Mark D. Hurwitz

Impact of the Percentage of Positive Prostate Cores on Prostate Cancer–Specific Mortality for Patients With Low or Favorable Intermediate-Risk Disease

PURPOSE We investigated whether pretreatment factors predicted time to prostate cancer-specific mortality (PCSM) after conventional-dose and conformal radiation therapy (CRT). PATIENTS AND METHODS Between 1988 and 2002, 421 patients with low (prostate-specific antigen [PSA] level < or = 10 ng/mL and biopsy Gleason score < or = 6) or favorable intermediate-risk (PSA > 10 to 15 ng/mL or biopsy Gleason score 3 + 4, but not both factors) disease underwent CRT (median dose, 70.4 Gy). Cox regression multivariable analysis was performed to determine whether the PSA level, Gleason score, T category, or the percentage of positive cores (% PC) predicted time to PCSM after CRT. After a median follow-up of 4.5 years, 117 (28%) patients have died. RESULTS The % PC was the only significant predictor (Cox P < or =.03). The relative risk of PCSM after CRT for patients with > or = 50% as compared with less than 50% PC was 10.4 (95% CI, 1.2 to 87; Cox P =.03), 6.1 (95% CI, 1.3 to 28.6; Cox P =.02), and 12.5 (95% CI, 1.5 to 107; Cox P =.02) in men with a PSA < or = 10 and Gleason score < or = 6, PSA < or = 10 and Gleason score < or = 7, and PSA < or = 15 and Gleason score < or = 6, respectively. By 5 years after CRT, 5% to 9% compared with less than 1% (log-rank P < or =.01) of these patients experienced PCSM if they had > or = 50% compared with less than 50% PC, respectively. CONCLUSION CRT dose-escalation techniques, the addition of hormonal therapy, or both should be considered in the management of patients with low or favorable intermediate-risk disease and > or = 50% PC.

Magnetic Resonance–Guided Focused Ultrasound for Patients With Painful Bone Metastases: Phase III Trial Results

Background Pain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases. Methods Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher’s exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. Results One hundred forty-seven subjects were enrolled, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day. Conclusions This multicenter phase III trial demonstrated that MRgFUS is a safe and effective, noninvasive treatment for alleviating pain resulting from bone metastases in patients that have failed standard treatments.

Utilizing Predictions of Early Prostate-Specific Antigen Failure to Optimize Patient Selection for Adjuvant Systemic Therapy Trials

PURPOSE Prostate-specific antigen (PSA) failure within 2 years after radical prostatectomy (RP) has been shown to be a clinically significant predictor of distant failure. This study was performed to estimate 2-year PSA failure rates on the basis of readily available clinical and pathologic factors to identify patients for whom effective adjuvant systemic therapy is needed. PATIENTS AND METHODS A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies, PSA level, and the pathologic findings at RP in 1,728 men provided clinically relevant information about PSA outcome after RP. A bootstrapping technique with 2,000 replications was used to provide 95% confidence intervals for the predicted 2-year PSA failure rates, which were determined on the basis of the independent clinical and pathologic predictors of PSA outcome. RESULTS The independent predictors of time to PSA failure included a percentage of positive prostate biopsies of greater than 34% (P: < or =.009), PSA level greater than 10 ng/mL (P: < or =.01), seminal vesicle invasion (P: =. 02), prostatectomy Gleason score of 8 to 10 (P: =.04), and positive surgical margins (P: =.0001). Predictions of 2-year PSA failure rates and bootstrap estimates of the 95% confidence intervals were arranged in a tabular format, stratified by independent clinical and pathologic predictors of PSA outcome. CONCLUSION Patients who are most likely to benefit from effective adjuvant systemic therapy after RP can be identified using readily available clinical and pathologic data.

What is the ideal radiotherapy dose to treat prostate cancer? A meta-analysis of biologically equivalent dose escalation

PURPOSE To determine if increasing the biologically equivalent dose (BED) via various radiation fractionation regimens is correlated with clinical outcomes or toxicities for prostate cancer. METHODS AND MATERIALS We performed a meta-analysis that included 12,756 prostate cancer patients from 55 studies published from 2003 to 2013 who were treated with non-dose-escalated conventionally fractionated external beam radiation therapy (non-DE-CFRT), DE-CFRT, hypofractionated RT, and high dose rate brachytherapy (HDR-BT; either mono or boost) with ⩾5-year actuarial follow-up. BEDs were calculated based on the following formula: (nd[1+d/(α/β)]), where n is the number of fractions, and d is dose per fraction; assuming an α/β of 1.5 for prostate cancer and 3.0 for late toxicities. Mixed effects meta-regression models were used to estimate weighted linear relationships between BED and the observed percentages of patients experiencing late toxicities or 5-year freedom from biochemical failure (FFBF). RESULTS Increases in 10 Gy increments in BED (at α/β of 1.5) from 140 to 200 Gy were associated with 5-unit improvements in percent FFBF. Dose escalation of BED above 200 Gy was not correlated with FFBF. Increasing BED (at α/β of 3.0) from 98 to 133 Gy was associated with increased gastrointestinal toxicity. Dose escalation above 133 Gy was not correlated with toxicity. CONCLUSIONS An increase in the BED to 200 Gy (at α/β of 1.5) was associated with increased disease control. Doses above 200 Gy did not result in additional clinical benefit.

Evolution of advanced technologies in prostate cancer radiotherapy

Conventional treatment options for clinically localized, low-risk prostate cancer include radical prostatectomy, external-beam radiotherapy (EBRT) and low-dose-rate brachytherapy. Advances in image-guided radiotherapy (IGRT) since the 1980s, the development of intensity-modulated radiotherapy (IMRT) during the 1990s and evidence from radiobiological models—which support the use of high doses per fraction—have developed alongside novel advanced radiotherapy modalities that include high-dose-rate brachytherapy (HDR-BT), stereotactic body radiotherapy (SBRT) and proton beam therapy. The relationship between the outcomes of and toxicities experienced by patients with prostate cancer treated with HDR-BT, SBRT and particle-beam therapy should provide urologists and oncologists an understanding of the continually evolving technology in prostate radiotherapy. On the basis of published evidence, conventionally fractionated EBRT with IMRT is considered the standard of care over conventional 3D conformal radiotherapy, whereas HDR-BT boost is an acceptable treatment option for selected patients with intermediate-risk and high-risk prostate cancer. SBRT and proton therapy should not be used for patients (regardless of disease risk group) outside the setting of a clinical trial. Finally, comparative effectiveness research should be conducted to provide a framework for evaluating advanced radiotherapy technologies by comparing the benefits and harms of available therapeutic options to optimize the risk:benefit ratio and improve cost effectiveness.

Todayʼs Thermal Therapy: Not Your Fatherʼs Hyperthermia: Challenges and Opportunities in Application of Hyperthermia for the 21st Century Cancer Patient

The realization that hyperthermia was an ideal complementary treatment to radiation and certain chemotherapeutic agents from a biologic perspective led to great enthusiasm for this modality over a quarter of a century ago. Unfortunately, this well-deserved enthusiasm quickly become tempered because of the inability to effectively heat tumors, particularly deep-seated ones with cumbersome first generation technology coupled with still-emerging understandings of thermal biology. Today as before, both challenges and opportunities remain in the application of hyperthermia for cancer patients. The lessons learned from the introduction of hyperthermia, a generation ago, are providing focus for application of this still-promising modality in todays clinic. These areas of challenge and opportunity include: thermal biology; treatment planning, delivery, and monitoring; successful high-quality clinical trials; and integration of thermal therapy with emerging technologies and therapeutic strategies both established and evolving. The progress made in understanding of thermal biology, physics, and bioengineering, coupled with advances in complementary clinical treatment modalities have all contributed to the next generation of clinical thermal therapy.

Hyperthermia, radiation and chemotherapy: the role of heat in multidisciplinary cancer care.

The compelling biologic basis for combining hyperthermia with modern cancer therapies including radiation and chemotherapy was first appreciated nearly half a century ago. Hyperthermia complements radiation as conditions contributing to radio-resistance generally enhance sensitivity to heat and sensitizing effects occur through increased perfusion/tumor oxygenation and alteration of cellular death pathways. Chemosensitization with hyperthermia is dependent on the particular mechanism of effect for each agent with synergistic effects noted for several commonly used agents. Clinically, randomized trials have demonstrated benefit including survival with the addition of hyperthermia to radiation or chemotherapy in treatment of a wide range of malignancies. Improvements in treatment delivery techniques, streamlined logistics, and greater understanding of the relationship of thermal dosimetry to treatment outcomes continue to facilitate wider clinical implementation. Evolving applications include thermal enhancement of immunotherapy, targeted drug delivery and application of principals of thermal biology towards integration of thermal ablation into multimodality oncologic care.

Focused ultrasound for treatment of bone tumours

Abstract Purpose: Focused ultrasound (FUS) is a modality with rapidly expanding applications across the field of medicine. Treatment of bone lesions with FUS including both benign and malignant tumours has been an active area of investigation. Recently, as a result of a successful phase III trial, magnetic resonance-guided FUS is now a standardised option for treatment of painful bone metastases. This report reviews the clinical applications amenable to treatment with FUS and provides background on FUS and image guidance techniques, results of clinical studies, and future directions. Methods: A comprehensive literature search and review of abstracts presented at the recently completed fourth International Focused Ultrasound Symposium was performed. Case reports and older publications revisited in more recent studies were excluded. For clinical studies that extend beyond bone tumours, only the data regarding bone tumours are presented. Results: Fifteen studies assessing the use of focused ultrasound in treatment of primary benign bone tumours, primary malignant tumours, and metastastic tumours meeting the search criteria were identified. For these clinical studies the responders group varied within 91–100%, 85–87% and 64–94%, respectively. Major complications were reported in the ranges 0%, 0–28% and 0–4% for primary benign, malignant and metastatic tumours, respectively. Conclusions: Image-guided FUS is both safe and effective in the treatment of primary and secondary tumours. Additional phase III trials are warranted to more fully define the role of FUS in treatment of both benign and malignant bone tumours.

International consensus on use of focused ultrasound for painful bone metastases: Current status and future directions

Abstract Focused ultrasound surgery (FUS), in particular magnetic resonance guided FUS (MRgFUS), is an emerging non-invasive thermal treatment modality in oncology that has recently proven to be effective for the palliation of metastatic bone pain. A consensus panel of internationally recognised experts in focused ultrasound critically reviewed all available data and developed consensus statements to increase awareness, accelerate the development, acceptance and adoption of FUS as a treatment for painful bone metastases and provide guidance towards broader application in oncology. In this review, evidence-based consensus statements are provided for (1) current treatment goals, (2) current indications, (3) technical considerations, (4) future directions including research priorities, and (5) economic and logistical considerations.

Hematologic Toxicity of Concurrent Administration of Radium-223 and Next-generation Antiandrogen Therapies

Purpose/Objectives: Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving concurrent Radium-223 and next-generation antiandrogen therapies with either enzalutamide or abiraterone. Materials/Methods: In a retrospective study, we analyzed patients who received Radium-223 as part of an early-access trial, and following FDA approval in May 2013, patients receiving Radium-223 as part of standard care. Radium-223 was given at standard dosing of 50 kBq/kg each month for 6 total cycles. Complete blood counts were performed before treatment monthly and following each injection. Blood counts from patients receiving Radium alone and concurrently with next-generation antiandrogens were compared. To date, 25 total patients were analyzed, with a median of 5 monthly doses received per patient. Fourteen patients received concurrent therapy during monthly Radium-223 with either enzalutamide (n=8) or abiraterone (n=6). Results: Six patients expired due to disease progression. Two patients discontinued treatment due to grade 3 myelosuppression. For patients receiving either Radium alone and with concurrent next-generation antiandrogen therapy, there did not appear to be any statistically significant differences between initial and nadir blood counts. Mean change from initial neutrophil count to nadir was 1.9×106/L in patients receiving Radium alone, versus 2.3×106/L in patients receiving concurrent therapy (P=0.77). Mean change from initial hemoglobin value to nadir was 1.5 g/L in patients receiving Radium alone, versus 1.8 g/L in patients receiving concurrent therapy (P=0.31). Mean change from initial platelet count to nadir was 52.3×109 cells/L in patients receiving Radium alone versus 70.6×109 cells/L in patients receiving concurrent therapy (P=0.39). Individual blood counts for each measured laboratory are included in the supplemental data. PSA was stable or decreased in 22% of patients receiving Radium alone versus 35% of patients receiving combination treatment (P=0.24). Conclusions: Concurrent administration of Radium-223 and next-generation antiandrogen therapies appears to be well tolerated with similar toxicities to standard administration of Radium-223 alone. This particular cohort of patients represents a high-risk, heavily pretreated group of patients with advanced metastatic disease and significant marrow burden. Despite these risk factors, hematologic toxicity was modest and was in the range expected for this risk group based on previous trials. To date, this is the first study investigating the toxicity of combination treatment. Further studies investigating the safety and efficacy of combination treatments are warranted.