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.

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.

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.

Dosimetric guidance on using brachytherapy (low-dose-rate or high-dose-rate) to offset a flawed permanent prostate implant.

PURPOSE: To provide practical dosimetric advice on mending suboptimal permanent implants using low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The problem is to make the combination of the two radiation treatments (the initial, flawed one and the compensatory boost) clinically isoeffective with the planned dose. METHODS AND MATERIALS: The device of isoeffective dose is the appropriate tool for this purpose as it accounts for the physical (temporal distribution of dose) and biologic (radiosensitivity, repair kinetics, proliferation rate) treatment settings. RESULTS: I give, as a function of separation time from the initial, flawed treatment, and stratified by risk group representative values for the additional dose (low-dose-rate or high-dose-rate) needed to make the combined treatment isoeffective with a prescription of 144Gy of permanently implanted (125)I seeds. CONCLUSIONS: Although the isoeffective dose concept, within the constraints stated in the text, is rigorously valid, its practical implementation depends importantly on the relevant radiobiologic parameters, and in this respect the reader is urged to use his own critical judgment.

Quality assurance/quality control issues for intraoperative planning and adaptive repeat planning of image-guided prostate implants.

The quality assurance/quality control purpose is this. We design a treatment plan, and we wish to be as certain as reasonably possible that the treatment is delivered as planned. In the case of conventionally planned prostate brachytherapy, implementing to the letter the implantation plan is rarely attainable and therefore can require adaptive replanning (a quality control issue). The reasons for this state of affairs include changes in the prostate shape and volume during implantation and treatment delivery (e.g., edema resolution) and unavoidable inaccuracy in the placement of the seeds in the prostate. As a result, quality-control activities (e.g., the need to monitor-ideally, on the fly-the target and urethral and rectal dosage) must be also addressed.

Combined brachytherapy with external beam radiotherapy for localized prostate cancer: reduced morbidity with an intraoperative brachytherapy planning technique and supplemental intensity-modulated radiation therapy.

PURPOSE: To report the acute and late treatment-related toxicities of combined permanent interstitial (125)I implantation delivered via real-time intraoperative planning and supplemental intensity-modulated radiotherapy (IMRT) for patients with clinically localized prostate cancer. METHODS AND MATERIALS: One hundred twenty-seven patients were treated with a combined modality (CM) regimen consisting of (125)I implantation (110Gy) using a transrectal ultrasound-guided approach followed 2 months later by 50.4Gy of IMRT directed to the prostate and seminal vesicles. Late toxicity was scored according to the NCI Common Terminology Criteria for Adverse Events toxicity scale. The acute and late toxicities were compared to a contemporaneously treated cohort of 216 patients treated with (125)I alone to a prescribed dose of 144Gy. RESULTS: The incidence of Grade 2 acute rectal and urinary side effects was 1% and 10%, respectively, and 2 patients developed Grade 3 acute urinary toxicities. The 4-year incidence of late Grade 2 gastrointestinal toxicity was 9%, and no Grade 3 or 4 complications have been observed. The 4-year incidence of late Grade 2 gastrourinary toxicities was 15% and 1 patient developed a Grade 3 urethral stricture, which was corrected with urethral dilatation. The percentage of patients who experienced resolution of late rectal and urinary symptoms was 92% and 65%, respectively. Multivariate analysis revealed that in addition to higher baseline International Prostate Symptom Score, those patients treated with implant alone compared to CM were more likely to experience Grade 2 acute urinary symptoms. Increased Grade 2 late rectal toxicities were noted for CM patients (9% vs. 1%; p=0.001) as well as a significant increase for late Grade 2 urinary toxicities (15% vs. 9%; p=0.004). CONCLUSIONS: Adherence to dose constraints with combination real-time brachytherapy using real-time intraoperative planning and IMRT is associated with a low incidence of acute and late toxicities. Acute urinary side effects were significantly less common for CM patients compared to those treated with implantation alone. Late Grade 2 rectal and urinary toxicities were more common for patients treated with CM compared to implant alone.

Five-year outcome of intraoperative conformal permanent I-125 interstitial implantation for patients with clinically localized prostate cancer.

PURPOSE: To report the 5-year tumor control and toxicity outcomes for patients with localized prostate treated with I-125 permanent implantation using an intraoperative real-time conformal planning technique. METHODS AND MATERIALS: Between January 1998 and June 2002, 367 patients with prostate cancer were treated with I-125 permanent interstitial implantation using a transrectal ultrasound-guided approach. Real-time intraoperative treatment planning which incorporated inverse planning optimization was used. The median follow-up time was 63 months. RESULTS: The median V100 and D90 were 96% and 173 Gy, respectively. In 96% of cases a D90 of >140 Gy was achieved. The median urethral and rectal doses were 100% and 33% of the prescription doses, respectively. The 5-year PSA relapse-free survival outcomes for favorable and intermediate risk patients according to the ASTRO definition were 96% and 89%, respectively. In these patients no dosimetric parameter was identified which influenced the biochemical outcome. Of 38% who developed acute Grade 2 urinary symptoms, 63% had resolution of their symptoms within a median time of 6 months. The incidence of late rectal and urinary Grade 3 or higher toxicities were 1% and 4%, respectively. Seven percent (n = 27) developed late rectal bleeding (Grade 2) and 19% experienced late Grade 2 urinary symptoms. CONCLUSION: Real-time intraoperative planning consistently achieved optimal coverage of the prostate with the prescription dose with concomitant low doses delivered to the urethra and rectum. Biochemical control outcomes were excellent at 5 years and late toxicity was unusual. These data demonstrate that real-time planning methods can consistently and reliably deliver the intended dose distribution to achieve an optimal therapeutic ratio between the target and normal tissue structures.

Intraoperative real-time planned conformal prostate brachytherapy: post-implantation dosimetric outcome and clinical implications.

PURPOSE: To report the dosimetric outcome of patients with clinically localized prostate cancer treated with I-125 permanent implantation using an intraoperative real-time conformal planning technique. METHODS AND MATERIALS: Five hundred and sixty-two patients with prostate cancer were treated with I-125 permanent interstitial implantation using a transrectal ultrasound-guided approach. Real-time intraoperative treatment planning software that incorporates inverse planning optimization was used. Dose-volume constraints for this inverse-planning system included: prostate V100 >or=95%, maximal urethral dose or=140 Gy was achieved. In these patients, the V100 and D90 values did not have a significant influence on PSA relapse-free survival outcomes. The median maximum rectal dose and urethral doses were 104 Gy (72% of the prescription dose) and 187 Gy (130% of the prescription dose). The average and maximum rectal doses exceeding 100% of the prescription dose were less than 1% and 10% of patients, respectively. Average and maximum urethral doses exceeding 150% of the prescription dose were noted in 3% and 24% of patients, respectively. Average and maximum urethral doses exceeded 120% of the prescription dose in 21% and 58% of patients, respectively. Among patients where >or=2.5 cm(3) of the rectum was exposed to the prescription dose, the incidence of late grade 2 toxicity rectal toxicity was 9% compared to 4% for smaller volumes of the rectum exposed to similar doses (p=0.003). No dosimetric parameter in these patients with tight dose confines for the urethra influenced acute or late urinary toxicity. CONCLUSION: Real-time intraoperative planning was associated with a 90% consistency of achieving the planned intraoperative dose constraints for target coverage and maintaining planned urethral and rectal constraints in a high percentage of implants. Rectal volumes of >or=2.5 cm(3) exposed to the prescription doses were associated with an increased incidence of grade 2 rectal bleeding. Further enhancements in imaging guidance for optimal seed deposition are needed to guarantee optimal dose distribution for all patients. Whether such improvements lead to further reduction in acute and late morbidities associated with therapy requires further study.

Automated finite-element analysis for deformable registration of prostate images.

Two major factors preventing the routine clinical use of finite-element analysis for image registration are: 1) the substantial labor required to construct a finite-element model for an individual patient's anatomy and 2) the difficulty of determining an appropriate set of finite-element boundary conditions. This paper addresses these issues by presenting algorithms that automatically generate a high quality hexahedral finite-element mesh and automatically calculate boundary conditions for an imaged patient. Medial shape models called m-reps are used to facilitate these tasks and reduce the effort required to apply finite-element analysis to image registration. Encouraging results are presented for the registration of CT image pairs which exhibit deformation caused by pressure from an endorectal imaging probe and deformation due to swelling.

Biologically-equivalent dose and long-term survival time in radiation treatments.

Within the linear-quadratic model the biologically-effective dose (BED)-taken to represent treatments with an equal tumor control probability (TCP)-is commonly (and plausibly) calculated according to BED(D) = -log[S(D)]/alpha. We ask whether in the presence of cellular proliferation this claim is justified and examine, as a related question, the extent to which BED approximates an isoeffective dose (IED) defined, more sensibly, in terms of an equal long-term survival probability, rather than TCP. We derive, under the assumption that cellular birth and death rates are time homogeneous, exact equations for the isoeffective dose, IED. As well, we give a rigorous definition of effective long-term survival time, T(eff). By using several sets of radiobiological parameters, we illustrate potential differences between BED and IED on the one hand and, on the other, between T(eff) calculated as suggested here or by an earlier recipe. In summary: (a) the equations currently in use for calculating the effective treatment time may underestimate the isoeffective dose and should be avoided. The same is the case for the tumor control probability (TCP), only more so; (b) for permanent implants BED may be a poor substitute for IED; (c) for a fractionated treatment schedule, interpreting the observed probability of cure in terms of a TCP formalism that refers to the end of the treatment (rather than T(eff)) may result in a miscalculation (underestimation) of the initial number of clonogens.

High-dose-rate interstitial brachytherapy in recurrent and previously irradiated head and neck cancers--preliminary results.

PURPOSE: Although high-dose-rate brachytherapy (HDRBT) offers significant advantages over low dose rate brachytherapy, there are scant data on improved local control (LC) and treatment-related complications in patients with recurrent head and neck (H&N) cancers. We report our preliminary results in patients with recurrent H&N cancers treated with interstitial HDRBT. METHODS AND MATERIALS: Thirty patients with recurrent H&N cancers were treated with HDRBT between September 2003 and October 2005. Seventy-seven percent (23/30) of the patients had either local or regional recurrence in the area of previous external beam radiation therapy. The treatment sites were oral cavity/oropharynx (11/30), neck (10/30), face/nasal cavity (6/30), and parotid bed (3/30). Whereas 18 patients underwent surgical resection followed by HDRBT, 3 patients were treated with combined external beam radiation and HDRBT, and the remaining 9 were treated with HDRBT alone. The dose and fractionation schedules used were 3.4Gy twice per day (b.i.d.) to 34Gy for postoperative cases, 4Gy b.i.d. to 20Gy when combined with 40-50Gy external beam, and 4Gy b.i.d. to 40Gy for definitive treatment. HDRBT was initiated 5 days after catheter placement to allow for tissue healing. RESULTS: With a median followup of 12 months, 6 local recurrences were observed 1-10 months after the procedure. The 2-year LC and overall survival outcomes for the entire group were 71% and 63%, respectively. Patients treated with surgical resection and HDRBT had an improved 2-year LC compared to the patients treated with HDRBT+/-external beam radiation alone (88% vs. 40%, p=0.05). Six Grade II and four Grade III complications were noted in five patients, all observed in the postoperative HDRBT group. CONCLUSION: The preliminary results of HDRBT indicate an acceptable LC and morbidity in recurrent H&N cancers. A planned surgical resection followed by HDRBT is associated with improved tumor control in these high-risk patients. Based on these encouraging results, prospective clinical trials are warranted using HDRBT in recurrent H&N cancers to decrease late toxicity.

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.

Calibration procedures for seeds preloaded in cartridges.

Radioactive seeds preloaded in sterilized cartridges or needles are commonly obtainable from manufacturers. Under the US regulations for control of radioactive materials, seed users are required to account for all seeds and independently verify their air kerma strength (SK). As a result, the viability of inspection schemes that rely on measurement of aggregate seeds is of interest. In this paper we consider the conditions (if any) under which cartridge inspection can satisfy regulatory requirements and still provide practical benefit (i.e., time savings) against the regular single-seed assay. The standards for comparison are the recommendations of AAPM TG40, AAPM TG56, and ACR's "Standard for the Performance of Manually Loaded Brachytherapy Sources." The practical benefit is judged in comparison to the effort required to apply the 10% assay recommendation of TG40 to seeds in cartridges. Two specific cartridge inspection schemes are considered: (a) measuring the SK of each cartridge in a batch; (b) measuring a single cartridge sampled at random from the batch. Unlike the 10% assay, which is defined (imperfectly, in our view) without reference to the prevalence of in-calibration seeds, the estimation of the relative merits of cartridge inspection methods must necessarily include such information and, as such, is manufacturer specific. In this paper results are provided for Oncura model 6711 125I seeds in shielded and unshielded Mick cartridges. We show that the only practically useful cartridge inspection scheme is the batch scheme applied to unshielded cartridges. The false positive rates associated with the other schemes are such that we expect to open a cartridge (and perform the 10% assay) at least 80% of the time. While anything less than 100% of the time is theoretically an improvement, this neglects the additional effort required to assay the cartridges.

Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer.

PURPOSE: To report PSA relapse-free survival and toxicity outcomes of prostate cancer patients who have undergone three-dimensional computer-optimized high-dose-rate (HDR) brachytherapy with external beam radiotherapy as definitive treatment. METHODS AND MATERIALS: One hundred five patients consecutively treated between 1998 and 2004 are reported. All patients were treated with HDR boost with lr 192 (5.5-7.0 Gy), based upon postimplant CT three-dimensional treatment planning using an in-house treatment plan optimization algorithm. Three-dimensional conformal external beam radiotherapy (45-50.4 Gy) was also administered 3 weeks after the HDR procedure. Toxicity was measured using National Cancer Institutes Common Toxicity Criteria and International Prostate Symptom Score indices. RESULTS: With a median followup of 44 months (8-79 months), the 5-year PSA relapse-free survival outcomes for low, intermediate and high-risk patients were 100%, 98%, and 92%, respectively, Median urinary toxicity, and 93% of patients denied rectal problems at the time of last followup. Erectile dysfunction was noted in 47% patients at the time of last followup, but overall 80% were able to achieve vaginal penetration when those who responded to sildenafil were included. CONCLUSION: Computer-optimized three-dimensional HDR prostate brachytherapy provides excellent disease control for even high risk localized prostate cancer. Significant toxicity has been minimal.

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.

Methodology for biologically-based treatment planning for combined low-dose-rate (permanent implant) and high-dose-rate (fractionated) treatment of prostate cancer.

PURPOSE: The combination of permanent low-dose-rate interstitial implantation (LDR-BRT) and external beam radiotherapy (EBRT) has been used in the treatment of clinically localized prostate cancer. While a high radiation dose is delivered to the prostate in this setting, the actual biologic dose equivalence compared to monotherapy is not commonly invoked. We describe methodology for obtaining the fused dosimetry of this combined treatment and assigning a dose equivalence which in turn can be used to develop desired normal tissue and target constraints for biologic-based treatment planning. METHODS AND MATERIALS: Patients treated with this regimen initially receive an I-125 implant prescribed to 110 Gy followed, 2 months later, by 50.4 Gy in 28 fractions using intensity-modulated external beam radiotherapy. Ab initio methodology is described, using clinically derived biologic parameters (alpha, beta, potential doubling time for prostate cancer cells [T(pot)], cell loss factor), for calculating tumor control probability isoeffective doses for the combined LDR and conventional fraction EBRT treatment regimen. As no such formalism exists for assessing rectal or urethral toxicity, we make use of semi-empirical expressions proposed for describing urethral and rectal complication probabilities for specific treatment situations (LDR and fractionation, respectively) and utilize the notion of isoeffective dose to extend these results to combined LDR-EBRT regimens. RESULTS: The application to treatment planning of the methodology described in this study is illustrated with real-patient data. We evaluate the effect of changing LDR and EBRT prescription doses (in a manner that remains isoeffective with 81 Gy EBRT alone or with 144 Gy LDR monotherapy) on rectal and urethral complication probabilities, and suggest that it should be possible to improve the therapeutic ratio by exploiting joint LDR-EBRT planning. CONCLUSIONS: We describe new methodology for biologically based treatment planning for patients who receive combined low-dose-rate brachytherapy and external beam radiotherapy for prostate cancer. Using relevant mathematical tools, we demonstrate the feasibility of fusing dose distributions from each treatment for this combined regimen, which can then be expressed as isoeffective dose distributions. Based on this information, dose constraints for the rectum and urethra are described which could be used for planning such combination regimens.

(32)P radioisotope therapy for recurrent pilocytic astrocytoma.

(32)P is a pure beta-emitter that has a depth of penetration of 2-3 mm and can be useful in the treatment of cystic lesions. Its effectiveness in the treatment of a selected brain tumor is illustrated here.

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.

Intraoperative dynamic dose optimization in permanent prostate implants.

PURPOSE: With the advent of intraoperative optimized planning, the treatment of prostate cancer with permanent implants has reached an unprecedented level of dose conformity. However, because of well-documented (and unavoidable) inaccuracies in seed placement into the gland, carrying out a plan results in a large degree of variability relative to the intended dose distribution. This brings forth the need to periodically readjust the plan to allow for the real positions of seeds already implanted. In this paper, an algorithm for performing this task, hereby described as intraoperative dynamic dose optimization (IDDO), is presented and assessed. METHODS AND MATERIALS: The general scheme for performing IDDO consists of three steps: (1) at some point during the implant, coordinates of implanted seeds are identified; (2) seed images are projected onto the reference frame of the ultrasound images for planning; and (3) the plan is reoptimized. Work on the first two steps is reported elsewhere. Here, we focus on the strategy for implementing the reoptimization step. An optimal treatment plan is first obtained based on initial operating room-acquired ultrasound images. We analyze the sensitivity and effect of the IDDO procedure with respect to the total number of reoptimizations performed. Specifically, we consider reoptimizing 2, 3, and 4 times. When two reoptimizations are used, half of the seeds from the initial optimal plan are implanted. The first reoptimization is performed on the remaining possible seed positions, and all the seeds designated in this reoptimized plan are implanted. The second (final) reoptimization is done on the remaining unused seed positions to ensure 100% coverage of the gland and to eliminate possible cold spots in the gland. Similarly, when three reoptimization steps are used, one-third of the seeds from the initial optimized plan, one-half of the seeds from the first reoptimization, and all seeds from the second reoptimization are implanted. The third (final) reoptimization is performed to assist in eliminating possible cold spots. Reoptimizing four times proceeds in a like manner. Fifteen patient cases are used for comparison. Strict dose bounds of 100% and 120% of the prescription dose are imposed on the urethra, and 100% coverage is imposed on the prostate volume. To assist in achieving good conformity, prostate contour points are assigned a target upper dose bound of 150% of the prescription dose. RESULTS: A two-way comparison is performed: (a) initial optimized plan, (b) IDDO plan. Postimplant dose analysis, coverage and conformity measures, as well as actual dose received by urethra and rectum are used to gauge the results. The initial optimized plan consistently provides 93% prescription dose coverage to the gland with average conformity index of 1.32. The urethra dose ranges within 100% to 150%, and the maximum dose delivered to the rectum reaches 91% of the prescription dose. On average, about 50% of the urethra receives more than 120% of the prescription dose, and 19% of the rectum volume receives more than the 78% upper dose limit. For the IDDO plan, 100% postimplant coverage with 1.16 conformity is achieved. Urethra and rectum dose is maintained within the prescribed 100% to 120% range and 78% upper bound, respectively. CONCLUSIONS: With real-time treatment planning, it is possible to dynamically reoptimize treatment plans to account for actual seed positions (as opposed to planned positions) and needle-induced swelling to the gland during implantation. Postimplant analysis shows that the final seed configuration resulting from the IDDO method yields improved dosimetry. The algorithmic design ensures that one can achieve complete coverage while maintaining good conformity, thus sparing excess radiation to external tissue. The study also provides evidence of the possibility of morbidity reduction to urethra and rectum (because of reduced dose delivered to these structures) via the use of IDDO planning. Clinical studies are needed to validate the importance of our approach.