Neutron Therapy for Cancer Treatment Using the U-120 Cyclotron Golovkov V.M.1, Lisin V.A.2, Musabaeva L.I.2, Gribova O.V.2, Velikaya V.V.2, Startseva J.A.2, Wagner A.R.1 1) National Research Tomsk Polytechnic University 2)Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences,

IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

Outline

• Neutron Source Performances for NT Using Cyclotron • Dosimetric and Radiobiological Studies •

Clinical Applications of NT for Cancer Treatment

•

Summary and Conclusion

IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

Background

• Neutrons have been used for therapy for more than 5 decades. • Unfortunately, due different reasons, the number of fast neutron facilities has decreased to a few centers worldwide.

• In Russia, there are only 2 centers using neutrons for treating cancer: in Tomsk and in Snezhinsk (Chelyabinsk region). • One of the challenges for radiation oncology is to overcome tumor radioresistance. • Neutron therapy is considered to be one of the possible ways to increase the efficiency of radiation therapy for malignant tumors resistant to photon irradiation.

IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

Development of NT in Tomsk •

1983. First use of fast neutrons for NT in Tomsk, Russia.

•

1984-1990. Dosimetric, radiobiological studies and creation of neutron and neutron-photon therapy program.

•

1986 -2006. Development and testing of neutron and neutronphoton therapy for certain types of cancer and methods on prevention of radiation-induced reactions to normal tissues using copper vapor laser irradiation and magneto-laser therapy.

•

2007-2013. Development of the fast neutron/neutron-photon therapy methods in the pre- and post- operating periods and as a palliative treatment of malignant tumors.

IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

Cyclotron as Neutron Source for Neutron Therapy

Deuteron beam: 13,6 MeV; 30 μA Average neutron energy – 6,3 MeV IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

Collimator and Neutron Beam Exit in Medical Treatment Room • Neutron fields - from 6 x 6 up to 15 x 15 cm2 • Dose rate at the point of patient location is about 0,15 Gy / min ( id =30 μA, 100 cm)

IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

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Monitor Coefficient Determination

D (S ) ref п K  m Dm ( S п )

IC ref

IC monitor 1- deuteron beam; 2 – target; 3 – beam current meter; 4,6 - preamplifiers; 5,7 – dosimeters; 7

Determination of Absorbed Doses of Neutrons and Gamma Radiation Using ICs with Walls Made of Different Material

k w (1) ( )n Dn  kt k w ( 2) ( )n Dn  kt

k w (1) ( ) D  D1 kt

Dn , Dγ

k w ( 2) ( ) D  D2 kt

D1 – indication of IC with polyethylene walls; D2 - indication of IC with carbon walls; Dn , Dγ - absorbed dose of neutrons and gammas;

kw, kt - specific kermas in IC wall and in the tissue. 8

Neutron and Gamma Dose Distribution Measurement in Water Phantom Layout of Measurements

1- deuteron beam; 2 – target; 3 – beam current meter; 4 - collimator; 5 - phantom; 6,8 - preamplifiers ;7,9 – dosimeters; 10 - device for IC shifting.

IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

9

Отношение дозы гамма-излучения к Ratio дозеDнейтронов, % γ / Dn , % 40 30 20 10 0 0

4

8

12

глубина, сантиметры Depth in phantom, cm

16

Neutron Dose Distribution Near the Entry on the Surface of Irradiated Tissue 100 % D n (X) % Доза,

80 60

R=0 см R=14 см

40 20 0 0

1

2

3

глубина, миллиметры Depth in tissue, mm 11

Absorbed Neutron Dose Distribution in Phantom for a Field of 12 x 12 cm дозы Распределение поглощенной нейтронов в плоскости для поля 12×12 см. кв.

80 %

60 %

40 %

20 %

10 %

10

12

Дозное поле за границами колиматора

/ D(0), D(Y) % % Доза,

Dose Area Outside the Collimator Field 4 3 photons фотоны neutrons нейтроны

2 1 0 10 20 30 40 50 60 70 80 сантиметры Y, cm

IAEA Technical Meeting on Research Reactor Users' Networks (RRUNs): advances in neutron therapy 1 – 4 July 2013 Mainz, Germany

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Empirical Equations of Approximation of Absorbed Neutron Dose Distribution along axis of the beam

D( x, S )  Do exp[ (3,08 103 x  0,107)( x  0,2 )]  4,4 10 3 (S  48) x in perpendicular direction to the beam axis

D ( x, y ) 

D( x, y  0)   2y 1    h  0,99  0,02 x 

 2, 2

 2 0 ,125x  ln 1   h0 , 99 0 , 02 x  

х – depth direction; y – coordinate in width field direction. S – area of the irradiating field; h – width of irradiating field; 14

Dependence of Neutron RBE on a Dose 9

ОБЭ RBE

7 NSD ММ

5 3 1 0

2

4

6

8

Доза нейтронов, Гр Neutron dose, Gy

Fast neutron RBE on the base of multitarget model (MM)

1,66 RBE ( Dn )   ln[1  (1  exp(1,22 Dn )) 0, 43 ] Dn [ Lisin V.A. et al. Radiobiologiya(rus), 1986, 5, p. 656-660]

15

TDF Model for Neutron and Neutron-Photon Therapy. 2

Dt , n  10  NSDn  T m

TDF  6,8 D

1,18 n ,i

i 1

0 ,11

N

H

0 , 04

 0 ,13 i

m

TDF  6,8 [(7,8 10  2  Dn ,i  0,96) Dn ,i ]1,18  H i0,13 i 1

iN

TDF  1.2 d i 1

1.538  ,i

H

0.169  ,i

m

 6,8[(7,8 102  Dн, j  0,96) Dн, j ]1,18  H н,0j,13 j 1

[ Lisin V.A. et al. Medicinskaya Radiologia(rus), 1988, 33,1, 45-47]

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Data for NT and Combined NT + GT Treatment Calculated by the Program for Each Patient 1. 2.

Duration of a therapy session in monitor units; Total absorbed doses obtained from each irradiation field taking into account contributions of all irradiation fields; 3. Absorbed doses in all critical organs, which are concerned by radiologist; 4. Coordinate of the point with maximum dose for a given irradiation plan; 5. Value of absorbed dose at maximum point of dose distribution; 6. Distribution of absorbed dose in irradiated tissue volume; 7. Distribution of isoeffective dose in irradiated tissue volume; 8. Acceptable value of TDF factor on skin and in lesion focus taking into account the area of irradiation field; 9. Operational value of TDF factor on skin and in lesion focus taking into account the area of irradiation field; 10. Total distribution of isoeffective dose of neutrons and gamma-radiation in case of combined neutron and gamma therapy.

17

Clinical Modalities for Neuron Therapy • Head and neck tumors: multimodality approach and radiation therapy for nasal cavity and paranasal sinus cancer, parotid gland and minor salivary gland cancer, thyroid cancer with unfavorable prognostic factors, cancer recurrence, metastases in lymph nodes and soft tissues, head and neck soft tissue sarcomas.

• Preoperative neutron therapy: Complex treatment of locally advanced breast cancer;

• Neutron and neutron-photon therapy of local breast cancer recurrence and metastatic disease;

Dose Fractionation Regimes of Fast Neutrons Used in Clinical Practice • Regime I: – 2 fractions per week, – 1.2 -1.4 Gy single radiation dose (3.2-3.1 RBE), 5.3 – 4.5 Gy photon-equivalent dose (PED), – 40 – 60 Gy total radiation dose per session, for 4-6 weeks;

• Regime II: – 3 fractions with a 48-72 hour interval, – 1.8-2.4 Gy single radiation dose (2.6 -2.8 RBE), 6.7 – 6.8 Gy PED, – 38 – 40 Gy total dose, for 8 -12 days.

First Clinical Treatment of Patients with Nasal Cavity and Paranasal Sinus Cancer (1984 -1994)

Treatment mode: pre-operating neutron therapy (38-40 Gy total photon-equivalent dose) Results: A 10-year follow-up was observed in 11 (29%) of the 38 patients There were no patients with a 10-year follow-up in the control group.

Thyroid cancer treatment with fast neutrons

Patients with thyroid cancer were divided into 2 groups. Group I consisted of 24 patients who underwent surgery followed by neutron or neutron-photon therapy. The total radiation dose in Group I patients was 52.5 Gy.

Group II was comprised of 20 patients who receive only neutron-photon therapy . The mean total radiation dose in Group II patients was 61 Gy (photon-equivalent dose). Contribution of fast neutrons to the total dose of neutron-photon therapy was 46-48%. The overall 5-year survival rates in group I and group II patient were 58 ±14.2 % and 40 ±2.8%, respectively. The method of neutron-photon therapy for inoperable thyroid cancer was developed (RF Patent).

Long-Term Results of Combined Treatment of Poorly Differentiated Thyroid Carcinoma

The patient 9 years later after combined treatment including neutron-photon therapy for thyroid cancer { Postoperative neutron-photon therapy, total dose of 53.5 Gy PED, neutron dose - 5.6 Gy (24 Gy photon-equivalent dose). Only I-II grade radiation-induced skin damages were observed.

Neutron Therapy for Patients with Head and Neck Cancer

Cancer of the left parotid gland. Parotidectomy - May 8, 1999 + 7.0 Gy postoperative neutron therapy. 3 years later (in March 20, 2002 ) it was not revealed any disease recurrence.

Local radiation-induced reactions in the patient with inoperable thyroid cancer.

Combined Neutron and Photon Therapy for a Patient with Parotid Cancer

Inoperable tumor of the parotid gland

Computed tomography of the patient

After neutron-photon therapy

Late Radiation-Induced Skin Injuries after Neutron Therapy A 57-year patient with malignant chemodectoma with metastases in lymph nodes on the left side of the neck. He received neutron therapy in November , 2002. 6 years later after treatment (May, 2008) no evidence of tumor recurrence was observed Radiation-induced skin reaction (teleangiectasia) was seen.

Palliative Neutron Therapy for Head Metastases of Breast Cancer

Before treatment

After treatment with 6 MeV fast neutrons

Breast Cancer: Indications for Preoperating Neutron Therapy

• local tumor spread (T3-4); • multicentic tumor growth for T2-4;

• tumor is localized in the internal quadrant and/or central part of the breast; • infiltrating tumor growth; • no response to neoadjuvant chemotherapy

The Regimen of Neutron-Photon Therapy for Locally Advanced Breast Cancer •

Neutron therapy is delivered to the breast area only;

•

Single radiation dose and the total radiation dose of fast neutrons are calculated according to the formula: D = (38 + 88 · ΔТ0,11 ·N-0,85)0,5 – 6,15,

where, D is a dose of fast neutrons per fraction; ΔТ is the interval between sessions; N is a number of fractions; •

2 tangential and opposite fields measuring 6 х 8 cm or 10 х 10 cm are used, the source to skin surface distance is 110 cm.

•

3 sessions with 48-72 hour interval are administered, 2.4 Gy single radiation dose and 7.2 Gy total radiation dose (from 38 to 40 Gy photon-equivalent dose).

Tolerability of Preoperating Neutron Therapy Radiation-induced reaction of breast cancer I-II grade erythema after 3 sessions of neutron therapy: 2.4 Gy single radiation dose, 48-72- hour interval, 7.2 total dose (38-40 Gy photon-equivalent dose), for 8-12 days

The 8-year Survival Rate without the Tumor Recurrence in Patients with Focally Advanced Цензу риров анные Beast Cancer

100% 95%

Исследу емая гру ппа Studied group Comparison group II b II в Гру ппа срав нения Comparison group II c II c Гру ппа срав нения

90% 85% 80% 75%

Log-Rank p = 0,001

70%

Зав ершенные

65% 1

2

3

4

5

6

7

8

Время (years) наблюдения (годы) Follow-up

The studied group – 96,0 ± 3,0 % Comparison group I - 74,4 ± 10,7 % Comparison group II - 69,8 ± 8,9 %

Control group - 57,9 ± 7,4 %

9

10

Rates of recurrence-free survival

0

Показатели безрецидивной выживаемости, %

Rates of recurrence-free survival

Показатели безрецидивной выживаемости, %

Зав ершенные

Цензу риров анные

100% 11

90%

Studied group Исследу емая гру ппа Контрольная Control group гру ппа

80%

70%

60%

Log-Rank p=0,00001 50% 0

1

2

3

4

5

6

7

Время наблюдения (годы) Follow-up (years)

8

9

10

11

Radiation-Induced Reactions to Normal Tissues after Pre-operating Neutron/Neutron-photon Therapy for Breast Cancer

Grade 2 radiation pneumofibrosis and radiation sclerosis of the 3-rd rib after neutron/photon therapy for breast cancer.

7 years later after preoperating neutron therapy: total dose of 7.2 Gy. No radiation induced damages are observed.

Short-term Response for Patients with Breast Cancer Local Recurrences Depending on the Type of Radiation Therapy Number of patients ( %) Treatment response

Neutron therapy : total dose - 40 - 60 Gy of PED (n=7)

Complete response

Neutron-photon therapy: total dose of 6065 Gy of PED (n=40)

Electron therapy: total dose of 60-65 Gy PED (n=41)

7 (100 %)

37 (93 %)

25 (61 %)

Partial response

-

3 (7 %)

5 (12 %)

Stable disease

-

-

11 (27 %)

Disease progression

-

-

-

Clinical Case: Neutron Therapy for Local Recurrence of Breast Cancer • Local recurrence of breast cancer (adenocarcinoma) 6 months later after preoperating large fraction gamma-therapy (44 Gy total dose) and radical mastectomy; • No effect after 4 cycles of xelod. • Neutron therapy, 2 direction of iradiation fields 10х10сm, 4 sessions: 1.76 Gy single radiation dose, 7.04 Gy total dose (35 Gy of the conventional photon therapy).

Response to Neutron and Laser Therapies for Local Recurrence of Breast Cancer • After treatment of radiation-induced epidermitis with copper vapor laser; • Complete regression of breast cancer local recurrence • The patient was followed up for 3.5 years with no evidence of re-recurrence in the treated area

Treatment of breast cancer recurrence

A 55-year patient with locally advanced breast cancer recurrence (T3N1M0)

A 55-year patient, 5 months later after neutron-electron therapy. Complete regression of recurrent tumor

Treatment of Local Recurrence from Breast Cancer

Local recurrence from breast cancer 3 years later after combined modality treatment including preoperative external beam radiation therapy delivered to the whole breast

A month later after neutron-photon therapy: total dose 60 Gy PED

Complete regression 3 months later after neutron-photon therapy

Late Radiation-Induced Damages to Normal Tissues after Neutron-Photon Therapy in Patients with Local Breast Cancer Recurrences

Radiation-induced skin ulcer 3 years later after neutronphoton therapy

Ulcer healing after ozone treatment.

Summary • Therapeutic channel for fast neutron therapy has been created on the cyclotron U-120; • Dosimetric neutron fields in phantom equivalent to tissue have been studied; • Adequate methods of dosimetric and radiobiologic treatment planning of NT using model of TDF, linear-square model, and dependence of neutron RBE on a dose have been developed. • Developed methods of NT have been validated during long clinical testing and satisfactory results with patients suffering from radiation resistant forms of malignant tumors have been shown.

References 1. L.I. Musabaeva et. al. Neutron Therapy on U120 cyclotron//Medicinskaya Radiologia i radiacionnaya bezopasnost (rus), 2013, v.58, №2.- p. 53-61. 2. RU Patents № 1693757, 1768181, 2021833, 2186591, 2286818, 2344851, 2444386. 3. [email protected] [email protected] [email protected]

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