Expanding the use of monoclonal antibody therapy of cancer by using ionising radiation to upregulate antibody targets.

BACKGROUND: Monoclonal antibody (mAb) therapy for the treatment of solid and haematologic malignancies has shown poor response rates as a monotherapy. Furthermore, its use is limited to tumours expressing certain molecular targets. It has been shown that single-dose radiation can induce immunogenic modulation that is characterised by cell-surface phenotypic changes leading to augmented tumour cell/cytotoxic T-cell interaction. METHODS: We examined radiation's ability to upregulate mAb therapy targets. We also used radiation to sensitise tumour cells to antibody-dependent cell-mediated cytotoxicity (ADCC). RESULTS: Radiation significantly increased cell-surface and total protein expression of mAb targets HER2, EGFR, and CD20. Focusing on HER2, targeted by trastuzumab, we observed significant upregulation of HER2 following radiation of 3 out of 3 breast cancer cell lines, one of which was triple negative, as well as in residential stem-cell populations. HER2 upregulation was sustained up to 96 h following radiation exposure and was largely dependent on intracellular reactive oxygen species. Improved ADCC and sensitisation to the antiproliferative effects of trastuzumab demonstrated the functional significance of radiation-induced HER2 upregulation. CONCLUSIONS: We show that single-dose radiation enhances mAb therapy. These findings highlight a mechanism for combining radiation with immunotherapy and expand the patient population that can be treated with targeted therapy.

The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

BACKGROUND: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT-drug development programmes before patent expiration. METHODS: We identified novel drug-radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time. RESULTS: The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001). CONCLUSIONS: Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug-RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes.

Costs of early adjuvant radiation therapy after radical prostatectomy: a decision analysis.

BACKGROUND: This analysis was carried out to evaluate the cost-effectiveness of adjuvant radiation therapy (ART) versus observation, using a decision analysis model based primarily upon the published results of the Southwest Oncology Group prospective trial (SWOG 8794). PATIENTS AND METHODS: A decision analysis model was designed to compare ART versus observation over a 10-year time horizon. Probabilities of treatment success, utilization of salvage treatments, and rates of adverse events were taken from published results of SWOG 8794. Cost inputs were based on 2010 Medicare reimbursement rates. Primary outcome measure was incremental cost per prostate-specific antigen (PSA) success (i.e. serum PSA level <0.4 ng/ml). RESULTS: ART results in a higher PSA success rate than observation with probability of 0.43 versus 0.22. The mean incremental cost per patient for ART versus observation was $6023. The mean incremental cost-effectiveness ratio was $26,983 over the 10-year period. CONCLUSIONS: ART appears cost effective compared with observation based upon this decision analysis model. Future research should consider more costly radiation therapy (RT) approaches, such as intensity-modulated RT, and should evaluate the cost-effectiveness of ART versus early salvage RT.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²7Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²7Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²7Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²7Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

Implementation and experimental results of 4D tumor tracking using robotic couch.

PURPOSE: This study presents the implementation and experimental results of a novel technique for 4D tumor tracking using a commercially available and commonly used treatment couch and evaluates the tumor tracking accuracy in clinical settings. METHODS: Commercially available couch is capable of positioning the patient accurately; however, currently there is no provision for compensating physiological movement using the treatment couch in real-time. In this paper, a real-time couch tracking control technique is presented together with experimental results in tumor motion compensation in four dimensions (superior-inferior, lateral, anterior-posterior, and time). To implement real-time couch motion for tracking, a novel control system for the treatment couch was developed. The primary functional requirements for this novel technique were: (a) the treatment couch should maintain all previous∕normal features for patient setup and positioning, (b) the new control system should be used as a parallel system when tumor tracking would be deployed, and (c) tracking could be performed in a single direction and∕or concurrently in all three directions of the couch motion (longitudinal, lateral, and vertical). To the authors' best knowledge, the implementation of such technique to a regular treatment couch for tumor tracking has not been reported so far. To evaluate the performance of the tracking couch, we investigated the mechanical characteristics of the system such as system positioning resolution, repeatability, accuracy, and tracking performance. Performance of the tracking system was evaluated using dosimetric test as an endpoint. To investigate the accuracy of real-time tracking in the clinical setting, the existing clinical treatment couch was replaced with our experimental couch and the linear accelerator was used to deliver 3D conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) treatment plans with and without tracking. The results of radiation dose distribution from these two sets of experiments were compared and presented here. RESULTS: The mechanical accuracies were 0.12, 0.14, and 0.18 mm in X, Y, and Z directions. The repeatability of the desired motion was within ±0.2 mm. The differences of central axis dose between the 3D-CRT stationary plan and two tracking plans with different motion trajectories were 0.21% and 1.19%. The absolute dose differences of both 3D tracking plans comparing to the stationary plan were 1.09% and 1.20%. Comparing the stationary IMRT plan with the tracking IMRT plan, it was observed that the central axis dose difference was -0.87% and the absolute difference of both IMRT plans was 0.55%. CONCLUSIONS: The experimental results revealed that the treatment couch could be successfully used for real-time tumor tracking with a high level of accuracy. It was demonstrated that 4D tumor tracking was feasible using existing couch with implementation of appropriate tracking methodology and with modifications in the control system.

Early toxicity predicts long-term survival in high-grade glioma.

BACKGROUND: Patients with high-grade gliomas are treated with surgery followed by chemoradiation. The risk factors and implications of neurological side effects are not known. METHODS: Acute and late ≥ grade 3 neurological toxicities (NTs) were analysed among 2761 patients from 14 RTOG trials accrued from 1983 to 2003. The association between acute and late toxicity was analysed using a stepwise logistic regression model. The association between the occurrence of acute NT and survival was analysed as an independent variable. RESULTS: There were 2610 analysable patients (86% glioblastoma, 10% anaplastic astrocytoma). All received a systemic agent during radiation (83% chemotherapy, 17% biological agents). Median radiation dose was 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis, older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, poor mental status and twice-daily radiation were associated with increased acute NT. In a stepwise logistic regression model the occurrence of acute NT was significantly associated with late NT (OR=2.40; 95% CI=1.2-4.8; P=0.014). The occurrence of acute NT predicted poorer overall survival, independent of recursive partitioning analysis class (median 7.8 vs 11.8 months). INTERPRETATION: Acute NT is significantly associated with both late NT and overall survival.

Zebrafish: an emerging model system for human disease and drug discovery.

In vivo studies represent an essential step in drug development and currently rely largely on mice, yet limitations of mammalian models motivated the search for complementary vertebrate model systems. This review focuses on zebrafish, Danio rerio, as a facile model system to study human disease and drug responses. Zebrafish are particularly suited for this purpose because they represent a vertebrate species, their genome is sequenced, and a large number of synchronously developing, transparent embryos can be produced. Zebrafish embryos are permeable to drugs and can easily be manipulated using well-established genetic and molecular approaches. Here, we summarize recent work on drug discovery and toxicity in zebrafish embryos. In addition, we provide a synopsis of current efforts to establish disease models in zebrafish focusing on neoplasia. The results of these studies highlight the potential of zebrafish as a viable addition to established animal models by offering medium and, potentially, high throughput capabilities.

Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk.

BACKGROUND: To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF). METHODS: 422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n=111), minimal residual disease (MRD) SRT (n=70) and SRT (n=83) were defined by PSA levels of <0.2, 0.2-0.49 and ⩾0.5 ng ml(-1), respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical-genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome. RESULTS: During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P<0.05). Adjusting for clinical-genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20-15.47) and 5.42 (95% confidence interval, 1.59-18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P=0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. CONCLUSIONS: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials.

E-mail and oncology: a survey of radiation oncology patients and their attitudes to a new generation of health communication.

Electronic mail (e-mail) is a powerful tool that can greatly enhance communication and has numerous potential applications within the medical profession. Physician-patient e-mail communication volume is increasing, but little research has addressed patient interests and concerns about this now commonplace technology. The goals of this study were to review the available literature regarding physician-patient e-mail practices, evaluate patient interest, assess patient perspectives about how e-mail communication might facilitate medical treatment and advice, and determine areas of patient concern regarding e-mail communication with their physicians. To this end, a population of cancer patients was sent a written survey designed to assess their access to e-mail and attitudes about physician-patient e-mail communication. We found that patients favored e-mail for increased convenience, efficiency, and timeliness about general health problems, while it was not favored for urgent matters.

Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade.

Antiandrogen therapy is an important modality in the treatment of prostate cancer. Recent research into the role of angiogenesis in tumour growth and metastasis has uncovered links between antiandrogen therapy, radiation therapy and angiogenesis, which have exciting implications for the treatment of prostate cancer. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) have been identified in prostate cancer cells and tumours, and androgens appear to stimulate VEGF. This article assesses the antiangiogenic effects of hormonal therapy and assesses the role that angiogenesis may play in the observed cooperation between hormonal and radiation therapies for prostate cancer.

Defining a future role for radiogenic therapy.

The goal of cancer therapy is to eliminate the cancer and/or to arrest further growth while decreasing normal tissue toxicity, i.e. to increase the therapeutic ratio. This review focuses on a group of therapeutics that are either (1) directly stimulated by radiation to produce either directly or indirectly cytotoxic agents (i.e. genes under the control of a radiation inducible promoter that produce a cytotoxic protein or an enzyme that converts a prodrug to an active form, respectively); (2) auger-electron emitting radiolabelled oligonucleotides, antibodies, nucleotide analogues, or other small molecules that are internalized; (3) radiation inducible genes that produce a ligand or transporter (or the like) which then can be targeted by cytotoxic agents (e.g. radiolabelled substance). We have termed this group of therapeutics radiogenic therapy.

Calcium-dependent translocation of sorcin to membranes: functional relevance in contractile tissue.

Sorcin, a 22 kDa calcium binding protein present in abundance in cardiac tissue and in multi-drug resistant cells and previously described as a soluble protein, is now shown to undergo a calcium-dependent translocation process from the cytosol to cellular membranes in both systems. The translocation process takes place also in E. coli BL21 cells that express recombinant sorcin, r-sorcin, and can be exploited in the purification of the protein. Calcium binding to purified r-sorcin occurs at micromolar concentrations of the metal and is accompanied by a conformational change that renders the protein soluble in the non-ionic detergent Triton X-114. This finding suggests that lipids are the target of sorcin on cellular membranes. The possible significance of the calcium-dependent translocation of sorcin in the specialized functions of sorcin-expressing cells is discussed.

The impact of postimplant edema on the urethral dose in prostate brachytherapy.

PURPOSE: The objective of this work is to determine the effect of timing of the postimplant CT scan on the assessment of the urethral dose. METHODS AND MATERIALS: A preimplant CT scan and two postimplant CT scans were obtained on 50 patients who received I-125 prostate seed implants. The first postimplant CT scan was obtained on the day of the implant; the second usually 4 to 9 weeks later (mean: 46 +/- 23 days; range: 27-135 days). The urethra was localized in each postimplant CT scan and a dose-volume histogram (DVH) of the urethral dose was compiled from each CT study. The relative decrease in the prostate volume between the first and second postimplant CT scans was determined by contouring the prostate in each CT scan. RESULTS: The prostate volume decreased by 27 +/- 9% (mean +/- SD) between the first and second postimplant CT scans. As a result, the averaged urethral dose derived from the second CT scan was about 30% higher. In terms of dose, the D(10), D(25), D(50), D(75), and D(90) urethral doses derived from the second CT scan were 90 +/- 56 Gy, 81 +/- 49 Gy, 67 +/- 42 Gy, 49 +/- 44 Gy, and 40 +/- 46 Gy higher, respectively. The increase in the urethral dose is correlated with the decrease in the prostate volume (R = 0.57, rho < 0.01). CONCLUSION: The assessment of the urethral dose depends upon the timing of the postimplant CT scan. The mean D(10) dose derived from the CT scans obtained at 46 +/- 23 days postimplant was 90 +/- 56 Gy higher than that derived from the CT scans obtained on the day of the implant. Because of this large difference, the timing of the postimplant CT scan needs to be specified when specifying dose thresholds for urethral morbidity.

Effect of post-implant edema on the rectal dose in prostate brachytherapy.

PURPOSE: To characterize the effect of prostate edema on the determination of the dose delivered to the rectum following the implantation of 125I or 103Pd seeds into the prostate. METHODS AND MATERIALS: From 3 to 5 post-implant computed tomography (CT) scans were obtained on 9 patients who received either 125I or 103Pd seed implants. None of the patients received hormone therapy. The outer surface of the rectum was outlined on each axial CT image from the base to the apex of the prostate. The D10 rectal surface dose, defined as the dose which encompasses only 10% of the surface area of the rectum, was determined from each CT scan by compiling a dose-surface histogram (DSH) of the rectal surface. The magnitude and half-life of the post-implant edema in each of these implants is known from the results of a previously published study based on the analysis of the serial CT scans. RESULTS: As the prostate edema resolved, the distance between the most posterior implanted seeds and the anterior surface of the rectum decreased. As a result, the D10 rectal surface dose increased with each successive post-implant CT scan until the edema resolved. The dose increased exponentially at approximately the same rate the prostate volume decreased. The D10 rectal surface dose at 30 days post-implant ranged from 16% to 190% (mean 68 +/- 50%) greater than on day 0. The dose on day 30 was at least 50% greater in 6 of 9 cases. CONCLUSION: The rectal surface dose determined by analysis of a post-implant CT scan of an 125I or 103Pd prostate seed implant depends upon the timing of the CT scan. The dose indicated by the CT scan on day 30 is typically at least 50% greater than that indicated by the CT scan on day 0. Because of this difference, it is important to keep the timing of the post-implant CT in mind when specifying dose thresholds for rectal morbidity.

Can extraprostatic extension be treated by prostate brachytherapy? An analysis based on postimplant dosimetry.

PURPOSE: To determine whether extraprostatic extension (EPE) can be treated by Pd-103 prostate implants. METHODS AND MATERIALS: The postimplant dosimetry of 22 consecutive Pd-103 prostate implants was analyzed to determine whether potential EPE was adequately treated. The implants were peripherally loaded and planned with a 3-5-mm dose margin at midgland. Seeds were not implanted outside of the capsule except at the base and apex. The postimplant dosimetry was based on a CT scan obtained 32 +/- 8 days postimplant. The radial distance between the prostate edge and the prescription isodose line was measured at the left lateral, left posterolateral, posterior, right posterolateral, and right lateral positions on each prostate contour. Similar measurements were made of the preplan dose margins. RESULTS: The mean postimplant dose margin was > or =4.5 mm at the midgland and apex of the prostate in agreement with the preplan. However, at the base, the mean margins at the five measurement locations were less than planned, typically ranging from 2.5 to 3.5 mm. The postimplant margin at the base was smaller than expected due to source placement errors, a correctable problem. CONCLUSIONS: Peripherally loaded Pd-103 prostate implants can deliver the prescription dose 3-5 mm outside the capsule, which is believed to be sufficient to treat 95-100% of EPE in favorable risk patients. However, dose coverage of EPE, like dose coverage of the prostate, is operator-dependent.

Edema associated with I-125 or Pd-103 prostate brachytherapy and its impact on post-implant dosimetry: an analysis based on serial CT acquisition.

PURPOSE: To characterize the magnitude and duration of post-implant edema following the implantation of I-125 or Pd-103 seeds into the prostate and to investigate its effect on the CT-based calculation of the total dose delivered by the implant. MATERIALS AND METHODS: A pre-implant CT scan and 3 to 5 serial post-implant CT scans were obtained on 10 patients who received either I-125 or Pd-103 seed implants. None of the patients received hormone therapy. The magnitude and duration of edema were determined from the change in the spatial distribution of the implanted seeds as the edema resolves. Dose volume histograms were compiled to determine the percentage of the prostate volume that received a dose equal to, or greater than, the prescribed dose. RESULTS: The magnitude of the edema, expressed as the ratio of the post- to pre-implant volume on the day of the procedure, ranged from 1.33 to 1.96 (mean 1.52). The edema decreased exponentially with time; however, the edema half-life (time for the edema to decrease by 1/2) varied from 4 to 25 days (mean 9.3 days). As the edema resolved, the percentage of the prostate that received a dose equal to or greater than the prescribed dose increased by at least 7% in 7 of the 10 patients and increased by more than 15% in 2. In those patients in whom dose coverage was unaffected by the resolution of edema, more than 90% of the prostate was covered by the prescribed dose in the initial CT scan. CONCLUSION: Post-implant edema increased the prostate volume by factors which ranged from 1.33 to 1.96 (mean: 1.52). The edema resolved exponentially with an edema half-life which varied from 4 to 25 days (mean: 9.3 days). Edema had a significant effect on the post-implant dosimetry in 7 of 10 cases. Factors that affect the impact of edema on the dosimetry are the magnitude of the edema and the planned margin between the prescribed isodose line and the periphery of the prostate.

A dynamic model for the estimation of optimum timing of computed tomography scan for dose evaluation of 125I or 103Pd seed implant of prostate.

PURPOSE/OBJECTIVE: The dosimetric evaluation of permanent 125I or 103Pd prostate implant is based on the assumption that both prostate and seeds are static throughout the entire treatment time which lasts months. However, the prostate is often edematous after the surgical implantation of seeds. Therefore, both the volume of the prostate and the seed locations change dynamically as the edema resolves. This effect has impact on the validity of postimplant analysis based upon a CT scan. If a CT scan is taken too early after implantation while there is edema in the prostate, the dose delivered by the implant may be underestimated. If the imaging is delayed too long, the dose may be overestimated. The magnitude of this effect depends on both of the half-life of the isotope used and the half-life and magnitude of the edema. This study describes a dynamic biomathematical model which takes edema into account in calculating the dose delivered by the implant and is used to investigate the optimum time to obtain the postimplant CT scan. MATERIALS AND METHODS: The dynamic biomathematical model is a numerical integration of the accumulated dose in which the prostate dimensions, the seed locations, and the source strength are all functions of time. The function which describes the change in prostate dimensions and seed locations as a function of time was determined in a separate study by analysis of serial postimplant CT scans. Dose-volume histograms (DVH) of the prostate for the total dose generated by the dynamic model are compared to DVHs generated by CT scans simulated for postimplant intervals ranging from 0 to 300 days after the implantation for 30 different combinations of the magnitude and duration of edema. RESULTS: DVHs of the prostate calculated by taking edema into account show that the time of obtaining a CT scan for postimplant analysis is critical to the accuracy of dose evaluations. The comparison of the DVHs generated by the dynamic model to those generated by the CT scans simulated for a range of postimplant intervals show that obtaining the CT scan too early tends to underestimate the total dose while obtaining the CT scan after the edema is resolved tends to overestimate it. The results show that the optimum timing of the CT scan depends upon the duration of the edema and the half-life of the radioisotope used. It is almost independent of the magnitude of the edema. Thus, a unique optimum time window for the imaging study cannot be defined for either 125I or 103Pd implants. However, an optimum time window can be identified for which the calculated dose, on the average, will generally differ from the actual dose by less than 5%, with a maximum error not exceeding 15%. Such a window is 4 to 10 weeks after the implantation for an 125I implant, and 2 to 4 weeks for a 103Pd implant. CONCLUSIONS: A dynamic biomathematical model to correct for the effects of edema in calculating the total dose delivered by an 125I or 103Pd seed implant has been developed. The model has been used to investigate the optimum time window during which the postimplant CT scans for analysis should be obtained.

Optimum timing for image-based dose evaluation of 125I and 103PD prostate seed implants.

PURPOSE/OBJECTIVE: Image-based dose evaluation of permanent brachytherapy implants for prostate cancer is important for optimal patient management after implantation. Because of edema caused by the surgical procedure in the implantation, if the dose evaluation is based on the images obtained too early after implantation, dose coverage will usually be underestimated. Conversely, if the images are obtained too late, the dose coverage will be overestimated. This study uses a biomathematical model to simulate edema and its resolution on 29 patients, so that the optimum time to obtain image scans and perform dose evaluation can be investigated and estimated. METHODS AND MATERIALS: Edema of a prostate and its resolution has been shown to follow an exponential function V(t) = V(0)(1 + deltaV[e-0.693t/Te - 1]) where deltaV is the initial relative increase in the prostate volume due to edema (and is related to edema magnitude), and Te (edema half-life) is the time for the edema to decrease by half in volume. In this study, edema was simulated by increasing the volume of preimplant prostate (obtained from ultrasound volume study) to a given magnitude of edema. Similarly, the locations of planned seeds were changed to their corresponding locations in the edematous prostate proportionally. The edema was then allowed to resolve according to the exponential function. The correct dose distribution was calculated by taking into account the dynamic variations of the prostate volume, seed locations, and source strengths with respect to time. Dose volume histograms (DVHs) were then generated from this dose distribution. The conventional postimplant DVHs, which assume the prostate volume and seed locations are as in the image scans and constant in time, were also calculated based on the simulated image scans for various days postimplantation. The conventional DVHs of prostate on various days after implantation were compared to the DVH calculated assuming dynamic conditions. The optimum timing for conventional postimplant dose evaluation was identified as the time at which a minimum difference between the conventional DVH and the dynamic model DVH was achieved. The analysis was done on 29 prostate seed implant patients for both 125I and 103Pd. The edema magnitude was assumed to be 30%, 40%, 50%, 75%, and 100% of original prostate volume, and the half-life of edema was assumed to be 4, 7, 10, 15, 20, and 25 days. In this study, the original volume of prostate varied from 17 cm3 to 91 cm3, and number of seeds in the implants varied from 57 to 119. RESULTS: The optimum timing was mainly dependent on the half-lives of edema and radionuclides, and varied slightly with edema magnitude, prostate volume, and number of seeds. It can be expressed as a function of edema half-life in the form of C0 + C1exp(-C2Te). However, if the dose evaluation was performed based on the image scans taken too early or too late, the error became larger, as the edema magnitude was larger. By averaging all 29 patients and various edemas, it was found that for 125I seed implants, if the postimplant dose evaluation is performed based on image scans taken between 5 and 9 weeks, the average error will be less than 5%, with a maximum possible error less than 10% in 80% coverage dose; for 103Pd seed implants, if the postimplant dose evaluation is performed based on image scans taken between 2 and 4 weeks, the average error will be less than 5%, with a maximum error less than 15% in 80% coverage dose. Because of edema, a conventional preimplant plan also overestimates dose coverage of prostate. On the average, a standard preimplant planning overestimates dose coverage by about 6% for 125I implants and 14% for 103Pd implants in our study. CONCLUSION: Based on the dynamic model, the optimum timing of image scans for postimplant dose evaluation of prostate seed implantation is 7 weeks postimplantation for 125I implants and about 3 weeks for 103Pd implants. (ABSTRACT TRUNCATED)

The efficacy of early adjuvant radiation therapy for pT3N0 prostate cancer: a matched-pair analysis.

PURPOSE: This study examines the effect of adjuvant radiation therapy (RT) on outcome in patients with pT3N0 prostate cancer and makes comparisons to a matched control group. METHODS AND MATERIALS: At our center, 149 patients undergoing radical prostatectomy were found to have pT3N0 prostate cancer, had an undetectable postoperative prostate-specific antigen (PSA) level, and had no immediate hormonal therapy. Fifty-two patients received adjuvant RT within 3 to 6 months of surgery. Ninety-seven underwent radical prostatectomy alone and were observed until PSA failure. From these two cohorts, we matched patients 1:1 according to preoperative PSA (<10 ng/ml vs. >10 ng/ml), Gleason score (<7 vs. > or =7), seminal vesicle invasion, and surgical margin status. Seventy-two patients (36 pairs) were included in the analysis. Median follow-up time was 41 months. We calculated a matched-pairs risk ratio for cumulative risk of PSA relapse (a rise above 0.2 ng/ml). RESULTS: After controlling for the prognostic factors by matching, there was an 88% reduction (95% confidence interval [CI]: 78-93%) in the risk of PSA relapse associated with adjuvant RT. The 5-year freedom from PSA relapse rate was 89% (95% CI: 76-100%) for patients receiving adjuvant RT as compared to 55% (95% CI: 34-79%) for those undergoing radical prostatectomy alone. CONCLUSIONS: These data suggest that adjuvant RT for pT3N0 prostate cancer may significantly reduce the risk of PSA failure as compared to radical prostatectomy alone. Its effect on clinical outcome awaits further follow-up.

The effect of treatment positioning on normal tissue dose in patients with prostate cancer treated with three-dimensional conformal radiotherapy.

PURPOSE: To prospectively assess the effect of supine vs. prone treatment position on the dose to normal tissues in prostate cancer patients treated with the three-dimensional conformal technique. METHODS AND MATERIALS: Twenty-six patients underwent three-dimensional treatment planning in both the supine and prone treatment positions. The planning target volume and normal tissue structures were outlined on each CAT scan slice, and treatment plans were compared to assess the effect of treatment position on the volume of rectum, bladder, and bowel exposed to the high dose of irradiation. RESULTS: The average dose to the rectal wall and the V95 (volume of rectal wall receiving at least 95% of the prescription dose) for the prone position were 64 and 24% of the prescription dose, respectively, compared to 72 and 29%, respectively, for the supine position (p < 0.05). When the average rectal wall dose was used as an endpoint, 14 of the 26 patients (54%) had an advantage for the prone position compared to 1 (4%) who demonstrated an advantage for the supine position (p < 0.0002). Similarly, when V95 of the rectal wall was used as a measure of comparison, 15 patients (58%) had an advantage for the prone position compared to 1 (4%) who demonstrated an advantage for the supine position (p < 0.0002). In 13 patients (50%), a change from supine to the prone position was associated with reduction of the V95 to levels < 30% of the prescription dose compared to 3 patients (11%) in whom such an advantage resulted from change of the prone to the supine position (p < 0.005). The effect of treatment position on the rectal wall dose was most pronounced in the region of the seminal vesicles. An increased volume of bowel was also noted in the supine position. The treatment position, however, had no significant impact on the dose to the bladder wall. CONCLUSIONS: Three-dimensional conformal radiotherapy for prostate cancer in the prone position is associated with significant reduction of the dose to the rectum and bowel resulting in an improvement in the therapeutic ratio.