Kevin Forsythe

YOUNG MEN HAVE EQUIVALENT BIOCHEMICAL OUTCOMES COMPARED WITH OLDER MEN AFTER TREATMENT WITH BRACHYTHERAPY FOR PROSTATE CANCER

PURPOSE To evaluate retrospectively the biochemical outcomes of young men treated with low-dose-rate brachytherapy for prostate cancer. METHODS AND MATERIALS From 1990 to 2005, 1,665 men with clinically localized prostate cancer were treated with low-dose-rate brachytherapy +/- hormone therapy (HT) +/- external beam radiotherapy and underwent > or = 2 years of follow-up. Patients were stratified on the basis of age: < or = 60 (n = 378) and >60 years (n = 1,287). Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/mL. Univariate and multivariate analyses were used to determine the association of variables with freedom from biochemical failure (FFbF). RESULTS Median follow-up was 68 months (range, 24-180) for men < or = 60 years and 66 months (range, 24-200) for men >60. For the entire group, the actuarial 5- and 8-year FFbF rates were 94% and 88%, respectively. Men < or = 60 demonstrated similar 5- and 8-year FFbF (95% and 92%) compared with men >60 (93% and 87%; p = 0.071). A larger percent of young patients presented with low-risk disease; lower clinical stage, Gleason score (GS), and pretreatment PSA values; were treated after 1997; did not receive any HT; and had a high biologic effective dose (BED) of radiation (all ps <0.001). On multivariate analysis, PSA (p = 0.001), GS (p = 0.005), and BED (p < 0.001) were significantly associated with FFbF, but age was not (p = 0.665). CONCLUSION Young men achieve excellent 5- and 8-year biochemical control rates that are comparable to those of older men after prostate brachytherapy. Young age should not be a deterrent when considering brachytherapy as a primary treatment option for clinically localized prostate cancer.

Intensity-Modulated Radiotherapy Causes Fewer Side Effects than Three-Dimensional Conformal Radiotherapy When Used in Combination With Brachytherapy for the Treatment of Prostate Cancer

PURPOSE To measure the benefits of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3D-CRT) when used in combination with brachytherapy for the treatment of prostate cancer. METHODS AND MATERIALS We conducted a retrospective review of all patients with localized prostate cancer who received external-beam radiotherapy (EBRT) in combination with brachytherapy with at least 1 year follow-up (n = 812). Combination therapy consisted of (103)Pd or (125)I implant, followed by a course of EBRT. From 1993 to March 2003 521 patients were treated with 3D-CRT, and from April 2003 to March 2009 291 patients were treated with IMRT. Urinary symptoms were prospectively measured with the International Prostate Symptom Score questionnaire with a single quality of life (QOL) question; rectal bleeding was assessed per the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. The Pearson χ(2) test was used to compare toxicities experienced by patients who were treated with either IMRT or 3D-CRT. Logistic regression analyses were also performed to rule out possible confounding factors. RESULTS Within the first 3 months after treatment, patients treated with 3D-CRT scored their urinary symptoms as follows: 19% mild, 44% moderate, and 37% severe; patients treated with IMRT scored their urinary symptoms as follows: 36% mild, 47% moderate, and 17% severe (p < 0.001). The 3D-CRT patients rated their QOL as follows: 35% positive, 20% neutral, and 45% negative; IMRT patients rated their QOL as follows: 51% positive, 18% neutral, and 31% negative (p < 0.001). After 1 year of follow-up there was no longer any difference in urinary morbidity between the two groups. Logistic regression confirmed the differences in International Prostate Symptom Score and QOL in the acute setting (p < 0.001 for both). Grade ≥ 2 rectal bleeding was reported by 11% of 3D-CRT patients and 7% of IMRT patients (p = 0.046); logistic regression analysis also confirmed this observation (p = 0.040). CONCLUSIONS When used in combination with brachytherapy, IMRT offers less Grade ≥ 2 rectal bleeding, less acute urinary toxicities, and is associated with a higher QOL compared with 3D-CRT.

Radiobiological rationale and clinical implications of hypofractionated radiation therapy.

Recent clinical trials of hypofractionated radiation treatment have provided critical insights into the safety and efficacy of hypofractionation. However, there remains much controversy in the field, both at the level of clinical practice and in our understanding of the underlying radiobiological mechanisms. In this article, we review the clinical literature on hypofractionated radiation treatment for breast, prostate, and other malignancies. We highlight several ongoing clinical trials that compare outcomes of a hypofractionated approach versus those obtained with a conventional approach. Lastly, we outline some of the preclinical and clinical evidence that argue in favor of differential radiobiological mechanisms underlying hypofractionated radiation treatment. Emerging data from the ongoing studies will help to better define and guide the rational use of hypofractionation in future years.

Outcomes for patients with extraprostatic prostate cancer treated with trimodality therapy, including brachytherapy, external beam radiotherapy, and hormone therapy.

PURPOSE To evaluate the efficacy of multimodality therapy consisting of hormone therapy (HT), brachytherapy (BT), and external beam radiotherapy (EBRT) in extraprostatic prostate cancer and identify factors with predictive value. METHODS AND MATERIALS Between June 1992 and October 2006, 97 patients with extraprostatic prostate cancer received permanent seed implant BT. Extraprostatic disease was defined by one or more of the following: positive seminal vesicle biopsy (n=56), positive lymph node dissection (n=8), or a clinical tumor stage of T3 (n=48). Treatment consisted of BT alone with (103)Pd or (125)I (n=4); HT and BT (n=3); BT and EBRT (n=2); or trimodality therapy with HT, BT, and EBRT (n=88). Median followup was 69 (range, 23-182) months. Freedom from biochemical failure (FBF) rates were calculated using the Phoenix criteria. RESULTS The 7-year actuarial FBF, freedom from distant metastases, disease-specific survival, and overall survival rates were 67%, 82%, 96%, and 81%, respectively. Biologically effective dose (BED) was the only variable significantly impacting FBF rates. FBF at 7 years was 60% vs. 74% for BED below 200 and 200 or above, respectively (p=0.048). Trends toward worse outcomes were noted with increasing Gleason score, with 7-year FBF rates of 86% vs. 71% vs. 55% for scores of 6 or less, 7, and 8-10, respectively (p=0.090). BED was the only significant predictor of FBF in multivariate analysis (p=0.032). None of the predictors were significant in multivariable analyses for the other outcomes studied. CONCLUSIONS Trimodality approach achieves durable biochemical control in most patients with historically poor prognosis T3 prostate cancer. BED above 200Gy was associated with superior FBF.

Predictors of Metastatic Disease after Prostate Brachytherapy

PURPOSE To identify predictors of metastatic disease after brachytherapy treatment for prostate cancer. METHODS AND MATERIALS All patients who received either brachytherapy alone (implant) or brachytherapy in combination with external beam radiation therapy for treatment of localized prostate cancer at The Mount Sinai Hospital between June 1990 and March 2007 with a minimum follow-up of 2 years were included. Univariate and multivariable analyses were performed on the following variables: risk group, Gleason score (GS), clinical T stage, pretreatment prostate-specific antigen level, post-treatment prostate-specific antigen doubling time (PSA-DT), treatment type (implant vs. implant plus external beam radiation therapy), treatment era, total biological effective dose, use of androgen deprivation therapy, age at diagnosis, and race. PSA-DT was analyzed in the following ordinate groups: 0 to 90 days, 91 to 180 days, 180 to 360 days, and greater than 360 days. RESULTS We included 1,887 patients in this study. Metastases developed in 47 of these patients. The 10-year freedom from distant metastasis (FFDM) rate for the entire population was 95.1%. Median follow-up was 6 years (range, 2-15 years). The only two significant predictors of metastatic disease by multivariable analyses were GS and PSA-DT (p < 0.001 for both variables). Estimated 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001). Estimated FFDM rates for PSA-DT of 0 to 90 days, 91 to 180 days, 181 to 360 days, and greater than 360 days were 17.5%, 67.9%, 74%, and 94.8%, respectively (p < 0.001). Estimated 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively. A demographic shift to patients presenting with higher-grade disease in more recent years was observed. CONCLUSIONS GS and post-treatment PSA-DT are both statistically significant independent predictors of metastatic disease. Patients with a high GS and/or short PSA-DT have a higher likelihood of developing metastatic disease and should be considered for systemic therapy.

Prognostic significance of p16 in locoregionally advanced head and neck cancer treated with concurrent 5-fluorouracil, hydroxyurea, cetuximab and intensity-modulated radiation therapy

A phase II trial was conducted to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) into a well-described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen. Patients with stage IVa-IVb or high-risk stage III squamous cell carcinomas were enrolled. Prior organ-conserving surgery or induction chemotherapy was allowed. IMRT was administered in 1.5 Gy fractions twice daily on days 1-5 of weeks 1, 3, 5, 7±9 for a total dose of 60-73.5 Gy. Concurrent systemic therapy consisted of 5-FU (600 mg/m2), HU (500 mg BID) and cetuximab (250 mg/m2). p16INK4A expression was assessed by immunohistochemistry. From January 2007 to January 2010, 65 patients (61 with stage IV disease; 31 with oropharyngeal primaries) were enrolled. At a median follow-up of 28 months, 2-year locoregional control, distant control, progression-free survival, event-free survival and overall survival were 79, 83, 72, 63 and 80%, respectively. In 48 patients with available pre-treatment tissue, p16 overexpression was associated with significantly increased distant control (p=0.03), progression-free survival (p=0.02), event-free survival (p=0.007) and overall survival (p=0.03). The most common grade 3-4 toxicities were mucositis (46%), leukopenia (18%), anemia (18%) and dermatitis (17%). Concurrent 5-FU, HU, cetuximab and SIB-IMRT is a highly active regimen, particularly in patients with p16-positive disease.