 disease
D

are favourable prognostic factors and defined a group of oligometastatic patients with
prolonged DFS and OS when they were treated with locally ablative
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therapy5,7,10,11,15,46,67,71,72,91,93. In some studies, patients with synchronous metastases

had poorer prognosis compared with those who presented with metachronous
EP

disease47,91,96, while in others no statistically significant difference was observed35,51,97.

The different prognosis may be explained because of a more indolent and slower
C

growing of metachronous disease. Although, therapeutic benefit is better established in

this group of good prognosis oligometastatic patients, the lack of efficacy of a
AC

comprehensive approach in patients with more than 1 metastatic lesions (2-5) or N2

disease has not been proved.
To put in context, chemotherapy in metastatic NSCLC showed an absolute
improvement of 9% at 12 months, increasing survival from 20% to 29%, or an absolute
increase in median survival of 1.5 months (from 4.5 to 6 months)98. In locally advanced
NSCLC setting, concomitant chemoradiation compared with sequential chemoradiation
has showed an increase OS rate of 5.7% at 3 years and increase of 4.5% at 5 years99 or a
prolongation of median OS from 14.6 months to 17 months100. The discovery of

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 ACCEPTED MANUSCRIPT
sensitizing mutations in epidermal growth factor receptor (EGFR) and the subsequent
development of EGFR tyrosine kinase inhibitors (TKIs) have substantially changed the
prognosis of in these subgroups of NSCLC patients, showing significant improvements
in PFS (median 8-13.7 months) and OS (median 19.3-31.6months) compared with
chemotherapy. Lately, others molecular alterations (ALK, ROS1, BRAF, etc.) have
been described and targeted therapies against them are licensed and being developed.

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However, only a small proportion of NSCLC patients present with one of these
targetable alterations. Oligometatatic disease is diagnosed between 7% and 26% of
metastatic NSCLC patients5,7. Although, N2-3 disease is an adverse prognostic factor,

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definitive treatment with chemoradiation or surgery to the primary and to the metastasis
may obtain median OS of 10-19 months and 3-year survival of 24-40%10,15,26,30,86. The

SC
benefit of aggressive thoracic therapy compared with more palliative approach remains
significant for patients with stage III 30.

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Recently, immune checkpoints inhibitors monoclonal antibodies against programmed
AN
death receptor 1 (PD-1), such as nivolumab or pembrolizumab, and the programmed
death ligand 1 (PD-L1) atezolizumab have demonstrated improved survival compared
with chemotherapy101-105. What is the role of immunotherapy in oligometastatic
M

disease?. Combining radiation therapy and immunotherapy is an attractive area under

D

study. Radiotherapy cell death can be immunogenic and can promote the production and
the presentation of tumour antigens increasing the antitumour immune responses
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achieved by checkpoint inhibitors. SBRT seems to be the most appropriate kind of

radiotherapy since SBRT has been to induce cellular expression of MHC I, adhesion
EP

molecules, costimulatory molecules, heat shock proteins, inflammatory mediators,

immunomodulatory cytokines, and death receptors to enhance antitumor immune
responses106. The abscopal effect, where radiotherapy to one metastatic site leads to
C

tumour regression in other sites, has been described in NSCLC patient treated with
AC

immunotherapy107. The synergism of SBRT and immunotherapy may be especially

relevant in oligometastatic disease where tumour burden is low.
Finally, “What is the impact of PET/CT in the management of oligometastatic disease?”
Currently, PET/CT is recommended for staging NSCLC due to its highest sensitivity for
mediastinal lymph nodes and distant metastasis108. PET/CT detects occult metastasis in
up to 16% of the patients for whom conventional staging methods fail 109. Tönnies et
al.92 investigated whether the use of PET/CT scan for preoperative staging influences
survival in NSCLC patients with resected solitary metastases. Sixty-six patients

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underwent surgery after an initial PET/CT scan, whereas 115 patients underwent
conventional preoperative staging by a spiral CT scan. The 5-year survival rates after
preoperative evaluation by PET/CT and by conventional CT were 58% and 33%,
respectively (p=0.01). Hence, a careful staging workup with PET/TC and brain MRI
(due to the limitations of PET in the brain) may be critical for confirming or ruling out
oligometastatic disease.

PT
With the limitation of most of the data come from retrospective series we propose a
therapeutic approach for oligometastatic patients (figure 1). Ongoing trials help us to

RI
define the best approach in this subgroup of patients.

Conclusions

SC
Despite the heterogeneity on the definition of oligometastatic status and the
retrospective methodology used in most studies, this type of metastatic cancer with

U
limited number of lesions (generally 1 to 5) has better prognosis compared with patients
AN
with polymetastatic disease. Long-term disease control, even cure, could be achieved by
ablative treatment of both primary tumour and metastases. Most lung cancer guidelines
have incorporated treatment recommendations for this subgroup of patients. ESMO
M

guidelines110 recommend systemic therapy and radical local treatment (high-dose

radiotherapy or surgery) for stage IV patients with one to three metastases at diagnosis.
D

Otherwise, NCCN guidelines versions 3.2017 111recommend aggressive local therapies

TE

to the metastatic and primary sites for patients classified as M1b stage according to the
8th Edition of the lung cancer staging system proposed by IASLC (only one metastatic
site). Whilst patients with multiple metastatic sites independently if they have two to
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five metastases o more should be treated with systemic treatment. In conclusion,

appropriate treatment for patients with multiple synchronous metastases remains
C

unknown and should be included within prospective clinical trials stratifying by number
AC

of metastases (2-3 vs. 4-5) and number of organs involved.

Acknowledgements

OJ acknowledges Spanish Society of Medical Oncology (SEOM) and CRIS Cancer

foundation to support the collaboration with the Royal Marsden Hospital. SP

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acknowledges NHS funding to the Royal Marsden Hospital / Institute of Cancer

Research NIHR-Biomedical Research Centre.

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https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

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Table 1. NSCLC patients with exclusively synchronous brain metastases who

received radical treatment

Study No. Syn/ Ablative therapy Median OS 1year

patients Meta No. (months) OS
Wronski et al 231 86/145 Surgery 231: 218 11 46.3%
CR; 13 PR

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Mussi et al 52 19/33 Surgery 52 11 6.9%
(syn)/
19%

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(meta)
(at 5y)
Chidel et al 33 33/0 Surgery±WBRT 6.9 12%

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24; SRS±WBRT 7; (at 3y)
WBRT 2
Billing et al 28 28/0 Surgery 28 24 64.3%

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Bonnette et al 103 103/0 Surgery 103 12.4 56%
Granone et al 30 20/10 Surgery±WBRT 30 23 (Syn)/11 95%
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(meta) (syn)/
50%
(meta)
Getman et al 32 16/16 Surgery±WBRT 9.3 37.5%
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13; SRS±WBRT (syn)/6.2 (syn)/

13, Surgery +SRS (meta) 31.3%
4 (meta)
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Furak et al 65 19/46 Surgery±WBRT 65 19 (syn)/12 24%

(meta) (syn)/
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16%
(meta)
at 5 y
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Girard et al 51 51/0 Surgery±WBRT 29 22.5 69%

Hu et al 84 84/0 Surgery 53; SRS 12 (surgery) 49.8%
31 ±WBRT 7.4 (SRS)
Flannery et al 42 42/0 SRS±WBRT 42 18 71.3%
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Yang et al 16 16/0 Surgery 16 64.9 97.1%

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Louie et al 35 35/0 Surgery±WBRT 35 7.8 30%

Lo et al 17 17/0 Surgery 14; SRS 3 52 63%
Arrieta et al 30 30/0 WBRT 30 31.8 71%
Gray et al 66 66/0 Surgery 21; SRS 26.4 (ATT) 71%
29; Surgery+SRS 10.4 (no (ATT)
7; WBRT 7 ATT) 46%
no
ATT
Salvador et al 54 54/0 Surgery 25; SRS 17.2 NR
14, WBRT 12
CR: complete resection; PR: partial resection; SRS: stereotactic radiosurgery;
WBRT: whole brain radiotherapy; ATT: aggressive thoracic therapy

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Table 2. NSCLC patients with isolated adrenal metastasis treated with

ablative treatment (surgery or SBRT)

Study Year of Ablative No 5-year

publication therapy of patients OS
Reyes et al 1990 Adrenalectomy 5 NR

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Higashiyama et al 1994 Adrenalectomy 5 NR
Wade et al 1998 Adrenalectomy 14 13%
Porte et al 2001 Adrenalectomy 43 11% (4y)

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Mercier et al 2004 Adrenalectomy 23 23.3%
Lucchi et al 2005 Adrenalectomy 14 35%
Pfannschmidt et al 2005 Adrenalectomy 11 NR

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Sebag et al 2006 Adrenalectomy 9 33%
Strong et al 2007 Adrenalectomy 29 NR
Raz et al 2011 Adrenalectomy 37 34%
Chawla et al 2008 SBRT 30 44% (1y OS)

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Barney et al 2010 SBRT 6 62% (1y OS)
Cassamassina et al 2011 SBRT 48 39.7% (1y OS)
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Holy et al 2011 SBRT 18 23 m (median OS)
Oshiro et al 2011 SBRT 19 56% (1y OS)
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Table 3. Cases reported of liver metastases from primary lung cancer treated with
surgery
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Author Year of No of DFS Treatment OS

publication cases (months) (months)
Di Carlo et al 2003 1 48 Cir >36

Nagashima et al 2004 1 6 Cir >60

Kim et al 2006 1 7 Cir/QT >60

Ileana et al 2010 2 16 Cir >21

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Table 4. Studies of hepatic lesions treated with SBRT

Study Year Nº Scheme Median 2-year

Lesions Follow – local
(LC up control
patients) (months) %
Herfath et al 2001 55 (4) 14-26 Gy/1 fr 6 67

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Hoyer et al 2006 141 (0) 45 Gy/3 frs 52 79
Milano et al 2008 54 (23*) 50 Gy/5 frs 41 67%

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Méndez-Romero et al 2006 45 (1) 30-37.5 Gy/3 frs 13 82
Rusthoven et al 2009 49 (10) 36-60 Gy/3 frs 16 92%

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Lee et al 2009 143 (2) 27.7-60 Gy/6 frs 10.8 71%**
Goodman DO 2016 106 (3) 42-60 Gy/ 4 frs 33.6 90.5%
Kirichenko et al 2016 114 (3)
U 36-60 Gy/ 4-6 frs 20.3 93.8%
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*Includes head and neck and oesophagus cancer patients; **1-year local control
Abbreviations: LC: lung cancer; fr: fraction.
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Table 5. Studies of SBRT in patients with lung metastases

Author and Pts Lung Schema BED 2-year 2-year

year LC OS
Onimaru 2003 45 55% 45 Gy/ 8 frs 76.8-105 80% 47%

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Wulf 2004 25 45% 30-36 Gy/ 3 frs 117.2-168.6 71% 33%

Yoon 2006 53 28% 30-40 Gy/3-4 frs NR 51% 51%

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Milano 2008 50 16% 50 Gy/10 frs NR 92% 50%
48Gy/6 frs

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Norihisa 2008 34 44% 48-60 Gy/4-5 frs 132 Gy 90% 84%

Brown 2008 35 22% 5-60 Gy/1-4 frs 6-110 Gy NR 72%

Rusthoven 2009 38 13%

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60 Gy/3frs NR 96% 39%
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Ricardi 2012 61 45.7% 26 Gy/1fx, 45 NR 89% 66%
Gy/3fx
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De Rose 2016 60 100% 48-60 Gy/3-8 frs >100 Gy 88.9% 74.6%

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Abbreviations: BED: biologically effective dose; fr: fraction; LC: local control; OS:
overall survival
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Figure 1. Therapeutic approach for wild type NSCLC patients with

oligometastatic disease

Oligometastatic NSCLC patients

(1-5 lesions)
ECOG PS 0-1

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PET/TC & brain MR

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2-5 metastatic
Solitary lesion
lesions

Comprehensive local
therapy (primary and
metastases) + systemic
chemotherapy
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Are the primary and the
metastasis suitable of
radical treatment?

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AN
Yes No

Systemic
Systemic
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chemotherapy (3-4
cycles) chemotherapy
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Response?
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PR/SD PD
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Continue with
Comprehensive local chemotherapy or
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therapy (primary and best supportive care

metastases)
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