Tumor-associated autoantibodies correlate with poor outcome in prostate cancer patients treated with androgen deprivation and external beam radiation therapy.

Standard cancer treatments trigger immune responses that may influence tumor control. The nature of these responses varies depending on the tumor and the treatment modality. We previously reported that radiation and androgen-deprivation therapy (ADT) induce tumor-associated autoantibody responses in prostate cancer patients. This follow-up analysis was conducted to assess the relationship between autoantibody responses and clinical outcome. Patients with non-metastatic prostate cancer received external beam radiation therapy (EBRT) plus neoadjuvant and concurrent androgen deprivation. Treatment-induced autoantibodies were detected in almost a third of patients receiving combinatorial ADT and EBRT. Unexpectedly, patients that developed autoantibody responses to tumor antigens had a significantly lower 5-year biochemical failure-free survival (BFFS) than patients that did not develop an autoantibody response. Thus, tumor-reactive autoantibodies may be associated with increased risk of biochemical failure and immunomodulation to prevent autoantibody development may improve BFFS for select, high-risk prostate cancer patients receiving both ADT and EBRT.

Combined therapeutic effects of adenoviral vector-mediated GLIPR1 gene therapy and radiotherapy in prostate and bladder cancer models.

OBJECTIVES: The objectives of this study are to explore the potential benefits of combining AdGlipr1 (or AdGLIPR1) gene therapy with radiotherapy using subcutaneous prostate and bladder cancer models. MATERIALS AND METHODS: Combination adenoviral vector-mediated gene therapy and radiotherapy were applied to 178-2 BMA and TSU-Pr1 cells in vitro and colony formation and apoptosis were analyzed. In addition, combination therapies were administered to mice bearing subcutaneous 178-2 BMA and TSU-Pr1 tumors, and tumor growth suppression and survival extension were compared with the monotherapies (AdGlipr1/AdGLIPR1 and radiotherapy) or control vector Adv/CMV/ßgal, as well as single-cycle treatment with 2-cycle treatment. RESULTS: Combination treatment significantly suppressed colony formation and increased apoptosis in vitro. In vivo, combination therapy produced significant 178-2 BMA and TSU-Pr1 tumor growth suppression and survival extension compared with the monotherapies or the control. Further tumor growth suppression and survival extension were observed after 2 cycles of the combination treatment. CONCLUSIONS: Combining AdGlipr1 (AdGLIPR1) with radiotherapy may achieve additive or synergistic tumor control in selected prostate and bladder tumors, and additional therapeutic effects may result with repeated treatment cycles.

Simultaneous couch and gantry dynamic arc rotation (CG-Darc) in the treatment of breast cancer with accelerated partial breast irradiation (APBI): a feasibility study.

The purpose of this study was to compare the dosimetry of CG-Darc with three-dimensional conformal radiation therapy (3D CRT) and volumetric-modulated arc therapy (RapidArc) in the treatment of breast cancer with APBI. CG-Darc plans were generated using two tangential couch arcs combined with a simultaneous noncoplanar gantry arc. The dynamic couch arc was modeled by consecutive IMRT fields at 10° intervals. RapidArc plans used a single partial arc with an avoidance sector, preventing direct beam exit into the thorax. CG-Darc and RapidArc plans were compared with 3D CRT in 20 patients previously treated with 3D CRT (group A), and in 15 additional patients who failed the dosimetric constraints of the Canadian trial and of NSABP B-39/RTOG 0413 for APBI (group B). CG-Darc resulted in superior target coverage compared to 3D CRT and RapidArc (V95%: 98.2% vs. 97.1% and 95.7%). For outer breast lesions, CG-Darc and RapidArc significantly reduced the ipsilateral breast V50% by 8% in group A and 15% in group B (p < 0.05) as compared with 3D CRT. For inner and centrally located lesions, CG-Darc resulted in significant ipsilateral lung V10% reduction when compared to 3D CRT and RapidArc (10.7% vs. 12.6% and 20.7% for group A, and 15.1% vs. 25.2% and 27.3% for group B). Similar advantage was observed in the dosimetry of contralateral breast where the percent maximum dose for CG-Darc, 3D CRT, and RapidArc were 3.9%, 6.3%, and 5.8% for group A and 4.3%, 9.2%, and 6.3% for group B, respectively (p < 0.05). CG-Darc achieved superior target coverage while decreasing normal tissue dose even in patients failing APBI dose constraints. Consequently, this technique has the potential of expanding the use of APBI to patients currently ineligible for such treatment. Modification of the RapidArc algorithm will be necessary to link couch and gantry rotation with variable dose rate and, therefore, enable the use of CG-Darc in clinical practice.

Coplanar versus noncoplanar intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) treatment planning for fronto-temporal high-grade glioma.

The purpose of this study was to compare dosimetric and radiobiological parameters of treatment plans using coplanar and noncoplanar beam arrangements in patients with fronto-temporal high-grade glioma (HGG) generated for intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT). Ten cases of HGG overlapping the optic apparatus were selected. Four separate plans were created for each case: coplanar IMRT, noncoplanar IMRT (ncIMRT), VMAT, and noncoplanar VMAT (ncVMAT). The prescription dose was 60 Gy in 30 fractions. Dose-volume histograms and equivalent uniform doses (EUD) for planning target volumes (PTVs) and organs at risk (OARs) were generated. The four techniques resulted in comparable mean, minimum, maximum PTV doses, and PTV EUDs (p ≥ 0.33). The mean PTV dose and EUD averaged for all techniques were 59.98 Gy (Standard Deviation (SD) ± 0.15) and 59.86 Gy (SD ± 0.27). Non-coplanar IMRT significantly reduced contralateral anterior globe EUDs (6.7 Gy versus 8.2 Gy, p = 0.05), while both ncIMRT and ncVMAT reduced contralateral retina EUDs (16 Gy versus 18.8 Gy, p = 0.03). Noncoplanar techniques resulted in lower contralateral temporal lobe dose (22.2 Gy versus 24.7 Gy). Compared to IMRT, VMAT techniques required fewer monitor units (755 vs. 478, p ≤ 0.001) but longer optimization times. Treatment delivery times were 6.1 and 10.5 minutes for coplanar and ncIMRT versus 2.9 and 5.0 minutes for coplanar and ncVMAT. In this study, all techniques achieved comparable target coverage. Superior sparing of contralateral optic structures was seen with ncIMRT. The VMAT techniques reduced treatment delivery duration but prolonged plan optimization times, compared to IMRT techniques. Technique selection should be individualized, based on patient-specific clinical and dosimetric parameters.

Sociotechnical evaluation of a clinical transformation project in a specialized cancer care centre.

The radiation therapy (RT) department at the British Columbia Cancer Agency - Vancouver Island Centre (VIC) is responsible for delivering radiation treatments to cancer patients from Vancouver Island, which has a population base of approximately 750,000. The purpose of this analysis is to examine a process transformation project undertaken by a VIC clinical champion using a sociotechnical approach and identify factors that influenced the project outcome. Beginning in January 2009, a radiation oncologist at VIC initiated a project to transform the clinical process of generating prescriptions for radiation therapy. The project objective was to replace the paper-based process for radiation therapy (RT) prescriptions with an electronic process to achieve benefits such as increased legibility, accuracy, and accessibility of prescriptions. The electronic prescription (e-Rx) process was designed and developed by health informatics students from the University of Victoria, and the new process was trialed and implemented for approximately half of the new patients seen by the VIC RT department. This pilot implementation was brought to a halt two weeks later, due to concerns raised by the RT department. Using a sociotechnical approach, the authors identify several factors that negatively impacted the project's successful implementation: lack of leadership endorsement and organizational strategy, insufficient formal and informal organizational power of the clinical champion, underestimation of complexity, and inadequate management of the implementation process. Although these factors have been well documented in the literature for large-scale system implementation projects, understanding the way by which they influence smaller-scale process transformation projects in highly specialized clinical settings may help future project managers and coordinators to set such projects up for success.

Helical TomoTherapy versus sterotactic Gamma Knife radiosurgery in the treatment of single and multiple brain tumors: a dosimetric comparison.

The objective was to compare the dosimetry of Helical TomoTherapy (TOMO) and Gamma Knife (GK) treatment plans for tumor and normal brain in the treatment of single and multiple brain tumors. An anthropomorphic Rando Head phantom was used to compare the dosimetry of TOMO and GK. Eight brain tumors of various shapes, sizes and locations were used to generate 10 plans. The radiation dose was 20 Gy prescribed to the 100% isodose line for TOMO plans and to the 50% for the GK plans. Dose Volume Histograms for tumor and brain were compared. Equivalent Uniform Dose (gEUD), Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) were performed and used for plan comparisons. Average minimum, mean, median and maximum tumor doses were 19.93, 27.83, 27.38, 39.60 Gy for GK and 20.17, 20.60, 20.59, 20.90 Gy for TOMO. Average gEUD values for tumor and normal brain were 25.0 and 7.2 Gy for GK and 20.7 and 8.1 Gy for TOMO. Conformity indices (CI) were similar for both modalities. Gradient indices (GI) were greater for TOMO. A combination plan was also generated using all eight tumors. TOMO was able to target all eight tumors simultaneously resulting in mean tumor and brain doses of 20.5 and 9.35 Gy, respectively. Due to the maximum limit of 50 beams per plan, GK was unable to provide a treatment plan for all eight tumors. GK provides an advantage for all tumor sizes with respect to tumor and normal brain dose. Clinical studies are needed to correlate these dosimetric findings with patient outcomes.

Intensity modulated radiation therapy versus three dimensional conformal radiation therapy for treatment of high grade glioma: a radiobiological modeling study.

Treatment of glioblastoma results in a median survival of 12 months. Radiation dose escalation trials for high grade gliomas have resulted in modest improvements in survival in selected patients with small peripheral tumors at the expense of normal brain toxicity. Neurotoxicity includes radiation necrosis but it is increasingly recognized that long-term survivors may develop neuro-cognitive deficits. Tumor control probability (TCP) and normal tissue complication probability (NTCP) are radiobiological models used to predict treatment outcomes. This study assesses the impact of radiation dose escalation from 59.6 Gy to 90 Gy on TCP and NTCP in ten patients planned with Three Dimensional Conformal Therapy (3DCRT) and Intensity Modulated Radiation Therapy (IMRT). No difference in TCP was observed between 3DCRT and IMRT at doses of 59.4 Gy and 90 Gy. However, dose escalation to 90 Gy resulted in about 25% relative TCP increase. Compared to 3DCRT, dose escalation with IMRT significantly reduced NTCP by 70% (10.75% v. 3.75%, respectively). As a result, highly conformal techniques are recommended to obviate radiation exposure of normal brain especially when radiation dose escalation is used. Further understanding of the molecular mechanisms underlying neurotoxicity will allow the development of more precise radiobiological predictive models and of approaches to prevent or treat radiation-induced brain damage.

Impact of tissue heterogeneity corrections in stereotactic body radiation therapy treatment plans for lung cancer.

This study aims at evaluating the impact of tissue heterogeneity corrections on dosimetry of stereotactic body radiation therapy treatment plans. Four-dimensional computed tomography data from 15 low stage non-small cell lung cancer patients was used. Treatment planning and dose calculations were done using pencil beam convolution algorithm of Varian Eclipse system with Modified Batho Power Law for tissue heterogeneity. Patient plans were generated with 6 MV co-planar non-opposing four to six field beams optimized with tissue heterogeneity corrections to deliver a prescribed dose of 60 Gy in three fractions to at least 95% of the planning target volume, keeping spinal cord dose <10 Gy. The same plans were then regenerated without heterogeneity correction by recalculating previously optimized treatment plans keeping identical beam arrangements, field fluences and monitor units. Compared with heterogeneity corrected plans, the non-corrected plans had lower average minimum, mean, and maximum tumor doses by 13%, 8%, and 6% respectively. The results indicate that tissue heterogeneity is an important determinant of dosimetric optimization of SBRT plans.

Helical tomotherapy in the radiotherapy treatment of Hodgkin's disease - a feasibility study.

Radiation therapy for advanced Hodgkin's disease often requires large fields and may result in significant exposure of normal tissues to ionizing radiation. In long-term survivors, this may increase the risk for late toxicity including secondary malignancies. 3DCRT has been successfully used to treat this disease but treatment delivery is often complex requiring matching of photon with electron beams, utilization of field-in-field techniques and of partial transmission blocks. HT is an arc-rotational intensity modulated radiation therapy technique proven to achieve superior target dose conformality and sharp dose gradients around critical normal tissues. HT however, has also been associated with higher volumes of low dose regions in normal tissues and therefore, higher integral dose. The present study was undertaken to compare the dosimetry of 3DCRT to HT in a pediatric patient with advanced HD. Clinical target volume (CTV) included bilateral lower cervical and supraclavicular areas, mediastinum, bilateral hili, left axilla and bilateral diaphragmatic lymph nodes. The planning target volume (PTV) was derived by circumferentially expanding the CTV by 1 cm. Whole lung and heart irradiation was also planned due to bilateral pleural and pericardial effusions. The prescribed radiation dose was 21 Gy to the PTV and 10.5 Gy to the whole lung and heart. Target coverage was comparable for both plans. The minimum, maximum and mean PTV doses were 18.61 Gy, 22.45 Gy and 21.52 Gy with 3DCRT and 19.85 Gy, 22.36 Gy and 21.39 Gy with HT, respectively. HT decreased mean normal tissue dose by 21.6% and 20.07% for right and left breast, 20.40% for lung, 30.78% for heart and 22.74% for the thyroid gland. Integral dose also decreased with HT by 46.50%. HT results in significant dosimetric gain related to normal tissue sparing compared to 3DCRT. Further studies are warranted to evaluate clinical applications of HT in patients with HD.

Stereotactic body radiation therapy (SBRT) and respiratory gating in lung cancer: dosimetric and radiobiological considerations.

The purpose of this study was to assess the impact of respiratory gating on tumor and normal tissue dosimetry in patients treated with SBRT for early stage non-small cell lung cancer (NSCLC). Twenty patients with stage I NSCLC were studied. Treatment planning was performed using four-dimensional computed tomography (4D CT) with free breathing (Plan I), near-end inhalation (Plan II), and near-end exhalation (Plan III). The prescription dose was 60 Gy in three fractions. The tumor displacement was most pronounced for lower peripheral lesions (average 7.0 mm, range 4.1-14.3 mm) when compared to upper peripheral (average 2.4mm, range 1.0-5.1 mm) or central lesions (average 2.9 mm, range 1.0-4.1 mm). In this study, the pencil beam convolution (PBC) algorithm with modified Batho power law for tissue heterogeneity was used for dose calculation. There were no significant differences in tumor and normal tissue dosimetry among the three gated plans. Tumor location however, significantly influenced tumor doses because of the necessity of respecting normal tissue constraints of centrally located structures. For plans I, II and III, average doses to central lesions were lower as compared with peripheral lesions by 4.88 Gy, 8.24 Gy and 6.93 Gy for minimum PTV and 0.98, 1.65 and 0.87 Gy for mean PTV dose, respectively. As a result, the mean single fraction equivalent dose (SFED) values were also lower for central compared to peripheral lesions. In addition, central lesions resulted in higher mean doses for lung, esophagus, and ipsilateral bronchus by 1.24, 1.93 and 7.75 Gy, respectively. These results indicate that the tumor location is the most important determinant of dosimetric optimization of SBRT plans. Respiratory gating proved unhelpful in the planning of these patients with severe COPD.

Tumor control probability (TCP) in prostate cancer: role of radiobiological parameters and radiation dose escalation.

The objective of this work was to assess the relative impact of radiobiological parameters and radiation dose escalation on Tumor Control Probability for prostate cancer patients treated with radiation. Radiobiological parameters included alpha/beta ratios, cell surviving fraction at 2 Gy (SF(2) and clonogenic cell density (CCD). Using the Niemierko method, TCP was calculated in ten prostate cancer patients as a function of increasing radiation doses (70-140 Gy), alpha/beta ratios (1.5-20), SF(2) (0.3-0.7) and CCD (10-20 million cells/cm(3). At 70 Gy and CCD of 10 million/cm(3), TCP was above 99% for SF(2) of 0.3 or 0.4, 97.4%-98.6% for SF(2) of 0.5 and less than 2% for SF(2) of 0.6 or 0.7. With dose escalation, TCP values above 99% were demonstrated at 80 Gy for SF(2) of 0.5 and 100 Gy for SF(2) of 0.6. For SF(2) of 0.7, TCP above 99% was demonstrated with 100 Gy and CCD of 10(4)cells/cm(3) or 140 Gy and CCD of 10(7) cells/cm(3). TCP decreased with lower alpha/beta of 1.5, but at a much smaller scale compared to SF(2) changes. TCP modeling predicts that SF(2) and CCD are dominant predictors of radioresistance in prostate cancer. Radiation doses of 100 Gy or greater may be required for tumors with SF(2) of 0.6 or above. Relating clinical tumor prognostic indicators such as Gleason score and PSA to radiobiological parameters will allow us to identify subsets of patients in need of higher radiation doses and adjuvant therapy to maximize treatment outcomes.

Impact of respiratory gating using 4-dimensional computed tomography on the dosimetry of tumor and normal tissues in patients with thoracic malignancies.

OBJECTIVE: The purpose of this study is to assess the dosimetric impact of gated CT plans on tumor and surrounding normal tissues in patients with primary thoracic malignancies. MATERIALS AND METHODS: Ten patients underwent treatment planning with gated and nongated CT at Wayne State University. Gated CT images were obtained at full inspiration, expiration, and at the 25th, 50th, and 75th percentile of respiratory effort. Planning treatment volume (PTV) margin for nongated and gated plans was 1.5 cm and 0.5 cm, respectively. The tumor prescription dose was 60 to 70 Gy at 2 Gy per fraction. RESULTS: Average PTV was 292.68 mL for gated and 575.17 mL for nongated plans. Gated plans resulted in higher minimum PTV doses and comparable mean and maximum doses when compared with nongated plans (53.52, 65.17, and 70.92 Gy vs. 48.06, 65.08, and 71.40 Gy, respectively). Volumes of lung receiving doses of 20 and 10 Gy or above were 26.26% and 30.96% for gated plans and 34.82% and 40.16% for nongated plans (P < 0.0001). Gated plans resulted in lower mean lung, esophageal, and heart doses compared with nongated plans (14.27, 17.28, and 10.86 Gy vs. 19.5, 21.85, and 16.45 Gy, respectively; P

Impact of endorectal balloon in the dosimetry of prostate and surrounding tissues in prostate cancer patients treated with IMRT.

The dosimetric effect of endorectal balloon repositioning or failure was assessed in 10 prostate cancer patients treated with intensity modulated radiation therapy (IMRT). Three extreme clinical scenarios were simulated by placing the balloon in the most superior and inferior positions within the rectum and by removing the balloon. Treatment planning was performed by obtaining a computed tomography (CT) image with the balloon in the most superior position (plan 1). Subsequently, the isodose lines of plan 1 were superpositioned over the anatomy of 2 other CTs, one obtained with the balloon in the most inferior position and another without the balloon (plans 2 and 3, respectively). Dose-volume histograms (DVHs) of the prostate and surrounding tissues were generated and compared for all 3 plans. The prescribed radiation dose to the prostate and seminal vesicles was 70 Gy in 35 fractions. Balloon repositioning resulted in significant changes only for the seminal vesicles, where the minimum doses decreased from 70.39 to 61.58 Gy, and the percent volume below 70 Gy increased from 1.62% to 8.39%. Balloon failure resulted in significant decreases in mean and minimum doses for prostate from 74.36 to 72.84 Gy and 67.62 to 50.96 Gy, respectively. Similar decreases in the mean and minimum doses were also observed for seminal vesicles from 74.21 to 64.43 Gy and 70.39 to 41.74 Gy, respectively. Balloon repositioning did not affect normal tissue doses, while balloon failure significantly decreased the upper rectum mean doses from 30.79 to 19.38 Gy. This study demonstrates that repositioning of the endorectal balloon results in increased dose inhomogeneity for seminal vesicles, while balloon failure causes significant prostate and seminal vesicle underdosing without overdosing normal tissues.

Role of ovarian transposition based on the dosimetric effects of craniospinal irradiation on the ovaries: a case report.

In this study, we present a case of laparoscopic ovarian transposition to preserve ovarian function in an adult female patient treated with craniospinal irradiation for standard risk medulloblastoma. The prescribed dose to the craniospinal axis was 2340 cGy at 180 cGy per fraction and was delivered with 6-MV photons. Before ovarian transposition, magnetic resonance imaging (MRI) of the pelvis was obtained for localization of the ovaries and was registered with the planning computed tomography (CT) scan. Surgical clips allowed for CT localization of the ovaries after transposition. As a result of ovarian transposition, mean and maximum radiation doses decreased from 983 to 68 cGy and 1624 to 84 cGy for the left ovary and from 166 to 87 cGy and 723 to 103 cGy for the right ovary, respectively. Review of the literature indicates that such radiation doses are below the threshold that causes ovarian dysfunction and infertility. We conclude that ovarian localization with an MRI of the pelvis can be offered to females undergoing craniospinal irradiation. Transposition of the ovaries provides an option to preserve ovarian function in cases where the ovaries would otherwise be included within the radiation field.

Intensity modulated radiation therapy versus three-dimensional conformal radiation therapy for the treatment of high grade glioma: a dosimetric comparison.

The present study compared the dosimetry of intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3D-CRT) techniques in patients treated for high-grade glioma. A total of 20 patients underwent computed tomography treatment planning in conjunction with magnetic resonance imaging fusion. Prescription dose and normal-tissue constraints were identical for the 3D-CRT and IMRT plans. The prescribed dose was 59.4 Gy delivered at 1.8 Gy per fraction using 4-10 MV photons. Normal-tissue dose constraints were 50-54 Gy for the optic chiasm and nerves, and 55-60 Gy for the brainstem. The IMRT plan yielded superior target coverage as compared with the 3D-CRT plan. Specifically, minimum and mean planning target volume cone down doses were 54.52 Gy and 61.74 Gy for IMRT and 50.56 Gy and 60.06 Gy for 3D-CRT (p < or = 0.01). The IMRT plan reduced the percent volume of brainstem receiving a dose greater than 45 Gy by 31% (p = 0.004) and the percent volume of brain receiving a dose greater than 18 Gy, 24 Gy, and 45 Gy by 10% (p = 0.059), 14% (p = 0.015), and 40% (p < or = 0.0001) respectively. With IMRT, the percent volume of optic chiasm receiving more than 45 Gy was also reduced by 30.40% (p = 0.047). As compared with 3D-CRT, IMRT significantly increased the tumor control probability (p < or = 0.005) and lowered the normal-tissue complication probability for brain and brainstem (p < 0.033). Intensity-modulated radiation therapy improved target coverage and reduced radiation dose to the brain, brainstem, and optic chiasm. With the availability of new cancer imaging tools and more effective systemic agents, IMRT may be used to intensify tumor doses while minimizing toxicity, therefore potentially improving outcomes in patients with high-grade glioma.

Phase I/II trial of external irradiation plus medium-dose brachytherapy given concurrently to liposomal doxorubicin and cisplatin for advanced uterine cervix carcinoma.

BACKGROUND AND PURPOSE: Although the standard of care for patients with locally advanced uterine cervix carcinoma is cisplatin-(CDDP-)based chemotherapy and irradiation (RT), the optimal regimen remains to be elucidated. A phase I/II study was conducted to evaluate the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of liposomal doxorubicin (Caelyx) combined with CDDP and RT for cervical cancer. PATIENTS AND METHODS: 24 patients with stage IIB-IVA were enrolled (Table 1). They all received external RT (up to 50.4 Gy) and two medium-dose rate (MDR) brachytherapy implants (20 Gy each at point A). The Caelyx starting dose of 7 mg/m2/week was increased in 5-mg/m2 increments to two levels. The standard dose of CDDP was 20-25 mg/m2/week. RESULTS: Concurrent chemoradiation (CCRT) sequelae and the DLTs (grade 3 myelotoxicity and grade 3 proctitis in five patients treated at the 17 mg/m2/week Caelyx dose level) are shown in Tables 2, 3, 4, and 5. After a median follow-up time of 17.2 months (range 4-36 months), four patients had died, 15 showed no evidence of progressive disease, and five (20.8%, 95% confidence interval [CI]: 12.5-29.1%) were alive with relapse (Figure 1). There were seven complete (29.1%, 95% CI: 19.8-38.4%) and 17 partial clinical responses (95% CI: 61.1-80.1%). The median progression-free survival was 10.4 months. Causes of death were local regional failure with or without paraaortic node relapse combined with distant metastases (Table 6). CONCLUSION: The MTD of Caelyx given concurrently with CDDP and RT was determined at the 12 mg/m2/week dose level. The above CCRT schema is a well-tolerated regimen, easy to administer in ambulatory patients, and results appear promising.

Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer.

The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.

IMRT versus conventional 3DCRT on prostate and normal tissue dosimetry using an endorectal balloon for prostate immobilization.

This study was undertaken to compare prostate and normal tissue dosimetry in prostate cancer patients treated with intensity-modulated radiation therapy (IMRT) and conventional 3-dimensional conformal radiotherapy (3DCRT) using an endorectal balloon for prostate immobilization. Ten prostate cancer patients were studied using both IMRT and conventional 3DCRT at Houston Veterans Affairs Medical Center. For IMRT, the prescription was 70 Gy at 2 Gy/fraction at the 83.4% isodose line, allowing no more than 15% of the rectum and 33% of the bladder to receive above 68 and 65 Gy, respectively. For conventional 3DCRT, a 6-field arrangement with lateral and oblique fields was used to deliver 76 Gy at 2Gy/fraction, ensuring complete tumor coverage by the 72-Gy isodose line. Mean doses for prostate and seminal vesicles were 75.10 and 75.11 Gy, respectively, for IMRT and 75.40 and 75.02 Gy, respectively, for 3DCRT (p > 0.218). 3DCRT delivered significantly higher doses to 33%, 50%, and 66% volumes of rectum by 3.55, 6.64, and 10.18 Gy, respectively (p < 0.002), and upper rectum by 7.26, 9.86, and 9.16 Gy, respectively (p < 0.007). 3DCRT also delivered higher doses to femur volumes of 33% and 50% by 9.38 and 10.19 Gy, respectively, (p < 0.001). Insignificant differences in tumor control probability (TCP) values between IMRT and 3DCRT were calculated for prostate (p = 0.320) and seminal vesicles (p = 0.289). Compared to 3DCRT, IMRT resulted in significantly reduced normal tissue complication probability (NTCP) only for upper rectum (p = 0.025) and femurs (p = 0.021). This study demonstrates that IMRT achieves superior normal tissue avoidance, especially for rectum and femurs compared to 3DCRT, with comparable target dose escalation.