Faculty Bibliography

PURPOSE/OBJECTIVE:To compare biochemical outcomes and morbidity associated with iodine-125 ((125)I) and palladium-103 ((103)Pd) brachytherapy as part of combined modality therapy for clinically localized prostate cancer. METHODS AND MATERIALS/METHODS:Between October 2002 and December 2008, 259 patients underwent prostate brachytherapy ((125)I prescription dose, 110Gy: n=199; (103)Pd prescription dose, 100Gy: n=60) followed by external beam radiotherapy (median dose, 50.4Gy). Eighty-seven patients also received neoadjuvant androgen deprivation therapy. Toxicities were recorded with CTCAE v 3.0, International Prostate Symptoms Score (IPSS), and International Index of Erectile Function questionnaires. RESULTS:Overall, acute Grade ≥2 genitourinary toxicity occurred in 21% and 30% of patients treated with (125)I and (103)Pd, respectively (p=0.16). There were no significant differences in IPSS change or urinary quality-of-life scores between the isotopes at 4, 6, or 12 months (p=0.20, 0.21, and 1.0, respectively). IPSS resolution occurred at a median of 11 and 6 months for (125)I and (103)Pd patients, respectively (p=0.03). On multivariate analysis, only the use of neoadjuvant androgen deprivation therapy was predictive of time to IPSS resolution (p=0.046). Late Grade ≥2 gastrointestinal toxicity occurred in 7% of (125)I patients and 6% of patients treated with (103)Pd. Of 129 potent patients at baseline, there was better erectile function in patients who received (103)Pd (p=0.02); however, the followup was shorter for these patients. The 5-year prostate-specific antigen relapse-free survival for (125)I and (103)Pd patients was 95.2% and 98.2% (p=0.73), respectively. CONCLUSION/CONCLUSIONS:There were no differences in acute or long-term genitourinary or gastrointestinal toxicity between (125)I and (103)Pd in combined modality therapy for prostate cancer. There may be less erectile toxicity with the use of (103)Pd; however, additional followup of these patients is needed. There was no significant difference in 5-year prostate-specific antigen relapse-free survival between (103)Pd and (125)I.

PURPOSE/OBJECTIVE:To identify predictors of biochemical tumor control and present an updated prognostic nomogram for patients with clinically localized prostate cancer treated with brachytherapy. METHODS AND MATERIALS/METHODS:One thousand four hundred sixty-six patients with clinically localized prostate cancer were treated with brachytherapy alone or along with supplemental conformal radiotherapy. Nine hundred one patients (61%) were treated with Iodine-125 ((125)I) monotherapy to a prescribed dose of 144Gy, and 41 (4.5%) were treated with Palladium-103 ((103)Pd) monotherapy to a prescribed dose of 125Gy. In patients with higher risk features (n=715), a combined modality approach was used, which comprised (125)I or (103)Pd seed implantation or Iridium-192 high-dose rate brachytherapy followed 1-2 months later by supplemental intensity-modulated image-guided radiotherapy to the prostate. RESULTS:The 5-year prostate-specific antigen relapse-free survival (PSA-RFS) outcomes for favorable-, intermediate-, and high-risk patients were 98%, 95%, and 80%, respectively (p<0.001). Multivariate Cox regression analysis identified Gleason score (p<0.001) and pretreatment PSA (p=0.04) as predictors for PSA tumor control. In this cohort of patients, the use of neoadjuvant and concurrent androgen deprivation therapy did not influence biochemical tumor control outcomes. In the subset of patients treated with (125)I monotherapy, D(90)>140Gy compared with lower doses was associated with improved PSA-RFS. A nomogram predicting PSA-RFS was developed based on these predictors and had a concordance index of 0.70. CONCLUSIONS:Results with brachytherapy for all treatment groups were excellent. D(90) higher than 140Gy was associated with improved biochemical tumor control compared with lower doses. Androgen deprivation therapy use did not impact on tumor control outcomes in these patients.

BACKGROUND:Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients. OBJECTIVE:Identify predictors of biochemical tumor control and distant metastases-free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT. DESIGN, SETTING, AND PARTICIPANTS/METHODS:This retrospective analysis comprised 2551 patients with clinical stages T1-T3 PCa. Median follow-up was 8 yr, extending >20 yr. INTERVENTION/METHODS:Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo. MEASUREMENTS/METHODS:A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed. RESULTS AND LIMITATIONS/CONCLUSIONS:Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels < 70.2 Gy and 70.2-79.2 Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse-free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes. CONCLUSIONS:Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.

BACKGROUND:With salvage radiation therapy (SRT) in the postprostatectomy setting, the need to deliver sufficient radiation doses to achieve a high probability of tumor control is balanced with the risk of increased toxicity. Intensity-modulated radiation therapy (IMRT) in the postprostatectomy salvage setting is gaining interest as a treatment strategy. OBJECTIVE:Compare acute and late toxicities in patients treated with IMRT and three-dimensional conformal radiation therapy (3D-CRT) in the postprostatectomy salvage setting. DESIGN, SETTING, AND PARTICIPANTS/METHODS:A total of 285 patients who were treated at our institution between 1988 and 2007 with SRT after radical prostatectomy for biochemical recurrence were identified. All medical records were reviewed and toxicity recorded. Median follow-up was 60 mo. INTERVENTION/METHODS:All patients were treated with SRT with either 3D-CRT (n=109) or IMRT (n=176). A total of 205 patients (72%) were treated with doses ≥70Gy. MEASUREMENTS/METHODS:Late gastrointestinal (GI) and genitourinary (GU) toxicities were recorded using the Common Terminology Criteria for Adverse Events v. 3.0 definition. RESULTS AND LIMITATIONS/CONCLUSIONS:The 5-yr actuarial rates of late grade ≥2 GI and GU toxicity were 5.2% and 17.0%, respectively. IMRT was independently associated with a reduction in grade ≥2 GI toxicity compared with 3D-CRT (5-yr IMRT, 1.9%; 5-yr 3D-CRT, 10.2%; p=0.02). IMRT was not associated with a reduction in risk of grade ≥2 GU toxicity (5-yr IMRT, 16.8%; 5-yr 3D-CRT, 15.8%; p=0.86), urinary incontinence (5-yr IMRT, 13.6%; 5-yr 3D-CRT, 7.9%; p=0.25), or grade 3 erectile dysfunction (5-yr IMRT, 26%; 5-yr 3D-CRT, 30%; p=0.82). Of patients who developed late grade ≥2 GI or GU toxicity, 38% and 44%, respectively, experienced resolution of their symptoms prior to the last follow-up. CONCLUSIONS:Our experience with high-dose IMRT in the postprostatectomy salvage setting demonstrates that the treatment can be delivered safely with an associated reduction in late GI toxicity.

PURPOSE/OBJECTIVE:Osteoradionecrosis (ORN) is a known complication of radiation therapy to the head and neck. However, the incidence of this complication with intensity-modulated radiation therapy (IMRT) and dental sequelae with this technique have not been fully elucidated. METHODS AND MATERIALS/METHODS:From December 2000 to July 2007, 168 patients from our institution have been previously reported for IMRT of the oral cavity, nasopharynx, larynx/hypopharynx, sinus, and oropharynx. All patients underwent pretreatment dental evaluation, including panoramic radiographs, an aggressive fluoride regimen, and a mouthguard when indicated. The median maximum mandibular dose was 6,798 cGy, and the median mean mandibular dose was 3,845 cGy. Patient visits were retrospectively reviewed for the incidence of ORN, and dental records were reviewed for the development of dental events. Univariate analysis was then used to assess the effect of mandibular and parotid gland dosimetric parameters on dental endpoints. RESULTS:With a median clinic follow-up of 37.4 months (range, 0.8-89.6 months), 2 patients, both with oral cavity primaries, experienced ORN. Neither patient had preradiation dental extractions. The maximum mandibular dose and mean mandibular dose of the 2 patients were 7,183 and 6,828 cGy and 5812 and 5335 cGy, respectively. In all, 17% of the patients (n = 29) experienced a dental event. A mean parotid dose of >26 Gy was predictive of a subsequent dental caries, whereas a maximum mandibular dose >70 Gy and a mean mandibular dose >40 Gy were correlated with dental extractions after IMRT. CONCLUSIONS:ORN is rare after head-and-neck IMRT, but is more common with oral cavity primaries. Our results suggest different mechanisms for radiation-induced caries versus extractions.

PURPOSE/OBJECTIVE:To compare concurrent cisplatin (CDDP) and radiation (RT) with cetuximab (C225) and RT for locally advanced head-and-neck cancer (LAHNC). METHODS AND MATERIALS/METHODS:This study retrospectively compared 174 consecutive, newly diagnosed LAHNC patients definitively treated from March 1, 2006, to April 1, 2008, with single-agent CDDP/RT (n = 125) or C225/RT (n = 49). We excluded patients who received additional concurrent, induction, or adjuvant systemic therapy; weekly cisplatin; prior head-and-neck radiotherapy; or primary surgical resection. Outcomes were analyzed by the Kaplan-Meier method, Cox model, and competing-risks analysis tools. RESULTS:The C225/RT patients were older and had decreased creatinine clearance. At a median follow-up of 22.5 months for living patients, the 2-year locoregional failure rate was 5.7% for CDDP/RT and 39.9% for C225/RT (p < 0.0001). The 2-year failure-free survival (FFS) and overall survival (OS) rates were 87.4% vs. 44.5% (p < 0.0001) and 92.8% vs. 66.6% (p = 0.0003), respectively, in favor of CDDP/RT. When the Cox proportional hazards model was used for multivariate analysis, treatment with CDDP/RT predicted for improved locoregional control (p < 0.0001), FFS (p < 0.0001), and OS (p = 0.01). Late Grade 3 or 4 toxicity or feeding tube dependence 9 months after completion of RT was observed in 21% of patients in the CDDP/RT cohort and 24% in the C225/RT cohort (p = 0.66). CONCLUSIONS:In this study of LAHNC patients, CDDP/RT achieved better locoregional control, FFS, and OS than C225/RT. Although the results were upheld on multivariate analysis, they must be interpreted cautiously because of the retrospective nature of the study and significant differences in patient selection. There was no statistically significant difference in late Grade 3 or 4 effects or feeding tube dependence.

The objective of this review is to present an overview of each modality and delineate how to best select patients who are optimal candidates for these treatment approaches. Prostate brachytherapy as a curative modality for clinically localized prostate cancer has become increasingly utilized over the past decade; 25% of all early cancers are now treated this way in the United States (1). The popularity of this treatment strategy lies in the highly conformal nature of radiation dose, low morbidity, patient convenience, and high efficacy rates. Prostate brachytherapy can be delivered by either a permanent interstitial radioactive seed implantation (low dose rate [LDR]) or a temporary interstitial insertion of iridium-192 (Ir192) afterloading catheters. The objective of both of these techniques is to deliver a high dose of radiation to the prostate gland while exposing normal surrounding tissues to minimal radiation dose. Brachytherapy techniques are ideal to achieve this goal given the close proximity of the radiation source to tumor and sharp fall off of the radiation dose cloud proximate to the source. Brachytherapy provides a powerful means of delivering dose escalation above and beyond that achievable with intensity-modulated external beam radiotherapy alone. Careful selection of appropriate patients for these therapies, however, is critical for optimizing both disease-related outcomes and treatment-related toxicity.

OBJECTIVES/OBJECTIVE:To assess the incremental value of diffusion-weighted (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI) to T2-weighted MRI (T2WI) in detecting locally recurrent prostate cancer after radiotherapy. METHODS:Twenty-four patients (median age, 70 years) with a history of radiotherapy-treated prostate cancer underwent multi-parametric MRI (MP-MRI) and transrectal prostate biopsy. Two readers independently scored the likelihood of cancer on a 1-5 scale, using T2WI alone and then adding DW-MRI and DCE-MRI. Areas under receiver operating characteristic curves (AUCs) were estimated at the patient and prostate-side levels. The apparent diffusion coefficient (ADC) from DW-MRI and the K(trans), k(ep), v(e), AUGC90 and AUGC180 from DCE-MRI were recorded. RESULTS:Biopsy was positive in 16/24 (67%) and negative in 8/24 (33%) patients. AUCs for readers 1 and 2 increased from 0.64 and 0.53 to 0.95 and 0.86 with MP-MRI, at the patient level, and from 0.73 and 0.66 to 0.90 and 0.79 with MP-MRI, at the prostate-side level (p values < 0.05). Biopsy-positive and biopsy-negative prostate sides differed significantly in median ADC [1.44 vs. 1.68 (×10(-3) mm(2)/s)], median K(trans) [1.07 vs. 0.34 (1/min)], and k(ep) [2.06 vs 1.0 (1/min)] (p values < 0.05). CONCLUSIONS:MP-MRI was significantly more accurate than T2WI alone in detecting locally recurrent prostate cancer after radiotherapy.

PURPOSE/OBJECTIVE:To evaluate the feasibility of dose-painting intensity-modulated radiation therapy (DP-IMRT) with a hypofractionated regimen to treat nasopharyngeal carcinoma (NPC) with concomitant toxicity reduction. METHODS AND MATERIALS/METHODS:From October 2002 through April 2007, 25 newly diagnosed NPC patients were enrolled in a prospective trial. DP-IMRT was prescribed to deliver 70.2 Gy using 2.34-Gy fractions to the gross tumor volume for the primary and nodal sites while simultaneously delivering 54 Gy in 1.8-Gy fractions to regions at risk of microscopic disease. Patients received concurrent and adjuvant platin-based chemotherapy similar to the Intergroup 0099 trial. RESULTS:Patient and disease characteristics are as follows: median age, 46; 44% Asian; 68% male; 76% World Health Organization III; 20% T1, 52% T2, 16% T3, 12% T4; 20% N0, 36% N1, 36% N2, 8% N3. With median follow-up of 33 months, 3-year local control was 91%, regional control was 91%, freedom from distant metastases was 91%, and overall survival was 89%. The average mean dose to each cochlea was 43 Gy. With median audiogram follow-up of 14 months, only one patient had clinically significant (Grade 3) hearing loss. Twelve percent of patients developed temporal lobe necrosis; one patient required surgical resection. CONCLUSIONS:Preliminary findings using a hypofractionated DP-IMRT regimen demonstrated that local control, freedom from distant metastases, and overall survival compared favorably with other series of IMRT and chemotherapy. The highly conformal boost to the tumor bed resulted low rates of severe ototoxicity (Grade 3-4). However, the incidence of in-field brain radiation necrosis indicates that 2.34 Gy per fraction is not safe in this setting.