A non-human primate model of acute liver failure suitable for testing liver support systems.

Acute hepatic failure is associated with high morbidity and mortality for which the only definitive therapy is liver transplantation. Some fraction of those who undergo emergency transplantation have been shown to recover native liver function when transplanted with an auxiliary hepatic graft that leaves part of the native liver intact. Thus, transplantation could have been averted with the development and use of some form of hepatic support. The costs of developing and testing liver support systems could be dramatically reduced by the availability of a reliable large animal model of hepatic failure with a large therapeutic window that allows the assessment of efficacy and timing of intervention. Non-lethal forms of hepatic injury were examined in combination with liver-directed radiation in non-human primates (NHPs) to develop a model of acute hepatic failure that mimics the human condition. Porcine hepatocyte transplantation was then tested as a potential therapy for acute hepatic failure. After liver-directed radiation therapy, delivery of a non-lethal hepatic ischemia-reperfusion injury reliably and rapidly generated liver failure providing conditions that can enable pre-clinical testing of liver support or replacement therapies. Unfortunately, in preliminary studies, low hepatocyte engraftment and over-immune suppression interfered with the ability to assess the efficacy of transplanted porcine hepatocytes in the model. A model of acute liver failure in NHPs was created that recapitulates the pathophysiology and pathology of the clinical condition, does so with reasonably predictable kinetics, and results in 100% mortality. The model allowed preliminary testing of xenogeneic hepatocyte transplantation as a potential therapy.

A 58-Year-Old Woman with Left-Sided Weakness and a History of a Pediatric Brain Tumor: A Case Report.

BACKGROUND: An uncommon but well-established complication of cranial irradiation is secondary neoplasm. This case presentation documents a radiation-induced malignant glioma 55 years after being diagnosed with "cerebral sarcoma," now defined as atypical meningioma. This not only represents the longest reported latency period for a patient initially receiving over 30 Gy, but also provides a valuable historical perspective of neuro-oncology. CLINICAL PRESENTATION: A 58-year-old female presenting with progressive left-sided upper and lower extremity weakness with a past medical history significant for "cerebral sarcoma" was diagnosed with glioblastoma multiforme. This patient had previously been treated with resection and adjuvant radiation therapy via a 280-kVP orthovoltage machine and received 3,390 rad to the posterior three-quarters of the skull for "cerebral sarcoma." CONCLUSION: A comprehensive investigation of the past medical history helped uncover a mysterious pediatric diagnosis, helped drive the management 5 decades later, and serves as a reminder that seemingly safe interventions may still cause harm.

Host conditioning and rejection monitoring in hepatocyte transplantation in humans.

BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

Prognostic implications of immediate PSA response to early salvage radiotherapy.

INTRODUCTION: Up to 25% of men with prostate cancer who undergo radical prostatectomy will recur. In this setting, salvage radiotherapy may cure patients with local recurrence, but is unable to cure those with occult metastatic disease. The objective of this study is to examine how prostate-specific antigen (PSA) response to radiotherapy predicts subsequent disease progression and survival. MATERIALS AND METHODS: Using a prospectively populated database of 3089 men who underwent open radical prostatectomy, 212 patients (7%) were identified who received early salvage radiotherapy for biochemical recurrence. The main outcome was time to disease progression after salvage radiotherapy. Patients were stratified by PSA response after radiotherapy: 1) PSA < 0.1 ng/mL, 2) persistently detectable PSA, and 3) rising PSA. RESULTS: Patients received salvage radiotherapy at a median PSA of 0.20 ng/mL (IQR 0.10-0.30 ng/mL). At a median follow up of 47.3 months, a total of 52 (25%) patients experienced disease progression. On multivariable analysis, both persistent PSA (HR 5.12; 95% CI 1.98-13.23) and rising PSA (HR 16.55; 95% CI 6.61-41.48) were associated with increased risk of disease progression compared to those with PSA < 0.1 ng/mL after adjusting for pre-radiotherapy PSA, Gleason score, margin status, stage, and time to radiotherapy. Only rising PSA was associated with an increased risk of cancer-specific and all-cause mortality. CONCLUSIONS: PSA response is associated with the risk of disease progression following salvage radiotherapy. This information can be used to counsel patients on the potential need for additional therapy and identify those at greatest risk for progression and cancer-related mortality.

Identification of Unique, Heterozygous Germline Mutation, STK11 (p.F354L), in a Child with an Encapsulated Follicular Variant of Papillary Thyroid Carcinoma within Six Months of Completing Treatment for Neuroblastoma.

Papillary thyroid carcinoma (PTC) is rare in children, although it is a known secondary malignancy after treatment for neuroblastoma (NB). The interval between NB treatment completion and PTC is usually more than 5 years. A 4-year-old, female patient with a high risk adrenal NB was found to have a 2.9-cm, right thyroid nodule on surveillance chest computed tomography (CT) 6 months after completion of her NB treatment (induction chemotherapy, tumor resection, autologous stem cell transplantation, external beam radiation to the abdominal tumor site, immunotherapy, and retinoic acid). Posttreatment surveillance included iodine-123-metaiodobenzylguanidine scans and CT scans. Fine-needle aspiration of the thyroid nodule diagnosed a follicular neoplasm, which was negative for BRAF, NRAS, KRAS, HRAS, PAX8/PPARg, and RET/PTC mutations, without evidence of metastatic NB. Nodule histology demonstrated an encapsulated follicular variant of PTC (FVPTC). Next-generation sequence analysis for a 46 cancer-gene profile was performed on both tumors with subsequent peripheral blood DNA testing. A heterozygous missense mutation in STK11 (F354L) was identified in both the NB and FVPTC. This mutation was also detected in peripheral blood mononuclear cells. Two additional heterozygous somatic missense mutations of uncertain significance were identified: KDR/VEGF receptor 2 (Q472H) on chromosome 4 and MET (N375S) on chromosome 7. To our knowledge, this is the shortest reported duration from completion of NB treatment to detection of thyroid cancer. The association of the STK11 gene with Peutz-Jeghers syndrome, lung adenocarcinomas, and medullary thyroid cancer leads to a possible association between this genetic variant and our patient's tumors.

Pseudoprogression of low-grade gliomas after radiotherapy.

BACKGROUND: Increasing mass effect following radiation therapy (RT) in patients with low-grade gliomas (LGGs) can be mistaken for tumor progression and/or malignant degeneration. Distinguishing pseudoprogression (PP) from true progression is crucial, with vastly different treatment approaches and prognoses. PROCEDURE: Patients treated with RT for LGGs through the Children's Hospital of Pittsburgh Neuro-Oncology Program are considered to have PP and managed conservatively if they develop increased mass effect within 3 years of RT. Pre-RT tumor area was compared to the maximum tumor size following RT and the size on the last follow-up scan by a central reviewer. RESULTS: Twenty-four children, median age 13 years, received external beam RT for LGG between March 2000 and August 2011. Thirteen patients (54.2%) developed an increase in tumor size compared to baseline beginning at a median of 6 months after RT and lasting for a median of 2.1 years (range 6.5 months to 5.1 years). Maximum tumor enlargement occurred at a median of 8 months after RT, with a range (5 months to 4.2 years). In all 13 cases, the tumor eventually decreased in size without additional anti-tumor therapy. Two patients (8.3%) developed true tumor progression. With a median follow-up of 4.9 years (range 1.0-12.4 years), all patients are alive. CONCLUSIONS: Pseudoprogression occurred in more than half of the children with LGG following RT, typically beginning within 8 months and often running a very protracted course. Late presentations can also occur.

A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury.

BACKGROUND: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. METHODS AND MATERIALS: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. RESULTS: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. CONCLUSIONS: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year WT survivors in the Childhood Cancer Survivor Study (CCSS). PROCEDURE: The CCSS, a multi-institutional retrospective cohort study, assessed WT survivors (N = 1,256), diagnosed 1970-1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (N = 4,023). RESULTS: The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard ratios (HR) were 2.0, 95% confidence interval (CI) 1.8-2.3 for grades 1-4 and 4.7, 95%CI 3.6-6.1 for grades 3 and 4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (prevalence ratio [PR] 1.7; 95%CI 1.2-2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI 1.9-4.0%) and of mortality was 6.1% (95%CI 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin-HR 6.6; 95%CI 1.6-28.3; doxorubicin ≤ 250 mg/m(2) -HR 13.0; 95%CI 1.9-89.7; doxorubicin >250 mg/m(2) -HR 18.3; 95%CI 3.8-88.2), SMN (standardized incidence ratio [SIR] 9.0; 95%CI 3.9-17.7 with and 4.9; 95%CI 1.8-10.6 without doxorubicin) and death. CONCLUSION: Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.

Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03.

PURPOSE: Although chemoradiotherapy plus resection is considered standard treatment for operable rectal carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant chemoradiotherapy in the treatment of locally advanced rectal carcinoma. PATIENTS AND METHODS: Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence. CONCLUSION: Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.

Initial outcomes analysis for large multicenter integrated cancer network implementation of intensity modulated radiation therapy for breast cancer.

To analyze the initial clinical outcomes for breast cancer patients treated with intensity-modulated radiation therapy (IMRT) in a large integrated cancer center network. A total of 495 patients with breast cancer received IMRT following breast conserving surgery among nine cancer centers. Seven community cancer centers span a 100-mile radial distance from the two central academic sites. All nine cancer centers followed the same clinical pathway guidelines for the radiotherapeutic management of breast cancer. IMRT planning for all centers was performed at one central location, D3 Advanced Radiation Planning Service. The median IMRT prescription dose was 50 Gy followed by a boost with median dose of 10 Gy. The median breast volume was 918 cm(3). The median Dose Homogeneity Index (DHI) was 93%. The median % of ipsilateral lung volume receiving >20 Gy was 4.6%. For left breast IMRT, the median % heart volume receiving more than 5% of prescription dose was 13.1. There was no statistical difference in the mean DHI, heart and lung dose between the academic and community sites. For all patients, NCI CTC Grades 0,1,2,3 for acute skin erythema was 16%, 55%, 28%, and 1%, respectively. The rates of Grade 0,1,2,3 acute skin desquamation were 75%, 20%, 4%, and 1%, respectively. There was no statistically significant difference in acute skin toxicities (>grade 2) among the academic and community cancer centers. With centralized processes, IMRT can be safely and effectively delivered in a large health system with an admixture of academic and community centers but long-term follow-up is necessary.

The incidence of arm edema in women with breast cancer randomized on the National Surgical Adjuvant Breast and Bowel Project study B-04 to radical mastectomy versus total mastectomy and radiotherapy versus total mastectomy alone.

PURPOSE: To determine the incidence and factors associated with the development of arm edema in women who participated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study B-04. METHODS AND MATERIALS: Between 1971 and 1974, the NSABP protocol B-04 randomized 1,665 eligible patients with resectable breast cancer to either (1) the Halstead-type radical mastectomy; (2) total mastectomy and radiotherapy to the chest wall, axilla, supraclavicular region, and internal mammary nodes if by clinical examination axillary nodes were involved by tumor; and (3) for patients with a clinically uninvolved axilla, a third arm, total mastectomy alone. Measurements of the ipsilateral and contralateral arm circumferences were to be performed every 3 months. RESULTS: There was at least one recorded measurement of arm circumferences for 1,457 patients (87.5% of eligible patients). There were 674 women (46.3%) who experienced arm edema at some point during the period of follow-up until February 1976. For radical mastectomy patients, total mastectomy and radiotherapy patients, and total mastectomy patients alone, arm edema was recorded at least once in 58.1%, 38.2%, and 39.1% of patients, respectively (p<.001) and at last recorded measurement in 30.7%, 14.8%, and 15.5%, respectively (p=or<.001). Increasing body mass index (BMI) also showed a statistically significant correlation with arm edema at any time (p=.001) and at last assessment (p=.005). CONCLUSIONS: Patients who undergo mastectomy, including those whose treatment plans do not include axillary dissection or postoperative radiotherapy, suffer an appreciable incidence of arm edema.

An association between postoperative radiotherapy for primary breast cancer in 11 National Surgical Adjuvant Breast and Bowel Project (NSABP) studies and the subsequent appearance of pleural mesothelioma.

OBJECTIVES: Among the minority of patients with pleural mesothelioma and no known exposure to asbestos, there have been case reports suggesting a possible association with previous radiotherapy. The association between radiotherapy for primary breast cancer and the subsequent occurrence of mesothelioma was investigated in women entered into 11 National Surgical Adjuvant Breast and Bowel Project (NSABP) prospective clinical trials for breast cancer. METHODS: Follow-up information was obtained on 22,140 patients entered into 11 NSABP clinical trials for treatment of primary breast cancer between 1971 and 1994. Postoperative radiotherapy was administered to 9342 patients, mainly after lumpectomy. Postlumpectomy patients were treated with radiotherapy just to the ipsilateral breast and without regional nodal irradiation. There were 12,798 patients who did not have postoperative radiotherapy, and almost all had mastectomy. RESULTS: Three pleural mesotheliomas were identified, and all occurred in the ipsilateral thorax of the irradiated patients (P = 0.009). All had received postlumpectomy breast irradiation for ductal carcinoma in situ. None had a known previous exposure to asbestos. CONCLUSIONS: There appears to be a small but statistically significant increased risk of developing mesothelioma following radiotherapy administered for primary breast cancer. However, in absolute numbers, the risk is too small to be considered a contraindication to administering radiotherapy when indicated.

Breast skin doses from brachytherapy using MammoSite HDR, intensity modulated radiation therapy, and tangential fields techniques.

Skin doses from brachytherapy using MammoSite HDR, Intensity Modulated Radiation Therapy (IMRT), and conventional tangential fields techniques were compared. For each treatment technique, skin doses were measured using paired thermoluminescent dosimeters placed on the patient's skin: (i) directly above the balloon catheter during MammoSite HDR brachytherapy treatments and (ii) 4 cm inside the treatment borders during the IMRT and conventional breast treatments. The mean dose measured was about 58% of the prescription dose for the patients treated using the MammoSite technique. On the other hand, for patients treated with IMRT and tangential fields, the mean dose was found to be about 69% and 71% of the corresponding prescription dose. This study suggests that in breast cancer radiation treatments the MammoSite HDR technique reduces skin doses compared to IMRT and tangential field techniques.

The Role for intensity modulated radiation therapy (IMRT) in pediatric population.

The purpose of this study was to evaluate our initial experience on the use of IMRT in children with tumors in eloquent or critical locations. Twenty-two children with a median age of 12 years (range 1-17) were treated using IMRT for tumors which were within 2 cm of a critical structure. The treatment locations were spine [2], head and neck [5], abdominopelvic [8], and intracranial [7]. Eighty-two percent (82%) of patients were treated with curative intent despite most patients having advanced or metastatic disease and two patients having previously received standard external beam radiation. IMRT was delivered with a 6MV linear accelerator using dynamic multileaf collimators with a median of six fields. The median follow-up was five months [1-21]. The median administered dose was 45 Gy. The median planning treatment volume (PTV) was 105.4 cc. For the intracranial lesions, the mean doses to the pituitary, brainstem, cochlea, optic nerve, and lens were 31%, 42%, 17%, 27%, and 6% of the total dose, respectively. For the head and neck tumors, the mean doses to the spinal cord and parotid glands were 47% and 49%, respectively. For the pelvic tumors, the mean dose to the bladder, rectum, and small bowel were 51%, 63%, and 22%, respectively. Local failure occurred in one patient. IMRT resulted in substantial sparing of surrounding critical structures and acceptable local control rate for these tumors in children. Further follow-up is needed to assess long-term local control and late effects.

Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials.

PURPOSE: Lymph node (LN) -negative breast cancer tumors > or = 5 cm occur infrequently, and their optimal management is not well defined. In this study, we assess patterns of locoregional failure (LRF) in LN-negative patients who underwent mastectomy, either with or without adjuvant chemotherapy or hormonal therapy and without postmastectomy radiation therapy (PMRT). PATIENTS AND METHODS: Of 8,878 breast cancer patients enrolled onto National Surgical Adjuvant Breast and Bowel Project B-13, B-14, B-19, B-20, and B-23 node-negative trials, 313 had tumors that were 5 cm or larger (median, 5.5 cm; range, 5.0 to 15.5 cm) at pathology and were treated by mastectomy. Median follow-up time was 15.1 years. Therapy included adjuvant chemotherapy in 34.2% of patients; tamoxifen in 21.1%; chemotherapy plus tamoxifen in 19.2%; and no systemic therapy in 25.5%. RESULTS: Twenty-eight patients experienced LRF. The overall 10-year cumulative incidences of isolated LRF, LRF with and without distant failure (DF), and DF alone as first event were 7.1%, 10.0%, and 23.6%, respectively. Cumulative incidences for isolated LRF as first event for patients with tumors of 5 cm or more than 5 cm were 7.0% and 7.2%, respectively (P = .9). For patients who underwent no systemic treatment, chemotherapy alone, tamoxifen alone, or chemotherapy plus tamoxifen, the incidences were 12.6%, 5.6%, 4.6%, and 5.3%, respectively (P = .2). The majority of failures occurred on the chest wall (24 of 28 patients). Multivariate analysis did not identify significant prognostic factors for LRF. CONCLUSION: In patients with LN-negative tumors > or = 5 cm who are treated by mastectomy with or without adjuvant systemic therapy and no PMRT, LRF as first event remains low. PMRT should not be routinely used for these patients.

Does breast size affect the scatter dose to the ipsilateral lung, heart, or contralateral breast in primary breast irradiation using intensity-modulated radiation therapy (IMRT)?

PURPOSE: To evaluate the relationship between the primary breast volume and dose received by the ipsilateral lung, heart (for left-breast cancers), and contralateral breast during primary breast irradiation using intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Sixty-five patients with breast carcinoma were treated using 6-MV photons with IMRT technique using the Eclipse Planning System following breast conserving surgery. All patients had a treatment planning CT scan. The primary breast, ipsilateral lung, and heart were contoured on the axial CT slices. The primary breast volume was calculated using the Eclipse Planning System. The mean ipsilateral lung and heart doses were obtained from the dose-volume histogram. The contralateral breast dose was measured using paired thermoluminescent dosimeters (TLDs) placed on the patient's contralateral breast, 4 cm from the center of the medial border of the primary breast irradiation field. RESULTS: The mean dose delivered with photons to the primary breast for all patients was 49.97 Gy. The mean volume of the primary irradiated breast was 1167.9 cc. As a percentage, the mean ipsilateral lung, heart, and contralateral breast doses were 11.2%, 6.1%, and 7.2%, respectively. The primary breast volume positively correlated with the contralateral breast dose (P < 0.0005). There was no significant correlation between the breast volume and the ipsilateral lung or heart dose (P = 0.463 and 0.943, respectively). CONCLUSION: This study suggests that the primary breast size significantly affects the scatter dose to the contralateral breast but not the ipsilateral lung or heart dose when using IMRT for breast irradiation.

Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers.

PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated. METHODS: Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography. RESULTS: Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion. CONCLUSION: Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

Intensity modulated radiation therapy (IMRT) reduces the dose to the contralateral breast when compared to conventional tangential fields for primary breast irradiation.

PURPOSE: To determine the dose received by the contralateral breast during primary breast irradiation using IMRT compared to conventional tangential field techniques. METHODS AND MATERIALS: Between March 2003 and March 2004, 83 patients with breast carcinoma were treated using 6, 10, or mixed 6/18 MV photons (65 with tangential IMRT technique and 18 with 3-dimensional technique using tangential fields with wedges) for primary breast irradiation following breast-conserving surgery. Paired thermoluminescent dosimeters (TLDs) were placed on each patient's contralateral breast, 4 and 8 cm from the center of the medial border of the tangential field. The TLDs were left on the patient during a single fraction and then measured 24 h afterwards. RESULTS: The mean dose delivered with photons to the primary breast for all patients was 4999 cGy (SD = 52) with a mean single fraction dose of 199 cGy (SD = 8). The mean percent of the prescribed dose to the contralateral breast measured at the 4- and 8-cm positions were 7.19% (SD = 2.28) and 4.63% (SD = 2.12), respectively, for patients treated with IMRT compared to 11.22% (SD = 2.73) and 10.70% (SD = 3.44), respectively, for the patients treated with conventional tangential field techniques. This represented a 36% and 57% reduction at the 4 and 8-cm contralateral positions, respectively, in the mean dose to the contralateral breast using IMRT compared to 3-D technique which was statistically significant (p < 0.0005, <0.0005, respectively). CONCLUSION: Primary breast irradiation with tangential IMRT technique significantly reduces the dose to the contralateral breast compared to conventional tangential field techniques.