Dose-volume constraints to reduce rectal side effects from prostate radiotherapy: evidence from mrc rt01 trial isrctn 47772397

Int. J. Radiation Oncology Biol. Phys., Vol. 76, No. 3, pp. 747–754, 2010 DOSE–VOLUME CONSTRAINTS TO REDUCE RECTAL SIDE EFFECTS FROM PROSTATE RADIOTHERAPY: EVIDENCE FROM MRC RT01 TRIAL ISRCTN 47772397 SARAH L. GULLIFORD, PHKERWYN FOO, F.R.A.N.Z.C.R.,y RACHEL C. MORGAN, M.SC.,z EDWIN G. AIRD, PH.D.,x A. MARGARET BIDMEAD, M.SC.,HELEN CRITCHLEY, PH.D.,{ PHILIP M. EVANS, D.PHIL.,STEFANO GIANOLINI, PH.D.,k W. PHILIP MAYLES, PH.D., A. ROLLO MOORE, M.SC.,BEATRIZ SA´NCHEZ-NIETO, PH.D.,MIKE PARTRIDGE, PH.D., MATTHEW R. SYDES, C.STAT,z STEVE WEBB, D.SC.,AND DAVID P. DEARNALEY, F.R.C.R.yy * Joint Department of Physics, Institute of Cancer Research and Royal Marsden National Health Service Foundation Trust, Sutton, United Kingdom; y Department of Radiation Oncology, Illawarra Cancer Care Centre, Wollongong Hospital, NSW, Australia; z Cancer Group, Medical Research Council Clinical Trials Unit, London, United Kingdom; x Department of Medical Physics, Mount Vernon Hospital, Northwood, United Kingdom; { Atomic Weapons Establishment, Aldermaston, United Kingdom; k Tomotherapy Inc., Culliganlaan, Diegem, Belgium; #Department of Physics, Clatterbridge Centre for Oncology, Wirral, United Kingdom; ** Servicio de Radioterapia, Clinica Alemana de Santiago, Santiago, Chile; and yy Department of Academic Urology, Institute of Cancer Research and Royal Marsden Hospitals, Sutton, United Kingdom Purpose: Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normaltissues. Comprehensive dose–volume analysis of the incidence of clinically relevant late rectal toxicities couldindicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining themid-to-high dose range ($50 Gy). Evidence is emerging that lower doses could also be important.
Methods and Materials: Data from a large multicenter randomized trial were used to investigate the correlationbetween seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) andan absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified usingodds ratios. Rectal dose–volume constraints were applied retrospectively to investigate the association ofconstraints with the incidence of late rectal toxicity.
Results: A statistically significant dose–volume response was observed for six of the seven endpoints for at least one ofthe dose levels tested in the range of 30–70 Gy. Statistically significant reductions in the incidence of these late rectaltoxicities were observed for the group of patients whose treatment plans met specific proposed dose–volume con-straints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treat-ment plans met increasing numbers of dose–volume constraints from the set of V30#80%, V40#65%, V50#55%,V60#40%, V65#30%, V70#15%, and V75#3%.
Conclusion: Considering the entire dose distribution to the rectum by applying dose–volume constraints such asthose tested here in the present will reduce the incidence of late rectal toxicity.
Prostate radiotherapy, rectal complications, late toxicity, dose–volume constraints.
and intensity-modulated RT techniques limit the volume of Late normal tissue effects limit the dose that can be safely normal tissue treated; however, to take full advantage of delivered during radical prostate radiotherapy (RT), but these methods, accurate knowledge of the dose response Phase III dose-escalation trials have demonstrated an advan- of the normal tissues is required. The side effects of RT in tage in disease control using higher doses Conformal the rectum significantly affect patients, and many attempts Note—An online CME test for this article can be taken at trial sponsor (Medical Research Council United Kingdom).
Acknowledgments—We acknowledge National Health Service Reprint requests to: Sarah L. Gulliford, Ph.D., Joint Department funding to the NIHR Biomedical Research Centre; we thank all of Physics, Institute of Cancer Research and Royal Marsden Na- the physicist from participating centers who provided dose cubes tional Health Service Foundation Trust, Cotswold Rd., Sutton for analysis; we also thank Sue Griffiths, Richard Stephens, Isobel SM2 5NG United Kingdom. Tel: (+44) 208-661-3675; Fax: (+44) Syndikus, John Graham, Claire Murphy, and Jacquie Nuttall who made major contributions to the organization and management of Supported and coordinated by the U.K. Medical Research Council, Institute of Cancer Research, and Cancer Research U.K. Section of Received Oct 15, 2008, and in revised form Feb 11, 2009.
Accepted for publication Feb 11, 2009.
Conflict of interest: M. Sydes and R. Morgan are employed by the I. J. Radiation Oncology d Biology d Physics have been made to link dosimetric parameters to the risk of The Medical Research Council RT01 multicenter random- ized controlled trial of conformal prostate RT, delivered either 64 or 74 Gy with neoadjuvant androgen suppression, accrued 843 patients and showed improvement in early effectiveness outcome measures for escalated doses.
In addition to the comprehensive data on late toxicity, which was collated, complete dosimetric data were available for 388 patients. This database provided an opportunity to examine Relative Rectal Volume (%)
the relationship between dose and volume and late effects in prostate RT using a variety of late rectal toxicity measures.
Dose (Gy)
Most studies of dose–volume effects in rectal toxicity have Fig. 1. Proposed dose–volume constraints for late rectal toxicity.
concentrated on the outcome measure of late rectal bleeding Two constraint sets tested connected by lines.
Although this endpoint is straightforwardto record, other symptoms, such as urgency, frequency, loose (LENT) endpoints and presented the analysis according to stools, and anal continence, are at least as important to the pa- the greatest grade of any toxicity type.
tients As RT techniques improve target conformal- The present study systematically tested the relationship ity, the incidence and severity of late rectal toxicity should between the volume of rectum receiving a broad range of decrease ; therefore, it is increasingly important to con- doses and the incidence of a number of different toxicities sider all toxicity grades that concern patients. Studies have in- as scored by clinicians and reported by the patients. The trans- vestigated the correlation between dosimetric parameters and lation of this dose–volume analysis into clinical practice was both bleeding and nonbleeding endpoints . The explored by applying two sets of suggested dose–volume con- most up-to-date results from the Italian AIROPROS 01-02 straints to investigate whether the incidence of rectal trial used self-reported questionnaire responses to toxicity was reduced for treatment plans that adhered to the measure the incidence of frequency/tenesmus/pain (as one in- constraints. summarizes the proposed dose–volume dicator), incontinence, and bleeding and reported a number of constraints from the published data and the constraint sets statistically significant volume cutoffs for the different dose levels. The Dutch multicenter trial used five specificsymptom indicators. Vargas et al. reported the correla-tions between the dosimetric parameters and the National Cancer Institute Common Toxicity Criteria, version 2.0, An analysis was undertaken of the correlation between the dose rectal endpoints. Another study pooled all Radiation distribution to the rectum resulting from RT to the prostate and Therapy Oncology Group/Late Effects of Normal Tissues late rectal toxicity measured using a range of scores. Treatment Table 1. Translation of late rectal toxicity scoring schemes to common grading scheme and baseline exclusion criteria management,distressingsymptoms, majorsurgical interventionor prolongedhospitalization, fatalcomplications Abbreviations: RMH = Royal Marsden Hospital; RTOG = Radiation Therapy Oncology Group; LENT = Late Effects of Normal Tissues; UCLA = University of California, Los Angeles; QOL = quality of life.
Dose–volume constraints to reduce rectal side effects d S. L. GULLIFORD et al.
Table 2. Patients who reported each grade of toxicity (common grading scheme) planning data were collected from participating RT01 centers and sess patients’ quality of life. Seven late rectal toxicity endpoints standardized using in-house software GUINESS (Graphical User In- were chosen to represent clinically relevant effects. These were terface for the aNalysis and modElling of clinical StudieS) . The (1) rectal bleeding (Royal Marsden Hospital scale), (2) proctitis (Ra- treatment planning data were imported, and the three-dimensional diation Therapy Oncology Group/European Organization for Re- dose distribution was reconstructed and analyzed for each patient.
search and Treatment of Cancer), (3) subjective assessment of Only patients with $2 years of follow-up and complete dosimetric sphincter control (LENT/SOMA), (4) subjective assessment of stool data were included in the present study. For each patient, the max- frequency (LENT/SOMA), (5) management of sphincter control imal side effect recorded during follow-up for each toxicity was (LENT/SOMA), (6) frequency of loose stools (UCLA-PCI), and used. The present study used a subset of the main trial data set; fro- (7) urgency (UCLA-PCI). Late toxicities were deemed to be those zen in November 2007 (median follow-up, 60 months).
reported at or after the 6-month assessment.
Normal tissue contours were reviewed centrally by one of us The toxicity scales were harmonized by taking the definitions of (H.C.), and minor adjustments were undertaken as necessary to en- each point on each scale and classifying them as none (Grade 0), sure consistency. The rectum was outlined from the anus taken at the mild (Grade 1), or moderate/severe (Grade 2), in terms of the affect level of the ischial tuberosities or 1 cm below the planning target on the patient. In this harmonization, the management of sphincter volume, whichever was more inferior to the rectosigmoid junction.
control classified using the LENT/SOMA system was dichoto- The conformal planning technique for the trial has been previously mized, because it was thought that the requirement of any manage- reported . In brief, the centers could use three or four fields in the ment intervention should be classified as Grade 2 (moderate/severe).
treatment plan for the initial 64 Gy. The treatment plans of patients lists how the different scoring schemes were translated into randomized to receive the additional 10 Gy to prostate only used a common scoring system. The worst recorded symptom level dur- four or six fields. The treatment plans of the patients who were pre- ing the follow-up period was analyzed for each outcome.
scribed 74 Gy with two separate phases were summed together to Because some of the mild symptoms considered in the present generate a combined dose–volume histogram. The only dose con- study were already prevalent in the trial population before treatment, straint placed on normal tissues in the trial protocol was that no the patients who reported symptoms before RT were excluded from area in the rectum or bladder outside the planning target volume the analysis of that endpoint only, according to the criteria listed in could receive more than the randomized prescription dose.
Detailed follow-up data were available for the late rectal toxicity To establish whether applying dose–volume constraints might re- endpoints assessed using physician-completed Royal Marsden duce the incidence of late rectal toxicity, two sets of constraints were Hospital scores , Radiation Therapy Oncology Group question- tested: those used in the current U.K. Conventional or Hypofractio- naires , and Late Effects of Normal Tissues/Subjective, Objec- nated High Dose Intensity Modulated Radiotherapy for Prostate tive, Management, Analytic (LENT/SOMA) grading . Also, Cancer (CHHiP ISRCTN97182923) trial (derived from a pub- the patient-completed University of California, Los Angeles, Pros- lished data review in 2000); and those recommended in the recent tate Cancer Index (UCLA-PCI) questionnaire was used to as- report by Fiorino et al. . We investigated the population effect Table 3. Odds ratios for an increase in rectal volume of 5%. Rectal bleeding and proctitis Abbreviations: OR = odds ratio; CI = confidence interval.
p # 0.01 (bold italics)p > 0.01, p < 0.05 (italics only) I. J. Radiation Oncology d Biology d Physics Table 4. Odds ratios for an increase in rectal volume of 5%. Stool frequency and sphincter control Abbreviations as in p # 0.01(bold italics)p > 0.01, p < 0.05 (italics only) on the incidence of the seven defined endpoints by comparing the in- cidence of complications for patients whose treatments plans failedeach constraint compared with those whose treatment plan achieved Data from 388 patients were available for analysis. summarizes the data of the patients who were excluded andthe number of patients who experienced each grade of toxic- ity for each endpoint. By definition, no baseline assessment Logistic regression analysis was used retrospectively to inves- was done for proctitis; therefore, all 388 patients were in- tigate how each of the defined endpoints was influenced by the dose distribution to the rectum (regarded as a solid rectum).
The ORs calculated for a 5% increase in the volume of rec- The two toxicity grades were dichotomized to consider the tum receiving each specified dose are listed in odds ratios (ORs) for experiencing any toxicity or moderate/se- The results are presented for any complication grade (Grades vere (Grade 2 or greater) toxicity. The volume of rectum receiv- 1 and 2) and moderate or severe toxicity only (Grade 2).
ing at least a defined dose level was the independent variable in The ORs for both rectal bleeding and proctitis ) in- each model and was treated as continuous. The resulting ORs creased progressively from 20 Gy to 70 Gy. For rectal bleed- were defined as the change in the odds of reporting a specifiedtoxicity, given a 5% absolute increase in the rectal volume receiv- ing (all grades), statistical significance was reached at 40 Gy ing at least the defined dose. An OR >1 indicates an increased (OR, 1.08) increasing to an OR of 1.25 at 70 Gy and for risk of reporting the specified late rectal toxicity. The ORs Grade 2 alone at 30 Gy (OR, 1.14) to 70 Gy (OR, 1.41). A were calculated using Stata, version 10 (College Station, TX) generally similar pattern was seen for proctitis.
for the discrete dose levels. The uncertainty of the ORs was sum- In contrast, the endpoints reporting stool frequency and marized using 95% confidence intervals; p < 0.05 was taken as sphincter control using the LENT/SOMA scheme showed lit- suggesting evidence of effect. ORs for the constraint analysis tle correlation with an increase in volume (A 5% in- were defined as the odds of reporting a specified late rectal tox- crease in volume at 50 and 60 Gy were statistically significant icity as a result of the treatment plan failing to meet a suggested (OR, 1.08–1.09) for stool frequency; 60 Gy was the only sta- constraint relative to the odds if the constraint had been met. ORs tistically significant dose level for sphincter control (OR, were calculated using the Statistical Program for Social Sciences,version 15 (SPSS, Chicago, IL).
1.12; Grades 1 and 2). For Grade 2 toxicity only, 65 Gy Table 5. Odds ratios for an increase in rectal volume of 5%. Rectal urgency and loose stools Abbreviations as in p # 0.01(bold italics)p > 0.01, p < 0.05 (italics only) Dose–volume constraints to reduce rectal side effects d S. L. GULLIFORD et al.
Table 6. Dose–volume constraints tested and number of constraints retrospectively to the dose–volume histograms Statistically significant ORs were observed for rectal bleeding (all grades) for the CHIiP trial constraints of 50–65 Gy (For Grade 2 toxicity, the range of statistically significant CHHiP constraints shifted upward to 60–70 Gy (OR, >2.5). Only the 40 Gy Fiorino constraint was statistically significant (Grades 1 and 2; OR, 1.57).
When considering all grades of proctitis, the 30 and 65 Gy CHHiP constraints were statistically significant. For Grade 2 proctitis, the CHHiP 50–70 Gy constraints and the 40–60 Gy constraints proposed by Fiorino et al. were statistically significant (ORs, 1.64–2.05).
In keeping with the results for a volume increase of 5% at a specified dose, few of the proposed dose–volume con-straints were statistically significant for endpoints defined us- Data in parentheses are percentages.
ing the LENT/SOMA criteria ). No significant resultswere found when considering Grade 2 toxicity only.
was statistically significant for sphincter control. No statisti- presents the results of applying the constraints for cally significant results were found for stool frequency the patient-reported endpoints of rectal urgency and loose (Grade 2) or management of sphincter control for any of stools. The ORs for rectal urgency (Grades 1 and 2) were sta- tistically significant for the Fiorino constraints for 40–60 Gy In contrast to these results, the patient-reported endpoints (ORs, 1.7–1.9). For Grade 2 toxicity, the same constraints from the UCLA-PCI questionnaire indicated a con- were statistically significant with ORs >2. The 40 Gy CHHiP sistently strong volume response for Grades 1 and 2 and constraint was statistically significant for both Grades 1 and 2 Grade 2 only, for doses of 30–40 Gy, respectively, to 60 and Grade 2 only. The results for loose stools (all grades) Gy for loose stools (OR, 1.10–1.15) and rectal urgency were statistically significant for the 30–60 Gy CHHiP con- (OR, 1.1–1.12), with less-consistent results as the dose in- straints (ORs, 1.67–2.48) and extended to 65 Gy for Grade creased to the prescription dose level.
2 only (OR, $2.4). The 40–60 Gy Fiorino constraints werestatistically significant for Grades 1 and 2 (OR, 1.88–2.24).
However, only the 40 Gy constraint remained significant summarizes the dose–volume constraints man- dated for the CHHiP trial and those proposed by Fiorino The overall effect of applying dose–volume constraints on et al. Also listed are the number of patients from the the incidence of rectal toxicity is summarized in The available RT01 data set whose rectal dose–volume histogram tightest set of constraints (i.e., the lowest allowed volume failed each constraint. None of the treatment plans of the from either CHHiP or Fiorino constraints at each dose level) 388 patients failed the 75 Gy constraint proposed by Fiorino was applied to the patient cohorts. They were volume receiv- et al. The ORs calculated by applying the dose–volume ing 30 Gy of #80%, 40 Gy of #65%, 50 Gy of #55%, 60 Gy Table 7. Odds ratios for the retrospective application of dose volume constraints. Rectal bleeding and proctitis Abbreviations as in p # 0.01(bold italics)p > 0.01, p < 0.05 (italics only) I. J. Radiation Oncology d Biology d Physics Table 8. Odds ratios for the retrospective application of dose volume constraints. Sphincter control and stool frequency Abbreviations as in p # 0.01(bold italics)p > 0.01, p < 0.05 (italics only) of #40%, 65 Gy of #30%, 70 Gy of #15%, and 75 of #3%.
receiving the highest doses is particularly important. (It is presents the maximal toxicity grade experienced (from important to consider the size of the OR rather than the size any of the seven endpoints) relative to the number of con- of the p value when assessing the effect of these results on straints which the treatment plan failed. It can be clearly ob- clinical practice.) However, for rectal urgency and loose served that the number of patients experiencing Grade 2 stools, our data suggest similar weight should be given to toxicity increases as more constraints are failed.
rectal volumes receiving $30 Gy. The variation in responsebetween toxicity endpoints demonstrated that different as-pects of the dose distribution to the rectum manifest in differ- ent functional and anatomic responses. This challenges the It has been shown that the incidence of late rectal toxicity concept that the rectum is a serial structure for which correlates with an increase in volume at specific dose levels.
a maximal dose is the only consideration when avoiding The results for rectal bleeding, proctitis, loose stools, and rec- tal urgency have demonstrated compelling evidence of vol- Previous studies investigating late rectal toxicity have ume effects for dose ranging from 30–40 Gy upward to the mainly focused on rectal bleeding and the rectal volume re- prescription dose. These results are consistent for mild and ceiving high radiation doses approaching the prescribed moderate/severe toxicities reported by the clinician and pa- dose. Thus, the dose–volume constraints investigated, and tients. The trend of increasing ORs with an increasing dose consequentially recommended, have tended to be in the for rectal bleeding and proctitis suggests that although a vol- ume effect exists for a broad range of doses, the volume straints for the CHHiP trial were determined from the Table 9. Odds ratios for the retrospective application of dose volume constraints. Rectal urgency and loose stools Abbreviations as in p # 0.01(bold italics)p > 0.01, p < 0.05 (italics only) Dose–volume constraints to reduce rectal side effects d S. L. GULLIFORD et al.
Maximum toxicity reported (any endpoint)
maximum toxicity grade
Proportion of patients reporting each
Number of constraints failed
Fig. 2. Summary of maximal toxicity grade reported (any endpoint) relative to number of constraints failed. Lowest vol-ume constraint taken at each dose level.
available published data (circa 2000) and are, therefore, most toxicity. It is clear from the published data that no global scor- relevant to rectal bleeding. More recently, an understanding ing system has been adopted, and many of the cited studies refer has emerged that volumes receiving lower doses might also to modified versions of the classic grading scales, the Radiation contribute to the development of late effects Therapy Oncology Group/European Organization for Re- . The recent Fiorino constraints are not just determined search and Treatment Cancer and LENT/SOMA. Without de- from rectal bleeding, for example, the constraint at 40 Gy tailed information on how the scoring has been modified, it is is implicitly defined for rectal incontinence.
difficult to directly compare the results. The work of Fiorino The CHHiP constraints relate well to rectal bleeding. Proc- et al. and subsequent correspondence with Bauman and titis, which is a composite endpoint combining rectal bleeding Rodrigues highlights many of the issues and summarizes with urgency, tenesmus, and other factors, was predicted by the stricter dose constraints for CHHiP at 65 and 70 Gy A strength of our analysis was the validation of previously and the Fiorino constraints at 50 and 60 Gy. The Fiorino proposed, in contrast to data-derived, constraints on an inde- constraints related well to rectal urgency and subjective pendent population of patients treated without predetermined sphincter control. Both Fiorino and CHHiP constraints pre- dose–volume histogram restrictions. Nevertheless, it is ac- dicted loose stools and stool frequency but for doses of #60 knowledged that the number of statistical tests performed on Gy. These two pairs of endpoints could obviously be linked our data might have resulted in some chance findings. In addi- and have a different pathophysiology. Both constraint sets tion, the dose levels tested are interrelated parameters of the showed considerable merit; however, neither can be regarded planned dose distributions. The interrelation was partly negated by the variety of different planning techniques used by partici- The results we have presented have indicated that the en- pating centers within the trial protocol. It is also acknowledged tire dose distribution to the rectum should be considered care- that the treatment plan is determined from a snapshot of the pa- fully during treatment planning. This is particularly pertinent tient’s anatomy at the computed tomography planning scan, it to inverse planning in which optimization constraints con- has been assumed for the present study that the snapshot is rep- centrating on doses close to the prescription might result in resentative of the volumes treated on a daily basis. However, large rectal volumes at lower doses that have been shown these limitations could well contribute to our observation that in the present study to correlate with several measures of one-third of patients experienced moderate/severe toxicity of late rectal toxicity. Obviously, the volumes receiving the dif- some type despite meeting all dose constraints. An additional ferent dose levels are interrelated, and it might be that the rea- factor might be individual variations in radiosensitivity, which son that large volumes receiving intermediate doses correlate is the subject of additional study We also acknowledge with late toxicity is a ‘‘dose bath effect’’ in which the func- that coincidental comorbidities might have contributed to the tionality of the epithelial cells is impaired, reducing the abil- ity to facilitate repair of higher dose neighboring regions.
A broad concordance has been reached in the published data that the application of dose–volume constraints can reduce laterectal toxicity . However, the proposed dose– The comprehensive analysis of dose–volume effects and volume constraints have varied (). A number of explana- constraints presented in the present study has provided substan- tions are possible for this variability, including RT technique, tial evidence that considering only the maximal or high-dose volume definition, choice of endpoint, and method of scoring region of the rectal dose distribution from a prostate RT plan I. J. Radiation Oncology d Biology d Physics might not minimize the risk of patients experiencing late rectal volume constraints using the currently available data should toxicity. It is recommended that appropriate rectal dose– be introduced into routine treatment planning for prostate RT.
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