Carbon Ions

PRESENT STATUS AND PERSPECTIVE FOR CARBON IONS

Carbon ion therapy is an innovative radiotherapy modality that is mostly dedicated to cancers considered as unresectable and radioresistant to photons. Its radiobiologic properties combine the advantages of the high-dose distribution conformity of protons for deep tumors (superior to photons and neutrons) and the higher biologic effectiveness (compared to photons and protons) of high linear energy transfer (LET) particles such as neutrons. Moreover, the combination of the biologic and ballistic properties of carbon ions greatly reduces the treatment period compared with photon or proton radiotherapy.

탄소이온 치료는 절제불가능하고 광자에 방사선저항을 띄는 암 치료에 적용할 수 있는 혁신적인 방사선치료 방식이다. 탄소이온 치료의 특성은 (1) 심부 종양에 대한 고선량 분포 균질도가 광자나 중성자에 비해 우수한 점, (2) 중성자처럼 높은 LET로  인해 광자와 양자에 비해 생물학적 효과가 높다는 점이다. 더욱이 탄소 이온의 생물학적 특성과 탄도 성질(아마도 브래그피크)덕에 광자 또는 양성자 방사선 치료에 비해 치료 기간을 크게 단축시킬 수 있다.

CARBON ION RADIOBIOLOGIC PROPERTIES: RATIONALE FOR PATIENT SELECTION

Figure20.1 Bragg peak (protons versus carbon ions versus photons)

Carbon ions for clinical applications are characterized by two main properties: (a) a depth-dose distribution with a sharp maximal energy deposition at a definite depth (the Bragg peak) related to the beam incidence energy, with almost no dose deposited beyond this peak (Fig. 20.1) and (b) a biologic efficiency increasing at the end of the beam’s range within the Bragg peak.

Although not demonstrated by large prospective randomized clinical trials, the potential clinical gains achievable by these ballistic advantages led to the definition of several “standard” indications for proton therapy (i.e., base of skull chordoma and chondrosarcoma, eye melanoma, selected pediatric brain tumors).23,24

임상에서 고려해야 할 탄소 이온의 특징은 브래그 피크로 특징지어진다. ((b)피크에서 에너지 전달을 대부분 하고, (a)피크 이후는 에너지 전달 거의 없음)

아직 대규모 무작위 임상 실험으로 입증되지 않았지만, 이러한 탄도 이점에 의해 양성자 치료의 Standerd Ix. 몇가지에서도(즉, 두개골 맥락종과 콘드로사르코마, 눈 흑색종, 선택된 소아 뇌종양) 임상적 이득이 있을 것으로 여겨진다.23,24

Dose Distribution: Bragg Peak and Spread-Out Bragg Peak

Although similar, there are some notable differences between the dose-depth distribution of protons and carbon ions that may have clinical impacts (the presence of a “fragmentation tail” for carbon ions owing to nuclear interactions, allowing high-quality PET imaging) and a very narrow penumbra for carbon ions compared to protons.24

거의 비슷하긴 하지만, 양자와 탄소 이온의 dose-depth distribution 차이(핵 상호작용에 의한 "fragmentation tail"의 존재로 인해 고품질 PET 이미징이 가능하다 <- 무슨 말인지 모르겠음)와 양성자에 비해 탄소 이온은 매우 좁은 penumbra(아래 그림에서 depth 10cm 이전을 보면 Carbon의 dose가 더 낮아서 normal tissue damage가 더 적다.)를 가진다는 점은 주목할만하다.24

Figure20.2 Spread-out Bragg peak (protons versus carbon ions versus…

Figure20.3 Design of a carbon ion spread-out Bragg peak (SOBP). The high LET region of the carbon ion beam is…

Similarly to protons, carbon ion beams are spread out to conform to the target, resulting in the spread-out Bragg peak (SOBP) after a low dose “plateau” within the entrance channel beyond the target (Figs. 20.2 and 20.3). This can be achieved using several techniques, mainly with passive scattering, but also with more advanced techniques (e.g., pencil beam with wobbling or uniform scanning) has to achieve a lower dose deposit within the normal tissue in the entrance of the beam (proximally to the tumor volume) while optimizing the distal dose distribution and therefore a higher dose distribution conformation.

양자와 유사하게, 탄소이온 빔도 타겟 근처에서 spread out하여, 타겟 전까지 저선량 "플라스타우(platau)" 후 타겟에서는 spread-out Bragg peak(SOBP)가 발생한다(그림 20.2와 20.3). (후략)

(Figure 20.1의 Bragg peak처럼 peak가 예리하다면 치료하기가 매우 까다롭겠지만, 실제로는 이 피크가 spead-out돼서 Figure 20.2 and 20.3처럼 되기 때문에(10~15cm depth) 치료에 용이하다는 뜻)

Integral Dose

Another advantage of particle beams is that fewer fields are required to achieve an acceptable dose distribution for difficult cases, which leads to a dramatic decrease of the integral dose (and potentially a lower incidence of radio-induced cancer, especially in pediatric indications) compared to intensity-modulated x-ray therapy (IMXT).32

입자 빔의 또 다른 장점은 선량 분포를 맞추기 어려운 케이스에서 허용 선량 분포를 달성하는 데 필요한 field 수가 적다는 것이며, 이는 강도 변조 X선 치료법(IMXT)에 비해 적층 선량의 극적인 감소(그리고 잠재적으로 소아 지표의 경우)를 초래한다. (대충 정상조직에 피해가 적다는 뜻)

Biologic Effectiveness and Equivalent Biologic Rate

As with neutrons, carbon ion interactions are characterized by a high LET that provides for a given physical dose for a higher biologic effect compared to low LET irradiation modalities (photons and protons). Therefore, the dose delivered with high LET particles is prescribed in Gray equivalents (GyE) or cobalt Gray equivalents (CGE) equal to the measured physical dose in Gray multiplied by a relative biologic efficiency (RBE) factor. The RBE is the ratio of the dose of radiation required to produce a certain biologic effect with photons relative to the dose required to produce the same effect with another form of ionizing radiation (such as protons and light ions).

 

Interestingly for clinical applications, this higher biologic efficiency, which may lead to a higher tumor control probability (TCP) for radioresistant tumors but may also increase the normal tissue complication probability (NTCP), is limited to the Bragg peak (thus to the SOBP). Within the “entrance” channel where the main proportion of organs at risk should be, there is no additional biologic effect.

 

The RBE of carbon ions is difficult to calculate; for dose-reporting purposes, a value of three is often utilized based on neutron experience. However, several other parameters should be taken into account, such as dose per fraction, fractionation, tissue type, target volume, and pO2 value at each point in the irradiated volume as well as the variation in RBE along the SOBP (higher at the distal part than at the proximal part)24 (Fig. 20.3). In NIRS, the LET dependency is taken into account in the design of clinical dose distribution by choosing the 10% survival of the human salivary gland tumor cells as end points; this was evaluated through TCP analysis for non–small cell lung cancer.33,34 The LEM, a generic model allowing for RBE-calculation in various tissue types and for various end points, has been developed and applied at GSI and is in use for biologic treatment planning at HIT.9,10

중성자와 마찬가지로, 탄소 이온은 고 LET로 인해 높은 생물학적 효과를 나타낸다. (중략. 이해 불가) RBE정의~.

흥미롭게도 임상에서는, 높은 생물학적 효율이 radioresistant 종양에 대한 종양 제어 확률(TCP)도 높이지만 정상 조직 합병증 확률(NTCP)도을 증가시킬 수 있기에, 이를 Bragg 피크(SOBP에 해당함)를 이용해서 조절해야한다. OAR(organs at risk, 보호해야 할 정상조직으로 이해하면 될 것 같습니다.)을 penumbra에 포함시킴으로써 추가적인 생물학적 효과를 피해야 한다.

(후략).

Dose Fractionation

The capacity for normal and cancer tissues to repair from sublethal radiation injury is sharply reduced with high LET radiation both for normal tissues and cancer cells. This leads to questioning the need for dose fractionation (applying a standard fractionation scheme with a low dose per fraction) justified in low LET therapy (photons and protons) by a higher kinetic of sublethal radiation injury repair for normal tissue versus radiosensitive tumors.

 

Experimental data with high LET particles did not find any differences in RBE values between tumor and normal cell lines in standard culture condition.35,36 However, experiments conducted with fast neutrons and carbon ions have demonstrated that increasing the dose per fraction tends to lower the RBE of both the tumor and normal tissues but with a more important decrease for the normal tissue given a higher therapeutic ratio for short-course hypofractionation schemes with carbon ion radiotherapy.35,37 At NIRS in Chiba, Japan, hypofractionated carbon ion radiotherapy has been investigated systematically for a variety of tumor entities, and it seems that a significant reduction of overall treatment time can be accomplished for many tumor entities without enhancing toxicity.8

정상조직과 암조직의 repair는 고 LET방사능에서는 급격히 감소한다(sublethal radioation injury만 repair되므로). 따라서 저 LET 치료에 최적화된 분할치료가 필요한가 하는 의문이 발생한다.

표준 배양 컬처에서 실험한 결과 고 LET 입자 조사시 종양과 정상 세포 사이에 RBE 차이를 나타내지 않았다..35,36 그러나 속중성자(fast neutrons)와 탄소 이온을 사용한 실험에서는 1회조사량을 증가시키면 종양과 정상 조직의 RBE가 감소하는 경향을 보였다. 그리고 탄소이온 방사선치료에서 short-course hypofractonation 시 정상조직에 RBE 감소라는 더 중요한 결과도 있었다.35,37 다양한 종양에 대한 hypofractionated 탄소이온 방사선치료 조사가 일본 Chiba NIRS에서 이루어졌고, 많은 종양군에서 toxicity 증가 없이 유의미한 OTT(overall treatment time)의 감소를 보여줬다.8

Applications for Patient Selection and Radiotherapy Schemes

To summarize, the best indications for carbon ions based on their biologic advantages over low LET radiation (photons and protons) and poor dose-depth distribution (photons and neutron) are tumors that demonstrate low radiosensitivity when treated with photons, particularly if the tumor is surrounded by radiosensitive normal tissue.

Carbon ion biologic and physical properties also justify the use of a larger fraction dose than that used in conventional radiotherapy schemes with an impact on patient quality of life (shorter overall treatment time) as well as a major economical impact (reduction of the cost for the health insurance).

요약하면, 저 LET 방사선(광자 및 양성자)과 poor dose-depth distribution(광자와 중성자)에 비해 생물학적 이점에 기초한 탄소 이온의 가장 좋은 적응증은 (1) 광자로 치료할 때 낮은 방사선 민감성을 보이는 종양이 (2) 특히 방사선에 민감한 정상 조직에 둘러싸여 있는 경우이다.

또한 탄소이온 생물학적 및 물리적 특성은 기존의 방사선 치료 계획에서 사용된 것보다 더 큰 fraction dose의 사용을 정당화하고, 따라서 환자의 qol(전체 치료 시간 단축)과 경제적 영향(건강보험 비용 절감)에 영향을 미친다.