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Pushing the Limits of Radiation Therapy for Prostate Cancer: Where Do We Go Next?
Abstract
There have been significant advancements in the quality and precision of radiation therapy (RT) for prostate cancer over the past two decades. The development and implementation of intensity-modulated radiation therapy has allowed for RT dose-escalation without parallel increases in treatment morbidity. Moreover, integration of androgen deprivation therapy with definitive RT has led to improvements in outcomes for certain subgroups of prostate cancer patients. In this review, we highlight several ongoing and developing technical advances that hold promise for further optimizing RT care, including proton beam therapy, inter- and intra-fractional image-guided dose-delivery, methods for improved target volume definition, and development of techniques for safely performing hypofractionation and stereotactic body radiotherapy. We also discuss the importance of investigating the potential benefit of integrating novel systemic therapies with prostate RT to further improve outcomes for patients with locally advanced prostate cancer.
... Subkutane PCa-Tumore in Ratten wurden mit Photonen bzw. 12 Schlussfolgernd ergibt sich, dass 12 C-RT besonders für undifferenzierte Tumore geeignet ist, da die RBW für den radioresistenten, anaplastischen AT1-Tumor am höchsten war und sich mit zunehmender Differenzierung verringerte. Ursache hierfür ist, dass die TCD 50 -Werte für 12 C-Ionen weniger abhängig vom Differenzierungsstatus sind, als bei Photonen-RT. ...
... Subkutane PCa-Tumore in Ratten wurden mit Photonen bzw. 12 Schlussfolgernd ergibt sich, dass 12 C-RT besonders für undifferenzierte Tumore geeignet ist, da die RBW für den radioresistenten, anaplastischen AT1-Tumor am höchsten war und sich mit zunehmender Differenzierung verringerte. Ursache hierfür ist, dass die TCD 50 -Werte für 12 C-Ionen weniger abhängig vom Differenzierungsstatus sind, als bei Photonen-RT. 12 ...
... Ursache hierfür ist, dass die TCD 50 -Werte für 12 C-Ionen weniger abhängig vom Differenzierungsstatus sind, als bei Photonen-RT. 12 ...
Zusammenfassung
Ziel der vorliegenden Arbeit war die Untersuchung der differenziellen Wirkung von Kohlen-stoffionen (12C) gegenüber einer Photonenbestrahlung in vivo anhand von drei verschie-denen Sublinien des syngenen Prostata- Adenokarzinoms (PCa) R3327 (AT1, HI und H) der Ratte sowie die Identifizierung Tumor- assoziierter Einflussfaktoren auf die Strahlenreaktion.
Subkutane PCa- Tumore in Ratten wurden mit Photonen bzw. 12C- Ionen (75 keV/ µm) unter Verwendung aufsteigender Einzel- (1 Fx) bzw. Zweifachdosen (2 Fx) bestrahlt. Primärer Endpunkt war die lokale Tumorkontrolle nach 300 Tagen. Basierend auf Dosis- Wirkungs-kurven (DWKs) wurde mittels TCD50 (Dosis für 50% Tumorkontrollwahrschein¬lichkeit) die relative biologische Wirksamkeit (RBW) von 12C- Ionen berechnet. Zusätzlich wurden Untersuchungen durchgeführt, um mögliche Kohlenstoffionen- spezifische Mechanismen der Strahlenreaktion zu identifizieren. Hierzu wurden in vivo tumor-physiologische Verände-rungen, strukturelle und funktionelle Bestrahlungseffekte auf histologischer Ebene, strahlen-bedingte Einflüsse auf die Genexpression sowie Tumorsubpopulationen mit Tumor- indu-zierenden Eigenschaften untersucht.
Für 12C- Bestrahlungen mit 1 Fx bzw. 2 Fx ergab sich eine RBW von 1,62 (H), 2,08 (HI) und 2,3 (AT1) bzw. 1,9 (H), 2,1 (HI) und 2,67 (AT1). Bestrahlungen mit isoeffektiven Dosen zeigten für Photonen und 12C- Ionen unterschiedliche Kinetiken der strahleninduzierten Effekte. Mittels Magnetresonanztomographie (MRT) und Histologie wurde im Vergleich zu Photonen eine schnellere und stärkere Gefäßpermeabilisierung durch 12C- RT festgestellt. Nach Bestrahlung wurden DNA- Reparaturmechanismen, Immunsystemkomponenten und Migration induziert, dagegen die Zellzyklusprogression, Adhäsion, Angiogenese und der aerobe Stoffwechsel reprimiert. Insbesondere die zeitliche Induktion von Signalkaskaden, Apoptose und Stressantworten zeigte sich abhängig von der Strahlmodalität. In den HI- und H-Sublinien wurden CD24+/CD45- Zellen als Tumor- induzierende Zellen (TICs) in vivo identifiziert und alle drei Sublinien in vitro durch Zellkulturetablierung weiteren molekular-biologischen Analysen zugänglich gemacht.
Schlussfolgernd ergibt sich, dass 12C- RT besonders für undifferenzierte Tumore geeignet ist, da die RBW für den radioresistenten, anaplastischen AT1-Tumor am höchsten war und sich mit zunehmender Differenzierung verringerte. Ursache hierfür ist, dass die TCD50- Werte für 12C- Ionen weniger abhängig vom Differenzierungsstatus sind, als bei Photonen- RT. 12C- Ionen inaktivieren Tumorzellen und Normalgewebsanteile sowie Gefäßstrukturen schneller und effektiver als Photonen. Die strahleninduzierte Genregulation nach Photonen- und 12C- RT betrifft ähnliche Funktionen, aber der zeitliche Verlauf variiert besonders in DNA- Reparaturmechanismen und Signalwegen des Zellüberlebens. Da CD24+/CD45- - Zellen in H- und HI-Tumoren als TICs identifiziert wurden, impliziert der unterschiedliche Einfluss von 12C- und Photonen- RT auf die CD24- Expression einen ersten Hinweis auf differenzielle Effekte der beiden Strahlmodalitäten auf putative Prostatakrebsstammzellen.
... The advent and widespread utilization of IMRT for Cooper BT et al . ChemoRT for prostate cancer prostate cancer has led to radiation oncologists routinely treating patients to doses of 78 Gy or greater [71] . ...
There are estimated to be 220800 cases of prostate cancer diagnosed in 2015, making up 26% of all cancer diagnoses. Fortunately, adenocarcinoma of the prostate is often a highly treatable malignancy. Even though the majority of prostate cancer patients present with localized disease, prostate cancer still accounts for over 27000 deaths a year. There is a subset of patients that are likely to recur after locoregional treatment that is thought of as a "high-risk" population. This more aggressive subset includes patients with clinical stage greater than T2b, Gleason score greater than 7, and prostate specific antigen greater than 20 ng/dL. The rate of biochemical relapse in this high risk group is 32%-70% within five years of definitive focal therapy. Given these discouraging outcomes, attempts have been made to improve cure rates by radiation dose escalation, addition of androgen depravation therapy, and addition of chemotherapy either sequentially or concurrently with radiation. One method that has been shown to improve clinical outcomes is the addition of chemotherapy to radiotherapy for definitive treatment. Concurrent chemoradiation with 5-fluorouracil, estramustine phosphate, vincristine, docetaxel, and paclitaxel has been studied in the phase I and/or II setting. These trials have identified the maximum tolerated dose of chemotherapy and radiation that can be safely delivered concurrently and established the safety and feasibility of this technique. This review will focus on the addition of concurrent chemotherapy to radiotherapy in the definitive management of high-risk prostate cancer.
... Advances have been made to improve the efficacy of RT in recent years. These include a dose-escalation strategy, a hypofractionation regimen, an incorporation of chemotherapy, and a new RT modality such as high-dose-rate brachytherapy and proton therapy (101)(102)(103)(104)(105)(106)(107)(108). Although biological, physical, and clinical rationales clearly support the use of these treatment modalities, their impact on radiation-induced NED remains unstudied. ...
Neuroendocrine differentiation (NED) in prostate cancer is a well recognized phenotypic change by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cells. NE-like cells lack the expression of androgen receptor and prostate specific antigen, and are resistant to treatments. In addition, NE-like cells secrete peptide hormones and growth factors to support the growth of surrounding tumor cells in a paracrine manner. Accumulated evidence has suggested that NED is associated with disease progression and poor prognosis. The importance of NED in prostate cancer progression and therapeutic response is further supported by the fact that therapeutic agents, including androgen deprivation therapy, chemotherapeutic agents, and radiotherapy, also induce NED. We will review the work supporting the overall hypothesis that therapy-induced NED is a mechanism of resistance to treatments, as well as discuss the relationship between therapy-induced NED and therapy-induced senescence, epithelial-to-mesenchymal transition, and cancer stem cells. Furthermore, we will use radiation-induced NED as a model to explore several NED-based targeting strategies for development of novel therapeutics. Finally, we propose future studies that will specifically address therapy-induced NED in the hope that a better treatment regimen for prostate cancer can be developed.
Stereotactic body radiotherapy (SBRT) involves the treatment of extracranial primary tumors or metastases with a few, high doses of ionizing radiation. In SBRT, tumor kill is maximized and dose to surrounding tissue is minimized, by precise and accurate delivery of multiple radiation beams to the target. This is particularly challenging, because extracranial lesions often move with respiration and are irregular in shape, requiring careful treatment planning and continual management of this motion and patient position during irradiation. This review presents the rationale, process workflow, and technology for the safe and effective administration of SBRT, as well as the indications, outcome, and limitations for this technique in the treatment of lung cancer, liver cancer, and metastatic disease. Cancer 2013;. © 2013 American Cancer Society.
Standard therapies for prostate cancer including radiation, prostatectomy, and hormone ablation have significant toxicities and recurrence risk. HSV-tk gene therapy may be effective in combination with radiation therapy due to complementary mechanisms and distinct toxicity profiles. Mouse prostate tumors transplanted subcutaneously were treated by either gene therapy involving intratumoral injection of AdV-tk followed by systemic ganciclovir or local radiation therapy or the combination of gene and radiation therapy. Both single-therapy modalities showed a 38% decrease in tumor growth compared to controls. The combined treatment resulted in a decrease of 61%. In addition the combined-therapy group had a mean survival of 22 days versus 16.6 days for single therapy and 13.8 days for nontreated controls. To analyze systemic anti-tumor activity, lung metastases were generated by tail vein injection of RM-1 prostate cancer cells on the same day that they were injected subcutaneously. The primary tumors were treated as before with AdV-tk followed by ganciclovir, radiation, or the combination. The number of lung nodules was reduced by 37% following treatment with AdV-tk, whereas radiotherapy alone had no effect on metastatic growth. The combination led to an additional 50% reduction in lung colonization. Primary tumors that received the combination therapy had a marked increase in CD4 T cell infiltrate. This is the first report showing a dramatic systemic effect following the local combination treatment of radiation and AdV-tk. A clinical study using this strategy has been initiated and patient accrual is ongoing.Keywords: gene therapy, radiotherapy, herpes simplex virus thymidine kinase, adenoviral vector, prostate cancer
There has been rapid adoption of newer radiation treatments such as intensity-modulated radiation therapy (IMRT) and proton therapy despite greater cost and limited demonstrated benefit compared with previous technologies.
To determine the comparative morbidity and disease control of IMRT, proton therapy, and conformal radiation therapy for primary prostate cancer treatment.
Population-based study using Surveillance, Epidemiology, and End Results-Medicare-linked data from 2000 through 2009 for patients with nonmetastatic prostate cancer.
Rates of gastrointestinal and urinary morbidity, erectile dysfunction, hip fractures, and additional cancer therapy.
Use of IMRT vs conformal radiation therapy increased from 0.15% in 2000 to 95.9% in 2008. In propensity score-adjusted analyses (N = 12,976), men who received IMRT vs conformal radiation therapy were less likely to receive a diagnosis of gastrointestinal morbidities (absolute risk, 13.4 vs 14.7 per 100 person-years; relative risk [RR], 0.91; 95% CI, 0.86-0.96) and hip fractures (absolute risk, 0.8 vs 1.0 per 100 person-years; RR, 0.78; 95% CI, 0.65-0.93) but more likely to receive a diagnosis of erectile dysfunction (absolute risk, 5.9 vs 5.3 per 100 person-years; RR, 1.12; 95% CI, 1.03-1.20). Intensity-modulated radiation therapy patients were less likely to receive additional cancer therapy (absolute risk, 2.5 vs 3.1 per 100 person-years; RR, 0.81; 95% CI, 0.73-0.89). In a propensity score-matched comparison between IMRT and proton therapy (n = 1368), IMRT patients had a lower rate of gastrointestinal morbidity (absolute risk, 12.2 vs 17.8 per 100 person-years; RR, 0.66; 95% CI, 0.55-0.79). There were no significant differences in rates of other morbidities or additional therapies between IMRT and proton therapy.
Among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity.
The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system. Ipilimumab is a monoclonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). We report a case of the abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy. Temporal associations were noted: tumor shrinkage with antibody responses to the cancer-testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. (Funded by the National Institutes of Health and others.).
Advances in the field of radiation oncology in the last decade resulted in an increasing number of opportunities to optimize therapy. Increased accuracy to deliver the dose to tumors while sparing normal tissues demands more precise delineation of the tumors. When considering to deliver a boost to more aggressive parts of tumors, intratumoral heterogeneity needs to be assessed accurately. Adaptive radiotherapy demands evaluation of response during the course of radiotherapy, in terms of both volumetric and functional changes. Molecular imaging with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has found its way into clinical practice for various indications in head and neck cancer and new applications are under investigation. In this review, an overview is provided of the current status and developments of the use of FDG-PET/CT in radiation oncology, describing the current status in radiation treatment planning, adaptation of therapy and the position compared to other imaging techniques.
Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant
prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate
cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial
cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and
the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to
bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic
cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple
signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including
androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this “two-compartment”
crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.
It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma.
From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years.
The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients.
Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.).
To evaluate the tolerability of escalating doses of stereotactic body radiation therapy in the treatment of localized prostate cancer.
Eligible patients included those with Gleason score 2 to 6 with prostate-specific antigen (PSA) ≤ 20, Gleason score 7 with PSA ≤ 15, ≤ T2b, prostate size ≤ 60 cm(3), and American Urological Association (AUA) score ≤ 15. Pretreatment preparation required an enema and placement of a rectal balloon. Dose-limiting toxicity (DLT) was defined as grade 3 or worse GI/genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 3). Patients completed quality-of-life questionnaires at defined intervals.
Groups of 15 patients received 45 Gy, 47.5 Gy, and 50 Gy in five fractions (45 total patients). The median follow-up is 30 months (range, 3 to 36 months), 18 months (range, 0 to 30 months), and 12 months (range, 3 to 18 months) for the 45 Gy, 47.5 Gy, and 50 Gy groups, respectively. For all patients, GI grade ≥ 2 and grade ≥ 3 toxicity occurred in 18% and 2%, respectively, and GU grade ≥ 2 and grade ≥ 3 toxicity occurred in 31% and 4%, respectively. Mean AUA scores increased significantly from baseline in the 47.5-Gy dose level (P = .002) as compared with the other dose levels, where mean values returned to baseline. Rectal quality-of-life scores (Expanded Prostate Cancer Index Composite) fell from baseline up to 12 months but trended back at 18 months. In all patients, PSA control is 100% by the nadir + 2 ng/mL failure definition.
Dose escalation to 50 Gy has been completed without DLT. A multicenter phase II trial is underway treating patients to 50 Gy in five fractions to further evaluate this experimental therapy.
Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer.
In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase.
In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache.
The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)
Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management.
To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer.
Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 1(1/2) and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009.
The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival.
A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported.
Patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.
Purpose
To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes.
Patients and Methods
Men with T1b-T2b prostate cancer and prostate-specific antigen ≤ 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes.
Results
A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade ≥ 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade ≥ 3 GI toxicity.
Conclusion
This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade ≥ 3 late urinary or rectal morbidity.
The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer.
We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429.
A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes.
The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)
Management decisions for patients with prostate cancer present a dilemma for both patients and their clinicians because prostate cancers demonstrate a wide range in biologic activity, with the majority of cases not leading to a prostate cancer related death. Furthermore, the current treatment options have significant side effects, such as incontinence, rectal injury and impotence. Key elements for guiding appropriate treatment include: distinction of organ-confined disease from extracapsular extension (ECE); and determination of tumor volume and tumor grade, none of which have been satisfactorily accomplished in today's pre-treatment paradigm. Magnetic resonance imaging (MRI) has the capability to assess prostate tissue, both functionally and morphologically. MRI as a staging tool has not shown enough consistency or sufficient accuracy for widespread adoption in clinical practice; yet, recent technical developments in MRI have yielded improved results. At our institution we have combined the use of new endorectal 3 Tesla MRI technology, T2-weighted, and high spatial resolution dynamic-contrast enhanced (DCE) MRI to non-invasively assess the prostate with higher signal-to-noise ratio and spatial resolution than previously achieved. This approach allows assessment of prostate-tissue morphology and kinetics, thus providing a non-invasive tool for tumor detection and staging and, consequently, directing biopsy and treatment specifically to diseased areas for a pre-treatment evaluation that can assist in the rational selection of patients for appropriate prostate cancer therapy.
A 160-MeV proton beam has been modified to irradiate patients with localized tumors by using conventional treatment schedules. This proton beam has the physical advantage over megavoltage x-rays of reducing the radiation dose to normal tissues adjacent to the tumor volume. A perineal proton technique used as boost therapy (2,000 to 2,500 rads) was evaluated in the definitive irradiation of 17 patients with localized prostatic carcinoma. This technique allows repeated daily treatment of the carefully defined target volume with a precision of ±2 mm. Total dose to the prostatic tumor, but not to the posterior rectum, has been increased by 500 to 700 rads. After 12 to 27 months of observation, no noteworthy rectal reaction has developed in a patient, easily managed urethral strictures have developed in two patients, and all but one are locally controlled.
(JAMA 241:1912-1915, 1979)
Results of extensive animal experiments show that with a high-energy
proton beam a sharply delineated lesion can be made at any desired site in the
central nervous system. (C.H.)
This article reviews The Physics of Radiation TherapyThe Physics of Radiation Therapy by Faiz M. Khan, Faiz M. Khan
Fourth Edition. , Baltimore and Philadelphia, 2009. 592 pp. (hardcover). Price: $199.00. ISBN: 9780781788564.
Local radiotherapy plus intratumoral syngeneic dendritic cell injection can mediate apoptosis/cell death and immunological tumor eradication in murine models. A novel method of coordinated intraprostatic, autologous dendritic cell injection together with radiation therapy was prospectively evaluated in five HLA-A2(+) subjects with high-risk, localized prostate cancer, using androgen suppression, 45 Gy external beam radiation therapy in 25 fractions over 5 weeks, dendritic cell injections after fractions 5, 15 and 25 and then interstitial radioactive seed placement. Serial prostate biopsies before and during treatment showed increased apoptotic cells and parenchymal distribution of CD8(+) cells. CD8(+) T-cell responses to test peptides were assessed using an enzyme-linked immunosorbent spot IFN-γ production assay, demonstrating some prostate cancer-specific protein-derived peptides associated with increased titer. In conclusion, the technique was feasible and well-tolerated and specific immune responses were observable. Future trials could further test the utility of this approach and improve on temporal coordination of intratumoral dendritic cell introduction with particular timelines of therapy-induced apoptosis.
Over the past 2 years, four new treatments have entered the treatment armamentarium for patients with castration-resistant prostate cancer (CRPC). Although these novel agents differ in their mechanism of action, they all face the same challenges: patient selection, timing of therapy and the cost/benefit of their use. In this review, we will discuss their development and implications when selecting treatment options for CRPC patients.
Over the past few years, a better understanding of the biology of CRPC has allowed us to develop rational therapies that have resulted in an improvement in the outcome of prostate cancer patients. Immunotherapy has entered the field and despite its limitations and challenges is here to stay. A better understanding of the long-term complications of androgen deprivation has changed the initial approach to most patients with advanced disease, and bone health has become a major focus in their management. Understanding the importance of the androgen receptor and other ligands has led to a dramatic paradigm shift in the treatment of patients with metastatic disease in which the androgen receptor becomes a central therapeutic target in the disease. Specific adrenal inhibitors and engineered super androgen receptor inhibitors have become the most promising agents in the disease. Similarly, chemotherapy has demonstrated clinical benefit and is now a standard of care in docetaxel-refractory patients.
The management of CRPC patients continues to evolve. Novel treatments recently approved by the US Food and Drug Administration have significantly impacted the outcome of CRPC. With the economic impact of their use, selecting the right patient, defining the appropriate timing and sequence of therapy have become critical facts that need to be followed when defining the contemporary treatment options for men with CRPC.
To investigate patients' willingness to participate (WTP) in a randomized controlled trial (RCT) comparing intensity-modulated radiotherapy (IMRT) with proton beam therapy (PBT) for prostate cancer (PCa).
We undertook a qualitative research study in which we prospectively enrolled patients with clinically localized PCa. We used purposive sampling to ensure a diverse sample based on age, race, travel distance, and physician. Patients participated in a semi-structured interview in which they reviewed a description of a hypothetical RCT, were asked open-ended and focused follow-up questions regarding their motivations for and concerns about enrollment, and completed a questionnaire assessing characteristics such as demographics and prior knowledge of IMRT or PBT. Patients' stated WTP was assessed using a 6-point Likert scale.
Forty-six eligible patients (33 white, 13 black) were enrolled from the practices of eight physicians. We identified 21 factors that impacted patients' WTP, which largely centered on five major themes: altruism/desire to compare treatments, randomization, deference to physician opinion, financial incentives, and time demands/scheduling. Most patients (27 of 46, 59%) stated they would either "definitely" or "probably" participate. Seventeen percent (8 of 46) stated they would "definitely not" or "probably not" enroll, most of whom (6 of 8) preferred PBT before their physician visit.
A substantial proportion of patients indicated high WTP in a RCT comparing IMRT and PBT for PCa.
A well-established body of literature supports the use of high-dose-rate (HDR) brachytherapy as definitive treatment for localized prostate cancer. Most of the articles describe HDR as a boost with adjuvant external beam radiation, but there is a growing experience with HDR monotherapy.
The American Brachytherapy Society has convened a group of expert practitioners and physicists to develop guidelines for the use of HDR in the management of prostate cancer. This involved an extensive literature review and input from an expert panel.
Despite a wide variation in doses and fractionation reported, HDR brachytherapy provides biochemical control rates of 85-100%, 81-100%, and 43-93% for low-, intermediate-, and high-risk prostate cancers, respectively. Severe toxicity is rare, with most authors reporting less than 5% Grade 3 or higher toxicity. Careful attention to patient evaluation for appropriate patient selection, meticulous technique, treatment planning, and delivery are essential for successful treatment.
The clinical outcomes for HDR are excellent, with high rates of biochemical control, even for high-risk disease, with low morbidity. HDR monotherapy, both for primary treatment and salvage, are promising treatment modalities.
Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient/tumor immobilization, image guidance, and treatment planning and delivery. This modality is safe and effective in both early stage primary cancer and oligometastases. Compared to the use of stereotactic radiosurgery for other tumor sites, SBRT is slow to be adopted in the management of genitourinary malignancies. Emerging data show the safety and efficacy of this treatment modality in prostate cancer. Preclinical data, clinical experience, and challenges are reviewed and discussed.
At the third annual Interactive Genitourinary Cancer Conference, held in Budapest from 30 April to 1 May 2011, the latest developments in the management of patients with high-risk localised and metastatic prostate cancer were discussed. Prostate cancer is the most common cancer in Western men and, for advanced disease, no curative agents are available. For men with high-risk localised disease there is debate about the best treatment approaches, with both radical prostatectomy and radiation therapy shown to improve outcomes. These approaches have started to be augmented as new techniques and therapies are developed. For instance, radiation therapy combined with androgen deprivation therapy has been shown to be more efficacious than radiation therapy alone, and there may also be a role for adjuvant/neoadjuvant chemotherapy. Ultimately a multidisciplinary approach will most probably result in the best outcomes for patients. The use of androgen deprivation therapy in men with prostate cancer needs to be monitored carefully, given that it results in adverse alterations in several metabolic parameters and an increased risk of further coronary events in men with cardiovascular disease in some studies. Until recently there were limited options for the management of men with advanced prostate cancer, but new agents for use in the post-docetaxel setting have recently been approved. These are cabazitaxel and abiraterone acetate, which have both shown a significant survival benefit in patients who have progressed on docetaxel. Additional agents, for these patients and for patients at other stages of disease, are in the later stages of development. The development of new agents has been aided by a greater understanding of the molecular mechanisms of resistance to current therapies and the recognition of new pathophysiological pathways. As the number of available therapeutic options increases, it will become increasingly important to tailor treatments to the individual patient. This may require the development of novel biomarkers or the use of existing or new predictive tools based on prognostic factors. To ensure optimal patient care, early and continuous involvement of the multidisciplinary team will be required.
Clinical Practice Points Numerous case reports of Spontaneous Regression (SR) of renal cell carcinoma lung metastases have been published. In our case, both regression and progression of metastatic disease were simultaneously detected in different organs after Stereotactic Radiosurgery and Stereotactic Body Radiotherapy (SRS-SBRT). Analysis of the findings suggests that the effect for spontaneous regression may be organ dependent and may not cross the blood-brain barrier. This report may stimulate investigators to look at the mechanisms of SRS-SBRT-induced SR. The findings may also impact the use of systemic therapy in patients who demonstrate SR After SRS-SBRT.
Intensity-modulated proton therapy (IMPT) is expected to improve treatment results with fewer side effects than other proton therapies. The purpose of this study was to evaluate the tumor sites for which IMPT was effective under the same beam calculation conditions by planning IMPT for typical cases treated with passive scattering proton therapy (PSPT). We selected 16 cases of nasal cavity, lung, liver or prostate cancers as typical tumor sites receiving PSPT. The dose distributions and dose volume histograms optimized by the IMPT were compared with those optimized by the PSPT. We took particular note of the doses to the skin and organs at risk (OAR) when PSPT was replaced by IMPT. Furthermore, an improvement of the beam angles was also performed to obtain better dose distributions in the IMPT. The IMPT with the same beam angles resulted in near-maximum doses to the skin of average 78%, 64%, 84% and 99% of the PSPT doses for nasal cavity, lung, liver, and prostate cancers, respectively. However, it was difficult to improve the dose homogeneity of the target volume. The change of the IMPT beam angles could reduce the doses to OARs and skin in the case of the nasal cavity, while it had limited effect in the other cases. We concluded that IMPT was effective for reducing the doses to some OARs when treating nasal cavity, lung, liver and prostate cancers. The selection of beam angles was important in the IMPT optimization, especially for nasal cavity cancers.
While the majority of men with localized prostate cancer who undergo a radical prostatectomy will remain disease free, men with certain clinical and pathological features are known to be at an increased risk for developing a biochemical recurrence and, ultimately, distant metastatic disease. The optimal management of these patients continues to be a source of controversy. To date, three randomized Phase III trials have demonstrated that adjuvant radiation therapy (ART) for patients with certain adverse pathological features results in an improvement in several clinically-relevant end points, including biochemical recurrence-free survival and overall survival. Despite the evidence from these trials showing a benefit for ART, many believe that ART results in overtreatment and unwarranted treatment morbidity for a significant number of patients. Many physicians, therefore, instead advocate for close observation followed by early salvage radiation therapy (SRT) at the time of a biochemical recurrence. The purpose of this review is to evaluate the evidence for and to distinguish between ART and early SRT. We will also highlight current and future areas of research for this patient population, including radiation treatment dose escalation, hypofractionation and androgen deprivation therapy. We will also discuss the cost-effectiveness of ART and early SRT.
Accurate delineation of the primary tumor and of involved lymph nodes is a key requisite for successful curative radiotherapy in non-small cell lung cancer (NSCLC). In recent years, it has become clear that the incorporation of FDG PET-CT scan information into the related processes of patient selection and radiotherapy planning has lead to significant improvements for patients with NSCLC. The use of FDG PET-CT information in radiotherapy planning allows better target volume definition, reduces inter-observer variability and encourages selective irradiation of involved mediastinal lymph nodes. PET-CT also opens the door for innovative radiotherapy delivery and the development of new concepts. However, care must be taken to avoid a variety of technical pitfalls and specific education is necessary, for clinicians and physicists alike.
Molecular imaging by means of PET provides a method to study the metabolic activity of tumors in vivo. (18)F- or (11)C-choline and occasionally (18)F- or (11)C-acetate, are used as tracers for prostate cancer, reflecting the phospholipid metabolism. The hybrid technology PET/computed tomography significantly reduces image fusion mismatch. The role of molecular imaging is increasing in radiation treatment planning for prostate cancer. Local prostate cancer recurrence after primary radiation treatment usually originates at the location of the primary tumor. Focusing the dose escalation on the actual tumor is an option to increase tumor control without increasing toxicity. Image-guided radiotherapy and intensity-modulated radiotherapy are prerequisite technologies for applying the simultaneous boost concept. Clinical results are needed in the near future to support the effectiveness of the concept.
Correspondence: Dr Wang, Department of Dermatology, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115 (lcwang@partners.org).Financial Disclosure: Dr Devlin is a compensated member of the Nucletron scientific advisory board. Dr Wang is a compensated member of the ImmunoGen scientific advisory board.Previous Presentation: This article was presented at the 2010 Society for Investigative Dermatology Meeting; May 5-8, 2010; Atlanta, Georgia.Additional Contributions: Elizabeth Martin, BA, and Jay Omobono, BHS, provided technical support.
To assess the value of positron emission tomography (PET)/computed tomography (CT) with either (18)F-choline and/or (11)C-acetate, of residual or recurrent tumour after radical prostatectomy (RP) in patients with a prostate-specific antigen (PSA) level of <1 ng/mL and referred for adjuvant or salvage radiotherapy.
In all, 22 PET/CT studies were performed, 11 with (18)F-choline (group A) and 11 with (11)C-acetate (group B), in 20 consecutive patients (two undergoing PET/CT scans with both tracers). The median (range) PSA level before PET/CT was 0.33 (0.08-0.76) ng/mL. Endorectal-coil magnetic resonance imaging (MRI) was used in 18 patients. Nineteen patients were eligible for evaluation of biochemical response after salvage radiotherapy.
There was abnormal local tracer uptake in five and six patients in group A and B, respectively. Except for a single positive obturator lymph node, there was no other site of metastasis. In the two patients evaluated with both tracers there was no pathological uptake. Endorectal MRI was locally positive in 15 of 18 patients; 12 of 19 responded with a marked decrease in PSA level (half or more from baseline) 6 months after salvage radiotherapy.
Although (18)F-choline and (11)C-acetate PET/CT studies succeeded in detecting local residual or recurrent disease in about half the patients with PSA levels of <1 ng/mL after RP, these studies cannot yet be recommended as a standard diagnostic tool for early relapse or suspicion of subclinical minimally persistent disease after surgery. Endorectal MRI might be more helpful, especially in patients with a low likelihood of distant metastases. Nevertheless, further research with (18)F-choline and/or (11)C-acetate PET with optimal spatial resolution might be needed for patients with a high risk of distant relapse after RP even at low PSA values.
To identify prognostic factors and evaluate biochemical control rates for patients with localized prostate cancer treated with either high-dose intensity-modulated radiotherapy (IMRT) or conventional-dose three-dimensional conformal radiotherapy 3D-CRT.
Four hundred sixteen patients with a minimum follow-up of 3 years (median, 5 years) were included. Two hundred seventy-one patients received 3D-CRT with a median dose of 68.4 Gy (range, 66-71 Gy). The next 145 patients received IMRT with a median dose of 75.6 Gy (range, 70.2-77.4 Gy). Biochemical control rates were calculated according to both American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definitions. Prognostic factors were identified using both univariate and multivariate analyses.
The 5-year biochemical control rate was 60.4% for 3D-CRT and 74.1% for IMRT (p < 0.0001, first ASTRO Consensus definition). Using the ASTRO Phoenix definition, the 5-year biochemical control rate was 74.4% and 84.6% with 3D-RT and IMRT, respectively (p = 0.0326). Univariate analyses determined that PSA level, T stage, Gleason score, perineural invasion, and radiation dose were predictive of biochemical control. On multivariate analysis, dose, Gleason score, and perineural invasion remained significant.
On the basis of both ASTRO definitions, dose, Gleason score, and perineural invasion were predictive of biochemical control. Intensity-modulated radiotherapy allowed delivery of higher doses of radiation with very low toxicity, resulting in improved biochemical control.
Radiation therapy is commonly used to treat localized prostate cancer; however, representative data regarding treatment-related toxicities compared with conservative management are sparse.
To evaluate gastrointestinal (GI) toxicities in men treated with either primary radiation or conservative management for T1-T2 prostate cancer.
We performed a population-based cohort study, using Medicare claims data linked to the Surveillance Epidemiology and End Results data. Competing risk models were used to evaluate the risks.
GI toxicities requiring interventional procedures occurring at least 6 mo after cancer diagnosis.
Among 41,737 patients in this study, 28,088 patients received radiation therapy. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 9.3 per 1000 person-years after three-dimensional conformal radiotherapy, 8.9 per 1000 person-years after intensity-modulated radiotherapy, 5.3 per 1000 person-years after brachytherapy alone, 20.1 per 1000 person-years after proton therapy, and 2.1 per 1000 person-years for conservative management patients. Radiation therapy is the most significant factor associated with an increased risk of GI toxicities (hazard ratio [HR]: 4.74; 95% confidence interval [CI], 3.97-5.66). Even after 5 yr, the radiation group continued to experience significantly higher rates of new GI toxicities than the conservative management group (HR: 3.01; 95% CI, 2.06-4.39). Because our cohort of patients were between 66 and 85 yr of age, these results may not be applicable to younger patients.
Patients treated with radiation therapy are more likely to have procedural interventions for GI toxicities than patients with conservative management, and the elevated risk persists beyond 5 yr.
There is little evidence comparing complications after intensity-modulated (IMRT) vs. three-dimensional conformal radiotherapy (CRT) for prostate cancer. The study objective was to test the hypothesis that IMRT, compared with CRT, is associated with a reduction in bowel, urinary, and erectile complications in elderly men with nonmetastatic prostate cancer.
We undertook an observational cohort study using registry and administrative claims data from the SEER-Medicare database. We identified men aged 65 years or older diagnosed with nonmetastatic prostate cancer in the United States between 2002 and 2004 who received IMRT (n = 5,845) or CRT (n = 6,753). The primary outcome was a composite measure of bowel complications. Secondary outcomes were composite measures of urinary and erectile complications. We also examined specific subsets of bowel (proctitis/hemorrhage) and urinary (cystitis/hematuria) events within the composite complication measures.
IMRT was associated with reductions in composite bowel complications (24-month cumulative incidence 18.8% vs. 22.5%; hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.79-0.93) and proctitis/hemorrhage (HR 0.78; 95% CI, 0.64-0.95). IMRT was not associated with rates of composite urinary complications (HR 0.93; 95% CI, 0.83-1.04) or cystitis/hematuria (HR 0.94; 95% CI, 0.83-1.07). The incidence of erectile complications involving invasive procedures was low and did not differ significantly between groups, although IMRT was associated with an increase in new diagnoses of impotence (HR 1.27, 95% CI, 1.14-1.42).
IMRT is associated with a small reduction in composite bowel complications and proctitis/hemorrhage compared with CRT in elderly men with nonmetastatic prostate cancer.
There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis.
Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was used for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), α (dose-response slope using very low doses per fraction), and the ratio α/β that characterizes dose-fractionation sensitivity.
There was no significant difference between the α/β value for the three risk groups, and the value of α/β for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the α/β value.
The overall α/β value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited-resource settings.
To describe biochemical relapse-free survival (BRFS) and late toxicity after combined high-dose rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT) in intermediate- and high-risk prostate cancer patients.
From March 2003 to September 2005, 64 men were treated by 3×7Gy HDR-B using one implant followed by 50Gy IMRT. Median age was 66.1 years; risk of recurrence was intermediate in 30 (47%) or high in 34 (53%) patients. Forty-four (69%) patients received hormonal therapy. Patients were treated with a median of 13 HDR-B applicators (range, 8-17). Biochemical relapse was defined according to Phoenix criteria. Toxicity was scored according to the Common Toxicity Criteria scale version 3.0.
Median followup was 5.1 years. The 3-year BRFS was 100% and 91% for intermediate- and high-risk patients. Late Grade 2 gastrointestinal (GI) toxicity occurred in 3 (4.7%) patients, late Grade 3 GI toxicity was absent. Late Grade 3 and 4 genitourinary (GU) toxicity was observed in 7 (10.9%) and 2 (3.1%) patients. The 5-year Grade 3 or higher late GU toxicity-free survival was associated with a higher number of HDR-B applicators (p=0.049).
The 3-year BRFS was excellent and late GI toxicity was negligible. However, the late Grade 3 and 4 GU toxicity was unacceptably high.
To report the own experience with 66 patients who received 18F-choline PET-CT (positron emission tomography-computed tomography) for treatment planning.
Image acquisition followed 1 h after injection of 178-355 MBq (18)F-choline. An intraprostatic lesion (GTV(PET) [gross tumor volume]) was defined by a tumor-to-background SUV (standard uptake value) ratio > 2. A dose of 76 Gy was prescribed to the prostate in 2-Gy fractions, with a simultaneous integrated boost up to 80 Gy.
A boost volume could not be defined for a single patient. One, two and three or more lesions were found for 36 (55%), 22 (33%) and seven patients (11%). The lobe(s) with a positive biopsy correlated with a GTV(PET) in the same lobe in 63 cases (97%). GTV(PET) was additionally defined in 33 of 41 prostate lobes (80%) with only negative biopsies. GTV(PET), SUV(mean) and SUV(max) were found to be dependent on well-known prognostic risk factors, particularly T-stage and Gleason Score. In multivariate analysis, Gleason Score > 7 resulted as an independent factor for GTV(PET) > 8 cm(3) (hazard ratio 5.5; p = 0.02) and SUV(max) > 5 (hazard ratio 4.4; p = 0.04). Neoadjuvant hormonal treatment (NHT) did not affect SUV levels. The mean EUDs (equivalent uniform doses) to the rectum and bladder (55.9 Gy and 54.8 Gy) were comparable to patients (n = 18) who were treated in the same period without a boost (54.3 Gy and 55.6 Gy).
Treatment planning with (18)F-choline PET-CT allows the definition of an integrated boost in nearly all prostate cancer patients - including patients after NHT - without considerably affecting EUDs for the organs at risk. GTV(PET) and SUV levels were found to be dependent on prognostic risk factors, particularly Gleason Score.
Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation.
From 2003-2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%.
The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%.
Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.
To assess early radiation therapy (RT)-induced variations in total choline (tCho) concentration measured by proton magnetic resonance spectroscopy (H-MRS) and in (18)F-labelled fluoromethylcholine (FCH) uptake measured by PET in a rodent tumour model.
Nine rats bearing syngenic rhabdomyosarcoma grafts in both thighs were irradiated (13 Gy, one fraction). H-MRS data and FCH-PET were acquired in the same imaging session prior to and 3, 9 and 16 days after external RT. Total choline concentration was expressed in arbitrary units as the area under the curve of the 3.2-ppm peak on H-MR spectra. FCH uptake was expressed as maximum standardized uptake value (SUV(max)) and as the % of injected dose per gram (%ID/g) after precise tumour delineation on hybrid PET-MR images. Pre- and post-RT data were compared using the Student's paired t test, and results were expressed as mean+/-S.D.
Seventeen tumours were available for analysis. A mean drop in choline concentration of 45% was observed 3 days after irradiation (P<.001), whereas a concomitant mean increase in SUV(max) of 41% was observed (P=.006). Choline concentration reincreased on later time points.
Opposite trend between increased FCH uptake and decreased tCho peak was observed at 3 days. Later (9 and 16 days), uptake remained stable and tCho peak reincreased.
To report long-term failure patterns and survival in a randomized radiotherapy dose escalation trial for prostate cancer.
A total of 301 patients with Stage T1b-T3 prostate cancer treated to 70 Gy versus 78 Gy now have a median follow-up of 9 years. Failure patterns and survival were compared between dose levels. The cumulative incidence of death from prostate cancer versus other causes was examined and regression analysis was used to establish predictive factors.
Patients with pretreatment prostate-specific antigen (PSA) >10 ng/mL or high-risk disease had higher biochemical and clinical failures rates when treated to 70 Gy. These patients also had a significantly higher risk of dying of prostate cancer. Patients <70 years old at treatment died of prostate cancer nearly three times more frequently than of other causes when they were radiated to 70 Gy, whereas those treated to 78 Gy died of other causes more frequently. Patients age 70 or older treated to 70 Gy died of prostate cancer as often as other causes, and those receiving 78 Gy never died of prostate cancer within 10 years of follow-up. In regression analysis, factors predicting for death from prostate cancer were pretreatment PSA >10.5 ng/mL, Gleason score 9 and 10, recurrence within 2.6 years of radiation, and doubling time of <3.6 months at the time of recurrence.
Moderate dose escalation (78 Gy) decreases biochemical and clinical failure as well as prostate cancer death in patients with pretreatment PSA >10 ng/mL or high-risk disease.
Radiation therapy (RT) for prostate cancer has made huge strides over the past two decades. The addition of image guidance has allowed radiation oncologists to ensure accurate delivery of increasingly precise radiation treatment plans using newer conformal therapy methods such as three-dimensional conformal RT, intensity-modulated RT, and proton beam RT. Regardless of the specific treatment technique, patients can depend on the treatment to target the moving prostate effectively while significantly sparing adjacent tissues, thereby reducing the morbidity of having to undergo prostate cancer therapy. This review summarizes the recent technical advances made in radiation dose delivery, including target volume definition, treatment planning, treatment delivery methods, and positional verification methods during RT.
Standard anti-cancer therapeutic modalities like chemotherapy and radiotherapy evoke host's reactions that include involvement of the immune system. Elucidation of these mechanisms offers the double advantage of enabling a more rational choice of cytotoxic therapy and exploring the combination with immunotherapy. Radiotherapy, a well established local anti-cancer approach, is a particularly interesting partner for immunotherapy, since it can be harnessed to specifically modify the immunogenicity of the primary tumor and its microenvironment, in the attempt to generate an in situ immunization of the host against a patient's own cancer.
Focal therapy has been proposed in recent years as a means of bridging the gap between radical prostatectomy and active surveillance for treatment of prostate cancer. The rationale for focal therapy comes from its success in treating other malignancies. One of the challenges in applying such an approach to the treatment of prostate cancer has been the multifocal nature of the disease. This review addresses the selection of potentially ideal candidates for focal therapy and discusses which modalities are currently being used and proposed for focal therapy. Setting and meeting guidelines for oncologic efficacy is a challenge we must embrace to safely deliver this potentially revolutionary approach to treating men with prostate cancer.
To assess the diagnostic accuracy of endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging for prediction of the pathologic stage of prostate cancer and the presence of clinically nonimportant disease in patients with clinical stage T1c prostate cancer.
The institutional review board approved-and waived the informed patient consent requirement for-this HIPAA-compliant study involving 158 patients (median age, 58 years; age range, 40-76 years) who had clinical stage T1c prostate cancer, had not been treated preoperatively, and underwent combined 1.5-T endorectal MR imaging-MR spectroscopic imaging between January 2003 and March 2004 before undergoing radical prostatectomy. On the MR images and combined endorectal MR-MR spectroscopic images, two radiologists retrospectively and independently rated the likelihood of cancer in 12 prostate regions and the likelihoods of extracapsular extension (ECE), seminal vesicle invasion (SVI), and adjacent organ invasion by using a five-point scale, and they determined the probability of clinically nonimportant prostate cancer by using a four-point scale. Whole-mount step-section pathology maps were used for imaging-pathologic analysis correlation. Receiver operating characteristic curves were constructed and areas under the curves (AUCs) were estimated nonparametrically for assessment of reader accuracy.
At surgical-pathologic analysis, one (0.6%) patient had no cancer; 124 (78%) patients, organ-confined (stage pT2) disease; 29 (18%) patients, ECE (stage pT3a); two (1%) patients, SVI (stage pT3b); and two (1%) patients, bladder neck invasion (stage pT4). Forty-six (29%) patients had a total tumor volume of less than 0.5 cm(3). With combined MR imaging-MR spectroscopic imaging, the two readers achieved 80% accuracy in disease staging and AUCs of 0.62 and 0.71 for the prediction of clinically nonimportant cancer.
Clinical stage T1c prostate cancers are heterogeneous in pathologic stage and volume. MR imaging may help to stratify patients with clinical stage T1c disease for appropriate clinical management.
Purpose
Detection of recurrence in prostate cancer patients with biochemical failure after radical prostatectomy by [11C]choline PET/CT depends on the prostate-specific antigen (PSA) level. The role of other clinical and pathological variables has not been explored.
Methods
A total of 2,124 prostate cancer patients referred to our Institution for [11C]choline PET/CT from December 2004 to January 2007 for restaging of disease were retrospectively considered for this study. Inclusion criteria were: previous treatment by radical prostatectomy, and biochemical failure, defined as at least two consecutive PSA measurements of >0.2 ng/ml. These criteria were met for 358 patients. Binary logistic analysis was used to investigate the predictive factors of [11C]choline PET/CT. PET/CT findings were validated using criteria based on histological analysis, and follow-up clinical and imaging data. Receiver operating characteristic (ROC) analysis was used to assess the performance of [11C]choline PET/CT in relation to PSA levels.
Results
The mean PSA level was 3.77 ± 6.94 ng/ml (range 0.23–45 ng/ml; median 1.27 ng/ml). PET/CT was positive for recurrence in 161 of 358 patients (45%). On an anatomical region basis, [11C]choline pathological uptake was observed in lymph nodes (107/161 patients, 66%), prostatectomy bed (55/161 patients, 34%), and in the skeleton (46/161 patients, 29%). PET/CT findings were validated using histological criteria (46/358, 13%), and follow-up clinical and imaging criteria (312/358, 87%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were, respectively, 85%, 93%, 91%, 87%, and 89%. In multivariate analysis, high PSA levels, advanced pathological stage, previous biochemical failure and older age were significantly (P
The aim of the study was to evaluate the impact of a dose escalation to an (18)F-choline PET-CT defined simultaneous integrated boost (IB) on the dose distribution and changes of the equivalent uniform dose (EUD).
PET-CT was performed in 12 consecutive patients for treatment planning. An intraprostatic lesion was defined by a tumour-to-background uptake value ratio >2 (GTV(PET)). Dose escalation was focused only on the intraprostatic lesion. Two comparisons were evaluated: whole prostate irradiation to 76 Gy+/-boost to 80 Gy (C1) and whole prostate irradiation to 66.6 Gy+/-boost to 83.25 Gy (C2).
PTV/GTV(PET)+margins were covered by a mean EUD of 75.9/76.1 Gy vs. 77.1/80.1 Gy (C1) and 66.5/66.2 Gy vs. 71.1/82.9 Gy (C2) (p<0.01, respectively). Concerning the organs at risk, EUD increased slightly with an additional boost (mean EUD for bladder: C1 53.2 Gy vs. 53.8 Gy; C2 43.0 Gy vs. 45.1 Gy; for rectum: C1 52.0 Gy vs. 52.6 Gy; C2 43.0 Gy vs. 45.4 Gy; p<0.01, respectively). The distance to the organs at risk had a significant impact on the respective maximum doses in the treatment plans with IB.
Treatment planning with IB allows an individually adapted dose escalation. The therapeutic ratio can be improved by a considerable dose escalation to the macroscopic tumour, but only minor EUD changes to the bladder and rectum.
Proton radiation is an emerging therapy for localized prostate cancer that is being sought with increasing frequency by patients. The physical properties of a proton beam make it ideal for clinical applications; the Bragg peak allows for deposition of dose at a well-defined depth with essentially no exit dose. Thus, high doses can be delivered to a target while largely sparing adjacent normal tissue. Proton radiation has proven effective in dose escalation for prostate cancer. This is important, as high-dose conformal radiation is now the standard form of external radiation for this disease. Intensity-modulated radiation therapy, which uses X-rays, is another means of delivering high radiation doses to the prostate and is currently the most widely used form of external radiation in the US. At present prices, it is probably more cost-effective than proton radiation; this could change. Clear dosimetric superiority of protons in the high-dose region has not yet been demonstrated. A dosimetric advantage may emerge as pencil-beam scanning replaces passive scanning, and intensity-modulated proton therapy becomes possible. This technique would be particularly well suited to partial prostate 'boosts', hypofractionation regimens and stereotactic delivery of radiation, all new approaches to prostate cancer that are being investigated.
To report on the outcomes of a phase I study of stereotactic body radiotherapy (SBRT) for treatment of liver metastases.
Patients with liver metastases that were inoperable or medically unsuitable for resection, and who were not candidates for standard therapies, were eligible for this phase I study of individualized SBRT. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%). Additional patients were treated at the maximal study dose (MSD) in an expanded cohort. Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks.
Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated. Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL). The highest RILD risk level investigated was safe, with no dose-limiting toxicity. Two grade 3 liver enzyme changes occurred, but no RILD or other grade 3 to 5 liver toxicity was seen, for a low estimated risk of serious liver toxicity (95% CI, 0 to 5.3%). Six (9%) acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) grade 4 toxicity (thrombocytopenia) were seen. The 1-year local control rate was 71% (95 CI, 58% to 85%). The median overall survival was 17.6 months (95% CI, 10.4 to 38.1 months).
Individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.
To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT).
From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years.
Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving > or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late > or = grade 2 GU toxicities (P=.049).
Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.
Hypofractionated radiation therapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic ratio with treatments delivered in larger-sized fractions. In addition, the associated reduction in fraction number produces attractive cost and patient convenience advantages as well. A still limited but growing number of hypofractionation trials have reported acceptable short-term levels of toxicity and biochemical control, but most have insufficient follow-up to ensure the long-term safety and efficacy of this approach. This situation will improve as many currently active trials mature, particularly several high-value randomized trials. In contrast, extreme hypofractionation, with schedules delivering only on the order of 5 fractions, is truly in its infancy for prostate cancer, with extremely limited tolerance and efficacy information currently available. Several uncertainties in the radiobiology of hypofractionation mitigate for an organized, cautious investigational approach. The fractionation response (alpha/beta ratio) of prostate cancers and, for that matter, late-responding normal tissues, has yet to be rigorously defined. Additionally, the linear-quadratic (LQ) model used in the design of hypofractionation schedules is subject to its own uncertainties, particularly with respect to the upper limit of fraction sizes for which it remains valid. Contemporary dose-escalated radiation therapy is already highly effective, making it imperative that ongoing and future studies of hypofractionation be performed in carefully designed, randomized clinical trials. Clinical validation permitting, the adaptation of hypofractionation as a standard of care could profoundly influence future management of localized prostate cancer.
A 160-MeV proton beam has been modified to irradiate patients with localized tumors by using convention treatment schedules. This proton beam has the physical advantage of megavoltage x-rays of reducing the radiation dose to normal tissues adjacent to the tumor volume. A perineal proton technique used as boost therapy (2,000 to 2,500 rads) was evaluated in the definitive irradiation of 17 patients with localized prostatic carcinoma. This technique allows repeated daily treatment of the carefully defined target volume with a precision of +/- 2 mm. Total dose to the prostatic tumor, but not to the posterior rectum, has been increased by 500 to 700 rads. After 12 to 27 months of observation, no noteworthy rectal reaction has developed in a patient, easily managed urethral strictures have developed in two patients, and all but one are locally controlled.
The survival of 232 patients with apparently localized carcinoma of the prostate is reported, who were treated between October 1964 and October 1984 by a radical course of external beam radiotherapy using a hypofractionation technique. Assessment was made in a retrospective analysis, noting influence of age, stage of disease at presentation, initial histology, dose of radiotherapy given and any subsequent treatment required, recorded up to October 1986. From this it will be seen that the development of a six fraction regime, given over a period of three weeks leads to comparable results to other reported series, whether assessed as a local response or by survival curves, and to the economical use of scarce resources, but even more important, is less wearing for patients than daily fractionation, with early and late morbidity being within acceptable limits.