A novel therapy for liver metastases: a concrete hope after

the first human treatment

T.Pinelli*, A.Zonta+, S. Altieri*, S.Barni++, A.Braghieri*, P.Pedroni*, P.Bruschi*, P.Chiari++, C.Ferrari+, F.Fossati*,

R.Nano++, S.Ngnitejen Tata+, U.Prati+, G.Ricevuti++, L.Roveda+, C.Zonta+

 *INFN, Pavia and Dept. of Nuclear and Theoretical Physics,

University of Pavia, Italy+Dept. of Surgery, Div. of General Surgery, University of

Pavia and Polyclinic S. Matteo, Pavia, Italy.++Dept. of Animal Biology, University of Pavia and Centre of

study for Histochemistry, C.N.R., Pavia, Italy.

The goal

Effective treatment of secondary liver metastases incidental to a primary tumour surgically resected

Such metastases are generally numerous and not completely detectable by the current diagnostic

methodologies (CT, NMR, PET etc)

No really effective solution by medical therapy, nor by surgery (both traditional and most recent techniques).

hepatic diffused tumours liver as the only organ affected

Estimated number of patients/year under these

conditions (Italy)

3400

Proposed solution

neutron irradiation of the entire liver to destroy all detected and undetected metastases

isolatedisolated liver treatment in a thermal neutron field where neutrons, coming from all directions, interact

with the whole organ

fundamental problem how to administrate lethal radiation doses to

neoplastic tissues while preserving healthy tissues

infusion of a solution of a boron-containing compound via blood circle

selective absorption in cancerous cells

liver explantation

thermal neutron irradiation of the explanted organ

10B(n,7Li (barn)

due to the short range of 4He and 7Li in tissues these particles release intense localized doses of radiation

just to the single cell

liver re-implantation

effective treatment is ensured when the ratio (T) of boron concentration in tumour (CT)

over normal tissues (CH) is:

CT/CH 3.5 – 4

research (in vivo on rats) of the proper boron-containing compounds ensuring such a

condition

further conditions:

neutron treatment must be concluded in few minutes to avoid damage to the patient in anhepatic condition

doses by gamma background and processes other than the neutron-boron reaction must be strongly reduced in comparison with the total

absorbed dose

uniform neutron flux distribution at irradiation position

minimum dose absorbed by tumour higher than 40 Gy-Eq

maximum dose given to normal tissues lower than 15 Gy-Eq, assumed as a conservative tolerance level

History of BNCT

Boron Neutron Capture Therapy was first proposed over half a century ago, and has been experimented in USA, Japan and Europe to treat malignant brain

tumours by collimatedcollimated thermal and epithermal neutrons.

Up to now the clinical trials did not produce satisfactory results

collimatedcollimated neutron beams are absolutely unfit to realize an effective therapy on the liver in presence

of diffuseddiffused cancerous nodules

Clinics

treatment of a 48 years old male on December 19th 2001.

patient’s liver contained more than 20 detected metastases following the removal of a colon-carcinoma few months before

self-graft procedure at S. Matteo Polyclinic (Pavia)

neutron therapy inside the thermal column of Triga Mark II reactor of the University of Pavia

time required for the complete operation around 46 hours

Clinics (details)

During two hours, a solution of BPA-Fructose (300 mg/Kg of the body weight) was infused via blood circle.

After 1 and 2 hrs from the infusion beginning, two biopsies were drawn, and boron concentration measured in both

tumour (47±2 ppm) and normal liver (8±1 ppm)

Liver explanted & immediately sent to the reactor Thermal neutron irradiation with a fluence of 4x1012 cm-2

Absorbed doses calculated for tumor and liver: 66±2 and 9±1 Gy respectively.

Liver returned to the surgery room and re-implanted

Remarks

Particularly relevant is the dose absorbed by normal liver, largely lower than the tolerance dose

Any other organ of the patient, except his liver, was free from radiation damage

10 days after treatment CT showed the liver in normal condition while metastases were in a severe necrotic state

After neutron therapy the number of metastases detected by CT resulted larger than those visible before the treatment, i.e.

neutron treatment operates everywhere inside the liver volume: small and large, visible and invisible metastases

are attacked with the same effectiveness

ConclusionsThe patient left the hospital 37 days after the treatment; before leaving,

he had recovered all of his functions and his general condition was good

One year after treatment all radiological and clinical checks indicated a positive trend of the patient’s condition. This time is already much

longer than the survival expected otherwise (one month)

This first human treatment gave tangible proof of the possibility to irradiate the explanted organ into a thermal neutron field with no use of

collimators, screens and similar. It is the first complete victory over the so far incurable pathology of cancer metastases

Five more treatments of diffused liver cancer authorised within February

Possibility for other organs (kidney, lung, testicle) under study