Radiotherapy and Oncology 90 (2009) 400–407

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Radiotherapy and Oncology

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Morbidity of prostate radiotherapy

Is there more than one proctitis syndrome? A revisitation using datafrom the TROG 96.01 trial

Anne Capp a, Mario Inostroza-Ponta b, Dana Bill l, Pablo Moscato b, Chi Lai l, David Christie c, David Lamb d,Sandra Turner e, David Joseph f, John Matthews g, Chris Atkinson h, John North i, Michael Poulsen j,Nigel A. Spry f, Keen-Hun Tai k, Chris Wynne i, Gillian Duchesne k, Allison Steigler l, James W. Denham l,*,1

a Calvary Mater Newcastle, Newcastle, NSW, Australiab Centre for Bioinformatics, Biomarker Discovery & Information-based Medicine, University of Newcastle, Newcastle, NSW, Australiac Premion, Tugun, Qld, Australiad Wellington Cancer Centre, Wellington, New Zealande Westmead Hospital, Sydney, NSW, Australiaf Sir Charles Gairdner Hospital, Perth, WA, Australiag Auckland Hospital, Auckland, New Zealandh Christchurch Hospital, Christchurch, New Zealandi Dunedin Hospital, Dunedin, New Zealandj Southern Zone Radiation Oncology, Mater Centre, Qld, Australiak Peter MacCallum Cancer Institute, Melbourne, Vic., Australial School of Medicine and Public Health, University of Newcastle, NSW, Australia

a r t i c l e i n f o

Article history:Received 23 July 2008Received in revised form 9 September 2008Accepted 12 September 2008Available online 24 October 2008

Keywords:ProctitisCTC scaleRadiation rectal toxicity

0167-8140/$ - see front matter � 2008 Elsevier Irelandoi:10.1016/j.radonc.2008.09.019

* Corresponding author. Address: University of NewRegion Mail Centre, NSW 2310, Australia.

E-mail address: jim.denham@newcastle.edu.au (J.W1 Presented orally by Professor J. Denham in his Ho

award lecture at the ECCO Symposium, Barcelona, Oct

a b s t r a c t

Purpose: We sought to categorize longitudinal radiation-induced rectal toxicity data obtained from menparticipating in a randomised controlled trial for locally advanced prostate cancer.Materials and methods: Data from self-assessed questionnaires of rectal symptoms and clinician recordedremedial interventions were collected during the TROG 96.01 trial. In this trial, volunteers were random-ised to radiation with or without neoadjuvant androgen deprivation. Characterization of longitudinalvariations in symptom intensity was achieved using prevalence data. An integrated visualization andclustering approach based on memetic algorithms was used to define the compositions of symptom clus-ters occurring before, during and after radiation. The utility of the CTC grading system as a means of iden-tifying specific injury profiles was evaluated using concordance analyses.Results: Seven well-defined clusters of rectal symptoms were present prior to treatment, 25 were seenimmediately following radiation and 7 at years 1, 2 and 3 following radiation. CTC grading did not con-cord with degree of rectal ‘distress’ and ‘problems’ at all time points. Concordance was not improved byadding urgency to the CTC scale.Conclusions: The CTC scale has serious shortcomings. A powerful new technique for non-hierarchicalclustering may contribute to the categorization of rectal toxicity data for genomic profiling studies anddetailed patho-physiological studies.

� 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 90 (2009) 400–407

In an earlier report from the TROG 96.01 prostate cancer trialChristie et al. showed that classic radiation-induced acute and laterectal toxicity profiles are not distinct, time separated entities [1].Rather, there is a tendency for these toxicities to manifest as inter-mittent, relapsing symptomatology with acute exacerbations,resulting in a prevalence of delayed rectal injury symptoms of

d Ltd. All rights reserved.

castle, Locked Bag 7, Hunter

. Denham).norary membership of ESTROober 2007.

approximately 10% at any given time after completingradiotherapy.

Common toxicity criteria (CTC) have been developed to enableconsistent toxicity scoring worldwide over a broad range of malig-nant and non malignant conditions [2]. The CTC for bowel injury issimilar in structure and scoring to the RTOG/EORTC toxicity scor-ing systems used previously for radiotherapy, which has lead toits wide acceptance for toxicity assessment in clinical trials involv-ing radiation. It is becoming increasingly apparent to clinicians andresearchers that the CTC system is flawed, particularly in the caseof rectal injury [2]. The clinical descriptors used in the CTC toxicityassessment are rectal bleeding, bowel frequency, diarrhea, and

A. Capp et al. / Radiotherapy and Oncology 90 (2009) 400–407 401

pain amalgamated with some management descriptors to providean indication of severity. They do not include descriptors of theresulting distress or social impact, nor rectal urgency, a commonand problematic symptom because it enforces lifestyle changes[3]. Rectal bleeding is over-represented in the scoring scale andits (and other symptoms) remittent nature cannot be capturedwithout frequent questionnaires. The CTC proctitis scoring systemuses the same descriptor combinations and scores to describe bothacute and late rectal toxicity syndromes. To overcome some of theproblems presented by the CTC grading system, other groups haveattempted to develop their own toxicity criteria i.e. LENT/SOMA [4]French Italian Glossary [5] and AADK [6], with some acceptance,predominately in Europe.

The 96.01 Trial Management Committee wished to study thegenetic determinants of rectal injury with the intention of definingsusceptible subgroups of men prior to treatment. This is only pos-sible if the injuries can be well characterized by available clinicaldata. The large volume of 96.01 data has enabled us to assesshow well the CTC criteria describe rectal injury in individuals asa prelude to the process of matching clinical and genetic data. Ithas also enabled us to explore ways to improve the recording oftreatment-induced normal tissue sequelae.

Materials and methods

TROG 96.01 was a multi-centre prospective randomised con-trolled trial, run in 18 centres throughout Australia and NewZealand. All centres received approval from local Ethical ReviewCommittees. From 1996 to 2000, patients with locally advancednon-metastatic prostate cancer who gave informed writtenconsent were randomised to receive either 0, 3 or 6 months ofneoadjuvant maximal androgen deprivation (goserelin and flutam-ide) prior to external beam radiotherapy delivered to the prostateand seminal vesicles (66Gy in 33 fractions to the ICRU point).Rectal symptom data were collected using a modified Litwinself-assessment questionnaire [7] and gastro-intestinal CTC (v.2)scores completed at randomisation, end of radiotherapy and at fourmonthly intervals for the first two years and at six monthlyintervals thereafter. Relevant symptom scores were combined withclinician-collected remedial intervention data to reconstitute a CTCproctopathy score. Additional rectal dysfunction variablesfrom the modified Litwin questionnaire, ‘distress’ and ‘problems’(inconvenience) caused by rectal symptoms were used to assesstheir impact on quality of life.

Statistical methods

Data collected at randomization (baseline symptoms), end ofradiotherapy and at all follow-up visits, 90 days (acute symptoms)and up to 5 years (delayed symptoms) after commencing radio-therapy have been analysed in this report. All three treatment armswere combined for this analysis.

PrevalencePrevalence is defined as the proportion of all living patients who

have an event at specified time points during the study period,regardless of whether recurrent cancer has developed. Prevalencerates of an event have been defined and given grades at varioustime points from randomisation to 5 years after completion oftreatment. Eight symptoms from the modified Litwin Question-naire have been presented graphically to highlight changes overtime in relation to treatment. Data from patients in all arms ofthe trial have been plotted together. The symptoms are urgency,bowel frequency, diarrhea, looseness, bleeding, mucus loss, pain,and abdominal cramps. The generalised estimating equations pro-cedure (GEE), a multiple logistic regression-like procedure that ad-

justs for multiple readings and variability over time was used todetermine the contribution of individual symptoms to distress at‘‘moderate” levels or greater, and symptom-related problems at‘‘moderate” levels or greater.

ConcordanceConcordance ratings between event grades, such as between

distress and symptom-related problem levels, were achieved usingcross tabulation matrices of data collected at all time points up to 5years from the end of radiotherapy. Concordance ratings have beendefined as the proportion of patients who have a pre-determinednumber of event grades that concord within pre-determined toler-ance limits.

Changes in concordance ratings over time were also sought.Progressive discordance over time, where CTC grade levels re-mained stable (or increased) but distress and/or symptom-relatedproblem levels decreased, were taken to indicate that some degreeof adaption had occurred. Conversely progressive increases in dis-tress and/or problem levels in a man whose CTC grade levels re-mained stable or decreased were taken to mean that‘‘sensitization” had occurred. This analysis was restricted to menwith at least six observations recorded during the trial up to 5years from end of radiotherapy.

Symptom cluster analysisSymptom clusters at baseline, end of radiotherapy and at

delayed time points (1, 2 and 3 years after end of radiotherapycombined) were sought using a novel non-hierarchical analyticprocess developed by Inostroza-Ponta et al. [8,9]. The eightsymptoms listed above were used in the clustering process [8,9].This process begins with the identification of ‘‘distances” betweendifferent symptoms. i.e. two or more symptoms that occur togetherin a given patient are ‘‘close” together. In order to define clinicallymeaningful ‘‘distances” between symptoms, symptom levels weredichotomised at the grades most likely to be associated with bowelproblems at moderate or greater levels. As a consequence eachpatient’s ‘‘symptom profile” is a one dimensional array of eightelements (in the case of baseline and end of radiotherapy data),each one of them a symptom expressed at a low level (0) or a highlevel (1). For the data collected at years 1, 2 and 3 post-radiother-apy each symptom profile is an array of 24 elements. The first 8correspond to the dichotomised symptoms reported at the end ofyear 1, the second 8 for year 2, and the third 8 for year 3.

Patients with profiles that contain two or more ‘‘close” symp-toms are grouped together in the first iteration. Repeated iterationsenable further ‘‘close” symptoms to be combined with existingcombinations of symptoms to build ‘‘clusters” of symptoms. Thesymptom clusters are built into a tree-like graph, and eventuallythe process starts to combine symptoms that are less ‘‘close”. Thenovel algorithm works by ‘excising’ links between cluster groupingsthat are beginning to become less similar, and recombining theremaining cluster groupings. This process results in the final identi-fication of ‘‘natural clusters”, sets of several symptom profiles whichhave a very high intra-cluster similarity and inter-cluster dissimi-larity. These ‘‘clusters” identify groups of patients with different,discrete symptom profiles that can be characterized by the ‘‘dis-tances” between their component symptoms. A more mathematicaldescription of this iterative process is given in the online appendix.

It is possible to identify a ‘‘core” symptom through this processof ‘‘building” the symptom profile clusters. Other symptoms are‘‘built on” to this core as the cluster is constructed. For example,in this data set, urgency was found to be at the ‘‘core” of manysymptom clusters, and bleeding was a ‘‘peripheral” symptom inmany clusters. Although uncertain at present, the ‘‘position” ofthe symptom in the cluster may be affected by the patho-physio-logical state of the patients.

402 Proctitis syndrome: A revisitation

Results

The 96.01 trial completed patient accrual in February 2000 after802 eligible men with localized T2b,c, T3 and T4, N0M0, cancerswere enrolled. Fully completed self-assessment questionnaireswere available from 766 men at randomisation, 749 at the end ofradiotherapy, and 503 at years 1, 2 and 3 combined.

Overview of CTC grades recorded

Fig. 1 illustrates that prior to any treatment, 45% of men alreadyhad symptom descriptors compatible with CTC rectal ‘‘toxicity”grades 1 and 2 and only 55% of men would have been assigned aCTC grade of 0 (i.e. no rectal toxicity symptoms). The same obser-vation can be made of the CTC gradings at the end of radiation andat maximum levels in the first three years following radiation.23.6% had symptom descriptors compatible with CTC Grade 0‘‘acute” proctitis, while 9.5% of patients had descriptors compatiblewith CTC Grade 0 ‘‘late” proctitis at all time points following radi-ation. Symptom descriptors compatible with CTC Grade 2 proctitiswere reported by almost a third of patients (32.9%) at some stagein the first 3 post-treatment years. The percentages presented inparentheses indicate that even though identical CTC grades wererecorded at each time point, a greater proportion of patients weredistressed by their symptoms and reported that they were experi-encing problems as a result at the end of radiation than at ran-domisation or in years 1, 2 and 3 combined after radiation.

Symptom time courses

The prevalence graphs, seen in Fig. 2, suggest that a number ofrectal symptoms at moderate or severe level (i.e. PGrade 2) suchas pain and diarrhea, peaked in intensity at radiotherapy comple-tion then returned to baseline levels in the first or second year fol-lowing treatment.

Rectal urgency and bowel frequency follow a different timecourse (Fig. 3). While both were highly prevalent during andshortly after radiation, severity diminished in the first year follow-ing radiation, but remained well above pre-treatment levels for 4(or more) years. Rectal bleeding was different again. Moderate de-grees of bleeding were not commonly recorded at the end of radi-ation, however bleeding intensity appeared to increase in the first

Baseline Acute Delayed

CTC Gd 0 CTC Gd 0 CTC Gd 0n = 443 n = 189 n = 76 = 55.2% = 23.6% = 9.5% [0.24%] [7.8%] [0.3%]

CTC Gd 1 CTC Gd 1 CTC Gd 1n = 334 n = 417 n = 462 = 41.6% = 52% = 57.6% [1.5%] [13.6%] [1.0%]

CTC Gd 2 CTC Gd >=2 CTC Gd >=2n = 196 n = 264 n = 25 = 24.4% = 32.9% = 3.1% [39.3%] [9.3%][12.5%]

[%]% experiencing moderate or severe distress/ problems

Fig. 1. Crude incidence of CTC grade distribution at baseline, end of treatment anddelayed time points. (The incidence of CTC grade at delayed time points is derivedfrom the greatest grade recorded up to three years after the end of radiotherapy.)The percentages in parentheses are the percentages of those experiencing moderateto severe distress and bowel problems.

three years following radiation and then diminish, but not to base-line levels.

The individualized toxicity symptom prevalence graphs demon-strate why combining all symptoms in a single proctopathy score(as has been done with the rectal CTC scores in Fig. 4) is not helpfulin defining subtypes of radiation injury either at the end of radia-tion or in successive years. This aggregation does not reflect thenatural history of delayed proctopathy, seen to be chronic withacute exacerbations when individual patient time course plotsare studied [1].

The relationship between symptoms and the distress and problemsthey cause

As men with proctopathic symptoms usually experiencemore than one symptom at any given time point, the GEE pro-cedure was used to model which individual rectal symptomswere associated with higher rates of perceived bowel distressand problems. Patient-assessed rectal dysfunction scores col-lected up to three years post completion of radiotherapy wereanalysed using these models (summarized in Table 1, presentedin the online supplement). The models suggest that rectal pain,which was relatively uncommon, was the symptom moststrongly influencing perceptions of distress. Diarrhea, bleedingand urgency were the next most distressing symptoms, whilebowel frequency, abdominal cramps and passage of mucus wereperceived to be the least distressing. A similar hierarchy wasobserved when perceptions of symptom-related problems wereexamined (see Table 1 (online)). Bleeding, diarrhea and urgencywere perceived to be the next most likely symptoms to causeproblems, while bowel frequency and mucus excretion werethe least likely to cause problems. Abdominal cramping wasthe only symptom to vary in the two hierarchies, being associ-ated with very limited distress levels, but with moderate prob-lem levels.

Concordance between CTC grade and the distress and problems causedby the underlying symptoms

Rectal dysfunction data during five years of post-treatment fol-low up were reviewed to assess the concordance between CTCproctopathy scores, urgency as a separate variable or incorporatedwith CTC proctopathy, and patient determined distress and bowelproblem levels (Table 1).

Concordance between patient reported bowel distress and pa-tient reported bowel problems was good in 38.2% and poor in29.8% of patients (Table 1a), indicating that these variables aretruly assessing different aspects of psychosocial functioning justi-fying the format and validity of the original questionnaire design[7]. CTC proctopathy and CTC proctopathy with urgency addeddid not concord strongly, with 49.7% exhibiting good concordance,22.8% having fair concordance and 27.5% having poor concordanceindicating that the addition of urgency significantly alters the CTCscoring system.

Concordance of the CTC criteria with distress and problems re-ported was not improved by the addition of urgency (Table 1b).Good concordance was exhibited between CTC proctopathy andbowel distress in 19.6% of patients, when urgency was added tothe CTC scale concordance with distress was good in only 12.4%of patients. The addition of urgency increased the proportion of pa-tients with poor concordance between the CTC and distress gradesfrom 9.7% to 23.8%.

Adaption to rectal dysfunction symptoms over time was inves-tigated by determining the proportion of men whose distress and/or problem levels improved over time while symptom levels re-mained constant or worsened. Evidence of ‘‘sensitization” was

CrampsPain

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Looseness Diarrhea

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ortio

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Time in years from randomisation

2 3 4 5

0 11 2 3 4 5 0 11 2 3 4 5

0 11 12 3 4 5 2 3 4 5

Fig. 2. Prevalence of rectal toxicity symptoms at Grade P 2 level that expressed themselves predominantly at the end of radiotherapy and resolved within the first or secondyear after radiation.

Time in years

Time in years

Time in years

Rectal Bleeding

Urgency

Bowel Frequency

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Fig. 3. Prevalence of rectal toxicity symptoms at grade P 2 that expressedthemselves at all time points.

Prevalence of CTC proctopathyat grade 2 or more (n=802)

Time in years

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Fig. 4. Prevalence of CTC grade 2 or more proctopathy scores over a 5 year periodfrom randomisation.

A. Capp et al. / Radiotherapy and Oncology 90 (2009) 400–407 403

sought by identifying the proportion of men whose distress/prob-lem levels deteriorated over time while symptom levels improved.Unfortunately the remittent nature of symptom severity levels

prevented any useful conclusions being drawn from this time-con-suming analytical process. However this analysis has not ruled out‘‘adaptive” or ‘‘sensitization” processes in small proportions of thetrial population.

Symptom clusters

Analysis using the clustering approach suggested the presenceof several symptom clusters at specific time points i.e. prior totreatment, (Table 2a) at the completion of radiotherapy (Table2b) and at years 1, 2 and 3 after radiotherapy combined (Table2c). Urgency and pain were identified as the main drivers of clustercomposition. In contrast rectal bleeding was prevalent, but onlycontributed ‘‘peripherally” to cluster composition.

The clusters identify clinically meaningful groups of patientswhose moderate or greater problems and distress are most likelyto be explained by similar individual symptoms. For example, Ta-ble 2a shows that prior to any treatment most patients had no ma-jor symptoms (90.3% were in the minimal symptoms cluster), butthere were also three small but distinct groups of patients whowere exhibiting significant symptoms. The symptoms of the firstgroup were most likely due to urgency (3.4%), the second to loose-ness (2.7%) and the third to cramps (1.4%).

Pre-treatment data (Table 2a) indicates that 90.3% of menwould fit into the minimal symptomatology cluster (i.e. no major

Table 1bConcordance between the listed variables at the same time point.

Concordance measuredbetweenthe following variables

Totalassessablepatients

Excellent 61 encounterwhere differenceis one point)

Good 2–4 encounterswhere difference isone point)

Moderate (>5 encountersdiffer by one OR <1 encounterdiffering by two points)

Poor >2 encountersdiffering by two ormore points)

CTC proctopathy & Bowel problem grade 794 8.8% 13.7% 60.8% 16.6%CTC proctopathy + urgency & Bowel problem grade 802 5.5% 7.7% 55.5% 31.3%CTC proctopathy & Bowel distress grade 802 7.7% 19.6% 63.0% 9.7%CTC proctopathy + urgency & Bowel distress grade 800 4.8% 12.4% 58.9% 23.8%

The CTC grade does not reflect the problems and distress that patients are reporting at the same time point very strongly, there was excellent concordance between CTC scoreand problem grade in only 8.8% of patients at the same time point. The addition of urgency to the CTC scale did not improve this concordance (excellent concordance was seenin only 5.5% in this case).

Table 1aConcordance between the variables listed at the same time point.

Concordance measuredbetween the following variables

Total assessablepatients

Good (concordanceof P6 values)

Fair (concordance of P6 valuesand discordance of 2–4 values)

Poor (discordanceof P5 values)

Bowel distress grade & Bowel problem grade 752 38.2% 32.0% 29.8%CTC proctopathy & CTC proctopathy + urgency 759 49.7% 22.8% 27.5%

A patient’s report of distress from bowel symptoms is different to a report of problems caused by the symptoms, these variables are distinct, they do not concord well. Theaddition of urgency alters the CTC scoring system, the CTC score does not concord very strongly with the score once urgency is added to the scale.

404 Proctitis syndrome: A revisitation

symptoms). Of these, 0.7% considered that they had a moderate orworse bowel problem, 7.8% had bowel frequency of three or moretimes per day and 9.7% noted rectal bleeding of small quantity ormore. Only 0.4% of these men would have moderate to severescores on the CTC proctopathy system. The remaining three symp-tom clusters, each comprise ten or more men. 11.5% of men in theurgency cluster perceived a moderate or worse bowel problemeven though the CTC proctopathy system did not indicate a singleman with a moderate to severe score in this cluster.

At completion of radiotherapy (Table 2b), 47.9% of men re-mained in the cluster with minimal symptom levels. Of these, only3.3% considered themselves to have a moderate or worse bowelproblem, in spite of the fact that 26.5% of these men were openingtheir bowels three or more times per day and 20.1% of them hadsmall quantities of per rectum blood loss. The remaining 12 symp-tom clusters (43.5% of total population) had higher rates of moder-ate to worse bowel problems, bowel frequency and rectal bleeding.Table 2b illustrates the previously described disparity between theCTC aggregate proctopathy scale and individual symptom preva-lence, for example there were 15 men in the cluster characterizedby frequency at the end of radiotherapy, only 6.7% of these consid-ered their bowel symptoms to be a significant problem (i.e. moderateor larger) despite 93.3% of them having to open their bowels morethan three times per day and 40% having blood loss. The CTC criteriawould classify only 13.3% of these patients as at least grade 2.

Once radiotherapy was completed, six main symptom clustersemerged (Table 2c). The majority of men (76.7%) were clusteredinto a group with minimal symptoms. Urgency was the dominantsymptom in 5 of the 6 symptoms-present clusters that were ob-served in the remaining men. All 6 of these clusters contained rel-atively large proportions of men with bowel frequency andbleeding. In 3 of the clusters, the percentage of men experiencingmoderate or worse problems due to their symptoms fell to 0% bythe end of the third post-treatment year reflecting some degreeof reduction in most or all symptom levels.

The chronicity of symptom-related problem levels as they relateto the severity of symptoms within clusters is clearly shown inFigs. 5 and 6. Fig. 5 indicates that men who were allocated to theminimal symptom clusters at randomisation, at the end of radia-tion or in the three years following radiation reported minor prob-lem levels at all three time points. In contrast, men allocated to thetwo largest symptoms-present clusters at the same time points(Fig. 6) reported greater than average problem levels at all three

time points, i.e. if a patient reports that his symptom-relatedproblems are moderate or severe at any one of these time points,it appears that the problems will remain moderate to severethroughout, up until at least 3 years post-radiation (Fig. 6),whereas if he starts out with minimal symptoms, he is likely toremain minimally symptomatic for at least 3 years (Fig. 5).

Discussion

We have a strong interest in the development of predictive as-says for normal tissue radiation injury based on genomic profiles.Pre-requisites are accurate clinical data and adequate sample sizes.Collection of accurate data depends strongly on the anatomical siteof injury and the ease with which its severity can be assessedreproducibly [10]. At some anatomical sites the injury can be read-ily visualized and its severity graded according to easily under-stood criteria. Unfortunately, rectal injury does not fall into thiscategory. The CTC grading scale is based on reported symptomsand remedial interventions. More accurate assessments are possi-ble using serial procto-sigmoidoscopic examinations and biopsies[11,12], but such assessments are rarely possible in the contextof a multi-centre trial. An issue to bedevil the use of the CTC grad-ing scale is the commonness of intercurrent bowel disorders thathave no relationship with radiation injury, but can produce someof the same symptoms. Even when symptoms can be attributed di-rectly to radiation-induced pathological processes it can be diffi-cult to understand how the symptoms reported relate to theinjury itself. For example, in a patient whose injury seems to beconfined to a very small portion of the rectum, the patho-physio-logical origins of the complaints of increased bowel frequency,diarrhea and abdominal cramping are puzzling.

The 96.01 trial has produced a rich source of symptom datawhose value has been increased enormously by concurrent mea-surement of symptom impact data. Our goal was to reliably iden-tify subgroups of men with discrete groups of symptomsattributable to rectal injury at varying severity levels. The CTCgrading scale was applied initially, but it quickly became clear thatwe would need to revisit the methods used to define proctopathicsyndromes [3]. The previous study was limited by the fact thatobservations were made at only one time point in a group ofresponders to a postal questionnaire. The current study is basedon serial observations made at specific time points in an entire(much larger) trial population.

Table 2aSymptom clusters identified at baseline (i.e. prior to treatment).

Cluster characterization* No. % Total Problem % Frequency % Bleeding % CTC Gd 2 %

Minimal 692 90.3 0.7 7.8 9.7 0.4Urgency only 26 3.4 11.5 23.1 15.4 0.0Looseness 21 2.7 4.8 19.0 14.3 14.3Cramps 11 1.4 10.0 18.2 27.3 72.7

Note: Symptom-related problems defined as ‘‘moderate or large”, frequency as ‘‘3 or more times per day”, bleeding as ‘‘small quantity or more” and CTC grade 2 as CTCgrade P 2. Abbreviations: Occ = occasional, Freq = frequency, Gd = Grade.

* Three clusters with less than 10 men in each cluster are not represented.

Table 2bSymptom clusters identified at the end of radiotherapy (acute).

Cluster characterization� No. % Total Problems % Frequency % Bleeding % CTC Gd2 %

Minimal 359 47.9 3.3 26.5 20.1 0.8Pain 75 10.0 37.3 46.7 44.0 2.7Urgency 49 6.5 12.2 55.1 28.6 2.0Urgency, pain 33 4.4 45.5 60.6 54.5 15.2Diarrhea 31 4.1 22.6 25.8 45.2 96.8Cramps, pain, urgency 29 3.9 82.8 69.0 55.2 72.4Diarrhea, pain, occ freq, loose 24 3.2 70.8 91.7 62.5 100.0Loose, occ freq, mucus, blood 21 2.8 38.1 71.4 52.4 42.9Frequency 15 2.0 6.7 93.3 40.0 13.3Diarrhea, urgency 14 1.9 28.6 71.4 28.6 100.0Mucus 11 1.5 9.1 72.7 54.5 100.0Freq, urgency, pain, mucus 11 1.5 90.9 10.0 90.9 100.0Urgency, mucus 10 1.3 30.0 60.0 30.0 100.0

� Twelve clusters with less than 10 men in each cluster are not represented.

Table 2cSymptom clusters identified at 1, 2 and 3 years after radiotherapy (delayed).

Cluster characterization� No. % Total Problem %yr 1

Problem %yr 2

Problem %yr 3

Frequencyyr 2 (%)

Bleedingyr 2 (%)

CTC Gd 2yr 2 (%)

Minimal occ bleeding, diarrhea, mucus 386 76.7 2.6 1.8 1.2 1.53 33.2 7.6Urgency yrs 2 and 3, occ freq, looseness,

blood30 6.0 6.7 26.7 12.5 56.7 60.0 33.3

Urgency yrs 1 and 2, occ yr 3, diarrhea,pain, mucus

24 4.8 8.3 8.3 14.3 41.7 62.5 33.3

Urgency yr 3, occ bleeding, mucus 23 4.6 4.3 0 0 26.1 47.8 4.3Looseness yr 1, occ yrs 2 and 3 18 3.6 11.1 5.5 0 33.3 55.6 13.9Urgency yr 2 15 3.0 6.7 13.3 0 33.3 40.0 6.7

� Twelve clusters with less than 10 men in each cluster are not represented.

A. Capp et al. / Radiotherapy and Oncology 90 (2009) 400–407 405

Firstly, it is appropriate to comment on why we felt that the useof the CTC proctitis scale was unsuited to our purpose. Our resultsconfirm earlier work indicating that faecal urgency which is not in-cluded in the CTC scale, is not only common, but is a troublesomesymptom that adversely affects normal daily life [1,3]. Men withsignificant faecal urgency frequently state that they restrict activi-ties to locations near a toilet for fear of soiling themselves. It is notinfrequent for these men to report that they have been embar-rassed by episodes of public faecal incontinence. Incorporation ofthis symptom into a revised grading scale seems essential. Weadded urgency to the existing CTC scale to discover whether theconcordance of the modified CTC scale with severity of the re-ported symptom-related problems would improve. The fact thatit did not suggests to us that the simple addition of an importantsymptom to the scale is an insufficient measure. In our opinion, acomplete revision of the grading scale is needed if the scale is toreflect the real problems experienced.

The difficulties we have experienced with the CTC scale do notend at this point. Aside from the poor correspondence between thecurrent scale and the related problems and distress experienced,the scale appears to greatly over-score the grade of minimal symp-toms that are common even in men yet to receive radiotherapy. Forexample, Fig. 1 indicates that only 55% of the trial population canbe classified as CTC grade 0 prior to any treatment, only 24% ofmen can be classified as CTC grade 0 acute proctitis, and only

10% of men have grade 0 delayed proctopathy! No experienced cli-nicians who have reviewed these figures, feel that these propor-tions reflect their own clinical observations. The CTC scale isintended for use in both the acute setting and the delayed settings.The symptom prevalence diagrams shown in Figs. 2 and 3 showquite clearly that some symptoms (rectal pain, abdominal cramp-ing, looseness and diarrhea) are far more prevalent than others atthe time of treatment and in the first few months after treatment.Some symptoms (such as rectal bleeding) are more prevalent 18 ormore months after treatment, while others (faecal urgency, mucusdischarge and increased bowel frequency) are prevalent at bothtime points.

In a previous report we used K-means clustering in an attemptto find out whether a number of different patho-physiological pro-cesses contribute to the clinical entity commonly known as‘‘chronic radiation proctitis” [3]. In the hope that a similar ap-proach would define subgroups of men with symptom clusters thatreflect the underlying pathological processes better than the CTCgrading system, we applied a novel clustering algorithm to thedata. This approach was developed by two of the authors (PMand MI) in collaboration with Dr Regina Berretta at Newcastle Uni-versity. Because we wanted this non-hierarchical approach toidentify symptom clusters that cause problems and/or distresswe dichotomized our categorical symptom scales at the point atwhich most patients classified the problems caused by their symp-

406 Proctitis syndrome: A revisitation

toms as being moderately severe or worse. The clusters identifiedby the algorithm are associated with a greater range of problemscores than the CTC grading scale achieves. Whether the resultingclusters reflect the presence of different patho-physiological pro-cesses, and are reproducible in other datasets remains to be seen.Several characteristics of the clusters identified at the three timepoints (baseline, end of radiation and post-radiotherapy years 1,2 and 3) are noteworthy. The first is that the sizes of the ‘‘no majorsymptoms” clusters at the three time points conform more closelyto the expectations of experienced clinicians than the sizes of thesubgroups of men with CTC grade 0 at these time points. The sec-ond is that symptom clusters identified at the end of radiation dif-fer considerably from those post-treatment years 1, 2 and 3. Forexample, at the end of radiation, clusters comprising symptomssuch as rectal pain, mucus loss, diarrhea and abdominal crampsare common, but uncommon at post-treatment years 1, 2 and 3.Conversely, rectal bleeding is a stronger component of the post-treatment years clusters. Faecal urgency, on the other hand, is anintegral component of most end of radiation and post-treatmentclusters. The third characteristic is that clusters that are associatedwith the highest reported problem levels almost inevitably includefaecal urgency, and frequently rectal pain. Finally, the longitudinalplots of problem prevalence presented in Figs. 5 and 6 make it clearthat men in the most troublesome symptom clusters at the end oftreatment, and in the first 3 years after, often have problematic

Minimal symptoms at baseline(n=692)

Minimal symptoms 1, 2 & 3 yearsafter RT (n=386)

Minimal symptoms at end of RT(n=359)

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Fig. 5. Prevalence of ‘‘moderate or severe” symptom-related problems at all timepoints in the: (a) 692 men who were in the ‘‘minimal symptoms” cluster atbaseline; (b) 359 men who were in the ‘‘minimal symptoms” cluster at the end ofradiation; (c) 386 men who were in the ‘‘minimal symptoms” cluster for years 1, 2and 3 after radiation.

symptoms prior to any treatment [13]. Furthermore men withtroublesome symptoms prior to treatment are more likely to expe-rience problematic symptoms at the end of radiation and in thesucceeding years [14].

An important question to ask is how the various symptomclusters identified relate to underlying radiation-induced patho-logical processes. This is not a straightforward issue [15]. Thetime course data presented in Figs. 2 and 3 suggest that ‘‘abnor-mal” patho-physiological symptoms present prior to radiationare aggravated by, or amplify, the inflammatory symptoms thatoccur during radiation as well as those relating to the more per-manent injuries present after radiation. The cluster data alsomake it clear that very troublesome solitary symptoms, attribut-able to isolated injuries of the mucosa (e.g. copious bleedingfrom telangiectases), are quite unusual. Most symptom clusterssuggest that the underlying injuries to the rectal wall are fullthickness. Moreover their symptom components suggest thatreactive physiological changes outside the irradiated rectal seg-ment contribute to the overall symptom cluster. A detailed dis-cussion of the mechanisms underlying ano-rectal symptoms isbeyond the scope of this paper but interested readers are direc-ted to some of the work by Yeoh and Andreyev [16,17]. Giventhe complexity of the issue it seems unlikely that straightfor-ward relationships between genomic profiles and symptomatol-ogy will emerge. This does not mean that attempts to seekrelationships should be abandoned, merely that any relationshipsdiscovered should be regarded as hypothesis-generating observa-

Two worst symptoms clusters atbaseline (n=37)

Three worst symptom clustersat end of RT (n=64)

Two worst symptom clusters1, 2 & 3 years after RT (n=54)

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Fig. 6. Prevalence of ‘‘moderate or severe” symptom-related problems at all timepoints in the: (a) 37 men in the two most severe problem clusters at baseline; (b) 64men in the three most severe problem clusters at the end of radiation; (c) 54 men inthe two most severe problem clusters at years 1, 2 and 3 after radiation.

A. Capp et al. / Radiotherapy and Oncology 90 (2009) 400–407 407

tions to be explored further with more detailed patho-physiolog-ical studies.

Another important question is the extent to which men adapt totheir symptoms over time, or, conversely, become sensitized tothem. We addressed this question by attempting to find outwhether problem and distress levels changed over time whilesymptom levels remain constant or vice versa. The fact that wecould not detect clear evidence that such divergences were occur-ring cannot be taken to mean that such phenomena do not exist.The remittent nature of many patients’ symptom time courses ren-dered this analytic approach problematic. Another confounding is-sue is the large variation in the degree of ‘‘stoicism” with whichmen respond to their problems. For example two men, with symp-toms that included significant faecal incontinence, claimed thatthey experienced no problems or distress, whereas several menwith occasional, mild rectal bleeding, reported that they were se-verely distressed.

Shortcomings of the study

A major flaw of this study is the absence of rectal dose-volumehistogram data [18–20], which will be available from our next trial(RADAR) [21]. Another limitation was the decrease in question-naire completion rates following treatment, limiting our clusteringanalysis study to the first three post-radiation years.

Conclusions

The CTC grading system has serious shortcomings and wouldbenefit from revision. Separate scales should be developed foracute and late effects to reflect symptoms that are prevalent atthese time points. Amongst other changes this would involveinclusion of faecal urgency in each scale.

Patho-physiological changes prior to treatment play a greaterrole in post-treatment symptom profiles than previously believedand this will need to be taken into account in correlative geneticstudies.

If correlative genetic studies are planned the complexity ofunderlying patho-physiological changes make it necessary to col-lect individual symptom, sign and intervention data in additionto combined grading scale data (such as CTC). This should includeuse of an instrument that allows grading of the entire range ofsymptoms, signs and interventions possible. At a minimum theinstrument should be employed prior to treatment, at the end ofradiation, and at multiple time points in the five years followingradiation.

The CTC grading scale is not a satisfactory basis for establishingpredictive assays that make use of genomic profiles. The powerfulnon-hierarchical clustering techniques that have been introducedin the field of functional genomics may make a useful contributionto the processing of clinical data in future efforts to define mean-ingful and reliable genomic profiles.

Acknowledgements

The 96.01 trial has been supported by groups from the NationalHealth & Medical Research Council of Australia, Astra Zeneca andSchering Plough Pty Ltd. Additional support for several authorshas been provided by the Hunter Medical Research Institute. Weare also indebted to many clinicians throughout Australia andNew Zealand who have participated in the trial and to Drs MartinHauer-Jensen, Jervoise Andreyev, Bert van der Kogel, Eric Yeoh andPeter O’Brien for many helpful discussions on this subject over sev-eral years.

We thank Rosemary Bradford for her tireless efforts in produc-ing this manuscript and the ESTRO Membership Award lecture inBarcelona in 2007, on which it is based. Ms Kristen Palmer andMrs Allison Kautto are thanked for their editorial assistance.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.radonc.2008.09.019.

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