Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms.

PURPOSE AND OBJECTIVE: Late rectal bleeding is a potentially dose limiting complication of three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. The frequency of late rectal bleeding has been shown to increase as the prescription dose rises above 70 Gy. The purpose of this study is to identify features of the cumulative dose-volume histogram (DVH) for the rectal wall that correlate with late rectal bleeding after 3D-CRT for prostate cancer. METHODS AND MATERIALS: Follow-up information on rectal bleeding is available for 261 and 315 patients treated using 3D-CRT at Memorial Sloan-Kettering Cancer Center for Stage T1c-T3 prostate cancer with minimum target doses of 70.2 and 75.6 Gy, respectively. All patients in this study were treated with a coplanar 6-field technique (2 lateral and 4 oblique fields). Patients were classified as having rectal bleeding if they bled (> or = Grade 2) before 30 months, and nonbleeding (< or = Grade 1) if they were without bleeding at 30 months, using the RTOG morbidity scale. Rectal bleeding was observed in 13 and 38 of the patients treated at 70.2 and 75.6 Gy, respectively. Treatment plans were analyzed for 39 nonbleeding and 13 bleeding patients receiving 70.2 Gy, and 83 nonbleeding and 36 bleeding patients receiving 75.6 Gy. Dose-volume histograms (DVHs) for the anatomic rectal wall were calculated. Average DVHs of the bleeding and nonbleeding patients were generated, and a permutation test was used to assess the significance of differences between them, for each dose group. The confounding effect of total rectal wall volume (V(RW)) was removed by calculating the average differences in DVHs between all combinations of bleeding and nonbleeding patients with similar V(RW)s. Finally, multivariate analysis using logistic regression was performed to test the significance of the DVH variables in the presence of anatomic, geometric, and medical variables previously found to correlate with rectal bleeding in a companion analysis of the same patients. RESULTS: The area under the average percent volume DVH for the rectal wall of patients with bleeding was significantly higher than those of patients without bleeding in both dose groups (p = 0.02, 70.2 Gy; p < 0.0001, 75.6 Gy). However, small V(RW)s were associated with rectal bleeding (p = 0.06, 70.2 Gy; p < 0.01, 75.6 Gy), resulting in an increase in average percent volumes exposed to all doses for patients with rectal bleeding. For patients with similar V(RW)s, rectal bleeding was significantly correlated with the volumes exposed to 46 Gy in both dose groups (p = 0.02, 70.2 Gy; p = 0.005, 75.6 Gy, tolerance in V(RW): 5 ccs). For the 75.6 Gy dose group, the percent volume receiving 77 Gy was significantly correlated with rectal bleeding (p < 0.005). Bivariate analysis using logistic regression, including V(RW) together with a single DVH variable, showed good agreement with the above analysis. Multivariate analysis revealed a borderline significant correlation of the percent volume receiving 71 Gy in the 70.2 Gy dose group. It also showed that the DVH variables were highly correlated with geometric and dosimetric variables previously found to correlate with rectal bleeding in multivariate analysis. CONCLUSION: Significant volume effects were found in the probability of late rectal bleeding for patients undergoing 3D-CRT for prostate cancer with prescription doses of 70.2 and 75.6 Gy. The percent volumes exposed to 71 and 77 Gy in the 70.2 and 75.6 Gy dose groups respectively were significantly correlated with rectal bleeding. The independent correlation of small V(RW) with rectal bleeding may indicate the existence of a functional reserve for the rectum. The independent association with larger percent volumes exposed to intermediate doses ( approximately 46 Gy) seen in both dose groups may indicate that a large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.

Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer.

PURPOSE: To compare acute and late toxicities of high-dose radiation for prostate cancer delivered by either conventional three-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS: Between September 1992 and February 1998, 61 patients with clinical stage T1c- T3 prostate cancer were treated with 3D-CRT and 171 with IMRT to a prescribed dose of 81 Gy. To quantitatively evaluate the differences between conventional 3D-CRT and IMRT, 20 randomly selected patients were planned concomitantly by both techniques and the resulting treatment plans were compared. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group toxicity scale. RESULTS: Compared with conventional 3D-CRT, IMRT improved the coverage of the clinical target volume (CTV) by the prescription dose and reduced the volumes of the rectal and bladder walls carried to high dose levels (P<0.01), indicating improved conformality with IMRT. Acute and late urinary toxicities were not significantly different for the two methods. However, the combined rates of acute grade 1 and 2 rectal toxicities and the risk of late grade 2 rectal bleeding were significantly lower in the IMRT patients. The 2-year actuarial risk of grade 2 bleeding was 2% for IMRT and 10% for conventional 3D-CRT (P<0.001). CONCLUSIONS: The data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.

Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response.

PURPOSE: The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. METHODS AND MATERIALS: Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy-13 patients, 75. 6 Gy-36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy-39 patients, 75.6 Gy-83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. RESULTS: A dose response for >/= Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with >/= Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p < 0.02), and 2) smaller anatomically defined rectal wall volume (p < 0.05). After 75.6 Gy, the following factors were significant: 1) smaller anatomically defined rectal wall volume (p < 0.01), 2) higher rectal D(max) (p < 0.01), 3) enclosure of rectal contour by Iso50 (p < 0.01), 4) patient age (p = 0.02), and 5) history of diabetes mellitus (p = 0.04). In addition to these five factors, acute rectal toxicity was also significantly correlated (p = 0.05) with late rectal bleeding when patients from both dose groups were combined in multivariate analysis. CONCLUSION: A multivariate logistic regression model is presented which describes the probability of developing late rectal bleeding after conformal irradiation of prostate cancer. Late rectal bleeding correlated with factors which may indicate that a greater fractional volume of rectal wall was exposed to high dose, such as smaller rectal wall volume, inclusion of the rectum within the 50% isodose on the isocenter slice, and higher rectal D(max).

A feasibility study of automated inverse treatment planning for cancer of the prostate.

PURPOSE: The development of automated "inverse planning," utilizing intensity-modulated radiation therapy (IMRT) raises the question of whether this new technique can provide a practical and efficient means of dose escalation in conformal treatment of cancer of the prostate. The purpose of this feasibility study was to determine a single set of inverse-planning parameters that can be used for a variety of different prostate patient geometries to automatically generate escalated dose (> or = 81 Gy) IMRT plans that satisfy normal tissue constraints for rectal and bladder walls. METHODS: We studied a subset of the 46 patients who were previously treated at Memorial Sloan Kettering Cancer Center (MSKCC) to a total dose of 81 Gy using a 3D conformal approach. Six patients were selected for our study and replanned using an analytical inverse-planning algorithm (referred to as OPT3D) applied to 8 intensity modulated, co-axial radiation beams. A set of more than a dozen inverse planning parameters were adjusted by trial and error until the resulting dose distributions satisfied the critical organ dose-volume constraints imposed by our study rules (D30 < or = 75.6 Gy and D10 < or = 80 Gy for the rectal wall; D15 < or = 80 Gy for the bladder wall) for the sample of patients selected. The OPT3D-generated plans were compared to hand-generated BEV plans using cumulative DVH analysis. RESULTS: A single set of inverse-planning parameters was found that was able to automatically generate IMRT plans meeting all critical organ dose-volume constraints for all but one of the patients in our study. [The exception failed to meet bladder dose constraints for both IMRT and BEV methods, due to extensive overlap between the planning target volume (PTV) and bladder contours]. Based upon analysis of the cumulative dose-volume histogram (DVH) for the prostate PTV, the D95 (DX is defined such that x% of the volume receives a dose > or = DX), averaged over all patients, was approximately 81 Gy. The average D90 and mean dose values were 85 Gy and 93 Gy, respectively. Although a similar D95 was achieved using the BEV-generated plans, the D90 and mean dose values were substantially higher for the inverse planning (OPT3D) method. CONCLUSION: This limited "paper study" shows IMRT with inverse planning to be a promising technique for the treatment of prostate cancer to high doses. We determined a small set of inverse-planning parameter values that was able to automatically design intensity-modulated radiotherapy (IMRT) plans for a subset of 6 patients previously treated at MSKCC to 81 Gy using BEV planning techniques. With one minor exception, the resulting plans succeeded in meeting predetermined dose-volume constraints while at the same time allowing an increase in the mean dose and D90 to the prostate PTV. These 8 field plans also resulted in reduced dosage to the femoral heads. This automated technique is efficient in terms of planning effort and, with proper software for computer-controlled MLC, may be appropriate for clinical use. The clinical feasibility of this approach for a larger group of patients is currently under study.

The effect of treatment positioning on normal tissue dose in patients with prostate cancer treated with three-dimensional conformal radiotherapy.

PURPOSE: To prospectively assess the effect of supine vs. prone treatment position on the dose to normal tissues in prostate cancer patients treated with the three-dimensional conformal technique. METHODS AND MATERIALS: Twenty-six patients underwent three-dimensional treatment planning in both the supine and prone treatment positions. The planning target volume and normal tissue structures were outlined on each CAT scan slice, and treatment plans were compared to assess the effect of treatment position on the volume of rectum, bladder, and bowel exposed to the high dose of irradiation. RESULTS: The average dose to the rectal wall and the V95 (volume of rectal wall receiving at least 95% of the prescription dose) for the prone position were 64 and 24% of the prescription dose, respectively, compared to 72 and 29%, respectively, for the supine position (p < 0.05). When the average rectal wall dose was used as an endpoint, 14 of the 26 patients (54%) had an advantage for the prone position compared to 1 (4%) who demonstrated an advantage for the supine position (p < 0.0002). Similarly, when V95 of the rectal wall was used as a measure of comparison, 15 patients (58%) had an advantage for the prone position compared to 1 (4%) who demonstrated an advantage for the supine position (p < 0.0002). In 13 patients (50%), a change from supine to the prone position was associated with reduction of the V95 to levels < 30% of the prescription dose compared to 3 patients (11%) in whom such an advantage resulted from change of the prone to the supine position (p < 0.005). The effect of treatment position on the rectal wall dose was most pronounced in the region of the seminal vesicles. An increased volume of bowel was also noted in the supine position. The treatment position, however, had no significant impact on the dose to the bladder wall. CONCLUSIONS: Three-dimensional conformal radiotherapy for prostate cancer in the prone position is associated with significant reduction of the dose to the rectum and bowel resulting in an improvement in the therapeutic ratio.

Three-dimensional conformal radiation therapy in localized carcinoma of the prostate: interim report of a phase 1 dose-escalation study.

Acute morbidity, late complications and tumor response were evaluated in 324 prostate cancer patients treated with 3-dimensional conformal radiation therapy in a phase I dose-escalation study. This radiotherapy technique targeted the prostate and seminal vesicles but effectively excluded the surrounding normal tissues. The minimum tumor dose was 64.8 to 66.6 Gy. in 87 patients, 70.2 Gy. in 138, 75.6 Gy. in 69 and 81.0 Gy. in 30. The treatment was well tolerated with minimal acute morbidity, observed in 15% of the patients who required medication for relief of rectal symptoms and in 34% for urinary symptoms. Two patients (0.6%) to date have had grades 3 and 4 late complications (Radiation Therapy Oncology Group morbidity grading system). The 3-year actuarial probability of survival with a normal serum prostate specific antigen level was 97% for patients with stages T1c and T2a, 86% with stage T2b, 60% with stage T2c and 43% with stage T3 disease. A multivariate analysis demonstrated that initial prostate specific antigen (20 ng./ml. or less versus more than 20 ng./ml.), stage (T2c or less versus T3) and Gleason score (6 or less versus 7 or more) were each significant independent variables that affected subsequent chemical relapse. The acute and long-term toxicities have been less compared with traditional treatment techniques. After the maximal tolerable dose with 3-dimensional conformal radiotherapy is established, future studies will test whether high dose conformal therapy has the potential to improve local tumor control and survival of patients with localized prostatic carcinoma.

Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.

PURPOSE: To determine the extent of reduction of volume of normal tissue structures exposed to high doses of radiation therapy (RT) after administration of neoadjuvant hormonal therapy (NHT) in patients with bulky, geometrically unfavorable prostatic cancers. METHODS AND MATERIALS: Twenty-two patients with bulky prostatic cancers were treated with a 3 month course of neoadjuvant leuprolide acetate and eulexin prior to three-dimensional (3-D) conformal radiotherapy. Patients were included if 3-D treatment planning revealed that either > 30% of the rectal wall would receive 95% of the prescription dose (D95) (n = 13); > or = 50% of the bladder wall would receive D95 (n = 10); or that any volume of small bowel would receive > or = 65% of the prescription dose (n = 16). All patients underwent simulation and conformal treatment planning before and after NHT. Pre and posthormone cumulative dose volume histogram (DVH) calculations for all normal tissue structures were analyzed and compared for each patient. RESULTS: The median percentage of target volume reduction after NHT was 25% (range: 3-52%). Ten of 13 patients (78%) whose prehormone rectal DVH demonstrated > 30% of the rectal wall receiving D95 responded to NHT with a median 25% (range: 16-48%) reduction of rectal volume receiving the D95. A median reduction of 50% (range: 6-64%) of the bladder volume receiving D95 was observed in nine of ten patients (90%), while 13 of 16 (81%) showed a reduction of small bowel volume to a median percentage of 88% (range: 67-100%) of the prehormonal values. CONCLUSION: Neoadjuvant hormonal therapy is an effective method for decreasing the size of bulky prostatic tumors as well as for optimizing the geometry of the target volume in relation to the adjacent normal tissue structures prior to radiation therapy. Such an approach allows for reduction of the volume of normal tissues exposed to high doses in the majority of treated patients. Currently, studies are underway to determine whether NHT will lead to a decreased likelihood of long-term complications associated with radiotherapy of bulky, geometrically unfavorable prostatic tumors, and permit the safe delivery of escalated dose levels using conformal treatment techniques.

Three-dimensional conformal radiation therapy in locally advanced carcinoma of the prostate: preliminary results of a phase I dose-escalation study.

PURPOSE: The acute morbidity of doses of 64.8-75.6 Gy and preliminary observations of late complications and tumor response using 3-dimensional conformal radiation therapy in carcinoma of the prostate are assessed. METHODS AND MATERIALS: 123 patients (Stage A2-12, B1-17, B2-43, C-51) were irradiated to the prostate and seminal vesicles using a 3-dimensional conformal radiation therapy technique. The median follow-up time was 15.2 months. The minimum tumor dose was 64.8-66.6 Gy in 49 patients, 70.2 Gy in 46, and 75.6 Gy in 28. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading system. RESULTS: This technique of 3-dimensional conformal radiation therapy was well-tolerated with minimal acute morbidity. Only 32% of patients had grade 2 or 3 acute morbidity requiring short-term medication for relief of urinary symptoms or diarrhea. Only one patient (0.8%) has so far developed a severe (grade 4) late complication. Serum prostate specific antigen concentrations normalized in 67% of patients (64/96) within 1-14 months (median 4.5 months) after treatment and were progressively decreasing at last measurement in an additional 22% (21/96). Abnormal rising prostate specific antigen levels were observed in 15 patients, 11 of whom have already developed other evidence of relapsing disease. CONCLUSION: Acute toxicity for the doses tested with this 3-dimensional conformal radiation therapy technique is reduced compared to traditional treatment techniques, and the initial tumor response as assessed by prostate specific antigen measurement is highly encouraging with prostate specific antigen levels returning to normal in the majority of patients. Based on these results, a further increase of the dose to 81 Gy has been implemented in accordance with the schema of an ongoing Phase I dose-escalation study.

Clinically relevant optimization of 3-D conformal treatments.

In this paper a method of computer-aided optimization of 3-D conformal treatment plans is presented which incorporates models to predict the clinical consequences of resulting dose distributions. Even though these models are simplistic, it is submitted that their intelligent use leads to treatment plans which indicate lower normal tissue complications and higher tumor control. Dose distribution data, biological models, and observed normal tissue and tumor response data are used to compute tumor control and normal tissue complication probabilities for each of the critical normal structures encountered in a treatment plan. These quantities are combined into a single score using an objective function which incorporates the importance of each end point as assessed by the physician. Using the "simulated annealing" method of optimization, the beam weights are adjusted to maximize the score. Additional constraints are applied to ensure consistency of the results of optimization with the judgment of the physician. These optimization methods have been applied to conformal treatment plans consisting of multiple fixed fields with conformal field shaping. The results indicate that the methods presented have considerable potential.

Improved dose distributions for 3D conformal boost treatments in carcinoma of the nasopharynx.

This study was designed to demonstrate the feasibility of 3-dimensional (3D) treatment planning in patients with carcinoma of the nasopharynx, and to explore its potential therapeutic advantage over the traditional 2-dimensional (2D) approach in this disease. Qualitative and quantitative comparisons between the two techniques were made for the boost portion of the treatment (19.8 Gy of a total 70.2 Gy treatment schedule) in 10 previously untreated patients and for the entire treatment in 5 patients with locally recurrent disease. The 2D and 3D plans were compared in each patient using dose-volume histograms (DVH's), tumor control probabilities (TCP's), normal tissue complication probabilities (NTCP's), and a new biologic figure of merit that describes the probability of uncomplicated control. Although there was no attempt to optimize the 3D treatment approach by using this method throughout the total treatment course (rather than for the boost only), it was still found that for each of the endpoints examined the 3D approach resulted in improved plans. An average of 22% of the target volume was underdosed at the 95% isodose level with the 2D plans compared to 7% with the 3D plans. The improved treatment planning by 3D increased the mean dose to the tumor volume by an average of 13% over 2D planning. The dose to normal structures such as the mandible and parotid glands was reduced with the 3D plans while the brain stem and spinal cord remained within tolerance limits. The probability of uncomplicated tumor control was increased by an average of 15% with 3D treatment planning compared to the 2D approach. Our findings demonstrate the potential of 3D planning for improving the treatment of carcinoma of the nasopharynx, but prospective studies are required to define the true clinical advantages of this methodology.