AAPM Task Group Report 267: A joint AAPM GEC-ESTRO report on biophysical models and tools for the planning and evaluation of brachytherapy.

Brachytherapy utilizes a multitude of radioactive sources and treatment techniques that often exhibit widely different spatial and temporal dose delivery patterns. Biophysical models, capable of modeling the key interacting effects of dose delivery patterns with the underlying cellular processes of the irradiated tissues, can be a potentially useful tool for elucidating the radiobiological effects of complex brachytherapy dose delivery patterns and for comparing their relative clinical effectiveness. While the biophysical models have been used largely in research settings by experts, it has also been used increasingly by clinical medical physicists over the last two decades. A good understanding of the potentials and limitations of the biophysical models and their intended use is critically important in the widespread use of these models. To facilitate meaningful and consistent use of biophysical models in brachytherapy, Task Group 267 (TG-267) was formed jointly with the American Association of Physics in Medicine (AAPM) and The Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) to review the existing biophysical models, model parameters, and their use in selected brachytherapy modalities and to develop practice guidelines for clinical medical physicists regarding the selection, use, and interpretation of biophysical models. The report provides an overview of the clinical background and the rationale for the development of biophysical models in radiation oncology and, particularly, in brachytherapy; a summary of the results of literature review of the existing biophysical models that have been used in brachytherapy; a focused discussion of the applications of relevant biophysical models for five selected brachytherapy modalities; and the task group recommendations on the use, reporting, and implementation of biophysical models for brachytherapy treatment planning and evaluation. The report concludes with discussions on the challenges and opportunities in using biophysical models for brachytherapy and with an outlook for future developments.

Real-time intraoperative evaluation of implant quality and dose correction during prostate brachytherapy consistently improves target coverage using a novel image fusion and optimization program.

PURPOSE: Our purpose was to describe the process and outcome of performing postimplantation dosimetric assessment and intraoperative dose correction during prostate brachytherapy using a novel image fusion-based treatment-planning program. METHODS AND MATERIALS: Twenty-six consecutive patients underwent intraoperative real-time corrections of their dose distributions at the end of their permanent seed interstitial procedures. After intraoperatively planned seeds were implanted and while the patient remained in the lithotomy position, a cone beam computed tomography scan was obtained to assess adequacy of the prescription dose coverage. The implanted seed positions were automatically segmented from the cone-beam images, fused onto a new set of acquired ultrasound images, reimported into the planning system, and recontoured. Dose distributions were recalculated based upon actual implanted seed coordinates and recontoured ultrasound images and were reviewed. If any dose deficiencies within the prostate target were identified, additional needles and seeds were added. Once an implant was deemed acceptable, the procedure was completed, and anesthesia was reversed. RESULTS: When the intraoperative ultrasound-based quality assurance assessment was performed after seed placement, the median volume receiving 100% of the dose (V100) was 93% (range, 74% to 98%). Before seed correction, 23% (6/26) of cases were noted to have V100 <90%. Based on this intraoperative assessment and replanning, additional seeds were placed into dose-deficient regions within the target to improve target dose distributions. Postcorrection, the median V100 was 97% (range, 93% to 99%). Following intraoperative dose corrections, all implants achieved V100 >90%. CONCLUSIONS: In these patients, postimplantation evaluation during the actual prostate seed implant procedure was successfully applied to determine the need for additional seeds to correct dose deficiencies before anesthesia reversal. When applied, this approach should significantly reduce intraoperative errors and chances for suboptimal dose delivery during prostate brachytherapy.

Impact of source position on high-dose-rate skin surface applicator dosimetry.

PURPOSE: Skin surface dosimetric discrepancies between measured and treatment planning system predicted values were traced to source position sag inside the applicator and to source transit time. We quantified their dosimetric impact and propose corrections for clinical use. METHODS AND MATERIALS: We measured the dose profiles from the Varian Leipzig-style high-dose-rate (HDR) skin applicator, using EBT3 film, photon diode, and optically stimulated luminescence dosimeter for three different GammaMedplus HDR afterloaders. The measured dose profiles at several depths were compared with BrachyVision Acuros calculated profiles. To assess the impact of the source sag, two different applicator orientations were considered. The dose contribution during source transit was assessed by comparing diode measurements using an HDR timer and an electrometer timer. RESULTS: Depth doses measured using the three dosimeters were in good agreement, but were consistently higher than the Acuros dose calculations. Measurements with the applicator face up were significantly (exceeding 10%) lower than those in the face down position, due to source sag inside the applicator. Based on the inverse square law, the effective source sag was evaluated to be about 0.5 mm from the planned position. The additional dose during source transit was evaluated to be about 2.8% for 30 seconds of treatment with a 40700 U (10 Ci) source. CONCLUSION: With a very short source-to-surface distance, the small source sag inside the applicator has a significant dosimetric impact. This effect is unaccounted for in the vendor's treatment planning template and should be considered before the clinical use of the applicator. Further investigation of other applicators with large source lumen diameter may be warranted.

Long-term outcome of magnetic resonance spectroscopic image-directed dose escalation for prostate brachytherapy.

PURPOSE: To report the long-term control and toxicity outcomes of patients with clinically localized prostate cancer, who underwent low-dose-rate prostate brachytherapy with magnetic resonance spectroscopic image (MRSI)-directed dose escalation to intraprostatic regions. METHODS AND MATERIALS: Forty-seven consecutive patients between May 2000 and December 2003 were analyzed retrospectively. Each patient underwent a preprocedural MRSI, and MRS-positive voxels suspicious for malignancy were identified. Intraoperative planning was used to determine the optimal seed distribution to deliver a standard prescription dose to the entire prostate, while escalating the dose to MRS-positive voxels to 150% of prescription. Each patient underwent transperineal implantation of radioactive seeds followed by same-day CT for postimplant dosimetry. RESULTS: The median prostate D90 (minimum dose received by 90% of the prostate) was 125.7% (interquartile range [IQR], 110.3-136.5%) of prescription. The median value for the MRS-positive mean dose was 229.9% (IQR, 200.0-251.9%). Median urethra D30 and rectal D30 values were 142.2% (137.5-168.2%) and 56.1% (40.1-63.4%), respectively. Median followup was 86.4 months (IQR, 49.8-117.6). The 10-year actuarial prostate-specific antigen relapse-free survival was 98% (95% confidence interval, 93-100%). Five patients (11%) experienced late Grade 3 urinary toxicity (e.g., urethral stricture), which improved after operative intervention. Four of these patients had dose-escalated voxels less than 1.0 cm from the urethra. CONCLUSIONS: Low-dose-rate brachytherapy with MRSI-directed dose escalation to suspicious intraprostatic regions exhibits excellent long-term biochemical control. Patients with dose-escalated voxels close to the urethra were at higher risk of late urinary stricture.

Local recurrence outcomes using the ³²P intraoperative brachytherapy plaque in the management of malignant lesions of the spine involving the dura.

PURPOSE: Sterilization of surgical margins for lesions involving the dura is complicated by the tolerance of the spinal cord and/or cauda equina, especially in the setting of prior radiation therapy (RT); use of intraoperative brachytherapy may allow local delivery of therapeutic dose without damaging sensitive structures. METHODS AND MATERIALS: Patients with malignant lesions involving the dura received intraoperative brachytherapy with a (32)P plaque after maximal resection of the tumor. Local recurrence (LR) was analyzed using competing risks analysis; overall survival was analyzed using Kaplan-Meier statistics. RESULTS: Between September 2009 and April 2013, 68 patients with 69 lesions in the spine were treated with the (32)P plaque. Median followup was 10 months. Most patients (n=59, 85.5%) had previously been treated with at least one course of prior RT to the treated site. About 38 (55%) lesions received postoperative RT (median dose, 30 Gy; range, 18-30 Gy). The LR and overall survival at 12 months were 25.5% (95% confidence interval [CI]=15.5-37%) and 59.5% (95% CI=46-73%), respectively. For patients who received postoperative RT, LR at 12 months was 18.5% (95% CI=7.5-33%) compared with 34% (95% CI=18-51%) for those who were treated with the plaque alone (p=0.08 and 0.04 on univariate and multivariable analysis, respectively). There were no acute or long-term complications from treatment observed in this cohort. CONCLUSIONS: The (32)P intraoperative brachytherapy plaque is a useful adjunct to surgical intervention for primary recurrent and metastatic lesions of the spine involving the dura, and is not associated with additional toxicity.

Optimal schedules of fractionated radiation therapy by way of the greedy principle: biologically-based adaptive boosting.

We revisit a long-standing problem of optimization of fractionated radiotherapy and solve it in considerable generality under the following three assumptions only: (1) repopulation of clonogenic cancer cells between radiation exposures follows linear birth-and-death Markov process; (2) clonogenic cancer cells do not interact with each other; and (3) the dose response function s(D) is decreasing and logarithmically concave. Optimal schedules of fractionated radiation identified in this work can be described by the following 'greedy' principle: give the maximum possible dose as soon as possible. This means that upper bounds on the total dose and the dose per fraction reflecting limitations on the damage to normal tissue, along with a lower bound on the time between successive fractions of radiation, determine the optimal radiation schedules completely. Results of this work lead to a new paradigm of dose delivery which we term optimal biologically-based adaptive boosting (OBBAB). It amounts to (a) subdividing the target into regions that are homogeneous with respect to the maximum total dose and maximum dose per fraction allowed by the anatomy and biological properties of the normal tissue within (or adjacent to) the region in question and (b) treating each region with an individual optimal schedule determined by these constraints. The fact that different regions may be treated to different total dose and dose per fraction mean that the number of fractions may also vary between regions. Numerical evidence suggests that OBBAB produces significantly larger tumor control probability than the corresponding conventional treatments.

On the probability of cure for heavy-ion radiotherapy.

The probability of a cure in radiation therapy (RT)-viewed as the probability of eventual extinction of all cancer cells-is unobservable, and the only way to compute it is through modeling the dynamics of cancer cell population during and post-treatment. The conundrum at the heart of biophysical models aimed at such prospective calculations is the absence of information on the initial size of the subpopulation of clonogenic cancer cells (also called stem-like cancer cells), that largely determines the outcome of RT, both in an individual and population settings. Other relevant parameters (e.g. potential doubling time, cell loss factor and survival probability as a function of dose) are, at least in principle, amenable to empirical determination. In this article we demonstrate that, for heavy-ion RT, microdosimetric considerations (justifiably ignored in conventional RT) combined with an expression for the clone extinction probability obtained from a mechanistic model of radiation cell survival lead to useful upper bounds on the size of the pre-treatment population of clonogenic cancer cells as well as upper and lower bounds on the cure probability. The main practical impact of these limiting values is the ability to make predictions about the probability of a cure for a given population of patients treated to newer, still unexplored treatment modalities from the empirically determined probability of a cure for the same or similar population resulting from conventional low linear energy transfer (typically photon/electron) RT. We also propose that the current trend to deliver a lower total dose in a smaller number of fractions with larger-than-conventional doses per fraction has physical limits that must be understood before embarking on a particular treatment schedule.

32P brachytherapy conformal source model RIC-100 for high-dose-rate treatment of superficial disease: Monte Carlo calculations, diode measurements, and clinical implementation.

PURPOSE: A novel (32)P brachytherapy source has been in use at our institution intraoperatively for temporary radiation therapy of the spinal dura and other localized tumors. We describe the dosimetry and clinical implementation of the source. METHODS AND MATERIALS: Dosimetric evaluation for the source was done with a complete set of MCNP5 Monte Carlo calculations preceding clinical implementation. In addition, the depth dose curve and dose rate were measured by use of an electron field diode to verify the Monte Carlo calculations. Calibration procedures using the diode in a custom-designed phantom to provide an absolute dose calibration and to check dose uniformity across the source area for each source before treatment were established. RESULTS: Good agreement was established between the Monte Carlo calculations and diode measurements. Quality assurance measurements results are provided for about 100 sources used to date. Clinical source calibrations were usually within 10% of manufacturer specifications. Procedures for safe handling of the source are described. DISCUSSION: Clinical considerations for using the source are discussed.

Favourable long-term outcomes with brachytherapy-based regimens in men ≤60 years with clinically localized prostate cancer.

OBJECTIVE: To report long-term outcomes of men ≤60 years treated with brachytherapy (BT) for low- and intermediate-risk prostate cancer. PATIENTS AND METHODS: Of 1655 patients treated with BT for clinically localized prostate cancer between January 1998 and May 2008 at Memorial Sloan-Kettering Cancer Center, 236 patients with National Comprehensive Cancer Network low- (n = 178) or intermediate-risk (n = 58) prostate cancer were ≤60 years old with a 3-year minimum follow-up, and represent the subjects of this report. Brachytherapy was given either as monotherapy (n = 169) or with external beam radiation therapy (EBRT; n = 67). Forty-four patients (19%) received neoadjuvant cytoreductive hormone therapy. The 'nadir+2' definition was used for prostate-specific antigen (PSA) recurrence. Common Terminology Criteria for Acute Events (CTCAE) v 3.0 was used to grade genitourinary (GU) and gastrointestinal (GI) toxicity. Potency was defined as the ability to obtain an erection suitable for intercourse or an International Index of Erectile Function score ≥ 22. The Kaplan-Meier method and Cox regression were used for statistical analysis. The median follow-up was 83 months. RESULTS: The 8-year PSA relapse-free survival (RFS), cancer-specific and overall survival rates for the entire cohort were 96, 99 and 96%, respectively. For patients with low-risk disease, the 8-year PSA RFS rate was 97% and for intermediate-risk patients it was 94% (P = 0.34). There was no difference in PSA RFS between BT alone and combined therapy (P = 0.17). Late grade ≥ 2 GU and GI toxicity was 14 and 3%, respectively. Of 150 patients potent before treatment, 76 (51%) were potent at last follow-up, with 50/76 (66%) using no medication. There was no significant difference in post-treatment potency between BT alone and BT with EBRT (P = 0.74). CONCLUSIONS: Brachytherapy provides patients aged ≤ 60 years with low- and intermediate-risk prostate cancer with excellent outcomes and has a low risk of significant long-term GU or GI morbidity. Erectile function is preserved in >50% of patients and the majority do not require erectile dysfunction medication.

Intraoperative and percutaneous iridium-192 high-dose-rate brachytherapy for previously irradiated lesions of the spine.

PURPOSE: Advances in stereotactic radiosurgery have improved local control of spine metastases, but local failure is still a problem and repeat irradiation is limited by normal tissue tolerance. A novel high-dose-rate (HDR) brachytherapy technique has been developed to treat these previously irradiated lesions. METHODS AND MATERIALS: Five patients with progressive disease at previously irradiated sites in the spine who were not amenable to further external beam radiation were treated. Catheters were placed intraoperatively in 2 patients and percutaneously implanted in 3 patients with image-guided techniques. Conformal plans were generated to deliver dose to target tissues and spare critical structures. Patients received single-fraction treatment using HDR iridium-192 brachytherapy. RESULTS: Median dose was 14 Gy (range, 12-18 Gy) with a median gross total volume D90 of 75% (range, 31-94%); spinal cord/cauda equina dose constraints were met. At a median followup of 9 months, no local progression of disease has been observed. Four patients had reduction in pain 1-4 weeks after treatment. No brachytherapy-related complications have been observed. CONCLUSIONS: Intraoperative and percutaneous iridium-192 HDR spine brachytherapy techniques were not associated with complications or acute toxicity. There has been no local progression at treated sites, and most patients experienced reduction in cancer-related pain.

A mechanistic description of radiation-induced damage to normal tissue and its healing kinetics.

We introduce a novel mechanistic model of the yield of tissue damage at the end of radiation treatment and of the subsequent healing kinetics. We find explicit expressions for the total number of functional proliferating cells as well as doomed (functional but non-proliferating) cells as a function of time post treatment. This leads to the possibility of estimating-for any given cohort of patients undergoing radiation therapy-the probability distribution of those kinetic parameters (e.g. proliferation rates) that determine times to injury onset and ensuing resolution. The model is suitable for tissues with simple duplication organization, meaning that functionally competent cells are also responsible for tissue renewal or regeneration following injury. An extension of the model to arbitrary temporal patterns of dose rate is presented. To illustrate the practical utility of the model, as well as its limitations, we apply it to data on the time course of urethral toxicity following fractionated radiation treatment and brachytherapy for prostate cancer.

Clinical outcomes of high-dose-rate brachytherapy and external beam radiotherapy in the management of clinically localized prostate cancer.

PURPOSE: To report prostate-specific antigen (PSA) relapse-free survival and treatment-related toxicity outcomes after combining high-dose-rate (HDR) brachytherapy with external beam radiotherapy (EBRT) for patients with clinically localized prostate cancer. METHODS AND MATERIALS: Between 1998 and 2009, 229 patients were treated with HDR brachytherapy followed 3 weeks later by supplemental EBRT. The HDR brachytherapy boost consisted of three fractions of (192)Ir (5.5-7.5Gy per fraction), and EBRT consisted of intensity-modulated radiotherapy delivering an additional 45.0-50.4Gy directed to the prostate gland and seminal vesicles. Median follow-up was 61 months. RESULTS: Seven-year PSA relapse-free survival for low-, intermediate-, and high-risk patients were 95%, 90%, and 57%, respectively (p<0.001). Among high-risk patients treated with biological equivalent doses in excess of 190Gy, 7-year PSA relapse-free survival was 81%. In multivariate analysis, Gleason scores of ≥8 predicted for increased risk of biochemical failure, whereas the use of short-term neoadjuvant androgen deprivation therapy did not influence tumor-control outcomes even among intermediate- or high-risk patients. Seven-year incidence of distant metastases for low-, intermediate-, and high-risk patients were 5%, 3%, and 17%, respectively. Seven-year incidence of late Grade 2 and 3 genitourinary toxicities were 22.1% and 4.9%, respectively and the 7-year incidence of Grade 2 and 3 gastrointestinal toxicities were 1% and 0.4%, respectively. CONCLUSION: HDR prostate brachytherapy in conjunction with supplemental EBRT results in excellent biochemical relapse-free survival rates with a low incidence of severe late genitourinary or gastrointestinal toxicities. The use of short-term neoadjuvant androgen deprivation did not influence long-term biochemical tumor control in this cohort.

Intraoperative high-dose-rate brachytherapy using dose painting technique: evaluation of safety and preliminary clinical outcomes.

PURPOSE: Intraoperative radiation therapy (IORT) allows delivery of tumoricidal doses of radiation to areas of potential residual microscopic disease while minimizing doses to normal tissues. IORT using high-dose-rate (HDR) brachytherapy allows dose modulation and delivery of concomitant boosts to high-risk areas. This study describes a novel technique of HDR-IORT with dose painting (DP) (HDR-IORT-DP) and evaluates the clinical outcomes. METHODS AND MATERIALS: Sixteen patients with recurrent cancers received HDR-IORT-DP at the time of radical resection. Of these patients, 13 had colorectal cancer, 2 had head and neck cancer, and 1 had a gynecologic malignancy. All received external beam radiation previously. Negative margin (R0) was obtained in 12 patients (75%) and microscopically positive margins (R1) in 4 patients (25%). RESULTS: The median total target and boost area were 45 and 8.5cm(2), and HDR-IORT and boost dose were 1500 and 1750cGy, respectively. Median followup was 14.9 months. The 2-year local control and overall survival were 80% and 20%, respectively. Eleven patients (69%) developed distant metastasis and were deceased at the time of the last followup. A total of 13 patients (19%) developed Grade 3 toxicity related to HDR-IORT; no grade 4+ toxicities were observed. CONCLUSIONS: HDR-IORT-DP technique is feasible, safe, and allows for dose escalation in locally advanced or recurrent previously irradiated tumors. To our knowledge, this is the first clinical report on HDR-IORT-DP. Further studies are warranted to evaluate efficacy in a larger patient cohort. Local control was encouraging in our patients.

Intraoperative 32P high-dose rate brachytherapy of the dura for recurrent primary and metastatic intracranial and spinal tumors.

BACKGROUND: Treatment of spinal and intracranial tumors with dural involvement is complicated by radiation tolerance of sensitive structures, especially in the setting of previous treatment. OBJECTIVE: To evaluate whether intraoperative brachytherapy with short-range sources allows therapeutic dose delivery without damaging sensitive structures. METHODS: The median doses of previous treatment were 3000 cGy (range, 1800-7200 cGy) for 8 patients with primary/recurrent and 17 patients with metastatic spinal tumors and 5040 cGy (range, 1300-6040 cGy) for 5 patients with locally recurrent and 2 patients with metastatic intracranial tumors. Patients underwent gross total or maximal resection of the tumor and were then treated with an intraoperative brachytherapy plaque consisting of a flexible silicone film incorporating P. A dose of 1000 cGy was delivered to a depth of 1 mm; the percent depth dose was less than 1% at 4 mm from the prescription depth. Median postoperative radiation doses of 2700 cGy (range, 1800-3000 cGy) were delivered to 15 spinal tumor patients and 3000 cGy (range, 1800-3000 cGy) to 3 intracranial tumor patients. The median follow-up was 4.4 months (range, 2.6-23.3 months) for spinal tumor patients and 5.3 months (range, 0.7-16.2) for intracranial tumor patients. RESULTS: At 6-month follow-up, for all spinal tumor patients, local progression-free survival and overall survival rates were both 83.3% (95% confidence interval [CI]: 62.3%-94.3%); for all intracranial tumor patients, the local progression-free survival rate was 62.5% (95% CI: 23.8%-90.9%) and the overall survival rate was 66.7% (95% CI: 26.7%-92.9%). There were no intraoperative or postoperative complications secondary to radiotherapy. CONCLUSION: Use of the P brachytherapy plaque is technically simple and not associated with increased risk of complications, even after multiple radiation courses. Local control rates were more than 80% in patients with proven radiation-resistant spinal disease.

A survey of current clinical practice in permanent and temporary prostate brachytherapy: 2010 update.

PURPOSE: To help establish patterns of care and standards of care of interstitial permanent low-dose-rate (LDR) and temporary high-dose-rate brachytherapy for prostate cancer and to compare the results with a similar 1998 American Brachytherapy Society (ABS) survey. METHODS AND MATERIALS: A comprehensive questionnaire intended to survey specific details of current clinical brachytherapy practice was provided to the participants of the seventh ABS Prostate Brachytherapy School. Responses were tabulated and descriptive statistics are reported. RESULTS: Sixty-five brachytherapy practitioners responded to the survey. Eighty-nine percent (89%) of respondents performed LDR and 49% perform high-dose-rate brachytherapy. The median number of years of experience for LDR brachytherapists increased from 5 to 10 years over the course of the 12 years since the preceding survey. Compared with the first ABS, a smaller proportion of respondents received formal brachytherapy residency training (43% vs. 56%) or formal "hands-on" brachytherapy training (15% vs. 63%). There has been a marked decline in the utilization of the Mick applicator (Mick Radio-Nuclear Instruments, Inc., Mount Vernon, NY, USA) (60% vs. 28%) and an increase in the use of stranded seeds (40% vs. 11%). Compliance with postimplant dosimetry was higher in the 2010 survey. CONCLUSION: This survey does suggest an evolution in the practice of LDR brachytherapy since 1998 and aids in identifying aspects that require further progress or investigation. ABS guidelines and other practice recommendations appear to impact the practice of brachytherapy.

American Brachytherapy Society consensus guidelines for high-dose-rate prostate brachytherapy.

PURPOSE: A well-established body of literature supports the use of high-dose-rate (HDR) brachytherapy as definitive treatment for localized prostate cancer. Most of the articles describe HDR as a boost with adjuvant external beam radiation, but there is a growing experience with HDR monotherapy. METHODS AND MATERIALS: The American Brachytherapy Society has convened a group of expert practitioners and physicists to develop guidelines for the use of HDR in the management of prostate cancer. This involved an extensive literature review and input from an expert panel. RESULTS: Despite a wide variation in doses and fractionation reported, HDR brachytherapy provides biochemical control rates of 85-100%, 81-100%, and 43-93% for low-, intermediate-, and high-risk prostate cancers, respectively. Severe toxicity is rare, with most authors reporting less than 5% Grade 3 or higher toxicity. Careful attention to patient evaluation for appropriate patient selection, meticulous technique, treatment planning, and delivery are essential for successful treatment. CONCLUSION: The clinical outcomes for HDR are excellent, with high rates of biochemical control, even for high-risk disease, with low morbidity. HDR monotherapy, both for primary treatment and salvage, are promising treatment modalities.

A comparison of the impact of isotope ((125)I vs. (103)Pd) on toxicity and biochemical outcome after interstitial brachytherapy and external beam radiation therapy for clinically localized prostate cancer.

PURPOSE: To compare biochemical outcomes and morbidity associated with iodine-125 ((125)I) and palladium-103 ((103)Pd) brachytherapy as part of combined modality therapy for clinically localized prostate cancer. METHODS AND MATERIALS: Between October 2002 and December 2008, 259 patients underwent prostate brachytherapy ((125)I prescription dose, 110Gy: n=199; (103)Pd prescription dose, 100Gy: n=60) followed by external beam radiotherapy (median dose, 50.4Gy). Eighty-seven patients also received neoadjuvant androgen deprivation therapy. Toxicities were recorded with CTCAE v 3.0, International Prostate Symptoms Score (IPSS), and International Index of Erectile Function questionnaires. RESULTS: Overall, acute Grade ≥2 genitourinary toxicity occurred in 21% and 30% of patients treated with (125)I and (103)Pd, respectively (p=0.16). There were no significant differences in IPSS change or urinary quality-of-life scores between the isotopes at 4, 6, or 12 months (p=0.20, 0.21, and 1.0, respectively). IPSS resolution occurred at a median of 11 and 6 months for (125)I and (103)Pd patients, respectively (p=0.03). On multivariate analysis, only the use of neoadjuvant androgen deprivation therapy was predictive of time to IPSS resolution (p=0.046). Late Grade ≥2 gastrointestinal toxicity occurred in 7% of (125)I patients and 6% of patients treated with (103)Pd. Of 129 potent patients at baseline, there was better erectile function in patients who received (103)Pd (p=0.02); however, the followup was shorter for these patients. The 5-year prostate-specific antigen relapse-free survival for (125)I and (103)Pd patients was 95.2% and 98.2% (p=0.73), respectively. CONCLUSION: There were no differences in acute or long-term genitourinary or gastrointestinal toxicity between (125)I and (103)Pd in combined modality therapy for prostate cancer. There may be less erectile toxicity with the use of (103)Pd; however, additional followup of these patients is needed. There was no significant difference in 5-year prostate-specific antigen relapse-free survival between (103)Pd and (125)I.

Predicting biochemical tumor control after brachytherapy for clinically localized prostate cancer: The Memorial Sloan-Kettering Cancer Center experience.

PURPOSE: To identify predictors of biochemical tumor control and present an updated prognostic nomogram for patients with clinically localized prostate cancer treated with brachytherapy. METHODS AND MATERIALS: One thousand four hundred sixty-six patients with clinically localized prostate cancer were treated with brachytherapy alone or along with supplemental conformal radiotherapy. Nine hundred one patients (61%) were treated with Iodine-125 ((125)I) monotherapy to a prescribed dose of 144Gy, and 41 (4.5%) were treated with Palladium-103 ((103)Pd) monotherapy to a prescribed dose of 125Gy. In patients with higher risk features (n=715), a combined modality approach was used, which comprised (125)I or (103)Pd seed implantation or Iridium-192 high-dose rate brachytherapy followed 1-2 months later by supplemental intensity-modulated image-guided radiotherapy to the prostate. RESULTS: The 5-year prostate-specific antigen relapse-free survival (PSA-RFS) outcomes for favorable-, intermediate-, and high-risk patients were 98%, 95%, and 80%, respectively (p<0.001). Multivariate Cox regression analysis identified Gleason score (p<0.001) and pretreatment PSA (p=0.04) as predictors for PSA tumor control. In this cohort of patients, the use of neoadjuvant and concurrent androgen deprivation therapy did not influence biochemical tumor control outcomes. In the subset of patients treated with (125)I monotherapy, D(90)>140Gy compared with lower doses was associated with improved PSA-RFS. A nomogram predicting PSA-RFS was developed based on these predictors and had a concordance index of 0.70. CONCLUSIONS: Results with brachytherapy for all treatment groups were excellent. D(90) higher than 140Gy was associated with improved biochemical tumor control compared with lower doses. Androgen deprivation therapy use did not impact on tumor control outcomes in these patients.

Tumor control probability in radiation treatment.

Patients undergoing radiation therapy (and their physicians alike) are concerned with the probability of cure (long-term recurrence-free survival, meaning the absence of a detectable or symptomatic tumor). This is not what current practice categorizes as "tumor control (TC);" instead, TC is taken to mean the extinction of clonogenic tumor cells at the end of treatment, a sufficient but not necessary condition for cure. In this review, we argue that TC thus defined has significant deficiencies. Most importantly, (1) it is an unobservable event and (2) elimination of all malignant clonogenic cells is, in some cases, unnecessary. In effect, within the existing biomedical paradigm, centered on the evolution of clonogenic malignant cells, full information about the long-term treatment outcome is contained in the distribution Pm(T) of the number of malignant cells m that remain clonogenic at the end of treatment and the birth and death rates of surviving tumor cells after treatment. Accordingly, plausible definitions of tumor control are invariably traceable to Pm(T). Many primary cancers, such as breast and prostate cancer, are not lethal per se; they kill through metastases. Therefore, an object of tumor control in such cases should be the prevention of metastatic spread of the disease. Our claim, accordingly, is that improvements in radiation therapy outcomes require a twofold approach: (a) Establish a link between survival time, where the events of interest are local recurrence or distant (metastatic) failure (cancer-free survival) or death (cancer-specific survival), and the distribution Pm(T) and (b) link Pm(T) to treatment planning (modality, total dose, and schedule of radiation) and tumor-specific parameters (initial number of clonogens, birth and spontaneous death rates during the treatment period, and parameters of the dose-response function). The biomedical, mathematical, and practical aspects of implementing this program are discussed.

Comparison of tumor control and toxicity outcomes of high-dose intensity-modulated radiotherapy and brachytherapy for patients with favorable risk prostate cancer.

OBJECTIVES: To compare the long-term, prostate-specific antigen relapse-free survival outcome and incidence of toxicity for patients with low-risk prostate cancer who underwent brachytherapy or intensity-modulated radiotherapy (RT). METHODS: A total of 729 consecutive patients underwent brachytherapy (n = 448; prescription dose 144 Gy) or intensity-modulated RT alone (n = 281; prescription dose 81 Gy). The prostate-specific antigen relapse-free survival using the nadir plus 2 ng/mL definition and late toxicity using the National Cancer Institute's Common Terminology Criteria for Adverse Events were determined. RESULTS: The 7-year prostate-specific antigen relapse-free survival rate for the brachytherapy and intensity-modulated RT groups was 95% and 89% for low-risk patients, respectively (P = .004). Cox regression analysis demonstrated that brachytherapy was associated with improved prostate-specific antigen relapse-free survival, even after adjustment for other variables. The incidence of metastatic disease between treatment sessions was low for both treatment groups. Late grade 2 gastrointestinal toxicity was observed in 5.1% and 1.4% of the brachytherapy and intensity-modulated RT groups, respectively (P = .02). No significant differences were seen between treatment groups for late grade 3 or greater rectal complications (brachytherapy 1.1% and intensity-modulated RT 0%; P = .19). Late grade 2 urinary toxicity occurred more often in the brachytherapy group than in the intensity-modulated RT group (15.6% and 4.3%, respectively; P < .0001). No significant differences were seen between the 2 treatment groups for late grade 3 urinary toxicity (brachytherapy 2.2% and intensity-modulated RT 1.4%; P = .62). CONCLUSIONS: Among low-risk prostate cancer patients, the 7-year biochemical tumor control was superior for intraoperatively planned brachytherapy compared with high-dose intensity-modulated RT. Although significant toxicities were minimal for both groups, modest, but significant, increases in grade 2 urinary and rectal symptoms were noted for brachytherapy compared with intensity-modulated RT.