Christina H. Son

Outcomes after whole brain reirradiation in patients with brain metastases.

PURPOSE Patients with brain metastases are often treated with whole brain radiation therapy (WBRT) for purposes of palliation. The treatment of those who experience subsequent intracranial disease progression can include a second course of WBRT, although there is controversy surrounding its safety and efficacy. This study examines the outcomes in patients at Massachusetts General Hospital who underwent reirradiation. PATIENTS AND METHODS We examined the medical records of 17 patients at Massachusetts General Hospital with brain metastases who were initially treated with WBRT between 2002 and 2008 and were subsequently retreated with a second course of WBRT. The median dose for the first course of WBRT was 35 Gy (range, 28-40 Gy), with a fraction size of 2 to 3 Gy (median, 2.5 Gy). The median dose at reirradiation was 21.6 Gy (range, 14-30 Gy), with a fraction size of 1.5 to 2 Gy (median, 1.8 Gy). RESULTS The second course of WBRT was administered upon radiographic disease progression in all patients. Of 10 patients with complete follow-up data, 8 patients experienced complete or partial symptom resolution, and 2 did not show clinical improvement. The time to radiographic progression was 5.2 months. The median overall survival for all patients after diagnosis of metastases was 24.7 months. The median survival time after initiation of reirradiation was 5.2 months (95% CI, 1.3-8.7). In 6 patients with stable extracranial disease, the median survival time after retreatment was 19.8 months (95% CI, 2.7-∞), compared with 2.5 months (95% CI, 0.8-5.5) for those with extracranial disease progression (p = 0.05). Acute adverse reactions occurred in 70.5% of patients but were mild to moderate in severity. CONCLUSION In select patients and especially those with stable extracranial disease, reirradiation may be an appropriate and effective intervention to provide symptomatic relief and slow intracranial disease progression. Side effects were minimal and did not cause substantial changes in quality of life.

Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT)

The selection of patients for oligometastasis‐directed ablative therapy remains a challenge. The authors report on clinical and molecular predictors of survival from a stereotactic body radiotherapy (SBRT) dose‐escalation trial for oligometastases.

Improved survival time trends in Hodgkin's lymphoma

There have been dramatic changes in the staging and treatment of Hodgkins lymphoma (HL) over the past 30 years. We undertook this study to determine if a stage migration had occurred and also examined if treatment associated with later years has improved survival. Patients with stage I‐IV HL between 1983 and 2011 were selected from the Surveillance, Epidemiology, and End Results database. Multivariable analysis (MVA) was performed using Cox proportional hazards modeling. The study cohort included 35,680 patients. The stage breakdown in 1983 according to A and B symptoms was follows: 18%, 21%, 12%, and 5% for stage IA, IIA, IIIA, and IVA disease, respectively, and 6%, 11%, 12%, and 15% for stage IB, IIB, IIIB, and IVB disease. The stage breakdown in 2011 according to A and B symptoms was follows: 9%, 29%, 10%, and 6% for stage IA, IIA, IIIA, and IVA disease, respectively, and 4%, 16%, 12%, and 13% for stage IB, IIB, IIIB, and IVB disease. The median follow‐up for the entire cohort is 6.1 years. On MVA, the HR for mortality of patients diagnosed in 2006 was 0.60 (95% Confidence Interval (CI): 0.52–0.70) compared to 1983. For stage I and II patients diagnosed in 2006 the HR was 0.62 (95% CI: 0.44–0.87) and 0.40 (95% CI: 0.30–0.55), respectively, compared to patients diagnosed in 1983. For stage III and IV patients diagnosed in 2006 the HR was 0.72 (95% CI: 0.53–0.98) and 0.74 (95% CI: 0.56–0.99), respectively, compared to patients diagnosed in 1983. This is the first study to demonstrate a significant stage migration in early stage Hodgkins lymphoma. Furthermore, these results demonstrate an improvement in survival over time for patients with Hodgkins lymphoma which was particularly notable for those with early stage disease.

High-risk Prostate Cancer Treated With Dose-escalated RT: An Analysis of Hormonal Therapy Use and Duration, and Prognostic Implications of PSA Nadir ≤0.2 to Select Men for Short-term Hormonal Therapy.

Objectives: To determine prognostic factors to select high-risk men receiving dose-escalated radiation therapy (RT) who will have favorable outcomes with short-term (ST) or no androgen deprivation therapy (ADT). Methods: Medical records of 458 men treated with definitive RT for high-risk, nonmetastatic prostate cancer at 3 academic referral centers from 1988 to 2009 were examined. Median dose was 76.4 Gy. Men received no ADT (n=105), STADT (<12 mo, n=194), or long-term ADT (LTADT: ≥12 mo, n=160). Univariate and multivariable analysis for freedom from distant metastases (FFDM) and cause-specific survival (CSS) were performed. Median follow-up was 71 months. Results: Seven-year FFDM was 83% and CSS was 91%. Multivariable analysis demonstrated that prostate-specific antigen (PSA) nadir ⩽0.2 (HR=0.36; 95% CI, 0.20-0.64) and Gleason score (GS) were associated with FFDM and CSS (all P<0.05). ADT duration was not associated (P>0.05). Those with PSA nadir ⩽0.2 ng/mL had improved outcomes. Men with GS 9 disease did poorly despite a PSA nadir ⩽0.2 ng/mL and had improved CSS with LTADT (95% vs. 71%, P<0.05). Conclusions: Select men with high-risk disease treated with dose-escalated RT may not require LTADT. In men treated with ADT, PSA nadir ⩽0.2 is an independent prognostic factor associated with FFDM and CSS. Men without GS 9 may have acceptable outcomes with STADT if PSA nadir is ⩽0.2 ng/mL. Further investigation is necessary to elucidate the role of PSA nadir in determining the optimal length of adjuvant ADT.

The impact of hormonal therapy on sexual quality of life in men receiving intensity modulated radiation therapy for prostate cancer

PURPOSE Sexual function is an important concern in men receiving intensity modulated radiation therapy (IMRT) for prostate cancer. Our aim was to study the impact of IMRT and androgen deprivation therapy (ADT) on sexual function over time and to report the effectiveness of sexual medications or aids. METHODS AND MATERIALS A total of 179 men, median age 69, received definitive IMRT for prostate cancer and completed 2 surveys (Expanded Prostate Cancer Index Composite-26 and a sexual medicines/devices survey) for at least 2 time points. Surveys were prospectively collected at baseline (before all therapy), and 2, 6, 12, 18, and 24 months after IMRT. Median dose was 76 Gy to the prostate. ADT was administered to 59% of patients (median duration 5 months, initiated 2 months before IMRT). Global scores were generated for the Expanded Prostate Cancer Index Composite-26 questions. Longitudinal analysis was performed by constructing a generalized estimation equations model, and clinical variables were tested for association with global scores. RESULTS Overall, there was a significant decline in global sexual score through 2 years. Men receiving ADT had a lower sexual score at 2 and 6 months, but this difference disappeared at 24 months. Analysis of individual sexual symptoms showed no significant difference at 24 months except that men on ADT were less likely to be sexually active (P = .02); this difference was not observed for men receiving short-term ADT only. Longitudinal analysis revealed that duration of ADT was the only factor associated with global sexual score. Phosphodiesterase inhibitors were attempted by roughly half of all men, with 66% experiencing benefit, whereas other aids were attempted by roughly 5% of men. CONCLUSIONS Although ADT adversely affected short-term sexual function, there was no significant difference in global score and most sexual symptoms by 24 months. These data are useful for anticipatory guidance regarding expectations after IMRT.

Estimating prognosis at the time of repeat whole brain radiation therapy for multiple brain metastases: The reirradiation score

Purpose Whole brain radiation therapy (WBRT) remains the standard of care for patients with multiple brain metastases, but more than half of treated patients will develop intracranial progression. Because there is no clear consensus on the optimal therapeutic approach, a prognostic index would be helpful to guide treatment options at progression. We explored whether the recursive partitioning analysis (RPA) score prior to repeat WBRT is predictive of survival. Methods and materials This multi-institutional pooled analysis included patients with 2 or more brain metastases from any solid primary tumor that was treated with 2 courses of WBRT. Information on demographics, disease characteristics, and intervals between courses was collected. RPA class was abstracted or retrospectively assigned, and descriptive statistics calculated. Median survival (MS) was determined using the Kaplan-Meier method and compared using log rank tests. Univariate and multivariate analyses were performed via Cox regression analysis. Results For 205 patients, the median age was 55 years (range, 25-83 years), 68% were female, 40.5% had non-small cell lung cancer, and 31.2% had small cell lung cancer. Prior to the second WBRT, 4.9% of patients were RPA class 1, 36.6% were RPA2, and 58.5% were RPA3, with an MS of 7.5 months (95% confidence interval [CI], 4.7-10.3), 5.2 months (95% CI, 3.7-6.7 months), and 2.9 months (95% CI, 2.2-2.9 months), respectively (P = .001). On univariate and multivariate analyses, a Karnofsky Performance Status of <80, extracranial metastases, interval between courses <9 months, small cell lung cancer histology, and uncontrolled primary significantly correlated with shorter MS. By assigning a score of 1 to each of these factors, a new prognostic index was created, the reirradiation (ReRT) score. Survival on the basis of ReRT score grouping ranged from 2.2 to 7.2 months and demonstrated significant differences in MS. Conclusions In the largest reported cohort to receive repeat WBRT, application of the RPA score was not predictive of MS. The new ReRT score is a simple tool based on readily available clinical information.

Bladder dose-volume parameters are associated with urinary incontinence after postoperative intensity modulated radiation therapy for prostate cancer

PURPOSE Urinary incontinence is a potential side effect of prostatectomy and intensity modulated radiation therapy (IMRT) for prostate cancer. There are limited data on dosimetric parameters that may predict for poor continence recovery in men who receive postoperative IMRT. METHODS AND MATERIALS Eighty-seven men with nonmetastatic prostate cancer who underwent prostatectomy followed by adjuvant (13%) or salvage (87%) IMRT were identified. The Expanded Prostate Cancer Index composite questionnaire was prospectively collected at baseline, 6 weeks, and 6, 12, 18, 24, 36, and 48 months post-IMRT. Relevant critical structures were contoured and dose-volume metrics collected. The primary endpoint was urinary continence global score. Longitudinal analysis using a generalized estimating equation model was performed. RESULTS There was no statistically significant change in Expanded Prostate Cancer Index composite urinary continence global scores over time as compared with baseline (all P > .05). In univariate analysis, bladder volume receiving 70 Gy (V70 Gy) and penile bulb V70 Gy were associated with urinary continence (odds ratio, 0.82; P < .05). In a multivariable model that included body mass index, distance between vesicourethral junction and genitourinary diaphragm, time from surgery, use of antihypertensive medications, age, diabetes, and bladder V70 Gy, only bladder V70 Gy (odds ratio, 0.82; P = .03) was associated with outcome. After 2 years, there was a significant difference in global score for those with V70 Gy < 42.27 versus ≥42.27 mL (all P < .05 at 2 and 3 years post-IMRT). CONCLUSION There was no significant change in patient-reported urinary continence scores after postprostatectomy IMRT. Bladder V70 Gy was independently associated with a decrease in urinary continence scores. Further evaluation is necessary to optimize quality of life in these men.

Initial experience using superflab as intravaginal packing during interstitial brachytherapy for advanced gynecologic cancer

Purpose Interstitial brachytherapy implemented for locally advanced gynecologic cancer can result in toxicity due to the proximity of organs at risk (OAR). We report our experience using superflab bolus as vaginal packing to displace OAR during interstitial brachytherapy. Material and methods Twelve patients with stage IB-IVA gynecologic cancer were treated with definitive chemoradiation including interstitial brachytherapy. A Syed template was used for a computed tomography (CT)-based pre-plan with magnetic resonance imaging (MRI) fusion. A 1-2 cm superflab bolus was cut and sterilized. The tandem and obturator were placed, and superflab was then inserted into the vagina. Interstitial needles were then placed through the template and superflab as per the pre-plan under transabdominal ultrasound guidance. Prescription doses ranged from 85-90 Gy EQD2 including external beam radiation therapy (EBRT). 5-6 Gy per fraction was delivered biologically effective dose (BID) over 2-3 days in 1-2 implants. Toxicities were evaluated post-treatment, 1 month, and 3 months. Results The rectum, bladder, and sigmoid had significant average displacement from the prescription isodose line. The average reduction in D2cc between pre- and post-implant was 5.19 Gy per fraction (p < 0.0001), 7.19 Gy (p < 0.0004), and 1.78 Gy (p < 0.003) for the rectum, bladder, and sigmoid, respectively. The high-risk target volume (HR-TV) received a median D90 of 104% (range, 58-122%) of the prescription dose, and 92% (range, 71-131%) in the pre-/post-implant plans, respectively (p = 0.4). Conclusions Our initial experience with superflab as vaginal packing demonstrates technical feasibility and dosimetric improvement for OAR.

Optimizing the Role of Surgery and Radiation Therapy in Urethral Cancer Based on Histology and Disease Extent

PURPOSE Urethral cancer is rare, with limited data guiding treatment. A national hospital-based registry was used to evaluate the role of local therapy in these patients. METHODS AND MATERIALS We performed a retrospective cohort study of patients who, between 2004 and 20013, received a diagnosis of T0-4N0-2 M0 urethral cancer. Local therapy was radiation therapy (RT), surgery (S), or S and RT (S+RT). The Cox proportional hazards model was used to assess the impact of therapy type on overall survival (primary endpoint). Subgroup analysis by extent of disease (early stage [T0-2 N0] vs locally advanced [T3+ or N+]) and histology was performed. RESULTS In our study, 2614 patients had a median follow-up of 28 months. Three-year overall survival was 54%. In 501 patients with locally advanced disease, S+RT was associated with improved survival versus S alone (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.42-0.80). There was no difference for patients with squamous cell carcinoma by treatment type, but patients with adenocarcinoma (RT vs S: HR 0.20; 95% CI, 0.07-0.60) or transitional cell carcinoma (S+RT vs S: HR 0.45, 95% CI, 0.26-0.77) had improved OS with RT as part of treatment. In 1705 early-stage patients, there was no association with survival when comparing S+RT versus S. CONCLUSIONS For patients with locally advanced disease and transitional cell carcinoma undergoing S, the addition of RT is associated with improved overall survival and should be considered. An RT-based approach may be preferred for adenocarcinoma, but there was no clear association with survival by therapy type for squamous cell carcinoma. This study is hypothesis generating; prospective trials are necessary.

Late toxicity after post-prostatectomy intensity modulated radiation therapy: Evaluating normal-tissue sparing guidelines

Purpose Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. Methods and materials 164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6 Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4 Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2 + (G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ≤35, 55%, and bladder-CTV V65, 40 ≤50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ≤20, 40, 80% and bladder V70, 65, 40 ≤30, 60, 80%, respectively) guidelines were evaluated. Results With a median follow-up time of of 33 months, the 4-year freedom from G2 + GI and GU toxicity were both 91%. G2 + GI (n = 12) and GU (n = 15) toxicity included 4% diarrhea (n = 6), 4% hemorrhage (n = 6), 1% proctitis (n = 1), and 4% urinary frequency (n = 7), 1% obstructive (n = 2), 2% cystitis (n = 3), and 3% incontinence (n = 5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P > .1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. Conclusions More than 90% of men were free from late G2 + toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.