Rectal Dose-volume Constraints Research Articles

Gastrointestinal Toxicity Prediction Not Influenced by Rectal Contour or Dose-Volume Histogram Definition

Rectal dose delivered during prostate radiation therapy is associated with gastrointestinal toxicity. Treatment plans are commonly optimized using rectal dose-volume constraints, often whole-rectum relative-volumes (%). We investigated whether improved rectal contouring, use of absolute-volumes (cc), or rectal truncation might improve toxicity prediction. Patients from the CHHiP trial (receiving 74 Gy/37 fractions [Fr] vs 60 Gy/20 Fr vs 57 Gy/19 Fr) were included if radiation therapy plans were available (2350/3216 patients), plus toxicity data for relevant analyses (2170/3216 patients). Whole solid rectum relative-volumes (%) dose-volume-histogram (DVH), as submitted by treating center (original contour), was assumed standard-of-care. Three investigational rectal DVHs were generated: (1) reviewed contour per CHHiP protocol; (2) original contour absolute volumes (cc); and (3) truncated original contour (2 versions; ±0 and ±2 cm from planning target volume [PTV]). Dose levels of interest (V30, 40, 50, 60, 70, 74 Gy) in 74 Gy arm were converted by equivalent-dose-in-2 Gy-Fr (EQD2α/β= 3 Gy) for 60 Gy/57 Gy arms. Bootstrapped logistic models predicting late toxicities (frequency G1+/G2+, bleeding G1+/G2+, proctitis G1+/G2+, sphincter control G1+, stricture/ulcer G1+) were compared by area-undercurve (AUC) between standard of care and the 3 investigational rectal definitions. The alternative dose/volume parameters were compared with the original relative-volume (%) DVH of the whole rectal contour, itself fitted as a weak predictor of toxicity (AUC range, 0.57-0.65 across the 8 toxicity measures). There were no significant differences in toxicity prediction for: (1) original versus reviewed rectal contours (AUCs, 0.57-0.66; P=.21-.98); (2) relative- versus absolute-volumes (AUCs, 0.56-0.63; P=.07-.91); and (3) whole-rectum versus truncation at PTV ± 2 cm (AUCs, 0.57-0.65; P=.05-.99) or PTV ± 0 cm (AUCs, 0.57-0.66; P=.27-.98). We used whole-rectum relative-volume DVH, submitted by the treating center, as the standard-of-care dosimetric predictor for rectal toxicity. There were no statistically significant differences in prediction performance when using central rectal contour review, with the use of absolute-volume dosimetry, or with rectal truncation relative to PTV. Whole-rectum relative-volumes were not improved upon for toxicity prediction and should remain standard-of-care.

A new target localization method for image-guided radiation therapy of prostate cancer

In imaged-guided radiation therapy (IGRT), target localization is usually done with rigid-body registration based on anatomy matching. Problems arise when the target volume can only be matched partially due to inter-fractional organ motion and deformation, resulting in deteriorated target coverage and critical structure sparing. A new target localization method is investigated in which the treatment target volume is aligned with the prescription isodose surface. Our study included 15 prostate patients previously treated with intensity-modulated radiation therapy (IMRT). Patient setup and target localization were performed using a CT-on-rails system before and after the IMRT treatment. IMRT plans were generated on the original simulation CTs (15) and the same MUs and leaf sequences were used to compute the dose distributions on post-treatment CTs (98) with the isocenter adjustments based on either anatomical structure matching or prescription isodose surface alignment. When patients were aligned with the traditional anatomy matching method, the dose to 95% of the CTV, D95, received 74.0 – 77.6 Gy and the minimum CTV dose, Dmin, was 61.9 – 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 35.7% of the treatment fractions. When patients were aligned using the new localization method, the dose to 95% of the CTV, D95, received 74.0 – 78.2 Gy and the minimum CTV dose, Dmin, was 68.4 – 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 17.3% of the treatment fractions. Traditional IGRT target localization based on anatomy matching is effective for population-based PTV margins but not ideal for those patients with large inter-fractional prostate rotation/deformation due to large rectal and bladder volume variation. The new method using the prescription isodose surface to align the target volume could improve the target coverage and rectal sparing for these patients, which can be implemented clinically to improve target dose delivery accuracy.

Dosimetric evaluation of image-guided radiation therapy for prostate cancer

The aim of this study was to investigate the dosimetric accuracy of imaged-guided radiation therapy for prostate patients using the in-room computed tomography (CT) target localization technique. A Siemens CT-on-rails system was used for patient setup and target localization for intensity-modulated radiation therapy (IMRT) of prostate cancer. Fifteen previously treated prostate patients were included in this retrospective study. CT-on-Rails scans were performed before and after the IMRT treatment under local IRB approval. A total of 15 original simulation CT scans and 98 post-treatment CT scans were contoured by the same oncologist to delineate the prostate target, bladder, and rectum. IMRT plans were generated on the original simulation CTs and the same MUs and leaf sequences were used to compute the dose distributions using post-treatment CTs. Varian Velocity deformable registration was used for the summation of the fractional doses and the cumulative doses were compared with the planned doses. For the 15 patients investigated, the mean isocenter shift was up to 4.0 mm in the left-right direction, 5.9 mm in the anterior-posterior direction and 5.6 mm in the superior-inferior direction due to interfractional organ motion. The mean rectal volume varied from 0.6 to 1.73 times and the mean bladder volume varied from 0.59 to 3.65 times between simulation and the end of treatment. The prescription dose to 95% of the PTV, Dp, was set to 76 Gy for all treatment plans. The dose to 95% of the clinical treatment volume (CTV), D95, was 74.0 to 77.6 Gy and the minimum CTV dose, Dmin, was 61.0 to 71.6 Gy, respectively, in the cumulative dose distributions. Detailed analyses showed that 7.1% of the treatment fractions had cold spots (< 85% of Dp) in the peripheral CTV, leading to Dmin < 64 Gy in the cumulative dose distributions for 4 patients. The rectal dose-volume constraints were violated in 35.7% of the treatment fractions while the bladder dose was much improved in 82.7% of the treatment fractions. The current IGRT procedure for patient setup and target localization using rigid-body registration based on contour/anatomy matching is effective for population-based PTV margins. For a small group of patients, specific PTV margins and/or real-time target monitoring/tracking will be necessary due to significant prostate deformation/rotation caused by inter- and intrafractional bladder and rectal volume variation.

Living with the Elekta Compact: Limitations and ways around them.

Elekta AB, Sweden has recently propagated the Elekta Compact--a low-cost, small-footprint, single energy (6MV), linear accelerator, in India. The absence of electron beams and the inability to seamlessly deliver inverse planned intensity modulated radiotherapy (IMRT) segments, mean that some out-of-the-box thinking is mandatory for the full range of required treatments in different clinical settings, but is ultimately very rewarding. Our department started off in July 2011, with the Elekta Compact, equipped with MLCi2 and a camera-based electron portal imaging device. For head-neck cancers, we have successfully utilized a 3D conformal class-solution of eight-to-nine oblique beams, with multiple segments, to deliver an adequate dose to the posterior neck, respecting spinal cord tolerance. Parotid gland sparing is possible in selected node-negative hypopharyngeal/laryngeal cancers. For prostate cancers, we have developed a forward-planned IMRT protocol to routinely deliver 76-80 Gy to the prostate, with margins, while conforming to the same rectal dose-volume constraints as in inverse IMRT. Response and tolerance have been excellent so far. In head-neck cancers, the majority (71%) of patients was locally advanced; however, complete response was achieved in 75% of the cases. Grade 3 acute toxicities were seen in only 7% of the cases and compliance overall was excellent, with no patients requiring a gap in treatment. We achieved biochemical control in 100% of the prostate cancer patients; no patients had grade 3 acute toxicities, and with a median follow-up of 12 months, have yet to see any late rectal bleeding. Although engineered for simplicity and versatility, the Compact requires some innovative thinking by clinicians/physicists to optimize the full range of its possibilities. However, upgrades like inverse IMRT delivery, which are in the pipeline, are urgently needed for it to be viable, especially in a single-accelerator department.

Rectal toxicity after intensity modulated radiotherapy for prostate cancer: Which rectal dose volume constraints should we use?

BackgroundTo define rectal dose volume constraints (DVC) to prevent ⩾grade2 late rectal toxicity (LRT) after intensity modulated radiotherapy (IMRT) for prostate cancer (PC). Material and methodsSix hundred thirty-seven PC patients were treated with primary (prostate median dose: 78Gy) or postoperative (prostatic bed median dose: 74Gy (adjuvant)–76Gy (salvage)) IMRTwhile restricting the rectal dose to 76Gy, 72Gy and 74Gy respectively. The impact of patient characteristics and rectal volume parameters on ⩾grade2 LRT was determined. DVC were defined to estimate the 5% and 10% risk of developing ⩾grade2 LRT. ResultsThe 5-year probability of being free from ⩾grade2 LRT, non-rectal blood loss and persisting symptoms is 88.8% (95% CI: 85.8–91.1%), 93.4% (95% CI: 91.0–95.1%) and 94.3% (95% CI: 92.0–95.9%) respectively.There was no correlation with patient characteristics. All volume parameters, except rectal volume receiving ⩾70Gy (R70), were significantly correlated with ⩾grade2 LRT. To avoid 10% and 5% risk of ⩾grade2 LRT following DVC were derived: R40, R50, R60 and R65 <64–35%, 52–22%, 38–14% and 5% respectively. ConclusionApplying existing rectal volume constraints resulted in a 5-year estimated risk of developing late ⩾grade2 LRT of 11.2%. New rectal DVC for primary and postoperative IMRT planning of PC patients are proposed. A prospective evaluation is needed.

Impact of changing rectal dose volume parameters over time on late rectal and urinary toxicity after high-dose intensity-modulated radiotherapy for prostate cancer: A 10-years single centre experience

Background. External beam radiotherapy is an excellent treatment for patients with prostate cancer (PC). Assessing long-term radiotherapy-induced toxicity is important. We evaluated the impact of implementing different rectal dose volume constraints (DVC) on late rectal and urinary toxicity.Material and methods. Six hundred and thirty-seven PC patients were treated with high-dose intensity-modulated radiotherapy (IMRT) in the primary (median dose of 78 Gy to the prostate) or postoperative setting [median dose of 74 (adjuvant) and 76 Gy (salvage) to the prostatic bed]. Three groups were defined according to different DVC applied over time. The incidence of late rectal and urinary toxicity was evaluated. Three-year actuarial risk estimations of grade 2–3 rectal and urinary toxicity were calculated (Kaplan-Meier statistics).Results. Median follow-up was five years. Overall, the incidence of late grade 3 and 2 rectal toxicity was 1% and 11%. The calculated three-year actuarial risk of developing late grade ≥ 2 rectal toxicity decreased from 16% to 7% and 5% for patients in Group 1, Group 2 and Group 3, respectively (p < 0.001). Respectively, 17 (4%) and 98 (24%) patients developed grade 3 and 2 late urinary toxicity in the primary setting. In the postoperative setting, 15 (6%) and 62 (26%) patients developed grade 3 and 2 urinary toxicity, respectively. The three-year actuarial risk of developing late ≥ grade 2 urinary toxicity in primary- and postoperative-treated patients was 22% and 23%, respectively. This was not significantly different between the three groups.Conclusion. The majority of patients developed no or only moderate rectal toxicity after high-dose IMRT for PC. Implementing different rectal DVC resulted in a significant decrease of late rectal toxicity without affecting urinary toxicity.

Narrow safety range of intraoperative rectal irradiation exposure volume for avoiding bleeding after seed implant brachytherapy

Background & PurposeRectal toxicity is less common after 125I seed implant brachytherapy for prostate cancer, and intraoperative rectal dose-volume constraints (the constraint) is still undetermined in pioneering studies. As our constraint failed to prevent grade 2 or 3 rectal bleeding (bled-pts) in 5.1% of patients, we retrospectively explored another constraint for the prevention of rectal bleeding.Materials and methodsThe study population consisted of 197 patients treated with the brachytherapy as monotherapy using real-time intraoperative transrectal ultrasound (US)-guided treatment at a prescribed dose of 145 Gy. Post-implant dosimetry was performed on Day 1 and Day 30 after implantation using computed tomography (CT) imaging. Rectal bleeding toxicity was classified by CTC-AE ver. 3.0 during a mean 29-month (range, 12-48 months) period after implantation. The differences in rV100s were compared among intraoperative, Day 1 and Day 30 dosimetry, and between that of patients with grade 2 or 3 rectal bleeding (the bled-pts) and of the others (the spared-pts). All patients were divided into groups based on provisional rV100s that were increased stepwise in 0.1-cc increments from 0 to 1.0 cc. The difference in the ratios of the bled-pts to the spared-pts was tested by chi-square tests, and their odds ratios were calculated (bled-OR). All statistical analyses were performed by t-tests.ResultsThe mean values of rV100us, rV100CT_1, and rV100CT_30 were 0.31 ± 0.43, 0.22 ± 0.36, and 0.59 ± 0.68 cc, respectively. These values temporarily decreased (p = 0.020) on Day 1 and increased (p = 0.000) on Day 30. There was no significant difference in rV100s between the bled-pts and spared-pts at any time of dosimetry. The maximum bled-OR was identified among patients with an rV100us value above 0.1 cc (p = 0.025; OR = 7.8; 95% CI, 1.4-145.8); an rV100CT_1 value above 0.3 cc (p = 0.014; OR = 16.2; 95% CI, 3.9-110.7), and an rV100CT_30 value above 0.5 cc (p = 0.019; OR = 6.3; 95% CI, 1.5-42.3).ConclusionBy retrospective analysis exploring rV100 as intraoperative rectal dose-volume thresholds in 125I seed implant brachytherapy for prostate cancer, it is proved that rV100 should be less than 0.1 cc for preventing rectal bleeding.

Searching for Optimal Dose–Volume Constraints to Reduce Rectal Toxicity after Hypofractionated Radiotherapy for Prostate Cancer

Aims Late rectal toxicity is a major concern for prostate cancer patients treated with radiotherapy. Rectal dose–volume constraints, set as guidelines to reduce its incidence, vary among institutions. From a group of patients uniformly treated with hypofractionated radiotherapy, we correlated the incidence of late rectal toxicity with rectal dose–volume rectal constraints as described in three randomised trials for prostate cancer. Materials and methods Favourable-risk prostate cancer patients received a dose of 66 Gy in 22 fractions without hormonal therapy. Toxicity was prospectively assessed using Common Toxicity Criteria v3. The whole or part of the rectum and rectal wall were contoured as an organ at risk for all patients. The rectal constraints of the RTOG 0126, RTOG 0415 and the PROFIT trials were used to correlate with late rectal toxicity. Results The median follow-up time was 58 months. Late rectal toxicity was 62, 20 and 18% for grades 0, 1 and 2/3, respectively. No statistically significant correlation was found between late rectal toxicity and the rectal constraints used in the three trials. The number of patients violating the recommended constraints was similar for the group with grade 2/3 toxicity and the group without any toxicity. Analysis derived from the actual dose–volume histogram dose parameters of this group of patients did not show a relationship between dose to volume of the rectum and late rectal toxicity that could generate a guideline of dose constraints. Conclusion For this group of patients, despite the use of recognised dose–volume constraint guidelines of three trials, we were unable to establish a relationship between these constraints and the late rectal toxicity registered. Further studies on the correlation of dosimetric parameters with rectal toxicity, particularly for hypofractionated regimens, are required. Non-dosimetric factors may also be involved in the risk of late rectal toxicity.

Using Bayesian logistic regression to evaluate a new type of dosimetric constraint for prostate radiotherapy treatment planning

Modern radiotherapy treatments can be optimized using dose-volume constraints which specify the volume of tumor and organs-at-risk receiving a given threshold dose. Careful derivation and evaluation of rectal constraints is essential to allow safe dose escalation in radiotherapy of prostate cancer. The authors present a new type of hybrid dosimetric constraint which comprises both volumetric and spatial factors of the dose-distribution. The authors also propose a framework to evaluate these constraints. The authors used data from the RT01 prostate radiotherapy trial (ISRCTN 47772397) to derive this set of hybrid constraints for the rectum based on measures extracted from dose-surface maps. For comparison, the authors also derive a set of dose-volume constraints. In order to evaluate these dosimetric constraints, the authors propose a new framework for predicting radiation-induced toxicities using Bayesian logistic regression with high-order interactions. The predictive power of the new RT01-based constraints, as well as of two sets of rectal dose-volume constraints proposed in the recent literature-The constraints proposed by other researchers [C. Fiorino, G. Fellin, T. Rancati, V. Vavassori, C. Bianchi, V. C. Borca, G. Girelli, M. Mapelli, L. Menegotti, S. Nava, and R. Valdagni, "Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: Preliminary results of a multicenter prospective study," Int. J. Radiat. Oncol., Biol., Phys. 70, 1130-1137 (2008)] and the constraints used in the conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer (CHHiP) trial [C. P. South, V. S. Khoo, O. Naismith, A. Norman, and D. P. Dearnaley, "A comparison of treatment planning techniques used in two randomised UK external beam radiotherapy trials for localised prostate cancer," Clin. Oncol. (R Coll. Radiol) 20, 15-21 (2008)]--were evaluated using a tenfold cross-validation with follow-up data from the RT01 trial. The predictive power was quantified using receiver-operator characteristic (ROC) curves. Toxicities considered were rectal bleeding, loose stools, and a global toxicity score. Dose-volume constraints had less predictive power than the new type of hybrid constraints. A probabilistic model for predicting rectal bleeding based on the dose-volume constraints proposed by other researchers [C. Fiorino, G. Fellin, T. Rancati, V. Vavassori, C. Bianchi, V. C. Borca, G. Girelli, M. Mapelli, L. Menegotti, S. Nava, and R. Valdagni, "Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: Preliminary results of a multicenter prospective study," Int. J. Radiat. Oncol., Biol., Phys. 70, 1130-1137 (2008)], the CHHiP dose-volume constraints, the RT01-based dose-volume constraints, and the hybrid constraints resulted in average areas under the ROC curves of 0.56, 0.58, 0.62, and 0.67, respectively. For predicting loose stools, the corresponding values were 0.57, 0.53, 0.66, and 0.71, respectively. The areas under the respective ROC curves for predicting the global toxicity score were 0.58, 0.55, 0.61, and 0.63. Thus, imposing the new type of hybrid constraints when generating a treatment plan should result in a reduction in the incidence of radiation-induced late rectal toxicity.

Clinical and dosimetric predictors of late rectal toxicity after conformal radiation for localized prostate cancer: Results of a large multicenter observational study

Purpose Assessing the predictors of late rectal toxicity after high-dose conformal radiotherapy for prostate cancer. Methods One thousand one hundred thirty-two patients entered a prospective observational multicentric study; late rectal toxicity was evaluated by a self-reported questionnaire. Results concerning bleeding and faecal incontinence of 718/1132 patients with a complete follow-up at 36 months were analysed. The correlation between a number of clinical–dosimetric parameters and moderate/severe toxicity was investigated by univariate and multivariate logistic analyses. Results Fifty-two (7.2%) and 57/718 (7.9%) patients were scored as moderate/severe bleeders and faecal incontinents, respectively; 19/57 incontinent patients showed persistent incontinence at 36 months. Bleeding was mainly correlated with V75 Gy while severe bleeding was mainly correlated with the previous abdominal/pelvic surgery; a different rectal dose–volume relationship in the two groups of patients (with/without surgery) was found. Moderate/severe acute toxicity was weakly correlated to late bleeding. The best predictor of faecal incontinence was acute toxicity (OR = 4 and 7 for chronic and actuarial incontinence, respectively). Conclusion The application of rectal dose–volume constraints limited the incidence of rectal bleeding. The risk of bleeding may be further reduced by limiting V75 Gy < 5% and, in the case of patients previously submitted to abdominal/pelvic surgery, V70 Gy < 15–20%. Faecal incontinence seems to be mainly a consequential effect after acute toxicity.

More Restrictive Rectal Dose-volume Constraints Should be Applied to 3D-CRT Prostate Cancer Patients Who Underwent Previous Abdominal Surgery

To evaluate and discuss the role of specific types of abdominal surgery (SURG) before radiation therapy (RT) as a risk factor for late rectal bleeding (lrb) in prostate cancer patients (pts) accrued in AIROPROS 0102 trial.

Dose–Volume Constraints to Reduce Rectal Side Effects From Prostate Radiotherapy: Evidence From MRC RT01 Trial ISRCTN 47772397

Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (>/=50 Gy). Evidence is emerging that lower doses could also be important. Data from a large multicenter randomized trial were used to investigate the correlation between seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) and an absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified using odds ratios. Rectal dose-volume constraints were applied retrospectively to investigate the association of constraints with the incidence of late rectal toxicity. A statistically significant dose-volume response was observed for six of the seven endpoints for at least one of the dose levels tested in the range of 30-70 Gy. Statistically significant reductions in the incidence of these late rectal toxicities were observed for the group of patients whose treatment plans met specific proposed dose-volume constraints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treatment plans met increasing numbers of dose-volume constraints from the set of V30<or=80%, V40<or=65%, V50<or=55%, V60<or=40%, V65<or=30%, V70<or=15%, and V75<or=3%. Considering the entire dose distribution to the rectum by applying dose-volume constraints such as those tested here in the present will reduce the incidence of late rectal toxicity.

4000 ORAL Update of the results of the Dutch multicenter randomized phase III trial comparing 68 Gy of external beam radiotherapy with 78 Gy for localized prostate cancer

To define rectal dose volume constraints (DVC) to prevent ⩾grade2 late rectal toxicity (LRT) after intensity modulated radiotherapy (IMRT) for prostate cancer (PC).Six hundred thirty-seven PC patients were treated with primary (prostate median dose: 78 Gy) or postoperative (prostatic bed median dose: 74 Gy (adjuvant)–76 Gy (salvage)) IMRT while restricting the rectal dose to 76 Gy, 72 Gy and 74 Gy respectively. The impact of patient characteristics and rectal volume parameters on ⩾grade2 LRT was determined. DVC were defined to estimate the 5% and 10% risk of developing ⩾grade2 LRT.The 5-year probability of being free from ⩾grade2 LRT, non-rectal blood loss and persisting symptoms is 88.8% (95% CI: 85.8–91.1%), 93.4% (95% CI: 91.0–95.1%) and 94.3% (95% CI: 92.0–95.9%) respectively.There was no correlation with patient characteristics. All volume parameters, except rectal volume receiving ⩾70 Gy (R70), were significantly correlated with ⩾grade2 LRT. To avoid 10% and 5% risk of ⩾grade2 LRT following DVC were derived: R40, R50, R60 and R65 <64–35%, 52–22%, 38–14% and 5% respectively.Applying existing rectal volume constraints resulted in a 5-year estimated risk of developing late ⩾grade2 LRT of 11.2%. New rectal DVC for primary and postoperative IMRT planning of PC patients are proposed. A prospective evaluation is needed.

Comparison of rectal dose-volume constraints for IMRT prostate treatment planning

The purpose of this paper is to compare different sets of rectal dose-volume constraints and to develop input criteria for the intensity-modulated radiation therapy (IMRT) of prostate cancer. The IMRI treatment plans were created using Varian planning system (CadPlan with Helios module) for ten patients with localized prostate cancer (isocenter dose 78 Gy). The posterior portion of rectum was contoured as an extra volume (help volume). Three sets of input parameters for rectum with gradually increasing priorities (25–50–75–90) were designed for the inverse treatment planning: 1. dose-volume constraints allowing no more than 50, 40, 20 and 10% of the rectum volume be irradiated to 50, 60, 70, and 75 Gy, respectively—volume-based plans, priorities 25–90 (V25-90 plans); 2. maximum dose constraint of 74.1 Gy for rectum—plans with limited maximum reactal dose, priorities 25–90 (M25-90 plans); 3. maximum dose constraint of 50 Gy for the help volume—plans with limited maximum dose for the help volume, priorities 25–90 (H25-90 plans). Dose homogeneity in the planning target volume (PTV) and the rectal volumes (RV) irradiated to 50, 60, 70, and 75 Gy (RV 50–75 Gy) were recorded. Rectum sparing improved for all the plans with increasing priority. While the M plans had the lowest RV 75 Gy values, the H plans gave the minimum RV 50–70 Gy values. Plans were considered acceptable if at least 98% of the PTV was treated to 95% of the prescribed dose. In particular plan groups, the V75, M75, and H50 plans, together with the V50+M75 and H50+M75 combined plans, satisfied this condition and yielded the lowest rectal doses. The H50+M75 combined plan allowed optimal sparing of rectum (RV 50 Gy 51.6%, RV 60 Gy 38.5%, RV 70 Gy 26.0%, and RV 75 Gy 9.1%, respectively). An optima set of dose-based rectal constraints (maximum rectal dose 74.1 Gy, maximum help volume dose 50 Gy) has been developed for Varian planning software. These parameters will constitute a starting point for the prostate IMRT plan optimization.

Is IMRT needed to spare the rectum when pelvic lymph nodes are part of the initial treatment volume for prostate cancer?

To assess whether a 4-field box technique (4FBT), along with its technical refinements, is an adequate approach in terms of rectal sparing and target coverage for patients with localized prostate cancer undergoing whole-pelvic radiotherapy followed by a prostate boost and whether or not intensity-modulated radiotherapy (IMRT) is needed. For 8 patients, 31 plans were generated, each of them differing in one or more features, including prescription (dose/volume) and/or technical factors. For the latter, several "solutions" to try to reduce the amount of irradiated rectal volume were addressed, including modifications of the 4FBT and the use of sequential IMRT. We constructed a database with 248 plans that were tested for their ability to meet a series of rectal dose-volume constraints at V50, V60, V65, V70, V75, and V75.6. Multivariate logistic regression was used to identify factors independently associated with the end point. Successful solutions were also compared in terms of coverage of both pelvic node and prostate planning target volume (PTV) by isodose 95%. At multivariate logistic regression, both rectal blocking and IMRT were independent predictors of the probability of meeting rectal dose-volume constraints during the pelvic and boost phases of treatment with close relative risks. However, on average, partial rectal blocking on lateral fields of 4FBT during whole-pelvic radiotherapy resulted in about 3% of pelvic node PTV being outside isodose 95%; only 2 of 8 patients had the pelvic nodal PTV covered similarly to what was achieved by whole-pelvis IMRT. Conversely, blocking the rectum during the last 3 fractions of the conformal boost showed a dosimetric coverage of prostate PTV similar to that achieved by IMRT boost. Interestingly, patient anatomic configuration was the strongest predictor of rectal sparing. Finally, the size of prostate margins to generate PTV was also independently associated with the probability of meeting rectal dose-volume constraints. In the dose range of 70-76 Gy to the prostate, IMRT and standard techniques are equally effective in meeting rectal dose-volume constraints. However, whole-pelvis IMRT might be preferable to standard techniques for its slightly superior PTV coverage.

Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy

We analyzed our experience treating localized prostate cancer with image-guided off-line correction with adaptive high-dose radiotherapy (ART) in our Phase II dose escalation study to identify factors predictive of chronic rectal toxicity. From 1999-2002, 331 patients with clinical stage T1-T3N0M0 prostate cancer were prospectively treated in our Phase II 3D conformal dose escalation ART study to a median dose of 75.6 Gy (range, 63.0-79.2 Gy), minimum dose to confidence limited-planning target volume (cl-PTV) in 1.8 Gy fractions (median isocenter dose = 79.7 Gy). Seventy-four patients (22%) also received neoadjuvant/adjuvant androgen deprivation therapy. A patient-specific cl-PTV was constructed using 5 computed tomography scans and 4 sets of electronic portal images by applying an adaptive process to assure target accuracy and minimize PTV margin. For each case, the rectum (rectal solid) was contoured from the sacroiliac joints or rectosigmoid junction (whichever was higher) to the anal verge or ischial tuberosities (whichever was lower), with a median volume of 81.2 cc. The rectal wall was defined using the rectal solid with an individualized 3-mm wall thickness (median volume = 29.8 cc). Rectal wall dose-volume histogram was used to determine the prescribed dose. Toxicity was quantified using the National Cancer Institute Common Toxicity Criteria 2.0. Multiple dose-volume endpoints were evaluated for their association with chronic rectal toxicity. Median follow-up was 1.6 years. Thirty-four patients (crude rate = 10.3%) experienced Grade 2 chronic rectal toxicity at a median interval of 1.1 years. Nine patients (crude rate = 2.7%) experienced Grade > or =3 chronic rectal toxicity (1 was Grade 4) at a median interval of 1.2 years. The 3-year rates of Grade > or =2 and Grade > or =3 chronic rectal toxicity were 20% and 4%, respectively. Acute toxicity predicted for chronic: Acute Grade 2-3 rectal toxicity (p < 0.001) including any acute rectal Grade 2-3 tenesmus (p = 0.02) and pain (p = 0.008) were significant predictors of chronic Grade > or =2 rectal toxicity. Any acute rectal toxicity (p = 0.001), any acute tenesmus (p = 0.03), and any acute diarrhea (p < 0.001) were also found to be predictive for chronic toxicity, as continuous variables. Dose-volume histogram predicted for chronic toxicity: Rectal wall absolute and relative V50, V60, V66.6, V70, and V72 and rectal solid relative V60-V72 were significantly associated with chronic Grade > or =2 rectal toxicity both as categorical and continuous variables (t test, linear regression) and when divided into subgroups (chi-square table). The chronic rectal toxicity Grade > or =2 risk was 9%, 18%, and 25% for the rectal wall relative V70 <15%, 25%-40%, and >40% respectively. The volume of rectum or rectal wall radiated to > or =50 Gy was a strong predictor for chronic rectal toxicity. Nonpredictive factors: Rectal solid/wall absolute or relative volumes irradiated to < or =40 Gy, dose level, and use of androgen deprivation were not found predictive. In our ART dose escalation study, rectal wall or rectum relative > or =V50 are closely predictive for chronic rectal toxicity. If rectal dose-volume histogram constraints are used to select the dose level, the risk of chronic rectal toxicity will reflect the risk of toxicity of the selected constraint rather than the dose selected as found in our study using an adaptive process. To select the prescribed dose, different dose-volume histogram constraints may be used including the rectal wall V70. Patients experiencing acute rectal toxicity are more likely to experience chronic toxicity.

Phase II dose escalation study of image-guided adaptive radiotherapy for prostate cancer: Use of dose–volume constraints to achieve rectal isotoxicity

In our Phase II prostate cancer Adaptive Radiation Therapy (ART) study, the highest possible dose was selected on the basis of normal tissue tolerance constraints. We analyzed rectal toxicity rates in different dose levels and treatment groups to determine whether equivalent toxicity rates were achieved as hypothesized when the protocol was started. From 1999 to 2002, 331 patients with clinical stage T1 to T3, node-negative prostate cancer were prospectively treated with three-dimensional conformal adaptive RT. A patient-specific confidence-limited planning target volume was constructed on the basis of 5 CT scans and 4 sets of electronic portal images after the first 4 days of treatment. For each case, the rectum (rectal solid) was contoured in its entirety. The rectal wall was defined by use of a 3-mm wall thickness (median volume: 29.8 cc). The prescribed dose level was chosen using the following rectal wall dose constraints: (1) Less than 30% of the rectal wall volume can receive more than 75.6 Gy. (2) Less than 5% of the rectal wall can receive more than 82 Gy. Low-risk patients (PSA < 10, Stage < or = T2a, Gleason score < 7) were treated to the prostate alone (Group 1). All other patients, intermediate and high risk, where treated to the prostate and seminal vesicles (Group 2). The risk of chronic toxicity (NCI Common Toxicity Criteria 2.0) was assessed for the different dose levels prescribed. HIC approval was acquired for all patients. Median follow-up was 1.6 years. Grade 2 chronic rectal toxicity was experienced by 34 patients (10%) (9% experienced rectal bleeding, 6% experienced proctitis, 3% experienced diarrhea, and 1% experienced rectal pain) at a median interval of 1.1 year. Nine patients (3%) experienced grade 3 or higher chronic rectal toxicity (1 Grade 4) at a median interval of 1.2 years. The 2-year rates of Grade 2 or higher and Grade 3 or higher chronic rectal toxicity were 17% and 3%, respectively. No significant difference by dose level was seen in the 2-year rate of Grade 2 or higher chronic rectal toxicity. These rates were 27%, 15%, 14%, 17%, and 24% for dose levels equal to or less than 72, 73.8, 75.6, 77.4, and 79.2 Gy, respectively (p = 0.3). Grade 2 or higher chronic rectal bleeding was significantly greater for Group 2 than for Group 1, 17% vs. 8% (p = 0.035). High doses (79.2 Gy) were safely delivered in selected patients by our adaptive radiotherapy process. Under the rectal dose-volume histogram constraints for the dose level selection, the risk of chronic rectal toxicity is similar among patients treated to different dose levels. Therefore, rectal chronic toxicity rates reflect the dose-volume cutoff used and are independent of the actual dose levels. On the other hand, a larger PTV will increase the rectal wall dose and chronic rectal toxicity rates. PTV volume and dose constraints should be defined, considering their potential benefit.

Rectal dose–volume constraints in high-dose radiotherapy of localized prostate cancer

Purpose To investigate the relationship between rectal bleeding and dosimetric-clinical parameters in patients receiving three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. Methods In a retrospective national study (AIROPROS01-01, AIRO: Associazione Italiana Radioterapia Oncologica), planning/clinical data for 245 consecutive patients with stage T1-4N0-x prostate carcinoma who underwent 3D-CRT to 70–78 Gy (ICRU point) were pooled from four Italian institutions. The correlation between late rectal bleeding and rectal dose–volume data (the percentage of rectum receiving more than 50, 55, 60, 65, 70, and 75 Gy [V 50–70]) and other dosimetric and clinical parameters were investigated in univariate (log–rank) and multivariate (Cox regression model) analyses. Median follow-up was 2 years. Results Twenty-three patients were scored as late bleeders according to a modified RTOG definition (Grade 2: 16; Grade 3: 7); the actuarial 2-year rate was 9.2%. Excepting V75, all median and third quartile V 50–70 values were found to be significantly correlated with late bleeding at univariate analysis. The smallest p value was seen for V 50 below/above the third quartile value (66%). The V70 (cut-off value: 30%) was found to be also predictive for late bleeding. In the high-dose subgroup (74–78 Gy), Grade 3 bleeding was highly correlated with this constraint. The predictive value of both V 50 and V 70 was confirmed by multivariate analyses. Conclusions The present article provides evidence for correlation between rectal DVH parameters and late rectal bleeding in patients treated with curative intent with 3D-CRT. To keep the rate of moderate/severe rectal bleeding below 5–10%, it seems advisable to limit V 50 to 60–65%, V 60 to 45–50%, and V70 to 25–30%.