Survival Analysis of Cancer Patients With FIGO Stage IIIA Endometrial Cancer.

OBJECTIVE: Endometrial cancer patients with positive serosa and/or adnexae (FIGO stage IIIA) have a variable prognosis and are at a significant risk for recurrence. We investigated how tumor characteristics and adjuvant treatments influence the overall survival (OS) and recurrence patterns in these patients and patients with positive cytology alone (previously classified as stage IIIA before 2009). MATERIALS AND METHODS: This multi-institution retrospective study reviewed 55 patients with positive serosa and/or adnexae and 18 patients with positive cytology only, surgically staged from 1990 to 2010. The study cohort was evaluated using the Kaplan-Meier estimates of OS and Cox proportional hazards modeling. RESULTS: The 5-year OS for all IIIA patients was 55%. Administration of adjuvant therapy was associated with improved OS when compared with surgery alone (P=0.0018). The 5-year OS was 20% for patients treated with surgery alone (n=10), 55% with surgery and radiation therapy (n=26), 75% with surgery and chemotherapy (n=7), and 79% with surgery followed by both radiation therapy and chemotherapy (n=12; P=0.005). The tumor characteristics showed that nonendometrioid histology (P=0.0143) and lymph vascular space invasion (P=0.0483) had a poorer OS. Recurrence occurred in 29% of IIIA patients, with 9% locoregional failures and 20% distant failures. Patients with positive cytology only had a similar OS to patients with positive serosa and/or adnexae (76% vs. 55%; P=0.104) and recurrence rate (22% vs. 29%; P=0.4101). CONCLUSIONS: This retrospective study suggests benefit from the use of adjuvant radiotherapy and chemotherapy for stage IIIA patients. We recommend further investigation of adjuvant therapies for IIIA patients in prospective studies and randomized clinical trials.

Technique, outcomes, and acute toxicities in adults treated with proton beam craniospinal irradiation.

BACKGROUND: Proton craniospinal irradiation (p-CSI) has been proposed to reduce side effects associated with CSI. We evaluated acute toxicities and preliminary clinical outcomes in a series of adults treated with p-CSI. METHODS: We reviewed medical records for 50 patients (aged 16-63 y) with malignancies of varying histologies treated consecutively with vertebral body-sparing p-CSI at MD Anderson Cancer Center from 2007 to 2011. Median CSI and total boost doses were 30.6 and 54 Gy. Forty patients received chemotherapy, varying by histology. Median follow-up was 20.1 months (range, 0.3-59). RESULTS: Median doses to the thyroid gland, pituitary gland, hypothalamus, and cochleae were 0.003 Gy-relative biological effectiveness (RBE; range, 0.001-8.5), 36.1 Gy-RBE (22.5-53.0), 37.1 Gy-RBE (22.3-54.4), and 33.9 Gy-RBE (22.2-52.4), respectively. Median percent weight loss during CSI was 1.6% (range, 10% weight loss to 14% weight gain). Mild nausea/vomiting was common (grade 1 = 46%, grade 2 = 20%); however, only 5 patients experienced grade ≥2 anorexia (weight loss >5% baseline weight). Median percent baseline white blood cells, hemoglobin, and platelets at nadir were 52% (range, 13%-100%), 97% (65%-112%), and 61% (10%-270%), respectively. Four patients developed grade ≥3 cytopenias. Overall and progression-free survival rates were 96% and 82%, respectively, at 2 years and 84% and 68% at 5 years. CONCLUSIONS: This large series of patients treated with p-CSI confirms low rates of acute toxicity, consistent with dosimetric models. Vertebral body-sparing p-CSI is feasible and should be considered as a way to reduce acute gastrointestinal and hematologic toxicity in adults requiring CSI.

Involved-field radiation therapy for locoregionally recurrent ovarian cancer.

OBJECTIVE: To evaluate the effectiveness of definitive involved-field radiation therapy (IFRT) for selected patients with locoregionally-recurrent ovarian cancer. METHODS: We retrospectively reviewed records of 102 epithelial ovarian cancer patients treated with definitive IFRT (≥45Gy). IFRT was directed to localized nodal (49%) and extranodal (51%) recurrences. RESULTS: The median time from diagnosis to IFRT was 36 months (range, 1-311), and the median follow-up after IFRT was 37 months (range, 1-123). Patients received a median of three chemotherapy courses before IFRT (range, 0-9). Five-year overall (OS) and progression-free survival (PFS) rates after IFRT were 40% and 24% respectively; the 5-year in-field disease control rate was 71%. Thirty-five patients (35%) had no evidence of disease at a median of 38 months after IFRT (range, 7-122), including 25 continuously without disease for a median of 61 months (range, 17-122) and 10 with salvage treatment following disease recurrence, disease-free for a median of 39 months after salvage treatment (range, 7-92). Eight clear cell carcinoma patients had higher 5-year OS (88% versus 37%; p=0.05) and PFS (75% versus 20%; p=0.01) rates than other patients. Patients sensitive to initial platinum chemotherapy had a higher 5-year OS rate than platinum-resistant patients (43% versus 27%, p=0.03). Patients who required chemotherapy for recurrence after IFRT often benefitted from longer chemotherapy-free intervals after than before IFRT. CONCLUSIONS: Definitive IFRT can yield excellent local control, protracted disease-free intervals, and even cures in carefully selected patients. RT should be considered a tool in the curative management of locoregionally-recurrent ovarian cancer.

Survival analysis of endometrial cancer patients with positive lymph nodes.

OBJECTIVE: Patients with endometrial cancer with positive lymph nodes (International Federation of Gynecology and Obstetrics stage IIIC) have a substantially worse prognosis. This study investigates how tumor characteristics and adjuvant treatments influence overall survival (OS) in stage IIIC patients. METHODS: This multi-institution, institutional review board-approved study is a retrospective review of 116 patients with surgically staged endometrial cancer with positive lymph nodes treated from 1995 to 2008. The study cohort was evaluated using Kaplan-Meier estimates of OS and proportional hazard modeling. RESULTS: The 5-year OS for all patients was 51%. Administration of adjuvant therapy was associated with improved OS when compared with surgery alone (P = 0.007). Five-year OS was 40% for patients treated with surgery alone (n = 26), 50% with surgery and chemotherapy (n = 8), 58% with surgery and radiotherapy (n = 43), and 54% with surgery followed by both radiotherapy and chemotherapy (n = 39). Patients who received radiotherapy (n = 82) had improved OS (57%) when compared with patients who did not (n = 34, OS = 42%; P = 0.001). Radiotherapy was associated with improved OS for patients with endometrioid histology, high-grade tumors, and positive para-aortic lymph nodes. Patients with nonendometrioid histology and low-grade tumors who received radiotherapy had a similar OS as those who did not. High-grade tumors (P < 0.001), nonendometrioid histology (P = 0.004), and more than 2 positive lymph nodes (P = 0.01) were associated with a poorer OS. After controlling for patient demographics and tumor characteristics, patients with high-grade tumors and more than 2 positive lymph nodes had a poorer OS, whereas patients who received radiotherapy had improved OS. CONCLUSIONS: This large institutional study of patients with lymph node-positive endometrial cancer identified prognostic factors associated with a poor OS. Radiotherapy was associated with improved survival and may be specifically indicated for patients with endometrioid histology, high-grade tumors, and positive para-aortic lymph nodes. We recommend further investigation of adjuvant therapies in randomized clinical trials.

Improving prostate brachytherapy quality assurance with MRI-CT fusion-based sector analysis in a phase II prospective trial of men with intermediate-risk prostate cancer.

PURPOSE: We combined sector analysis with MRI-CT fusion to comprehensively assess postimplant dosimetry after prostate brachytherapy. METHODS AND MATERIALS: Subjects were 50 men with intermediate-risk prostate cancer treated with (125)I brachytherapy in a prospective phase II clinical trial. On Day 30 after the implantation, dosimetry was evaluated in the prostate base, midgland, and apex regions on fused MRI-CT scans and CT scans. Volumes of each sector receiving 100% of the prescribed dose (V100) and doses to 90% of each sector (D90) were also calculated on the ultrasonogram used for treatment planning and compared with values derived from CT and fused MRI-CT scans. RESULTS: Fused MRI-CT scans revealed lower-than-expected doses for the whole prostate (V100=91.3%, D90=152.9Gy) compared with CT scans (98.5% and 183.6Gy, p<0.0001) and lower doses to the prostate base (V100=79%, D90=130Gy) vs. CT (96% and 170Gy, p<0.0001). However, lower doses to the prostate base did not adversely affect biochemical outcomes in men with biopsy-proven disease at the base. At a median followup time of 42 months, the mean prostate-specific antigen level for all patients was 0.3ng/mL, and no patient had experienced biochemical or clinical progression or recurrence. CONCLUSIONS: MRI-CT fusion-based sector analysis was feasible and revealed significantly lower doses to the prostate base than doses estimated from CT alone, although this did not affect biochemical outcomes. MRI-CT fusion-based sector analysis may be useful for developing MRI-based dosimetric markers to predict disease outcomes and treatment-related morbidity.

Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma.

PURPOSE: Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma. METHODS AND MATERIALS: Forty adult medulloblastoma patients treated with x-CSI (n=21) or p-CSI (n=19) at the University of Texas MD Anderson Cancer Center from 2003 to 2011 were retrospectively reviewed. Median CSI and total doses were 30.6 and 54 Gy, respectively. The median follow-up was 57 months (range 4-103) for x-CSI patients and 26 months (range 11-63) for p-CSI. RESULTS: p-CSI patients lost less weight than x-CSI patients (1.2% vs 5.8%; P=.004), and less p-CSI patients had >5% weight loss compared with x-CSI (16% vs 64%; P=.004). p-CSI patients experienced less grade 2 nausea and vomiting compared with x-CSI (26% vs 71%; P=.004). Patients treated with x-CSI were more likely to have medical management of esophagitis than p-CSI patients (57% vs 5%, P<.001). p-CSI patients had a smaller reduction in peripheral white blood cells, hemoglobin, and platelets compared with x-CSI (white blood cells 46% vs 55%, P=.04; hemoglobin 88% vs 97%, P=.009; platelets 48% vs 65%, P=.05). Mean vertebral doses were significantly associated with reductions in blood counts. CONCLUSIONS: This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. Patients treated with p-CSI experienced less treatment-related morbidity including fewer acute gastrointestinal and hematologic toxicities.

Convergence of nanotechnology with radiation therapy-insights and implications for clinical translation.

Improvements in accuracy and efficacy in treating tumors with radiation therapy (RT) over the years have been fueled by parallel technological and conceptual advances in imaging and image-guidance techniques, radiation treatment machines, computational methods, and the understanding of the biology of tumor response to RT. Recent advances in our understanding of the hallmarks of cancer and the emergence of strategies to combat these traits of cancer have resulted in an expanding repertoire of targeted therapeutics, many of which can be exploited for enhancing the efficacy of RT. Complementing this advent of new treatment options is the evolution of our knowledge of the interaction between nanoscale materials and human tissues (nanomedicine). As with the changes in RT paradigms when the field has encountered newer and maturing disciplines, the incorporation of nanotechnology innovations into radiation oncology has the potential to refine or redefine its principles and revolutionize its practice. This review provides a summary of the principles, applications, challenges and outlook for the use of metallic nanoparticles in RT.

Evaluation of the fullerene compound DF-1 as a radiation protector.

BACKGROUND: Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells. METHODS: In vitro radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for gammaH2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry. RESULTS: DF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer gammaH2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls. CONCLUSIONS: DF-1 has modest activity as a radiation protector in vivo. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1.

A population-based study of subsequent primary malignancies after endometrial cancer: genetic, environmental, and treatment-related associations.

PURPOSE: To examine the risk of subsequent primary malignancies (SPMs) in women diagnosed with endometrial cancer. METHODS AND MATERIALS: The National Cancer Institute's Survival, Epidemiology, and End Results database was used to determine the risk of SPM after endometrial cancer in 69,739 women diagnosed between 1973 and 2005. Standardized incidence ratios were calculated (observed/expected [O/E]) for SPM sites. RESULTS: Median follow-up was 11.2 years, representing 757,567 person-years of follow-up. The risk of SPM was significantly increased for small intestine (O/E = 1.48; 99% confidence interval [CI], 1.03-2.05), colon (O/E = 1.16; CI, 1.09-1.24), vagina (O/E = 2.71; CI, 1.86-3.8), and urinary bladder (O/E = 1.41; CI, 1.25-1.59) SPMs and decreased for oral cavity and pharynx (O/E = 0.75; CI, 0.6-0.93), lung and bronchus (O/E = 0.78; CI, 0.72-0.84), and esophagus (O/E = 0.58; CI, 0.37-0.86) SPMs. Patients receiving external-beam radiotherapy for endometrial cancer had an increased risk of colon (p < 0.001), bladder (p < 0.001), vagina (p = 0.04), and soft-tissue (p = 0.014) SPMs. Patients treated with brachytherapy had an increased risk of bladder SPM (p = 0.006). A positive bidirectional association with endometrial cancer was observed for colorectal cancer, with a negative bidirectional association for oropharyngeal and lung cancers. CONCLUSIONS: Genetic, environmental, and treatment-related factors influence SPM risk. Genetic factors may contribute to the increased risk of colorectal cancer. Smoking's negative effect on endometrial cancer risk factors might explain the decreased risk of lung and oropharyngeal cancer. Patients treated with radiotherapy likely have a small but significantly increased risk of bladder, vagina, colon, and soft-tissue SPM.

In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 kinase.

PURPOSE: The mitogen-activated protein (MAP) kinase pathway is important for cell proliferation, survival, and differentiation, and is frequently up-regulated in cancers. The MAP kinase pathway is also activated after exposure to ionizing radiation. We investigated the effects of AZD6244 (ARRY-142886), an inhibitor of MAP kinase/extracellular signal-regulated kinase 1/2, on radiation response. EXPERIMENTAL DESIGN: The effects of AZD6244 on the in vitro radiosensitivity of human cancer cell lines (A549, MiaPaCa2, and DU145) were evaluated using clonogenic assays. DNA damage repair was evaluated using gammaH2AX, and mitotic catastrophe was measured using nuclear fragmentation. Cell cycle effects were measured with flow cytometry. Growth delay was used to evaluate the effects of AZD6244 on in vivo tumor radiosensitivity. RESULTS: Exposure of each cell line to AZD6244 before irradiation resulted in an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1, ranging from 1.16 to 2.0. No effects of AZD6244 on radiation-induced apoptosis or persistence of gammaH2AX foci after irradiation were detected. Cells treated with AZD6244 had an increased mitotic index and decreased Chk1 phosphorylation at 1 and 2 hours after irradiation. Mitotic catastrophe was increased in cells receiving AZD6244 and irradiation compared with the single treatments. In vivo studies revealed that AZD6244 administration to mice bearing A549 tumor xenografts resulted in a greater than additive increase in radiation-induced tumor growth delay (dose enhancement factor of 3.38). CONCLUSIONS: These results indicate that AZD6244 can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect involves an increase in mitotic catastrophe.

Performing nondiagnostic research biopsies in irradiated tissue: a review of scientific, clinical, and ethical considerations.

PURPOSE: Recent development of drugs that target specific pathways in tumors has increased scientific interest in studying drug effects on tumor tissue. As a result, biopsies have become an important part of many early-phase clinical trials. Performing nondiagnostic tumor biopsies raises technical and ethical concerns mostly related to the use of a potentially harmful procedure with no potential benefit to the patient. This issue is complicated by uncertainty about whether performing biopsies in irradiated fields adds significant risk. This article reviews the clinical, scientific, and ethical considerations involved in performing nondiagnostic tumor biopsies in competent adults for research purposes, with a focus on biopsies performed in the setting of therapeutic irradiation. METHODS: Clinical trials that performed biopsies during or within 4 months of the completion of radiotherapy were identified with a literature review. RESULTS: Twenty-nine studies with 2,160 patients were identified. Sixteen of 29 studies reported adverse events (AEs) but did not report active evaluation for biopsy complications. Ten studies did not mention AEs within the study report. At least three studies actively evaluated patients for biopsy complications. Taking this into consideration, 17 (>1%) of 2,160 patients were reported to have biopsy complications, although reporting of AEs was suboptimal in most studies. CONCLUSION: Limited data suggest that biopsies can be performed in irradiated tissues without clinically significant excess risk. Ongoing and future trials including nondiagnostic research biopsies should record and report AEs related to this procedure to provide additional data on safety and toxicity.

Clinical biomarkers of angiogenesis inhibition.

INTRODUCTION: An expanding understanding of the importance of angiogenesis in oncology and the development of numerous angiogenesis inhibitors are driving the search for biomarkers of angiogenesis. We review currently available candidate biomarkers and surrogate markers of anti-angiogenic agent effect. DISCUSSION: A number of invasive, minimally invasive, and non-invasive tools are described with their potential benefits and limitations. Diverse markers can evaluate tumor tissue or biological fluids, or specialized imaging modalities. CONCLUSIONS: The inclusion of these markers into clinical trials may provide insight into appropriate dosing for desired biological effects, appropriate timing of additional therapy, prediction of individual response to an agent, insight into the interaction of chemotherapy and radiation following exposure to these agents, and perhaps most importantly, a better understanding of the complex nature of angiogenesis in human tumors. While many markers have potential for clinical use, it is not yet clear which marker or combination of markers will prove most useful.

The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer.

BACKGROUND: The 10-yr survival rate of patients with differentiated thyroid cancer exceeds 90%. These patients may be at elevated risk for secondary cancers. METHODS: The risk of nonthyroid second primary malignancies after differentiated thyroid cancer was determined in 30,278 patients diagnosed between 1973 and 2002 from centers participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Median follow-up was 103 months (range, 2-359 months). Risk was further assessed for the addition of radioisotope therapy, gender, latency to development of secondary cancer, and age at thyroid cancer diagnosis. RESULTS: There were 2158 patients who developed a total of 2338 nonthyroid second primary malignancies, significantly more than that expected in the general population [observed/expected (O/E) = 1.09; 95% confidence interval (CI), 1.05-1.14; P < 0.05; absolute excess risk per 10,000 person-years (AER) = 6.39]. A significantly greater risk of second primary malignancies over that expected in the general population was for patients treated with radioisotopes (O/E = 1.20; 95% CI, 1.07-1.33; AER = 11.8) as well as for unirradiated patients (O/E = 1.05; 95% CI, 1.00-1.10; AER = 3.53). However, the increased risk was greater for the irradiated vs. the unirradiated cohort (relative risk = 1.16; 95% CI, 1.05-1.27; P < 0.05). Gender did not affect risk. The greatest risk of second primary cancers occurred within 5 yr of diagnosis and was elevated for younger patients. CONCLUSIONS: The overall risk of second primary malignancies is increased for thyroid cancer survivors and varies by radioisotope therapy, latency, and age at diagnosis.