Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

: To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer.

: We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74–78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24–102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity.

: At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p <0.0001 for all comparisons), the absolute rectal volume appeared to be a factor only at the higher doses of 70, 75.6, and 78 Gy (p = 0.0514, 0.0016, and 0.0021, respectively). The following variables also correlated with toxicity on the univariate analysis: maximal dose to the clinical target volume, maximal dose to rectum, maximal dose to the rectum as a percentage of the prescribed dose, and maximal dose delivered to 10 cm³ of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p = 0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p <0.05 for all comparisons).

: Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup.     

Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen ≥10 ng/ml

: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer.

: We report the biochemical freedom from disease (bNED) rates (BNED) failure in Prostate Specific Antigen (PSA) ≥ 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (<10, 10–19.9, and ≥20 ng/ml). Dose was stated to be at the center of prostate gland.

: There was significant improvement in bNED survuval for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10–19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA ≥ 20 ng/ml (p = 0.003 and 0.02, respectively).

: Increasing dose above 71 or 73 Gy did not result in improved bNED survuval for patient with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in the patients. A significant improvement in bNED survuval was noted for patients with pretreatment PSA ≥ 10 ng/ml treated above 71 of 73 Gy; further dose escalation studies are warranted.     

Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial

A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer.

A total of 305 Stage T1–T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis.

There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA ≤10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy.

An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives ≥70 Gy to <25% should be used.     

Ultrasound image fusion for external beam radiotherapy for prostate cancer

: To determine whether real-time ultrasound imaging and targeting system for the treatment of prostate cancer was feasible. The initial phase of this project included a study to develop and determined (a) software for the fusion of ultrasound images to standard x-rays obtained during simulation, and (b) the potential reduction in field size with real time imaging.

: During 13 patient simulations a transrectal ultrasound image was obtained. Orthogonal x-ray films were acquired with the rectal probe in place. Both the x-ray and ultrasound images were digitized and a fusion image was created of the prostate position in relation to the probe, bladder, and rectum. The two-dimensional area of the rectum, bladder, and prostate was determined in the lateral projection. Potential conformal blocks were designed for the lateral portals in a four-field treatment technique.

: The transrectal ultrasound probe enabled real-time prostrate imaging. The lateral field size can be reduced to 6.08 × 5.68 cm² ± 0.62 × 0.48 cm² from the standard 8 × 8 cm² field. The posterior rectal wall was physically displaced out of the lateral field. The area of the rectum included in the lateral field in 1.75 cm² ± 0.85 cm².

: The prostate position can be determined with certainty on a regular basis with transrectal ultrasonography. The amount of normal tissue in the high dose volume can be reduced. This approach may reduce acute and chronic morbidity and allow further dose escalation.     

High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients

To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT).

Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6–60 months).

Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of ≥ late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of ≥ late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively.

These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.     

Radiotherapy treatment for isolated loco-regional recurrence of rectosigmoid cancer following definitive surgery: Peter maccallum cancer institute experience, 1981–1990

: To assess the success of external beam radiation treatment in the management of loc-regional recurrence of rectosigmoid cancer.

: A retrospective analysis f 135 patients with locally recurrent rectosigmid cancer presenting to Peter MacCallum Cancer Institute between january 1981 and December 1990 was undertaken. Patients were treated with three different dose ranges of radiotherapy: 50–60 Gy (“Radical” group), 45 Gy (“High-dose palliative” group), and <45 Gy (“Low-dose palliative” group). Symptomatic response rates and overall survival for each group were determined.

: Symptomatic response rates of 85, 81, and 56% were achieved in the radical, high-dose palliative, and low-dose palliative groups, respectively. Estimated median survival times were 17.9, 14.8, and 9.1 months for the radical, high-dose palliative, and low-dose palliative groups, respectively.     

Late morbidity profiles in prostate cancer patients treated to 79-84 Gy by a simple four-field coplanar beam arrangement

PURPOSE: To describe the frequency and magnitude of late GI and GU morbidity in prostate cancer patients treated to high dose levels with a simple three-dimensional conformal technique. METHODS AND MATERIALS: A total of 156 intermediate- and high-risk patients were treated between January 1, 1992 and February 28, 1999 with a simple four-field three-dimensional conformal technique to 79-84 Gy. All patients were treated with a four-field conformal technique; the prostate received 82 Gy and the seminal vesicles and periprostatic tissue 46 Gy. GI and GU toxicity was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Morbidity Grading Scale and compared using Kaplan-Meier estimates. RESULTS: The late Grade 2 GI complication rate was 9% and 38% at 3 years for patients treated with and without rectal blocking, respectively (p = 0.0004). No Grade 3 late GI complications developed. The rate of Grade 2 late GU complications was 5%, 8%, and 12% at 12, 24, and 36 months, respectively. The Grade 3 late GU complication rate was 2% at 36 months. These differences were not statistically significant. CONCLUSION: The treatment method described is a simple four-field conformal technique that can be easily implemented in the general radiation community. A dose of 79-84 Gy can be safely delivered to the prostate, with a 9% rate of late Grade 2 GI, 12% rate of late Grade 2 GU, and 2% rate of late Grade 3 GU complications.     

A dose-escalation trial with the adaptive radiotherapy process as a delivery system in localized prostate cancer: analysis of chronic toxicity

PURPOSE: To evaluate the validity of the chosen adaptive radiotherapy (ART) dose-volume constraints while testing the hypothesis that toxicity would not be greater at higher tumor dose levels. MATERIALS AND METHODS: In the ART dose escalation/selection trial, treatment was initiated with a generic planning target volume (PTV) formed as a 1-cm expansion of the clinical target volume (CTV). After the first week of therapy, the patient was replanned with a patient-specific PTV, constructed with CT and electronic portal images obtained in the first 4 days of treatment. A new multileaf collimator beam aperture was used. A minimum dose prescribed to the patient-specific PTV, ranging 70.2-79.2 Gy, was determined on the basis of the following rectal and bladder constraints: <5% of the rectal wall has a dose >82 Gy, <30% of the rectal wall has a dose >75.6 Gy, <50% of the bladder volume has a dose >75.6 Gy, and the maximum bladder dose is 85 Gy. A conformal four-field and/or intensity-modulated radiotherapy (IMRT) technique was used. Independent reviewers scored toxicities. The worst toxicity score seen was used as per the Common Toxicity Criteria grade scale (version 2). We divided the patients into three separate groups: 70.2-72 Gy, >72-75.6 Gy, and >75.6-79.2 Gy. Toxicities in each group were quantified and compared by the Pearson chi-squared test to validate our dose escalation/selection model. Grades 0, 1, 2, and 3 were censored as none vs. each category and none vs. any. RESULTS: We analyzed patients with follow-up greater than 1 year. The mean duration of follow-up was 29 months (range, 12-46 months). We report on 280 patients, mean age 72 years (range, 51-87 years). Only 60 patients received adjuvant hormones. Mean pretreatment prostate-specific antigen level was 9.3 ng/mL (range, 0.6-120 ng/mL). Mean Gleason score was 6 (range, 3-9). The lowest dose level was given to 49 patients, the intermediate dose to 131 patients, and 100 patients received the highest dose escalation. One hundred eighty-one patients (65%) were treated to a prostate field only and 99 patients (35%) to prostate and seminal vesicles. Chronic genitourinary and/or gastrointestinal categories were incontinence, persistent urinary retention, increased urinary frequency/urgency, urethral stricture, hematuria, diarrhea, rectal pain, bleeding, ulcer, fistula, incontinence, and proctitis. Toxicity at the high dose level was not different from toxicity at the intermediate or lower dose levels. No significant difference was observed in any of the individual toxicity categories. CONCLUSIONS: By applying the ART process--namely, developing a patient-specific PTV--to prostate cancer patients, significant dose escalation can be achieved without increases in genitourinary or gastrointestinal toxicity. Our data validate the rectal and bladder dose-volume constraints chosen for our three-dimensional conformal and IMRT prostrate radiotherapy planning.     

Dose-Volume Histograms for bladder and rectum

: A careful examination of the foundation upon which the concept of the Dose-Volume Histogram (DVH) is built, and the implications of this set of parameters on the clinical application and interpretation of the DVH concept has not been conducted since the introduction of DVHs as a tool for the quantitative evaluation of treatment plans. The purpose of the work presented herein is to illustrate problems with current methods of implementing and interpreting DVHs when applied to hollow anatomic structures such as the bladder and rectum.

: A typical treatment plan for external beam irradiation of a patient with prostate cancer was chosen to provide a data set from which DVH curves for both the bladder and rectum were calculated. The two organs share the property of being shells with contents that are of no clinical importance. DVHs for both organs were computed using a solid model and using a shell model. Typical treatment plans for prostate cancer were used to generate DVH curves for both models. The Normal Tissue Complication Probability (NTCP) for these organs is discussed in this context.

: For an eight-field conformal treatment plan of the prostate, a bladder DVH curve generated using the shell model is higher than the corresponding curve generated using the solid model. The shell model also has a higher NTCP. A six-field conformal treatment plan slo results in a higher DVH curve for the shell model. A treatment plan consisting of bilateral 120-degree arcs, results in a higher DVH curve for the shell model, as well as a higher NTCP.

: The DVH concept currently used in evaluation of treatment plans is problematic because current practices of defining exactly what constitutes “bladder” and “rectum.” Commonly used methods of tracing the bladder and rectum imply use of a solid structure model for DVHs. In reality, these organs are shells and the critical structure associated with NTCP is obviously and indisputably the shell, as opposed to its contents. Treatment planning algorithms for DVH computation should thus be modified to utilize the shell model for these organs.     

Preoperative radiotherapy in rectal carcinoma-Aspects of acute adverse effects and radiation technique

: To explain a possible association between treatment technique and postoperative mortality adter preoperative radiotherapy of rectal carcinoma, the dose distributions were compared in model experiments.

: Preoperative radiotherapy with a three-beam technique delivered in five fractions to 25 effects of this treatment, both acute and late, have been low. In a parallel trial using an identical fractionation schedule and total dose but with a two-beam technique, the postoperative mortality was higher. Two-, three-, and four-beam techniques were analyzed in 20 patients with computed tomography based, three-dimensional dose planning. Dose distributions and dose-volume histograms in the planning target volume (PTV) and in the organs at risk were considered. A numerical “biological” model was used to compare the techniques.

: The two-beam and the four-beam box techniques give the most homogeneous distributions in the PTV, although all techniques results in dose distributions that would be considered adequate, provided 16 MV or higher photon energies are used. Three- and four-beam techniques show advantages over the two-beam technique with respect to organs at risk, particularly the small bowel. With the two-beam technique and the upper beam limit at mid-L4, the volume of the bowel that receives >95% of the prescribed dose, and hence, is included in the treated volume (TV), is more twice as large as that with three- and four-beam techniques, and that of the total body between 1.5 and 2 times as large. The results of the analyses using the biological model indicate that the three- and four-beam techniques result in less small bowel complication rates than the two-bowel technique. The integral energy to the total body is similar for all treatment modalities compared.

: The volume of bowel included in the TV, rather than the energy imparted to the body, influences postoperative mortality, and emphasizes the importance of precise radiotherapy planing to minimize normal tissue toxicity.     

Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer

Purpose: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT).

Methods and Materials: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose–volume histograms. The recurrences were classified as 1) “in-field,” in which 95% or more of the recurrence volume (V_recur) was within the 95% isodose; 2) “marginal,” in which 20% to 95% of V_recur was within the 95% isodose; or 3) “outside,” in which less than 20% of V_recur was within the 95% isodose.

Results: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68–90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared.

Conclusions: The majority of local-regional recurrences after conformal and segmental IMRT were “in-field,” in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.     

Principal component analysis-based pattern analysis of dose-volume histograms and influence on rectal toxicity

PURPOSE: The variability of dose-volume histogram (DVH) shapes in a patient population can be quantified using principal component analysis (PCA). We applied this to rectal DVHs of prostate cancer patients and investigated the correlation of the PCA parameters with late bleeding. METHODS AND MATERIALS: PCA was applied to the rectal wall DVHs of 262 patients, who had been treated with a four-field box, conformal adaptive radiotherapy technique. The correlated changes in the DVH pattern were revealed as "eigenmodes," which were ordered by their importance to represent data set variability. Each DVH is uniquely characterized by its principal components (PCs). The correlation of the first three PCs and chronic rectal bleeding of Grade 2 or greater was investigated with uni- and multivariate logistic regression analyses. RESULTS: Rectal wall DVHs in four-field conformal RT can primarily be represented by the first two or three PCs, which describe approximately 94% or 96% of the DVH shape variability, respectively. The first eigenmode models the total irradiated rectal volume; thus, PC1 correlates to the mean dose. Mode 2 describes the interpatient differences of the relative rectal volume in the two- or four-field overlap region. Mode 3 reveals correlations of volumes with intermediate doses ( approximately 40-45 Gy) and volumes with doses >70 Gy; thus, PC3 is associated with the maximal dose. According to univariate logistic regression analysis, only PC2 correlated significantly with toxicity. However, multivariate logistic regression analysis with the first two or three PCs revealed an increased probability of bleeding for DVHs with more than one large PC. CONCLUSIONS: PCA can reveal the correlation structure of DVHs for a patient population as imposed by the treatment technique and provide information about its relationship to toxicity. It proves useful for augmenting normal tissue complication probability modeling approaches.     

A comparison of coplanar four-field techniques for conformal radiotherapy of the prostate.

BACKGROUND AND PURPOSE: Conformal radiotherapy of the prostate is an increasingly common technique, but the optimal choice of beam configuration remains unclear. This study systematically compares a number of coplanar treatment plans for four-field irradiation of two different clinical treatment volumes: prostate only (PO) and the prostate plus seminal vesicles (PSV). MATERIALS AND METHODS: A variety of four-field coplanar treatment plans were created for PO and PSV volumes in each of ten patients. Plans included a four-field 'box' plan, a symmetric plan having bilateral anterior and posterior oblique fields, a plan with anterior oblique and lateral fields, a series of asymmetric plans, and a three-field plan having anterior and bilateral fields for comparison. Doses of 64 and 74 Gy were prescribed to the isocentre. Plans were compared using the volume of rectum irradiated to greater than 50% (V50), 80% (V80) and 90% (V90) of the prescribed dose. Tumour control probabilities (TCP) and normal tissue complication probabilities (NTCP) for the rectum, bladder and femoral heads were also evaluated. Femoral head dose was limited such that less than 10% of each femoral head received 70% of the prescribed dose. RESULTS: For the PO group, the optimal plan consisted of anterior oblique and lateral fields (Rectal V80 = 23.8+/-5.0% (1 SD)), while the box technique (V80 = 26.0+/-5.8%) was less advantageous in terms of rectal sparing (P = 0.001). Similar results were obtained for the PSV group (Rectal V80 = 43.9+/-5.0% and 47.3+/-5.5% for the two plan types, respectively, P = 0.001). The three-field plan was comparable to the optimal four-field plan but gave higher superficial body dose. With dose escalation from 64 to 74 Gy, the mean TCP for the optimal plan rose from 52.0+/-2.8% to 74.1+/-2.0%. Meanwhile, rectal NTCP for the optimal plan rose by 3.5% (PO) or 8.4% (PSV), compared to 4.7% (PO) or 10.1% (PSV) for the box plan. CONCLUSIONS: For PO volumes, a plan with gantry angles of 35 degrees, 90 degrees, 270 degrees and 325 degrees offers a high level of rectal sparing and acceptable dose to the femoral heads for all patients, while for PSV volumes, the corresponding plan has gantry angles of 20 degrees, 90 degrees , 270 degrees and 340 degrees. Using these plans, the gain in TCP resulting from dose escalation can be achieved with a smaller increase in anticipated rectal NTCP.     

Inclusion of geometric uncertainties in treatment plan evaluation

: To correctly evaluate realistic treatment plans in terms of absorbed dose to the clinical target volume (CTV), equivalent uniform dose (EUD), and tumor control probability (TCP) in the presence of execution (random) and preparation (systematic) geometric errors.

: The dose matrix is blurred with all execution errors to estimate the total dose distribution of all fractions. To include preparation errors, the CTV is randomly displaced (and optionally rotated) many times with respect to its planned position while computing the dose, EUD, and TCP for the CTV using the blurred dose matrix. Probability distributions of these parameters are computed by combining the results with the probability of each particular preparation error. We verified the method by comparing it with an analytic solution. Next, idealized and realistic prostate plans were tested with varying margins and varying execution and preparation error levels.

: Probability levels for the minimum dose, computed with the new method, are within 1% of the analytic solution. The impact of rotations depends strongly on the CTV shape. A margin of 10 mm between the CTV and planning target volume is adequate for three-field prostate treatments given the accuracy level in our department; i.e., the TCP in a population of patients, TCP_pop, is reduced by less than 1% due to geometric errors. When reducing the margin to 6 mm, the dose must be increased from 80 to 87 Gy to maintain the same TCP_pop. Only in regions with a high-dose gradient does such a margin reduction lead to a decrease in normal tissue dose for the same TCP_pop. Based on a rough correspondence of 84% minimum dose with 98% EUD, a margin recipe was defined. To give 90% of patients at least 98% EUD, the planning target volume margin must be approximately 2.5 Σ + 0.7 σ − 3 mm, where Σ and σ are the combined standard deviations of the preparation and execution errors. This recipe corresponds accurately with 1% TCP_pop loss for prostate plans with clinically reasonable values of Σ and σ.

: The new method computes in a few minutes the influence of geometric errors on the statistics of target dose and TCP_pop in clinical treatment plans. Too small margins lead to a significant loss of TCP_pop that is difficult to compensate for by dose escalation.     

A pilot study of topical intrarectal application of amifostine for prevention of late radiation rectal injury

Clinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken.

Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, Karnofsky performance status ≥70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy in 20 patients and 73.8 Gy in 9 patients. Therapy was delivered using a 4-field technique with three-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. Amifostine was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most patients underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up.

All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 patients (33%) developed rectal bleeding (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 patients developed Grade 1 and Grade 2 telangiectasia, respectively. This was mostly confined to the anterior rectal wall. No visible mucosal edema, ulcerations, or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four patients (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific proctitis (n = 1), diverticular disease of the sigmoid colon (n = 1), rectal polyp (n = 1), and ulcerative colitis (n = 1). Symptoms developed significantly more often in patients receiving 500–1000 mg than in patients receiving 1500–2500 mg amifostine (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test).

Intrarectal application of amifostine is feasible and well tolerated. Systemic absorption of amifostine and its metabolites is negligible, and close monitoring of patients is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.     

Intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate immobilization: acute toxicity and dose-volume analysis

PURPOSE: To report acute toxicity and to evaluate the relationship between dose-volume effects and acute toxicity in patients with localized prostate cancer, treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Acute toxicity (both lower gastrointestinal [GI] and genito-urinary [GU]) in 100 patients treated with IMRT definitively to a prescribed dose of 70 Gy were assessed using RTOG scoring criteria. A rectal balloon was used for prostate immobilization. Mean doses to seminal vesicles, prostate, bladder, and rectum were recorded. Average irradiated bladder and rectal volumes above 65, 70, and 75 Gy were assessed. A relationship between dose volume and clinical toxicity was evaluated. All patients completed the full duration of acute toxicity assessment. RESULTS: Mean doses to the prostate and seminal vesicles were 75.8 and 73.9 Gy. This represents a moderate dose escalation. Acute GI toxicity profile was very favorable. Eleven percent and 6% of the patients had grade 1 and 2 GI toxicity, respectively, while 83% had no GI complaint. For GU complaints, 38% and 35% had grade 1 and 2 toxicity, respectively, while 27% had no complaints. There was no grade 3 or higher acute GI or GU toxicity. Mean doses to the bladder were 22.8, 23.4, and 26.1 Gy for grade 0, 1, and 2 GU toxicity, respectively (p = 0.132). There is no statistically significant relationship between acute GU toxicity and the bladder volume receiving > 65 Gy, > 70 Gy, or > 75 Gy. In evaluating acute GI toxicity, there are very few grade 1 and 2 events. No relationship was found between acute rectal toxicity and mean rectal dose or irradiated rectal volumes receiving more than 65, 70, and 75 Gy. CONCLUSION: The findings are important with regard to the safety of IMRT, especially in reducing acute GI toxicity. Dose escalation with IMRT using a prostate immobilization technique is feasible. The findings are also important because they contribute to the clinical and dosimetric correlation aspect in the use of IMRT to treat prostate cancer. A larger cohort may be needed to determine if there is a relationship between acute GU toxicity and (a) mean bladder dose and (b) irradiated bladder volume receiving > 65 Gy, > 70 Gy, or > 75 Gy. A larger cohort of patients treated to a higher dose may be needed to show a relationship between dose volume and acute GI toxicity.     

Dose optimization of fractionated external radiation and high-dose-rate intracavitary brachytherapy for FIGO stage IB uterine cervical carcinoma

: To determine the optimal dose combination scheme of external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary radiation (ICR) for maximizing tumor control while conferring an acceptable late complication rate in the treatment of Stage IB uterine cervical cancer.

: We retrospectively analyzed 162 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB squamous cell carcinoma of the uterine cervix who received definitive RT between May 1979 and December 1990. Before HDR-ICR, all patients received EBRT to a total dose of 40–46 Gy (median 45), administered during 4–5 weeks to the whole pelvis. HDR-ICR was given 3 times weeks to a total dose of 24–51 Gy (median 39) at point A, using a dose of 3 Gy/fraction. Central shielding from EBRT was begun after the delivery using 20–45 Gy (median 40) of the external dose. The total dose to point A, calculated by adding the EBRT biologically effective dose (BED) and the ICR BED to point A, was 74.1–118.1 Gy (mean 95.2). The rectal point dose was calculated at the anterior rectal wall at the level of the cervical os. The local control rate, survival rate, and late complication rate were analyzed according to the irradiation dose and BED.

: The initial complete response rate was 99.4%. The overall 5-year survival rate and 5-year disease-free survival rate was 91.1% and 90.9%, respectively. The local failure rate was 4.9%, and the distant failure rate was 4.3%. Late complications were mild and occurred in 23.5% of patients, with 18.5% presenting with rectal complications and 4.9% with bladder complications. The mean rectal BED (the sum of the external midline BED and the ICR rectal point BED) was lower in the patients without rectal complications than in those with rectal complications (125.6 Gy vs. 142.7 Gy, p = 0.3210). The late rectal complication rate increased when the sum of the external midline BED and the rectal BED by ICR was ≥131 Gy (p = 0.1962). However, 5-year survival rates did not increase with the external midline BED (p = 0.4093). The late rectal complication rate also increased, without a change in the survival rate, when the sum of the external midline BED and the ICR point A BED was >90 Gy.

: In treating Stage IB carcinoma of the uterine cervix with HDR-ICR, using fractions of 3 Gy, it is crucial to keep the point A BED at ≤90 Gy to minimize late rectal complications without compromising the survival rate. To achieve this goal, appropriate central shielding from EBRT is needed.