Oligometastases

PROF.S.SUBBIAH et.al
OLIGOMETASTASES
Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

Theories of metastasis
Seed and Soil theory
• In 1889, Stephen Paget theorized that
circulating tumor cells would “seed” to an
amenable “soil”, suggesting that metastasis
was not a matter of chance.
• Metastasis would result only if the seed and
soil are compatible

Halstead theory
• 1894-cancer was an orderly disease
• Progressed in a contiguous manner
• Direct extension from the primary tumor
through the lymphatics, to the lymph nodes,
and then to distant sites.
• Implications-Radical breast surgeries

Systemic theory
• First suggested by Keynes and further
developed by Fisher
• Small/clinically apparent tumors were an early
manifestation of systemic disease.
• Nodal involvement was not part of an orderly
contiguous extension but rather a marker of
distant metastases. According to this theory,
local control alone would not impact survival

Spectrum theory
• first described for breast cancer metastases in
1994
• Disease at the time of presentation fell into a
spectrum ranging from indolent disease to
widely metastatic
• Degree of clonal evolution determines the
ability of the tumor to metastasize

• The spectrum theory was refined just one year
later to describe the limited metastasis of any
solid tumor and the term ‘oligometastasis’
was coined

• Hellman and Weichselbaum originally
proposed the state of oligometastases in 1995
based on a consideration of the multistep
nature of cancer progression.
• Existence of an oligometastatic state that was
an “intermediate between purely localized
lesions and those widely metastatic”

Definition
• No consensus on the definition
• A generic definition is available
• A malignancy that has progressed to a limited
number of hematogenous metastases,
defined in most studies as 1–3 or 1–5
metastatic lesions.

• Oligometastases is a disease concept that is
defined by a state of limited systemic
metastatic tumors for which local ablative
therapy could be curative
• By definition,the purpose of local treatment
for oligometastases is cure,and the primary
outcome to be analyzed should be disease-
free survival

• 1–5 metastatic lesions
• a controlled primary tumor being optional,
• but where all metastatic sites must be safely
treatable.

Imaging and Biomarkers
• No biomarker for the identification of patients
with true oligometastatic disease is clinically
available, the diagnosis of oligometastatic
disease is based solely on imaging findings
• The current scarcity of biomarkers has made
imaging the most relevant diagnostic method
for defining oligometastatic disease

Biology of Oligometastasis

MicroRNA
• MicroRNA profiling has shown a possible
method to distinguish patients with
oligometastases from those with
polymetastatic disease.

Examples of pro-metastatic microRNAs include
• microRNA-10b (upregulated in primary breast
tumors that had metastasized)
• microRNA-21 (correlated with advanced
stage, incidence of metastases, and poor
outcomes in breast and pancreatic tumors)
• microRNA- 373/520c (increased expression in
breast metastases)

Molecular signatures
• Colorectal cancer and Renal cell cancer
• Role of host ?- polymorphisms associated with
genes in cellular adhesion,motility and cell to
cell interaction

Spectrum of Oligometastasis

Five questions and Nine distinct states of
oligometastasis

5 Questions
1. Does the patient have a history of polymetastatic disease
before current diagnosis of oligometastatic disease?
2. Does the patient have a history of oligometastatic disease
before the current diagnosis of oligometastatic disease?
3. Has oligometastatic disease been first diagnosed more than 6
months after the primary cancer diagnosis?
4. Is the patient under active systemic therapy at the time of
oligometastatic disease diagnosis?
5. Are any oligometastatic lesions progressive on current
imaging?

9 Distinct States

Dynamic oligometastatic model
• Defines the oligometastatic state at one time
point in the patient’s history.
• However, one patient might develop several and
different states of oligometastatic disease
throughout the course of disease
• Results in multiple courses of radical local and
systemic treatment
• OligoCare prospective cohort trial
(NCT03818503) to assess the prognostic value
and their acceptance and compliance in routine
practice.

Controversies in treatment
Favouring curative approach
• Decreases overall tumour
burden
• Decreases morbidity
Increases survival
• Novel treatment options
with acceptable safety
profiles
Against curative approach
• OGM may denote indolent
disease not warranting
potentially toxic treatment
• Locally directed treatment
will not alter the natural
course of the disease
• Treatment paradigms are
controversial due to limited
data available

Local vs Systemic treatment
• Systemic adjuvant therapy in addition to local
treatment with complete ablation has some
effect on micrometastases and would obscure
the significance of the local treatment.
• To reveal the significance of local treatment
on the outcome of cure,the treatment
modality for clinical research on
oligometastases should only be local ablation.

Therapeutic options
• Radiation therapy-SBRT
• Surgery
• RFA
• Cryotherapy
• Intra-arterial embolisation
• Combining with immunotherapy

SBRT
• Beams converge on a target site
• higher-dose, hypofractionated, more efficient
treatment regimens can be delivered within
narrow margins sparring adjacent organs
• Completed in 1–5 sessions, as compared to
conventional radiation therapy that is
delivered in smaller doses 5 days/week over
≥ 6 weeks.

Why SBRT for OGM?
• Shorter exposure-less REPAIR time
• Shorter exposure-rules out REPOPULATION
• High dose per fraction causes LOCAL VASCULAR
DESTRUCTION –indirect death of tumour cells
• No Role of REDISTRIBUTION-cells die in all
phases of cell cycle in SBRT-can overcome
radioresistance
• Abscopal effect /Enhanced immunosurveillance

Abscopal effect
• Regression in tumors distant to the targeted
field of radiation
• Recovery of antitumour immunity
• Release of anti-tumor proliferative antigens and
cytokines
• damaged tissues in irradiated sites may stimulate
the immune system-Matzinger et al
• modify its microenvironment by producing
inflammatory cytokines that may increase its
immune responsiveness –Lee et al

• Irradiated tumor is converted into a ‘vaccine’
that promotes tumor specific T cells to bestow
immune memory against non-treated tumors

NRG –BR001 trial
• Phase 1 trial-SBRT to multiple sites is safe and
feasible

OLIGOMETASTATIC BREAST
CANCER

Radiotherapy in OMBC

Radiotherapy in OMBC
• SABR was associated with an improvement in
overall survival, meeting the primary endpoint
of this trial, but three (4·5%) of 66 patients in
the SABR group had treatment-related death.
• Phase 3 trials are needed to conclusively show
an overall survival benefit, and to determine
the maximum number of metastatic lesions
wherein SABR provides a benefit.

Bone metastasis
• Bone metastases in particular were amenable to
radiotherapy, with no lesions recurring as
opposed to 10 of 68 lesions in other organs
recurring
• Ideal candidate for Spine SBRT
Oligometastatic disease
 No mechanical instability
No epidural disease
Radioresistant disease or progression after
conventional RT

Surgery of the primary-M1 Trial
• In the overall study population (N = 350) of
patients with MBC who were responding to
anthracycline based chemotherapy, they
found no benefit of loco-regional therapy
(LRT) in terms of OS

Pulmonary metastasectomy
• No high quality prospective data
• Pooling the available literature- outcomes of
patients undergoing local resection with or
without concurrent systemic therapy
• Pooled five-year overall survival rate was 46%,
and solitary pulmonary metastasis was found
to be a significant prognostic factor favoring
improved OS.

Liver metastasectomy
• Only 4–5% of patients have isolated liver
involvement.
• Outcome evaluated according to different
subtypes and clinical features
• triple negative (TN) disease, time to
metastasis < 24 months, and ≥ 3 lesions are
significant predictors of poor survival.
• Surgery vs TACE vs RFA

Future
• A phase III study in the Netherlands
(NCT01646034) is assessing the role of high
dose chemotherapy with carboplatin,
thiotepa, and cyclophosphamide in
oligometastatic breast cancer

• Multiple trials are evaluating the use of SABR
and/or traditional surgery in addition to
standard of care systemic therapy in the first
line setting for newly diagnosed OMBC
(CLEAR, NCT03750396; STEREO-SEIN
, NCT02089100; NCT02364557)

• Novel pilot phase I study in Australia is
evaluating the role of SABR followed by 6
months of anti-PD1 therapy with
pembrolizumab, with a goal of showing both
safety and enhanced immune activation
(BOSTON-II, NCT02303366)

PULMONARY METASTASECTOMY

Criteria for surgical resection
THOMFORD et al
 Definitive control of the primary tumour has
occurred or is possible
 Absence of extrathoracic metastatic disease
 Lung metastases amenable to complete
resection
 Patient can tolerate the procedure
 No better treatment alternative

Potential for extrathoracic spread
IRLM(Intl registry of lung metastasis) database
• STS
• Osteosarcoma
• Colorectal cancer
• Breast cancer (Decreasing frequency)
• Renal cancer
• Melanoma
• Head and neck cancer

Treatment modality
• Gold standard- Surgical
PS precluding thoracic surgery or complete
resection not possible
• SBRT
• RFA
• MWA
• CRYO
Devita- Rather than comparing the treatment
modalities,prudent complimentary use of all is
appropriate

Postmetastasectomy outcomes
IRLM Database
• Resectability of the disease
• Single or multiple metastasis
• DFI >36 months
Patients with favourable risk in all 3 criteria could
anticipate 50% survival at 5 years compared to
<15% with unfavourable risk in all 3 criteria

HEPATIC METASTASECTOMY

Prognostic factors
Traditional
(MSKCC Clinical risk score)
• Node positive primary
cancer
• DFI <12 months
• CEA>200ng/ml
• Max hepatic tumor
size>5cm
• Multifocal hepatic tumors
Modern era
• Tumour responsiveness to
chemotherapy
• Resectability(FLR)

Treatment modalities
• Hepatic resection-surgery
• Thermal ablation
• SBRT
• Portal vein embolisation
• Transarterial therapy(HAI,TAE,TACE)
• Selective internal RT (SIRT)
• Whole liver RT(WLRT)-not for oligomets

Trial-CLOCC
• 119 patients with unresectable colorectal liver
metastases (n < 10 and no extrahepatic disease)
received systemic treatment alone or systemic
treatment plus aggressive local treatment by
radiofrequency ablation ± resection.
• IMPROVED OS

LIMITED BRAIN METASTASIS

Treatment options
• Surgery
• Surgery +WBRT
• WBRT +- Surgery
• WBRT +- SRS
• SRS +- WBRT

WBRT vs WBRT+SRS

SURGERY+SRS vs SURGERY+WBRT
Salvage SRS is non inferior to WBRT in limited
brain metastasis(1-4)

ADRENAL METASTASECTOMY

Adrenalectomy vs SBRT
• SBRT has shown promising results in selected
patients with limited toxicity
• Effective alternative for patients not eligible for
surgical resection
• Prospective clinical trials are necessary

OLIGOMETASTATIC GASTRIC
CANCER

• AIO/FLOT3 trial
• RENAISSANCE/AIO-FLOT5 trial
• Positive prognostic factors(AIO)
o younger age ,better performance status
o limited number of metastatic sites (<3 sites), and
limited number (5 lesions)
o favourable parenchymal location (unilobar) and
small size of hepatic lesions

OLIGOMETASTATIC OVARIAN
CANCER

• Between May 2012 and December 2016, 82
consecutive patients (156 lesions) were
treated
• In a good proportion of patients,SBRT can
allow for lasting treatment and a lengthy
toxicity-free interval
• Drug holiday
• Extends the role of RT in Ovarian cancer

OLIGOMETASTATIC PROSTATE
CANCER

Standard of care Vs adding focal
therapies
• Standard of care-
ADT +- Docetaxel/abiraterone
• STAMPEDE TRIAL- RT did not improve survival for
unselected patients,but can be a standard of care for
selected low metastatic burden patients

Take home message
• Multiple definitions-General consensus
• Dynamic Oligometastatic model
• Technological development of focal ablative
therapies
• Large phase III trials are needed for being
accepted as routine clinical practice
• Research-Signatures for identifying oligomets

Oligometastases

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