targeted patient enrollment was not met.

This study uses a novel, recently developed unconventional radiotherapy technique which consists of three high-dose fractions directed to special segments of unresectable bulky tumors.

This is a mono-centric, prospective, two-arms, feasibility study in which the investigator will enroll up to 22 patients with locally advanced or metastatic cancers with at least one bulky (≥6cm) lesion. This study uses a novel, recently developed unconventional radiotherapy technique, consisting of a short course (3 fractions) high dose partial irradiation targeting exclusively the hypoxic segment of unresectable bulky tumors while sparing the peritumoral immune microenvironment for induction of immune-mediated tumoricidal bystander and abscopal effects.

The present study will explore the potential biological and physical advantages of particle-based radiotherapy to deliver a highly conformal radiation dose to the hypoxic tumor segment defined by using hypoxia-specific Copper-64-Diacetyl-bis (N4-methylthiosemicarbazone) Positron Emission Tomography-Computer Tomography (64Cu-ATSM PET-CT) and dynamic contrast enhanced Magnetic Resonance Tomography imaging. Based on tumor location, volume and risk factors related to nearby organs at risk, patients will be divided in the "high-dose" or "reduced-dose" group which will be treated with different dose-schedules according to risk factors.

Additionally, radiotherapy will be administered at the precise timing, determined individually for each patient, based on the serially mapped homeostatic immune fluctuations by monitoring blood levels of the inflammatory markers. The objective is to synchronize the radiation treatment with the favorable, most reactive anti-tumor immune response phase, in order to break tumor´s immune-tolerance locally and systemically.

Inclusion Criteria:

1. Written informed consent obtained from the patient prior to performing any treatment-related procedures.
2. Biopsy proven malignant unresectable solid bulky primary or recurrent tumor (diameter of at least 6 cm or greater, except for the Central Nervous System (CNS) tumors), or in a case of lack of recent biopsy progression on at least two consecutive radiological examinations, with biopsy proof in the past. Presence of locally advanced (cN+) and/or metastatic disease will be accepted in order to allow for assessment of the abscopal effects.
3. Ineligibility for standard treatments including surgery, conventional (whole tumor) radiotherapy and systemic therapy, or being in progression or stable (with no response to systemic treatment) under systemic therapy.
4. A minimum time interval from last dose of systemic therapy before radiotherapy of two weeks; Systemic therapy may be resumed 4 weeks following radiotherapy in order to permit assessment of the treatment efficacy.
5. Median life expectancy of >2 months.
6. Age > 18 years.
7. Adequate bone marrow function as follows below: Haemoglobin ≥ 8.0 g/d; Absolute neutrophil count (ANC) ≥ 1.5 x 10ꝰ/L (> 1500 per mm3); Platelet count ≥ 100 x 10ꝰ/L (>100,000 per mm3).
8. Female patients must either be of non-reproductive potential (i.e. post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) OR women of fertile age must have adequate conception prevention measures and must have a negative serum pregnancy test upon study entry.
9. Patient is willing and able to comply with the follow up including scheduled visits and examinations.

Exclusion Criteria:

1. Patients without bulky lesions.
2. Tumors suitable for the standard therapies including surgery, conventional (whole tumor) irradiation and systemic therapies.
3. Median life expectancy of less than 2 months.
4. Contraindication to i.v. Computer Tomography and Magnetic Resonance Tomography contrast medium administration, particularly estimated glomerular filtration rate (GFR) less than 45 mL/min/1.73 m2.
5. History of autoimmune disease.
6. Current or prior use of immunosuppressive medication within 14 days before enrollment with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
7. History of primary immunodeficiency.
8. History of allogeneic organ transplant.
9. Uncontrolled intercurrent comorbidity including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, active bleeding diatheses including any patient known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent.
10. Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
11. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. (Note: criterion will be evaluated on the four eyes principle, evaluated by both Principle Investigator and Sub-Investigators.)
12. Patients with uncontrolled seizures.