Maria T. Vlachaki

Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer--a preliminary report.

PURPOSE To report the preliminary results of a Phase I/II study combining radiotherapy and in situ gene therapy (adenovirus/herpes simplex virus thymidine kinase gene/valacyclovir) with or without hormonal therapy in the treatment of prostate cancer. METHODS AND MATERIALS Arm A: low-risk patients (T1-T2a, Gleason score <7, pretreatment PSA <10) were treated with combined radio-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated radiotherapy. Arm B: high-risk patients (T2b-T3, Gleason score >or=7, pretreatment PSA >or=10) were treated with combined radio-gene therapy and hormonal therapy. Hormonal therapy was comprised of a 4-month leuprolide injection and 2-week use of flutamide. Arm C: Stage D1 (positive pelvic lymph node) patients received the same regimen as Arm B, with the additional 45 Gy to the pelvic lymphatics. Treatment-related toxicity was assessed using Cancer Therapy Evaluation Program common toxicity score and Radiation Therapy Oncology Group (RTOG) toxicity score. RESULTS Thirty patients (13 in Arm A, 14 in Arm B, and 3 in Arm C) completed the trial. Median follow-up was 5.5 months. Eleven patients (37%) developed flu-like symptoms (Cancer Therapy Evaluation Program Grade 1) of fatigue and chills/rigors after gene therapy injection but recovered within 24 h. Four patients (13%) and 2 patients (7%) developed Grade 1 and 2 fever, respectively. There was no patient with weight loss. One patient in Arm B developed Grade 3 elevation in liver enzyme, whereas 11 and 2 patients developed Grade 1 and 2 abnormal liver function tests. There was no Grade 2 or above hematologic toxicity. Three patients had transient rise in creatinine. There was no RTOG Grade 3 or above lower gastrointestinal toxicity. Toxicity levels were as follows: 4 patients (13%), Grade 2; 6 patients (20%), Grade 1; and 20 patients (67%), no toxicity. There was 1 patient with RTOG Grade 3 genitourinary toxicity, 12 patients (40%) with Grade 2, 8 patients (27%) with Grade 1, and 9 patients (30%) with no toxicity. No patient dropped out from the trial or had to withhold treatment because of severe toxicity. CONCLUSIONS This is the first trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of radiotherapy by combining in situ gene therapy. Initial experience has demonstrated the safety of this approach. There is no added toxicity to each therapy used alone. Long-term follow-up and larger cohort studies are warranted to evaluate long-term toxicity and efficacy.

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≤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≤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≤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. PACs number: 87.53 Tf

CLINICAL EXPERIENCE WITH INTENSITY-MODULATED RADIATION THERAPY (IMRT) FOR PROSTATE CANCER WITH THE USE OF RECTAL BALLOON FOR PROSTATE IMMOBILIZATION

The implementation of intensity-modulated radiation therapy (IMRT) is the result of advances in imaging, radiotherapy planning technologies, and computer-controlled linear accelerators. IMRT allows both conformal treatment of tumors and conformal avoidance of the surrounding normal structures. The first patient treated with Peacock IMRT at Baylor College of Medicine took place in March 1994. To date, more than 1500 patients have been treated with IMRT; more than 700 patients were treated for prostate cancer. Our experience in treating prostate cancer with IMRT was reviewed. Patient and prostate motions are important issues to address in delivering IMRT. The Vac-Lok bag-and-box system, as well as rectal balloon for immobilization of patient and prostate gland, respectively, are employed. Treatment planning also plays a very important role. IMRT as a boost after conventional external beam radiotherapy is not our treatment strategy. To derive maximal benefits with this new technology, all patients received full course IMRT. Three separate groups of patients receiving (1) primary IMRT, (2) combined radioactive seed implant and IMRT, and (3) post-prostatectomy IMRT were addressed. Overall, toxicity profiles in these patients were very favorable. IMRT has the potential to improve treatment outcome with dose escalation while minimizing treatment-related toxicity.

Long-term outcome of treatment for ann arbor stage 1 Hodgkin's disease : Patterns of failure, late toxicity and second malignancies

PURPOSE Radiation therapy results in excellent short-term survival in patients with early-stage Hodgkins disease. However, the optimal therapeutic scheme that achieves the highest disease-free survival with the minimum long-term toxicity is yet to be determined. An analysis of the patterns of failure and late complications after radiation therapy was conducted to address this question. METHODS AND MATERIALS A retrospective study was conducted of 145 patients with Stage I Hodgkins disease treated at M. D. Anderson Cancer Center from 1967 through 1987. Follow-up extended from a minimum of 30 to 339 months, with a median period of observation of 16.5 years. All the patients were treated with radiation therapy and, and 16 received combination MOPP-based chemotherapy as part of their initial treatment. The radiotherapy technique, was involved/regional in 71 (49%), extended in 62 (43%), and subtotal nodal irradiation in 12 patients. The median total dose was 40 Gy. RESULTS The actuarial freedom from progression at 10 and 20 years was 76% and 69%, respectively. Forty of 145 patients relapsed (27.6%). The site of primary disease was cervical adenopathy in 30 (75%), axillary in 7 (17.5%), mediastinal in 2 patients and subdiaphragmatic in one patient. Twenty-two patients were treated with involved/regional technique (55%), 17 with extended (42.5%), and 1 with subtotal nodal irradiation technique. There were three in field and four marginal recurrences. Six relapses occurred in non-irradiated nodal regions at the same side of the diaphragm and 17 in non-irradiated transdiaphragmatic lymph nodes (57.5%). Nine patients (22.5%) relapsed with visceral disease. Nineteen patients (47.5%) relapsed within the first 2 years, 15 (37.5%) 3 to 10 years after diagnosis and the remaining 6 (15%) after 10 years. Eleven of 40 patients died of disease after the first or subsequent relapses (27.5%). Three of six patients with late relapses had progression in viscera but only two died with disease. Thirty-eight of 145 patients developed late toxicity from the treatment (26.2%). Twenty-three patients experienced ischemic heart disease (15.9%), only 13 of whom received mediastinal irradiation (9%). Fifteen patients developed secondary malignant solid tumors (10.3%). Nine of those (6.2%) occurred within the irradiation field (two were also treated with chemotherapy). Two additional patients, one of whom received chemotherapy as part of the initial treatment, died of acute myelogenous leukemia. Non-Hodgkins lymphoma and lung cancer were the most common second malignancies. CONCLUSIONS Limited field radiotherapy results in a significant number of relapses in non-irradiated, especially transdiaphragmatic lymph nodes. Subtotal nodal irradiation can prevent some relapses and therefore improve freedom from progression. Careful design of the treatment fields may decrease the risk of morbidity and mortality from coronary artery disease and second malignancies in early-stage Hodgkins disease. Careful long-term surveillance may permit early detection and management of late relapses and treatment complications.

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. PACS number: 80

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). Noncoplanar 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. PACS number: 87

Astro research fellowship: the role of bcl-2 and glutathione in an antioxidant pathway to prevent radiation-induced apoptosis

PURPOSE The expression of the bcl-2 proto-oncogene has been associated with resistance to radiation-induced apoptosis. There is evidence that the bcl-2 protein acts in an antioxidant pathway to block the effects of reactive oxygen species that mediate apoptosis possibly by increasing the levels of intracellular glutathione. Our hypothesis is that pretreatment of radiation-sensitive cells, known to lack bcl-2 expression, with antioxidants will reduce radiation-induced apoptosis. For this purpose, the apoptotic response to radiation and the intracellular levels of GSH were tested before and after pretreatment with antioxidants in two murine lymphoma cell lines, a radiation-resistant, bcl-2- expressing (LY-ar) line and a radiation-sensitive, non-bcl-2-expressing (LY-as) line. METHODS AND MATERIALS LY-ar and LY-as cells were irradiated at 0,1,2,3, and 4 hours before collection. The intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were determined by the use of the fluorescent dye o-phthalaldehyde. LY-as cells were treated with GSH ethyl-ester for 1 and 2 hours after irradiation. Apoptotic response was measured by the DNA fragmentation assay. The radiation dose was 2.5 Gy. RESULTS After irradiation, the apoptotic rate of LY-ar and LY-as cells was 10-20% and 50-70% respectively. LY-ar cells had higher intracellular GSH and GSSG levels compared to LY-as cells by 69.9% and 91.9% respectively and the GSH/GSSG ratio in LY-ar and LY-as cells was 15.09 and 17.09 respectively. GSH levels did not change during the first 2 hours after irradiation; however, there was a 49% and 84% reduction at 3 and 4 hours after irradiation, respectively, times at which the LY-as cells have already fragmented their DNA. Treatment of LY-as cells with GSH ethyl-ester at a concentration of 7 mM for 1 and 2 hours resulted in 70% and 231% increases in the intracellular GSH levels respectively. Treatment of LY-as cells with GSH ethyl-ester for 1 and 2 hours also conferred a 25-50% decrease in their apoptotic response after irradiation. CONCLUSIONS GSH and GSSG levels are elevated in radiation-resistant, bcl-2-expressing murine lymphoma cells compared to radiation-sensitive, non-bcl-2-expressing cells. GSH levels decline only in radiation-sensitive cells after irradiation but this appears to occur at the time of apoptotic cell death. Exogenous thiols increase intracellular GSH levels and repress radiation-induced apoptosis. In conclusion, intracellular thiols appear to be involved in protecting cells from apoptotic cell death. Further investigation should be directed in identifying substances which by lowering intracellular thiols may result in sensitization to radiation.

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 2.4 mm, 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. PACS numbers: 87.55.‐x, 87.55.kd, 87.90.+y

Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-α mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adβgal, Adβgal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

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 ≤ 0.003). Conclusions:4-Dimensional computed tomography (4D-CT) respiratory gating significantly decreases target volumes and normal tissue dosing. With the emerging image-guided radiation therapy technology, 4D-CT treatment planning may be used for radiation dose escalation with tighter radiation fields and has the potential for improving outcomes in patients with thoracic malignancies.