Interventional Radiation Oncology (IRO): Transition of a magnetic resonance simulator to a brachytherapy suite.

PURPOSE: As a core component of a new gynecologic cancer radiation program, we envisioned, structured, and implemented a novel Interventional Radiation Oncology (IRO) unit and magnetic resonance (MR)-brachytherapy environment in an existing MR simulator. METHODS AND MATERIALS: We describe the external and internal processes required over a 6-8 month time frame to develop a clinical and research program for gynecologic brachytherapy and to successfully convert an MR simulator into an IRO unit. RESULTS: Support of the institution and department resulted in conversion of an MR simulator to a procedural suite. Development of the MR gynecologic brachytherapy program required novel equipment, staffing, infrastructural development, and cooperative team development with anesthetists, nurses, therapists, physicists, and physicians to ensure a safe and functional environment. Creation of a separate IRO unit permitted a novel billing structure. CONCLUSIONS: The creation of an MR-brachytherapy environment in an MR simulator is feasible. Developing infrastructure includes several collaborative elements. Unique to the field of radiation oncology, formalizing the space as an Interventional Radiation Oncology unit permits a sustainable financial structure.

Postoperative complications following intraoperative radiotherapy in abdominopelvic malignancy: A single institution analysis of 113 consecutive patients.

BACKGROUND: Intraoperative radiotherapy (IORT) has advantages over external beam radiation therapy (EBRT). Few studies have described side effects associated with its addition. We evaluated our institution's experience with abdominopelvic IORT to assess safety by postoperative complication rates. METHODS: Prospectively collected IRB-approved database of all patients receiving abdominopelvic IORT (via high dose rate brachytherapy) at Johns Hopkins Hospital between November 2006 and May 2014 was reviewed. Patients were discussed in multidisciplinary conferences. Those selected for IORT were patients for whom curative intent resection was planned for which IORT could improve margin-negative resection and optimize locoregional control. Perioperative complications were classified via Clavien-Dindo scale for postoperative surgical complications. RESULTS: A total of 113 patients were evaluated. Most common diagnosis was sarcoma (50/113, 44%) followed by colorectal cancer (45/113, 40%), most of which were recurrent (84%). There were no perioperative deaths. A total of 57% of patients experienced a complication Grade II or higher: 24% (27/113) Grade II; 27% (30/113) Grade III; 7% (8/113) Grade IV. Wound complications were most common (38%), then gastrointestinal (25%). No radiotherapy variables were significantly associated with complications on uni/multi-variate analysis. CONCLUSIONS: Our institution's experience with IORT demonstrated historically expected postoperative complication rates. IORT is safe, with acceptable perioperative morbidity.

Alignment of multiradiation isocenters for megavoltage photon beam.

The accurate measurement of the linear accelerator (linac) radiation isocenter is critical, especially for stereotactic treatment. Traditional quality assurance (QA) procedure focuses on the measurement of single radiation isocenter, usually of 6 megavoltage (MV) photon beams. Single radiation isocenter is also commonly assumed in treatment planning systems (TPS). Due to different flattening filters and bending magnet and steering parameters, the radiation isocenter of one energy mode can deviate from another if no special effort was devoted. We present the first experience of the multiradiation isocenters alignment on an Elekta linac, as well as its corresponding QA procedure and clinical impact. An 8 mm ball-bearing (BB) phantom was placed at the 6 MV radiation isocenter using an Elekta isocenter search algorithm, based on portal images. The 3D radiation isocenter shifts of other photon energy modes relative to the 6 MV were determined. Beam profile scanning for different field sizes was used as an independent method to determine the 2D multiradiation isocenters alignment. To quantify the impact of radiation isocenter offset on targeting accuracy, the 10 MV radiation isocenter was manually offset from that for 6 MV by adjusting the bending magnet current. Because our table isocenter was mechanically aligned to the 6 MV radiation isocenter, the deviation of the table isocentric rotation from the "shifted" 10 MV radiation isocenter after bending magnet adjustment was assessed. Winston-Lutz test was also performed to confirm the overall radiation isocenter positioning accuracy for all photon energies. The portal image method showed the radiation isocenter of the 10 MV flattening filter-free mode deviated from others before beam parameter adjustment. After the adjustment, the deviation was greatly improved from 0.96 to 0.35 mm relative to the 6 MV radiation isocenter. The same finding was confirmed by the profile-scanning method. The maximum deviation of the table isocentric rotation from the 10 MV radiation isocenter was observed to linearly increase with the offset between 6 and 10 MV radiation isocenter; 1 mm radiation isocenter offset can translate to almost 2 mm maximum deviation of the table isocentric rotation from the 10 MV radiation isocenter. The alignment of the multiradiation isocenters is particularly important for high-precision radiotherapy. Our study provides the medical physics community with a quantitative measure of the multiradiation isocenters alignment. A routine QA method should be considered, to examine the radiation isocenters alignment during the linac acceptance.

Effects of X-ray radiation on complex visual discrimination learning and social recognition memory in rats.

The present report describes an animal model for examining the effects of radiation on a range of neurocognitive functions in rodents that are similar to a number of basic human cognitive functions. Fourteen male Long-Evans rats were trained to perform an automated intra-dimensional set shifting task that consisted of their learning a basic discrimination between two stimulus shapes followed by more complex discrimination stages (e.g., a discrimination reversal, a compound discrimination, a compound reversal, a new shape discrimination, and an intra-dimensional stimulus discrimination reversal). One group of rats was exposed to head-only X-ray radiation (2.3 Gy at a dose rate of 1.9 Gy/min), while a second group received a sham-radiation exposure using the same anesthesia protocol. The irradiated group responded less, had elevated numbers of omitted trials, increased errors, and greater response latencies compared to the sham-irradiated control group. Additionally, social odor recognition memory was tested after radiation exposure by assessing the degree to which rats explored wooden beads impregnated with either their own odors or with the odors of novel, unfamiliar rats; however, no significant effects of radiation on social odor recognition memory were observed. These data suggest that rodent tasks assessing higher-level human cognitive domains are useful in examining the effects of radiation on the CNS, and may be applicable in approximating CNS risks from radiation exposure in clinical populations receiving whole brain irradiation.

High-dose-rate intraoperative radiation therapy: the nuts and bolts of starting a program.

High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed.

Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells.

Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the "non-oncogene" addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded "client" proteins, that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K-Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γ-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4-1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G 2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies.

Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer.

Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)) versus high-dose-rate endorectal brachytherapy (EBT). Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5-fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P < 0.001). There was a trend towards higher rate of pathologic CR for EBT (P = 0.06). Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P = 0.025). Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes.

Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma.

UNLABELLED: (153)Sm-ethylenediamine tetramethylene phosphonic acid ((153)Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of (153)Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radiobiologic modeling and examined the relationship between tumor AD and response. METHODS: Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of (153)Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of (153)Sm-EDTMP (37.0-51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after (153)Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates. RESULTS: On average, a 5-fold increase in the AA led to a 4-fold increase in the mean tumor AD over the high- versus low-dose-treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low-dose therapy were 1.48-14.6 and 0.98-3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93-59.3 and 1.89-12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively). CONCLUSION: The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low- and high-dose therapy, respectively. A dose-response relationship was observed for transient tumor volume shrinkage.

Robotic needle guide for prostate brachytherapy: clinical testing of feasibility and performance.

PURPOSE: Optimization of prostate brachytherapy is constrained by tissue deflection of needles and fixed spacing of template holes. We developed and clinically tested a robotic guide toward the goal of allowing greater freedom of needle placement. METHODS AND MATERIALS: The robot consists of a small tubular needle guide attached to a robotically controlled arm. The apparatus is mounted and calibrated to operate in the same coordinate frame as a standard template. Translation in x and y directions over the perineum ±40 mm are possible. Needle insertion is performed manually. RESULTS: Five patients were treated in an institutional review board-approved study. Confirmatory measurements of robotic movements for initial 3 patients using infrared tracking showed mean error of 0.489 mm (standard deviation, 0.328 mm). Fine adjustments in needle positioning were possible when tissue deflection was encountered; adjustments were performed in 54 (30.2%) of 179 needles placed, with 36 (20.1%) of 179 adjustments of >2mm. Twenty-seven insertions were intentionally altered to positions between the standard template grid to improve the dosimetric plan or avoid structures such as pubic bone and blood vessels. CONCLUSIONS: Robotic needle positioning provided a means of compensating for needle deflections and the ability to intentionally place needles into areas between the standard template holes. To our knowledge, these results represent the first clinical testing of such a system. Future work will be incorporation of direct control of the robot by the physician, adding software algorithms to help avoid robot collisions with the ultrasound, and testing the angulation capability in the clinical setting.

Dynamic intraoperative dosimetry for prostate brachytherapy using a nonisocentric C-arm.

PURPOSE: To evaluate a prototypical system of dynamic intraoperative dosimetry for prostate brachytherapy using registered ultrasound and fluoroscopy (RUF) with a nonisocentric C-arm (GE OEC, Salt Lake City, UT) and to compare intraoperative dosimetry of RUF as well as ultrasound-based seed localization (USD) with Day 0 CT dosimetry. METHODS: Seed positions were independently determined using RUF and USD. RUF uses a radio-opaque fiducial for registration to ultrasound and 3-dimensional reconstruction of seeds relative to prostate using nonisocentric C-arm fluoroscopy. Postimplant CT was performed on Day 0. Squared differences between dosimetric measures for RUF vs. CT and USD vs. CT were calculated and mean squared differences evaluated. Paired t test was used to evaluate which method was more closely aligned with CT. Accuracies of USD and RUF compared with CT were estimated using a nonparametric approach. RESULTS: Six patients were treated and compared with USD. RUF identified areas of underdosage intraoperatively in all patients and median 5 additional seeds were placed. In 40 of 42 measures, RUF was equally or more closely correlated with CT than USD. USD showed statistically significant variation from CT for 6 of 7 parameters compared with 1 of 7 parameters for RUF. Mean squared differences from CT were significantly smaller for RUF in 4 of 7 parameters compared with USD. CONCLUSIONS: Dynamic intraoperative dosimetry is possible with a conventional nonisocentric C-arm. Compared with an USD method, RUF-based intraoperative dosimetry was more closely aligned with immediate postimplant CT. RUF identified areas of underdosage, which were not detected using USD.

A novel process for introducing a new intraoperative program: a multidisciplinary paradigm for mitigating hazards and improving patient safety.

BACKGROUND: Since the Institute of Medicine's report, To Err is Human, was published, numerous interventions have been designed and implemented to correct the defects that lead to medical errors and adverse events; however, most efforts were largely reactive. Safety, communication, team performance, and efficiency are areas of care that attract a great deal of attention, especially regarding the introduction of new technologies, techniques, and procedures. We describe a multidisciplinary process that was implemented at our hospital to identify and mitigate hazards before the introduction of a new technique: high-dose-rate intraoperative radiation therapy, (HDR-IORT). METHODS: A multidisciplinary team of surgeons, anesthesiologists, radiation oncologists, physicists, nurses, hospital risk managers, and equipment specialists used a structured process that included in situ clinical simulation to uncover concerns among care providers and to prospectively identify and mitigate defects for patients who would undergo surgery using the HDR-IORT technique. RESULTS: We identified and corrected 20 defects in the simulated patient care process before application to actual patients. Subsequently, eight patients underwent surgery using the HDR-IORT technique with no recurrence of simulation-identified or unanticipated defects. CONCLUSION: Multiple benefits were derived from the use of this systematic process to introduce the HDR-IORT technique; namely, the safety and efficiency of care for this select patient population was optimized, and this process mitigated harmful or adverse events before the inclusion of actual patients. Further work is needed, but the process outlined in this paper can be universally applied to the introduction of any new technologies, treatments, or procedures.

High-resolution, small animal radiation research platform with x-ray tomographic guidance capabilities.

PURPOSE: To demonstrate the computed tomography, conformal irradiation, and treatment planning capabilities of a small animal radiation research platform (SARRP). METHODS AND MATERIALS: The SARRP uses a dual-focal spot, constant voltage X-ray source mounted on a gantry with a source-to-isocenter distance of 35 cm. Gantry rotation is limited to 120 degrees from vertical. X-rays of 80-100 kVp from the smaller 0.4-mm focal spot are used for imaging. Both 0.4-mm and 3.0-mm focal spots operate at 225 kVp for irradiation. Robotic translate/rotate stages are used to position the animal. Cone-beam computed tomography is achieved by rotating the horizontal animal between the stationary X-ray source and a flat-panel detector. The radiation beams range from 0.5 mm in diameter to 60 x 60 mm(2). Dosimetry is measured with radiochromic films. Monte Carlo dose calculations are used for treatment planning. The combination of gantry and robotic stage motions facilitate conformal irradiation. RESULTS: The SARRP spans 3 ft x 4 ft x 6 ft (width x length x height). Depending on the filtration, the isocenter dose outputs at a 1-cm depth in water were 22-375 cGy/min from the smallest to the largest radiation fields. The 20-80% dose falloff spanned 0.16 mm. Cone-beam computed tomography with 0.6 x 0.6 x 0.6 mm(3) voxel resolution was acquired with a dose of <1 cGy. Treatment planning was performed at submillimeter resolution. CONCLUSION: The capability of the SARRP to deliver highly focal beams to multiple animal model systems provides new research opportunities that more realistically bridge laboratory research and clinical translation.

The small-animal radiation research platform (SARRP): dosimetry of a focused lens system.

A small animal radiation platform equipped with on-board cone-beam CT and conformal irradiation capabilities is being constructed for translational research. To achieve highly localized dose delivery, an x-ray lens is used to focus the broad beam from a 225 kVp x-ray tube down to a beam with a full width half maximum (FWHM) of approximately 1.5 mm in the energy range 40-80 keV. Here, we report on the dosimetric characteristics of the focused beam from the x-ray lens subsystem for high-resolution dose delivery. Using the metric of the average dose within a 1.5 mm diameter area, the dose rates at a source-to-surface distance (SSD) of 34 cm are 259 and 172 cGy min(-1) at 6 mm and 2 cm depths, respectively, with an estimated uncertainty of +/-5%. The per cent depth dose is approximately 56% at 2 cm depth for a beam at 34 cm SSD.

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein.

Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists ("XAntag"; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC(50) in the range of 2 to 5 mumol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream "effector" caspases (caspase-3 and caspase-7) versus the upstream "initiator" caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation.

The heat shock response: role in radiation biology and cancer therapy.

Since prehistoric times, elevated temperatures have been used to treat cancer in a variety of forms. In modern times (the last 40 years) efforts have concentrated on combining heat with other anti-tumour modalities, principally ionizing radiation and some chemotherapeutic drugs. Despite the emphasis on combined therapy, rodent data relating to heat sensitivity and thermal tolerance development assumed principal importance. These considerations suggested treating at 43 degrees C as a target temperature and fractionation schemes emphasizing thermal tolerance avoidance. Concomitantly crucial data on heat-induced tumour reoxygenation and its temperature dependence were largely ignored. In reality these were unrealistic and undesirable goals. The preponderance of evidence now suggests that lower temperatures (40-42 degrees C) administered more frequently, optimally immediately before and during each administration of ionizing radiation, are likely to yield optimal results. Factoring in trimodality therapy and other combinations of chemotherapeutic drugs will require some modifications of such fractionation schemes.

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

PURPOSE: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. METHODS AND MATERIALS: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. RESULTS: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. CONCLUSION: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue.

PURPOSE: A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low alpha/beta ratio), more typical of the surrounding late-responding normal tissue. METHODS AND MATERIALS: Earlier estimates of alpha/beta for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age. RESULTS: The estimated value of alpha/beta from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This alpha/beta value is considerably less than typical values for tumors (> or =8 Gy), and more comparable to values in surrounding late-responding normal tissues. CONCLUSIONS: This analysis provides strong supporting evidence that alpha/beta values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.