REVIEW

Particle therapy for cancers: a new weapon in radiation therapy

Guo-Liang Jiang

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2012

Abstract Particle irradiation started to draw attention in the past decade and has now become a hotspot in theradiation oncology community. This article reviews the most advanced developments in particle irradiation,focusing on the characteristics of proton and carbon ions in radiation physics and radiobiology. The Bragg peak ofphysical dose distribution causes proton and carbon beams to optimally meet the requirement for cancerirradiation because the Bragg peak permits the accurate concentration of the dose on the tumor, thus sparing theadjacent normal tissues. Moreover, carbon ion has more radiobiological benefits than photon and proton beams.These benefits include stronger sterilization effects on intrinsic radio-resistant tumors and more effective killing ofhypoxic, G0, and S phase cells. Compared with the most advanced radiation techniques using photon, such asthree-dimensional conformal radiation therapy and intensity-modulated radiation therapy, proton therapy hasyielded more promising outcomes in local control and survival for head and neck cancers, prostate carcinoma, andpediatric cancers. Carbon therapy in Japan showed even more promising results than proton therapy. The localcontrols and overall survivals were as good as that treated by surgery in early stages of non-small cell lung cancer,hepatocellular carcinoma, prostate carcinoma, and head and neck cancers, especially for such highly resistanttumors as melanoma. The non-invasive nature of particle therapy affords more patients with chances to receiveand benefit from treatment. Particle therapy is gradually getting attention from the oncology community.However, the cost of particle therapy facilities has limited the worldwide use of this technology.

Keywords radiation therapy; particle therapy; proton; carbon; cancer

Introduction

Radiation therapy has been widely used in the management ofcancers, and has become one of the major modalities forcancer patient care. In the past two decades, modern radiationtherapy technologies, three-dimensional conformal radiationtherapy (3DCRT), and intensity modulated radiation therapy(IMRT) have been developed and gradually applied in clinics.Given that these techniques could concentrate irradiationdoses on the tumor while sparing the adjacent normal tissuesand organs, significantly improved local controls andsurvivals were obtained without an increase in irradiation-induced toxicity. Therefore, this technique becomes acommon tool in cancer irradiation. However, a number ofproblems and defects are exhibited by these techniques. Forexample, these approaches deliver low doses to a largevolume of normal tissues and expose the patient’s entire body

to a low irradiation dose, thus increasing the risk ofirradiation-induced second malignancies, particularly inyoung patients. Moreover, tumors that are highly resistantto irradiation, such as melanoma and sarcomas, cannot becontrolled even with very high doses. Therefore, furtherexploration of new irradiation technology in the radiationtherapy field is needed.

Particle beam therapy is one of the new irradiation toolsunder development, which shows promising potential inradiation therapy. Therefore, this type of therapy has drawnconsiderable attention from the oncology community over thepast two decades. This article reviews radiation physics,radiobiology, and clinical experience in particle irradiation topresent this frontier in radiation therapy and to promote it asone of the multidisciplinary approaches to cancer patient care.

History of particle therapy

Particle irradiation for cancers started in 1952 in LawrenceBerkeley National Laboratory, USA. The particle used for

Received September 7, 2011; accepted March 12, 2012

Correspondence: jianggl@shca.org.cn

Front. Med. 2012, 6(2): 165–172DOI 10.1007/s11684-012-0196-4

cancer therapy in large-scale clinical trials was the fastneutron in the 1970s. However, this particle was laterabandoned because of intolerable toxicity and complications.Several particles, including proton, helium, carbon, neon, – π,and so on, have been clinically studied to treat malignancies.Lately proton and carbon beams have been demonstrated asthe optimal particles for the clinical irradiation of cancers. In1991, Loma Linda University Medical Center (LLUMC)established the first dedicated synchrotron for cancer therapyin the world [1]. The National Institute of RadiologicalScience (NIRS) in Chiba, Japan, is most famous for carbonbeam irradiation. NIRS started to treat cancers in 1994, andover 6 000 patients have been treated to date [2]. Preliminaryresults demonstrate that the local controls and survivals aftercarbon ion therapy were as good as those treated by surgeryfor prostate carcinoma, early-stage non-small cell lungcarcinoma (NSCLC), and liver cancers. Moreover, particletherapy is a non-invasive treatment and is thus suitable formore patients, such as those suffering from cardiovasculardiseases and poor liver function. The encouraging outcome ofproton and carbon irradiation reported in the literaturemotivates an increasing number of hospitals to show interestin particle irradiation. Although particle irradiation isbelieved to be a new tool for radiation oncology in thecoming years, not many hospitals in the world are planning orbuilding particle therapy facilities because such facilities arevery expensive.

Physics and radiobiology of particleirradiation

Physics [3]

The physical dose distribution of particle beams, includingproton and carbon, have been found to be the mostappropriate for cancer therapy. At present, the irradiationbeams widely used in clinics are photons, including the γ rayfrom 60Co, orthovoltage X-ray, and megavoltage X-ray fromliner accelerators. The physical dose distribution of photon ischaracterized by a build-up effect in the first centimeters,followed by an exponential decrease as the photon beam goesdeep into the tissue. In contrast, the physical dose distributionof charged particle beams, such as proton and carbon ions, isshown in Fig. 1. The energy deposited at a certain penetrationdepth is inversely proportional to the ion energy, and nearlyall energy is released at the end of beam track, forming a veryhigh-dose region with little or no dose deposited beyond thisregion. This high-dose region is named the “Bragg peak” afterWilliam Bragg, who discovered it in 1904. When a 135 MeVproton beam penetrates a tissue, the deposited dose followsthe following pattern: low dose at the first 10 cm, called theplateau phase and progression to the “Bragg peak” untilalmost no dose remains. For carbon beam, however, a “tail”dose exists beyond the “Bragg peak,” indicating that a

fraction of the dose remains after the “Bragg peak.” Overall,the physical dose distribution of particle beams is optimal forcancer irradiation therapy. For example, for a tumor between10 and 16 cm beneath the skin surface (Fig. 1), photon beamirradiation delivers a 100% to 150% dose to the tumor at theentrance irradiation dose, assuming that the entrance dose inthe skin is defined as 100%, and the normal tissues in front ofand behind the tumor receive 150% to 200% and 100% of theentrance dose, respectively. Thus, when a tumor is irradiatedby photons, the normal tissues adjacent to it also receivesignificant doses, as high as or even higher than that the tumorreceives. In contrast, the tumor receives 400% to 500% of theentrance dose for particle beams, whereas the normal tissuesin front receive 100% of the entrance dose and those behindthe tumor receive no dose. These favorable physical proper-ties of particle beams permit highly precise dose localizationfor cancer therapy, which can spare normal tissues in front ofand beyond the “Bragg peak.” However, “Bragg peak” widthis quite narrow, and the diameter of tumors is typically large,which means that the “Bragg peak” cannot cover the totaltumor volume. Thus, a method called spreading-out of the“Bragg peak” is developed, which could be achieved viapassive beam modification systems with ridge filters forproton beam with the fixed energy generated by cyclotron orby adjusting beam energies for protons from synchrotron.However, the dose in the plateau phase increases when the“Bragg peak” is spreading out (boarding) because of multiplebeam scans with different energies, which adds up eachplateau phase dose.

High-dose distribution must conform to the three-dimen-sional tumor shape to spare the adjacent normal organs andtissues. The most commonly used methods are scattering

Fig. 1 Physical dose distributions of photon, proton and carbonbeams. Irradiation dose to skin is taken as 100%. There is a tumorlocated 10 cm to 16 cm beneath the skin.

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systems that enlarge beam profile and allow the geometricbeam shape to conform to the tumor shape with collimators orblocks. A compensator should be applied to allow the distaledge of the high dose shape to conform to the tumor distaledge. A block and a compensator should be constructed foreach irradiation beam, which is a time-consuming and labor-intensive task. Therefore, intensity-controlled raster scanningtechnique is developed, which uses small pencil beams ofvariable energy. For geometric matching with tumor shape, ascanning beam can actively draw any shape conforming to thetumor shape and can also deposit “Bragg peaks” at certaindepths by adjusting beam energies. For the beam-scanningtechnique, the tumor is scanned one slice at a time, startingwith the furthest slice and continuously to the closest slice.Finally, an extremely precise filling of the target volume isachieved, which could include up to 5 000 voxels within3 min to 5 min with an individually calculated number ofparticles. With this particle irradiation technology, dosedistributions are far superior to photon 3DCRT or IMRT asdemonstrated by Chiang in lung cancer [4]. In Chiang’sdosimetric study a very high dose could be concentrated onthe lung tumor with good conformity in both proton andphoton IMRT therapies. However, proton delivered asignificantly lower dose to the normal lung compared withphoton. When stage I NSCLC (n = 10) was irradiated to66 Gy by photon 3DCRT, the mean lung V5 (percentage oflung volume that receives ≥ 5 Gy in total lung volume), V10

(percentage of lung volume that receives ≥ 10 Gy in totallung volume), and V20 (percentage of lung volume thatreceives ≥ 20 Gy in total lung volume) were 31.8%, 24.6%,and 15.8%, respectively, whereas they were 13.4%, 12.3%,and 10.9%, respectively when those patients were irradiatedto 87.5 Cobalt Gray equivalent (GyE) by proton beam (P =0.002). For stage III NSCLC (n = 15) the mean lung V5, V10,and V20 were 54.1%, 46.9%, and 34.8%, respectively whenlung tumors were irradiated to 63 Gy with photon 3DCRT,whereas those percentages were 39.7%, 36.6%, and 31.6%,respectively, when irradiated by proton with 74 GyE (P =0.002). Doses to the lung, spinal cord, heart, esophagus, andintegral doses in all cases were lower with proton therapycompared with IMRT. Irradiation-induced complicationswould be significantly reduced in proton therapy comparedwith photon because of the low doses deposited to normaltissues and organs.

Radiobiology [5–8]

Linear energy transfer (LET) for ionization beams defines theenergy deposited along the ion’s path. LET is found to be auniversal parameter for radiobiological effects and correlateswith relative radiobiological effect (RBE), that is, higher LETresults in higher RBE. The track diameter of different ions isnot proportional to LET but is dependent on particle energy.However, although RBE tends to increase with LET, eachtype of beam can produce a range of LET values, such that

LET alone does not totally correlate with RBE. Moreover,given that carbon ions have larger particle size than protons,proton and carbon ion beams with the same LET displaydifferent RBE.

The RBE of proton beam is 1.0 to 1.1 in in vitro and in vivoexperiments, indicating that the biologic effect of proton isslightly higher than that of 60Cobalt. However, RBEs forcarbon are mixed with low LET in the entrance plateau andhigh LET in the “Bragg peak” area. Thus, the RBEs of carbondiffer. Cell irradiation damage is the damage to DNA. DNAdamage is of three types, namely, base, single strand break(SSB), and double strand break (DSB). SSB is more easilyrepaired than DSB damage. Moreover, low LET DSB damageis generally more readily repaired than high LET DSBdamage because high LET causes “clustered” damage,whereas low LET damage is more detached.

After photon and proton irradiation, a majority of DNAdamage is SSB, which is repairable. However, after carbonirradiation with “Bragg peak” dose, at least 70% of DNAdamage becomes DSB. Therefore, carbon produces signifi-cantly more severe DNA damage compared with photon andproton, thus inducing more cell death by apoptosis. Asillustrated in Fig. 2 by colony-forming assay the survivalcurve bends with a “shoulder” at low dose ranges of photonirradiation (acute hypoxic cells), which indicates damagerepair. In contrast, the cell survival curve is a straight lineexponentially without a “shoulder,” suggesting the absence ofrepair after carbon irradiation within the “Bragg peak” dose(acute hypoxic cells). Therefore, carbon has high RBE in the“Bragg peak.” Compared with photon and proton irradiation,carbon has a stronger effect in terms of cell killing, whichincludes three aspects. First, cell radiosensitivity is increasedby the carbon beam. Cell killing in photon and protonirradiation is generally cell cycle phase dependent, with the Sand G0 phases being irradiation resistant, whereas cells in theG2 and M phases are sensitive. When cells are irradiated with“Bragg peak” of carbon beam, no radiosensitivity differencesare observed among the G0, G1, S, G2, and M phases, and allcell cycling phases are sensitive. Hence, radiosensitivity isincreased by carbon irradiation, especially for irradiation-resistant S and G0 phases. Second, hypoxic tumor cells thatare highly resistant to photon and proton are no longerresistant to carbon irradiation. For low-LET beams in hypoxictumors, cells are 2.5 times to 3 times more radioresistant thannormoxic cells, that is, cell killing exhibits oxygen depen-dence with an oxygen enhancement ratio (OER) of 2.5 to 3for hypoxic cells, implying that hypoxic cells need 2.5 timesto 3 times more photon dose to be sterilized. In contrast,carbon beam has an OER of 1, suggesting that hypoxic cellsare as sensitive as oxygenated cells. As shown in Fig. 2, boththe survival curves of acute and chronic hypoxia cells exhibit“shoulders” after photon irradiation. However, the“shoulders” disappear, and the slope of curve becomessteeper after “Bragg peak” irradiation of carbon ion, whichindicates an increase in the radiosensitivity of hypoxic cells.

Guo-Liang Jiang 167

From Fig. 2, the shape and slope of survival curves of theoxygenated, acute, and chronic hypoxic cells are evidentlyalike, which implies that photon-resistant hypoxic cells are assensitive as oxygenated cells to carbon ion. Third, carbonirradiation can effectively kill intrinsic photon-resistanttumors, such as bone and soft tissue sarcomas, melanomas,and so on. Such malignancies are highly resistant to photonbeams, but could be controlled by carbon irradiation. Overall,a carbon beam produces stronger cell killing in “Bragg peak”area compared with photon and proton beams. However,carbon therapy is a double-edged sword. If normal tissues andorgans are exposed to “Bragg peak” of carbon beam, thedamage is also severe.

Clinical experience

Up to 2009, a total of 78 275 patients had been treated byparticles, including 67 097 by proton, 7 151 by carbon, 1 100by – π, 2 054 by helium, and 873 by other particles. Inradiation physics, radiobiology, and clinical practice, nowa-days proton and carbon are recognized as the most optimalparticles for cancer irradiation. The outcome reported in theliterature showed superiority to treatment by photons in termsof tumor control, survivals, irradiation-induced complica-tions, and quality of life. At present, 28 particle therapyfacilities are in use worldwide, which are located in Japan,USA and Europe, and 18 facilities are currently under

construction. A carbon therapy facility is available inLanzhou, Gansu, China, and a new one is under constructionin Shanghai.

Proton therapy

LLUMC is the first to use a dedicated synchrotron to generateproton for cancer therapy since 1991. All cancers that aresuited to photon irradiation are also indications for protontherapy. However, proton is more advantageous to tumors inthe base of the skull, orbit, central nervous system, andpediatric patients.

(1) NSCLC. LLUMC treated 67 cases of stage I NSCLC byproton with 51 GyE to 60 GyE in 10 fractions over twoweeks. All patients were not qualified for surgery because ofcardiovascular disease or poor pulmonary function. None ofthe patients showed irradiation-related symptoms, such asearly and late complications in the esophagus, heart, andlungs. With median follow-up time of 30 months, three-yearlocal control and survival were 74% and 72%, respectively[9]. Nihei reported 37 cases of inoperable stage I NSCLCwith proton of 70 GyE to 94 GyE in 20 fractions, resulting intwo-year progression-free survival of 80%, two-year overallsurvival of 84%, and locoregional progression-free survivalsof 79% (stage Ia) and 60% (stage Ib) [10]. Iwata reported theNagoya experience on stage I NSCLC using proton (57patients) and carbon beam (23 patients). Irradiation doseswere 80 GyE in 20 fractions or 60 GyE in 10 fractions for

Fig. 2 Cell survival curves after X-ray and “Bragg peak” irradiation of carbon ion (illustration). Curves with hollow circles (oxia),squares (chronic hypoxia), and triangles (acute hypoxia) are irradiated by X-ray, and those with solid circles, squares, and triangles areirradiated by carbon beam.

168 Particle therapy for cancers

proton and 52.8 GyE in four fractions for carbon. For all 80patients with the median follow-up period of 35.5 months forliving patients, three-year overall survival, cause-specificsurvival, and local control rates were 75% (IA: 74%; IB:76%), 86% (IA: 84%; IB: 88%), and 82% (IA: 87%; IB:77%), respectively. Irradiation-related toxicity was slight,with grade 3 of pulmonary toxicity in one patient [11].

Proton therapy had been tried for locally advancedNSCLC. A retrospective study was conducted for protontherapy in 35 stage II to IIIb patients (stage II, 5; stage IIIA,12; stage IIIB, 18). Their median age was 70.3 years. Themedian proton dose given was 78.3 GyE (67.1 GyE to 91.3GyE) without chemotherapy. Local progression-free survivalwas 93.3% at one year and 65.9% at two years. Four patients(11%) developed local recurrence, 13 (37%) regionalrecurrence, and 7 (20%) distant metastases. The progres-sion-free survival rate was 59.6% at one year and 29.2% attwo years. The overall survival rate was 81.8% at one yearand 58.9% at two years. Grade 3 or greater toxicity was notobserved. A total of 15 patients (42.9%) developed Grade 1and 6 patients (17.1%) developed Grade 2. Proton irradiationfor stage II-III NSCLC without chemotherapy resulted ingood local control and low toxicity, and hence it could beintergraded with chemotherapy [12].

Sejpal et al. from M.D. Anderson retrospectively analyzedtreatment-related toxicity in NSCLC treated by concurrentchemotherapy and irradiation (3DCRT, 74 cases; IMRT, 66cases; proton, 62 cases). The study found fewer incidencesof ≥ Grade 3 pneumonitis and esophagitis in the protongroup (2% and 5%). On the other hand, the incidences were30% and 18% in the 3DCRT group and 9% and 44% in IMRTgroup (P < 0.001 for all) despite higher irradiation dose totumor in proton (74 CGE) than in 3DCRT (63 Gy) and IMRT(63 Gy) [13].

Overall, from a limited number of studies, proton therapyshowed encouraging outcomes for medical inoperable early-stage NSCLC and locally advanced NSCLC with mildirradiation-related toxicity.

(2) Prostate carcinoma. LLUMC is the first to report protontherapy for prostate carcinomas. As early as 1998, theyreported 643 patients with localized prostate carcinomatreated with protons, with or without photons. Treatmentswere 74 GyE to 75 GyE at 1.8 GyE to 2.0 GyE per fraction.The overall disease-free survival rate was 89% at five years.The 4.5-year disease-free survival was 100% for patients withinitial prostate-specific antigen (PSA) of < 4.0 ng/ml, and89%, 72%, and 53% for patients with initial PSA levels of4.1 ng/ml to 10.0 ng/ml, 10.1 ng/ml to 20.0 ng/ml,and > 20.0 ng/ml, respectively. Patients with post-treatmentPSA nadir below 0.5 ng/ml did significantly better than thosewhose nadir values were between 0.51 and 1.0 ng/mlor > 1.0 ng/ml. The corresponding five-year disease-freesurvival rates were 91%, 79%, and 40%, respectively.Minimal radiation proctitis was seen in 21% of patients,and toxicity of greater severity was observed in less than 1%

[14]. LLUMC later summarized 1 255 cases of prostatecarcinoma irradiated by proton and reported PSA-freesurvival of 73% at 10 years. Acute complication ofgrade ≥ 3 in gastrointestinal (GI) and genitourinary (GU)systems occurred in < 1%, and late GI and GU toxicity ofgrade ≥ 3 occurred in 1% [15].

(3) Chordoma in base of skull. Igaki’s summary of the localcontrol rates in the literature for proton therapy showed thatthe five-year local control rates were 46% to 73% at fiveyears, in contrast 17% to 39% for photon treatment [16].

(4) Hepatocellular carcinoma (HCC): Kawashima reported30 inoperable HCC patients irradiated with proton. A dose of76 GyE in 20 fractions was delivered over five weeks. After amedian follow-up time of 31 months, local progression-freerate and overall survival rate at two years were 96% and 66%,respectively. Four patients died of hepatic insufficiency [17].

Chiba et al. conducted a retrospective study on protonbeam therapy for HCC. A total of 192 lesions in 162 HCCpatients were treated by proton with or without transarterialembolization and percutaneous ethanol injection. The patientswere medically unsuitable for surgery because of hepaticdysfunction, multiple foci, or recurrence after surgery. Themedian total dose of proton irradiation was 72 Gy in 16fractions over 29 days. The overall survival rate for all 162patients was 23.5% at five years. The local control rate at fiveyears was 86.9% for 192 tumors among the 162 patients. For50 patients associated with the least impaired hepaticfunctions and a solitary tumor, the survival rate at five yearswas 53.5%. Patients had very few acute reactions totreatments and a few late sequelae during and after treatment[18].

For medically inoperable or unresectable HCC, transarter-ial chemoembolization is the most commonly used treatment,but yields about 10% of three-year survival [19]. Therefore,proton provides a good treatment alternative for HCC patientswho are unfit for surgery.

Carbon therapy

Only a few hospitals worldwide provide carbon therapy, withthe majority from NIRS [2,20]. This institute has treated over6 000 patients using carbon beam. The high LET in the“Bragg peak” results in stronger radiobiological effect ofcarbon compared with photon and proton, which requires thephysical irradiation dose to be transferred to biologic dose byan RBE of 3. Therefore, the carbon dose thereafter isexpressed as GyE, which is the physical dose multiplied bythree.

(1) NSCLC: Since 1994, NIRS has conducted a series ofclinical trials to determine the most suitable irradiationschedule for early-stage NSCLC. NIRS started with afractionation of 18 fractions in six weeks (18 fr/6 wks), andthe total doses were escalated from 59.4 GyE to 95.4 GyE.Shift fractionation was then conducted at nine fractions inthree weeks (9 fr/3 wks), four fractions in one week

Guo-Liang Jiang 169

(4 fr/1 wk), and single dose. A range of doses was applied,beginning with low dose and escalating to high dose. A totalof 322 stage I NSCLC patients were enrolled, with all patientsbeing medically inoperable or refusing surgery. The study isstill ongoing. The optimal fractionations are 90 GyE for18 fr/3 wks, 72 GyE for 9 fr/3 wks, and 52.8 GyE and 60 GyEfor stage Ia and Ib for 4 fr/1 wk, respectively. However, theoptimal total dose for the single-dose schedule remainsundefined. For the 131 patients who received 4 fr/1 wk and9 fr/4 wks fractionation irradiation, the five-year local controlrates were 98.6% and 89.7%, and the five-year overallsurvivals were 63.1% and 50% for stage Ia and Ib,respectively. For the 121 patients irradiated by single doseof 36 GyE, the five-year local control and overall survival was79.2% and 63.6%, respectively. On the other hand, irradiationinduced side-effects and toxicity were slight, with < 5% ofGrades 3 to 4 early toxicity in skin and lung, and 2% of Grade2 late toxicity. Moreover, in this cohort, 56% of the patientswere medically inoperable, and 66% were over 80 years old.The local control and overall survival treated by carbon are asgood as that treated by surgery [21–23].

(2) HCC: NIRS conducted a trial similar to that for NSCLCto determine the optimal fractionation in the 1990s. Theystarted with 49.5 GyE to 79.5 GyE in 15 fractions in 5 weeks(15 fr/5 wks), followed by total doses of 32 GyE to 69.6 GyEin 12 fractions in 3 weeks (12 fr/3 wks), 8 fractions in 2 weeks(8 fr/2 wks), 4 fractions in 1 week (4 fr/1 wk), and 2 fractionsin 2 days (2 fr/2 d). Schedules of 4 fr/1 wk and 2 fr/2 d wererepeated after a more advanced irradiation technique was usedin 2005. To date, 392 HCC patients have been enrolled. Thefive-year local control rates were 93%, 86%, 86%, and 81%,respectively, for 4 fr/1 wk, 8 fr/2 wks, 12 fr/3 wks, and15 fr/5 wks, comparable with that reported from surgery[24]. Moreover, five-year local controls were slightly betterfor a tumor diameter ≤ 5 cm than for > 5 cm (90% vs.86%). With respect to hepatic toxicity, which was evaluatedvia Child-Pugh scores three months after irradiation, 40% to65% of the patients maintained their scores, and the rest hadscores reduced by 0 to 1 point in different fractionations. Atthree to 12 months after irradiation, 40% to 55% of thepatients still had unchanged scores, whereas others droppedby 1 to 2 points [25,26].

(3) Prostate carcinoma: Three different fractionation regi-mens were tried at NIRS, namely, 66 GyE in 20 fractions overfive weeks, 63 GyE in 20 fractions over five weeks, and57.6 GyE in 16 fractions over four weeks. The last regimen(57.6 GyE) has been demonstrated to be appropriate withminimum side effects. A total of 903 prostate carcinomashave been summarized, and carbon irradiation yielded five-year overall survival and PSA-free survivals of 94.9% and90.9%, respectively. For high risk patients (GS 8-10 and T3),the five-year overall survival was 87%. Notably, 2.3% of GIand 5.1% of GU toxicity rates were recorded. The NIRS studyon prostate carcinomas irradiated with carbon beam showedan outcome similar to that reported in surgery and proton and

photon IMRT. Local control and survival for high riskpatients were better than those treated by other modalities.

(4) Head and neck cancers: Several tumors are photon andproton resistant. Such tumors include adenocarcinomas (AC),adenoid cystic carcinomas (ACC), papillary carcinoma (PC),and malignant melanomas (MM). NIRS reported 195 cases(AC 27, ACC 70, PC 13, MM 85) irradiated with carbon ion.The five-year local control rates were 76%, 74%, 81%, and75%, and the five-year overall survivals were 47%, 70%,26%, and 75%, respectively, for AC, ACC, PC, and MM.However, their outcome would be dismal if treated withphotons [27].

(5) Osteosarcoma: This tumor is extremely resistant tophoton irradiation. NIRS irradiated 81 patients with carbonion, which yielded a five-year overall survival of 34%, and42% of sarcomas in pelvis and sacrum were administeredwith doses of 64 GyE to 70.4 GyE in 16 fractions.

(6) Skull-base tumors: A national institute of heavy ion inGermany (GSI) treated 96 patients with chordoma in the baseof skull by carbon ion with a median total dose of 60 GyEdelivered in 20 fractions over three weeks, and they showedlocal control rate of 81% and 70% and overall survival of91.8% and 88.5% at three and five years, respectively [28].

(7) Soft tissue sarcomas and chondrosarcomas: Soft tissuesarcomas and chondrosarcoma are radioresistant and are notindicated for photon irradiation. Imai reported a five-yearlocal control rate of 96% for unresectable sacral chordomas (n= 32) after carbon irradiation with a median of 70.4 GyE [29].NIRS also used carbon to irradiate unresectable bone and softtissue tumors (n = 57), resulting in three-year local controland overall survival of 73% and 46%, respectively [30]. GSIalso employed carbon beam to treat spinal and sacrococcy-geal chordomas and chondrosarcomas with similar results tothat in NIRS.

(8) Recurrent rectal cancer: Locally recurrent rectal cancerafter surgery is generally incurable with modern therapies.NIRS irradiated 65 patients with local recurrences aftersurgery with total doses up to 73.6 GyE, resulting in three-year local control of 82% and three- and five-year overallsurvivals of 65% and 55%, respectively. Irradiation-relatedtoxicities were acceptable [26].

Debate of particle therapy

The value of particle therapy in cancer therapy is currentlybeing debated. In terms of physical dose distribution ofparticle beams, particle beams unquestionably deliversignificantly less doses to normal tissues, which could reduceirradiation-induced mortality and morbidity and allow fordose escalation to improve disease control and survivalwithout increased toxicity. On the other hand, the photonIMRT technique could satisfy most dose requirements interms of dose conformity in tumors. However, consideringthe high cost of facilities, some people think that the

170 Particle therapy for cancers

development of proton therapy is not worthwhile because nodifference is observed between the biologic effect of photonand proton. Moreover, clinical trials from single-arm studiesshow encouraging outcomes by proton therapy, but no clearevidence of benefit is shown in well-designed prospectivestudies [31]. However, people with a positive attitude towardproton believe that proton beam should be further developedbased on the optimum characteristic of physical dosedistribution and available data. Heavy-ion therapy is morecontroversial. More favorable opinions have been given inJapan and Germany, and a number of heavy ion centers arebeing constructed based on their clinical experience andfavorable outcomes in carbon therapy. In contrast, nohospitals are building heavy ion centers in the USA atpresent despite the heavy-ion therapy started from LawrenceBerkley National Laboratory, USA. The predominant concernis the irradiation injuries of normal tissues and organs inheavy ion therapy.

Challenges to particle therapy techniques include doseuncertainty in the moving targets of lung and liver cancerpatients, dose calculation inaccuracy in inhomogeneityregions, and so on. Hypofractionation has been used inparticle therapy, but further study is needed to determine theoptimal fractionation.

In summary, the following points could be drawn from thisreview: (1) Preliminary data in the literature on particletherapy (proton and carbon beams) show more promisinglocal control, survival, and significantly reduced irradiation-related toxicity for several cancers compared with photon3DCRT/IMRT; (2) The local control and survival of patientstreated by proton, especially carbon, are as good as those ofpatients treated by surgery for early-stage NSCCL, HCC,prostate carcinoma, and some radiation-resistant head andneck cancers. Nevertheless, good outcomes should bereconfirmed by large-scale prospective clinical trials;(3) Particle irradiation provides more opportunities oftreatment for cancer patients, especially for elderly patientswith medical co-morbidities; (4) Proton therapy is at a maturestage with over 60 000 patients treated, but only 7 000 caseshave been treated with carbon ion. Given the lethal damage toboth tumor and normal tissues, an accurate irradiation isabsolutely necessary. Moreover, such an approach willrequire more advanced technology and experience, as wellas a greater understanding of radiobiological effects.

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