A review of stereotactic ablative radiotherapy for nonmetastatic renal cell carcinoma.

Renal cell carcinoma (RCC) is an uncommon malignancy whose incidence has been increasing over the past few decades, posing treatment challenges for elderly or infirm patients who are not surgical candidates. Stereotactic ablative radiotherapy (SABR) has emerged as a promising non-invasive treatment modality for RCC. The high dose-per-fraction used in SABR overcomes some of the mechanisms of radioresistance that has hindered the effective treatment of RCC with conventional radiotherapy. For primary RCC, local control rates for SABR exceed 90%, with typically minimal grade 3 or higher toxicities, offering a viable alternative for inoperable patients and those not eligible for or unable to tolerate radiofrequency or cryotherapy ablation. SABR can also be used in patients with a solitary kidney as a strategy for renal preservation to avoid need for dialysis. Given its excellent local control rates, low toxicity and preservation of renal function, SABR offers an attractive alternative to more invasive modalities for treatment of localized RCC.

Clinical and radiographic response of a paravertebral hemangioma to radiotherapy.

Hemangiomas can arise anywhere in the body. While vertebral hemangiomas are common, atypical hemangiomas with paraspinal and epidural extension are rare. We present a case of a patient who presented with persistent cough and anorexia from a paravertebral hemangioma that invaded the adjacent vertebrae and neural foramen causing moderate spinal canal stenosis. She was treated with stereotactic body radiotherapy to prevent the development of symptomatic spinal cord compression. The hemangioma underwent significant shrinkage and her cough resolved. This case demonstrates impressive and sustained clinical and radiographic response of a paraspinal hemangioma to stereotactic body radiotherapy.

Association of PSA kinetics after testosterone recovery with subsequent recurrence: secondary analysis of a phase III randomized controlled trial.

PURPOSE: After cessation of androgen deprivation therapy (ADT), testosterone gradually recovers to supracastrate levels (> 50 ng/dL). After this, rises in prostate-specific antigen (PSA) are often seen. However, it remains unknown whether early PSA kinetics after testosterone recovery are associated with subsequent biochemical recurrence (BCR). METHODS: We performed a secondary analysis of a phase III randomized controlled trial in which newly diagnosed localized prostate cancer patients were randomly allocated to ADT for 6 months starting 4 months prior to or simultaneously with prostate RT. We calculated the PSA doubling time (PSADT) based on PSA values up to 18 months after supracastrate testosterone recovery. Competing risk regression was used to evaluate the association of PSADT with relative incidence of BCR, considering deaths as competing events. RESULTS: Overall, 313 patients were eligible. Median PSADT was 8 months. Cumulative incidence of BCR at 10 years from supracastrate testosterone recovery was 19% and 11% in patients with PSADT < 8 months and ≥ 8 months (p = 0.03). Compared to patients with PSADT of < 4 months, patients with higher PSADT (sHR for PSADT 4 to < 8 months: 0.36 [95% CI 0.16-0.82]; 8 to < 12 months: 0.26 [0.08-0.91]; ≥ 12 months: 0.20 [0.07-0.56]) had lower risk of relative incidence of BCR. CONCLUSIONS: Early PSA kinetics, within 18 months of recovery of testosterone to a supracastrate level, can predict for subsequent BCR. Taking account of early changes in PSA after testosterone recovery may allow for recognition of potential failures earlier in the disease course and thereby permit superior personalization of treatment.

Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer.

BACKGROUND: We performed a secondary analysis of ACIS study to determine if synchronous versus metachronous metastatic presentation has any association with survival and treatment response to dual androgen receptor axis-targeted therapy (ARAT) in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC). METHODOLOGY: In this phase III randomized controlled trial, docetaxel naïve mCRPC patients were randomized to either apalutamide or placebo combined with abiraterone and prednisone. Multivariable Cox regression models were applied to determine the adjusted association of M-stage with radiographic progression-free survival (rPFS) and overall survival (OS). To determine the heterogeneity of treatment effect based on metastatic stage (M-stage) at presentation, Cox regression was applied with interaction terms between M-stage and treatment. RESULTS: Among 972 patients, 432 had M0, 334 had M1, while M-stage at presentation was unknown in 206. There was no association of M-stage at presentation with rPFS in patients with prior local therapy (LT) (hazard ratio for M1-stage: 1.22 [95% confidence interval: 0.82-1.82]; unknown: 1.03 [0.77-1.38]) or without prior LT (M1-stage: 0.87 [0.64-1.19]; unknown: 1.15 [0.77-1.72]) with no significant heterogeneity. Similarly, there was no association of M-stage with OS in patients with prior LT (M1-stage: 1.04 [0.81-1.33]; unknown: 0.98 [0.79-1.21]) or without prior LT (M1-stage: 0.95 [0.70-1.29]; unknown: 1.17 [0.80-1.71]) with no significant heterogeneity. Based on M-stage at presentation, we did not find any significant heterogeneity in treatment effect on rPFS (interaction p = 0.13), and OS (interaction p = 0.87). CONCLUSION: M-stage at presentation had no association with survival in chemotherapy-naïve mCRPC. We did not find any statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation.

Development and validation of a multivariable prognostic model in de novo metastatic castrate sensitive prostate cancer.

BACKGROUND: Metastatic castrate sensitive prostate cancer (mCSPC) is a heterogeneous disease state with variable prognosis. Although several life-prolonging systemic agents are available, there is no robust multivariable model to predict prognosis and improve risk stratification in mCSPC. The objective of this study was to build and validate a multivariable prognostic model to predict overall survival (OS) in mCSPC. METHODS: We used data from LATITUDE, a phase III randomized controlled trial in which men with de novo mCSPC were randomly allocated to either ADT plus abiraterone or ADT with placebo. Patients with non-missing data (n = 1,058) were randomly split in a 70:30 ratio to training (n = 743) and testing (n = 315) sets. Elastic net regression was used for variable selection. A multivariable Cox regression model for OS was then fitted using the selected variables. The predictive accuracy of the model was assessed on the testing set using the time-dependent area under curve (tAUC) with bootstrapped confidence intervals [CI] primarily for OS and secondarily for radiographic progression-free survival (rPFS). RESULTS: The 11 prognostic variables in the final model were performance status, number of skeletal metastases, Gleason score, presence of liver metastasis, worst pain score, albumin, lactate dehydrogenase, prostate-specific antigen, hemoglobin, and treatment regimen. The tAUC for predicting OS at 2- and 3-years was 0.74 (95% CI, 0.67-0.80) and 0.72 (95% CI, 0.65-0.77), respectively. The tAUC for rPFS at 2- and 3-years was 0.72 (95% CI, 0.65-0.77) and 0.77 (95% CI, 0.70-0.82), respectively. CONCLUSIONS: A prognostic model for men with de novo mCSPC was developed and validated in an independent testing set. Our model had high accuracy for predicting OS and rPFS. The model includes commonly used clinical and laboratory parameters and can guide risk stratification of these patients for participation in future trials.

Association of dynamic change in patient-reported pain with survival in metastatic castrate sensitive prostate cancer-exploratory analysis of LATITUDE study.

BACKGROUND: Pain is an important dimension of quality-of-life in patients with metastatic castrate-sensitive prostate cancer (mCSPC). However, it is unclear if dynamic change in pain over time can predict for overall survival (OS) or progression-free survival (PFS) in these patients. METHODS: This is an exploratory analysis of LATITUDE, a phase III randomized study, in which men with de novo mCSPC were randomized to receive either ADT plus abiraterone versus ADT alone. Information was collected on patient-reported worst pain score (WPS) and pain-interference score (PIS) from the Brief Pain Inventory-Short Form. A Bayesian joint modelling approach was used determine the association of dynamic change in WPS and PIS with OS and PFS. RESULTS: Overall, 1125 patients with at least 3 measurements on pain scores were eligible. On Cox multivariable regression, increase in baseline WPS was associated with inferior OS (hazard ratio [HR] 1.049 [95% confidence intervals [CI] 1.015-1.085]; time dependent area under curve [tAUC] 0.64) and PFS (HR 1.045 [1.011-1.080]; tAUC: 0.64). Increase in baseline PIS was associated with inferior OS (HR 1.062 [1.020-1.105]; tAUC: 0.63) but not with PFS (HR 1.038 [0.996-1.08]). On independent joint models, an increase in the current value of WPS by 1-unit was associated with inferior OS (HR 1.316 [1.258-1.376]; tAUC 0.74) and PFS (HR 1.319 [1.260-1.382]; tAUC 0.70). Similar association was seen for increase in the current value of PIS with OS (HR 1.319 [1.261-1.381]; tAUC 0.73) and PFS (HR 1.282 [1.224-1.344]; tAUC 0.73). CONCLUSIONS: The above findings highlight the potential dynamic interplay between patient-reported pain with OS and PFS in mCSPC. Compared to baseline pain, such dynamic assessment of pain was found to have superior predictive ability and thus has the potential to tailor subsequent treatment based on response to initial therapy beyond its role as a very important dimension of quality-of-life.

Association of Short-Term Patient-Reported Outcomes With Long-Term Oncologic Outcomes in Localized Prostate Cancer Patients Treated With Radiation Therapy and Androgen Deprivation Therapy in a Randomized Controlled Trial.

PURPOSE: Both oncologic outcomes and patient-reported outcomes are pivotal in prostate cancer (PCa). However, it remains unknown if there is any association between these 2 outcomes. In this secondary analysis of a randomized controlled trial, we investigated the association of short-term changes in patient-reported outcome with long-term event-free survival (EFS) and metastasis-free survival (MFS) in localized PCa. METHODS AND MATERIALS: Localized PCa patients with a Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen (PSA) <30 ng/mL were randomized to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiation therapy or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy. Patient-reported symptom burden was evaluated using the European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ)-PR.25. Clinically meaningful deterioration (CMD) was defined as a ≥10-point worsening at any time within 10 months postrandomization regardless of subsequent improvement. Landmark analyses were performed to determine the association of CMD of urinary and bowel symptoms separately with EFS and MFS in patients who responded to the baseline questionnaire, were alive, and were event free at 10 months. RESULTS: Overall, 393 patients had responded to the baseline QLQ. One patient died, and 1 patient had failure within 10 months. Therefore, 391 patients were eligible for the landmark analyses. After adjusting for age, Gleason score, PSA, performance status, and treatment group, CMD of urinary symptoms was associated with worse EFS (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.21-2.65) and MFS (HR, 1.69; 95% CI, 1.11-2.57). Considering deaths as competing events, CMD of urinary symptoms was associated with a significant increase in the relative incidence of progression (subdistribution HR, 2.42; 95% CI, 1.12-5.20). However, no association was found between CMD of bowel symptoms and EFS or MFS. CONCLUSIONS: In this study, short-term CMD of urinary symptoms was associated with significantly inferior EFS and MFS and an increase in the relative incidence of progression. Further investigations are needed to explore the biological rationale of such association in the context of ADT and radiation therapy.

Surgery and dose-escalated radiotherapy for a de novo intracranial squamous cell carcinoma of the cerebellopontine angle.

We report an extremely rare case of de novo intracranial squamous cell carcinoma of the cerebellopontine angle. The patient underwent craniotomy for debulking of the lesion to relieve mass effect on the brainstem and to establish a tissue diagnosis. Cancer staging revealed no other primary cancers and no evidence of metastatic disease. Postoperatively, he received image-guided intensity-modulated radiotherapy to the tumor bed followed by fractionated radiosurgery boost to the gross residual disease for a total average dose of 7000 cGy. He had a complete response to radiation and remains 42-months' disease-free post-treatment.

Patient-Reported Outcomes From a Phase 3 Randomized Controlled Trial Exploring Optimal Sequencing of Short-Term Androgen Deprivation Therapy With Prostate Radiation Therapy in Localized Prostate Cancer.

PURPOSE: Two phase 3 randomized controlled trials (OTT-0101, RTOG-9413) and a meta-analysis have shown an impact of sequencing of androgen deprivation therapy (ADT) and radiation therapy on oncologic outcomes in prostate cancer (PCa). However, the impact of sequencing strategy on health-related quality of life (HR-QoL) is unclear. Here, we present the patient-reported HR-QoL outcomes from the OTT-0101 study. METHODS AND MATERIALS: In this trial, patients with PCa with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen level <30 ng/mL were randomly assigned to neoadjuvant and concurrent ADT for 6 months, starting 4 months before or concurrent with prostate radiation therapy, or concurrent and adjuvant ADT for 6 months, starting simultaneously with prostate radiation therapy. HR-QoL was assessed using European Organisation for Research and Treatment of Cancer QoL questionnaires. Time until definitive deterioration was defined as time from random allocation to the first deterioration of at least 10 points with no further improvement of ≥10 points or if the patient experienced progression, died, or dropped out after deterioration, resulting in missing data. Stratified log-rank tests were applied for between-group comparisons of time-to-event estimates. RESULTS: Overall, 393 patients (194 and 199 in the 2 arms, respectively) were evaluable, except 214 (101 and 113 in the 2 arms, respectively) for sexual function. Five-year rates of freedom from definitive deterioration of urinary symptoms, bowel symptoms, and sexual activity were 33.5%, 33.1%, and 38.5% in the neoadjuvant group and 34.1%, 35.4%, and 36.7% in the adjuvant group, respectively, with no significant between-group differences. The adjuvant approach was associated with a reduced risk of definitive deterioration of sexual function (hazard ratio, 0.68; 95% confidence interval, 0.49-0.94; P = .02). With respect to clinical relevance, the mean change in score for sexual function showed only a small to moderate difference favoring the adjuvant group at and beyond 3 years. CONCLUSIONS: In this study, no differences were found in the bowel or urinary symptoms between the adjuvant and neoadjuvant approach. Considering a significant likelihood of type I and type II errors and because of a lack of a persistent and clinically meaningful between-group difference in mean score changes over time, our findings do not confer a clear and conclusive picture of the impact of sequencing strategy on sexual function.

CSF Rhinorrhea: A Rare Clinical Presentation of Choroid Plexus Papilloma.

Choroid plexus papilloma (CPP) is a rare brain tumour occurring mostly in infants and children. Most CPPs are intraventricular and present with symptoms and signs of increased intracranial pressure (ICP). This case report describes a middle-aged female who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhea from a tumour located in the cerebellopontine angle (CPA). She underwent craniotomy with subtotal tumour resection and remained progression and rhinorrhea-free for several years. Upon clinical progression, the patient was treated with Cyberknife stereotactic radiosurgery. The patient clinically improved and demonstrated a favourable radiologic response to radiosurgery.

Impact of Treating Physician on Radiation Therapy Related Severe Toxicities in Men with Prostate Cancer.

PURPOSE: The impact of treating physician on radiation therapy (RT) related toxicity is unclear. We carried out a secondary analysis of a randomized controlled study to determine whether the risk of RT-related late toxicities in patients with prostate cancer varies depending on the treating radiation oncologist. METHODS AND MATERIALS: This is a secondary analysis of a phase 3 randomized controlled study in which patients with prostate cancer with Gleason score ≤7, clinical stage T1b-T3a, and prostate-specific antigen <30 ng/mL were randomized to receive androgen suppression for 6 months, starting either 4 months before or concurrently with definitive prostate radiation therapy. Incidence of late RT-related toxicity was estimated using Kaplan-Meier methods. We applied multivariable semiparametric shared frailty models with gamma distribution to determine the between-physician variation in the hazard of late RT-related grade ≥3 gastrointestinal, genitourinary, or overall toxicity. Patient level covariables included age, risk group, year of enrollment, and treatment regimen. Frailty variance, a measure of unexplained heterogeneity, was estimated with 95% confidence intervals (CIs). Statistical significance was suggested when the lower limit of the 95% CI for the frailty variance was >0. The Commenges-Andersen test was used for P value estimation. RESULTS: Overall, 426 patients were treated by 9 radiation oncologists. On log-rank test, there was a significant difference in the cumulative incidence of overall grade ≥3 toxicities (P = .001) and grade ≥3 gastrointestinal toxicity (P = .01) among the physician-based clusters. The frailty variance for overall late grade ≥3 toxicity was 0.31 (95% CI, 0.02-1.39; P = .01). The frailty variance for the grade ≥3 gastrointestinal and genitourinary toxicity was 0.84 (95% CI, 0.00-4.20; P = .11) and 0.11 (95% CI, 0.00-1.13; P = .31), respectively. CONCLUSIONS: In our study, the hazard of overall RT-related late grade ≥3 toxicity varied significantly depending on treating radiation oncologist. Further studies are required to explore the underlying processes that lead to such variations in clinical trials involving radiation therapy in prostate cancer.

Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis.

PURPOSE: There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa. METHODS: MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS). RESULTS: The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups. CONCLUSION: The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Adrenal oligometastasis cured with stereotactic ablative radiotherapy.

Stereotactic ablative radiotherapy (SABR) has emerged as an effective, noninvasive alternative to surgery in patients with oligometastatic disease. Historically, select patients with adrenal oligometastases have been treated with adrenalectomies which can offer durable local control and reasonable survival rates. SABR is a promising noninvasive treatment alternative to surgery capable of delivering ablative doses of radiation to the tumor with the goal of achieving durable local control of adrenal metastases. We report on a case of a patient who underwent initial surgical resection for a locally advanced lung adenocarcinoma and subsequently developed an early, biopsy-proven, oligometastatic recurrence in the adrenal gland. He underwent chemotherapy and SABR using CyberKnife to the adrenal metastasis and is in remission 7 years after treatment with no late toxicity. Fractionated SABR is an attractive noninvasive alternative to surgery for adrenal metastases. This case demonstrates that select patients with adrenal oligometastases, can achieve long-term remission and even cure following SABR.

Impact of Sequencing of Androgen Suppression and Radiation Therapy on Testosterone Recovery in Localized Prostate Cancer.

PURPOSE: We performed a secondary analysis of a phase 3 randomized trial to determine the influence of sequencing of radiation therapy and androgen deprivation therapy (ADT) on posttreatment testosterone recovery and implications of testosterone recovery on subsequent relapse. METHODS AND MATERIALS: Patients with localized prostate cancer with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen <30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate radiation therapy (NHT arm) or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy (CAHT arm). Full testosterone recovery (FTR) was defined as recovery of testosterone to >10.5 nmol/L in patients with baseline ≥10.5 nmol/L or to baseline level in patients with baseline <10.5 nmol/L. Restricted mean survival time (RMST) since ADT initiation to supracastrate testosterone level (>1.7 nmol/L), and to FTR was compared between the arms using a truncation time point of 36 months. RESULTS: The adjusted difference in RMST to supracastrate testosterone between the CAHT and NHT arm was 1.5 months (95% confidence interval [CI], 0.5-2.5; P = .005). No difference was noted in RMST to FTR between the arms (18.7 vs 18.5 months, adjusted difference: 0.5; 95% CI, -1.4 to 2.4; P = .61). There was no evidence of heterogeneity of treatment effect (interaction P = .76) on risk of relapse over subgroups stratified by testosterone recovery to supracastrate level at 15 months after start of ADT. Based on a multistate Markov model, no independent effect of time to FTR on risk of subsequent relapse was observed (adjusted hazard ratio: 1.02; 95% CI, 0.96-1.08). CONCLUSIONS: Patients should be counseled that an additional 12 months on average is needed for FTR to occur after treatment with prostate radiation therapy and 6 months of ADT. This is independent of the sequencing of ADT and radiation therapy. Furthermore, recovery of testosterone does not appear to affect the risk of subsequent relapse.

A novel mosaic variant on SMC1A reported in buccal mucosa cells, albeit not in blood, of a patient with Cornelia de Lange-like presentation.

Mosaicism in Cornelia de Lange syndrome (CdLS) has been reported in clinically diagnosed CdLS patients with negative molecular testing using blood as the specimen, particularly in the NIPBL gene. Here we report a novel mosaic variant in SMC1A identified in the buccal swab DNA of a patient with a mild CdLS phenotype. Our patient presented with global developmental delay, dysmorphic features, microcephaly, and short stature, with no limb defect. Face2Gene, a digital tool that analyzes facial morphology, demonstrated a 97% match between our patient and the CdLS gestalt. An initial next-generation sequencing (NGS)-based CdLS panel test, including NIPBL, HDAC8, RAD21, SMC1A, and SMC3, completed using DNA isolated from leukocytes, was negative, and subsequent trio exome sequencing was nondiagnostic. The exome identified biallelic variants of uncertain significance in a candidate gene, NSMCE2 In the pursuit of a molecular diagnosis, a second NGS-based CdLS panel test was ordered on a buccal swab specimen and a novel variant, c.793_795delGAG (p.Glu265del) in SMC1A, was detected at 60% mosaicism. Retrospective analysis of the former panel and exome data revealed the SMC1A variant at 4% and 2%, respectively, both far below standard reporting thresholds. Given that mosaicism has been frequently reported in CdLS, we suggest selecting a different tissue for testing in clinically suspected CdLS cases, even after negative molecular results via blood specimen.

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats.

Evidence suggests that noradrenergic signaling may play a role in mediating alcohol-drinking behavior in both rodents and humans. We have investigated this possibility by administering clonidine to alcohol-drinking rats selectively bred for alcohol preference (P line). Clonidine is an α2-adrenergic receptor agonist which, at low doses, inhibits noradrenergic signaling by decreasing norepinephrine release from presynaptic noradrenergic neurons. Adult male P rats were given 24 h access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 h daily. Rats received intra-peritoneal (IP) injections with clonidine (0, 10, 20, 40, or 80 µg/kg body weight [BW], 10-11 rats/treatment group) once/day at 30 min prior to onset of the daily 2 h alcohol access period for 2 consecutive days. Clonidine, in doses of 40 or 80 µg/kg BW, significantly reduced alcohol intake on both days of treatment (p<0.001). Two weeks later, rats were treated with clonidine for 5 consecutive days and clonidine, in doses of 40 or 80 µg/kg BW, reduced alcohol intake on all 5 treatment days (p < 0.001). Clonidine did not alter water consumption during the daily 2 h free-choice between alcohol and water. In a separate group of male P rats, clonidine (40 µg/kg BW) suppressed intake of a saccharin solution (0.04 g/L). These results are consistent with and complement our previous findings that the α1-adrenergic receptor antagonist, prazosin, decreases voluntary alcohol drinking in alcohol-preferring rats, but suggests that effects of clonidine may not be specific for alcohol. The results suggest that although activation of the noradrenergic system plays an important role in mediating voluntary alcohol drinking, care is needed in selecting which drugs to use to suppress central noradrenergic signaling in order to maximize the selectivity of the drugs for treating alcohol-use disorders.