In this phase I feasibility study, the investigators evaluate the combination of
lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local hyperthermia and
cyclophosphamide (C), for the local treatment of the primary breast tumour in patients with
metastatic breast cancer.
When heated to 40-43 degrees Celsius (ºC), LTLD releases a very high concentration of
doxorubicin locally within seconds. Hyperthermia of the primary tumour will be induced by
Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) on a dedicated
Sonalleve MR-HIFU breast system.
The investigators hypothesize that by substituting doxorubicin (A) in the AC-chemotherapy
regimen for the combination of LTLD and MR-HIFU induced hyperthermia, optimal local tumour
control can be achieved without compromising systemic toxicity or efficacy.
This will be the first study to evaluate LTLD with MR-HIFU hyperthermia in breast cancer
Advances in systemic treatment led to improved overall survival in patients with metastatic
breast cancer. Various studies suggest that by obtaining loco-regional control, overall
survival in advanced disease can further be improved.
Pre-operative chemotherapy can be used in metastatic breast cancer to make radical removal of
the primary tumor feasible, while simultaneously maintaining control of already present
metastatic sites. The doxorubicin and cyclophosphamide regimen (AC) is well-known both in
(neo-)adjuvant setting as in treatment of metastatic breast cancer. At present, optimal local
control in advanced breast cancer using adequate dosing of doxorubicin is hampered by its
toxic systemic effects. Therefore the investigators aim to increase doxorubicin deposition in
the primary tumor without interfering with systemic efficacy and toxicity, by combining
lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local mild hyperthermia,
induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated
to 40-43 ºC, ThermoDox releases a very high concentration of doxorubicin locally within
seconds. In the absence of hyperthermia, ThermoDox leads to a similar biodistribution and
antitumor efficacy to free doxorubicin. MR-HIFU allows for controlled heating of deep-seated
This is a single-arm phase I feasibility study in 12 patients with de novo stage IV (distant
metastasis at the time of diagnosis) her2-negative breast cancer, who have not received
previous chemotherapy. The study treatment consists of up to 6 cycles at 21-day intervals of
ThermoDox (50mg/m2) administered during MR-HIFU induced hyperthermia (60 minutes at 40-42 ᵒC)
and cyclophosphamide (600 mg/m2) administered afterwards. A dedicated MR-HIFU breast system
integrated with a clinical 1.5 Tesla Magnetic Resonance Imaging (MRI) scanner will be used
for safe and controlled heating of the tumour. Primary endpoints are safety, tolerability and
feasibility. Secondary endpoint is efficacy, assessed by radiological response.
In the Biobank side study, extra blood samples will be collected. These samples will be used
for further research on not yet determined topics related to breast cancer.
Patients must meet all of the following inclusion criteria:
1. Histologically confirmed adenocarcinoma of the breast and planned for palliative
chemotherapy with doxorubicine en cyclophosphamide
2. Biopsy-proven stage tumor 1-2, any nodes, metastasis 1 (T1-2AnyNM1) at diagnosis of
3. Non-pregnant, non-lactating female at least 18 years of age. If patient is of
child-bearing age, she must have a negative serum pregnancy test prior to enrollment
and must agree to practice an acceptable form of birth control while on study.
4. The tumor is located within the reach of the HIFU beam (based on pre-treatment Dynamic
Contrast Enhanced (DCE-) MRI findings).
5. The distance of the tumor from the skin, nipple, and pectoral wall is at least 1.0 cm
(based on pre-treatment DCE-MRI findings).
6. The target breast is expected to fit in the cup of the dedicated MR-HIFU breast system
(based on pre-treatment MRI findings).
7. The patient weighs less than 90 kg (restrictment of the HIFU table top).
8. Provide written informed consent and willing to comply with protocol requirements.
Patients will be excluded if any of the following conditions are observed:
1. Her2-positive disease or classic invasive lobular carcinoma (ILC).
2. A treatment plan with curative intent is available.
3. Any prior chemotherapy treatment for invasive breast cancer (previous anti-hormonal
therapy is allowed)
4. Any prior therapy with anthracyclines
5. Radiologically confirmed brain metastases. Patients with clinically suspected brain
metastases at screening should have a CT/MRI of the brain prior to study entry.
6. Any concomitant malignancy or previous malignancy in the last 5 years, except basal
cell or squamous cell cancer of the skin or in situ carcinoma of the cervix. Subjects
with a prior contralateral breast malignancy more than 5 years ago can be included if
they did not receive any chemotherapy.
7. Any previous malignancy in the unilateral breast (even if more than 5 years ago)
8. Prior sensitivity (including rash, dyspnea, wheezing, urticarial, or other symptoms)
attributed to any liposomal-encapsulated drug.
9. Baseline laboratory values:
Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L, Platelets < 75 x 10^9/L, Hemoglobin <
5.6 mmol/L (9 g/dl), Total Bilirubin > 1.5 x upper limit of normal, Alanine
Transaminase (ALAT) and Aspartate Transaminase (ASAT) > 2.5 x upper limit of normal >5
x upper limit of normal in case of liver metastases, Estimated Glomerular Filtration
Rate (eGFR) < 30 ml/min/1.73m2.
10. World Health Organization Performance Status (WHO-PS) >2.
11. Left Ventricular Ejection Fraction <50% (validated by baseline scan).
12. History of:
1. Acute coronary syndrome in the last year
2. Cerebral vascular accident in the last year
3. Abnormal cardiac stress testing within last 6 months
4. Symptomatic coronary artery disease
5. Uncontrolled hypertension or cardiomyopathy
6. Cardiac valvular surgery or open heart surgery in the last year
7. Known structural heart disease
13. Any condition which may interfere with the hyperthermia portion of the trial such as:
functioning cardiac pacemaker; metal plates, rods or prosthesis of the chest wall,
breast prosthesis in the treated breast, severe numbness and/or tingling of the chest
wall or breast, skin grafts and/or flaps on the breast or chest wall, scar tissue or
surgical clips in the HIFU beam path.
14. Active infection
15. Body temperature > 38.0 degrees Celsius on the day of a MR-HIFU treatment.
16. Concurrent use of any of the following prohibited medications within a reasonable
wash-out time: protease inhibitors, cyclosporine, carbamazepine, phenytoin, valproic
acid, paclitaxel, trastuzumab and other liposomal drugs (Abelect, Ambisome, Nyotran,
etc.) or lipid-complexed drugs.
17. Caution will be exercised with all the medications mentioned in appendix C, for
interactions are theoretically possible.
18. Contraindications to MR imaging (e.g., pacemaker in situ, severe claustrophobia, metal
implants incompatible with the MRI-scan, body size incompatible with MR bore).
19. Contraindications to gadolinium-based contrast agent, including prior allergic
reaction to gadolinium-based contrast agent, and/or renal failure.
20. Contraindications to sedation and analgesia with propofol and Remifentanil, including
history of Chronic Obstructive Pulmonary Disease (COPD) that results in the inability
to perform a physical activity corresponding with a Metabolic Equivalent (MET(57)) of
4; dependence on artificial ventilation at home; sleep apnea or an American Society of
Anesthesiologists (ASA) classification ≥4.
21. Inability to lie in prone position.
22. A medical or psychiatric condition or other circumstances which would significantly
decrease the chances of understanding the informed consent process, obtaining reliable
data, achieving study objectives, or completing the study treatment and/or