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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.

Endoluminal brachytherapy (EBT) has been shown to be an effective neoadjuvant monotherapy for rectal adenocarcinoma. Radiographic predictors of response are used to guide treatment in rectal cancer; however, no predictors of response to EBT have been identified. This is a single-institutional prospective study from 2010 to 2013. Analysis included 17 patients undergoing EBT and 13 patients undergoing conventional external beam chemoradiation (CRT). Clinical response to therapy was assessed with serial MRI and PET/CT variables. Pathological response to therapy was assessed using tumor regression grade (TRG) and compared with clinical response. EBT and CRT patients did not differ with respect to age, sex, race, carcinoembryonic antigen, or clinical stage of disease. There was a similar rate of pathologic complete response for both groups, with a trend towards more TRG 0 with EBT compared with CRT (35.3% vs. 7.7%, p = 0.08). Four days of EBT resulted in a significantly greater reduction in tumor volume on MRI than did CRT (92.7% vs. 63.1%, p = 0.004). Using receiver operating characteristic analysis, change in peak standardized uptake value was the best predictor for complete pathologic response in EBT patients (sensitivity 67%, specificity 82%). False-positive findings for nodal disease on MRI were seen in 59% of EBT patients and 23% of CRT patients. This study demonstrates that EBT is an effective alternative with similar response rates to CRT. However, the inability of MRI and PET/CT to discern reactive from malignant tumor and nodes may pose limitations in their use for guiding further therapy. Larger randomized studies are needed.

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. PACS number: 87.55.Qr, 87.56.bd, 87.56.Fc

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.

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 G2-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.

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.

153Sm-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of 153Sm-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 153Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of 153Sm-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 153Sm-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.

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 coor- dinate 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. Confirma- tory 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 ofO2 mm. 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 algo- rithms to help avoid robot collisions with the ultrasound, and testing the angulation capability in the clinical setting. 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

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).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.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.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.

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.

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°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°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 combinatio...

Combining long duration mild temperature hyperthermia (LDMH) and low dose-rate (LDR) brachytherapy to enhance therapeutic killing of cancer cells was proposed many years ago. The cellular and tumour research that supports this hypothesis is presented in this review. Research describing LDMH interaction with pulsed brachytherapy and high dose-rate brachytherapy using clinically relevant parameters are compared with LDMH/LDR brachytherapy. The mechanism by which LDMH sensitizes LDR has been established as the inhibition of sublethal damage repair. The molecular mechanisms have been shown to involve DNA repair enzymes, but the exact nature of these processes is still under investigation. The relative differences between LDMH interactions with human and rodent cells are presented to help in the understanding of possible roles of LDMH in clinical application. The role of LDMH in modifying tumour blood flow and its possible role in LDR sensitization of tumours is also presented. The positive aspects of LDMH-brachytherapy for clinical application are sixfold; (1) the thermal goals (temperature, time and volume) are achievable with currently available technology, (2) the hyperthermia by itself has no detectable toxic effects, (3) thermotolerance appears to play a minor if any role in radiation sensitization, (4) TER of around 2 can be expected, (5) hypoxic fraction may be decreased due to blood flow modification and (6) simultaneous chemotherapy may also be sensitized. Combined LDMH and brachytherapy is a cancer therapy that has established biological rationale and sufficient technical and clinical advancements to be appropriately applied. This modality is ripe for clinical testing.

Purpose : A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low α/β ratio), more typical of the surrounding late-responding normal tissue. Methods and Materials : Earlier estimates of α/β 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 α/β 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 α/β value is considerably less than typical values for tumors (≥8 Gy), and more comparable to values in surrounding late-responding normal tissues. Conclusions : This analysis provides strong supporting evidence that α/β 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.

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.

Colorectal cancer is the third most common malignancy and the third leading cause of cancer-related death in the United States, with more than 40,000 rectal cancer cases diagnosed each year.1 Standard treatment for localized (ie, resectable) rectal cancer includes 5-fluorouracil (5-FU)-based chemoradiation therapy followed by surgery. Improved radiation technology including image-guided radiation therapy (RT) and brachytherapy (contact therapy) can allow for the delivery of higher doses of RT to the rectal tumor over a shorter time period. These treatments may result in improved outcomes; however, they require fiducial markers to allow better localization and targeting of the rectal tumor. In this retrospective study, we evaluated the role of gold fiducial markers in patients receiving neoadjuvant endorectal brachytherapy in patients with localized rectal tumors.

Materials/Methods Five patients were treated for localized rectal cancer using 192Ir HDR brachytherapy in conjunction with surgery. FDG-PET images were acquired before HDR therapy and 6–8 weeks after treatment (prior to surgery). Treatment planning was done on a commercial workstation and the dose grid was calculated. The two PETs and the treatment dose grid were registered to each other. The difference in PET SUV values before and after HDR was plotted versus absorbed radiation dose for each voxel. The voxels were then separated into bins for every 400 cGy of absorbed dose and the bin average values plotted similarly. Back to Article Outline

Purpose: Data were analyzed from recent experiments with the end point of late rectal obstruction in rats, involving acute and various protracted radiation exposures. Because the end point is of direct relevance both for brachytherapy as well as external beam radiotherapy, the goal was to estimate the linear-quadratic (LQ) parameters α/β and T 1/2 , which are of importance for designing improved protraction/fractionation schemes. Methods and Materials: The data were fit to the LQ model, both in its standard form and in a form in which two different components of sublethal damage repair—fast and slow—are assumed. The design of the experiments was such that both slow and reasonably fast sublethal damage repair components should be separately estimated, if they were contributing to a significant degree. Results: LQ parameter estimates were α/β = 4.6 Gy [4.0, 5.5] and T 1/2 = 70.2 min [59.1, 91.4]. Despite the experimental design facilitating detection of a rapid component of repair, no statistically robust evidence for a very fast repair component was found. Conclusions: The long estimated repair time for a late-responding normal-tissue end point with direct relevance to brachytherapy suggests a variety of possible brachytherapy protocols that may be more efficacious than continuous low dose rate irradiation. Just as a difference in α/β ratios between early- and late-responding tissues are a central tenet in radiotherapy, so corresponding differences in T 1/2 values have the potential to be exploited, particularly for brachytherapy.

We have developed a novel system for examining the possible contribution of small heat shock proteins (hsp) to tumor growth. L929 fibrosarcoma cells, which do not express significant levels of endogenous hsp25, were stably transfected with either murine hsp25 or human hsp27. Both transfected genes were over-expressed and the respective proteins were phosphorylated in L929 cells. L929 cells transfected with hsp25 exhibited enhanced tumor growth compared to control transfected L929 cells upon s.c. injection into nude mice. In contrast, cells transfected with hsp27 exhibited delayed tumor progression in comparison to controls. Although these 2 heat shock genes and respective proteins are structurally very similar, they apparently exhibit distinct effects on tumor growth in this system.

Low-dose-rate prostate brachytherapy is a treatment option for low- and mid-risk prostate cancer through introduction of radioactive seeds into the prostate. Seed placement deviations are common and associated with postoperative complications. Dynamic dosimetry is a method to accurately localize the true position of the seeds inside the tissue, calculate the delivered dose, and adapt the implant plan accordingly to compensate for seed placement deviations in the operating room. A practical method for dynamic dosimetry relies on localization of the implanted seeds in 3D space from several C-arm images and registering them to a 3D ultrasound volume of the prostate region. In this chapter we introduce a system and workflow for intraoperative dosimetry for prostate brachytherapy. In the suggested workflow, C-arm images are acquired from different angles and are used to reconstruct the seeds in 3D space. For this purpose, we rely on a method based on dimensionality reduced linear programming to match the projections of a seed in different images and localize the seed positions after automatic C-arm pose correction. In the next step of the workflow, the reconstructed seeds are registered to an ultrasound volume of the prostate in a point-to-volume registration scheme. We tested our method on data from 16 patients and compared our dosimetry results with results from Day-1 CT. In comparison, we achieved absolute error of 2.2 ± 1.8 % (mean ± STD) in estimating the percentage of the prostate volume that receives 100 % of the prescribed dose (V100) and absolute error of 10.5 ± 9.5 % in prediction of the minimum dose delivered to 90 % of the prostate (D90).

Background. Several recent studies have suggested radiosensitizing effects of paclitaxel, a microtubular inhibitor. To test the universality of this finding, the interaction between paclitaxel and radiation treatment of cell lines derived from three common human carcinomas MCF-7 (breast cancer) ; DUT-145 (prostate cancer) ; and HT-29 (colon cancer) was evaluated. The study focused on the ability of paclitaxel to block cells at the G2-M phase of the cell cycle and potentially enhance the radiation sensitivity of the cells. Methods. All cell lines were exposed to three different clinically achievable paclitaxel concentrations ranging from 2 nM to 25 nM. Paclitaxel pretreatment for 12 and 24 hours before radiation was tested in all three cell lines. The radiation dose ranged from 0 to 8 Gy delivered in a single fraction. Cellular survival after treatment with paclitaxel and/or radiation was determined by clonogenic assay. Cell cycle distribution as determined by flow cytometry was performed after various dose-time combinations of paclitaxel. Results. Cytotoxicity studies with paclitaxel alone demonstrated a time-dependent and dose-dependent survival relationship for all three cell lines. Resultant surviving fractions were in the range of 5 to 90% after 24-hour exposure to paclitaxel alone. The interaction between paclitaxel and radiation was primarily additive in each of the three cell lines for all paclitaxel dose-time combinations studied. Flow cytometric analysis failed to reveal a prominent G2-M block in all three cell lines after paclitaxel treatment for 24 hours. Conclusions. Paclitaxel lacked a radiosensitizing effect on MCF-7, DUT-145, and HT-29 cells in this study. These results should be considered when designing clinical trials that use paclitaxel as a potential radiosensitizer of certain human carcinomas. Cancer 1995 ; 75 :2262-8.

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.

1. 1.|We investigated the relationship between heat-induced perturbation of cell cycle progression and cytotoxicity at low temperature hyperthermia in three human cell lines human breast carcinoma cells (MCF-7) and human prostatic adenocarcinoma cells (DUT-145 and PC-3). 2. 2.|MCF-7 cells which were resistant to mild hyperthermia exhibited a G 1 block during heating at 41°C. In contrast, DUT-145 and PC-3 cells which were sensitive to mild hyperthermia failed to accumulate in G 1 -phase. Both DUT-145 and PC-3 cells progressed through S-phase and accumulated in the G 2 /M-phase. These results rule out any species-based generalization for heat sensitivity. 3. 3.|Electron micrographs and gel electrophoresis data show the accumulation of mitotic-like cells and DNA fragmentation during mild hyperthermia in prostatic carcinoma cells. 4. 4.|These results suggest that cell death is associated, at least partly with DNA fragmentation, perhaps apoptosis in prostatic carcinoma cells.

Clinical application of long duration hyperthermia at temperatures42 degrees C has traditionally been avoided because of the possibility of chronic thermotolerance development, such as is observed with rodent cells. In support of long duration hyperthermia, both rodent and human cells have been shown to be sensitized to low dose-rate irradiation by simultaneous heating at 40 or 41 degrees C. The relationship between these supposed contradictory responses to hyperthermia were investigated in rat 9L gliosarcoma cells in vitro. Thermotolerance developed during 41 degrees C heating with or without concurrent low dose-rate irradiation. Thermotolerance reached a maximum within 6 h during 41 degrees C heating and remained stable for at least 24 h. When cells were returned to 37 degrees C after heating at 41 degrees C for 6 h, thermotolerance remained stable for at least 12 h. The time course of thermotolerance development correlated with that of induction of 41 degrees C radiation sensitization. Radiation sensitization, on the other hand, was shown to be independent of thermotolerance because the protein synthesis inhibitor cycloheximide prevented thermotolerance induction but had no effect on radiation sensitization. We conclude that thermotolerance development during concurrent clinical application of long duration mild temperature hyperthermia and low dose-rate irradiation should not be a factor in altering treatment outcome.

Purpose: Preferential amplification of low dose-rate irradiation toxicity in tumor cells is one way of improving presently applied brachytherapy. Low temperature hyperthermia applied to a tumor volume during irradiation is one candidate for reaching this goal. The ranges of relevant temperatures and dose-rate have been determined in a tissue culture system. In addition, the role of inhibition of sublethal damage repair in inhibition of dose-rate sparing has been investigated. Methods and Materials: Dose-rate modification by long duration, mild hyperthermia was investigated in rat 9L gliosarcoma cells at dose-rates between 0.0833 and 132 Gy/hr. Enhancement of toxicity was measured using the colony formation technique. Results: A biphasic dose-rate effect curve was observed when cells were irradiated at 37C. The dose required to kill 99% of cells irradiated at 37°C increased sharply between 20 and 5 Gy/hr and also below 1 Gy/hr. When cells were irradiated at 41°C, dose-rate sparing disappeared from 132 to 0.0833 Gy/hr. Elimination of dose-rate sparing appeared to be caused by both inhibition of sublethal damage repair and blockage of cell proliferation. The temperature threshold for sensitizing low dose-rate irradiation was determined attemperatures between 24°C and 41°C during 0.5 Gy/hr irradiation. Temperature dependent sensitization occurred above 39°C. The mechanisms by which low temperature hyperthermia sensitizes low dose-rate irradiation was investigated using split dose experiments. Survival curve shoulder recovery was inhibited when cells were incubated at 41°C between acute irradiations. This effect appeared to be caused by both inhibition of recovery from sublethal damage from the first radiation and preheating sensitization of the second irradiation. In single acute dose experiments, sensitization from preheating at 41°C increased gradually over a 6 hr period. Conclusions: The mechanism by which 41°C hyperthermia sensitizes low dose-rate irradiation is inhibition of radiation repair at medium dose rates and inhibition of repair and proliferation at very low dose rates. If low temperature hyperthermia is able to sensitize human tumor cells to brachytherapy similar to what has been described with 9L gliosarcoma cells, the addition of this modality could potentially greatly improve presently applied therapy.

The development of a brachytherapy technique that will use a scanning source to simulate continuous low dose rate irradiation holds the possibility of improving dose distributions and other clinically relevant factors as well as enhancing radiation safety. Rat 9L gliosarcoma cells growing in vitro have been used as a model to determine the role of fraction size when individual pulses of irradiation are given at appropriate intervals to result in an overall dose rate that is identical to currently applied continuous low dose rate irradiation. With an overall dose rate of 0.5 Gy/hr, cell killing was identical for fractionation schemes of 0.25 Gy every 0.5 hr, 1.00 Gy every 2.0 hr, and 3.00 Gy every 6.0 hr. The cell sensitivity of these schemes was also identical to continuous irradiation at the same overall dose rate. Increasing the fraction size to 6.0 Gy with intervals of 12 hr increased the cytotoxicity. This breaking point was above the D q (3.9 Gy) of acutely irradiated 9L cells. These data support the hypothesis that continuous low dose rate irradiation can be simulated by fractionated high dose rate irradiation as long as the fraction size remains less than the D q of the acute radiation response of the cells and the overall dose rate remains constant. The role of simultaneous heating at 41°C during pulsed and continuous low dose rate irradiation was also investigated. Substantial sensitization was observed for both continuous low dose rate irradiation and pulse simulated low dose rate irradiation. The D o thermal enhancement ratios were 1.98 and 1.92, respectively. The above results demonstrate that modalities utilizing intermittent high dose rate irradiation can be designed such that they will be equivalent to continuous low dose rate irradiation, and that in either case simultaneous extended low temperature heating can greatly enhance the cytotoxic effects of these irradiations.

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.

Brachytherapy (radioactive seed insertion) has emerged as one of the most effective treatment options for patients with prostate cancer, with the added benefit of a convenient outpatient procedure. The main limitation in contemporary brachytherapy is faulty seed placement, predominantly due to the presence of intra-operative edema (tissue expansion). Though currently not available, the capability to intra-operatively monitor the seed distribution, can make a significant improvement in cancer control. We present such a system here.Intra-operative measurement of edema in prostate brachytherapy requires localization of inserted radioactive seeds relative to the prostate. Seeds were reconstructed using a typical non-isocentric C-arm, and exported to a commercial brachytherapy treatment planning system. Technical obstacles for 3D reconstruction on a non-isocentric C-arm include pose-dependent C-arm calibration; distortion correction; pose estimation of C-arm images; seed reconstruction; and C-arm to TRUS registration.In precision-machined hard phantoms with 40-100 seeds and soft tissue phantoms with 45-87 seeds, we correctly reconstructed the seed implant shape with an average 3D precision of 0.35 mm and 0.24 mm, respectively. In a DoD Phase-1 clinical trial on six patients with 48-82 planned seeds, we achieved intra-operative monitoring of seed distribution and dosimetry, correcting for dose inhomogeneities by inserting an average of over four additional seeds in the six enrolled patients (minimum 1; maximum 9). Additionally, in each patient, the system automatically detected intra-operative seed migration induced due to edema (mean 3.84 mm, STD 2.13 mm, Max 16.19 mm).The proposed system is the first of a kind that makes intra-operative detection of edema (and subsequent re-optimization) possible on any typical non-isocentric C-arm, at negligible additional cost to the existing clinical installation. It achieves a significantly more homogeneous seed distribution, and has the potential to affect a paradigm shift in clinical practice. Large scale studies and commercialization are currently underway.

To demonstrate the computed tomography, conformal irradiation, and treatment planning capabilities of a small animal radiation research platform (SARRP).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.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 of1 cGy. Treatment planning was performed at submillimeter resolution.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.

Purpose: Brachytherapy (radioactive seed insertion) has emerged as one of the most effective treatment options for patients with prostate cancer, with the added benefit of a convenient outpatient procedure. The main limitation in contemporary brachytherapy is faulty seed placement, predominantly due to the presence of intra-operative edema (tissue expansion). Though currently not available, the capability to intra-operatively monitor the seed distribution, can make a significant improvement in cancer control. We present such a system here. Methods: Intra-operative measurement of edema in prostate brachytherapy requires localization of inserted radioactive seeds relative to the prostate. Seeds were reconstructed using a typical non-isocentric C-arm, and exported to a commercial brachytherapy delivery system. Technical obstacles for 3D reconstruction on a non-isocentric C-arm include pose-dependent C-arm calibration; distortion correction; pose estimation of C-arm images; seed reconstruction; and C-arm to TRUS registration. Results: In precision-machined hard phantoms with 40-100 seeds and soft tissue phantoms with 45-87 seeds, we correctly reconstructed the seed implant shape with an average 3D precision of 0.35 mm and 0.24 mm, respectively. In a DoD Phase-1 clinical trial on 6 patients with 48-82 planned seeds, we achieved intra-operative monitoring of seed distribution and dosimetry, correcting for dose inhomogeneities by inserting an average of 4.17 (1-9) additional seeds. Additionally, in each patient, the system automatically detected intra-operative seed migration induced due to edema (mean 3.84 mm, STD 2.13 mm, Max 16.19 mm). Conclusions: The proposed system is the first of a kind that makes intra-operative detection of edema (and subsequent re-optimization) possible on any typical non-isocentric C-arm, at negligible additional cost to the existing clinical installation. It achieves a significantly more homogeneous seed distribution, and has the potential to affect a paradigm shift in clinical practice. Large scale studies and commercialization are currently underway.

To investigate the possibility that heat-induced protein degradation may play a role in heat killing of mammalian cells, we have compared cellular survival and protein degradation rates for cells treated with cycloheximide, puromycin, or histidinol. These three compounds all inhibit protein synthesis and protect against the lethal effects of heat shock. When cells were treated with histidinol for 2 h before heating, as well as during heating at 43 degrees C for 3 h, they became resistant to heat killing. Histidinol treatment (5 mM) induced a 10,000-fold increase in surviving fraction from 10(-5) to 10(-1), and the protective effect was similar to that of 0.1 mM cycloheximide or 0.2 mM puromycin. Despite the similarity in heat protection for the three compounds, the protein degradation rate of 1.8%/h at 37 degrees C was increased by 34% by histidinol and decreased 20% by cycloheximide or puromycin. At 43 degrees C none of these compounds had a significant effect on the protein degradation rate. Therefore the intracellular degradation of relatively long-lived proteins does not appear to play a significant role in either heat killing or the phenomenon of heat protection. Instead, since maximum protection from heat killing was observed for all three compounds when protein synthesis was inhibited by 90-95%, heat protection probably results from an event(s) that is caused by inhibition of protein synthesis.

Intra-operative guidance in Transrectal Ultrasound (TRUS) guided prostate brachytherapy requires localization of inserted radioactive seeds relative to the prostate. Seeds were reconstructed using a typical C-arm, and exported to a commercial brachytherapy system for dosimetry analysis. Technical obstacles for 3D reconstruction on a non-isocentric C-arm included pose-dependent C-arm calibration; distortion correction; pose estimation of C-arm images; seed reconstruction; and C-arm to TRUS registration. In precision-machined hard phantoms with 40-100 seeds, we correctly reconstructed 99.8% seeds with a mean 3D accuracy of 0.68 mm. In soft tissue phantoms with 45-87 seeds and clinically realistic 15° C-arm motion, we correctly reconstructed 100% seeds with an accuracy of 1.3 mm. The reconstructed 3D seed positions were then registered to the prostate segmented from TRUS. In a Phase-1 clinical trial, so far on 4 patients with 66-84 seeds, we achieved intraoperative monitoring of seed distribution and dosimetry. We optimized the 100% prescribed iso-dose contour by inserting an average of 3.75 additional seeds, making intra-operative dosimetry possible on a typical C-arm, at negligible additional cost to the existing clinical installation.

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 IC50 in the range of 2 to 5 μmol/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. [Mol Cancer Ther 2007;6(3):957–66]

Purpose Ultrasound tracking of target motion relies on visibility of vascular and/or anatomical landmark. However this is challenging when the target is located far from vascular structures or in organs that lack ultrasound landmark structure, such as in the case of pancreas cancer. The purpose of this study is to evaluate visibility, artifacts and distortions of fusion coils and solid gold markers in ultrasound, CT, CBCT and kV images to identify markers suitable for real-time ultrasound tracking of tumor motion in SBRT pancreas treatment. Methods Two fusion coils (1mm × 5mm and 1mm × 10 mm) and a solid gold marker (0.8mm × 10mm) were embedded in a tissue–like ultrasound phantom. The phantom (5cm × 12cm × 20cm) was prepared using water, gelatin and psyllium-hydrophilic-mucilloid fiber. Psylliumhydrophilic mucilloid acts as scattering medium to produce echo texture that simulates sonographic appearance of human tissue in ultrasound images while maintaining electron density close to that of water in CT images. Ultrasound images were acquired using 3D-ultrasound system with markers embedded at 5, 10 and 15mm depth from phantom surface. CT images were acquired using Philips Big Bore CT while CBCT and kV images were acquired with XVI-system (Elexta). Visual analysis was performedmore » to compare visibility of the markers and visibility score (1 to 3) were assigned. Results All markers embedded at various depths are clearly visible (score of 3) in ultrasound images. Good visibility of all markers is observed in CT, CBCT and kV images. The degree of artifact produced by the markers in CT and CBCT images are indistinguishable. No distortion is observed in images from any modalities. Conclusion All markers are visible in images across all modalities in this homogenous tissue-like phantom. Human subject data is necessary to confirm the marker type suitable for real-time ultrasound tracking of tumor motion in SBRT pancreas treatment.« less

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 >10.0 ng/mL, Gleason score >7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-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

Purpose: Immobilization devices combine rigid patient fixation as well as comfort and play a key role providing the stability required for accurate radiation delivery. In the setup step, couch re-positioning needed to align the patient is derived via registration of acquired versus reference image. For subsequent fractions, replicating the initial setup should yield identical alignment errors when compared to the reference. This is not always the case and further couch re-positioning can be needed. An important quality assurance measure is to set couch tolerances beyond which additional investigations are needed. The purpose of this work was to study the inter-fraction couch changes needed to re-align the patient and the intra-fraction stability of the alignment as a guide to establish the couch tolerances. Methods: Data from twelve patients treated on the Accuray CyberKnife (CK) system for fractionated intracranial radiotherapy and immobilized with Aquaplast RT, U-frame, F-Head-Support (Qfix, PA, USA) was used. Each fraction involved image acquisitions and registration with the reference to re-align the patient. The absolute couch position corresponding to the approved setup alignment was recorded per fraction. Intra-fraction set-up corrections were recorded throughout the treatment. Results: The average approved setup alignment was 0.03±0.28mm, 0.15±0.22mm, 0.06±0.31mm in the L/R, A/P, S/I directions respectively and 0.00±0.35degrees, 0.03±0.32degrees, 0.08±0.45degrees for roll, pitch and yaw respectively. The inter-fraction reproducibility of the couch position was 6.65mm, 10.55mm, and 4.77mm in the L/R, A/P and S/I directions respectively and 0.82degrees, 0.71degrees for roll and pitch respectively. Intra-fraction monitoring showed small average errors of 0.21±0.21mm, 0.00±0.08mm, 0.23±0.22mm in the L/R, A/P, S/I directions respectively and 0.03±0.12degrees, 0.04±0.25degrees, and 0.13±0.15degrees in the roll, pitch and yaw respectively. Conclusion: The inter-fraction reproducibility should serve as a guide to couch tolerances, specific to a site and immobilization. More patients need to be included to make general conclusions.

655 Background: Rectal cancer affects over 40,000 patients in the US per year. The current standard of care for patients with localized rectal cancer is neoadjuvant radiation therapy with concurrent chemotherapy (NCRT) followed by surgery; however, it has shown no proven survival benefit for locally advanced rectal cancer patients. Preliminary results show that a short course of radiation therapy, using high-dose rate endorectal brachytherapy (Endo-HDR), may be as effective with less toxicity and delay to time of surgery. This requires the placement of fiducial markers, using an endoscopic ultrasound guided method (EUS), into the tumor for accurate source placement and treatment. Our aim is to compare three different types of fiducials in terms of visibility and migration. Methods: 12 patients with locally advanced rectal cancer that received Endo-HDR and EUS guided fiducial placement were retrospectively evaluated at JHH. Results: 12 patients underwent EUS guided placement of 42 fiducials. For 11 of our 12 patients, the mean number of fiducials placed per patient was 3.63 (SD 1.03) using a 19-gauge needle. One patient received 2 fiducials using a 22- gauge needle. Of the 12 patients that received fiducials, 3 received traditional fiducials (TF), 8 received segmented fiducials (SF) and 1 received foldable fiducials. All fiducials were clearly visible. The mean number of fiducials that detached from implanted site before surgery for patients with TFs was 0.667, and for patients with SFs was 0.875 (p=0.744). The median migration distance, as measured by interfiduciary distance, for segmented fiducials was significantly larger when compared to traditional fiducials (0.45 cm for SF compared to 0.1 cm for TF; p=0.049) Conclusions: SFs appear to be less stable, with regards to migration, in the rectum when compared to traditional fiducials in our patient population. These differences could be due to placement difficulty or operator dependent differences. Improvement in fiducial structure is required in order to help decrease migration and detachment and maximize visualization, which will lead to more accurate administration of Endo-HDR.

Traditional therapies for advanced prostate cancer are unable to cure a majority of patients. An approach to therapy we have tested involves production of nitric oxide (NO) by introduction of replication defective adenovirus containing the DNA sequences for inducible nitric oxide synthase (iNOS). An adenovirus vector with an iNOS cDNA and a CMV promoter (Ad5-CMV-iNOS) was constructed and tested. The production of nitric oxide in prostate cancer cells after infection with Ad5-CMV-iNOS was measured. Maximum NO release rate occurred when cells were infected at multiplicity of infection (MOl) 15 and after 24 to 36 hours incubation. Direct cell killing of cells growing in monolayer commenced within 1 day after infection and occurred at MOl greater than 5. An in vitro cell survival investigation utilized Du-145 and PC-3 prostate tumor cells growing to high density in a collagen matrix. Both control viral vector and Ad5-CMV-iNOS produced direct cell kill but no radiation sensitization in these cell systems. Sensitization was not observed in either aerobic or hypoxic conditions. Sensitization was also not observed after Ad5-CMV-iNOS gene therapy of Du-145 and PC-3 xenograft tumors in nude mice as assayed by the in vivo/in vitro method.

Advances in computer and imaging technologies in the last 5 years have made possible significant improvement in our ability to optimize and deliver a patient’s treatment. The imaging information also enables us to have a better understanding of geometric treatment uncertainty and to develop effective strategies to ensure accurate treatment. Smaller planning target volumes and higher radiation doses can now be prescribed for improving local control. A comprehensive review of these advances has recently been published [1]. It is important to note that improvement in the geometric accuracy of treatment delivery does not necessarily result in an improvement in local control. Critical biological features of a tumor, such as the extent of micro-invasion, nonuniform cell doubling time and non-uniform radio-sensitivity are largely unknown and ignored in treatment planning. Consequently, important questions such as the merits of uniform or non-uniform dose distribution cannot be resolved.