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Advances in Radiation Therapy:Conventional to 3D, to IMRT, to 4D,and BeyondM. Kara Bucci, MD; Alison Bevan, MD, PhD; Mack Roach III, MD

ABSTRACT Modern advances in computers have fueled parallel advances in imaging tech-

nologies. The improvements in imaging have in turn allowed a higher level of complexity to be

incorporated into radiotherapy treatment planning systems. As a result of these changes, the

delivery of radiotherapy evolved from therapy designed based primarily on plain (two dimen-

sional) x-ray images and hand calculations to three-dimensional x-ray based images incorpo-

rating increasingly complex computer algorithms. More recently, biologic variables based on

differences between tumor metabolism, tumor antigens, and normal tissues have been incor-

porated into the treatment process. In addition, greater awareness of the challenges to the

accuracy of the treatment planning process, such as problems with set-error and organ move-

ment, have begun to be systematically addressed, ushering in an era of so-called Four-

Dimensional Radiotherapy. This review article discusses how these advances have changed the

way the most common neoplasms are treated now and will be treated in the near future. (CA

Cancer J Clin 2005;55:117–134.) © American Cancer Society, Inc., 2005.

INTRODUCTION

The greatest challenge for radiation therapy or any cancer therapy is to attain the highest probability of curewith the least morbidity. The simplest way in theory to increase this therapeutic ratio with radiation is toencompass all cancer cells with sufficient doses of radiation during each fraction, while simultaneously sparingsurrounding normal tissues. In practice, however, we have been hampered by our abilities to both identify thecancer cells and target them with radiation. Over the past decade, enormous progress has been made on bothfronts. Technical improvements in the application of x-rays, computed tomography scans, magnetic resonanceimaging with and without spectroscopy, ultrasound, positron emission tomography scans, and electronic portalimaging—and our understanding of their limitations— have greatly improved our ability to identify tumors.Although, 15 years ago, we became aware that the position of target volumes (such as lung nodules andprostates) can be mobile and highly variable, we were poorly equipped to compensate for this motion. Similarly,when treating patients with cancers of the head and neck, we knew that high doses to the salivary glands causeddry mouth, a reduction in taste, and poor dental health, but we were unable to reduce these side effects withoutrisking a compromise in cure.

Modern radiotherapy has evolved from non-site-specific techniques using bony anatomy and hand-drawnblocking toward specialized planning incorporating three-dimensional reconstructions of images and computeroptimization algorithms. Corresponding to these changes, there has been specialization in the types of technologyused for different cancer sites. For example, the obvious advantages associated with sparing the salivary glands havepushed intensity modulated radiotherapy (IMRT) in the standard treatment of head and neck cancer faster than othercancer sites. A different set of strategies was required to address organ movement and set-up error problems associatedwith the treatment of prostate cancer. Respiratory movements associated with lung cancer and the opportunity toreduce treatment times for adjuvant breast irradiation also resulted in the development of unique site-specific

Dr. Bucci is Clinical Instructor, De-partment of Radiation Oncology,University of California, San Fran-cisco, CA.

Dr. Bevan is Clinical Instructor,Department of Radiation Oncology,University of California, San Fran-cisco, CA.

Dr. Roach is Professor, Depart-ments of Radiation Oncology, Med-ical Oncology, and Urology,University of California, San Fran-cisco, CA.

This article is available online athttp://CAonline.AmCancerSoc.org

CA Cancer J Clin 2005;55:117–134

Volume 55 Y Number 2 Y March/April 2005 117

solutions. In this review, we highlight theunique features of some of the common sitesand how new technologies are being used nowand are likely to be used in the near future.

IMRT: A MORE SOPHISTICATED FORM OF THREE-DIMENSIONAL CONVENTIONAL RADIOTHERAPY

Two-dimensional (2D) radiotherapy consistedof a single beam from one to four directions.Beam setups were usually quite simple; plans fre-quently consisted of opposed lateral fields or four-field “boxes” (Figure 1). Three-dimensional(3D), or CT-based, planning was a major ad-vance because it took into account axial anatomyand complex tissue contours such as the hourglassshape of the neck and shoulders. While 3D plan-ning allowed for accurate dose calculations tosuch irregular shapes, we were still limited in thecorrections we could make. As its name implies,intensity-modulated radiation allows us to mod-ulate the intensity of each radiation beam, so eachfield may have one or many areas of high inten-sity radiation and any number of lower intensityareas within the same field, thus allowing forgreater control of the dose distribution with thetarget. By modulating both the number of fieldsand the intensity of radiation within each field,we have limitless possibilities to sculpt radiationdose (see Figure 2). Advanced treatment planningsoftware has furthered our ability to modulateradiation dose. Instead of the clinician choosingevery beam angle and weighting, computer op-timization techniques can now help determinethe distribution of beam intensities across a treat-ment volume, which often include a nonintuitivedistribution of “beamlets,” or 1-cm2 areas ofisointensity. For a more in-depth review ofIMRT, the reader is referred to the IMRT Col-laborative Working Group paper.1

Despite the capability of planning and calcu-lating doses accurately to within millimeters, weare limited by our inability to identify micro-scopic disease with such accuracy. We are alsolimited by the logistic difficulties of immobilizinga patient for the duration of an IMRT treatment(typically 15–30 minutes). Patients and tumorsmove both as a result of voluntary movement andvisceral motion such as respiration and digestion.Additionally, when we’re successful, tumors

shrink with treatment. Patients may lose weightover the course of the treatment, which willfurther alter their geometry and therefore dosim-etry.2,3 The next direction in radiation oncologyis to account for this movement and is be-ing called four-dimensional (4D) conformal ra-diotherapy (CRT), a logical progression from3D CRT.

Researchers have recently developed mega-voltage cone-beam CT (MVCT) for clinicaluse.4 MVCT will allow the reconstruction of theactual daily-delivered dose based on the patient’sanatomy in real time.5 This will lead to “adaptiveradiotherapy,” the modulation of prescriptionand delivery based on the actual daily delivereddose, as opposed to planned dose.6

ADVANCES IN RADIOTHERAPY FORPROSTATE CANCER

An increasing number of men choose radio-therapy for the treatment of localized prostatecancer because of the perception that there is alower risk of impotence and incontinence7 Ra-diotherapy also avoids the need to take as muchtime off from work and is thus is less disruptive interms of daily living. The downside of radiother-apy is a higher risk of rectal complications.8,9

Some men also are fearful that the results ofradiotherapy may not be as good as radical pros-tatectomy. Recent data based on a large numberof patients suggest that with higher doses of ex-ternal beam radiation (�72Gy) or brachytherapy,the likelihood of remaining disease-free at fiveyears is comparable with radical prostatectomy.10

Although these data are from nonrandomizedstudies, they suggest that there are not likely to belarge differences in the cancer control rates in thefirst five years after treatment. Furthermore, thereis no good evidence that there are more latefailures after either form of radiotherapy than afterprostatectomy.11–15

3D CRT first became available in the mid1980s, and by the early 1990s reports fromseveral institutions supported the notion thatcompared with conventional therapy, rectaltoxicity was lower than expected despite higherdoses. In a multicenter Phase I-II study, inves-tigators from the Radiation Therapy Oncology

Advances in Radiation Therapy

118 CA A Cancer Journal for Clinicians

Group (RTOG) demonstrated that radiation-induced gastrointestinal complications ap-peared to be substantially lower than expected

at various dose levels.16–18 Similar preliminaryresults were reported from two small Phase IIIstudies using cruder techniques.19–21 How-

FIGURE 2 Highly Conformal Intensity Modulated Radiotherapy Head and Neck Plans.A, Parotid sparing in a patient with nasopharynx cancer. B, Sparing of optic structures in a patient with sinonasal cancer.

FIGURE 1 A, Two opposing beams of single intensities, represented by the yellow arrows, create a single-dose distribution through a na-sopharynx tumor (GTV in red, CTV in purple) and normal tissue alike. B, Simplified schematic of intensity modulated radiotherapy allowsmultiple beams of different intensities from any number of angles about the patient (in this case, eight angles) to create a highly sculpteddose distribution with relative sparing of the brain, brainstem, and parotid glands. Isodose lines from actual patient.



ever, the side effects reported in both of thesetrials appeared to be somewhat higher than inthe larger multicenter RTOG trial. Further-more, with longer follow-up, the incidence oflate rectal bleeding was higher on the high dosearm in one of these studies, despite the use of3D technology for the last part of treatment (orthe “boost” dose).21 Other studies that haveused 3D planning for the entire course of treat-ment, rather than just the last part of the treat-ment, had a lower incidence of gastrointestinalcomplications.16,22 The major lesson learned isthat the risk of late complications may be in-creased if the 3D radiotherapy technique doesnot compensate for the additional dose. Exter-nal beam radiation doses in excess of 70 Gy arerequired to yield the best results,10,21,23,24 butthe optimal dose remains to be determined.

Although there are no prospective randomizedclinical studies proving that IMRT reduces com-plications compared with 3D CRT, improve-ments in the radiation dose distribution withIMRT are easily shown.25–29 Sequential doseescalation studies conducted at Memorial SloanKettering Cancer Center support the notion thatthe use of IMRT can reduce morbidity com-pared with 3D CRT.30 In their analysis of over772 patients who received doses in excess of 81Gy (roughly 20% higher doses conventionallyused in the past), with a median follow-up of 24months, only 4.5% developed acute Grade 2 rec-tal toxicity, and none experienced acute Grade 3or greater toxicity. Based in part on such favor-able reports and with widespread availability,IMRT has become the standard therapy at manyacademic and private institutions. Despite the im-proved dose distribution associated with IMRT,the application of this technology to routine prac-tice is limited by the increased potential for treat-ment errors that can result from organ movementand or daily errors in patient positioning.31 Thechallenge of ever more accurately delivering ra-diotherapy precipitated the need for improvedimage-guided strategies spawning the concepts ofimage guided radiotherapy (IGRT) and 4DCRT. The fourth dimension in this setting refersto the impact of time on the position and/orshape of the target volume.

Moving Towards Image-GuidedFour-Dimensional Radiotherapy

Recent advances in the accurate delivery ofradiotherapy for prostate cancer have involvedthree critical steps. The first step involves se-lecting the proper target (eg, prostate only ver-sus prostate and pelvic lymph nodes). Next, thetarget must be accurately defined using an im-aging modality (usually CT) such that the ap-propriate fields and beam weights can bedetermined manually or with computerized as-sistance (inverse planning). Finally, a vigorousquality assurance program that allows correc-tions for day-to-day setup variations and targetmotion is crucial.

Determining and Defining the Appropriate TargetVolume to Irradiate

The recent findings of a large Phase III trialconducted by the RTOG (9,413) have nowmade it clear that patients with intermediate tohigh-risk disease (defined as patients with a riskof lymph node involvement of � 15%) benefitfrom prophylactic pelvic nodal radiotherapyadministered with neoadjuvant hormonal ther-apy. The risk of lymph node involvement ex-pressed as a percentage (LN �) in this studywas estimated by the equation (LN �) � (2/3)prostate specific antigen � �(Gleason Score �6) � 10�.32 A recently completed subset anal-ysis also suggests that the use of a so-calledmini-pelvic (MP) radiotherapy (a field usuallydesigned such that the top of the field is at thebottom of the sacral iliac joints and typicallymeasures approximately 10 to 11 � 11 cm) isnot an adequate replacement for whole pelvic(WP) radiotherapy.33 The risk of disease pro-gression associated with MP radiotherapy wasgreater than with WP and not statistically dif-ferent from prostate only radiotherapy. MPradiotherapy was also associated with a higherrisk of gastrointestinal complications than pros-tate only radiotherapy and not statistically dif-ferent from WP radiotherapy.

After determining that the pelvic lymph nodesrequire treatment, the next major question iswhere are they actually located in an individualpatient? The standard approach has been to sim-



ply use bony landmarks and plain pelvic x-rays orCT scans to design the treatment fields that coverdrainage patterns of the associated vascular struc-tures. Unfortunately, there is a higher incidenceof gastrointestinal and urinary morbidity associ-ated with the use of a large field compared withtreatment limited to the prostate. Radiotherapythat spares greater portions of the bowel andbladder and delivers the highest doses selectivelyto nodal areas at greatest risk should theoreticallyprovide a therapeutic advantage. A number ofimaging modalities have been incorporated intodefining the nodal target volumes, includingIndium-111 labeled prostate specific membraneantigen antibody (Capromab Pendetide)-basedimaging and high-resolution MRI after intra-venous administration of lymphotropic super-paramagnetic ferrous-oxide nanoparticles.34–36

Fusion of multiple imaging modalities such asIndium-111 Capromab Pendetide volume datasets withMRI and CT appears to improve theaccuracy in assessing potential sites for salvageradiotherapy in patients with progression afterradical prostatectomy (Table 1).35 Future studiesshould help determine whether incorporatingthese or other imaging modalities will improveour ability to cure prostate cancer and/or reducethe morbidity of our treatment.

Accurately Defining the Prostate andIntraprostatic Disease

Despite the fact the CT scans are the stan-dard imaging modality for defining the prostatefor external beam radiotherapy, a number ofstudies have demonstrated that there is signifi-cant interobserver variation with CT, and thatMRI is more precise in defining the prostateanatomy.37–39 Clearly more work is needed inthis area, with real potential to reduce morbid-ity by minimizing the doses of radiation deliv-ered not only to the rectum, bladder, and penis(see discussion below) but also muscles thatmay control sphincter function. Accurately de-fining subregions within the prostate that con-tain the largest concentration of tumor could intheory help guide therapy because these are theregions most likely to be sites of recurrencesafter radiotherapy.

Recent studies have shown that it is feasible toselectively target areas of higher tumor burdenwithin the prostate, known as dominant intra-prostatic lesions (DIL) by applying informationprovided by multiple biopsies and endorectalMRI with spectroscopy.26 An example is shownin Figure 3. In this example, these investigatorsdemonstrated that it was technically possible todeliver 9,000 cGy to two different areas of theprostate while not exceeding the tolerance ofsurrounding normal tissues and hence, at least intheory, not increasing the risk of side effects.28

Preliminary data suggest that MRI with spectros-copy may also play a role in following responsesto radiotherapy and could provide an early sur-rogate endpoint for clinical trials comparing ex-ternal beam radiotherapy with brachytherapy.40

After defining the prostate as precisely aspossible, an even greater challenge arises fromthe realization that setup error and organmovement limit our ability to deliver definitiveradiotherapy with the desired precision. Thestandard of practice for monitoring daily setupinvolves the use of weekly port films.41 This inessence assumes that a 20% sampling (ie, on oneof five days) of setup provides an accurate re-flection of what is happening the other 80% ofthe time. Unfortunately, on more than oneoccasion patients have asked me, “why is it thaton the days port films are taken, some therapistsspend more time setting me up for treatmentthan on the other days?” This suggests that theweekly port film may be a biased sample thatpoorly represents the accuracy of the averagesetup. In addition, pretreatment port films donot allow corrections to be made to account fororgan movement.

TABLE 1 Comparison of Positive Indium-111Capromab Pendetide SPECT Findings Before andAfter Image Fusion with Magnetic ResonanceImaging or Computer Tomography

Uptake

PositiveBefore

andAfter

PositiveBefore,

NegativeAfter

NegativeBefore,Positive

After

Prostate bed 55 9 0Lymph nodes 32 61 10Seminal vesicles 0 4 3Total 87 74 13

Modified from Schettino J, Kramer EL, Noz ME, et al.35



4D IGRT to Reduce Toxicity

A number of recent studies have demon-strated that the accuracy of delivering treat-ment for localized prostate cancer can beimproved with the use of online imaging.42–45

Investigators at the University of CaliforniaSan Francisco (UCSF) have shown that thegold marker seeds can be placed into theprostate for routine daily monitoring usingan electronic portal imaging device (EPID)and can provide an accurate guide such thattreatments can be delivered within �2 mm.Implanted seeds don’t migrate significantly ifproperly placed.42 EPID-based online imag-ing is probably somewhat more accurate thanfirst generation ultrasound-based systems be-cause of less interobserver variability. Intra-prostate markers appear to be particularlycritical to the accurate treatment of obesepatients who are at a very high risk for setuperrors because of inconsistencies associatedwith using skin marks in these patients.45 Anexample of how gold marker seeds can beused to accurately target small volume isshown in Figure 4A-D. This patient had abiopsy-proven recurrence after radical pros-tatectomy, and his tumor was marked withtwo gold seeds as shown in the AP and lateralport films (Figure 4A,B). Figure 4C is a dig-

itally reconstructed radiograph, and Figure4D demonstrates that the location of thetumor can be easily seen on this later EPID-based image while the patient is lying on thetable immediately before each treatment.This allows a very small margin to be used sothat the dose of radiation incidentally re-ceived by the rectum is minimized.

Promise of Potency Sparing Radiotherapy?

The preponderance of the peer reviewed pub-lished literature suggest that sexual function tendsto be slightly better following treatment withradiotherapy compared with radical prostatecto-my.7 Of note, these findings are based on datapublished before the recent body of evidence thatsuggests radiation-induced impotence is related tothe dose of radiation received by the proximalportion of the penis (bulb).46–49 Data based onanimal studies, as well as retrospective and limitedprospective data from patients treated with 3DCRT and brachytherapy, suggest that the risk ofimpotence can be substantially reduced if the bulb(most proximal portion) of the penis is sparedduring radiotherapy.46,47,49,50 The potential forradiotherapy to be the preferred approach forpotency preservation is strengthened further bythe relatively high response rate to sildenafil (upto 75% or more).51,52 IMRT can be used to

FIGURE 3 IMRT Prostate Plan.A, Sagittal and B, axial treatment planning computed tomography slices of an intensity modulated radiotherapy plan of adominant intraprostatic lesion. 7 field IMRT plan allows dose escalation of 90 Gy to small volume of tumor within theprostate (orange volume) and highly conformal dose of 76 to the prostate (red volume). Yellow arrow highlights thesharp dose gradient by the bulb of the penis. The 90-Gy isodose line covers the dominant intraprostatic lesion (shownin orange) and the 75.6-Gy line covers the prostate (shown in red). The bladder (shown in blue) and the rectum (shownin purple) are spared.



substantially reduce the dose of radiation deliv-ered to the bulb of the penis.53,54 Figure 3A (seeblack arrow) demonstrates how a very sharp dosegradient can be generated between the prostateand the bulb of the penis using IMRT to poten-tially reduce the risk of impotence.

Conclusions About Advances in Radiotherapy forProstate Cancer

The improvements in accurately definingthe prostate and regions of dominant intra-prostatic disease as well as an increasedawareness about when treatment of regionaldisease is appropriate have ushered in a newera in understanding how to define our targetvolumes in men with clinically localized dis-ease. These developments occurred concur-rently with enhancements in our ability toapply radiotherapy incorporating computeroptimization and online monitoring to allow

corrective actions to be taken for day-to-daysetup error and organ movement. In theyears to follow, altered fractionation schemesand the addition of cytotoxic and biologicagents are likely to result in further improve-ments in our radiotherapy-based options andoutcomes.

ADVANCES IN RADIATION THERAPY FOR HEAD ANDNECK CANCERS

Head and neck, while an uncommon tumorsite, is an important site in radiotherapy forseveral reasons. First, as IMRT has becomewidely used in the head and neck to decreasethe substantial radiation-related toxicities, pre-liminary clinical outcome data are emergingfrom this area. Second, the recent publicationof multiple major, practice-changing random-ized trials in this area55–58 highlight the clinical

FIGURE 4 Gold Marker Seeds Can Be Used to Accurately Target the Prostate.This patient had a biopsy proven recurrence after radical prostatectomy. His tumor was marked with three gold seedsas shown in the A, AP and B, lateral simulation films. Digitally reconstructed radiograph C demonstrates that the loca-tion of the tumor can be easily seen in D, an electronic portal imaging device based image, taken while the patient islying on the table immediately before treatment.



relevance of biologic principles such as alteredfractionation, chemosensitization, and molecu-lar targeting.

Technologic Advances

Any technologic improvements must bebacked by clinical data showing an actual ben-efit to patients. The expected benefit from ad-vanced treatment planning such as 3D CRTand IMRT and improved patient localizationmethods introduced in tandem with thesetechniques is two-fold: (1) improvement intumor control and (2) decrease in side effectsand toxicities. The potential for an improve-ment in tumor control lies within the ability toincrease the tumor dose, either by more accu-rately delivering 100% of the prescription doseto the tumor or through dose-escalation (ie,prescribing doses higher than those that havebeen traditionally used). Decrease in toxicityshould naturally follow from a decrease in doseto normal tissue; however, this must be sup-ported by clinical data. IMRT has been used inthe head and neck region at several academicinstitutions, including ours, since 1995, suchthat we now have clinical results on a patientcohort extending back nearly 10 years.59

Rationale for IMRT in Head and Neck

The head and neck is an ideal site for IMRTdue to the complex geometry of this area andthe severity of radiation-associated toxicity.Frequently, the distance between either grosstumor (gross tumor volume) or areas at highrisk for microscopic disease (clinical target vol-ume) and critical structures such as optic appa-ratus, inner ear, or salivary gland is no morethan a few millimeters. Traditionally it has beenextremely difficult or impossible to delivera tumoricidal dose of radiation to the targetvolume while limiting the dose just a few mil-limeters away. Furthermore, the geometric rela-tionships are complex. Targets are not centered ina 2D plane between critical structures; rather theyare eccentric in a 3D volume, such as the ethmoidsinuses in relation to both optic nerves, retinas,optic chiasm, and brain.

The toxicity from head and neck radiotherapyis among the worst seen in the field. Radiationtoxicities are defined as acute or late; acute tox-icities are those seen during treatment and areusually self-limited, and late toxicities are thoseseen months to years after treatment and can bepermanent. Acute toxicities related to radiation ofthe head and neck region include mucositis andits accompanying dysphagia and odynophagia,salivary changes including increased salivary vis-cosity, and dermatitis as severe as confluent moistdesquamation. Late toxicities include xerostomia,sensorineural hearing loss, and the potentially cat-astrophic complication of vision loss. Loss of sal-ivary function is by far the most common ofthese. Xerostomia negatively impacts quality oflife, interfering with speech and swallowing andcan contribute to the widely feared complicationof mandibular osteoradionecrosis. Because of itspotential to decrease dose to normal tissue andtherefore spare toxicity, IMRT has been utilizedin this area since its inception, and we now haveup to seven-year follow-up on patients treatedwith this technique.

Clinical Results

The initial UCSF experience with IMRT innasopharynx cancer was published in 2002.60

With a median follow-up of 31 months for 67patients, the 4-year estimates of local progression-free survival, distant-metastasis-free survival, andoverall survival were 97%, 66%, and 88%, respec-tively. These results compare favorably with his-torical controls61 and have held up with longerfollow-up.59 Grade 2 (“moderate”) xerostomiadecreased from a 64% incidence at 3 months to2.4% at 24 months, while Grade 0 (“no xerosto-mia”) increased from 8% to 66%.

Other investigators using IMRT for headand neck cancers have also reported a lowincidence of xerostomia.62 Importantly, the re-duction in xerostomia has been shown to cor-respond with an improvement in quality oflife.63

Claus et al. reported on 47 patients treatedwith IMRT for sinonasal cancers; early toxicitydata are available on 32 patients.64,65 Whilelong-term toxicity endpoints such as opticnerve and retinal toxicities are not available,



there was no evidence of a common acute sideeffect—dry eye.

While technologic advances are exciting andenticing to the practitioner, the major im-provement in cancer outcomes over the lastdecade have been gained through exploitingthe known biologic behavior of cancer. Thedifference in damage caused by therapeuticagents to cancer cells versus healthy cells isknown as the therapeutic ratio. The greaternumber of cancer cells killed with the fewestnumber of healthy cells damaged provides ahigher therapeutic ratio. Maximizing this ratiois the goal of oncology. This ratio can be mod-ulated through several ways. The classic bio-logic explanation for any therapeutic ratioadvantage from radiotherapy is the “4 Rs”:(DNA) repair, redistribution (throughout thecell cycle), repopulation (or the rate at whichcells divide), and reoxygenation (the diffusionof oxygen into a tumor as it shrinks in size). Allfour of these Rs have different mechanisms andhappen at different rates in normal cells versuscancer cells. Fractionated radiation, or a limiteddose each day over a four to seven week courserather than a large amount of radiation at once,capitalizes on all four Rs.

Hyperfractionation

Standard radiation fractionation is a courseof 1.8 to 2.0 Gy/day in single daily doses.Accelerated fractionation refers to deliveringthe same total dose over a shortened treatmenttime, most often through the use of twice orthrice daily fractions. Hyperfractionation refersto the same total delivered dose over the sametreatment time but in an increased number offractions; smaller fractions are delivered morefrequently than once daily. Multiple differentschemes have been used in the head and neckarea, most notably 1.1 to 1.2 Gy twice daily,1.6 Gy twice daily with a planned 2 weekbreak, and accelerated fractionation with con-comitant boost, which delivers 1.8 Gy daily, 5days a week to a large field, with a 1.5 Gy“boost” field as a second daily dose during thelast 12 days.

Early in vitro work showed the potential toexpand the therapeutic ratio by altering radiation

fractionation,66,67 and early trials confirmed theclinical benefit of altered fractionation in head andneck cancer68 and other sites, most notablylung.69 The landmark trial confirming the benefitof altered fractionation in head and neck cancer isRTOG 90–03.55 This 4-arm, 1,073 person trialcompared once-daily radiation (70 Gy in 35 frac-tions over 7 weeks) with 3 different altered frac-tionation schemes: 1.2 Gy twice daily to 81.6 Gy(68 fractions over 7 weeks), 1.6 Gy twice dailywith a planned 2 week break to 67.2 Gy (42fractions over 6 weeks), and the concomitantboost regimen of 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field asa second daily treatment for the last 12 treatmentdays (72 Gy/42 fractions/6 weeks).

Both the purely hyperfractionated regimen(1.2 Gy twice daily to 81.6 Gy) concomitantboost showed a significant improvement in localcontrol over the control arm with no increase inlong term toxicities despite an increase in acutetoxicities. Since the publication of this trial in2000, twice-daily radiation for all or part of thetreatment course is considered standard whentreating moderately advanced squamous cell headand neck cancers with radiation alone. More ad-vanced cancers should be treated with a combi-nation of chemotherapy and radiotherapy.

Concurrent Chemotherapy and Radiation

Organ-preservation therapy became a stan-dard treatment option for laryngeal cancer afterthe publication of the VA Larynx Trial in1991.70 This landmark trial randomized pa-tients to definitive surgery (with postoperativeradiation as needed) versus two cycles of cis-platin and 5-fluorouracil followed by an assess-ment for response, with a third cycle ofchemotherapy and radiation therapy for re-sponders or salvage surgery for nonresponders.This regimen became the standard organ-preservation regimen until it was directly com-pared with concurrent chemoradiotherapy inRTOG 91–11. This three-arm trial random-ized 547 patients to 1) induction cisplatin plusfluorouracil followed by radiotherapy, 2) radio-therapy with concurrent administration of cis-platin, or 3) radiotherapy alone. The rates oflaryngeal preservation, the primary endpoint,



were 75%, 88%, and 70%, respectively. Localcontrol was also significantly improved in theconcurrent arm, with local control rates of61%, 78%, and 56%, respectively. For patientssimilar to those included in the study (ie, thosewith Stage III of IV tumors without significantinvasion of the base of tongue or gross destruc-tion of thyroid or cricoid cartilage), concurrentchemoradiotherapy with cisplatin is now thestandard of care. Organ preservation has be-come more common in other subsites withinthe head and neck as well, including the hy-popharynx71 and oropharynx,72 after random-ized trials have shown no increased benefitfrom primary surgery.

Oropharyngeal cancer has notably become lessof a surgical disease over the last five years, as curerates with organ preservation therapy are widelyrecognized to equal those achieved with surgeryfollowed by postoperative radiation therapy.72,73

Preliminary, single-institution results of IMRT inthe treatment of oropharynx cancer have recentlybeen published, both for radiation alone in early-stage cancer74 and chemoradiation in locoregion-ally advanced oropharyngeal cancer.75 Results inthis site, as in the nasopharynx, have been quiteencouraging, with two-year locoregional controlrates of 91% for early-stage disease and 89% foradvanced stage in these small series of selectedpatients. To further investigate IMRT in thetreatment of both oropharyngeal and nasopha-ryngeal cancer, the RTOG is currently conduct-ing two single-arm, Phase II trials testing thefeasibility of IMRT delivery in multi-institutionalsettings. Xerostomia will be prospectively evalu-ated in both trials.

While neoadjuvant chemotherapy followedby radiation alone is no longer a standard treat-ment option for head and neck cancer, neoad-juvant chemotherapy followed by concurrentchemoradiotherapy has not been directly com-pared with concurrent chemoradiotherapy in amulticenter randomized trial. A valid concernis the inevitable delay in treatment that occursduring the approximately two weeks necessaryfor radiation planning. A single cycle of che-motherapy may be given in this interval andwill usually result in both debulking of thetumor and a decrease in the patient’s ability totolerate a full course of chemoradiation; pa-

tients who have received a cycle of chemother-apy before starting radiation are more likely toexperience radiation-related toxicities earlierand are more likely to require treatment breaks.It is not known if any advantage to giving anearly cycle of chemotherapy can offset theknown disadvantages of treatment breaks anddelays76,77and the hazards of accelerated re-population.78,79

Concurrent Chemoradiotherapy in thePostoperative Setting

While it logically follows that if concurrentchemotherapy confers a benefit to radiation inthe definitive setting, it would add a similarbenefit in the postoperative setting; this had notbeen shown until the publication of two land-mark trials earlier this year.57,58 Two similartrials, one in the United States and one inEurope, randomized high-risk, postoperativepatients with head and neck cancers to radia-tion alone versus concurrent chemoradiationwith cisplatin, 100 mg/m2 every 3 weeks. Inboth studies, the chemoradiation arm demon-strated a local control benefit, and in the Eu-ropean trial, the chemoradiation arm showedan overall survival advantage as well.

Biologic Targeted Therapy

The epidermal growth factor receptor(EGFR) has been an attractive target for therapybecause of its upregulation in nearly two-thirds ofsolid tumors and its association with malignantphenotypes. Preclinical models demonstrated en-hancement of radiation sensitivity with blockadeof the EGFR, and it was hypothesized that acombination of anti-EGFR therapy with radia-tion would lead to improved outcome in epithe-lial cancers such as those of the head and neck. Arecent randomized trail of 424 patients affirmedthis hypothesis. Patients with advanced head andneck cancer were randomized to received radia-tion alone or with cetuximab (also know asC225, or Erbitux), a monoclonal, chimericmurine-human antibody. The addition ofcetuximab increased two-year survival from55% to 62%, with a near doubling in median



survival from 28 to 54 months. Skin toxicitywas increased, however, with Grade 3 to 4skin reactions in 34% of patients on thecetuximab arm versus 18% on the radiationalone arm.76,80 While these results need to beconfirmed by further studies, cetuximab isnow a reasonable option for radiation pa-tients with advanced cancer who are unsuit-able for or unable to receive chemotherapy.

The combined role of chemotherapy andhyperfractionation is unknown. This ques-tion is being addressed by the ongoingRTOG study 01–29, which randomizes pa-tients to concurrent cisplatin with standardfractionation radiation or concurrent cispla-tin with the concomitant boost regimen oraccelerated fractionation. A question for fu-ture trials is the role of cetuximab with con-current chemoradiation.

ADVANCES IN RADIOTHERAPY FORBREAST CANCER

Breast cancer is the most common form ofnondermatologic cancer in women.81,82 Asmore women choose breast conservation ther-apy (BCT), breast radiation therapy is a largecomponent of a radiation oncology practice.The advances in radiation technology havemade standard radiotherapy much more preciseand discriminating.

Until recently, the total time and dose ofstandard radiation had not significantly changedin over 20 years with the exception of a pos-sible 10 to 16 Gy electron boost to the surgicalcavity.83,84 Nagging questions persisted, driv-ing current clinical research into a new era,particularly for women with early-stage breastcancer who are candidates for BCT. The keyquestions are: can we shorten the duration ofstandard breast irradiation, can we treat a por-tion of the breast instead of the whole, and canwe select women who can avoid radiotherapyaltogether?

The issue of avoiding radiotherapy in BCT hasbeen explored in the past and recently revisited intwo current articles published in the New EnglandJournal of Medicine.85,86 Before these articles, theNational Surgical Adjuvant Breast and Bowel

Project-21 trial randomized approximately 1,000women of all ages with invasive tumors less orequal to 1 cm treated with lumpectomy andaxillary node dissection to radiotherapy and ta-moxifen, radiotherapy and placebo, or tamoxifenalone. The cumulative incidence of ipsilateralbreast tumor recurrence was 2.8%, 9.3%, and16.5%,87 respectively. Distant metastases andoverall survival were the same for all groups. Thisstudy did not select patients based on age, estro-gen receptor status, or grade. The first of the twoNew England Journal articles, from the PrincessMargaret Hospital, randomized 769 women aged50 years or older with node negative invasivebreast cancer 5 cm or less to breast irradiation andtamoxifen versus tamoxifen alone. Again, therewas no difference in the rates of relapse or overallsurvival; however, local recurrence in the breastand axilla were significantly reduced in the radio-therapy arm including a subgroup analysis ofthose with tumors less than 2 cm.86 The onlystudy where the authors concluded that it may bereasonable to omit breast irradiation and treatwith tamoxifen alone randomized 636 womenwho were 70 years or older with estrogenreceptor-positive, early-stage breast cancer (nodenegative and �2 cm) to breast irradiation plustamoxifen or tamoxifen alone and at five yearsmedian follow-up showed a rate of local or re-gional recurrence rate of 1% and 4%, respectively,with no significant difference in the rates of mas-tectomy, distant metastases, and overall survival.85

The main criticism of the study is that longerfollow-up is needed.

The eligibility for BCT is assessed by clinicalexamination, imaging studies, pathology, indi-vidual preference, and expected cosmetic out-come (best with small tumor to large breastsize). Still today, women who qualify for breastpreservation may opt for a mastectomy to avoidthe 5 to 6.5 weeks of Monday through Fridayradiotherapy. Radiotherapy is often at the tailend of surgery and months of chemotherapy,presenting a final test of endurance and a newsource of anxiety. Distance from the radiationfacility plays a factor in the decision makingprocess, as the inconvenience of daily transpor-tation and the time commitment must be in-tegrated into an already busy schedule.88



Two current aspects of breast irradiation arehot topics and have provided the momentumfor ongoing and future investigations. The firstof these is the role of advanced treatment tech-niques in producing conformal homogeneousdose throughout the breast while attempting toprotect the critical structures such as the ribs,lung, and heart. The second is the provocativetopic of shortening the course of radiotherapy.The current climate for addressing acceleratedtreatment is often mixed with the concept ofonly treating a portion of the breast, or partialbreast irradiation, instead of the whole breast.In part, this is because the design of the populardevices used to deliver the radiation can onlytreat the part of the breast at highest risk ofrecurrence—the surgical cavity and the adja-cent tissue. Candidates for accelerated irradia-tion are low-risk, early-stage patients for whicha variety of definitions apply.

3D CRT and IMRT

As mentioned in previous sections, CT-basedtreatment planning in conjunction with new ca-pabilities of the linear accelerator has revolution-ized radiotherapy for breast cancer. Targets andavoidance structures can be easily defined on axialimaging. The goal of treatment planning softwarealgorithms is to produce discriminating radiationfields that conform to the breast, chest wall,and/or regional nodes to achieve a homogenousdose to the breast and decrease or avoid dose tothe ribs, lung, and most importantly the heart.This technology allows us to adapt the treatmentto fit the variety of breast and chest wall shapes.

More frequently, radiation oncologists areusing IMRT to treat the breast or chest wallbecause of the possible decreased dose deliv-ered to the heart and lung.89–91 Long-termfollow-up studies are needed to confirm theclinical benefit of these improvements in dosedelivery. Previously, breast irradiation con-sisted of two fields, one on each side of thebreast, generated from 2D planning techniques.With IMRT, we typically use six to eight fieldsor more (Figure 5). At UCSF, we utilize a typeof IMRT called segmental multileaf collimatorIMRT (SLMC-IMRT), in which each fieldconsists of a series of multileaf collimator shapes

delivered from the same angle. The multiplesegmental fields at select orientations are undercomputer control, and the radiation is onlyturned on when the multileaf collimator leavesare fixed in place. In general, several plans aregenerated for each patient. More fields are notnecessarily better using SLMC-IMRT forbreast and chest wall irradiation and requirelonger treatment times and possibly more scat-ter radiation.

Accelerated Breast Irradiation

The Canadians have pioneered hypofrac-tionated radiotherapy in early-stage breastcancer patients. This technique, used to treatthe whole breast, delivers a slightly higher sin-gle daily dose (�2.0 Gy) of radiation but de-creases the total number of treatments to 16over 3 weeks rather than 25 to 28 over 5 to 6weeks. A large randomized trial compared stan-dard daily doses of whole breast radiation (2 Gy� 25 fractions) with a hypofractionated courseof radiation (2.66 Gy � 16 fractions). With amedian follow-up of 6 years, the local failurerate was 3% in both arms with no difference incosmesis or toxicity.92 While hypofraction-ation is not as popular as standard whole breastirradiation for young patients in the UnitedStates due to the lack of long-term toxicitydata, select institutions including ours have be-gun to offer it in select cases. In our experience,patients tolerate hypofractionation well, in fact,maybe even better than standard fractionation.

There are several methods for deliveringaccelerated partial breast irradiation (APBI), in-cluding intracavitary and interstitial brachy-therapy and 3D conformal external beam andintraoperative radiation. All of these techniquesare investigational and are being tested on pro-spective, multi-institutional randomized trials.Interstitial brachytherapy involves implantingmultiple catheters into the high-risk portion ofthe breast in the operating room and postop-eratively loading these catheters with high doserate radiation sources to a dose of 34 Gy in 10twice-daily fractions with high dose iridim-192over 5 days. Up to five-year follow-up datasuggest that this technique is comparable withwhole breast irradiation in terms of safety and



efficacy.93,94 Intracavitary brachytherapy usesthe new balloon-based catheter device, Mam-mosite (Proxima Therapeutics, Alpharetta,GA), which is Food and Drug Administrationapproved for safety and performance based on aPhase I/II eight center study with 43 pa-tients.94,95 The balloon is inserted into thelumpectomy site at the time of surgery in theoperating room and inflated with saline to con-form to the topography of the cavity (Figure 6).Outside of the operating room, the balloon isloaded with a single radioactive point source toa dose of 34 Gy in 10 twice-daily fractions over

5 days with iridium-192. The balloon is thendeflated and removed. Mammosite is muchsimpler to use, and many radiation facilitieshave started using Mammosite routinely intheir practice, despite the small number of pa-tients in the Phase II trial.

The other two types of APBI use externalbeam radiotherapy. Intraoperative radiotherapydelivers low energy electrons or 50 kV photons tothe surgical cavity with a single dose of radiationin the operating room.96–98 The fourth methoduses a conventional external beam source and3D-conformal or IMRT planning software to

FIGURE 5 Six- to Eight-field Intensity Modulated Radiotherapy–Segmental Multileaf Collimator Technique Leads toHomogenous Dose Distributions Throughout the Breast.A to D, Axial slices from superior to inferior.



deliver 3.8 Gy per fraction for 10 twice-dailyfractions over 5 days after the patient has healedfrom surgery.99

Given the intense interest in these techniques,the National Surgical Adjuvant Breast and BowelProject and RTOG are opening a trial that ran-domizes patients with early-stage breast cancer tostandard whole breast radiotherapy or APBI. Ifrandomized to APBI, one is further randomizedto either (1) interstitial implants, 2) Mammosite,or (3) 3D-conformal radiotherapy.100 The trialhas been approved by the National Cancer Insti-tute and should begin accruing later this year.

The Targeted Intraoperative RadiotherapyTrial is a Phase III international random-ized, controlled, multicenter trial investigat-ing superficial, intracavitary radiation with anew device called Intrabeam (Zeiss Surgical,

Oberkochen, Germany).101 Intrabeam deliverslow energy x-rays (50 kV) using a choice ofspherical applicators that conform to the surgi-cal cavity and treat to a depth of 1 cm, afterwhich the dose falls off steeply. Once the de-vice is inserted and the edges of the cavity arepulled around the applicator to be in contactwith the surface, the time of treatment variesfrom 20 to 40 minutes depending on the size ofthe applicator (Figure 7). The dose falls from 20Gy at 0.2 cm to 5 Gy at 1 cm, which translatesto a treated area of tissue in a 1-cm circumfer-ential rim around the resection rite. Patientsmust be carefully selected for tumors that arelikely to have only this limited area at risk if theoverlying skin is within this 1-cm perimeter,serious skin injury may occur. Alternatively, anirregular cavity or hematoma/seroma mayplace the target tissue too far from high-dosearea, potentially increasing the risk of diseaserelapse.

The Targeted Intraoperative RadiotherapyTrial randomizes patients to standard whole-beam radiotherapy (5 to 6.6 weeks) versus a singledose of radiation with this investigational device.Sentinel lymph node biopsy is performed at thetime of the excision. Patients may require furthersurgery, chemotherapy, and/or standard wholebreast irradiation if the pathology reveals high-risk features such as an extensive intraductal com-ponent, positive lymph nodes, positive surgicalmargins, or high histological grade. The primaryendpoint of the study is local control. Secondaryendpoints are site of relapse, relapse-free andoverall survival, and late toxicity.

There is intense pressure to bring a new era ofbreast irradiation into fruition from patients, phy-sicians, and manufacturers of new devices. It isimportant that we moderate our enthusiasm.Lack of long-term data from large-scale, multi-institutional, randomized trials, limited efficacydata, and lack of establishment of equivalency ofAPBI and whole breast irradiation create uncer-tainties in the expected results.100 The foremostconcern is progression-free outcome and second-arily, long-term cosmesis of the breast. Breastcancer can remain dormant for years before be-coming clinically apparent, so long-termfollow-up is mandatory. Because late effects such

FIGURE 6 A, The Mammosite balloon-based catheterdevice. B, A computed tomography scan of the ballooninflated with sterile saline. Photos courtesy of Mammos-ite.



FIGURE 7 Top, Intrabeam device delivering radiation therapy in the operating room. A-D, Intrabeam inserted into thesurgical cavity. Reprinted with permission from Vaidya et al.101



as fibrosis, telangiectasias, retraction, and fat ne-crosis often become clinically apparent as late as10 years after treatment, follow-up of at least 10years is mandatory to fully asses the long-termside effects of treatment. In locations where con-ventional fractionated breast radiation therapy isreadily available and accessible, APBI will not berecommended by most practitioners outside ofthe setting of clinical trials until long-term safetyand efficacy data are available. The RTOG hasrecently opened a Phase I/II trial to evaluate 3DCRT confined to the lumpectomy cavity (formore information, visit www.rtog.org).

Other uncertainties of APBI are the opti-mal dose and fractionation schemes, the basicprinciples of radiobiology. The various tech-niques differ in volume of breast tissue irra-diated, and it is crucial the exact site ofrelapse is documented. There are quality as-surance considerations such as individ-ual practitioner’s techniques, consistency oftreatment planning, and dose homogeneity.Again, patient selection has a tremendousimpact on the interpretation of trial results.As of now, we do not know who can avoidradiotherapy altogether. Advances in molec-

ular profiling and new imaging techniquesmay eventually help us select those fortunatepatients in the future.

SUMMARY

In summary, there have been several excit-ing technical advances in radiation therapy,including IMRT, IGRT, and 4D RT, andseveral investigational new devices in the treat-ment of breast cancer. These modalities aremore commonly finding their way into clinicalpractice, and early data are emerging on theireffectiveness. Data have recently become avail-able confirming the advantages to concurrentchemotherapy and targeted therapies such ascetuximab with concurrent radiation in thehead and neck, adding to data about the role ofcombined modality therapy in other sites, suchas lung and colorectal cancers, gained over thelast decade. We are optimistic that the nextdecade is likely to yield more advances regard-ing the role of radiotherapy in an increasinglymultidisciplinary oncology environment.

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