Trends in estimated PARP inhibitor eligibility and benefit among US epithelial ovarian cancer patients.

OBJECTIVE: To estimate the annual percentage of patients with epithelial ovarian cancer (EOC) who could be eligible for and benefit from PARP inhibitor therapy amidst changing US Food and Drug Administration (FDA)-approved indications. METHODS: This is a simulated retrospective observational study using publicly available data on patients with advanced-stage EOC. PARPi eligibility is based on FDA approvals and withdrawals from 2014 through 2023, along with published demographic and genomic data. Clinical trial data is used to estimate treatment benefit. PARPi including olaparib, niraparib, and rucaparib are analyzed in aggregate with sub-analyses by molecular classification and treatment timing. Results are reported as the percentage of EOC patients appropriate for any cancer-directed therapy. RESULTS: PARPi were approved for 9 different indications in EOC between 2014 and 2021; reduced to 6 indications by 2023. Eligibility increased from 2.0% (95% CI,1.3%-1.6%) in 2014 to a maximum of 93.4% (95% CI,90.1%-94.6%) in 2021. The maximum percentage of patients with 2-year PFS benefit was 22.0% (95% CI, 17.2%-26.8%) in 2021, projected to decrease to 13.0% (95% CI, 9.9%-15.9%) in 2024. Most of this decrease was seen in the homologous recombination deficient, BRCA wild-type population (8.4% to 4.0%). CONCLUSIONS: PARPi eligibility increased at a greater rate than benefit resulting in a low population-level benefit-to-eligibility ratio until 2021. Recent FDA withdrawals improved this ratio with an accompanied decrease in the absolute number of patients benefiting. To further optimize population-level benefit-to-eligibility ratio of targeted therapies in ovarian cancer, we need to identify better biomarkers, treatment combinations, and novel therapeutic targets.

Sentinel Lymph Node Evaluation in Early-Stage Vulvar Cancer.

OPINION STATEMENT: Sentinel lymph node mapping (SLNM) and dissection (SLND) should be used as an alternative to full inguinofemoral lymph node dissection (IFLND) in select patients with early-stage vulvar cancer. IFLND is associated with high postoperative complications such as wound breakdown, lymphedema, lymphocyst formation, and infection. SLND in select patients offers a safe, effective, and less morbid alternative. Candidates for SLND include patients with a unifocal vulvar tumor less than four centimeters, clinically negative lymph nodes, and no prior inguinofemoral surgeries. SLND should ideally be performed by a high-volume SLN surgeon. Most commonly, SLND is performed using both radiocolloid lymphoscintigraphy (e.g., Technetium-99) and a visual tracer such as blue dye; however, near infrared imaging with indocyanine green injection is becoming more widely adopted. Further prospective studies are needed to examine the safety and efficacy of various techniques for SLND. SLND has been demonstrated to be cost-effective, especially when including perioperative complications. Further studies are needed to demonstrate quality of life differences between IFLND and SLND.

ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE.

Ovarian cancer is a complex disease associated with multiple genetic and epigenetic alterations. The emergence of treatment resistance in most patients causes ovarian cancer to become incurable, and novel therapies remain necessary. We identified epigenetic regulator ATPase family AAA domain-containing 2 (ATAD2) is overexpressed in ovarian cancer and is associated with increased incidences of metastasis and recurrence. Genetic knockdown of ATAD2 or its pharmacological inhibition via ATAD2 inhibitor BAY-850 suppressed ovarian cancer growth and metastasis in both in vitro and in vivo models. Transcriptome-wide mRNA expression profiling of ovarian cancer cells treated with BAY-850 revealed that ATAD2 inhibition predominantly alters the expression of centromere regulatory genes, particularly centromere protein E (CENPE). In ovarian cancer cells, changes in CENPE expression following ATAD2 inhibition resulted in cell-cycle arrest and apoptosis induction, which led to the suppression of ovarian cancer growth. Pharmacological CENPE inhibition phenotypically recapitulated the cellular changes induced by ATAD2 inhibition, and combined pharmacological inhibition of both ATAD2 and CENPE inhibited ovarian cancer cell growth more potently than inhibition of either alone. Thus, our study identified ATAD2 as regulators of ovarian cancer growth and metastasis that can be targeted either alone or in combination with CENPE inhibitors for effective ovarian cancer therapy.

A mouse model of repeated traumatic brain injury-induced hearing impairment: Early cochlear neurodegeneration in the absence of hair cell loss.

PURPOSE: Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide. Mounting evidence suggests that even mild TBI injuries, which comprise >75% of all TBIs, can cause chronic post-concussive neurological symptoms, especially when experienced repetitively (rTBI). The most common post-concussive symptoms include auditory dysfunction in the form of hearing loss, tinnitus, or impaired auditory processing, which can occur even in the absence of direct damage to the auditory system at the time of injury. The mechanism by which indirect damage causes loss of auditory function is poorly understood, and treatment is currently limited to symptom management rather than preventative care. We reasoned that secondary injury mechanisms, such as inflammation, may lead to damage of the inner ear and parts of the brain used for hearing after rTBI. Herein, we established a model of indirect damage to the auditory system induced by rTBI and characterized the pathology of hearing loss. METHODS: We established a mouse model of rTBI in order to determine a timeline of auditory pathology following multiple mild injuries. Mice were subject to controlled cortical impact at the skull midline once every 48 h, for a total of 5 hits. Auditory function was assessed via the auditory brainstem response (ABR) at various timepoints post injury. Brain and cochleae were collected to establish a timeline of cellular pathology. RESULTS: We observed increased ABR thresholds and decreased (ABR) P1 amplitudes in rTBI vs sham animals at 14 days post-impact (dpi). This effect persisted for up to 60 days (dpi). Auditory temporal processing was impaired beginning at 30 dpi. Spiral ganglion degeneration was evident at 14 dpi. No loss of hair cells was detected at this time, suggesting that neuronal loss is one of the earliest notable events in hearing loss caused by this type of rTBI. CONCLUSIONS: We conclude that rTBI results in chronic auditory dysfunction via damage to the spiral ganglion which occurs in the absence of any reduction in hair cell number. This suggests early neuronal damage that may be caused by systemic mechanisms similar to those leading to the spread of neuronal death in the brain following TBI. This TBI-hearing loss model provides an important first step towards identifying therapeutic targets to attenuate damage to the auditory system following head injury.

Multispectral optoacoustic tomography (MSOT): Monitoring neurovascular changes in a mouse repetitive traumatic brain injury model.

BACKGROUND: Evidence suggests that mild TBI injuries, which comprise > 75% of all TBIs, can cause chronic post-concussive symptoms, especially when experienced repetitively (rTBI). rTBI is a major cause of cognitive deficit in athletes and military personnel and is associated with neurovascular changes. Current methods to monitor neurovascular changes in detail are prohibitively expensive and invasive for patients with mild injuries. NEW METHOD: We evaluated the potential of multispectral optoacoustic tomography (MSOT) to monitor neurovascular changes and assess therapeutic strategies in a mouse model of rTBI. Mice were subjected to rTBI or sham via controlled cortical impact and administered pioglitazone (PG) or vehicle. Oxygenated and deoxygenated hemoglobin were monitored using MSOT. Indocyanine green clearance was imaged via MSOT to evaluate blood-brain-barrier (BBB) integrity. RESULTS: Mice subjected to rTBI show a transient increase in oxygenated/total hemoglobin ratio which can be mitigated by PG administration. rTBI mice also show BBB disruption shortly after injury and reduction of oxygenated/total hemoglobin in the chronic stage, neither of which were affected by PG intervention. COMPARISON WITH EXISTING METHODS: MSOT imaging has the potential as a noninvasive in vivo imaging method to monitor neurovascular changes and assess therapeutics in mouse models of rTBI. In comparison to standard methods of tracking inflammation and BBB disruption, MSOT can be used multiple times throughout the course of injury without the need for surgery. Thus, MSOT is especially useful in research of rTBI models for screening therapeutics, and with further technological improvements may be extended for use in rTBI patients.

Current Issues in the Management of Patients With Newly Diagnosed Advanced-Stage High-Grade Serous Carcinoma of the Ovary.

Ovarian cancer is the most common cause of mortality in patients with gynecologic malignancies. Advanced-stage high-grade serous carcinoma accounts for most ovarian cancer cases. Current issues in the management of patients with newly diagnosed advanced-stage high-grade serous ovarian cancer include decisions on primary versus interval cytoreduction, hyperthermic intraperitoneal chemotherapy, maintenance therapy, incorporation of bevacizumab, and germline and somatic genetic testing. Evidence and guidelines regarding these topics are addressed in this review.

Cost-effectiveness of hyperthermic intraperitoneal chemotherapy at primary cytoreduction of epithelial ovarian cancer based on residual disease status.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin when used at the time of interval cytoreductive surgery (ICS) after neoadjuvant chemotherapy (NACT) has been shown to provide a survival advantage compared to interval cytoreduction alone for patients with advanced epithelial ovarian cancer in a cost-effective manner. A recent large multi-center retrospective cohort study showed a survival advantage with HIPEC given during primary debulking surgery compared to surgery alone. While there is an ongoing randomized controlled trial examining HIPEC at the time of primary cytoreductive surgery (PCS) before chemotherapy (OVHIPEC-2), there is currently no study of this practice in the United States or cost data to inform incorporation of this practice. To help guide the use of HIPEC in the upfront setting until the results of the OVHIPEC-2 are available in 2026, a decision-analytic cost-effectiveness model of the US healthcare sector was developed for patients undergoing PCS with or without HIPEC. Effectiveness inputs were extracted from a Chinese retrospective cohort study of 425 patients who underwent PCS with HIPEC and 159 patients who underwent PCS alone. We found incremental cost effectiveness ratios (ICER) of $9,789 per life year saved (LYS) for optimal PCS, $18,164/LYS for suboptimal PCS, and $7,854/LYS for all patients. Our findings provide preliminary data to support that HIPEC at the time of primary cytoreductive surgery can be considered cost-effective regardless of residual disease status when using a standard willingness to pay threshold.

Cost-effectiveness of Maintenance Therapy Based on Molecular Classification Following Treatment of Primary Epithelial Ovarian Cancer in the United States.

Importance: There are large randomized clinical trials-SOLO-1 (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy [December 2018]), PRIMA (A Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy [September 2019]), and PAOLA-1 (Platine, Avastin and Olaparib in 1st Line [December 2019])-reporting positive efficacy results for maintenance regimens for women with primary, advanced epithelial ovarian cancer. The findings resulted in approval by the US Food and Drug Administration of the treatments studied as of May 2020. However, there are pressing economic considerations given the many eligible patients and substantial associated costs. Objective: To evaluate the cost-effectiveness of maintenance strategies for patients with (1) a BRCA variant, (2) homologous recombination deficiency without a BRCA variant, or (3) homologous recombination proficiency. Design, Setting, and Participants: In this economic evaluation of the US health care sector using simulated patients with primary epithelial ovarian cancer, 3 decision trees were developed, one for each molecular signature. The maintenance strategies evaluated were olaparib (SOLO-1), olaparib-bevacizumab (PAOLA-1), bevacizumab (PAOLA-1), and niraparib (PRIMA). Base case 1 assessed olaparib, olaparib-bevacizumab, bevacizumab, and niraparib vs observation of a patient with a BRCA variant. Base case 2 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination deficiency without a BRCA variant. Base case 3 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination proficiency. The time horizon was 24 months. Costs were estimated from Medicare claims, wholesale acquisition prices, and published sources. Probabilistic sensitivity analyses with microsimulation were then conducted to account for uncertainty and assess model stability. One-way sensitivity analyses were also performed. The study was performed from January through June 2020. Main Outcomes and Measures: Incremental cost-effectiveness ratios (ICERs) in US dollars per progression-free life-year saved (PF-LYS). Results: Assuming a willingness-to-pay threshold of $100 000/PF-LYS, none of the drugs could be considered cost-effective compared with observation. In the case of a patient with a BRCA variant, olaparib was the most cost-effective (ICER, $186 777/PF-LYS). The third-party payer price per month of olaparib would need to be reduced from approximately $17 000 to $9000 to be considered cost-effective. Olaparib-bevacizumab was the most cost-effective in the case of a patient with homologous recombination deficiency without a BRCA variant (ICER, $629 347/PF-LYS), and bevacizumab was the most cost-effective in the case of patient with homologous recombination proficiency (ICER, $557 865/PF-LYS). Even at a price of $0 per month, niraparib could not be considered cost-effective as a maintenance strategy for patients with homologous recombination proficiency. Conclusions and Relevance: The findings of this study suggest that, at current costs, maintenance therapy for primary ovarian cancer is not cost-effective, regardless of molecular signature. For certain therapies, lowering the drug price alone may not make them cost-effective.

The gender authorship gap in gynecologic oncology research.

Female first authorship and senior authorship in academic obstetrics and gynecology has increased over time but gender-specific publishing data are lacking within gynecologic oncology. We examined contribution by gender to the subspecialty's flagship journal, Gynecologic Oncology, over five decades, from 1972 to 2014, to identify trends in gender representation. Chi-square tests were used to compare gender distributions within and between the first and last years studied (1972-73 and 2014) as well as linear regression to model trends over time. Female first and senior authorship increased significantly from 1972 to 2014 (first: χ2 = 20.9, p < .01; senior: χ2 = 9.9, p < .01). The number of female first authors increased markedly after 2000. Male senior authors still outnumber female senior authors. Papers with senior female authors were more likely to have female first authors, suggesting a mentorship role. Subspecialty-wide gender equity initiatives should encourage continued mentorship of women by female colleagues.

Association of serum androgens and coronary artery calcium scores in women.

OBJECTIVE: To determine the association between serum androgens measured by high-resolution liquid chromatography-mass spectrometry and coronary artery calcium (CAC) scores. DESIGN: Cross-sectional study. SETTING: Academic institution. PATIENT(S): A total of 239 women, aged 40-75 years, with CAC testing and complete cardiovascular disease risk evaluation. Total T, DHEA, and androstenedione were measured using high-resolution liquid chromatography-mass spectrometry, whereas E2 and sex hormone-binding globulin were measured using commercial assays. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Independent associations between CAC scores and sex steroids. RESULT(S): Overall, 164 subjects had a CAC score < 10, 48 had a CAC score between 10 and 100, and 27 had a score > 100. There were no differences in sex hormone levels between women with CAC scores > 10 vs. CAC scores ≤ 10. In multivariable models adjusting for age, body mass index, and low-density lipoprotein cholesterol, a higher T/E2 ratio was associated with an elevated CAC score, with an unadjusted odds ratio associated with 1-SD change in log-transformed T/E2 of 1.38 (95% confidence interval 1.01-1.89) and adjusted OR 1.02 (95% confidence interval 1.002-1.04). Total T, DHEA, androstenedione, sex hormone-binding globulin, and E2 levels were not associated with increased CAC. CONCLUSION(S): In the general population, there are mixed reports regarding the relationship between serum androgens and risk factors for cardiovascular disease, and limited information on the relationship between androgens and subclinical atherosclerosis. Our study shows that increased androgens relative to estrogens may have a weak but independent association with subclinical atherosclerosis, as measured by CAC scores.

Activated cofilin exacerbates tau pathology by impairing tau-mediated microtubule dynamics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aß is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aß. However, the molecular link between tau and cofilin remains unclear. In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of cofilin mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic C. elegans. The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling that promotes tauopathy.

Preoperatively predicting non-home discharge after surgery for gynecologic malignancy.

OBJECTIVE: Returning home after surgery is a desirable patient-centered outcome associated with decreased costs compared to non-home discharge. Our objective was to develop a preoperative risk-scoring model predicting non-home discharge after surgery for gynecologic malignancy. METHODS: Women who underwent surgery involving hysterectomy for gynecologic malignancy from 2013 to 2015 were identified from the Michigan Surgical Quality Collaborative database. Patients were divided by discharge destination, and a multivariable logistic regression model was developed to create a nomogram to assign case-specific risk scores. The model was validated using the National Surgical Quality Improvement Program (NSQIP) database. RESULTS: Non-home discharge occurred in 3.1% of 2134 women. The proportion of non-home discharges did not differ by cancer diagnosis (uterine 3.5%, ovarian 2.5%, and cervical 1.6%, p = 0.2). Skilled nursing facilities were the most common non-home destination (68.2%). Among patients with comorbidities (hypertension, diabetes, coronary artery disease, chronic obstructive pulmonary disease /dyspnea, arrhythmia, and history of deep vein thrombosis/pulmonary embolism), non-home discharge was more common in women with 1 (adjusted OR [aOR] 3.4; p = 0.03) or ≥2 of these comorbidities (aOR 5.1; p = 0.003) compared to none. Non-home discharge was more common after laparotomy (aOR 6.7; p < 0.0001) than laparoscopy, and in those aged ≥70 years (aOR 3.4; p < 0.0001) with American Society of Anesthesiologists class ≥ 3 (aOR 4.5; p = 0.0004) and dependent functional status (aOR 8.7; p < 0.0001). The model C-statistic was 0.89. When the model was applied to 4248 eligible patients from the NSQIP dataset, the C-statistic was 0.84 (95% CI: 0.79-0.89). CONCLUSIONS: Non-home discharge after surgery for gynecologic malignancy was predicted with high accuracy in this retrospective analysis.

Therapeutic Impact of Nanoparticle Therapy Targeting Tumor-Associated Macrophages.

Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest antiangiogenic therapy-induced hypoxia can induce tumor "stemness" as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor-associated macrophages (TAM). As such, TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) nanoparticles deplete TAMs in both solid tumor and ascites models of ovarian cancer. As a therapeutic agent, these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to antiangiogenic therapy, (ii) prevent antiangiogenic therapy-induced increases in cancer stem-like cells in both murine and human tumor cell models, (iii) prevent antiangiogenic therapy-induced increases in VEGF-C, and (iv) prevent antiangiogenic therapy-induced BRCA1 gene expression. Combined, this work strongly supports the development of TAM-targeted nanoparticle therapy. Mol Cancer Ther; 17(1); 96-106. ©2017 AACR.

Timing of and Reasons for Unplanned 30-Day Readmission After Hysterectomy for Benign Disease.

OBJECTIVE: To characterize timing and reasons associated with unplanned 30-day readmissions after hysterectomy for benign indications. METHODS: We performed a retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Project database files from 2012 to 2013. We identified patterns of 30-day readmission after benign hysterectomy for all surgical approaches (abdominal, laparoscopic, vaginal). Readmission timing was determined from discharge date and readmission diagnoses were tabulated. Statistical analyses included χ tests and multivariable logistic regression. RESULTS: The 30-day readmission rate was 2.8% (1,118/40,580 hysterectomies). Readmissions complicated 3.7% (361/9,869) of abdominal, 2.6% (576/22,266) of laparoscopic, and 2.1% (181/8,445) of vaginal hysterectomies. Readmissions were more likely when hysterectomy was performed abdominally (adjusted odds ratio [OR] 1.45, 95% confidence interval [CI] 1.2-1.76) but not laparoscopically (adjusted OR 1.1, 95% CI 0.9-1.4) compared with a vaginal approach. Eighty-two percent of readmissions occurred within 15 days of discharge. The shortest median time to readmission was associated with pain (3 days), and the longest was associated with noninfectious wound complications (10 days). Surgical site infection was the most common diagnosis (abdominal 36.6%, laparoscopic 28.3%, vaginal 32.6%). Surgical site infections, surgical injuries, and wound complications combined accounted for 51.5% of abdominal, 51.9% of laparoscopic, and 50.8% of vaginal hysterectomy readmissions. Medical complications such as cardiovascular events and venous thromboembolism were responsible for 5.8% of abdominal, 6.9% of laparoscopic, and 8.8% of vaginal hysterectomy readmissions. Surgical injuries were responsible for more readmissions after laparoscopic (unadjusted OR 2.3, 95% CI 1.48-3.65) and vaginal hysterectomies (unadjusted OR 2.3, 95% CI 1.29-3.97) than abdominal cases. CONCLUSION: Readmissions after hysterectomy tend to occur shortly after discharge. Most readmissions are related to surgical issues, most commonly surgical site infection. Medical complications, including venous thromboembolism, account for less than 10% of readmissions. Readmission reduction efforts should focus on early postdischarge follow-up, preventing infectious complications, and determining preventability of surgical-related reasons for readmission.

Readmissions after major gynecologic oncology surgery.

OBJECTIVES: To examine the underlying indications, timing, and risk factors associated with unplanned hospital readmissions after major surgery for a gynecologic malignancy. METHODS: This is a retrospective database cohort study utilizing the National Surgical Quality Improvement Program database (NSQIP). The association between risk factors with respect to 30-day unplanned readmission was modeled using logistic regression. Timing of readmission and the primary reason of readmission was abstracted from the database. RESULTS: Overall, the unplanned readmission rate was 6.5% (832/12,804). On multivariate analysis, operative time≥3h (OR 1.39, p<0.001), open abdominal surgery (OR 2.2, p<0.001), any complication prior to discharge (OR 1.6, p<0.001), two or more additional surgical procedures (OR 1.34, p=0.003), or cervical cancer as the site of primary disease (OR 1.30, p=0.05) were noted to be independent predictors of readmission. To provide a convenient calculation of overall probability of readmission, we developed a nomogram of factors significantly predicting readmission. Overall, infections were a cause of 45% of the readmissions. Surgical Site Infections were the most common reason, accounting for 29.2% of all readmissions. A majority of the readmissions (approximately 75%) were within two weeks of discharge from the hospital. CONCLUSIONS: Efforts to reduce readmission rates should focus on identifying patients at a high risk of readmission and reducing surgical site infections. Additionally, prospective evaluation of interventions targeted at reducing readmissions should focus on the first two weeks after discharge from the hospital.

A Pragmatic Evaluation of the National Cancer Institute Physician Data Query (PDQ)®-Based Brief Counseling on Cancer-Related Fatigue among Patients Undergoing Radiation Therapy.

PURPOSE: Cancer-Related Fatigue (CRF) negatively affects quality of life among cancer patients. This study seeks to evaluate the outcome and patient receptiveness of a brief counseling program based on National Cancer Institute (NCI) PDQ® information to manage CRF when integrated into Radiation Therapy (RT). METHODS: We conducted a prospective cohort study among patients undergoing non-palliative RT. Patients with stage I-III tumors and with Karnofsky score 60 or better were given a ten-minute behavioral counseling session during the first two weeks of RT. The Brief Fatigue Inventory (BFI) was administered at baseline/end of RT. RESULTS: Of 93 patients enrolled, 89% found the counseling useful and practical. By the end of RT, 59% reported increased exercise, 41.6% sought nutrition counseling, 72.7% prioritized daily activities, 74.4% took daytime naps, and 70.5% talked with other cancer patients. Regarding counseling, patients who had received chemotherapy prior to RT had no change in fatigue (-0.2), those who received RT alone had mild increase in fatigue (0.7, p=0.02), and those who received concurrent chemotherapy experienced a substantial increase in fatigue (3.0 to 5.2, p=0.05). Higher baseline fatigue and receipt of chemotherapy were predictive of worsened fatigue in a multivariate model (both p<0.01). CONCLUSION: Our data suggests that brief behavioral counseling based on NCI guidelines is well accepted by patients showing an uptake in many activities to cope with CRF. Those who receive concurrent chemotherapy and with higher baseline fatigue are at risk for worsening fatigue despite of guideline-based therapy.