Fused Radioimmunoscintigraphy for Treatment Planning

Prostate Cancer Imaging

RIUS0003(Cytogen)_04-12.qxd 12/4/06 13:19 Page S11 PROSTATE CANCER IMAGING Fused Radioimmunoscintigraphy for Treatment Planning Rodney J. Ellis, MD,*† Deborah A. Kaminsky, DPh* *Department of Radiation Oncology, Aultman Hospital, Canton, OH; †Department of Radiology, Northeastern Ohio Universities College of Medicine, Roostown, OH, and Department of Urology, Case School of Medicine, Cleveland, OH Advances in imaging technologies, including computerized tomography (CT) and single-photon emission tomography (SPECT), are improving the role of imaging in prostate cancer diagnosis and treatment. Hybrid (SPECT/CT) imaging, in particular, shows an increased sensitivity for identification of prostate cancer. Published studies have also recently proposed a new paradigm in the administration of radiation therapy for prostate cancer, favoring doseescalation strategies to improve tumor control for localized disease. Conventional dose-escalation protocols have previously relied primarily on margin extension to the entire prostate gland to achieve dose-escalation; extending increased risk to radiosensitive normal structures. A newer strategy proposes use of advanced imaging to confine dose-escalation to biological target volumes identified on capromab pendetide SPECT/CT-fused image sets or imageguided radiation therapy (IGRT). This strategy defines a shift in radiation dosimetry and planning from uniform glandular prescription dosing with doseescalation applied generically to the peripheral regions and margin extension; to dose-escalation confinement to discrete regions of known disease as defined by focal uptake on radioimmunoscintigraphy fusion with anatomic image sets, with minimal margin extension. The introduction of advanced imaging for IGRT in prostate cancer has also introduced an improved capability for the early-identification of patients at risk for metastatic disease, where more aggressive therapeutic interventions may prove beneficial. [Rev Urol. 2006;8(suppl 1):S11-S19] © 2006 MedReviews, LLC Key words: ProstaScint • Brachytherapy • Radiotherapy • SPECT/CT • Biological target volumes • Prostate cancer • Survival dvances in computerized tomography (CT), magnetic resonance imaging (MRI), and single-photon emission tomography (SPECT) are rapidly improving the role of imaging in prostate cancer diagnosis and treatment, with hybrid (SPECT/CT) imaging showing increased sensitivity for identification of disease.1 Recently published studies have proposed a new paradigm in the administration of radiation therapy, favoring dose-escalation strategies for improved probability of tumor control in prostate cancer patients undergoing A VOL. 8 SUPPL. 1 2006 REVIEWS IN UROLOGY S11 RIUS0003(Cytogen)_04-12.qxd 12/4/06 13:19 Page S12 Fused Radioimmunoscintigraphy continued high-dose therapy for localized tumors.2,3 This review focuses on evidencebased data supporting the clinical role of dose-escalation strategies, in particular, the use of capromab pendetide (ProstaScint®; Cytogen Corporation, Princeton, NJ) SPECT image sets coregistered with CT scans or SPECT/CT fusion-identified biological target volumes (BTV) for dose-escalation targeting or image-guided radiation therapy (IGRT).4,5 The review highlights the key published literature that defines radiotherapy prescription dose strategies, prostate imaging, and image co-registration methodologies that enable IGRT dose escalation to discrete tumor targets identified by radioimmunoscintigraphy. These newer strategies support a shift from dose-planning protocols that use uniform prescription doses to the prostate gland volume, with margin extension and peripheral dose escalation, to radiation planning that is based on uniform glandular prescription dosing and minimal margin extensions, with dose escalation to BTV defined by focal uptake on fused radioimmunoscintigraphy image sets. Included in the review are recent applications of dose-escalation strategies in intensity-modulated radiation therapy (IMRT) and 3-dimensional (3-D) conformal therapy. We also highlight recently published data suggesting a larger potential role for SPECT/CT ProstaScint in treatment selection for patients who are at high risk for local (periprostatic) extension of disease and may benefit from dual therapy applications, such as seed implant plus external beam radiation using conformal therapies such as 3-D or IMRT.5 Radiation Therapy and Prescription Dose Radiation therapy is recognized as an effective treatment for prostate adenocarcinoma. Targeted radiation ther- S12 VOL. 8 SUPPL. 1 2006 apies include low-dose rate (LDR) brachytherapy or permanent seed implant and high-dose rate (HDR) or temporary source treatment, IMRT, and conformal 3-D therapies. Collectively, these conformal therapies present the opportunity to refine dose delivery and thus accomplish dose escalation in regions shown to be positive for focal uptake on radioimmunoscintigraphy, indicating a high likelihood for bulky disease. In this manner, molecular imaging can allow individualized conformal treatments with therapy intensification directed to discrete tumor targets. Dose escalation achieved through conformal external beam radiation therapy (EBRT) has previously been shown to improve biochemical disease control,6,7 presumably by surpassing the tolerance of radio-resistant cancer cells.2 Given the major source of error in target definition for EBRT of the prostate, conformal dose distribution for radiotherapy planning has evolved to emphasize the application of extended treatment margins around glandular target volumes.8 Treatment planning systems use the following common target definitions: gross target volume (GTV), defined as the volume containing detectable tumor tissue; clinical target volume (CTV), defined as the volume surrounding the GTV, including a volume with suspected microscopic disease extensions; and, due to the uncertainties in target delineation or daily positioning, the planning target volume (PTV). Additionally, clinically useful radiation therapy dosimetry indexes are commonly used to describe target volumes for brachytherapy—the volume of prostate receiving 100% of the prescribed dose (V100) and the maximal dose received by 90% of the prostate volume (D90)—as comparative parameters. The V100 and D90 dosimetric quantifiers for LDR brachytherapy have been shown to be REVIEWS IN UROLOGY independent predictors, with V100 perhaps superior to D90 for predicting freedom from biochemical recurrence.9 Dosimetric guidelines for prostate cancer brachytherapy planning have previously focused on uniform loading characteristics, subsequently adjusted to define a modified-uniform peripheral loading scheme, typically applied with minimum peripheral dose definitions. The American Association of Physicists in Medicine Task Group No. 6410 formally recognized the trend of LDR practitioners to correct for inherent uncertainties in the implant procedure by prescribing dose coverage using a planning volume larger than the prostate volume, by increasing the total activity implanted by 15%, or by increasing prescribed dose plans several millimeters outside the gland, to effectively achieve a dose-escalation strategy of overplanning through the use of expanded PTV beyond the CTV. In current planning applications, the interpretation and application of target extension remain a major source of variation and error in target delineation, frequently overestimating the actual target volume.8 Transperineal ultrasound (TRUS) brachytherapy has been shown to improve the control and delivery of prescribed doses of radiation and is considered an effective treatment for patients with localized prostate cancer.11,12 Recently, radioimmunoscintigraphy image sets co-registered to CT and MRI have been applied to TRUS-guided treatment planning systems to define BTV, so as to prescribe dose-escalation targeting to discrete areas of tumor foci within the prostate gland.5 In the same manner that the introduction of computerized treatment planning systems revolutionized radiotherapy preplanning, postplan dosimetric evaluations, and intraoperative planning protocols, BTV dose-escalation targeting RIUS0003(Cytogen)_04-12.qxd 12/4/06 13:19 Page S13 Fused Radioimmunoscintigraphy strategies may represent the next major refinement in radiation therapy planning. The identification of tumor targets for dose escalation is impaired by the limitations of the imaging technologies commonly used for radiation therapy planning, such as ultrasound, MRI, and CT. Their use has been historically limited because these standard imaging techniques cannot confidently distinguish between normal recognized for its ability to define zonal anatomy and critical structures adjacent to the prostate.18 Approved in the United States by the Food and Drug Administration a decade ago for use in staging prostate cancer in recurrent disease and high-risk patient populations, ProstaScint has struggled to find its place in routine clinical practice, due to limited long-term prospective outcome studies and a relatively high reported rate of false- The use of dose escalation to discrete tumor targets identified by radioimmunoscintigraphy has been shown to benefit biochemical disease-free survival and reduce radiotherapy-related morbidity for prostate cancer. and malignant prostate tissue.13,14 The use of dose escalation to discrete tumor targets identified by radioimmunoscintigraphy has been shown to benefit biochemical disease-free survival (bDFS) and reduce radiotherapyrelated morbidity for prostate cancer.15 Imaging of the Prostate The utility of CT and MRI in the management of prostate cancer is predominantly for anatomic definition. Microvessel density within the prostate, as demonstrated on quantitative CT perfusion, is found in only a minority of patients, with tumor location being statistically significant in only localized high-volume, poorly differentiated prostate cancer when evaluated with contrast enhancement using a 16-slice scanner.16 Although MRI and CT image fusion with CTbased dose calculations are routinely used for prostate treatment planning, MRI-based digitally reconstructed radiographs alone do not provide adequate bony structure information for treatment planning.17 Dynamic 16slice contrast-enhanced CT imaging has demonstrated visible enhancement of prostate cancer in only a minority of subjects, but CT is well positive findings. In most institutions today, ProstaScint imaging is used to delineate metastatic disease from local disease, including staging in those patients who are considering radical prostatectomy or radiotherapy and are at high risk for metastases, when discordance exists among prostate-specific antigen (PSA), Gleason score, and prostate examination; in post-prostatectomy or post-radiated patients with an increasing PSA or any other sign suggesting recurrence; in post-prostatectomy patients with positive surgical margins for whom adjunct radiotherapy is being demonstrations detailing the optimization of radioimmunoscintigraphy including patient preparation, study interpretation, and reporting. In a series of 49 patients, the authors reported an 83% accuracy for surgical confirmation of disease localization to areas of focal uptake on SPECT image sets, reporting that accuracy doubled with image fusion versus SPECT alone. A recent study16 provides verification that the newer SPECT post-processing techniques, using attenuation correction methods, improve the quantitative accuracy and precision of indium-111 (111In)-based molecular images such as capromab pendetide. New hybrid imaging solutions, such as the Precedence SPECT/CT (Philips Medical Systems, Andover, MA), the Millennium VG Hawkeye (GE Healthcare, Waukesha, WI), and the Symbia SPECT/CT (Siemens Medical Solutions, Northbrook, IL), are likely to further enhance the accuracy and ease-of-use parameters for SPECT imaging agents. Whereas newer hybrid systems include cutting-edge reconstruction techniques and attenuation correction, providing new levels of SPECT image resolution, SPECT image reconstruction techniques were also shown to independently use CT data for generating transmission im- A recent study provides verification that the newer SPECT post-processing techniques, using attenuation correction methods, improve the quantitative accuracy and precision of indium-111-based molecular images such as capromab pendetide. considered; or in post-prostatectomy or post-radiated patients whose PSA does not decline to expected levels following treatment.19 Sodee and colleagues20 have published an update on their use of fused capromab pendetide imaging for prostate cancer, with case study ages, thereby allowing line-source or point-source transmission image adoption for SPECT and CT co-registered image sets.16 In much the same way that automatic and semiautomatic image registration methods have been used to incorporate positron emission VOL. 8 SUPPL. 1 2006 REVIEWS IN UROLOGY S13 RIUS0003(Cytogen)_04-12.qxd 20/4/06 1:52 Page S14 Fused Radioimmunoscintigraphy continued Figure 1. VariSeed 7.2 brachytherapy treatment planning software showing “work in progress” for postoperative assessment of CT-based treatment planning with SPECT image fusion to the planning CT scan, for improved accuracy of biological target volume contouring directly within the planning software. tomography (PET) data into radiotherapy treatment planning in relatively rigid anatomic sites, such as the head and neck (with overall accuracy reported as
2 and
4 mm in phantom and patients, respectively),21 so SPECT/CT data may now be applied to prostate treatment planning for more precise delivery of dose to target volume. Several commercial medical device vendors have recently adopted treatment planning functions that enable computer-enhanced contouring of SPECT/CT findings for IMRT and brachytherapy applications. Figure 1 illustrates the VariSeed treatment planning software (Varian Medical Systems, Palo Alto, CA), which may be used to assess brachytherapy source placement postoperatively through image co-registration of CT and SPECT datasets, that has been developed for SPECT/CT BTV contouring as a work in progress. The SPECT/CT BTV contouring option is also being evaluated for use on the Varian Eclipse product for IMRT and 3-D conformal planning. Other examples of works in progress for automated SPECT/CT data integration for IMRT planning include the Pinnacle System (Philips Medical Systems, Cleveland, OH) and CORVUS (North American Scientific, Chatsworth, CA). Figure 2 illustrates the capabilities of the Pinnacle System IMRT planning program for dose escalation of 2 separate prostate BTVs in the right and left base, which were identified by diagnostic SPECT/CT fusion software and hand-transferred into the planning system, as demonstrated on sagittal, transverse, and coronal planes. The application of radioimmunoscintigraphy data with fusion to CT or MRI in doseescalation contouring using treatment planning systems, as a first step, should begin with optimized SPECT data, including advanced postprocessing functions. DeWyngaert and colleagues22 provide an excellent imaging protocol for 111In ProstaScint image acquisition, including dual Figure 2. Treatment planning of intensity-modulated radiation therapy, using Pinnacle System treatment planning software for 2 separate biological target volumes (BTVs) located in the right and left base, identified by diagnostic SPECT/CT image fusion software then hand-transferred into the planning system for dose escalation to 80 Gy to each BTV, with 76 Gy to the prostate volume. Left to right: transverse, sagittal, and coronal planes. S14 VOL. 8 SUPPL. 1 2006 REVIEWS IN UROLOGY RIUS0003(Cytogen)_04-12.qxd 12/4/06 13:19 Page S15 Fused Radioimmunoscintigraphy isotope imaging with technetium99m-labeled red blood cells, Boolean subtraction of bone marrow, image fusion with CT/MRI, and contouring for adaptation of BTV dose escalation in treatment planning. Image Fusion for Treatment Planning The co-registration of functional and anatomic image sets can be accomplished in several ways. The first method is carried out simply by the clinician’s ability to visualize separate image sets and mentally transfer where the region of interest in 1 set relates to a location within the second set. The merging of image data may also be accomplished by manual contour transfer, in which a region of interest from a molecular study (SPECT or PET) is adopted by manual transfer into treatment planning studies, such as a CT planning system for IMRT. These clinical methods are necessarily unsophisticated, leaving much to be desired in terms of accuracy and reproducibility of treatment-volume definition. Image co-registration software has greatly facilitated the use of image fusion for diagnostic applications of fused image sets, such as SPECT/CT and PET/CT. In therapy planning, CT scans are commonly used as a reference set for dosimetry calculations and planning. Until recently, only rarely have CT image sets been fused with secondary datasets for planning, as in the example of CT fused with MRI for central nervous system lesions such as glioblastoma multiforme and, more recently, the use of PET scans fused with CT for planning in lung or head and neck cancers. The ability to co-register or fuse CT and MRI image sets with SPECT for contour applications in treatment planning systems has been driven by institutionally developed software programming, but is now evolving within commercial systems. When our group began to explore the use of SPECT images to direct prostate brachytherapy, our first attempts were limited to the use of 4 expanded SPECT-alone images obtained in transverse cuts through the pelvis rostral to the dorsal venous plexus at 1 cm intervals. It quickly became evident that SPECT image sets alone failed to provide adequate reference points to the normal mispositioned between studies. Thus, we learned to rely on natural internal fiducial landmarks such as the vascular structures and bone marrow reserves to co-register the 2 studies. The most commonly useful landmarks in prostate imaging are the femoral vessels and acetabulum and pubic symphysis in the transverse plane; the pubic symphysis and sacrum in the sagittal plane; and the iliac crest, The advent of the hybrid SPECT/CT systems introduced the ability to remove much of the guesswork in obtaining accurately co-registered images and further assures that the prostate has not moved out of position between diagnostic studies. anatomy to be of significant use clinically. We began to use SPECT/CT image fusion in early 1997, using a commercially available software solution available from Picker (at that time marketed under the commercial name Odyssey). We later made the transition to a fusion software program developed in-house at the University Hospitals of Cleveland (Cleveland, OH), which has since evolved into commercially available software marketed as MIM (MIMvista, Cleveland, OH). Our early work with SPECT/CT fused prostate studies included registration attempts with external fiducial markers. Markers were attached to the patient’s skin surface in an anterior and right/left lateral position for visualization on both CT and SPECT through the application of a dilute 111 In-soaked cotton ball contained within the CT-compatible fiducial marker. We soon found, however, that this marker system was less reliable than predicted, as the marker would frequently become displaced between studies as the patient was moved from nuclear medicine to CT, or the patient might become rotated or otherwise hips, and iliac vessels in the coronal plane.23 The advent of the hybrid SPECT/CT systems introduced the ability to remove much of the guesswork in obtaining accurately co-registered images and further assures that the prostate has not moved out of position between diagnostic studies. Fiducial markers implanted during prostate brachytherapy have been shown to easily and practically guide subsequent image-guided EBRT.24 In addition, fiducial marker placement under ultrasound guidance is now commonly used for gland localization before radiation therapy treatment. Billing and coding practices for fiducial marker placement have evolved with the adoption of unlisted procedures, as dedicated codes under the Physicians’ Current Procedural Terminology or CPT (American Medical Association) have not been available. Communication updates published by the American Urological Association (AUA) Coding Hotline advise the use of CPT Code 55899 (an unlisted procedure for use with the male genital system) and CPT Code 76942 (for ultrasonic guidance for needle placement) for coding activities related to VOL. 8 SUPPL. 1 2006 REVIEWS IN UROLOGY S15 RIUS0003(Cytogen)_04-12.qxd 20/4/06 1:53 Page S16 Fused Radioimmunoscintigraphy continued the placement of prostate gland markers for radiotherapy.25 As with the use of most unlisted procedures, claim submissions may require supporting documentation. The AUA has also recently announced that collaborative efforts with the American Society for Therapeutic Radiology and Oncology (ASTRO) have resulted in the anticipated release of a new dedicated CPT code for marking prostate locations, later in 2006. Radioimmunoscintigraphy and Treatment Planning Recognizing the need for a clinically accepted technique for planning brachytherapy based on the distribution of tumor foci within the prostate, our group devised a radioimmunoguided imaging technique to address the problem.5 We incorporated findings of intraprostatic focal uptake on radioimmunoscintigraphy into radiation planning to define BTVs for dose escalation. We initially reported correlation of areas of increased intraprostatic intensity observed on fused SPECT/CT images with biopsy results, in a small series of patients, to evaluate the accuracy of the technique in localizing intraprostatic disease. The SPECT and preoperative CT scans were co-registered for correlation with needle biopsy specimens. For each patient, 12 biopsy samples were acquired by transperineal biopsy procedure during prostate brachytherapy, in a sagittal sextant fashion (1 cm to the left and right of midplane). Histopathology specimens were then evaluated for comparison with pre-therapy in vivo image sets. The 84 samples resulted in SPECT/CT image correlation with biopsy cores with 80% overall accuracy, 79% sensitivity, 80% specificity, 68% positive predictive value, and 88% negative predictive value. Overall, the study concluded that CT scans fused with SPECT images were beneficial in identifying S16 VOL. 8 SUPPL. 1 2006 adenocarcinoma foci within the prostate, as confirmed by histopathologic results. These data were used to validate the development of a protocol of dose escalation to radioimmunoscintigraphy-identified BTV.26 RadioimmunoscintigraphyGuided Radiation Therapy Advances in SPECT image-acquisition parameters, advanced post-processing, and co-registration capabilities developed over the past decade have increased the feasibility of clinical adoption of molecular targets, such as the prostate-specific membrane antigen (PSMA), which is recognized by the murine-based monoclonal antibody 7E11.c5.3, commercially available as a kit for the preparation of 111 In ProstaScint. Previous studies have shown that tissue expression of PSMA is highly restricted to prostate tissues. Upregulation of PSMA has been observed with increasing pathologic grade, but not with clinical stage.27 Our group evaluated early feasibility and acute toxicity studies that have been validated through publication of 4-year biochemical outcomes after radioimmunoguided TRUS brachytherapy for patients with localized prostate adenocarcinoma.4 Most recently,5 we have reported long-term bDFS rates with dose escalation to BTV identified with SPECT/CT image fusion, demonstrating bDFS rates superior to those of other, comparable study groups. In this long-term prospective outcome trial, patients were treated with definitive radiation therapy for clinically localized prostate adenocarcinoma (T1c-T3b NxM0) using a LDR brachytherapy dose escalation to BTV identified with SPECT/CT. In total, 239 patients were treated with or without conformal EBRT. Intraprostatic BTV dose targets were escalated to 150% of the prostate volume prescription dose. Seven-year actuarial bDFS rate for the entire cohort was 88.0% by the ASTRO consensus definition of PSA failure.5 These data demonstrate improved survival rates for similar patient cohorts when compared with Quaranta and colleagues’ meta-analysis11 comparing radical prostatectomy and brachytherapy for localized prostate cancer for low-, intermediate-, and high-risk patient cohorts (Table 1). Survival rates in our study compare favorably with all maximum survival and range of survival data for the reported study groups.5 Table 1 7-Year Biochemical Disease-Free Survival by ASTRO Consensus for Low-, Intermediate-, and High-Risk Patient Cohorts, Compared With 5-Year Survival Data in Meta-Analysis Low-Risk Intermediate-Risk High-Risk 7-year survival 96% 116 patients 87% 72 patients 72.5% 51 patients 5-year survival, meta-analysis 87.4%, Range 66%-94% 2234 patients 74.3%, Range 34%-83% 1224 patients 49.7%, Range 15%-69% 416 patients ASTRO, American Society for Therapeutic Radiology and Oncology. Data from Ellis RJ et al5 and Quaranta BP et al.11 REVIEWS IN UROLOGY RIUS0003(Cytogen)_04-12.qxd 12/4/06 13:19 Page S17 Fused Radioimmunoscintigraphy Dose Escalation and Radioimmunoscintigraphy for IMRT Zelefsky and coauthors2 defined new standards for curative radiotherapy for prostate cancer with a dose-escalation strategy that uses 3-D conformal therapy. More recently, Zietman and coauthors3 published a randomized trial demonstrating that highdose radiotherapy cut the risk of prostate cancer recurrence in a series of 393 patients with localized prostate cancer, randomized to receive a total radiotherapy dose of 70.2 Gy (conventional) or 79.2 Gy (high), with dose boost delivered using protonbeam therapy. The 5-year biochemical failure-free (bFF) rates for the highand conventional-dose groups were 80.4% and 61.4%, respectively (P
.001), representing a 49% reduction in failure risk with high-dose radiotherapy. A similar reduction in risk was observed in both low- and higher-risk patients. Importantly, the 2 cohorts were also reported comparable for toxicity, with about 1.5% of patients in each group experiencing acute urinary or rectal morbidity of at least moderate severity. Similarly, the rates of late morbidity in each group were also around 1.5%.3 Schild and colleagues28 have demonstrated early feasibility and PSA responses were deemed favorable. In this protocol, the authors reported that
40% of the rectal/bladder volume can receive  65 Gy;
30% of the rectal/bladder volume,  70 Gy;
10% of the rectal/bladder volume,  75 Gy; and
1% (1.8 cc) of the rectal/bladder volume,  81 Gy; and that the full thickness of the femur should not receive  50 Gy. Observations and Conclusion Although radiation therapy and prostatectomy are demonstrated as highly efficient in treating low- and intermediate-risk disease, much more work remains to be done in several areas: the treatment of high-risk patients, the reduction of therapy-related morbidities that adversely affect quality of life, and the reduction of recurrent disease following definitive therapy. The use of radioimmunoscintigraphy in radiation therapy planning has been shown, through long-term follow-up, to improve bDFS (most significantly in high-risk patients) while minimizing treatment-related morbidity through improved radiation targeting. Additionally, these data suggest that radioimmunoscintigraphy may prove useful in the staging of disease for distant versus localized disease. In our The 5-year biochemical failure-free rates for the high- and conventionaldose groups were 80.4% and 61.4%, respectively (P
.001), representing a 49% reduction in failure risk with high-dose radiotherapy. A similar reduction in risk was observed in both low- and higher-risk patients. satisfactory acute toxicity results in a small patient cohort, using an IMRT to irradiate the entire prostate (75.6 Gy/42 fractions with 10 MV photons) with simultaneous boost (82 Gy) to regions of tumor burden found on SPECT/CT capromab pendetide datasets, for which acute toxicity and cohort, patients positive for extraperiprostatic disease have shown a 3-fold increase in bDFS failure when compared with patients who have only localized or periprostatic (seminal vesicle involvement) uptake on radioimmunoscintigraphy—even when nodal involvement could not be con- firmed through a secondary study, such as biopsy, due to the location of the disease.5 Early identification of these high-risk patients may aid in selection for multimodality treatments, such as brachytherapy plus IMRT or 3-D conformal therapy, as well as long-term hormonal therapy. Our group has also described the translation of the SPECT/CT fusion and BTV dose-escalation protocol from a research center (Case University Hospitals of Cleveland, Cleveland, OH) to a community practice (Aultman Hospital, Canton, OH) in a Society of Nuclear Medicine abstract.29 In this publication, we also demonstrated the ability to use SPECT/CT fused radioimmunoscintigraphy datasets to guide biopsy. A patient with rising PSA level who was followed up for several years and had multiple repeat negative biopsies was referred to us for radiation therapy following a final positive diagnosis after a saturation biopsy procedure (Figure 3). Whereas the patient (age 59, PSA 11 ng/mL, T1cNxMo, II Gleason 6 [3 + 3]) had endured a total of 60 individual core biopsy samples to arrive at a positive diagnosis (right gland: 5 of 8 cores positive), we acquired an additional positive biopsy sample (in a single needle stick) at the time of permanent brachytherapy procedure, using the SPECT/CT image to guide needle placement.29 The use of advanced molecular imaging in radiotherapy improves target volume selection for dose escalation. Identification of focal uptake on hybrid radioimmunoscintigraphy image sets within radiation treatment planning systems allows molecular data to be considered as part of each patient’s unique treatment plan. This can potentially improve bDFS while maintaining quality-of-life parameters following definitive radiation therapy. IGRT represents significant improvements in accuracy in the VOL. 8 SUPPL. 1 2006 REVIEWS IN UROLOGY S17 RIUS0003(Cytogen)_04-12.qxd 12/4/06 13:19 Page S18 Fused Radioimmunoscintigraphy continued delivery of radiation therapy for prostate cancer. The adoption of radioimmunoscintigraphy data into treatment plans for contouring of BTVs for dose-escalation targets incrementally improves our ability to safely deliver higher radiation doses to tumor. New dose-verification and motion-control systems, combined with biological data and molecular imaging, continue to improve radiation control of cancer, perhaps allowing treatment of different stages and types of tumors in the future. References 1. 2. Figure 3. SPECT/CT image fusion for case example presented at the 52nd Annual Meeting of the Society of Nuclear Medicine, Toronto, June 19-22, 2005, demonstrating the ability of SPECT/CT to identify occult tumor foci located in the right anterior base with histopathologic confirmation obtained at the time of image-guided brachytherapy. Schettino CJ, Kramer EL, Noz ME, et al. Impact of fusion of indium-111 capromab pendetide volume data sets with those from MRI or CT in patients with recurrent prostate cancer. AJR Am J Roentgenol. 2004;183:519-524. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys. 1998; 41:491-500. Main Points • Evidence-based data support the clinical role of dose-escalation strategies, in particular, the use of capromab pendetide (ProstaScint) single-photon emission tomography (SPECT) image sets co-registered with computerized tomography (CT) scans or SPECT/CT fusion-identified biological target volumes (BTV) for dose-escalation targeting or image-guided radiation therapy. • High-dose radiotherapy cut the risk of prostate cancer recurrence in a series of patients with localized prostate cancer, randomized to receive a total radiotherapy dose of 70.2 Gy (conventional) or 79.2 Gy (high), with dose boost delivered using protonbeam therapy. • Transperineal ultrasound (TRUS) brachytherapy improves the control and delivery of prescribed doses of radiation and is considered an effective treatment for patients with localized prostate cancer. Radioimmunoscintigraphy image sets co-registered to CT and magnetic resonance imaging have been applied to TRUS-guided treatment planning systems to define BTV, so as to prescribe dose-escalation targeting to discrete areas of tumor foci within the prostate gland. • Recently published long-term outcome data support the shift from dose-planning protocols that used uniform prescription doses to the prostate gland volume, with margin extension and peripheral dose escalation, to planning based on uniform glandular prescription dosing and minimal margin extensions, with dose escalation to BTV defined by focal uptake on fused radioimmunoscintigraphy image sets. • A correlation of areas of increased intraprostatic intensity observed on fused SPECT/CT images with biopsy results, in a small series of patients, found SPECT/CT image correlation with biopsy cores with 80% overall accuracy, 79% sensitivity, 80% specificity, 68% positive predictive value, and 88% negative predictive value. • The advent of the hybrid SPECT/CT systems introduced the ability to remove much of the guesswork in obtaining accurately co-registered images and further assures that the prostate has not moved out of position between diagnostic studies. • The use of dose escalation to discrete tumor targets identified by radioimmunoscintigraphy benefits biochemical disease-free survival and reduces radiotherapy-related morbidity for prostate cancer. S18 VOL. 8 SUPPL. 1 2006 REVIEWS IN UROLOGY RIUS0003(Cytogen)_04-12.qxd 12/4/06 13:19 Page S19 Fused Radioimmunoscintigraphy 3. 4. 5. 6. 7. 8. 9. 10. 11. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:12331239. Ellis RJ, Vertocnik A, Kim EY, et al. Four-year biochemical outcomes after radioimmunoguided transperineal brachytherapy for patients with localized prostate adenocarcinoma. Int J Radiat Oncol Biol Phys. 2003;57:362-370. Ellis RJ, Kim EY, Zhou H, et al. Seven-year biochemical disease-free survival rates following permanent prostate brachytherapy with dose escalation to biological tumor volumes (BTVs) identified with SPECT/CT image fusion [abstract 121]. Brachytherapy. 2005;4(2):107. Pollack A, Zagars GK, Smith LG, et al. 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