1. Clinical Application of Carbon Therapy
Thank you chairman, Good Morning. This is Mi-Sook Kim, a oncologist of Korea Institute of Radiological and Medical Sciences. My talk is clinical application of carbon therapy
Mi-Sook Kim, MD, PhD
Department of Radiation Oncology
Korea Institute of Radiological and Medical Sciences

2. Contents Cancer statistics in Korea
Short history of technology development of radiotherapy
Introduction of world wide facility for C-ion treatment
Benefit of Carbon ion(C-ion) compared to X-ray or proton therapy in cancer tx
Clinical experiences in Japan

3. Cancer statistics in Korea
Death Rate
# of Ca. Patients
In the beginning, I’m gonna talk about the cancer statistics in Korea, The right picture shows the number of cancer patient occurred in Korea since 2000 and it is gradually increasing.
(per 100,000 of population)
No. of patients received RT
: approximately 30% of cancer patient at 2011
Korea Ministry of Health & Welfare
No. of patients received RT
: approximately 30% of cancer patients at 2011

4. 3 modality for treatment of Cancer
Surgery
Radiotherapy
Chemotherapy
Case
- Early cancer to moderately advanced
cancer
- Local cancer (not diverged nor
scattered)
- Early cancer to local advanced cancer
- Local cancer
- Leukemia or cancers diffused in the
whole body
Advantage
- High curability
- Non invasive treatment
- High technology of RT can replace operation in some selected case
- In some cases, life prolonging effects is
remarkable
Disadvantage
- It may cause serious loss of form of
function
- Unsuitable for elderly patient or
patients with physical weakness
- Limited side effects left
In general, side effects are strong.
not curative treatment
This is the table of the treatment tool for cancer. The therapies for cancer consists of three parts, surgery, radiotherapy, and chemotherapy. For the radiotherapy, s big advantages compared with other therapies, that having minimum loss of form of function as well as minimum burden during the treatment.
Now multimodality treatment with surgery, RT, and chemotherapy
is the recent concept in cancer treatment. The goal of multimodality treatment is to
increase cure rate, prolong life and improve quality of life through taking advantage of each treatment.
Roughly, 50-60% of cancer diagnosed patients would be cured.

5. Development of Conventional RT
GammaKnife
Linac (1961)
Cobalt teletherapy (1950)
The radiotherapy could be classified conventional Radiation Therapy using x-ray beam and particle therapy using neutron, proton, and carbon. Those pictures show the first treatment of cobalt teletherapy, Linac, and Gamma knife. Also, Boron Neutron Capture Therapy has been started since 1950s This treatment method is no longer used for the patient.
3D-CRT 2D

6. Evolving Radiation Therapy machines
X-ray beam
Tomotherapy
IMRT
CyberKnife
These are the radiation treatment machine. The machines have evolved from 2 demensional technique to 3D, 4 D and SABR for decades. These radiation machines are dedicating for precise treatment incluindg IMRT, SABR or radiosurgery. They are very expensive machine but fortunately
Almost of radiation oncology department have one of these machines
VMAT
TrueBeam

7. ( proton, alpha particle, neutron) Neutron Therapy (KCCH)
Particle therapy
( proton, alpha particle, neutron)
Cobalt teletherapy (1950)
Gamma-knife
radiosurgery (1968)
Linac (1961)
Neutron Therapy (KCCH)
Proton Therapy (1954)
BNCT (alpha particle) at Hanaro
The radiotherapy could be classified conventional Radiation Therapy using x-ray beam and particle therapy using neutron, proton, and carbon. Those pictures show the first treatment of cobalt teletherapy, Linac, and Gamma knife. Also, Boron Neutron Capture Therapy has been started since 1950s This treatment method is no longer used for the patient.

8. Heavy Ion beam therapy
beam of such ions as carbon (C), neon (Ne), silicon (Si) or argon (Ar), etc.
Moreover, the particle therapy using proton beam is generally used in the US, it was started in Nowadays, the other method using another particle is spotlighted, named carbon therapy. Ne, Si, and Ar are used for only the experimental purpose, and the carbon is the only particle that is clinically used after proton therapy was introduced.
G Kraft et al, 2009

9. Charged Particle Therapy Facilities
This is the scheme of charged particle therapy facilities in the world. The red C mark shows doing carbon ion radiotherapy in the present and green C mark shows planning stage or under construction. In Europe, there are 3 facilities are doing carbon therapy, two of them are in Germany and one of them is Italy. And other 4 facilities, two of them are Germany, France and Austria each, are under construction. In Asia, there are 4 facilities doing on carbon, three of them are in Japan, and one of them is in China. And Korea in Busan is planning to carbon therapy in In US, one spot is planning to the carbon therapy. c

10. Japan – NIRS the world’s first heavy-ion accelerator dedicated to medical use
The HIMAC facility was completed in October 1993 as.
Size: 60 x 120 m
Construction cost: $326 million
(Building $146 million)
(machine $180 million)

11. Germany - Heidelberg world-wide first scanning beam, robotic couch for the two fixed beam room, 600 ton weighted moving gantry for one room
. Also, they has two ion sources extractor, proton and carbon.

12. Japan - Gunma Univ.
This is the specification of Gunma Univ Carbon center. Building is 60m multiply 45m multiply 15m and it has three room, room A has only horizontal beam line and room B has both horizontal and vertical beam line and room C has only vertical beam line. The other room is using for research. The diameter of synchrotron is 20 meter and it is down-sized synchrotron machine compared to others. Maximum energy is 400 Mev per nucleon and Dose rate is 5 Gy equivalent per minute. Carbon ion is generated from Ion generator and accelerated via Linear accelerator and move to the synchrotron.

13. C-ion & proton : Physical Advantage
Bragg peak
Entrance dose
X-ray>>Proton>C-ion
Tumor
The physical advantage of carbon ion is bragg peak, it is, as you know, the particle transfers the energy to not a normal tissue but only to tumor. Generally, radiation therapy using x-ray beam occurs unnecessary expose to the normal tissue because it has not enough energy and it is the uniqueness of particle therapy. The carbon beam compared with proton beam has less entrance dose as you see in this picture, and Carbon beam has less penumbra compared with proton beam. The proton beam shows the beam broadening as the depth is increased, but the carbon beam are showing unchangeable characteristics regardless of depth increased.

14. C-ion & proton vs X-ray : Physical Advantage
So, clinically, the carbon beam transfers big amount of energy to the tumor, so most of more than 90% of dose can precisely cover the tumor and unnecessary dose is not irradiated to the normal tissue, but the conventional RT, on the left side, not only more than 90% Irradiated area is spread according to the beam directions but also more the 50% irradiated area is significantly increased because of its physical characteristic.

15. C-ion vs proton or X-ray - Biological Advantage
High LET : dense breakage of DNA , no repair during tretment
RBE (Relative biological effect)
C-ion (3)>>Proton (1.1)>X-ray(1.0)
Produce strong cancer killing effect
Especially in radioresistant cells
Clincally C-ion treatment is suitable for refractory cancer
Carbone ion produce high linear energy deposit in cancer cell which mean it has very strong cancer killing effect compared to X-ray or proton.

16. C+ + X-ray or proton : gravel Rock
Speak figuratively, X-ray or proton compared to gravel, but carbon & heavy charged particle compared to rock So the biological effect to kill the tumor cell is more stronger in carbon beam compared to proton or X-ray

17. Clinical experiences in Japan
Carbon ion therapy
Clinical experiences in Japan
Let me introduce the clinical data using carbon beam ion. Clinical data is ususally focusing to Japane due to their extensive experience throurgh whole body tumor

18. Indications of C-ion RT
Large tumor in any site
Radioresistant tumor
Recurrent tumor after conventional RT

19. Prostate cancer
Another exampe is prostate cancer which is most frequent tumor in cocaican male, and also in Asian male in Japnae and Korea showed the rapid increase in incidence. For treatment of prostate cancer, radiaiton therapy is very effectve treatement as surgery and ourcome for opeable prostate cancer is similar between two modlaity. The most important thing is to reduce treatment related complication. Among the variable technology of radiation therapy era including 3D or IMRT or carbon ion treatment, Carbon ion can reduce the most radiation dose of rectum, which is the most radio-sensitive normal surrounding tissue of prostae tissue

20. Results of Prostate cancer
RT methods
Dose
No. of patients
5yr DFS (%)
(PSA>20ng/ml)
Conventional RT
67-77
189 51
3D CRT
>76
232
26-63
IMRT
81-86
772
81 (3yr)
Proton 75
643 57
Carbon (NIRS) 66
182 80

21. Complications in Prostate cancer
RT methods
Dose
No. of patients
Complications (> Grade 2)
Rectum (%)
Urology (%)
Conventional RT
67-77
189 15 9
3D CRT
>76
232 11 7
IMRT
81-86
772 2 10
Proton 75
643 4 5
Carbon (NIRS) 66
182 1

22. Osteosarcoma C5 vertebra Sacrum Re-ossification
Osteosarcoma is cancer originated from bone which is known as raidoresistant tumor. This neck spine orginated osteosarcoma is very large and usually can not be cured by conventional RT. Amzingly, the tumor was disappeared. And sarcum area showed same reslut.

23. Maxillary sinus tumor
These case of advanced head and neck cancer rarely has chance of cure when they treated by conventional RT but carbone treatment showed marked tumor regression and gave the cure chance.

24. Sacral Chordoma
Sacral chordoma is rare tumor and is known as radiorasistent tumor. This result is very impressive to me. Under my experience, acually, chodoma is never expected to show like this result when is treated by conventional radiaition therapy .

25. Conclusion
Radiation technology is rapidly developed.
In technology aspect, recent X-ray radiation therapy machine: precise, free beam allocation, dedicated image validation tool.
So this technology already achieved more easy, more precise, more safe, less break-down time.
In clinical aspect, RT goal achieve high local control with less toxicity
In small sized tumor(< 5cm diameter) and well capsulated tumor, recent technology of X-ray RT already achieved similar local control as surgery.
Vision of C-ion therapy achieve high local control with acceptable toxicity in large tumor and radioresistant tumor. And finally it would give the cure chance for refractory cancer patients in the future.
C-ion machine still has technological obstacle. Limited beam allocation, limited validation tool for dosimetry, complicated gantry and etc. If C-ion technology adopt , it can develop more rapidly. And then, we can make final goal, the victory over tumor through C-ion.
For the LINAC treatment, the conventional RT generally used 20 times of multi fractions. It means the small amount of therapeutic dose, about 2 Gy, is irradiated for 20 times each. On the other hands, another method only uses 1 to 3 times irradiation for the increasing Local control and decreasing complication. This method of radiation therapy is so called Stereotactic Body Radiation Therapy, SBRT.
Oligometastasis means limited number of clincally detectable metastatic tumor. OM was hypothesized that the extent of disease exists in a transitional state between localizmed and widespread systtemic disease. In this model, oligometastatic disease has the potential of progressing to metastatic disease. So local control of OM may improve systemic control. 25

26. Thank you
Thank you 26

27. Lung cancer (stage I)
This is v

28. Results of Lung cancer (stage I)
Peripheral type
No.
Local control (%)
5yr survival (%)
Conventional RT
149 56 22
SBRT
245 86 47
Proton
(Tsukuba Univ.) 28 57 30
Carbon (NIRS) 51 95 76
Surgery (Japan)
4264 - 60

29. Liver cancer

30. Results of Osteosarcoma of Pelvis
Studies
Radiations
No. of patients
5yr survivals (%)
Total (%)
Surgery+RT
Inoperable
RT only
USA
photon 40 34 41 10 UK 36 18
German 89
27-30
Japan
(NIRS)
carbon 29 46 -

31. Carbon Ion - Biological Advantage
Benefit for large fraction dose
Carbon ion Tx can finish by 1-10 fractions
1~2 days to 2 weeks by carbon ion RT
6~8 weeks by X-ray or proton RT
Ando et al, 2005
In terms of fractionation effect, the RBE values of low-LET carbon ions (14-20 keV/um) is not different between the tumor growth delay and the skin reaction. But the therapeutic gain is larger at the high-LET carbon ions with a large dose per fraction. So, it only needs 2 weeks for whole treatment whereas x-ray and proton RT need 6 to 8 weeks for whole procedure of treatment.

32. Carbon Ion - Biological Advantage
Overcome of radiation tolerance against hypoxic
tumor cells
Blood vessel
oxygen
Carbon ion
X-ray
Radiation is less sensitive at the hypoxic cell. So in case of x-ray beam radiation is well effects on the oxic cell which is near the blood vessel, however it doesn’t work well at the hypoxic cell. On the other hand, carbon can overcome the hypoxic barrier, so it can work for the tumor which is located in the hypoxic area.

33. Facilities in the world
Carbon ion therapy
Facilities in the world

34. Cancer statistics in Korea
Death Rate
# of Ca. Patients
In the beginning, I’m gonna talk about the cancer statistics in Korea, The right picture shows the number of cancer patient occurred in Korea since 2000 and it is gradually increasing.
(per 100,000 of population)
Korea Ministry of Health & Welfare

35. Backgrounds of radiotherapy
Carbon ion therapy
Backgrounds of radiotherapy

36. Single-wedged kitchen knife
Double-wedged sword
past
Now
For the LINAC treatment, the conventional RT generally used 20 times of multi fractions. It means the small amount of therapeutic dose, about 2 Gy, is irradiated for 20 times each. On the other hands, another method only uses 1 to 3 times irradiation for the increasing Local control and decreasing complication. This method of radiation therapy is so called Stereotactic Body Radiation Therapy, SBRT.
Oligometastasis means limited number of clincally detectable metastatic tumor. OM was hypothesized that the extent of disease exists in a transitional state between localizmed and widespread systtemic disease. In this model, oligometastatic disease has the potential of progressing to metastatic disease. So local control of OM may improve systemic control. 36

37. Beginning of Radiation therapy
X-ray beam
Conventional RT
Neutron beam
Cobalt teletherapy (1950)
Gamma-knife
radiosurgery (1968)
Linac (1961)
The radiotherapy could be classified conventional Radiation Therapy using x-ray beam and particle therapy using neutron, proton, and carbon. Those pictures show the first treatment of cobalt teletherapy, Linac, and Gamma knife. Also, Boron Neutron Capture Therapy has been started since 1950s This treatment method is no longer used for the patient.
Boron Neutron Capture Therapy (1950s)

38. Particle therapy Proton beam Heavy ion beam
beam of protons (nuclei of hydrogen)
Heavy ion beam
beam of such ions as carbon (C),
neon (Ne), silicon (Si) or argon (Ar),
etc.
Proton therapy (1954)
Moreover, the particle therapy using proton beam is generally used in the US, it was started in Nowadays, the other method using another particle is spotlighted, named carbon therapy. Ne, Si, and Ar are used for only the experimental purpose, and the carbon is the only particle that is clinically used after proton therapy was introduced.

39. Japan-Chiba NIRS
The HIMAC facility was completed in October 1993 as the world’s first heavy-ion accelerator dedicated to medical use. Since June 21, 1994, at NIRS, more than 5,400 patients have been treated with both proton and carbon-ion beams. A utilization ratio of proton and carbon are 82% and 18%, respectively. There are two rotating gantries for protons, and three treatment rooms are prepared for carbons and protons.

40. Japan-Gunma Univ.
This is the specification of Gunma Univ Carbon center. Building is 60m multiply 45m multiply 15m and it has three room, room A has only horizontal beam line and room B has both horizontal and vertical beam line and room C has only vertical beam line. The other room is using for research. The diameter of synchrotron is 20 meter and it is down-sized synchrotron machine compared to others. Maximum energy is 400 Mev per nucleon and Dose rate is 5 Gy equivalent per minute. Carbon ion is generated from Ion generator and accelerated via Linear accelerator and move to the synchrotron.

41. Indications of C-ion RT
Large tumor in any site
Radioresistant tumor
Recurrent tumor after conventional RT
I already said the benefit of Carbon ion radiation therapy compared to covnenitonal radiaiton therapy or proton therapy in point or physical and biological aspect. In the tumor which is not curable by just conventinal radiation therapy , carbone beam is tried to cure that kind of tumor
And also the treatment time is shorter and shorter like 1weeks program, which shorter treatment time improve quality of life of patients. Through whole body, brain head and neck and esophgeal lunglvier pancreas pro….. Are all indicated for this carbone treatment