esmo e-learning optimal management of oligometastatic

OPTIMAL MANAGEMENT OF OLIGOMETASTATIC DISEASE IN SOLID TUMOURS

Konstantinos Tsapakidis

Consultant in Medical Oncology

Department of Medical Oncology

Faculty of Medicine, School of Health Sciences

University Hospital of Larissa, Greece

THE OLIGOMETASTASIS HYPOTHESIS

BACKGROUND

▪ Metastasis accounts for 80% to 90% of cancer related mortality and is one of the dominant challenges in

cancer therapy

▪ The metastatic process involves a complex series of steps whereby tumour cells spread from the primary tumour

▪ Only a tiny proportion of cancer cells have clonogenic potential to successfully colonise secondary organs

▪ In general, patients with adult solid tumours who develop metastases have been considered to have widespread

disease and to be incurable

THE IDEA - BIOLOGICAL SPECTRUM

1. Barney J, Churchill E. Adenocarcinoma of the Kidney with Metastasis to the Lung: Cured by Nephrectomy and Lobectomy, J Urol 1939;42(3):269–76. © 1939 by The American Urological Association Education and

Research, Inc.; 2. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8–10.

Local

disease Metastatic diseaseOligometastatic

disease

Samuel Hellman

Adenocarcinoma of the kidney with

metastasis to the lung

Cured by nephrectomy and lobectomy

Dellinger Barney J, Churchilll EJ, From the surgical

services of the Massachusetts General Hospital

DEFINITION - PROBLEMS

▪ Less than 3 or 5

▪ Primary

▪ Imaging (old vs. new)

▪ It’s a situation between local and extensive disease

▪ The problem is if it is a definable biological entity or the advent of sensitive imaging technologies

DEFINITIONS

Palma DA, et.al. Nat Rev Clin Oncol. 2014;11(9):549-57.

Oligometastatic A malignancy that has progressed to a limited number of haematogenous metastases, defined in most

studies as 1–3 or 1–5 metastatic lesions.

Synchronous oligometastasis A clinical scenario in which oligometastatic disease is detected at the time of diagnosis of the primary

tumour

Metachronous oligometastasis The development of oligometastatic disease after treatment of the primary tumour. The interval for

classification of ‘metachronous’ versus ‘synchronous’ is not standardised

OligorecurrenceOligometastasis in the setting of a controlled primary tumour

Oligoprogression Progression of a limited number of metastatic deposits, while all other metastases are controlled with

systemic therapy

Ablative therapy A term that includes surgical resection, stereotactic radiotherapy, radiofrequency ablation, although these

might differ in efficacy and toxicity profiles

Immortal time bias This bias arises when a study includes a span of follow-up time during which an outcome (death) could

not occur for patients included in the study. Immortal time is also known as a ‘death-free interval’.

DEFINITION

An example: prostate cancer

1. Tabata K, et al. Pulm Med 2012;2012:541656; 2. Ahmed KA, et al. Front Oncol 2013;2:215; 3. Berkovic P, et.al. Clin Genitourin Cancer 2013;11: 27–32; 4. Schick U, et al. Acta Oncol 2013;52:1622–8; 5. Decaestecker K,

et.al. Radiat Oncol 2014;9:135;6. Ost P, et.al. Eur.Urol 2016;69:9–12.

Author/Site n Number of

met.Sites of metastases Detection

Tabata et al. 35 ≤5 Bone only; each site <50% size of vertebral body Bone scan

Ahmed et al. 17 ≤5 NS 11C-choline PET–CT (n=7), MRI (n=6), biopsy (n=1), CT

(n=1), 11C-choline PET–CT and MRI (n=2)

Berkovic et al. 24 ≤3 Bone or LN 1. Bone scan + 18F-FDG PET–CT(n=20)

2. Bone scan + 11C-choline PET–CT(n=4)

Schick et al. 50 ≤4 NS 1. Bone scan + 18F-choline PET–CT

2. Bone scan + 11C-acetate PET–CT

Decaestecker et al. 50 ≤3 Bone or LN1. 18F-FDG PET–CT(n=32)

2. 18F-choline PET–CT (n=18)

Ost et al. 119 ≤3 Any 18F-FDG PET–CT (n=24) or 18F-choline PET–CT (n=92)

DEFINITION OF METASTASIS

Reyes DK, Pienta KJ. Oncotarget. 2015;6(11): 8491-524; Paget S. Lancet 1889;1:571–3.

Stephen Paget (1855–1926)From Wellcome Collection. Available under Creative

Commons Attribution (CC BY 4.0) terms and conditions

https://creativecommons.org/licenses/by/4.0

Circulating tumour cells would “seed” to an amenable “soil”

BioDigital, Inc.

DEFINITION OF METASTASIS

William Stewart

Halsted

Contiguous manner Particular

Site

James Ewing Bernard Fisher

Systemic

Theory

Samuel Hellman

Spectrum

Theory

Reyes DK, Pienta KJ. Oncotarget 2015;6(11):8491–524

METASTASIS

Reyes DK, Pienta KJ. Oncotarget 2015;6(11): 8491–524

Oligometastasis

Systemic disease

Spectrum

Theory

Samuel Hellman

Spectrum

Theory

HALLMARKS OF CANCER: THE NEXT GENERATION

Reprinted from Cell, 144(5), Hanahan D, et.al. Hallmarks of Cancer: The Next Generation, 646–74, Copyright (2011), with permission from Elsevier.

Full metastatic phenotype

OLIGOMETASTATIC VS. SYSTEMIC DISEASE

Reyes DK, Pienta KJ. Oncotarget 2015;6(11):8491–524. Reproduced under the terms of Attribution 3.0 License (CC by 3.0). Available at: https://creativecommons.org/licenses/by/3.0/. Accessed January 2020.

▪ Types of mutations present in the cancer cells (quality of the diaspora migrants)

▪ Quality of the original tumour site (factors in the homeland)

▪ The quality of the new hostland (factors that allow immigrants to establish and flourish)

https://creativecommons.org/licenses/by/3.0/

PRECLINICAL MODELS OF OLIGOMETASTASIS

Tumour heterogeneity

From N Engl J Med, Gerlinger M, et al. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing, 366(10), 883–92, Copyright © 2012 Massachusetts Medical Society. Reprinted with permission

from Massachusetts Medical Society.

Biopsy sites

PRECISION IN TARGETING OLIGOMETASTASES

Imaging, treatments, biomarkers

Imaging

▪ PET-CT

▪ 68Ga-PSMA PET

Treatments

▪ Stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS)

▪ Cryoablation

▪ Minimally invasive surgery

Biomarkers

▪ Circulating tumour cells and DNA

▪ MicroRNAs (miRNAs)

THE BIOLOGY OF OLIGOMETASTASIS

Preliminary investigation of microRNAs (miRNAs) from patients with

oligometastasis (1-5 metastases) who underwent stereotactic body RT

(SBRT)

Lussier YA, et.al. PLoS One 2011;6(12):e28650. © 2011 Lussier, et al. Reproduced under the terms of the Creative Commons Attribution License.

Available at: https://creativecommons.org/licenses/by/4.0/. Accessed January 2020

▪ miRNAs in metastatic samples (biopsy specimens derived from metastatic

tumours) correctly classified oligo vs. polymetastatic phenotype

▪ All seven polymetastatic samples are clustered together

▪ Eight out of ten oligometastatic samples cluster together

▪ This suggests that the oligo vs. polymetastatic phenotype is overriding other

predictable groupings such as histology of primary tumour and metastatic site

HOW COMMON IS CANCER?

SEER Cancer Statistics Review, 1975-2017, National Cancer Institute

Common Types of Cancer Estimated New Cases 2018 Estimated Deaths 2018

1. Breast Cancer (Female) 252,710 40,610

2. Lung and Bronchus Cancer 222,500 155,870

3. Prostate Cancer 161,360 26,730

4. Colon and Rectum Cancer 135,430 50,260

5. Melanoma of the Skin 87,110 9,730

6. Bladder Cancer 79,030 16,870

7. Non-Hodgkin Lymphoma 72,240 20,140

8. Kidney 65,340 14,970

9. Leukaemia 62,130 24,500

10. Endometrial Cancer 61,380 10,920


SEER Cancer Statistics Review, 1975-2017, National Cancer Institute

Common Types of Cancer Estimated New Cases 2018Estimated Deaths

2018metastatic

Percent Surviving

5 Years

1. Breast Cancer (Female) 252,710 40,610 7% (1-3%) 89.7% (27,4%)

2. Lung and Bronchus Cancer 222,500 155,870 > 50 % 18.1% (5,2%)

3. Prostate Cancer 161,360 26,730 6-7% 98.2% (30,5%)

4. Colon and Rectum Cancer 135,430 50,260 25% (liver) 64.9% (14,2%)

5. Melanoma of the Skin 87,110 9,730 30% 91.7% (24,8%)

6. Bladder Cancer 79,030 16,870 14% 77.1% (4,6%)

7. Non-Hodgkin Lymphoma 72,240 20,140

8. Kidney 65,340 14,970 22% 74,8% (12%)

9. Leukaemia 62,130 24,500

10. Endometrial Cancer 61,380 10,920


Breast Cancer


Author, yearProspective (P) or Retrospective (R)

Sample size

Definition- Oligometastases Therapy Endpoint Conclusion

Kobayashi, 2012 R 751–2 organs with met lesions, ≤5

lesions/ organ, ≤5 cm lesion diameter

+/− CT, then+/− local therapy + CT

10-yr OS- 59.2%; 20-yr OS 34.1%

Prognosis of OMBC superior to that of MBC

Bojko, 2004 P 48 1 organ with 1-few met lesionsSurgery or RT + CT, then

peripheral- blood-stem-cell transplant

MOS- 42.2 mthsCombined modality therapy safe in

OMBC; promising relapse-free survival

Milano, 2009 P 40 ≤5 met lesions Curative-intent SBRT 4-yr OS- 59%; MOS- NRSBRT may yield prolonged survival

+ perhaps cure in select OMBC

Mimoto, 2014 R 141–2 organs with met lesions,

≤5 lesions/organ, ≤5 cm lesion diameter

Surgery

10-yr OS- 59.2%, 20-yr OS-34.1%; CD44+/ CD24–/

low tumour cells in 9% OMBCvs. 73% non-OMBC

In OMBC, low levels of cancer-initiating cells may be associated with better

prognosis

Vander Walde, 2012

R 12 ≤3 sitesCT, then peripheral stem

cell rescue3-yr OS- 73% Therapy was safe

Nieto, 2002 R 60

Low tumour burden, with met lesion could be either excised en bloc

before HDC, or encompassed with a single RT field w curative intent.

CTMOS- 80 mths; #5-yr OS 62%

Possibly re-evaluate current tenet that early detection MBC is of no benefit

Bourgier, 2010 R 159 1 met site RT vs. RT + surgery3-yr OS- RT- 39%

vs. RT+ surg- 57%; equivalent when adjusted for prognostic factors

In sub-analysis, OMBC had better metastatic PFS as compared to patients

with >1 met site


Lung Cancer


1st Author, Year P or R Size Definition Therapy Endpoint

DeRuysscher, 2012 P 39 <5 synchronous mets Local trt to mets MOS-13.5 mths; 3-yr OS- 17.5%

Collen, 2014 P 26 ≤5 met lesions SBRT to primary and all mets MOS- 23 mths; 1-yr OS- 67%

Khan, 2006 R 23 1–2 sites CT + local- regional therapy MOS- 20 mths

Nieder, 2014 R 23 Maximum of 3 metastases to 1 organActive therapy, irrespective of

specific treatment receivedMOS- 11.7 mths

Guerra 2012 R 78 <5 mets at diagnosis Definitive CRT to primary + mets 3-yr OS- 25%

Collaud, 2012 R 29 Synchronous single organ metLung resection and local trt to

metsMOS- 20.5 mths

Congedo, 2012 R 53Resected primary with 1–2 met lesions

considered to be resectableTrt with curative intent 5-yr OS- 24%; MOS- 19 mths

Hasselle 2012 R 25 ≤5 metsHypofractionated image-guided

RT (HIGRT)MOS- 22.7 mths; 18-mth OS- 52.9%

CONSOLIDATIVE STEREOTACTIC BODY RADIATION

THERAPY

Is there a role for consolidative stereotactic body radiation therapy following first-line

systemic therapy for metastatic lung cancer? A patterns-of-failure analysis

Rusthoven KE, et al. Acta Oncol 2009;48(4):578–83

Retrospective

OLIGOMETASTATIC LUNG CANCER

Example

De Ruysscher D, et.al. J Thorac Oncol. 2012;7(10):1547–55.

Eligibility Criteria

▪ ≤5 synchronous

lesions amenable for

radical treatment

N=40

Chemo «S» or RT

Characteristics No. of pt

Metastatic lesion

Adrenal gland 4 (10.3%)

Bone 7 (17.9%)

Gastro-hepatic ligament 1 (2.6%)

Liver 1 (2.6%)

Lung 1 (2.6%)

Lymph node 2 (5.1%)

Muscle 2 (5.1%)

Ovary 1 (2.6%)

Pleura 3 (7.7%)

Number metastases

1 34 (87.2%)

2 4 (10.3%)

3 1 (2.6%)

OLIGOMETASTATIC LUNG CANCER

Example

Reprinted from J Thorac Oncol, 7(10), De Ruysscher D, et.al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450), 1547–

55, Copyright 2012, with permission from Elsevier..

▪ Median OS: 13.5 months

▪ 1-year OS: 56.4%

▪ 2-year OS: 23.3%


Prostate Cancer


1st Author, Year P / RSample

sizeDefinition- Oligometastases Therapy Endpoints

Berkovic, 2013 R 24

Biochemical recurrence after curative

treatment to primary (RP, RT, or both), then

≤3 synchronous asymptomatic mets

SBRT

Androgen deprivation therapy-free survival

(ADT-FS) 1-, 2-yr: 82%, 54%;

clinical progression-free survival 1-, 2-yr:

72%, 42%

Ost, 2014 R 450Metachronous mets with controlled primary,

+ underwent MDT for recurrent PCaRT or LND About 50% PFS at 1–3 yrs post-MDT

Ahmed, 2013 R 17 ≤5 met lesions SBRT

Local control: 100% at 6 mo; cancer specific

survival (CSS): 6- and 12-mo 100%;

freedom from distant progression (FFDP):

6- and 12-mo 74%, 40%

Ost, 2014 R 80 Metachronous metsMets- ADT,

AS, or MDTMedian PCSS: 6.6 yrs

Decaestecker, 2014 R 50 ≤3 metachronous asymptomatic mets

SBRT (2 RT

schedules used)

+/− HT

Median PFS: 19 mos;

median ADT-FS: 25 mos;

2-, 5-yr PCSS: 96%, 90%

Author, YearP /

RSize Definition- Oligometastases Therapy Endpoint

Engels, 2012 P 24 ≤5 metsResected primary tumour, and inoperable

mets treated with helical tomotherapy1-yr OS: 78%

Dellas, 2012 P 91–3 mets or local recurrence plus max.

2 metsCT + 3D-CRT to all met lesions

3/9 pts survived 3.5–4.4 yrs;

DLT not documented

Van den

Begin, 2014R 47 Resected primary + ≤5 mets, liver, lung, LNs SBRT 1-yr OS: 53%

Filippi, 2014 R 40Resected primary + 1–5 lung mets, max

diameter <5 cm

3D conformational RT or image guided

volumetric modulated arc therapy5-yr OS: 39%

Kang, 2010 R 591–4 met lesions confined to 1 organ, largest

<7 cm, progressive after CT

Met lesions progressed after chemo,

then treated SBRT5-yr OS- 29%

Salah, 2012 R 927 Underwent lung metastasectomy Lung metastasectomy 5-yr OS: 54.3%.

Bae, 2012 R 41 Met lesions confined to 1 organ 3 fractions SBRT 5-yr OS: 38%

Salah, 2013 R 148 Repeat resection of pulmonary mets Repeat resection of lung met5-yr OS: 52% for 1 lung met

resection

Comito, 2014 P 821–3 inoperable mets in 1 organ (live

r or lung)SBRT 3-yr OS: 43%


Colon Cancer


COLORECTAL CANCER PULMONARY

OLIGOMETASTASES:

Pooled analysis and construction of a clinical lung metastasectomy

prognostic model

Salah S, et al. Ann Oncol 2012;23(10):2649–55

Clinical variable No. of patients (%)

Pre-thoracotomy CEA (ng/ml)

≥5 240 (26)

<5 474 (51)

Missing data 213 (23)

Status of lymph nodes in thorax

Involved 75 (8)

Not involved 424 (46)

Sampling or dissection not carried out 297 (32)


Type of surgical resection

Sublobectomy 555 (60)

Lobectomy 186 (20)

Pneumonectomy 12 (1)


Retrospective

Eligibility Criteria

▪ ≤5 lesions

▪ Confined to one or

both lungs

N=148

Surgical resection

OLIGOMETASTATIC COLORECTAL CANCER

Example

Reprinted from Ann Oncol, 23(10), Salah S, et.al. Colorectal cancer pulmonary oligometastases: pooled analysis and construction of a clinical lung metastasectomy prognostic model, 2649–55, Copyright 2012, with

permission from Elsevier on behalf of the European Society for Medical Oncology

Variable No. of patients (%) P value

Pre-thoracotomy CEA (ng/ml)

≥5 240 (26)<0.001

<5 474 (51)

DFI (months)

<36 603 (65)0.031

≥36 310 (33)

Number of metastatic nodules

≥2 364 (39)<0.001

1 558 (60)

▪ Risk categories according to number of poor

prognostic factors:

good risk = 0 or 1 factor

intermediate risk = 2 factors

poor risk = 3 factors

p<0.001 (overall)

p<0.001

p<0.001

▪ OS 5-year: 54.3%

▪ OS 5-year 1 vs. ≥2: 60.5% – 44.6% (p<0.0001)

Pro

po

rtio

n s

urv

ivin

g

Time after resection of the first pulmonary metastases (months)


1st Author,

YearP/R

Sample

size

Definition-

OligometastasesTherapy Endpoint Conclusion

Essner, 2004 R 877 1 met Curative surgery

5-yr OS: 29 mths if mets 1 site,

16 mths if mets 2–3 sites, 14 mths if

met ≥4 sites.

5-yr OS: 17% disease-free if distant

mets in <36 mths, 30% if >36 mths

Pts with limited mets should be

considered for curative resection

Knisely, 2012 R 77 Brain mets treated

with SRS

SRS to brain

mets, then 35%

of group received

ipilimumab

MOS: 21.3 mths in ipilimumab group

vs. 4.9 mths in no-ipilimumab group.

2-yr OS: 47% in ipilimumab group and

19.7% in no-ipilimumab group

Survival of patients with melanoma and

brain mets managed with ipilimumab +

SRS can exceed expected 4–6 mths


Melanoma


Kidney Cancer

1. Barney J, Churchill E. J Urol 1939;42:269–276; 2. Loh J, et.al. Future Oncol 2014;10(5):761–74.

1st Author, Year P/ RSample

sizeDefinition- Oligometastases Therapies Endpoints

Mickisch, 2001 P 85N/A- patients identified as having

metastatic RCC

Surgery + interferon OR

interferon only

TTP (5 vs 3 mths) + MOS (17 vs. 7 mths) in

Surgery + interferon vs interferon only

Flanigan, 2001 P 241N/A- patients identified as having

metastatic RCC

Surgery followed by interferon

OR interferon alone

Surgery followed by interferon MOS:

11.1 mths vs. interferon alone MOS: 8.1 mths

Bang, 2012 R 27Localised soft tissue mass <7 cm

+ ≤5 lesions in 1 organCryoablation 5-yr OS: 27%

Ranck, 2013 R 18 Limited metastatic diseaseSBRT: 3 fractions or

10 fractions2-yr OS: 85%

Thibault, 2014 R 13 <5 spinal mets SBRT1-yr OS: 83.9% in OM RCC (n=13)

vs. 52.5% in non-OM RCC (n=24)

▪ The first anecdotal evidence was a case with kidney cancer and metastasis to the lung (1939)1

▪ 5-year survival as high as 45% in those who achieve complete resection

STEREOTACTIC BODY RADIOTHERAPY

For the treatment of oligometastatic renal cell carcinoma

Ranck MC, et al. Am J Clin Oncol. 2013;36(6):589-95.

Number

First site of metastasis (single site)

Clear cell 14

Papillary 2

Chromophobe / Unknown renal origin 1 / 1

Location

Bone 11

Abdominal lymph node 10

Mediastinum/hilum 10

Mediastinum/hilum 7

Lung 4

Kidney 2

Adrenal 2

Liver / Soft tissue 2 / 1

Retrospective

Eligibility Criteria▪ ≤5 lesions

N=18

SBRT

OLIGOMETASTATIC KIDNEY CANCER

Example

Median follow-up: 16.2 months

At 2 years, for all patients (N=18):

• estimate lesion control: 91.4%

• overall survival: 85.0%

→ In oligometastatic renal cell carcinoma, SBRT produces promising estimate lesion control with

minimal toxicity

Ranck MC, et al. Am J Clin Oncol. 2013;36(6):589-95.


Bladder Cancer

Conti A, et al. Eur Urol 2017;16(12):309–15

▪ Bladder cancer (BC) represents one of the tumours for which the characteristics of oligometastases

remain unclear

▪ This may be partly explained by the different and more aggressive biological behaviour

1st Author, Year P or RSample

size

Definition-

OligometastasesTherapy Endpoint Conclusion

Siefker-Radtke

2004R 31 1 met Curative surgery

5-yr OS: 33%

Median time to progression:

7 mths

Pts who responded to prior chemotherapy

and one met should be considered for

curative resection

Lehmann, 2008 R 44 1 met

Curative surgery

±Chemotherapy

5-yr OS: 27%

OS: 35 mo

PFS: 19 mo

Long-term cancer control and possible cure

can be achieved in a subgroup of patients

following surgical removal of UCM

CONSIDERATIONS

1. Weichselbaum RR. J Clin Oncol 2018:JCO1800847 [Epub ahead of print]; 2. Palma DA. Nat Rev Clin Oncol 2014;11(9):549–57

▪ The four most common cancers: 90,000 patients have oligometastases

▪ Specific mechanisms of oligometastasis are relatively underinvestigated

▪ The use of different definitions of oligometastases

▪ Insufficient tumour models - control arm

▪ Limited human clinical trials and relevant databases

▪ The most robust testing of ablative metastasis-directed therapy has occurred in patients with limited intracranial

metastases

▪ Can we cure any patients once their cancer has spread?

▪ Radiotherapy and radiofrequency, are the main local treatments alternative to surgery

OPTIMAL MANAGEMENT OF OLIGOMETASTATIC DISEASE IN SOLID TUMOURSRole of Radiotherapy

Maria Tolia

Assistant Professor of Radiotherapy

Radiotherapy/Radiation Oncology Dept

Faculty of Medicine, School of Health Sciences,

University of Thessaly - University Hospital of Larissa, Greece

THE OLIGOMETASTASISRADIOTHERAPY HYPOTHESIS

RADIOTHERAPY

Patients with metastasis limited in number and organ site might be cured by ablative therapies

such as radiotherapy

The aim is to replace, delay, or complement the introduction of systemic treatments, relieve

symptoms and/or extend overall and disease-free survival

Weichselbaum R, et al. J Clin Oncol 2018;36:3240–50;

Palacios EA. World J Clin Oncol 2019;10(2):38–51;

Palacios EA, et al. World J Clin Oncol 2015;6(4):30–4.

Palacios EA, et al. World J Clin Oncol 2015;6(4):30–4.

Radiotherapy and radiofrequency

are the main local treatments

alternative to surgery

MOLECULAR AND CLINICAL STAGING OF METASTASIS

Pitroda SP, et al. Nat Commun 2018;9(1):1793

It represents an important issue in order to define metastatic stage and decide about

radiotherapy delivery

The molecular composition of the tumour and host’s response to metastasis are most likely

to be critical determinants of the tumour spread

Clinical risk score

Primary tumour type

Positive lymph nodes at the time of initial resection

Metastasis size

Number of metastatic lesions

Overall tumour burden

Tumour markers levels

Time of appearance of first metastasis

Pace of tumour progression at presentation and after treatment

= Prognostic Factors

Pitroda SP, et al. Nat Commun 2018;9(1):1793.

CLINICAL RISK SCORE

Clinical risk score

Age

Number of treated organs

Prior chemotherapy for primary disease

Treated liver metastases

Performance status

= Prognostic Factors

Hong JC, et al. PLoS One 2018;13(4):e0195149.

CLINICAL RISK SCORE

Most favourable risk groups of oligometastatic patients

Breast, renal cell and prostate primary cancer

<3 metastases

Age <62 years

Hong JC. et al. PLoS One 2018;13(4):e0195149.

MOST FAVOURABLE RISK GROUPS

RADIOTHERAPY IS A CYTOTOXIC TREATMENT OF

LOCALISED DISEASE

Hall EJ, Giaccia AJ. Radiobiology for the Radiologist (ed 7). Philadelphia, PA, Wolters Kluwer Health/Lippincott Williams & Wilkins, 2012; Weichselbaum RR, et al. Nat Rev Clin Oncol 2017;14:365–79; Image from:

Carvalho HA, et al. Clinics (Sao Paulo) 2018;73(suppl 1):e557s. Reproduced under the terms of the Creative Commons License (https://creativecommons.org/licenses/by/4.0/. Accessed January 2020).

Local irradiation produces both positive (immune

stimulatory) and negative (immune suppressive)

inflammatory/immune-mediated effects


RADIOTHERAPY

Radiotherapy can be an alternative local ablative weapon in cases of:

• Surgical limitations

• Associated comorbidities

• In case of patients’ refusal of other treatments (such as chemotherapy, surgery)

Yan Li, et al. JBUON 2017;22(4):831–7.

MODERN RADIOTHERAPY TECHNIQUES

Modern radiotherapy techniques such as Stereotactic Radiosurgery (SRS) and Stereotactic

Body Radiotherapy (SBRT), are noninvasive methods and can have a significant role in the

management of oligometastatic and oligoprogressive disease

Dupic G, et al. Cancer Radiother 2017; 21(5): 404-10

Buergy D, et al. Anticancer Res 2018; 38(8):4789-96

STEREOTACTIC BODY RADIOTHERAPY (SBRT)

Stereotactic Body Radiotherapy (SBRT) is the evolution of Stereotactic Radiosurgery (SRS)

because of the need to treat extracranial tumours

Palacios EA, et al. World J Clin Oncol 2015;6(4):30–4

Palacios EA, et al. World J Clin Oncol 2019;10(2):38–51

NEWER RADIATION TECHNIQUES

The newer radiation techniques can deliver high-dose focused radiation with limited

surrounding normal tissue damage

For example SBRT uses doses of 10-24 Gy, delivered in 1-5 fractions

Hall EJ, Giaccia AJ, Radiology for the Radiologist (ed 7), Philadelphia, PA, Wolters Kluwer Health/Lippincott Williams & Wilkins, 2012.

PALLIATIVE PATIENTS

In palliative patients, short-course radiotherapy such as Hypofractionated Image-guided

Radiation Therapy, complemented with supportive care, can be considered

Hypofractionated: Delivery of more dose per fraction, in less fractions

Buergy D, et al. Anticancer Res 2018;38(8):4789–96; Milano MT, et al. Radiother Oncol 2019;131:45–51


SBRT is the treatment of choice when complete local ablation of a metastatic lesion is indicated

Alternative to conventional palliative radiation in primary treatment, re-irradiation and in the post-

operative setting

No randomised trials to support its practice

Tseng CL, et al. Global Spine J 2017;7(2):179–97

• Not yet clear

• Direct effect of radiation on clonogenic cancer cells

• Abscopal effect = Out of field systemic phenomenon

a regression of non-irradiated lesions distant from the

irradiated tumour site.

• Post-radiation anti-tumour inflammatory reactions and

immune processes

THE MECHANISM OF STEREOTACTIC RADIOTHERAPY

EFFECT

This case was generously provided by Dr. Yoshiyuki Suzuki (Department of

Radiation Oncology, Gunma University Graduate School of medicine, Japan)

Before local

radiotherapy

After local

radiotherapy

Jereczek-Fossa BA, et al. Rep Pract Oncol Radiother 2015;20(6):472–83.

IMAGING FOR OLIGOMETASTATIC DISEASECan have a major impact on radiotherapy decision

De Souza NM, et al. Int J Cancer. 2019;144(3):422–30.

The use of whole-body approaches such as

18F-FDG-positron emission tomography (PET)/CT

Whole‐body MRI

18F-Choline-PET/CT

68Ga-prostate specific membrane antigen-PET/CT, and

PSMA prostate-specific membrane antigen-PET/CT

are useful in detection of metastatic foci and more accurate in target

volume radiotherapy delineation.

WHOLE-BODY APPROACH

FIDUCIAL MARKERS OR RADIOFREQUENCY

TRANSPONDERS

The insertion of fiducial markers or radiofrequency transponders into

the tumour can allow for real-time tracking tumour motion during

radiotherapy delivery

Wild AT, et al. Visc Med 2017;33:54–61;

Tanaka O, et al. Int Clin Med 2 2018;doi: 10.15761/ICM.1000116. Reproduced under the terms of the under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/. Accessed

January 2020)

https://blausen.com/en/video/calypso-system/


COMBINATION OF STEREOTACTIC RADIOTHERAPY WITH SYSTEMIC THERAPIES

RADIOTHERAPY COMBINATION

Immunotherapy in combination with radiotherapy may be increased in a number of

metastatic oncologic patients amenable to cure.

There is a potential synergic effect between immunotherapy and ablative radiotherapy within

the tumour microenvironment.

Improvements in the molecular staging of metastasis, immunotherapy strategies, and

radiotherapy delivery techniques can improve the disease outcome.

Wechselbaum R, et al. J Clin Oncol 2018;36:3240–50

1. Bones

2. Pulmonary

3. Liver

4. Brain

5. Lymphonodal

6. Adrenal

7. Mixed

INDICATIONS OF RADIOTHERAPY

in the treatment of the following oligometastatic sites:

Metastases

Palacios EA, et al. World J Clin Oncol 2015;6(4):30–4; Yan Li, et al. JBUON 2017;22(4):831–7.


No randomised trials to support its practice

SBRT regimens can achieve 1-yr local control rates of 77–100%, 90–100%, and 81–95% for

oligometastases of the lung, liver, and spine, respectively

Toxicity of grade ≥3 with SBRT techniques is consistently low: <10% in the lung, <5% in the liver,

and <2%/8% for neurologic/non-neurologic toxicity in the spine, respectively

Tseng C-L, et al. Global Spine J 2017;7(2):179–97; Wild AT, Yamada Y. Visc Med 2017;33:54–61.

MANAGEMENT OF BONE –SPINAL METASTASES

STEREOTACTIC BODY RADIOTHERAPY

In postoperative setting of spinal oligometastases

May be used in case of post operative epidural progression

An epidural-sparing, horse shoe-type clinical target volume where epidural disease is confined

to the anterior vertebral part

A donut-shaped distribution may be used where the entire epidural space is

covered circumferentially

Chan MW, et al. J Neurosurg Spine 2016;24:652–9.

Tseng C-L, et al. Global Spine J 2017;7(2):179–97

TREATMENT DECISION-MAKING

Treatment decision-making is a complex process. There are some factors that should be considered:

• Patient factors: severity of pain, age, neurological function, comorbidities, estimated life expectancy,

performance status

• Oncologic factors: tumour histology (radiosensitive neoplasm e.g. myeloma, lymphoma), molecular

characteristics, overall disease burden, rapidly progressive disease

• Treatment-specific factors: degree of spinal instability, presence and grade of epidural disease, spinal location,

radiographic appearance, prior surgical or radiation treatment

Tseng C-L, et al. Global Spine J 2017;7(2):179–97

LIVER METASTASIS –RADIOTHERAPY

For patients suffering from painful liver metastasis, relief can be offered from irradiation.

Stereotactic body radiotherapy can achieve higher rates of local control while minimising the

irradiation of surrounding healthy liver parenchyma.

Higher stereotactic body radiotherapy doses and smaller tumour volumes are associated with

improvement of Local Control and Overall Survival.

Mahadevan A, et al. Radiat Oncol 2018;13(1):26.

PAINFUL LIVER METASTASIS

LUNG METASTASES –RADIOTHERAPY

Widder J, et al. Radiother Oncol 2013;107(3):409–13; Wild AT. Yamada Y. Visc Med 2017;33(1):54–6.

Survival outcomes following SBRT for pulmonary oligometastases from colorectal cancer are

encouraging

Retrospective data show that survival is no worse after SBRT compared to lung metastasectomy

SURVIVAL OUTCOMES

OVERALL SURVIVAL RATES – LOCAL CONTROL RATES

Overall survival rates at 1, 3, and 5 years were similar for metastasectomy and SBRT at 87, 62,

and 41% vs. 98, 60, and 49%, respectively

At 2 years, local control rates were similar at 90% for metastasectomy and 94% for SBRT

Prospective head-to-head studies are needed

Widder J, et al. Radiother Oncol 2013;107(3):409–13; Wild AT. Yamada Y. Visc Med 2017;33(1):54–6.

IN CONCLUSION Radiotherapy in oligometastatic patients…

➢ May offer a survival and local control benefit

➢ May be an alternative local treatment in case of:

➢ surgical limitations, associated comorbidities, or in

patients’ refusal of other treatment

NEWER RADIOTHERAPY TECHNIQUES

Newer radiotherapy techniques such as:

Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiotherapy combined with

advancements in imaging and systemic therapy can allow the use of radiation as an effective

local ablative treatment

Hall EJ, Giaccia AJ, Radiology for the Radiologist (ed 7), Philadelphia, PA, Wolters Kluwer Health/Lippincott Williams & Wilkins, 2012.

Terminology of Oligometastasis

(From the Greek)

“Metastasis”: removal from one place to another

“Oligos”: Few

TAKE HOME MESSAGES

▪ Can we cure any patients once their cancer has spread? It’s a question that oncologists

have been asking for some time, and are still asking

▪ Metastases are the leading cause of cancer death, with systemic chemotherapy being the

standard but rarely curative therapy, with the exception of patients with very sensitive

histology's (germ-cell tumours)

▪ During the evolution of some tumours, an intermediate metastatic state exists between

absent and widespread metastases, called oligometastasis(es), introduced by S Hellman

and RR Weichselbaum in 1995

TAKE HOME MESSAGES

▪ It is likely the tip of the iceberg, because most patients who are characterised as having

‘oligometastatic’ disease actually harbour undetectable micrometastases at the time of

treatment that will likely cause future disease progression

▪ Some patients achieve long-term survival after ablative treatment

▪ treatment of their metastasis extends their survival, or whether their long survival is merely due to the

presence of slow-growing, indolent disease

▪ Better predictive and prognostic biomarkers are urgently required to determine which

patients harbour micrometastases that will progress and render the treatment futile,

including circulating tumour cells and microRNA expression profiles

TAKE HOME MESSAGES

▪ Randomised trials should be conducted now, before increasing clinical experience and

expert opinion alter the balance of equipoise and render accrual impossible

▪ One potential solution to the problem of disease burden and heterogeneity within

metastasis is ablative types of treatments combined with systemic treatments

▪ Stereotactic body radiotherapy (SBRT) can treat mets in multiple organs in a patient,

including some mets not eligible for surgery

THANK YOU!

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