ESTRO 36 Abstract Book

ESTRO 36 2017

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parameters are examples. More selective radiotherapy

techniques are being tested in large trials including gating

or tracking techniques together with IMRT or intensity

modulated proton therapy. Including surgery may improve

the therapeutic ratio in selected patients, if lobectomy is

adequate. Large treatment volumes were successfully

treated by dose escalated hyperfractionated and

accelerated radiotherapy schedules in patients with

locally advanced lung cancer together with concurrent

chemotherapy. Limited volume hypofractionation at the

primary tumor site and limited hilum or mediastinum is

another way to overcome repopulation. Adenocarcinomas

with druggable driver mutations have a considerably

better prognosis than tumors without. Targeted therapies

are attractive partners for radiotherapy to inhibit

repopulation and perhaps repair. New concepts emerge

for using genetic vulnerabilities of tumor cells other than

driver mutations for drug-induced synthetic lethality

resulting in a highly selective treatment of tumor cells in

combination with radiotherapy. For relapsing patients or

patients with synchronous oligometastatic disease,

stereotactic ablative radiotherapy RT to various sites can

offer long term control complementing better systemic

therapy options. Immunotherapy is now an established

second line treatment in metastatic NSCLC and an

interesting combination partner for radiotherapy whereas

the latter can increase expression of tumor-associated

antigens.

These advantages will be bundled into new

radiotherapeutic concepts that have to be tested against

standard conventionally fractionated radiotherapy and

concurrent chemotherapy in future well designed

randomized trials.

SP-0011 The use of biomarkers for individualized

treatment in NSCLC

J. Belderbos

Netherlands Cancer Institute Antoni van Leeuwenhoek H

ospital, Amsterdam, The Netherlands

A biomarker is a biological substance, that can be

detected by a laboratory or imaging technique allowing an

assessment of the disease presence and/or progression.

Blood samples to analyze biomarkers have the advantage

that they are fast, minimal invasive and easy to obtain.

Blood-biomarkers may be related to hypoxia (osteopontin

(OPN), carbonic anhydrase IX (CA-IX)), inflammation

(Transforming growth factor beta1 (TGF-β1), interleukin-

6 (IL-6), IL-8, and C-reactive protein (CRP)), tumour load

(carcinoembryonic antigen (CEA), and cytokeratin

fragment 21-1 (Cyfra 21-1)) or growth factors (vascular

endothelial growth factor(VEGF)). Besides clinical factors

like patient characteristics (age, gender, WHO-PS, weight

loss) and tumor characteristics (tumor volume, stage,

lymph nodes) several biomarkers have been shown to be

associated with disease progression and survival of NSCLC

patients treated with radio(chemo)therapy. In addition to

dosimetric parameters biomarkers may also be helpful to

predict toxicity or radio-resistance.

Blood-biomarkers to predict the risk of normal tissue

damage by radio(chemo)therapy pre-, during and post-

radio(chemo)therapy:

Inflammatory cytokines are made by many cells within the

lung, including the alveolar macrophages, Type II

pneumoncytes,

lymphocytes

and

lung

fibroblasts. Transforming growth factor beta1 (TGF-β1) is

a cytokine that has been extensively studied as a marker

predictive of radiation pneumonitis (RP). Patients with

NSCLC have increased pre-treatment levels of TGFb1 and

that increased levels were associated with a higher mean

lung dose (MLD) and a higher incidence of RP. But

especially the observation of an increasing ratio of pre- to

intra-treatment TGFb1 for Stage III NSCLC treated with

definitive radio(chemo)therapy was predictive of RP. More

recently single nucleotide polymorphism rs1982073:T869C

of the TGF-β1gene was reported to be associated with the

risk of RP in NSCLC patients treated with definitive

radio(chemo)therapy. Therefore

genotype

rs1982073:T869C of the TGF-β1 gene may serve as a

reliable predictor of RP (Yuan JCO 2009). Certain

polymorphisms of the VEGF gene have also been

correlated with the incidence and severity of RP.

Circulating interleukin-6 (IL-6) and interleukin-8 (IL-8)

levels levels pre-, during and post-RT have been

correlated with an increased risk of RP as well.

Blood-biomarkers associated with disease progression and

survival of NSCLC patients treated

with

radio(chemo)therapy:

A prediction model for 2-year survival was developed for

NSCLC patients treated with curative intent with

radio(chemo)therapy using different blood-biomarkers

related to hypoxia, inflammation, immune response and

tumour load by the MAASTRO group (Dehing-Oberije

IJROBP 2011). They concluded that biomarkers CEA and

interleukin-6 (IL-6) have an added prognostic value for

survival of NSCLC patients. More recently the same group

demonstrated and validated in two large cohorts of NSCLC

patients the added value of blood-biomarkers related to

hypoxia (OPN) and tumour load (Cyfra 21-1) (Carvalho

Radiother Oncol, 2016) on survival.

Blood-biomarkers associated with radio-resistance:

Deletion of KEAP1 has been linked with tumor

aggressiveness, metastasis and resistance to oxidative

stress and radiotherapy in lung squamous cell carcinomas.

Using the pre-RT plasma samples KEAP1/NRF2 mutations

increased radio-resistance in a small group of patients

with NSCLC and predicted local tumor recurrence in

radiotherapy patients (Jeong Cancer Discovery 2017).

These recent findings are of potential clinical relevance

and could lead to personalized treatment strategies for

tumors with KEAP1/NRF2 mutations.

Conclusion: Combining blood-biomarkers and established

prediction parameters into a single model is expected to

improve the ability to predict normal tissue damage and

treatment response as compared to either variable alone

and could lead to personalized treatment strategies.

SP-0012 Abscopal responses in metastatic non-small

cell lung cancer (NSCLC): a phase II study of combined

radiotherapy and ipilimumab

S. Formenti

E. Golden, A. Chachoua, K. Pilones, S.

Demaria

Weill Cornell Medical Center of Cornell University, New

York- NY, USA

CTLA-4 immune checkpoint blockade in metastatic and

locally advanced NSCLC patients has demonstrated

disappointing results (J Clin Oncol 2009, 27: suppl; abstr

8071). Conversely, our group has generated extensive pre-

clinical evidence that the combination of CTLA-4 blockade

and local radiotherapy induces responses outside the

radiation field (abscopal effect) in syngeneic models of

metastatic cancer (Clin Cancer Research 2005, 11: 728-

734). We also reported a dramatic abscopal response in a

patient with refractory metastatic NSCLC treated with

combined radiotherapy (RT) and ipilimumab, a

monoclonal antibody against CTLA-4, (Cancer Immunol Res

2013, 1: 365-372), who remains alive and disease free five

years later, without any other additional treatment. We

have conducted a phase I-II trial to investigate

effectiveness and safety of ipilimumab and localized RT to

a metastasis in patients with metastatic NSCLC, to elicit

an individualized vaccine, that is effective systemically,

as reflected by objective abscopal responses (Formenti

and Demaria, JNCI 2013). Patients with chemo-refractory

metastatic NSCLC, PS 0-2, and ³2 measurable lesions

(³1cm) were eligible. Patients received ipilimumab

(3mg/kg i.v.) within 24 hrs of starting RT (6Gy x5 or

9.5GyX3 daily fractions) to one lesion. Ipi was repeated

every 21 days x3. Optional biopsies and serial blood draws