Brachytherapy 12 (2013) 199e201

Editorial

High-dose-rate strictures: A theory of cancer meets anatomic reality

We read with interest the Volume 12, Issue 1 of Brachy-therapy, in which Hindson et al. (1) provide another ina growing list of articles on the problem of stricturesfollowing high-dose-rate implants for prostate cancer (2, 3).In their large fraction schedule, the 2-year actuarial stric-ture rate jumped to an alarming 30%. The authors recom-mended a decrease in maximum fraction size to decreasethe risk to acceptable levels. Calling this conclusion intoquestion are articles delivering a comparable dose per frac-tion, but without a prohibitive level of strictures (4). Thewide range in stricture rates with the same high-dose-rateschedule poses a challenge to sorting out the responsibleanatomic, technical, and biologic factors. Solving this isimperative and is similar in urgency to the challenge ofrectal fistulas with permanent seed implants a few yearsago. It is a serious, potentially life-altering complicationrequiring a well-defined, clinically achievable solution. Inthe modern era, treatment success is defined as cure andquality of life. Potential anatomic, technical, and biologicfactors are worth reviewing to fully define the challengeand proposed solutions.

The complex anatomy at the prostate apex has beena challenge for all prostate cancer therapies, includingsurgery, cryotherapy, and radiation. First, although mostarticles refer to the external sphincter as below the prostate,it actually projects into the prostate up to 2 cm, as demon-strated in Fig. 1. The verumontanum, the expansion of theurethra within the prostate just above the sphincter, is easilyvisualized as the cystoscope passes through the sphincter. Itis important to note that the prostate apex itself is notdirectly visible by cystoscopy, and the lowest point withinthe prostate that is visible is the verumontanum. This clearlandmark is used as an inferior limit for transurethral resec-tion, and tissue below the verumontanum is not removed toavoid damaging the intraprostate sphincter, which wouldresult in incontinence.

Second, the prostate apex consists of peripheral zonetissue. Unlike the anatomy at the base, where the transitionzone is dominant and has a low rate of cancer involvement,the entire apex is at high risk of cancer involvement. It is,therefore, imperative to treat the entire apex, but in doingso one inevitably exposes the intraprostate sphincter to fulldose.

Third, the full length of the sphincter varies considerably(5). The distance from the apex to the penile bulb where thesphincter terminates can range from 0.5 cm to greater than

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3 cm (Fig. 2). The stricture risk is self-evident when oneconsiders that outside of the few minutes a day when thesphincter is open for urination or ejaculation, it is in theclosed position. Also, within the bulbar urethra, just belowthe sphincter is a sharp turn in the urethra at which pointnonradiation strictures commonly occur.

Because of the apex anatomy, many prostate cancer ther-apies have been compromised by the technical intricaciesaround aggressively treating the cancer while consideringa functional structure within the target. The apex continuesto be the most common site of positive margin for surgeonswho are concerned with preserving as much sphincterlength as possible (6). Cryotherapy treatments had an unac-ceptable rate of incontinence when the entire apex wastreated, leading to the solution of running warm waterthrough a catheter to avoid total ablation of the sphincter,but risking incomplete freezing of the peripheral zone (7).At the American Brachytherapy Society training coursefor prostate brachytherapy in Chicago, two high-dose-rateinstructors sparred over the challenge at the prostate apex.One used a cystoscopic examination to mark the verumon-tanum and defined the apex as 1 cm below this. This isclearly a strategy to limit strictures by limiting the lengthof sphincter treated to high dose. It is possible that evenif strictures form after a 1-cm segment of sphincter, theseremain amenable to standard urological correction. Theproblem with this strategy is that some men have greaterthan 1 cm of prostate tissue below the verumontanum(Fig. 1). The objection of the second practitioner was thatthe 1-cm strategy risked underdosing the apex peripheralzone tissue. His response was ‘‘We must treat the wholeprostate.’’

Although the notion of limiting dose to the apex to avoidcomplications is objectionable, and could be considereda radiation oncology version of the cryotherapy solution,it may well turn out that the definitive resolution to stric-tures will involve some consideration of the length ofsphincter exposed. It would appear that this strategy wasformulated with a clear understanding of anatomy and thenature of the challenge. With article after article repeatingthe notion that strictures occur below the prostate and notwithin the prostate in the intraprostatic sphincter, there isa clear indication that very few understand the basicanatomic challenge to large fractions at the prostate apex.Urology experts in sphincter function and stricture repairconfirm that strictures from radiation extend into the

hed by Elsevier Inc. All rights reserved.

Fig. 1. Coronal view through the prostate apex. Note the entire apex is PZ. The intraprostate portion of the external SPH projects within the prostate to the

TZ. The sphincter extends through the GUD to the penile bulb. The left panel demonstrates a lengthy external sphincter with extension through 40% of

the prostate and the right panel demonstrates a shorter sphincter with less extension. TZ5 transition zone; PZ5 peripheral zone; SPH5 sphincter;

GUD5 genitourinary diaphragm; U5 urethra.

200 Editorial / Brachytherapy 12 (2013) 199e201

prostate up to the verumontanum. This is no longer bulbo-membranous urethra but prostate urethra. A potential solu-tion could be to define the length of sphincter projectinginto the prostate from the apex on MRI before brachyther-apy and possibly select patients in whom this length is1 cm. Most would fall in this range, and in the few resultantstrictures from full-dose therapy, less aggressive urologicinterventions such as dilation, could be used to managethem. To treat the entire prostate without taking this intoaccount would expose those men with a lengthy intrapro-static sphincter to risk of more lengthy, refractory strictures.

There are technical considerations to consider beyonddefinition of apex level. The issue of catheter movementout of the prostate and into the genitourinary diaphragmis a well-established issue with several solutions (8, 9). Thiswas ruled out as a cause in the current manuscript. Theother important consideration is planning of the externalbeam portion in combined modality patients. As Fig. 2demonstrates, the actual prostate may reside relatively highin the pelvis, with a very long external sphincter. On CTscans, the clear demarcation of the prostate apex may bedifficult, and it would be possible to overestimate the apexextent well beyond the actual apex (10). Such exposure of

Fig. 2. Sagittal view demonstrating a prostate positioned superior in the pelvis

contour overestimating the prostate inferior extent; the GUD appears on CT as

margin, a significant length of sphincter would be treated unnecessarily, predispos

the genitourinary diaphragm adds nothing to treatment effi-cacy but may increase the odds of stricture with the high-dose-rate boost. MRI planning for the external beamportion may well be necessary to limit the stricture problemfurther.

The biologic theory that drives the collapsing of high-dose-rate treatments into fewer and fewer larger fractionsis the low a/b model for prostate cancer radiosensitivity(11). In this hypothesis, prostate cancer cells are thoughtto behave more as normal tissues do, and large fractionsare thought to be necessary to eradicate such cells. Outsideof a few thoughtful reviews, the low a/b hypothesis used tojustify such schemes is unchallenged (12). The complexityof prostate cancers, with Gleason grade ranging from nearnormal to essentially anaplastic, would question thishypothesis. Low-grade cells, close to normal in anatomy,may behave as normal tissues and may be resistant to stan-dard radiation, but these are not the life-threatening prostatecancers. To visualize that a Gleason 10 cell has the samebiology as a Gleason 6 does not seem plausible, and manyof the studies used to calculate the low a/b depended on themore plentiful but lower grade cancers. It is abundantlyclear from recent reports on combined external beam and

with a GUD 3.2 cm in length. The right panel demonstrates a CT-based

a circular form contiguous with the prostate. If expanded 0.5 cm from the

ing to stricture with high-dose-rate boost. GUD5 genitourinary diaphragm.

201Editorial / Brachytherapy 12 (2013) 199e201

boost strategies that dose and not dose/fraction is critical(13). A high-quality permanent implant boost deliveringdoses over months (14, 15) can match the efficacy stagefor stage of any high-dose-rate schedule delivered overdays (16e18). This clinical outcome in aggressive prostatecancers is not consistent with a large dose per fractionrequirement to cure prostate cancer.

The stricture complications are in the end not a bafflingmystery, but a direct reflection of a normal functional tissuebehaving in a predictable fashion when exposed to largefractions. We forget at our peril that vulnerable normaltissues trump any theory of cancer and must always definewhat dose and fractionation is safe and prudent (19). Thehopeful and exciting aspect in this literature is that if thelength of sphincter is limited, the stricture rate and severitymay be decreased to an acceptable level. An MRI beforetherapy, which is so useful in carefully assessing tumorfeatures (20), would allow a well-defined measure of the in-traprostatic sphincter length and improve high-dose-ratetreatment planning. This pre-MRI assessment detailingcritical variations in normal structures has already beenhelpful in predicting postsurgical outcomes such as con-tinence (21) and sexual function (22), and in all likelihoodwill contribute as much to optimizing quality-of-lifeoutcomes after prostate cancer radiation therapy as wepursue the modern goal of successful therapy, namely cureand quality of life.

Patrick W. McLaughlin, MDVrinda Narayana, PhD

Department of Radiation OncologyAssarian Cancer Center

University of Michigan Medical Center47601 Grand River

Novi, MI 48374E-mail address: mclaughb@umich.edu

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