Shelly X. Bian

Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer

BACKGROUND Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P=0.004). Recursive partitioning analysis of men without ADT classified Gleason 4+3=7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P=0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P=0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P=0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P=0.380). CONCLUSION The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.BACKGROUND Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380). CONCLUSION The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Management of Prostate Cancer in Elderly Men

Elderly men comprise a large percentage of men diagnosed with prostate cancer (PrCa). Although localized PrCa is often indolent, older men tend to be diagnosed with higher-stage disease and are more likely to die from PrCa than younger men. Multiple factors other than age play an important role in determining who will benefit from active treatment, such as comorbid conditions, life expectancy, and tumor characteristics. Careful consideration of such factors can help prevent the overtreatment of elderly men with low-risk disease and undertreatment of elderly men with high-risk disease. Management decisions should be individualized by weighing the benefits of treatment against potential risks and side effects pertinent to the elderly population, whether evaluating for surgery, radiation, or androgen deprivation.

Is there an impact of heart exposure on the incidence of radiation pneumonitis? Analysis of data from a large clinical cohort

Abstract Background. The goal of the present study was to determine, in a large clinical cohort, whether incidental radiation exposure to the heart during definitive radiotherapy of inoperable non-small cell lung cancer (NSCLC) detectably increased the risk of radiation pneumonitis (RP) beyond that resulting from radiation exposure to lung. Material and methods. Data were analyzed from all patients who received definitive three-dimensional (3D) concurrent radiotherapy or intensity-modulated radiotherapy for the treatment of NSCLC over a 10-year period at our institution, except those who had previous lung cancer or for whom radiation treatment plans were unavailable for calculation of heart and lung dose-volume histograms (DVHs). Parameters computed from heart and lung DVHs included mean lung dose (MLD), effective lung dose computed using volume parameter n = 0.5 (Deff), mean heart dose (MHD), percentage of heart receiving > 65 Gy (V65), and minimum dose to the hottest 10% of heart (D10). Univariate and multivariate normal-tissue complication probability (NTCP) models were used to analyze incidence of Grade ≥ 2 or Grade ≥ 3 RP as a function of these and other parameters. Results. The study cohort included 629 patients, with crude rates of Grade ≥ 2 RP and Grade ≥ 3 RP of N = 263 (42%) and N = 124 (20%), respectively. Univariate NTCP models based on dosimetric lung parameters (MLD and Deff) fit the data better than models based on univariate heart parameters (heart D10, heart V65 or MHD). In multivariate modeling, incorporation of heart parameters did not significantly improve the fit of RP risk models based on lung parameters alone (p > 0.38 in each case). Conclusions. In this large clinical cohort, there was no evidence that incidental heart exposure during radiotherapy of NSCLC had a detectable impact on the occurrence of moderate or severe RP.

Tolerance of Orthotopic Ileal Neobladders to Radiotherapy: A Multi-institutional Retrospective Study

Micro‐Abstract The present multi‐institutional retrospective study describes the tolerance of orthotopic neobladders to moderate doses of pelvic radiotherapy in 25 patients. In the setting of high‐risk muscle‐invasive bladder cancer, adjuvant radiotherapy is currently under investigation in multiple international clinical trials. To the best of our knowledge, the present study is the first to report that orthotopic neobladders can tolerate moderate doses of pelvic radiotherapy without significant toxicity. Background: The present retrospective study analyzed the tolerance of orthotopic ileal neobladders to radiotherapy by reviewing the acute and late toxicity in patients who underwent postoperative radiotherapy after radical cystectomy/cystoprostatectomy. Materials and Methods: A multi‐institutional database was created for patients who had undergone radical cystectomy/cystoprostatectomy and neobladder reconstruction, followed by adjuvant radiotherapy (RT). The patient and tumor characteristics were recorded. The RT data were reviewed to determine the treatment technique used, the radiation dose received by the neobladder, and acute and late toxicity evaluated using the Common Terminology Criteria for Adverse Events, version 4.0, scale. Results: A total of 25 patients were included, with a median age of 64 years. Of the 25 patients, 18 received a dose of 45 to 50.4 Gy. The most common reasons for postoperative radiotherapy were close or positive surgical margins and pT3‐pT4 or N+ disease. Ten patients underwent intensity modulated RT. All but 1 patient completed the RT course. Of the patients who completed their RT schedule, none had grade ≥ 3 acute gastrointestinal toxicity. One patient who received concurrent chemotherapy developed grade 3 acute genitourinary toxicity. Three patients reported late grade 1 genitourinary toxicity (frequency of urination, mild leakage at night), with no reports of chronic gastrointestinal toxicity. None of the patients experienced neobladder perforation, leak, or fistula. Conclusion: The use of moderate doses of pelvic RT (range, 45‐50.4 Gy) was well tolerated among the 25 patients who underwent RT after cystoprostatectomy with orthotopic neobladder creation. This finding supports the use of postoperative RT to moderate doses in this patient population when clinically indicated.

Prognostic factors for melanoma brain metastases treated with stereotactic radiosurgery.

OBJECTIVE Stereotactic radiosurgery (SRS) is routinely used to treat brain metastases from melanoma due to their radioresistant nature. The median survival for these patients is 4-6 months, according to earlier studies. The aim of this study was to evaluate prognostic factors that influence survival in patients with metastatic melanoma to the brain treated with SRS. METHODS This retrospective analysis included all patients with melanoma brain metastases treated with SRS at the University of Southern California between 1994 and 2015. For the entire cohort, the authors performed a multivariable Cox regression analysis with an end point of survival. Covariates included number of lesions, total intracranial tumor volume, age, sex, and treatment date prior to 2005 or 2005 onward. In the subset of patients with > 1 lesion, additional multivariable Cox regression was performed, with covariates of Karnofsky Performance Scale, Graded Prognostic Assessment, Recursive Partitioning Analysis, timing of metastases (synchronous/metachronous), change in lesion number, and previous whole-brain radiation therapy or resection in addition to the previously mentioned covariates. Overall survival (OS) was calculated from the day SRS was performed to the date of last follow-up or date of death. RESULTS A total of 401 patients were available for analysis. The median follow-up was 35.1 months for patients alive at the time of analysis, and the median OS was 7.7 months for the entire cohort (95% CI 6.7-8.3 months). In the entire cohort, greater number of brain lesions, higher total intracranial tumor volume, age > 50 years, treatment prior to 2005, and male sex were found to be statistically significant factors associated with worse survival. The strongest risk factors for decreased OS were tumor volume > 10 cm3 and ≥ 5 lesions, with hazard ratios for risk of death of 1.7 and 2.2, respectively. In the subset of patients with > 1 lesion, tumor volume > 10 cm3 and no resection were the only factors significantly associated with decreased OS, with hazard ratios of 1.9 and 2.0 (hazard ratio of 0.49 for resection), respectively. CONCLUSIONS This study suggests that greater lesion number, higher intracranial tumor volume, older age, treatment prior to 2005, and male sex have prognostic significance for decreased OS in patients with melanoma brain metastases treated with SRS. Additionally, in the subset of patients with > 1 lesion, only higher total tumor volume and no resection were associated with worse survival.

Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects

OBJECTIVETumor and edema volume changes of brain metastases after stereotactic radiosurgery (SRS) and ipilimumab are not well described, and there is concern regarding the safety of combination treatment. The authors evaluated tumor, edema, and adverse radiation-induced changes after SRS with and without ipilimumab and identified associated risk factors.METHODSThis single-institution retrospective study included 72 patients with melanoma brain metastases treated consecutively with upfront SRS from 2006 to 2015. Concurrent ipilimumab was defined as ipilimumab treatment within 4 weeks of SRS. At baseline and during each follow-up, tumor and edema were measured in 3 orthogonal planes. The (length × width × height/2) formula was used to estimate tumor and edema volumes and was validated in the present study for estimation of edema volume. Tumor and edema volume changes from baseline were compared using the Kruskal-Wallis test. Local failure, lesion hemorrhage, and treatment-related imaging changes (TRICs) were analyzed with the Cox proportional hazards model.RESULTSOf 310 analyzed lesions, 91 were not treated with ipilimumab, 59 were treated with concurrent ipilimumab, and 160 were treated with nonconcurrent ipilimumab. Of 106 randomly selected lesions with measurable peritumoral edema, the mean edema volume by manual contouring was 7.45 cm3 and the mean volume by (length × width × height)/2 formula estimation was 7.79 cm3 with R2 = 0.99 and slope of 1.08 on line of best fit. At 6 months after SRS, the ipilimumab groups had greater tumor (p = 0.001) and edema (p = 0.005) volume reduction than the control group. The concurrent ipilimumab group had the highest rate of lesion response and lowest rate of lesion progression (p = 0.002). Within the concurrent ipilimumab group, SRS dose ≥ 20 Gy was associated with significantly greater median tumor volume reduction at 3 months (p = 0.01) and 6 months (p = 0.02). The concurrent ipilimumab group also had the highest rate of lesion hemorrhage (p = 0.01). Any ipilimumab was associated with higher incidence of symptomatic TRICs (p = 0.005). The overall incidence of pathologically confirmed radiation necrosis (RN) was 2%. In multivariate analysis, tumor and edema response at 3 months were the strongest predictors of local failure (HR 0.131 and HR 0.125) and lesion hemorrhage (HR 0.225 and HR 0.262). Tumor and edema response at 1.5 months were the strongest predictors of TRICs (HR 0.144 and HR 0.297).CONCLUSIONSThe addition of ipilimumab improved tumor and edema volume reduction but was associated with a higher incidence of lesion hemorrhage and symptomatic TRICs. There may be a radiation dose-response relationship between SRS and ipilimumab when administered concurrently. Early tumor and edema response were excellent predictors of subsequent local failure, lesion hemorrhage, and TRICs. The incidence of pathologically proven RN was low, supporting the relative safety of ipilimumab in radiosurgery treatment.

No Acute Changes in LVEF Observed With Concurrent Trastuzumab and Breast Radiation With Low Heart Doses

Introduction/Background: Treatment for HER2‐postitive breast cancer often includes trastuzumab, breast/chest wall (CW) radiation (RT), and anthracyclines, all of which have cardiac toxicity. We aimed to evaluate the relationship between heart dose and acute left ventricular ejection fraction (LVEF) changes in patients who received concurrent trastuzumab and breast/CW RT with and without anthracycline use. Patients and Methods: We retrospectively reviewed all nonmetastatic breast cancer patients from 2008 to 2015 who received concurrent trastuzumab and breast/CW RT. Baseline LVEF was compared with the LVEF closest to treatment completion as well as with the lowest post‐treatment LVEF. LVEF changes were correlated with laterality, heart dosimetric parameters, and doxorubicin use. Results: Eighty‐eight patients were included in our analysis. The median follow‐up was 45 months. Forty‐one patients were right‐sided and 47 left‐sided. Thirty‐one patients received doxorubicin, 16 right‐sided and 15 left‐sided. Mean heart dose was 1.10 Gy and 3.63 Gy for right‐ and left‐sided patients, respectively (P < .001). In the entire cohort, a significant LVEF decrease of 3.0% was observed pre‐ and post‐treatment. There was a significant effect of doxorubicin (P = .013) and a nonsignificant effect of RT laterality (P = .088) on LVEF change. The test of interaction between doxorubicin and laterality was not significant (P = .90). No significant association was found between LVEF change and heart dosimetric parameters, including percent volume of heart receiving 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), and 45 Gy (V45), and maximum dose. Similar results were found when baseline LVEF was compared with the lowest post‐treatment LVEF. Conclusion: With cardiac doses < 4 Gy, declines in LVEF were not related to tumor laterality or heart dosimetric parameters. Statistically significant LVEF decreases were mainly attributed to doxorubicin. Micro‐Abstract: Treatment for HER2‐positive breast cancer often includes trastuzumab, breast/chest wall (CW) radiation (RT), and anthracyclines, all of which have known cardiac toxicity. In 88 patients who received concurrent trastuzumab and breast/CW RT, with and without anthracyclines, we found significant acute left ventricular ejection fraction declines to be attributable to doxorubicin alone, and not to heart radiation dose.

Percent of Tracer Clearance at 40 Minutes in MAG3 Renal Scans Is More Sensitive Than T1/2 for Symptomatic Ureteropelvic Junction Obstruction

OBJECTIVE To increase the diagnostic sensitivity of standard MAG3 diuretic renal scans for ureteropelvic junction obstruction (UPJO) by exploring the utility of an alternative measurement P40, the percentage of maximal tracer counts present at 40 minutes. MATERIALS AND METHODS Patients with strong clinical and anatomic evidence for UPJO may have a normal T1/2, making definitive diagnosis difficult. We reviewed the charts of 142 consecutive patients who underwent successful laparoscopic or robotic-assisted laparoscopic pyeloplasty for UPJO between 2005 and 2015. Both pre- and postoperative renal scan images were available for 37 symptomatic patients with primary unilateral UPJO and 2 kidneys. We defined P40 as the percentage of maximal tracer counts present at 40 minutes. We identified the upper limit of normal (97.5th percentile, +2SD) for P40 using the preoperative renal scans from the unaffected kidney. We compared the sensitivity of P40 to T1/2 to identify symptomatic UPJO. RESULTS In our cohort, 51% of symptomatic patients (n = 19) had a normal T1/2 (median 8.9 minutes; interquartile range: 7.5 minutes) and 49% (n = 18) had an abnormal T1/2 (median: 40 minutes; interquartile range: 0 minute). None of the patients had an abnormal P40 on their unaffected kidney. All patients with an abnormal T1/2 also had an abnormal P40. P40 increased the sensitivity of the renal scan from 49% (n = 18 of 37) to 73% (n = 27 of 37) when compared to T1/2. The majority of patients (95%) demonstrated an improvement in P40 after pyeloplasty. CONCLUSION P40 markedly increases the sensitivity of a renal scan for diagnosing symptomatic UPJO and may be another valuable marker in addition to T1/2 to document functional improvement in drainage after pyeloplasty.

A Single-Center Experience with Prone Retroperitoneoscopic Versus Open Renal Surgery in Children: An Age- and Procedure-Matched Comparison

PURPOSE We determined how surgical outcomes differ among children undergoing prone retroperitoneoscopic (RP) and open total and partial nephrectomies for benign renal disease. PATIENTS AND METHODS A retrospective analysis was performed, using medical records of children who were undergoing benign renal surgery at a single institution from 2001 to 2010. Patients were divided into open or RP cohorts, then subdivided into those who were undergoing total or partial nephrectomies. A further breakdown by age (<3 years and ≥3 years) was performed. Bilateral nephrectomies were separately evaluated. Surgical outcomes were compared across groups. RESULTS There were 308 (333 renal units) children who underwent RP (n=154) or open (n=154) total or partial nephrectomies, 25 of which were bilateral (20 RP, 5 open); 199 patients underwent total nephrectomies (RP n=118, open n=81), and 109 underwent partial nephrectomies (RP n=36, open n=73). After controlling for age and concomitant procedures, operative times were similar for the RP total and bilateral nephrectomy groups, but longer for the RP partial nephrectomy group, compared with their open counterparts. In both total and partial nephrectomies, the RP group had a shorter hospital stay. There were no open conversions in any of the RP groups and no differences in complications in the total, partial, and bilateral analyses. There were 13 patients who previously received peritoneal dialysis (8 bilateral RP, 3 unilateral RP, and 2 unilateral open), all of whom resumed dialysis in a mean of 1.11 days. CONCLUSIONS This is the largest series to date that compares RP and open renal surgeries in children. The RP and open approaches were comparably safe and efficacious. Hospital stays were significantly shorter in the RP total and partial groups, although operative times were significantly longer in the RP partial nephrectomy group. Prone retroperitoneoscopic surgery should be considered a viable option for renal surgery at any age.

The growing importance of lesion volume as a prognostic factor in patients with multiple brain metastases treated with stereotactic radiosurgery

Stereotactic Radiosurgery (SRS) is considered standard of care for patients with 1–3 brain metastases (BM). Recent observational studies have shown equivalent OS in patients with 5+ BM compared to those with 2–4, suggesting SRS alone may be appropriate in these patients. We aim to review outcomes of patients treated with SRS with 2–4 versus 5+ BM. This analysis included consecutive patients from 1994 to 2015 treated with SRS. Of 1017 patients, we excluded patients with a single BM and patients without adequate survival data, resulting in 391 patients. All risk factors were entered into univariate analysis using Cox proportional hazards model, and significant factors were entered into multivariate analysis (MVA). We additionally analyzed outcomes after excluding patients with prior surgery or whole‐brain radiotherapy (WBRT). Median follow‐up was 7.1 months. Median KPS was 90, mean age was 59, and most common histologies were melanoma and lung. Median tumor volume was 3.41 cc. Patients with 2–4 BM had a median OS of 8.1 months compared to 6.2 months for those with 5+ BM (P = 0.0136). On MVA, tumor volume, KPS, and histology remained significant for OS, whereas lesion number did not. Similar results were found when excluding patients with prior surgery or WBRT. Rather than lesion number, the strongest prognostic factors for patients undergoing SRS were tumor volume >10 cc, KPS, and histology. BM number may therefore not be the most important criterion for candidacy for SRS. Patients with 5 or more BM should be considered for SRS.