Akila N. Viswanathan

Acute and Chronic Graft-Versus-Host Disease After Allogeneic Peripheral-Blood Stem-Cell and Bone Marrow Transplantation: A Meta-Analysis

PURPOSE Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures. METHODS An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed. RESULTS Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P=.006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P <.001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P <.001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05). CONCLUSION Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.

Night Shift Work and the Risk of Endometrial Cancer

Melatonin has several oncostatic properties, including possible anti-estrogenic and anti-aromatase activity, and seems to be linked with fat metabolism. Night workers have lower levels of melatonin, which may predispose them to develop cancer. Endometrial cancer risk is influenced significantly by hormonal and metabolic factors; therefore, we hypothesize that night workers may have an increased risk of endometrial cancer. Of the 121,701 women enrolled in a prospective cohort study, 53,487 women provided data on rotating night shift work in 1988 and were followed through on June 1, 2004. A total of 515 women developed medical record-confirmed invasive endometrial cancer. We used Cox regression models to calculate multivariate relative risks (MVRRs), controlling for endometrial cancer risk factors. Women who worked 20+ years of rotating night shifts had a significantly increased risk of endometrial cancer [MVRR, 1.47; 95% confidence interval (95% CI), 1.03-1.14]. In stratified analyses, obese women working rotating night shifts doubled their baseline risk of endometrial cancer (MVRR, 2.09; 95% CI, 1.24-3.52) compared with obese women who did no night work, whereas a nonsignificant increase was seen among non-obese women (MVRR, 1.07; 95% CI, 0.60-1.92). Women working rotating night shifts for a long duration have a significantly increased risk of endometrial cancer, particularly if they are obese. We speculate that this increased risk is attributable to the effects of melatonin on hormonal and metabolic factors. Our results add to growing literature that suggests women who work at night may benefit from cancer prevention strategies.

Radiation Dose–Volume Effects of the Urinary Bladder

An in-depth overview of the normal-tissue radiation tolerance of the urinary bladder is presented. The most informative studies consider whole-organ irradiation. The data on partial-organ/nonuniform irradiation are suspect because the bladder motion is not accounted for, and many studies lack long enough follow-up data. Future studies are needed.

Consensus Guidelines for Delineation of Clinical Target Volume for Intensity-Modulated Pelvic Radiotherapy for the Definitive Treatment of Cervix Cancer

PURPOSE Accurate target definition is vitally important for definitive treatment of cervix cancer with intensity-modulated radiotherapy (IMRT), yet a definition of clinical target volume (CTV) remains variable within the literature. The aim of this study was to develop a consensus CTV definition in preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group. METHODS AND MATERIALS A guidelines consensus working group meeting was convened in June 2008 for the purposes of developing target definition guidelines for IMRT for the intact cervix. A draft document of recommendations for CTV definition was created and used to aid in contouring a clinical case. The clinical case was then analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with kappa statistics as a measure of agreement between participants. RESULTS Nineteen experts in gynecological radiation oncology generated contours on axial magnetic resonance images of the pelvis. Substantial STAPLE agreement sensitivity and specificity values were seen for gross tumor volume (GTV) delineation (0.84 and 0.96, respectively) with a kappa statistic of 0.68 (p < 0.0001). Agreement for delineation of cervix, uterus, vagina, and parametria was moderate. CONCLUSIONS This report provides guidelines for CTV definition in the definitive cervix cancer setting for the purposes of IMRT, building on previously published guidelines for IMRT in the postoperative setting.

Platelet-derived growth factor and fibronectin-stimulated migration are differentially regulated by the Rac and extracellular signal-regulated kinase pathways

Directed cell migration is essential for a variety of important biological processes ranging from development and angiogenesis to metastasis. Ras plays a pivotal role in the signaling cascade that governs chemotaxis of fibroblasts toward platelet-derived growth factor-BB (PDGF-BB). Ras activates multiple downstream pathways, which include the extracellular signal-regulated kinase (ERK), Rac, and Ral signaling cascades. We therefore investigated the role of the Rac and ERK pathways in cell migration. We showed that migration of fibroblasts toward PDGF-BB is inhibited by expression of dominant negative Asn-17 Rac1. Blocking of the ERK pathway by either expression of dominant negative Ala-218/Ala-222-mitogen-activated protein kinase kinase (A218/A222-MEK1) or by a MEK-specific inhibitor did not inhibit migration toward PDGF-BB. In contrast, migration toward soluble fibronectin was suppressed by inhibition of the ERK pathway but not by Asn-17 Rac1 expression. These results indicate that directed cell migration mediated by different receptor classes in response to different ligands differentially utilizes the Rac and ERK pathways and suggest that Rac might play a critical role in pathological processes such as angiogenesis and metastasis.

American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy.

PURPOSE This report presents an update to the American Brachytherapy Society (ABS) high-dose-rate (HDR) brachytherapy guidelines for locally advanced cervical cancer. METHODS Members of the ABS with expertise in cervical cancer formulated updated guidelines for HDR brachytherapy using tandem and ring, ovoids, cylinder, or interstitial applicators for locally advanced cervical cancer. These guidelines were written based on medical evidence in the literature and input of clinical experts in gynecologic brachytherapy. RESULTS The ABS affirms the essential curative role of tandem-based brachytherapy in the management of locally advanced cervical cancer. Proper applicator selection, insertion, and imaging are fundamental aspects of the procedure. Three-dimensional imaging with magnetic resonance or computed tomography or radiographic imaging may be used for treatment planning. Dosimetry must be performed after each insertion before treatment delivery. Applicator placement, dose specification, and dose fractionation must be documented, quality assurance measures must be performed, and followup information must be obtained. A variety of dose/fractionation schedules and methods for integrating brachytherapy with external-beam radiation exist. The recommended tumor dose in 2-Gray (Gy) per fraction radiobiologic equivalence (normalized therapy dose) is 80-90Gy, depending on tumor size at the time of brachytherapy. Dose limits for normal tissues are discussed. CONCLUSION These guidelines update those of 2000 and provide a comprehensive description of HDR cervical cancer brachytherapy in 2011.

Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas

PURPOSE To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials. METHODS AND MATERIALS One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The following were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified. RESULTS The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa_R, Adnexa_L, Prostate, SeminalVesc, PenileBulb, Femur_R, and Femur_L. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed. CONCLUSIONS Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research.

American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part I: general principles.

PURPOSE To develop brachytherapy recommendations covering aspects of pretreatment evaluation, treatment, and dosimetric issues for locally advanced cervical cancer. METHODS Members of the American Brachytherapy Society (ABS) with expertise in cervical cancer brachytherapy formulated updated recommendations for locally advanced (Federation of Gynecology and Obstetrics Stages IB2-IVA) cervical cancer based on literature review and clinical experience. RESULTS The ABS recommends the use of brachytherapy as a component of the definitive treatment of locally advanced cervical carcinoma. Precise applicator placement is necessary to maximize the probability of achieving local control without major side effects. The ABS recommends a cumulative delivered dose of approximately 80-90Gy for definitive treatment. The dose delivered to point A should be reported for all brachytherapy applications regardless of treatment-planning technique. The ABS also recommends adoption of the Groupe Européen Curiethérapie-European Society of Therapeutic Radiation Oncology (GEC-ESTRO) guidelines for contouring, image-based treatment planning, and dose reporting. Interstitial brachytherapy may be considered for a small proportion of patients whose disease cannot be adequately encompassed by intracavitary application. It should be performed by practitioners with special expertise in these procedures. CONCLUSIONS Updated ABS recommendations are provided for brachytherapy for locally advanced cervical cancer. Practitioners and cooperative groups are encouraged to use these recommendations to formulate their clinical practices and to adopt dose-reporting policies that are critical for outcome analysis.

Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States

PURPOSE To determine the trends in brachytherapy use in cervical cancer in the United States and to identify factors and survival benefits associated with brachytherapy treatment. METHODS AND MATERIALS Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 7359 patients with stages IB2-IVA cervical cancer treated with external beam radiation therapy (EBRT) between 1988 and 2009. Propensity score matching was used to adjust for differences between patients who received brachytherapy and those who did not from 2000 onward (after the National Cancer Institute alert recommending concurrent chemotherapy). RESULTS Sixty-three percent of the 7359 women received brachytherapy in combination with EBRT, and 37% received EBRT alone. The brachytherapy utilization rate has decreased from 83% in 1988 to 58% in 2009 (P<.001), with a sharp decline of 23% in 2003 to 43%. Factors associated with higher odds of brachytherapy use include younger age, married (vs single) patients, earlier years of diagnosis, earlier stage and certain SEER regions. In the propensity score-matched cohort, brachytherapy treatment was associated with higher 4-year cause-specific survival (CSS; 64.3% vs 51.5%, P<.001) and overall survival (OS; 58.2% vs 46.2%, P<.001). Brachytherapy treatment was independently associated with better CSS (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.57-0.71), and OS (HR 0.66; 95% CI, 0.60 to 0.74). CONCLUSIONS This population-based analysis reveals a concerning decline in brachytherapy utilization and significant geographic disparities in the delivery of brachytherapy in the United States. Brachytherapy use is independently associated with significantly higher CSS and OS and should be implemented in all feasible cases.

IMPACT OF RADIOTHERAPY ON FERTILITY, PREGNANCY, AND NEONATAL OUTCOMES IN FEMALE CANCER PATIENTS

PURPOSE Radiation has many potential long-term effects on cancer survivors. Female cancer patients may experience decreased fertility depending on the site irradiated. Oncologists should be aware of these consequences and discuss options for fertility preservation before initiating therapy. METHODS AND MATERIALS A comprehensive review of the existing literature was conducted. Studies reporting the outcomes for female patients treated with cranio-spinal, abdominal, or pelvic radiation reporting fertility, pregnancy, or neonatal-related outcomes were reviewed. RESULTS Cranio-spinal irradiation elicited significant hormonal changes in women that affected their ability to become pregnant later in life. Women treated with abdomino-pelvic radiation have an increased rate of uterine dysfunction leading to miscarriage, preterm labor, low birth weight, and placental abnormalities. Early menopause results from low-dose ovarian radiation. Ovarian transposition may decrease the rates of ovarian dysfunction. CONCLUSIONS There is a dose-dependent relationship between ovarian radiation therapy (RT) and premature menopause. Patients treated with RT must be aware of the impact of treatment on fertility and explore appropriate options.