Faculty Bibliography

What is the best way to manage patients with intermediate-risk prostate cancer? One of the most controversial aspects of treatment is the role of short-term androgen deprivation therapy in combination with definitive radiotherapy. In two randomised trials of patients with mostly intermediate-risk prostate cancer, increased overall survival was reported when short-term androgen deprivation therapy was added to radiotherapy. However, radiation doses in these studies were far below the current standard of care. This limitation, in combination with the heterogeneous nature of the cancers classified as intermediate risk, has complicated the application of these trial results to modern clinical practice. In this Review, we discuss clinical evidence for and against use of short-term androgen deprivation therapy with dose-escalated radiotherapy for patients with intermediate-risk prostate cancer.

CONTEXT/BACKGROUND:High-risk prostate cancer (PCa) is a potentially lethal disease. It is clinically important to identify patients with high-risk PCa early on because they stand to benefit the most from curative therapy. Because of recent advances in PCa management, a multimodal approach may be advantageous. OBJECTIVE:Define high-risk PCa, and identify the best diagnostic and treatment patterns for patients with clinically localized and locally advanced disease. A critical analysis of published results following monomodal and/or multimodal therapy for high-risk PCa patients was also performed. EVIDENCE ACQUISITION/METHODS:A review of the literature was performed using the Medline, Embase, Scopus, and Web of Science databases as well as the Cochrane Database of Systematic Reviews. EVIDENCE SYNTHESIS/RESULTS:High-risk PCa accounts for ≤ 15% of all new diagnoses. Compared with patients with low- and intermediate-risk PCa, patients with high-risk PCa are at increased risk of treatment failure. Unfortunately, no contemporary randomized controlled trials comparing different treatment modalities exist. Evaluation of the results published to date shows that no single treatment can be universally recommended. Most often, a multimodal approach is warranted to optimize patient outcomes. CONCLUSIONS:A significant minority of patients continue to present with high-risk PCa, which remains lethal in some cases. Outcomes following treatment of men with high-risk tumors have not substantially improved over time. However, not all high-risk patients are at the same risk of PCa progression and death. At present, a multimodal approach seems the best way to achieve acceptable outcomes for high-risk PCa patients.

UNLABELLED:Study Type--Therapy (practice patterns). Level of Evidence 2b. What's known on the subject? And what does the study add? The treatment of locally advanced prostate cancer varies widely even though there is level one evidence supporting the use of multimodality therapy as compared with monotherapy. This study defines treatment patterns of locally advanced prostate cancer within the United States and identifies predicators of who receives multimodality therapy rather than monotherapy. OBJECTIVE:• To identify treatment patterns and predictors of receiving multimodality therapy in patients with locally advanced prostate cancer (LAPC). PATIENTS AND METHODS/METHODS:• The cohort comprised patients ≥66 years with clinical stage T3 or T4 non-metastatic prostate cancer diagnosed between 1998 and 2005 identified from the Surveillance, Epidemiology and End Results (SEER) cancer registry records linked with Medicare claims. • Treatments were classified as radical prostatectomy (RP), radiation therapy (RT) and androgen deprivation therapy (ADT) received within 6 and 24 months of diagnosis. • We assessed trends over time and used multivariable logistic regression to identify predictors of multimodality treatment. RESULTS:• Within the first 6 months of diagnosis, 1060 of 3095 patients (34%) were treated with a combination of RT and ADT, 1486 (48%) received monotherapy (RT alone, ADT alone or RP alone), and 461 (15%) received no active treatment. • The proportion of patients who received RP increased, exceeding 10% in 2005. • Use of combined RT and ADT and use of ADT alone fluctuated throughout the study period. • In all 6% of patients received RT alone in 2005. • Multimodality therapy was less common in patients who were older, African American, unmarried, who lived in the south, and who had co-morbidities or stage T4 disease. CONCLUSIONS:• Treatment of LAPC varies widely, and treatment patterns shifted during the study period. • The slightly increased use of multimodality therapy since 2003 is encouraging, but further work is needed to increase combination therapy in appropriate patients and to define the role of RP.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To develop and validate a simple prognostic tool that would help predict larynx preservation outcome. STUDY DESIGN/METHODS:A retrospective review of 3 prospective studies. METHODS:We reviewed consecutive chemotherapy/radiation protocols for patients (n = 170) with advanced, resectable, squamous cell, larynx, or pharynx cancer treated at Memorial Sloan-Kettering Cancer Center from 1988 to 1995 with larynx preservation intent. The outcome was successful larynx preservation. Model validation used data from U. S. Department of Veterans Affairs larynx preservation study. RESULTS:The developed model added one point for each poor prognostic covariate present (show in parentheses) and was given the acronym TALK: T stage (T4), albumin (<4 g/dL), maximum alcohol/liquor use (≥6 drinks/day or heavy drinking), and Karnofsky performance status (<80%). The 3-year larynx preservation rates by TALK score were 65% (0), 41% (1-2), and 6% (3-4), P < .0001; on validation, the TALK 3-4 group was particularly well demarcated. CONCLUSIONS:The TALK score is an easily applied and valid tool that should assist treatment selection.

PURPOSE: To analyze the effect of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) on treatment outcomes in patients treated with definitive intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC). METHODS AND MATERIALS: Between September 1998 and April 2009, a total of 442 patients with squamous cell carcinoma of the oropharynx were treated with IMRT with curative intent at our center. Thirty patients treated postoperatively and 2 additional patients who started treatment more than 6 months after diagnosis were excluded. A total of 340 patients with restorable treatment plans were included in this present study. The majority of the patients underwent concurrent platinum-based chemotherapy. The pGTV and nGTV were calculated using the original clinical treatment plans. Cox proportional hazards models and log-rank tests were used to evaluate the correlation between tumor volumes and overall survival (OS), and competing risks analysis tools were used to evaluate the correlation between local failure (LF), regional failure (RF), distant metastatic failure (DMF) vs. tumor volumes with death as a competing risk. RESULTS: Median follow-up among surviving patients was 34 months (range, 5-67). The 2-year cumulative incidence of LF, RF and DF in this cohort of patients was 6.1%, 5.2%, and 12.2%, respectively. The 2-year OS rate was 88.6%. Univariate analysis determined pGTV and T-stage correlated with LF (p < 0.0001 and p = 0.004, respectively), whereas nGTV was not associated with RF. On multivariate analysis, pGTV and N-stage were independent risk factors for overall survival (p = 0.0003 and p = 0.0073, respectively) and distant control (p = 0.0008 and p = 0.002, respectively). CONCLUSIONS: In this cohort of patients with OPC treated with IMRT, pGTV was found to be associated with overall survival, local failure, and distant metastatic failure.

PURPOSE/OBJECTIVE:To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. PATIENTS AND METHODS/METHODS:Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). RESULTS:The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a high single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). CONCLUSION/CONCLUSIONS:High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.

What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long-term follow-up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non-uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long-term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000-2010. Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient number of 100 in each risk group (50 for high-risk group). A statistical analysis (standard deviational ellipse) of the study outcomes suggested that, in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease. For intermediate-risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high-risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone or EBRT. It is anticipated that the study will assist physicians and patients in selecting treatment for men with newly diagnosed prostate cancer.

PURPOSE: To update the Memorial Sloan-Kettering Cancer Center's experience with intensity-modulated radiotherapy (IMRT) in the treatment of oropharyngeal cancer (OPC). METHODS AND MATERIALS: Between September 1998 and April 2009, 442 patients with histologically confirmed OPC underwent IMRT at our center. There were 379 men and 63 women with a median age of 57 years (range, 27-91). The disease was Stage I in 2%, Stage II in 4%, Stage III in 21%, and Stage IV in 73% of patients. The primary tumor subsite was tonsil in 50%, base of tongue in 46%, pharyngeal wall in 3%, and soft palate in 2%. The median prescription dose to the planning target volume of the gross tumor was 70 Gy for definitive (n = 412) cases and 66 Gy for postoperative cases (n = 30). A total 404 patients (91%) received chemotherapy, including 389 (88%) who received concurrent chemotherapy, the majority of which was platinum-based. RESULTS: Median follow-up among surviving patients was 36.8 months (range, 3-135). The 3-year cumulative incidence of local failure, regional failure, and distant metastasis was 5.4%, 5.6%, and 12.5%, respectively. The 3-year OS rate was 84.9%. The incidence of late dysphagia and late xerostomia >/=Grade 2 was 11% and 29%, respectively. CONCLUSIONS: Our results confirm the feasibility of IMRT in achieving excellent locoregional control and low rates of xerostomia. According to our knowledge, this study is the largest report of patients treated with IMRT for OPC

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 provide updated American Brachytherapy Society (ABS) guidelines for transrectal ultrasound-guided transperineal interstitial permanent prostate brachytherapy (PPB). METHODS AND MATERIALS/METHODS:The ABS formed a committee of brachytherapists and researchers experienced in the clinical practice of PPB to formulate updated guidelines for this technique. Sources of input for these guidelines included prior published guidelines, clinical trials, published literature, and experience of the committee. The recommendations of the committee were reviewed and approved by the Board of Directors of the ABS. RESULTS:Patients with high probability of organ-confined disease or limited extraprostatic extension are considered appropriate candidates for PPB monotherapy. Low-risk patients may be treated with PPB alone without the need for supplemental external beam radiotherapy. High-risk patients should receive supplemental external beam radiotherapy if PPB is used. Intermediate-risk patients should be considered on an individual case basis. Intermediate-risk patients with favorable features may appropriately be treated with PPB monotherapy but results from confirmatory clinical trials are pending. Computed tomography-based postimplant dosimetry performed within 60 days of the implant is considered essential for maintenance of a satisfactory quality assurance program. Postimplant computed tomography-magnetic resonance image fusion is viewed as useful, but not mandatory. CONCLUSIONS:Updated guidelines for patient selection, workup, treatment, postimplant dosimetry, and followup are provided. These recommendations are intended to be advisory in nature with the ultimate responsibility for the care of the patients resting with the treating physicians.