proton therapy for non–small cell lung cancer: current evidence and future directions

I N V I T E D R E V I E W

Proton therapy for non–small cell lung cancer: Currentevidence and future directionsShervin M. Shirvani & Joe Y. Chang

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Keywordsintensity modulated proton therapy; non-smallcell lung cancer; proton therapy.

CorrespondenceJoe Y. Chang, Department of RadiationOncology, The University of Texas MDAnderson Cancer Center, 1515 HolcombeBoulevard, Houston, TX 77030, USA.Tel: +1 713 563 2337Fax: +1 713 563 2331Email: [email protected]

Received: 14 October 2011;accepted 18 November 2011.

doi: 10.1111/j.1759-7714.2011.00095.x

Abstract

Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deathworldwide. Radiation dose escalation can improve survival in NSCLC patients but isoften limited by adverse effects. One promising radiotherapy modality is protonradiotherapy, which, because of its physical characteristics, delivers minimal exitdose beyond the target volume and thus results in better sparing of normal tissuesthan does photon radiotherapy. Passive-scattering proton therapy and intensity-modulated proton therapy have shown promise in the treatment of early-stage andlocally advanced non–small cell lung cancer. However, more studies are needed tooptimize proton therapy, particularly intensity-modulated proton therapy, toaddress motion and density changes and to guide appropriate patient selection.

Introduction

Non–small cell lung cancer (NSCLC) is the leading cause ofcancer death in the world.1 In the United States, two publichealth pressures may increase lung cancer’s burden on thehealth care system. First, as the “baby boom” generation ages,the number of elderly patients with lung cancer is expected toincrease from about 213 500 in 2010 to more than 314 000 by2030.2,3 Second, the National Lung Screening Trial revealedthat annual lung cancer screening with low-dose computedtomography (CT) over a 3-year period reduced overall mor-tality in high-risk patients compared with lung cancer screen-ing with chest radiography.4 If patients, physicians, andpolicymakers are guided by this trial’s findings, many addi-tional lung cancer diagnoses will likely be uncovered byscreening CT. The anticipated increase in lung cancer inci-dence in the United States underscores the need for new,effective therapies for NSCLC.

Clinical evidence suggests that intensifying the delivereddose when using radiotherapy can improve local diseasecontrol and survival rates. However, dose escalation inNSCLC patients is limited by the risk of the severe toxicities in

intrathoracic structures, including the lungs, heart, esopha-gus, and spinal cord. Proton therapy has the potential to limitradiation-induced toxic effects: unlike photons, which causeionizing damage throughout the beam path, particularly inthe exit dose path, protons penetrate tissue and deposit thebulk of their energy at a particular depth, the Bragg peak,which is a function of the protons’ initial energy and densityof the tissue in the beam path. Because this depth-dose distri-bution is characterized by dose deposition in a specificallydelineated target and minimal exit dose (Fig 1), proton radia-tion holds the promise of limiting the dose to the intendedvolume and reducing the exposure of at-risk organs such asuninvolved lung and the heart, esophagus, and spinal cord(Fig 2). This feature of proton therapy may be particularlybeneficial in patients who have limited pulmonary reserve orwho are vulnerable to additional toxicity from concurrentchemotherapy.

Despite proton therapy’s theoretical advantages, there areseveral points of controversy regarding its use for NSCLC.Thetechnical requirements of high-quality proton beam therapypose challenges to the broad adoption of the treatment. More-over, given the higher cost premium of proton therapy, some

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Thoracic Cancer 3 (2012) 99–108 © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd 99

Figure 1 Spread Out Bragg Peaks (SOPB) of distinct lengths measured at MD Anderson Cancer Center. Abbrev. PDD, Proton Depth Dose.

Figure 2 Comparison of proton therapy (I) and photon therapy (II) in a centrally located early-stage tumor using the same ablative dose regimen. Thelow-dose exposure of normal structures including the esophagus (E), heart (H), aorta (A), and spinal cord (SC) is diminished in the proton plan. Thecoverage of the gross tumor volume (GTV) and planning target volume (PTV) is similar for both treatments.

Proton therapy for NSCLC S.M. Shirvani & J.Y. Chang

100 Thoracic Cancer 3 (2012) 99–108 © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd

clinicians demand a definitive side-by-side comparison ofproton therapy with newer photon radiotherapy techniquessuch as 3-dimensional (3D) conformal radiotherapy(3DCRT) and intensity-modulated radiotherapy (IMRT)before changing practice. Herein, we review the technicalaspects of proton therapy for NSCLC and evaluate the clinicalevidence for its use in patients with early-stage and advancedNSCLC.

General technical and biologicalaspects of proton therapy

A proton beam consisting of a single energy generates anarrow Bragg peak of limited clinical utility. To cover a tumorvolume, the spread-out Bragg peak – a series of Bragg peaksalong a continuum of energies – is used to create a uniformdose distribution that covers the length of the target volumebut avoids dose delivery to distal structures (Fig 1). Theradiation dose delivered with proton beam therapy isexpressed as cobalt-Gray equivalents (CGE) which reflectsthe fact that a conversion factor is needed to determine thedose of protons needed to exert the same effect as dose pre-scriptions based on photon radiation. This factor, called therelative biological effectiveness (RBE), is defined as the ratioof the photon radiation dose necessary to achieve a specificbiological effect in an experimental system to the protonradiation dose required to achieve the same biological effect.For proton therapy, the RBE is generally accepted to be 1.1.5

Another useful concept for reviewing the proton therapyliterature is the concept of biological effective dose. Althougha thorough discussion of radiobiology is beyond the scope ofthis review, at the very least it is important to note that theeffect of radiation on tissues is dependent on the total dosedelivered as well as the dose delivered in each session (calledthe “fraction size”). In general, a regimen that combines asmaller total dose coupled with a large fraction size can exertthe same biological effect as a regimen that uses a larger totaldose with a smaller fraction size. Therefore, when comparingtwo regimens of radiotherapy, it is useful to first convert eachof the regimens into a quantity that combines fraction size(FS) and total dose (TD) into a single value, which is calledthe biological effective dose (BED):

BED TD FS= × + ( )( )1 α β

In this equation, the a/b ratio is a radiobiological parameterthat reflects the radiosensitivity of the relevant tissues. Usingthe BED to compare different regimens is particularly impor-tant when considering the treatment of early-stage tumors, aswill be discussed below.

Two modes of proton therapy are currently in use. Inpassive-scattering proton therapy (PSPT), 3D treatmentplanning is used to deliver a conformal dose distribution.During treatment, a compensator is used to shape the distal

edge of the beam, while an aperture is used to limit the perim-eter of the radiation field.6,7 The second mode, scanning beamproton therapy, utilizes pencil-beam scanning with differentenergies to deliver treatment to each of the individual “spots”or voxels that constitute the tumor, to generate a shapedproton beam dose distribution. Intensity-modulated protontherapy (IMPT) is an inverse treatment planning procedurethat uses an objective function to simultaneously optimizethe intensity and energy of the pencil beam required todeliver the appropriate radiation dose to each of the hundredsof voxels in the tumor volume.8 Another form of scanningbeam technology, uniform scanning, is used at some institu-tions to deliver radiation to planes or layers of tissue with auniform dose instead of dose painting of individual voxels.

Although both passive scattering and pencil-scanningtechnologies take advantage of the Bragg peak to limit theradiation dose to normal structures, the conformalityachieved with pencil-scanning methods like IMPT is gener-ally better than that achieved with PSPT. However, the greaterprecision achieved with IMPT means that there is less marginfor error and this can be a significant disadvantage for mobiletargets. Therefore this technology has not been implementedfor intrathoracic tumors at most institutions. At our center,we are currently investigating IMPT for lung cancer in pre-clinical studies, but we have limited the use of this technologyin clinical practice to a subset of mediastinal tumors with verylimited motion (<5 mm).

Advantages and challenges ofproton therapy

The theoretical advantage of proton radiotherapy overphoton radiotherapy is the formers superiority in sparingnormal tissues. Two approaches can be used to improve clini-cal outcomes in patients who undergo proton radiotherapy.First, radiation oncologists can maintain set dose constraintsand deliver an escalated radiation dose to the target volume.Alternatively, radiation oncologists can keep the prescriptiondose constant and minimize radiation exposure to normaltissue as far below dose constraints as technically feasible.

Illustrating the first strategy, two studies at MD AndersonCancer Center have shown that, given a constant set ofnormal tissue dose constraints, higher radiation doses can beachieved with proton therapy than with photon therapy.Chang et al. generated 3DCRT, IMRT, and PSPT plans for 25patients with either stage I or stage III NSCLC.6 Using protontherapy, the investigators found that they could radicallyincrease the allowable radiation dose to the tumor whileremaining within the dose constraints. Among the patientswith stage I NSCLC, the mean total volumes of lung receivingat least 5 Gy (V5), 10 Gy (V10), or 20 Gy (V20) were 31.8%,24.6%, and 15.8%, respectively, for 66-Gy photon 3DCRTplans, whereas the lung received less dose on all three

S.M. Shirvani & J.Y. Chang Proton therapy for NSCLC


measures (V5, V10, and V20 of 13.4%, 12.3%, and 10.9%,respectively) with proton therapy, despite escalating the doseto 87.5 CGE (a 33% increase). For patients with stage IIINSCLC, the mean total lung V5, V10, and V20 were 54.1%,46.9%, and 34.8%, respectively, for 63-Gy photon 3DCRTplans, whereas they were 39.7%, 36.6%, and 31.6%, respec-tively, for proton therapy with dose escalation to 74 CGE. Inall cases, the radiation doses to the lung, spinal cord, heart,and esophagus as well as the integral radiation dose werelower with proton therapy than with 3DCRT or IMRT. Morerecently, Zhang et al. conducted a virtual clinical study inwhich they compared IMRT, PSPT, and IMPT in a group ofpatients with locally advanced diseases who could not receivemore than 63 CGE via IMRT.8 They calculated dose-volumehistograms for each technique and found that IMPT sparedthe lung, heart, spinal cord, and esophagus more than IMRTor PSPT did, thereby allowing treatment with a higher radia-tion dose. In fact, the investigators found that the dose inthese patients could be escalated to a mean maximum tumordose of 84.4 CGE (range, 79.4–88.4 CGE) while keepingwithin the parameters of normal tissue sparing.

Other dosimetric studies have examined the feasibility ofusing a constant prescribed target dose and minimizingradiation exposure to normal tissue to improve toxicity pro-files in NSCLC patients. Register et al. compared using PSPT,IMPT, and photon-based radiotherapy to deliver stereotacticradiation regimens of 50 Gy in 4 fractions for centrallylocated stage I NSCLC. Both proton-based techniquesresulted in lower doses to the lungs, aorta, brachial plus, heart,and spinal cord than their photon counterparts.9 Hoppe et al.conducted a similar comparison of photon and proton ster-eotactic treatment in eight patients and as in the study by Reg-ister et al., proton-based radiotherapy spared more normaltissues than photon-based radiotherapy did. The differencewas especially marked in the lungs, where the mean radiationdose using proton therapy was an average of 2.17 CGE lowerthan those using photon-based techniques.10 MacDonaldet al. compared PSPT, IMPT, and photon stereotactic bodyradiotherapy (SBRT) for early-stage NSCLC. Like Registeret al. and Hoppe et al., MacDonald et al. found that theproton plans delivered a lower radiation dose to the lungs,esophagus, bronchial tree, and spinal cord than photon-basedradiotherapy did, though proton radiotherapy delivered aslightly higher radiation dose to the skin and chest wall.11 Thisfinal point is controversial as a recent study by Ciura et al.demonstrated that proton therapy using three or four beamsspared more chest wall than photon-based treatment.12

Both PSPT and IMPT pose technical challenges that mustbe addressed to provide high-quality treatment. Because ofthe characteristics of the Bragg peak, the same dosimetric fea-tures that allow radiation oncologists to reduce the radiationdose to normal tissue make proton treatment less forgivingwhen it comes to tumor motion and density changes.13–17

Therefore, precision is of the utmost importance when usingproton radiation for NSCLC, and planning that takes respira-tory motion into account is critical. Fortunately, protonradiotherapy systems are designed to limit the effect ofmotion on radiation accuracy. Four-dimensional (4D) CT(4DCT) planning enables the irradiation of a tumor acrossan entire respiratory cycle or within a specific phase of thecycle.18–21 In addition, a variety of external body frames anddevices facilitate high reproducibility of the patient’s positionto minimize interfractional changes due to set-up errors.21

Whenever possible, and particularly when ablative regimensare used, on-board axial imaging should be performed at thetime of treatment to verify the accuracy of the radiation fieldto within a millimeter. In select patients, adaptive re-planningshould be used to compensate for anatomic changes andtumor shrinkage, as these phenomena can drastically alter theradiation dose distribution of the original plan.16,17

Because treatment planning for PSPT is similar to that for3DCRT, complicated dose distributions are challenging tocreate, particularly when the dose must be conformed toeccentric or curved shapes. IMPT is better able than PSPTto conform dose in this way, but the greater precision of IMPTmakes meticulous quality assurance and respiratory compen-sation even more imperative. To that end, robust optimiza-tion of the IMPT plan can significantly improve conformalityand minimize the uncertainty of radiation dose delivery thatmotion or anatomy changes pose. We previously demon-strated that optimal proton radiotherapy plans required 4Dtargeting of an internal gross tumor volume, based on themaximal intensity projection of the tumor throughout theentire respiratory phase.22 In a follow-up study at our institu-tion, researchers collected weekly 4DCT data from eightpatients undergoing photon-based radiotherapy, designed aproton plan based on the initial simulation, and recalculatedthe dose distribution on each of the weekly scans.17 We foundthat up to 25% of the clinical target volume (CTV) could bemissed during the course of therapy if skin markers were theonly method used for patient set-up and 9% of the CTV couldbe missed if daily X-rays were used for bony alignment.However, consistent with the findings of our first study, suffi-cient CTV coverage over the course of therapy was achieved iftumor motion was taken into account with 4DCT at initialtreatment planning. Further studies investigating the deliveryof proton therapy to moving targets are ongoing at our insti-tution and others.

Clinical outcomes inEarly-Stage NSCLC

Historically, conventionally fractionated radiotherapy was analternative for NSCLC patients with early-stage NSCLC whowere not candidates for (or who refused) surgery. To respectthe dose constraints of normal tissues, radiation oncologists



typically used photon radiation to deliver 60–66 Gy to thetumor in 1.8- or 2.0-Gy fractions. Although this strategycured some patients, the outcomes were generally poor, with5-year local control rates of 30–50% and overall survival ratesof 10–30%.23,24

One explanation for these poor results is that conventionalphoton radiation could at most deliver a biologically effectivedose (BED) of 80 Gy before radiation-induced toxicitieslimited further dose escalation, which was not sufficient toexert complete tumoricidal effect. Supporting the notion thata higher dose can result in better tumor control, dose escala-tion has been actively studied in the past two decades as con-formal radiation techniques that could spare normal tissueshave become increasingly available. These clinical investiga-tions confirmed a dose-response relationship both in termsof local control and overall survival duration.24–28 Conse-quently, radiation oncologists have sought to achieve higherBEDs to obliterate tumors while avoiding excessive toxicity tonormal tissues. The use of conformal techniques includingproton therapy to improve the dose distribution of the treat-ment plan and/or the use of larger fraction sizes (hypofrac-tionation) have facilitated this effort.

Demonstrating the improved efficacy of higher BED, clini-cal investigations have found that stereotactic photon radio-therapy achieves local control rates of 80–98% in patientswith early-stage tumors.29–42 In fact, Onishi et al. found thatamong different SBRT regimens, a BED of at least 100 Gy isassociated with a higher 5-year local control rate (91.9% vs.73.6%) and longer overall survival (88.4% vs. 69.4%) than aBED of less than 100 Gy.30 A BED of at least 100 Gy canusually be achieved safely with 54–60 Gy delivered in 3 frac-tions or 48–50 Gy in 4 fractions prescribed to an isodoseline encompassing the planning target volume, provided thelesion is peripherally located and at least two cm away frommajor normal structures. Given the proper institutionalresources, experience, and quality assurance, grade 3–4toxicity rates in such patients are expected to range from 0%to 15%.29,34,39,40,43

For most peripheral tumors, photon-based SBRT isusually adequate to treat the lesion with high accuracyand low toxicity, and currently the cost of SBRT is less

than proton-based treatments. However, hypofractionatedproton therapy may have utility in improving the toxic-therapeutic ratio in patients with tumors located near sensi-tive central structures or superiorly near the brachial plexus.In such patients, using photons to deliver the ablative dose-fractionation schemes described above can result in signifi-cant morbidity and life-threatening complications such assevere pneumonitis, tracheal or great vessel rupture, esoph-ageal ulceration, and spinal cord myelopathy.44,45 One phaseII study of 70 patients who received 60–66 Gy in 3 fractionsrevealed that the 2-year severe toxicity rate was significantlyhigher in patients with central lesions than in patientswith peripherally located disease.46 At MD Anderson CancerCenter, more than 400 patients with early-stage or recurrentNSCLC less than four cm in diameter have received 50 Gy in4 fractions with heterogeneity correction in both peripher-ally and centrally located lesions.47–49 At 24 months medianfollow-up, the local control rate for all lesions was higherthan 95%. Although patients with peripheral lesions hadminimal toxicity, some patients with centrally locatedlesions experienced severe grade 3 or 4 chronic toxicity,and in others, the planning target volume had to be com-promised to adhere to dose-volume constraints.48 In a dif-ferent kind of high-risk scenario, we found that treatingrecurrent NSCLC in a previously irradiated field withstereotactic photon radiation achieved local control in 95%of patients but caused grade 3 or 4 pneumonitis in 27% ofpatients.49

One strategy to avoid toxicity in these high risk casesis to continue to use photon-based SBRT with a gentlerdose-fraction regimen (70 Gy in 10 fractions, for instance).However, an important alternative worth exploring is to takeadvantage of the dosimetric advantages of proton radio-therapy over photon-based stereotactic treatment. As of thetime of this review, relatively few clinical studies have pro-spectively investigated the use of proton therapy in patientswith early-stage NSCLC (Table 1). Bush et al., who used real-time fluoroscopy to verify patient position and no specificaction to correct for respiratory movements, treated 68patients with 51–60 CGEs delivered in 10 fractions.53 Despitethe older technique and a BED of less than 100 CGE (per

Table 1 Selected studies of proton therapy for early-stage non-small cell lung cancer

Trial Dose/fraction size (CGE) Local control Overall survival

ProspectiveChang (2010) [50] 87.5/2.5 89% (2 years) 54.5% (2 years)Iwata (2010) [51] 80/4 or 60/6 81% (3 years) 73% (3 years)Hata (2007) [52] 50–60/5–6 95% (2 years) 74% (2 years)Bush (2004) [53] 60/6 74% (3 years) 44% (3 years)

RetrospectiveNihei (2006) [54] 70–94/3.5–4.7 84% (2 years) 80% (2 years)Shioyama (2003) [55] 49–93/2–6 57% (5 years) 29% (5 years)



Bush, the BED was 82 CGE for patients whose received 60CGE in 10 fractions), the 3-year local control and cause-specific survival rates were 74% and 72%, respectively. More-over, no patients experienced acute radiation pneumonitis orearly or late esophageal or cardiac toxicity. Nihei et al., usingtechniques that included 3DCT simulation, respiratorygating, and real-time digital radiography for position verifi-cation, treated 37 patients with 60 CGE delivered in 6 frac-tions and reported a local control rate of 95% at 24 months.54

Hata et al. treated 21 patients who had stage I NSCLC with 50or 60 CGE delivered in 10 fractions and reported 2-yearoverall and cause-specific survival rates of 74% and 86%,respectively.52 The authors noted that all but one of theirradiated tumors were controlled during follow-up and thatthe toxicity profile was promising with no grade 3 or higherreactions.

Chang et al. conducted a phase I/II prospective study ofproton therapy for inoperable centrally or superiorlylocated stage IA (T1N0M0) NSCLC, any stage IB(T2N0M0) NSCLC, and selected stage II (T3N0M0)NSCLC. Unlike the aforementioned studies, in which verylarge fraction sizes were used, Chang et al. employed moremodest hypofractionation to treat 18 patients with a totaldose of 87.5 CGE delivered in 2.5-CGE fractions.50 At amedian follow-up time of 16.3 months, no patient hadexperienced grade 4 or 5 toxicity. The most commonadverse effects were grade 2 dermatitis (67% of patients),grade 2 fatigue (44%), grade 2 pneumonitis (11%), grade 2esophagitis (6%), and grade 2 chest wall pain (6%). Localcontrol was achieved in 88.9% of patients; however, 38.9%of patients developed metastatic disease in regional lymphnodes or distant organs. Iwata et al. reported similar prom-ising local control and overall survival rates at 3 years of81% and 73%, respectively, in a prospective trial of 57patients treated with a dose-fraction regimen of either 80CGE in 20 fractions or 60 CGE in 10 fractions.51 Grade 3pneumonitis only occurred in one patient who was treatedwith the higher dose. Notably, seven rib fractures and threeinstances of grade 3 dermatitis occurred in the 80 Gy arm,underlining the importance of reviewing the entrance dosewhen utilizing high-dose proton therapy.

Finally, in a retrospective review of modest hypofraction-ation, Shioyama et al. reviewed 28 patients who had stage INSCLC with proton radiation with a median total dose of76 CGE delivered in a median 3 CGE per fraction (range,2–6 CGE per fraction).55 The 5-year overall survival rate was70%, and local control was achieved in 89% of patientswith stage IA (<3 cm in diameter) disease. Only one patientdeveloped grade 3 acute toxicity, and minimal late toxicitywas observed. That these latter three studies demonstrateoutcomes comparable to those achieved with photon stereo-tactic approaches, despite the use of less intensive fraction-ation, is striking. Thus we conclude that for high-risk, large,

centrally located, or superiorly located tumors, modestlyhypofractionated proton therapy is an appealing strategy forachieving a high BED while allowing normal tissues torecover between fractions.

It is notable that despite their heterogeneity of doses,fractionation schemes, and techniques for positioning,immobilization, respiratory compensation, and geometricverification, the aforementioned studies all achieved excel-lent local control of the primary tumor and very favorabletoxicity profiles. However, whether proton therapy shouldbe used instead of photon-based techniques depends onspecific patient circumstances and clinical judgment. Threetypes of patients with early-stage NSCLC may be especiallywell-suited to receive proton therapy instead of photon-based radiotherapy: Those whose photon plan has an unac-ceptably high risk of radiation pneumonitis; those whocannot receive ablative photon radiotherapy because of thetumor’s proximity to critical structures; and those withrecurrent lesions in a previously irradiated field. To clarifythe relative clinical benefits of proton therapy and deter-mine whether the financial cost of the treatment is justified,researchers at MD Anderson are developing a prospectiverandomized study to directly compare ablative protontherapy with ablative photon-based radiotherapy using adose of 50 Gy in 4 fractions in patients with early-stage orrecurrent NSCLC.

Clinical outcomes in locallyadvanced NSCLC

Locally advanced (stage III) lung cancer is characterized bylarge primary tumors and the involvement of mediastinalnodes that are directly adjacent to central critical structures.In addition to these cancers’ high rate of metastatic spread,local tumor invasion is a significant contributor to mortalityand multiple prospective studies have demonstrated thatimproved local control is associated with better overall sur-vival durations.56–58

The proximity of advanced tumors to critical central struc-tures poses a challenge in delivering radiation therapy inpatients with NSCLC. As a result of this proximity, very highdoses per fraction cannot be used without causing graveinjury. Instead, the radiation dose must be escalated byincreasing the total dose delivered with conventional frac-tionation (1.8–2.0 Gy), moderately increasing the fractionsize (2.5–5.0 Gy), or using a radiosensitizing agent to increasethe effectiveness of the radiation. The goal of the first twoapproaches is to deliver a boost to the regions at highest riskof recurrence – perhaps as defined by imaging features such aspositron emission tomography positivity – while maintain-ing a conventional fractionation regime for the low-riskareas. As all strategies are expected to magnify the amount of



incidental radiation toxicity, organ dose constraints can limittheir feasibility.

Virtual dosimetric comparison studies have shown thatproton plans result in less radiation exposure of normaltissues than do photon plans, thereby enabling dose escala-tion. Several studies have confirmed the utility of usingprotons in locally advanced NSCLC to increase the radiationdose while avoiding normal tissue. Nakayama et al. retrospec-tively reviewed 35 patients with stage II or III NSCLC whowere not candidates for, or who refused surgery, and insteadwere treated with proton therapy without concurrent chemo-therapy (Table 2).60 The median proton dose delivered was78.3 CGE (range, 67.1–91.3 CGE), and the median follow-uptime was 16.9 months. The overall and local progression-freesurvival rates were 81.8% and 93.3%, respectively, at one yearand 58.9% and 65.9%, respectively, at two years. No grade3 or higher toxicity was observed. Similarly, Sejpal et al.recently published a retrospective analysis of 62 patientswith locally advanced NSCLC who were treated with protontherapy and concurrent platinum- or taxane-based chemo-therapy at MD Anderson between 2006 and 2008 and com-pared their outcomes with those of patients in earlier eraswho were treated with 3DCRT or IMRT. The median totalradiation dose was 74 CGE for the proton group and 63 Gyfor the two photon cohorts. Although the patients in theproton cohort received a higher radiation dose, their rates ofpneumonitis, esophagitis, and hematologic toxicity werelower than those observed in the patients in the photoncohort.61

Chang et al. recently completed a phase II study of 44patients with stage III NSCLC who received 74 CGE via con-ventional fractionation (2 CGE per fraction) with weeklyconcurrent carboplatin and paclitaxel.59 Despite the very highintensity of this treatment course, no grade 4 or 5 toxicitiesoccurred, and grade 3 toxicities were minimal: the mostcommon nonhematologic grade 3 toxicities were dermatitisin five patients, esophagitis in five patients, and pneumonitisin one patient. Due to the tolerability of this regimen, patientswere more likely to complete treatment. The median overallsurvival duration was 29.4 months, and the overall survivaland progression-free survival rates at 1 year were 86% and63%, respectively.

Although the findings of these retrospective and single-arm prospective studies are compelling, phase III studies

comparing photon- with proton-based radiotherapy wouldprovide better guidance for selecting between these twomodalities. Therefore, researchers at MD Anderson arecurrently conducting a randomized trial to compare image-guided adaptive conformal photon therapy with image-guided passive-scattering proton therapy for locally advancedNSCLC; the primary endpoint of this trial is time to grade3 radiation pneumonitis (NCT00915005). MD Andersonresearchers are also conducting an ongoing prospective phaseI/II study to review a treatment regimen of 60 Gy in 15fractions to determine whether proton radiation can behypofractionated this way in the setting of locally advanceddisease. We anticipate that the results from these trials willadd to the body of knowledge of proton therapy in locallyadvanced NSCLC and aid clinical decisions regarding thisdeadly disease.

Finally, we draw attention to the preliminary results ofRTOG 0617 which was first presented earlier this year.62

In this 2 ¥ 2 factorial trial, patients were treated usingphoton-based chemoradiation and were randomizedto two radiation doses (60 Gy and 74 Gy) and to concurrentchemotherapy with or without Cetuximab. Surprisinglythe preliminary analysis at 11 months showed that there wasno overall survival improvement in the group randomizedto the higher radiation dose. One interpretation of thisoutcome is that dose escalation is not oncologicallybeneficial, but this runs counter to basic biology anda large body of evidence, including prospective phaseII and III trials. A competing explanation is that 74 Gyis too toxic when delivered by the photon-based radiationtechnologies used in RTOG 0617. It is also possible that74 Gy is still an inadequate dose (the early-stage NSCLCdata suggests the need for BED of 100 Gy in the absenceof radiosensitizers, but this dose threshold has not beenclearly assessed in the presence of concurrent chemo-therapy) and a higher biological dose using image-guided hypofractionated radiotherapy should be consid-ered. If these latter interpretations turn out to be correct,proton-based radiation techniques may offer an advan-tage over photon-based radiotherapy by allowing forsuperior normal tissue dosimetry. This puzzling trialresult has resulted in much debate, and we hope thatthese issues are further clarified when the final outcomes arepublished.

Table 2 Selected studies of proton therapy for locally advanced non-small cell lung cancer

Trial Dose/fraction size (CGE) Chemotherapy Local control Overall survival

ProspectiveChang (2011) [59] 74/2 Carboplatin/paclitaxel 90% (2 years) 56% (2 years)

RetrospectiveNakayama (2011) [60] 67.1–91.3/2–3.3 None 66% (2 years) 59% (2 years)



Conclusion

Due of its physical characteristics, proton radiation is apromising modality for delivering intensive local therapy toimprove local control and survival durations in NSCLCpatients. Virtual studies have consistently demonstrated thedosimetric advantages of proton-based radiotherapy overphoton-based radiotherapy in sparing normal thoracic struc-tures, and promising clinical outcomes have been describedfor patients with early-stage and locally advanced NSCLCwho received proton therapy. The technical challenges andexpense of proton therapy demand further technique optimi-zation and clinical studies. The completion of ongoingrandomized trials will help determine the comparative effec-tiveness of proton therapy and whether this technologyshould be broadly adopted for the treatment of NSCLC.

Acknowledgments

The authors would like to thank the faculty and staff of theMD Anderson Proton Center for their contributions topatient care and the research cited in this manuscript.

Disclosure

The authors have no conflicts of interest to disclose.

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proton therapy for non–small cell lung cancer: current evidence and future directions

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