Mitchell Liu

Predictive Factors for Acute and Late Urinary Toxicity After Permanent Prostate Brachytherapy: Long-Term Outcome in 712 Consecutive Patients

PURPOSE To describe the frequency of acute and late Radiation Therapy Oncology Group (RTOG) urinary toxicity, associated predictive factors, and resolution of International Prostate Symptom Score (IPSS) in 712 consecutive prostate brachytherapy patients. METHODS AND MATERIALS Patients underwent implantation between 1998 and 2003 (median follow-up, 57 months). The IPSS and RTOG toxicity data were prospectively collected. The patient, treatment, and implant factors were examined for an association with urinary toxicity. The time to IPSS resolution was examined using Kaplan-Meier curves, and multivariate modeling of IPSS resolution was done using Cox proportional hazards regression analysis. Logistic regression analysis was used to examine the factors associated with urinary toxicity. RESULTS The IPSS returned to baseline at a median of 12.6 months. On multivariate analysis, patients with a high baseline IPSS had a quicker resolution of their IPSS. Higher prostate D90 (dose covering 90% of the prostate), maximal postimplant IPSS, and urinary retention slowed the IPSS resolution time. The rate of the actuarial 5-year late urinary (>12 months) RTOG Grade 0, 1, 2, 3, and 4 was 32%, 36%, 24%, 6.2%, and 0.1%, respectively. At 7 years, the prevalence of RTOG Grade 0-1 was 92.5%. Patients with a larger prostate volume, greater number of needles, greater baseline IPSS, and use of hormonal therapy had more acute toxicity. On multivariate analysis, the significant predictors for late greater than or equal to RTOG toxicity 2 were a greater baseline IPSS, maximal postimplant IPSS, presence of acute toxicity, and higher prostate V150 (volume of the prostate covered by 150% of the dose). More recently implanted patients had less acute urinary toxicity and patients given hormonal therapy had less late urinary toxicity (all p < 0.02). CONCLUSION Most urinary symptoms resolved within 12 months after prostate brachytherapy, and significant long-term urinary toxicity was very low. Refined patient selection and greater technical experience in prostate brachytherapy were associated with less urinary toxicity.

Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial

BackgroundStereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control. Survival outcomes for patients with oligometastatic disease treated with SABR appear promising, but conclusions are limited by patient selection, and the lack of adequate controls in most studies. The goal of this multicenter randomized phase II trial is to assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone.MethodsAfter stratification by the number of metastases (1-3 vs. 4-5), patients will be randomized between Arm 1: current standard of care treatment, and Arm 2: standard of care treatment + SABR to all sites of known disease. Patients will be randomized in a 1:2 ratio to Arm 1:Arm 2, respectively. For patients receiving SABR, radiotherapy dose and fractionation depends on the site of metastasis and the proximity to critical normal structures. This study aims to accrue a total of 99 patients within four years. The primary endpoint is overall survival, and secondary endpoints include quality of life, toxicity, progression-free survival, lesion control rate, and number of cycles of further chemotherapy/systemic therapy.DiscussionThis study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with oligometastatic disease, and will inform the design of a possible phase III study.Trial registrationClinicaltrials.gov identifier: NCT01446744

Rectal toxicity and rectal dosimetry in low-dose-rate 125I permanent prostate implants: A long-term study in 1006 patients

OBJECTIVE To describe the acute and late rectal toxicity in 1006 prostate brachytherapy patients implanted 1998-2003. To determine whether rectal dose-volume histogram as well as patient and treatment factors were associated with rectal toxicity. METHODS AND MATERIALS Median followup was 60.7 months. Rectal dosimetry was calculated as dose-volume histogram of the rectum using Day 28 CT-based dosimetry and expressed as volume of the rectum in cc receiving 50%, 100%, and 150% of the prescription dose (VR(50cc), VR(100cc), and VR(150cc), respectively). Univariate and multivariate analyses were performed to examine the influence of patient, implant, dosimetry, and learning curve factors on the development of acute and late toxicities using a modified Radiation Therapy Oncology Group (RTOG) scale. Acute toxicity was analyzed using logistic regression and late toxicity using Cox proportional hazards regression. Analysis of variance was used to examine the association between rectal toxicity and rectal dose. RESULTS Rectal dosimetry in 93.5% and rectal toxicity in 96.2% have been recorded. Median VR(100)=1.05cc. Late RTOG Grades 0, 1, 2, 3, and 4 were recorded in 68%, 23%, 7.3%, 0.9%, and 0.2% patients, respectively. On multivariate analysis, acute RTOG ≥2 rectal toxicity was associated with urinary retention (p=0.036) and learning curve (p=0.015); late RTOG ≥2 was associated with the presence of acute toxicity (p=0.0074), higher VR(100) (p=0.030) and learning curve (p=0.027). CONCLUSIONS Late rectal RTOG ≥2 rectal toxicity in this cohort was 8%. Increased VR(100), presence of acute rectal toxicity, and learning curve were associated with higher rate of late RTOG ≥2 toxicity. Severe late rectal toxicity after prostate brachytherapy was rare.

Normal Tissue Complication Probability (NTCP) modeling of late rectal bleeding following external beam radiotherapy for prostate cancer: A Test of the QUANTEC-recommended NTCP model

Abstract Purpose/background. Validating a predictive model for late rectal bleeding following external beam treatment for prostate cancer would enable safer treatments or dose escalation. We tested the normal tissue complication probability (NTCP) model recommended in the recent QUANTEC review (quantitative analysis of normal tissue effects in the clinic). Material and methods. One hundred and sixty one prostate cancer patients were treated with 3D conformal radiotherapy for prostate cancer at the British Columbia Cancer Agency in a prospective protocol. The total prescription dose for all patients was 74 Gy, delivered in 2 Gy/fraction. 159 3D treatment planning datasets were available for analysis. Rectal dose volume histograms were extracted and fitted to a Lyman-Kutcher-Burman NTCP model. Results. Late rectal bleeding (>grade 2) was observed in 12/159 patients (7.5%). Multivariate logistic regression with dose-volume parameters (V50, V60, V70, etc.) was non-significant. Among clinical variables, only age was significant on a Kaplan-Meier log-rank test (p=0.007, with an optimal cut point of 77 years). Best-fit Lyman-Kutcher-Burman model parameters (with 95% confidence intervals) were: n = 0.068 (0.01, +infinity); m =0.14 (0.0, 0.86); and TD50 = 81 (27, 136) Gy. The peak values fall within the 95% QUANTEC confidence intervals. On this dataset, both models had only modest ability to predict complications: the best-fit model had a Spearmans rank correlation coefficient of rs = 0.099 (p = 0.11) and area under the receiver operating characteristic curve (AUC) of 0.62; the QUANTEC model had rs=0.096 (p= 0.11) and a corresponding AUC of 0.61. Although the QUANTEC model consistently predicted higher NTCP values, it could not be rejected according to the χ2 test (p = 0.44). Conclusions. Observed complications, and best-fit parameter estimates, were consistent with the QUANTEC-preferred NTCP model. However, predictive power was low, at least partly because the rectal dose distribution characteristics do not vary greatly within this patient cohort.

SEGMENTAL URETHRAL DOSIMETRY AND URINARY TOXICITY IN PATIENTS WITH NO URINARY SYMPTOMS BEFORE PERMANENT PROSTATE BRACHYTHERAPY

PURPOSE To determine whether segmental urethral dosimetry is predictive for the degree of urinary morbidity after prostate brachytherapy in patients with no urinary symptoms before prostate brachytherapy. METHODS AND MATERIALS Between May 2000 and November 2005, 1,107 patients underwent iodine-125 monotherapy with urethral sparing techniques. A total of 166 patients fulfilled the selection criteria: baseline (International Prostate Symptom Score) IPSS < or =5, no androgen deprivation therapy, and prostate ultrasound planning volumes (PUTV) <45 mL. The median follow-up was 44 months. Urinary morbidity was defined by maximum increase in IPSS, time to IPSS resolution, maximum Radiation Therapy Oncology Group (RTOG) score, time to RTOG resolution, and urinary retention. Surrogate deviated urethra was contoured and doses calculated at the base, mid-prostate, apex, and urogenital diaphragm. Univariate and multivariate analysis was used to evaluate urethral and prostate dosimetry, age, PUTV, and number of needles for their association with urinary morbidity. RESULTS Urethral dose was fairly constant in all urethra segments except prostate base, where the variation in does was large. On multivariate analysis, higher urethral base D50, V100, and larger PUTV were predictive for higher maximum increase in IPSS. Higher urethral base V100 and larger PUTV predicted for prolonged IPSS resolution. Higher urethral base D50 and larger needle number predicted for longer RTOG resolution. Higher urethral base V100 predicted for RTOG > or =2 toxicity. CONCLUSIONS Radiation dose to the urethral base, larger PUTV, and needle number, predicted for increased urinary toxicity after prostate brachytherapy. Correlation between urinary morbidity and urethral base dosimetry may reflect a large variation in urethral dose observed at the prostate base.

Effect of bladder filling on doses to prostate and organs at risk: a treatment planning study

In the present study, we aimed to evaluate effects of bladder filling on dose–volume distributions for bladder, rectum, planning target volume (PTV), and prostate in radiation therapy of prostate cancer. Patients (n=21) were scanned with a full bladder, and after 1 hour, having been allowed to void, with an empty bladder. Radiotherapy plans were generated using a four‐field box technique and dose of 70 Gy in 35 fractions. First, plans obtained for full‐ and empty‐bladder scans were compared. Second, situations in which a patient was planned on full bladder but was treated on empty bladder, and vice versa, were simulated, assuming that patients were aligned to external tattoos. Doses to the prostate [equivalent uniform dose (EUD)], bladder and rectum [effective dose (Deff)], and normal tissue complication probability (NTCP) were compared. Dose to the small bowel was examined. Mean bladder volume was 354.3 cm3 when full and 118.2 cm3 when empty. Median prostate EUD was 70 Gy for plans based on full‐ and empty‐bladder scans alike. The median rectal Deff was 55.6 Gy for full‐bladder anatomy and 56.8 Gy for empty‐bladder anatomy, and the corresponding bladder Deff was 29.0 Gy and 49.3 Gy respectively. In 1 patient, part of the small bowel (7.5 cm3) received more than 50 Gy with full‐bladder anatomy, and in 6 patients, part (2.5 cm3−30 cm3) received more than 50 Gy with empty‐bladder anatomy. Bladder filling had no significant impact on prostate EUD or rectal Deff. A minimal volume of the small bowel received more than 50 Gy in both groups, which is below dose tolerance. The bladder Deff was higher with empty‐bladder anatomy; however, the predicted complication rates were clinically insignificant. When the multileaf collimator pattern was applied in reverse, substantial underdosing of the planning target volume (PTV) was observed, particularly for patients with prostate shifts in excess of 0.5 cm in any one direction. However, the prostate shifts showed no correlation with bladder filling, and therefore the PTV underdosing also cannot be related to bladder filling. For some patients, bladder dose–volume constraints were not fulfilled in the worst‐case scenario—that is, when a patient planned with full bladder consistently arrived for treatment with an empty bladder. PACS numbers: 87.53.‐j, 87.53.Kn, 87.53.Tf

Internal fiducial markers can assist dose escalation in treatment of prostate cancer: result of organ motion simulations

Use of internal fiducial markers and electronic portal imaging (EPI) to realign patients has been shown to significantly reduce positioning uncertainties in prostate radiation treatment. This creates the possibility of improving the treatment by decreasing the planning target volume (PTV) margin added to the clinical target volume (CTV), which in turn may allow dose escalation. Conformal treatment plans for three prostate cancer patients were evaluated by using different PTV margins with dose prescription of 70 Gy/35 fr initially. Two beam arrangements, 4-field-box (4FB) and 4-field-oblique (4FO), were used. Then, two dose escalation schemes, 74 Gy and 78 Gy, with tighter PTV margins, were chosen from the first simulation and were tested. A Monte Carlo model was developed to simulate the daily geometric uncertainty and calculate the dose to each organ. After the whole treatment, dose-volume histograms were produced and tumour control probability, prostate equivalent uniform dose and the effective dose to critical organs were calculated. By comparing these radiobiological metrics, optimized dose escalation schemes were found. The results show that using internal fiducial markers and EPI, the prescription dose can be escalated to 78 Gy/39 fr with a 4 mm PTV margin. Based on the available dose-response data for intermediate risk prostate patients, this is estimated to result in a 20% increase of local control and significantly reduced rectal complications.

Computed tomography determination of prostate volume and maximum dimensions: a study of interobserver variability

OBJECTIVE (1) To evaluate the reproducibility of prostate volume, maximum dimensions and geometrical center coordinates determination using computed tomography (CT) and (2) to identify patterns of interobserver variability. MATERIALS AND METHODS Forty patients, suitable for our brachytherapy program, were selected for the study. All patients underwent CT scanning and the prostate volumes were determined by three radiation oncologists. Measurements of geometrical center coordinates, maximum organ dimensions in the anterior-posterior (AP), lateral (Lat) and longitudinal (Long) axes as well as prostate volumes were recorded. This yielded 840 measurements of seven variables for analysis. The means and corresponding standard deviations (SD) of each variable were calculated for each patient. The SDs were then averaged and presented as indices of dispersion. Average variations from the mean were also calculated for each observer along with the SDs. RESULTS Analysis of the geometrical center coordinates revealed acceptable variability amongst observers. For the AP, Lat and Long coordinates the SDs were 0.78, 0.89 and 1.72 mm, respectively. The corresponding values for the maximum organ dimensions were 2.54, 2.72 and 4.43 mm, respectively. While the volumes outlined by observer B were less than or equal to the mean in 95% of cases and those of observer C were greater than or equal to the mean in 93% of cases, the volumes of observer A were equally distributed above and below the mean (48% in both cases). CONCLUSION The determination of the geometrical center coordinates was reproducible amongst observers. The largest variations were seen with the Long axis. The volume determination is more variable. However, a characteristic trend was seen amongst observers when their volumes were compared to the mean volumes of the group.

A Phase II Trial of a Soy Beverage for Subjects Without Clinical Disease With Rising Prostate-Specific Antigen After Radical Radiation for Prostate Cancer

Our objective was to evaluate the tolerability and effect of a daily soy beverage in prostate cancer patients with biochemical failure after radiotherapy. Patients with rising prostate-specific antigen (PSA) after radical radiation for prostate cancer were instructed to consume 500 ml of soy beverage daily for 6 mo. Tolerability of the soy beverage and compliance were assessed. PSA doubling times before and after the consumption of soy were compared. Thirty-four subjects were enrolled; 5 withdrew before 1 mo of soy for reasons unrelated to soy consumption. All remaining 29 subjects were included in the analysis. Mean consumption of the assigned soy beverage was 93%. Mild gastrointestinal upset (38%) not affecting soy consumption was the commonest side effect. PSA showed a declining trend in 4 patients (13.8%), and there was a > 100% prolongation of PSA doubling time in 8 patients (27.6%). However, PSA doubling time also showed a 50% or more shortening in 5 patients (17.2%). In our cohort of North American subjects, 6 mo of a daily soy beverage was well tolerated and was associated with a declining trend or more than 2 times prolongation of PSA doubling time in 41% of subjects. Confirmatory studies are warranted.

CT slice index and thickness: Impact on organ contouring in radiation treatment planning for prostate cancer

Objective: To assess the impact of CT slice index and thickness (3 mm versus 5 mm) on (i) prostate volume, dimensions, and isocenter coordinates, (ii) bladder and rectal volumes, and (iii) DRR quality, in the treatment of prostate cancer. Methods: 16 patients with prostate cancer underwent two planning CT‐scans using 3 and 5 mm slice index/thickness. Prostate, bladder, and rectum were outlined on all scans. Prostate isocenter coordinates, maximum dimensions, and volumes were compared along with bladder and rectal volumes. Bladder volumes and maximum diameters were further investigated using a second observer. A comparative analysis of DRR quality was conducted as well as a dosimetric analysis using DVH. Results: The differences in measurements of prostate volume, isocenter coordinates and maximum dimensions between the 3 and 5 mm scans, were small and not statistically significant. Similar finding was seen for rectal volume. However, bladder volume was always larger on the 3 mm scan (mean difference=27.9 cc;  SE=4.8 cc;  95% CI:  17.7−38.2 cc;  p<0.001) and the findings were reproduced with the second observer (mean difference=31.9 cc;  SE=4.7 cc;  95% CI:  21.9−41.9 cc;  p<0.001). The differences in volume are caused by a slight increase in (1) the measurement of the longitudinal dimensions on the 3 mm scans, and (2) the slice by slice measured bladder area on the 3 mm scans. The latter is due to partial volume effect. The 3 mm DRR were slightly better than the 5 mm DRR. The bladder DVH differed significantly in some patients. Conclusion: Bladder volume is significantly larger on the 3 mm scans. Differences in contoured areas may be accounted for, in part, by the partial volume effect. PACS number(s): 87.57.–s, 87.53.–j