Radioterapia nella malattia
oligometastatica
Fiorenza De Rose, M.D.,
Radiotherapy and Radiosurgery Dep.
Humanitas Clinical and Research Hospital
OUTLINE
• Definition of oligometastatic state
• Local ablative approach : SBRT
• Selection of patients
• SBRT in OMBC: clinical results
• Future directions
Definition of oligometastatic state
Hellman S, Weichselbaum RR. JCO 1995 An oligometastatic state is an “intermediate state
between purely localized lesions and those widely metastatic”. The state was expounded to be “amenable to a curative therapeutic strategy” and “amenable to localized therapy”.
Definition of oligometastatic state
Widely Metastatic Disease Limited Metastatic Disease
• Distinct clinical state
• Metastases limited in number and site (3 to 5 in 1-3 sites)
• More indolent biology
• Amenable to local ablative approaches
Definition of oligometastatic state
Oligometastatic state includes different clinical situations
Oligometastases de novo
Definition of oligometastatic state
Induced oligometastases
CT / OT
Oligometastatic state includes different clinical situations
Definition of oligometastatic state
Oligometastatic state includes different clinical situations
Oligoprogression
Follow up
Oligometastatic Breast Cancer
Prevalence of OMBC
Salama JK, Chmura SJ. The role of Surgery and ablative radiotherapy in oligometastatic breast cancer.
Seminars in Oncology 2014; 41 (6): 790-797
«49 – 57 % of metastatic breast cancer patients enrolled on major phase II and phase III clinical trials of systemic therapy have 2 or fewer clinically detected metastases»
OUTLINE
• Definition of oligometastatic state
• Local ablative approach : SBRT
• Selection of patients
• SBRT in OMBC: clinical results
• Future directions
• Surgery
• SBRT
• MWA
• RFA
• HIFU
Local ablative therapies
Of the 5 most common cancer types, colorectal cancer has been the subject of the largest number of
studies of metastasectomy with demonstrated 5-year survival rates of >50%, and 10-year survival ranging from 17% to 36%.
The role of metastasectomy in other cancer types remains more controversial. Multiple
metastasectomy series have now been published for breast cancer, lung cancer, and melanoma, all of which with relatively favorable survival in carefully selected patients, but the series are smaller and less frequently report long-term follow-up.
Bartlett EK Cancer 2015
Surgery
Metastasectomy increases local control with significant improvement
of survival in selected patients
Most patients are inoperable for comorbidities or sites of metastases
Surgery vs SBRT
Stereotactic body radiation therapy (SBRT) is an external beam radiation therapy method used to very precisely deliver a high dose of radiation to an extracranial target within the body, using either a single dose or a small number of fractions.
The ability to deliver a single or a few fractions of high-dose ionizing radiation with high targeting accuracy and rapid dose falloff gradients encompassing tumors within a patient provides the basis for the development of SBRT.
2010
SBRT
2015
SBRT
Most common sites:
lung (90%)
spine (68%)
liver (63%)
bones (58%)
adrenals (39%)
OUTLINE
• Definition of oligometastatic state
• Local ablative approach : SBRT
• Selection of patients
• SBRT in OMBC: clinical results
• Future directions
Selection of patients
deSouza NM et al
2017
18
F-FDG PET/CT is favoured in breast cancer (with WB-MRI as an alternative) but needs supplementing with liver-specific MRI
Brain imaging (MRI) is only warranted in the presence of extra-cranial disease
or in patients with neurological symptoms
Selection of patients
… we have identified microRNA expression features of a potential classifier that predict the distinct outcomes of metastatic patients who maintained stable oligometastatic disease from those who progressed to polymetastases.
We also provide biological confirmation for molecular differences, in this case the microRNA regulation, that underlie oligometastic to polymetastatic progression.
MicroRNA Expression Characterizes Oligometastasis(es)
Yves A. Lussier1,2,3,4*, H. Rosie Xing1,2,5,6. , Joseph K. Salam a8. , Nikol ai N. Khodarev1,5. , Yong Huang1,3. , Qingb ei Zhang3,6. , Sajid A. Khan7. , Xinan Yang3. , Michael D. Hassell e5. , Thomas E. Darg a5, Renuk a Malik5, Hanli Fan6, Saman t ha Perakis5, Mat t hew Filippo5, Kimb erly Corbin5, Younghee Lee3, Mit ch ell C.
Posner7, St even J. Chmura5, Samuel Hellman2,5, Ralph R. Weichselbaum1,2,5*
1 Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, United States of America, 2 Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois, United States of America, 3 Department of Medicine Center for Biomedical Informatics, University of Chicago, Chicago, Illinois, United States of America, 4 Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America, 5 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois, United States of America, 6 Department of Pathology Committee on Cancer Biology, University of Chicago, Chicago, Illinois, United States of America, 7 Department of Surgery, University of Chicago, Chicago, Illinois, United States of America, 8 Department of Radiation Oncology Duke University Medical Center, Durham, North Carolina, United States of America
Abst ract
Background: Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by # 5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments. However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy.
Methods: Here, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy.
Results: Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived microRNAs discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an oligometastatic cell line resulted in polymetastatic progression.
Conclusions: These results demonstrate a biological basis for oligometastases and a potential for using microRNA expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment.
Cit at ion: Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y, et al. (2011) MicroRNA Expression Characterizes Oligometastasis(es). PLoS ONE 6(12): e28650.
doi:10.1371/journal.pone.0028650
Edit or: Mikhail V. Blagosklonny, Roswell Park Cancer Institute, United States of America Received October 10, 2011; Accept ed November 11, 2011; Published December 13, 2011
Copyright : ß 2011 Lussier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Ludwig Center for Metastasis Research Grant, the Center for Radiation Therapy, the Chicago Tumor Institute, Dr. Lloyd Old, Mr. and Mrs. Vincent Foglia and the Foglia foundation, Lung Cancer Research Foundation, the Cancer Research Foundation and the following NIH Grants: K22 LM008308-04, 5UL1RR024999-04, University of Chicago Comprehensive Cancer Center (5P30CA014599-35), National Center for the Multi Scale Analysis of Genomic and Cellular Networks (MAGNeT; 5U54CA121852-5). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Com pet ing Int erest s: The authors have declared that no competing interests exist.
* E-mail: rrw@radonc.uchicago.edu (RRW); ylussier@uic.edu (YAL) . These authors contributed equally to this work.
Int roduct ion
Metastases are the leading cause of cancer death. Standard therapies for most metastatic cancers are systemic chemotherapy, hormonal manipulation or newer targeted therapies. However, these agents are rarely curative. We proposed that during the evolution of some tumors, an intermediate metastatic state exists called oligometastasis(es). We hypothesized that these patients, exhibiting a less aggressive biology with limited [1,2,3] cumulative metastasis(es) in less than 4 months from time of first metastatic progression, could potentially benefit from metastasis-directed therapy [1,3]. This hypothesis was based on long-term survival following surgical resection of limited lung [2], liver [4,5], or adrenal metastases[6] from a variety of primary sites. An oligometastatic state is a common clinical presentation although
it has only recently received attention as a defined subset of metastasis [1,7,8]. Employing radiotherapy improvements, termed hypofractionated image-guided radiotherapy (HIGRT) or stereo- tactic body radiotherapy (SBRT), we [9] and others [8] treated metastatic lesions using a few high-doses of radiotherapy in inoperable patients with # 5 metastasis(es). Initial reports demon- strated long-term disease free survival in some treated patients [8,9,10,11]. However, many oligometastatic patients developed widespread cancer progression and were subsequently classified as polymetastatic (. 5 new metastatic sites, see m ethods). We hypothesized that molecular markers could be developed for identifying patients who would fail to become polymetastatic. We analyzed microRNA expression derived from paraffin blocks of patients who were oligometastatic at time of treatment with curative intent radiotherapy. We report unique prioritized features
PLoS ONE | www.plosone.org 1 December 2011 | Volume 6 | Issue 12 | e28650
2011
A candidate classifier using expression levels of 3 microRNAs (miR-23b, miR-449a, and miR-449b) predicted survival among 17 patients who had primary tumor microRNA expression data available
Selection of patients
Wong AC, et al.
2016
Selection of patients
2013
Selection of patients
2018
Selection of patients
2009
2016
1 metastatic lesion (versus 2– 5) Smaller tumor volume
Bone-only disease
Stable or regressing lesions prior to SBRT
DFI >12 months
Hormonal receptor positivity Medical therapies after SBRT
2015 Positive hormone receptor status
Pathologic nodal stage of primary cancer Solitary bone metastasis
Whole-lesion RT
OUTLINE
• Definition of oligometastatic state
• Local ablative approach : SBRT
• Selection of patients
• SBRT in OMBC: clinical results
• Future directions
Clinical results: SBRT in OMBC
MBC patients 25.9% 5-year OS
(SEER database Cancer Statistic Review, 2015)
59% 4-year OS
Clinical results: SBRT in OMBC
«This review provides preliminary evidence that ablative radiotherapy
may play an important role in management of oligometastatic breast
cancer and its use is rapidly gaining consensus due to its non-invasive
nature, excellent safety profile, established efficacy in achieving durable
local control in a cost-effective manner»
Clinical results: SBRT in OMBC
BMBC incidence between 3% and 6% in early-stage, and up to 30% in stage IV disease
Triple negative MBC patients have 25-46% estimated probability of brain recurrence (vs 10% in Hormone receptor positive HER2 negative MBC)
High heterogeneity in dose/fractionation and modalities (WBRT/SRS/Surgical resection) 2-year LC ranged from 73% to 83% and 2-year OS from 41% to 21%
Radionecrosis ranged from 4% to 10,6% (excluding Geraud et al study)
Clinical results: SBRT in OMBC
OS 2-years 66% - 95%
PFS 2-years 18% - 53%
LC 1-3 years. 87% - 98%
TOX </= 2
OUTLINE
• Definition of oligometastatic state
• Local ablative approach : SBRT
• Selection of patients
• SBRT in OMBC: clinical results
• Future directions
Future directions
2016
Future directions
2017
… local SBRT is able to induce systemic effects influencing the antitumor immune response in oligometastatic BC patients. Liquid biopsy may thus represent a useful resource to monitor the potential immunogenic effect of SBRT that in turn could contribute to the curative potential of this treatment not only locally but also systemically.
Ongoing trials
SABRT-COMET Trial: Standard of care (Palliative RT and CT) +/- SBRT
- Any primary tumor site- Maximum 3 metastases in any single organ system (i.e. lung, liver, brain, bone)
- Primary endpoint: OS
- Closed for accrual (99 partecipants)
NRG BR002: Standard of care systemic therapy +/- SBRT or Surgery
- Breast cancer only- 1-2 Metastatic lesions
- Primary endpoints: PFS - OS
- Open for accrual (402 partecipants)
CORE Trial: Standard of care (CT, HT, Surgery or Palliative RT) +/- SBRT
- Breast, Prostate and NSCLC- A maximum of 2 different organs (e.g liver, lung, bone, nodal) may contain metastases but the total number of lesions must not exceed 3
- Primary endpoint: PFS
- Open for accrual (206 partecipants)
Stereotactic radiation also doubled survival without cancer growth
.Patients who received stereotactic ablative radiotherapy experienced a median overall survival of 41 months vs 28 months in the standard radiation arm (P = .09).
Progression-free survival was 12 months in the stereotactic arm vs 6 months for those who received standard radiation (P = .001).
Ongoing trials
Prospective Non-randomized Phase II Study on SBRT for
Medically Inoperable Lung and Liver Oligometastases From Breast Cancer
Breast cancer only
Lung and liver lesions < 5 (with maximum diameter < 5 cm) DFI (Disease-free interval) > 1 year
No extrapulmonary and/or extrahepatic disease
or other metastatic sites stable or responding after chemotherapy
Partecipating centers: Humanitas Rozzano, IRCCS Negrar (57 partecipants) Primary endpoints: Toxicity and LC
Start date July 2015
Standard of Care + SBRT
Lung and liver stereotactic radiation therapy (SRT) in oligometastatic breast cancer patients medically inoperable, using VMAT RapidArc approach. Chemotherapy completed at least 3 weeks before treatment and started at least 2 weeks after treatment is allowed. Systemic therapies other than chemotherapy allowed (i.e hormonal therapies and/or immunotherapy)
OPEN FOR ACCRUAL
Registry Trials
