1. 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.

2. 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).

3. hepatic diffused tumours liver as the only organ affected Estimated number of patients/year under these conditions (Italy) 3400

4. Proposed solution neutron irradiation of the entire liver to destroy all detected and undetected metastases isolated isolated 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

5. 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 10 B(n,  7 Li (  barn) due to the short range of 4 He and 7 Li in tissues these particles release intense localized doses of radiation just to the single cell liver re-implantation

6. effective treatment is ensured when the ratio (T) of boron concentration in tumour (C T ) over normal tissues (C H ) is: C T /C H  3.5 – 4 research (in vivo on rats) of the proper boron- containing compounds ensuring such a condition

8. 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

9. History of BNCT collimated 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 collimated thermal and epithermal neutrons. Up to now the clinical trials did not produce satisfactory results collimated diffused collimated neutron beams are absolutely unfit to realize an effective therapy on the liver in presence of diffused cancerous nodules

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

11. 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 4x10 12 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

12. 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

13. Conclusions The 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