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1.  Prostate cancer (early) 
Clinical Evidence  2006;2006:1805.
Prostate cancer is the sixth most common cancer in the world, and 85% of cases are diagnosed in men over the age of 65 years. In men with well to moderately differentiated prostate cancer that remains within the capsule, clinical progression-free survival is 70% at 5 years, and 40% at 10 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for early prostate cancer? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding hormone therapy to external beam radiation therapy, or to brachytherapy; adding neoadjuvant hormone therapy to surgery alone, or to surgery plus adjuvant hormone therapy; brachytherapy alone; external beam radiation therapy alone; hormone therapy plus standard care; immediate hormone therapy; radical prostatectomy; and watchful waiting.
Key Points
Prostate cancer is the sixth most common cancer in the world and 85% of cases are diagnosed in men over the age of 65 years. Subclinical prostate cancer is thought to be very common and increases with age, with an estimated prevalence of 30% in men aged 30-39 years, increasing to over 75% in men aged over 85 years.Risk factors include black ethnic origin, family history of prostate cancer and diet.In men with well to moderately differentiated prostate cancer that remains within the capsule, clinical progression free survival is 70% at 5 years and 40% at 10 years.Age adjusted mortality rates for prostate cancer do not seem to be affected by national PSA screening and treatment rates.
This review focuses on clinically localised disease that has not extended beyond the prostate capsule (TNM classification system T0, T1, T2, and American Urologic Staging system stages A and B).
Radical prostatectomy may reduce mortality compared with watchful waiting in men with clinically localised prostate cancer, but the benefits in quality adjusted life expectancy seem to be moderate. Radical prostatectomy may reduce overall and prostate cancer mortality and metastasis, but increases the risk of urinary and sexual dysfunction.
The benefits of external beam radiation therapy (EBRT) or brachytherapy compared with watchful waiting or radical prostatectomy are unknown. EBRT increases the risk of erectile dysfunction and toxicity to the surrounding tissues. Long term survival after EBRT depends on pre-treatment PSA level and tumour differentiation.
Hormone therapy may be used as neoadjuvant therapy before surgery or radiotherapy, concurrently with radiation therapy, or as an adjuvant to other treatments or usual care. Evidence of benefit from hormone therapy in early prostate cancer is very limited. Neoadjuvant hormone therapy may improve biochemical free survival when used with EBRT, but not when given before surgery plus adjuvant hormonal therapy. Immediate hormone therapy in men with clinically localised prostate cancer may reduce disease progression but may not reduce overall mortality, although few adequate studies have been found. Adjuvant hormonal therapy may reduce disease progression but may not improve overall survival compared with placebo.Hormone therapy is associated with increased rates of gynaecomastia and breast pain.
PMCID: PMC2907626  PMID: 19454100
2.  The need for, and utilization of prostate-bed radiotherapy after radical prostatectomy for patients with prostate cancer in British Columbia 
Three randomized trials have demonstrated that post-radical prostatectomy (RP) radiotherapy decreases biochemical relapse for those with adverse pathology. Our purpose was to describe the incidence of pathologic risk factors for recurrence in a contemporary series of patients treated with RP and to describe the use of post-RP radiotherapy.
All incident prostate cancers diagnosed between January 2005 and December 2007 were identified from the tumour registry. Cases were then linked to radiotherapy records which included dose and modality (external beam radiotherapy and brachytherapy). The pathology reports in the tumour registry were reviewed for pathologic stage, grade and margin status.
We identified 9223 patients with prostate cancer. Overall, 36.3% of patients treated with RP had positive margins, and may have benefited from adjuvant radiotherapy. After RP, 332 (15%) patients had radiotherapy to the prostate bed; of these, only 25 (1.1%) received truly adjuvant radiotherapy (delivered within 6 months with a prostate-specific antigen of <0.2 ng/mL). Of the 2181 patients treated with RP, 270 (12%) were seen by a radiation oncologist within 6 months of RP. Of the 1015 patients (47%) with adverse RP pathology (positive margins, extracapsular extension or seminal vesicle invasion), 230 (23%) were seen by a radiation oncologist within 6 months of RP.
Not all patients with adverse prostatectomy pathology were seen by a radiation oncologist post-prostatectomy, and very few received adjuvant radiotherapy despite almost half of them having risk factors for relapse.
PMCID: PMC3328560  PMID: 22511413
3.  Transperineal prostate brachytherapy, using I-125 seed with or without adjuvant androgen deprivation, in patients with intermediate-risk prostate cancer: study protocol for a phase III, multicenter, randomized, controlled trial 
BMC Cancer  2010;10:572.
The optimal protocol for 125I-transperineal prostatic brachytherapy (TPPB) in intermediate-risk prostate cancer (PCa) patients remains controversial. Data on the efficacy of combining androgen-deprivation therapy (ADT) with 125I-TPPB in this group remain limited and consequently the guidelines of the American Brachytherapy Society (ABS) provide no firm recommendations.
Seed and Hormone for Intermediate-risk Prostate Cancer (SHIP) 0804 is a phase III, multicenter, randomized, controlled study that will investigate the impact of adjuvant ADT following neoadjuvant ADT and 125I-TPPB. Prior to the end of March, 2011, a total of 420 patients with intermediate-risk, localized PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from 20 institutions, all of which have broad experience of 125I-TPPB. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will initially undergo 3-month ADT prior to 125I-TPPB. Those randomly assigned to adjuvant therapy will subsequently undergo 9 months of adjuvant ADT. All participants will be assessed at baseline and at the following intervals: every 3 months for the first 24 months following 125I-TPPB, every 6 months during the 24- to 60-month post-125I-TPPB interval, annually between 60 and 84 months post-125I-TPPB, and on the 10th anniversary of treatment.
The primary endpoint is biochemical progression-free survival (BPFS). Secondary endpoints are overall survival (OS), clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, acceptability (assessed using the international prostate symptom score [IPSS]), quality of life (QOL) evaluation, and adverse events. In the correlative study (SHIP36B), we also evaluate biopsy results at 36 months following treatment to examine the relationship between the results and the eventual recurrence after completion of radiotherapy.
These two multicenter trials (SHIP0804 & SHIP36B) are expected to provide crucial data regarding the efficacy, acceptability and safety of adjuvant ADT. SHIP36B will also provide important information about the prognostic implications of PSA levels in intermediate-risk PCa patients treated with 125I-TPPB.
Trial registration
NCT00664456, NCT00898326, JUSMH-BRI-GU05-01, JUSMH-TRIGU0709
PMCID: PMC2984426  PMID: 20964826
4.  National Practice Patterns and Time Trends in Androgen Ablation for Localized Prostate Cancer 
Recent reports have suggested that growing numbers of patients with localized prostate cancer are receiving androgen deprivation therapy as primary or neoadjuvant treatment, yet sparse clinical evidence supports the use of such treatment in some contexts. We describe national trends in the use of androgen deprivation therapy for localized disease and identify sociodemographic variables that are associated with its use.
CaPSURE™ is an observational database of 7195 patients with prostate cancer. For this study, 3439 of these patients were included who were diagnosed since 1989, had clinical staging information available, and were treated with radical prostatectomy, radiation therapy, or primary androgen deprivation therapy (PADT). High-, intermediate-, or low-risk groups were defined by serum prostate-specific antigen level, Gleason sum, and clinical tumor stage. Time trends in use of PADT and neoadjuvant androgen deprivation therapy (NADT) were analyzed, and a multivariable logistic regression model was used to identify sociodemographic factors associated with various treatments. All statistical tests were two-sided.
Rates of PADT use have risen sharply from 4.6% to 14.2%, 8.9% to 19.7%, and 32.8% to 48.2% (all P<.001) in low-, intermediate-, and high-risk groups, respectively. NADT use likewise has increased in association with radical prostatectomy (2.9% to 7.8% of patients, P = .003) and external-beam radiotherapy (9.8% to 74.6%, P<.001) across all risk levels combined. Rates among patients treated with brachytherapy also have risen but the rise was not statistically significant. (7.4% to 24.6%, P = .100).
Rates of both PADT and NADT are increasing across risk groups and treatment types. Additional clinical trials must define more clearly the appropriate role of hormonal therapy in localized prostate cancer, and future results should shape updated practice guidelines.
PMCID: PMC2994265  PMID: 12837834
5.  Obesity and Prostate Cancer: Weighing the Evidence 
European urology  2012;63(5):800-809.
Obesity and prostate cancer (PCa) affect substantial proportions of Western society. Mounting evidence, both epidemiologic and mechanistic, for an association between the two is of public health interest. An improved understanding of the role of this modifiable risk factor in PCa etiology is imperative to optimize screening, treatment, and prevention.
To consolidate and evaluate the evidence for an epidemiologic link between obesity and PCa, in addition to examining the proposed underlying molecular mechanisms.
Evidence acquisition
A PubMed search for relevant articles published between 1991 and July 2012 was performed by combining the following terms: obesity, BMI, body mass index and prostate cancer risk, prostate cancer incidence, prostate cancer mortality, radical prostatectomy, androgen-deprivation therapy, external-beam radiation, brachytherapy, prostate cancer and quality of life, prostate cancer and active surveillance, in addition to obesity, BMI, body mass index and prostate cancer and insulin, insulinlike growth factor, androgen, estradiol, leptin, adiponectin, and IL-6. Articles were selected based on content, date of publication, and relevancy, and their references were also searched for relevant articles.
Evidence synthesis
Increasing evidence suggests obesity is associated with elevated incidence of aggressive PCa, increased risk of biochemical failure following radical prostatectomy and external-beam radiotherapy, higher frequency of complications following androgen-deprivation therapy, and increased PCa-specific mortality, although perhaps a lower overall PCa incidence. These results may in part relate to difficulties in detecting and treating obese men. However, multiple molecular mechanisms could explain these associations as well. Weight loss slows PCa in animal models but has yet to be fully tested in human trials.
Obesity appears to be linked with aggressive PCa. We suggest clinical tips to better diagnose and treat obese men with PCa. Whether reversing obesity slows PCa growth is currently unknown, although it is an active area of research.
PMCID: PMC3597763  PMID: 23219374
Estrogen; Insulin; Obesity; Prostate cancer; Review; Testosterone; Weight change
6.  High-dose-rate brachytherapy and hypofractionated external beam radiotherapy combined with long-term hormonal therapy for high-risk and very high-risk prostate cancer: outcomes after 5-year follow-up 
Journal of Radiation Research  2013;55(3):509-517.
The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent 192Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25–94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.
PMCID: PMC4014151  PMID: 24222312
high-dose-rate brachytherapy; prostate cancer; androgen deprivation therapy; high-risk; very high-risk
7.  Using linked routinely collected health data to describe prostate cancer treatment in New South Wales, Australia: a validation study 
Population-based patterns of care studies are important for monitoring cancer care but conducting them is expensive and resource-intensive. Linkage of routinely collected administrative health data may provide an efficient alternative. Our aim was to determine the accuracy of linked routinely collected administrative data for monitoring prostate cancer care in New South Wales (NSW), Australia.
The NSW Prostate Cancer Care and Outcomes Study (PCOS), a population-based survey of patterns of care for men aged less than 70 years diagnosed with prostate cancer in NSW, was linked to the NSW Cancer Registry, electronic hospital discharge records and Medicare and Pharmaceutical claims data from Medicare Australia. The main outcome measures were treatment with radical prostatectomy, any radiotherapy, external beam radiotherapy, brachytherapy or androgen deprivation therapy, and cancer staging. PCOS data were considered to represent the true treatment status. The sensitivity and specificity of the administrative data were estimated and relevant patient characteristics were compared using chi-squared tests.
The validation data set comprised 1857 PCOS patients with treatment information linked to Cancer Registry records. Hospital and Medicare claims data combined described treatment more accurately than either one alone. The combined data accurately recorded radical prostatectomy (96% sensitivity) and brachytherapy (93% sensitivity), but not androgen deprivation therapy (76% sensitivity). External beam radiotherapy was rarely captured (5% sensitivity), but this was improved by including Medicare claims for radiation field setting or dosimetry (86% sensitivity). False positive rates were near 0%. Disease stage comparisons were limited by one-third of cases having unknown stage in the Cancer Registry. Administrative data recorded treatment more accurately for cases in urban areas.
Cancer Registry and hospital inpatient data accurately captured radical prostatectomy and brachytherapy treatment, but not external beam radiotherapy or disease stage. Medicare claims data substantially improved the accuracy with which all major treatments were recorded. These administrative data combined are valid for population-based studies of some aspects of prostate cancer care.
PMCID: PMC3206422  PMID: 21978077
8.  Brachytherapy in the therapy of prostate cancer – an interesting choice 
Contemporary Oncology  2013;17(5):407-412.
Brachytherapy is a curative alternative to radical prostatectomy or external beam radiation [i.e. 3D conformal external beam radiation therapy (CRT), intensity-modulated radiation therapy (IMRT)] with comparable long-term survival and biochemical control and the most favorable toxicity. HDR brachytherapy (HDR-BT) in treatment of prostate cancer is most frequently used together with external beam radiation therapy (EBRT) as a boost (increasing the treatment dose precisely to the tumor). In the early stages of the disease (low, sometimes intermediate risk group), HDR-BT is more often used as monotherapy. There are no significant differences in treatment results (overall survival rate – OS, local recurrence rate – LC) between radical prostatectomy, EBRT and HDR-BT. Low-dose-rate brachytherapy (LDR-BT) is a radiation method that has been known for several years in treatment of localized prostate cancer. The LDR-BT is applied as a monotherapy and also used along with EBRT as a boost. It is used as a sole radical treatment modality, but not as a palliative treatment. The use of brachytherapy as monotherapy in treatment of prostate cancer enables many patients to keep their sexual functions in order and causes a lower rate of urinary incontinence. Due to progress in medical and technical knowledge in brachytherapy (“real-time” computer planning systems, new radioisotopes and remote afterloading systems), it has been possible to make treatment time significantly shorter in comparison with other methods. This also enables better protection of healthy organs in the pelvis. The aim of this publication is to describe both brachytherapy methods.
PMCID: PMC3934024  PMID: 24596528
HDR brachytherapy; LDR brachytherapy; prostate cancer; seeds
9.  Combined brachytherapy and external beam radiotherapy without adjuvant androgen deprivation therapy for high-risk prostate cancer 
To report the outcomes of patients treated with combined iodine-125 (I-125) brachytherapy and external beam radiotherapy (EBRT) for high-risk prostate cancer.
Between 2003 and 2009, I-125 permanent prostate brachytherapy plus EBRT was performed for 206 patients with high-risk prostate cancer. High-risk patients had prostate-specific antigen ≥ 20 ng/mL, and/or Gleason score ≥ 8, and/or Stage ≥ T3. One hundred and one patients (49.0%) received neoadjuvant androgen deprivation therapy (ADT) but none were given adjuvant ADT. Biochemical failure-free survival (BFFS) was determined using the Phoenix definition.
The 5-year actuarial BFFS rate was 84.8%. The 5-year cause-specific survival and overall survival rates were 98.7% and 97.6%, respectively. There were 8 deaths (3.9%), of which 2 were due to prostate cancer. On multivariate analysis, positive biopsy core rates and the number of high-risk factors were independent predictors of BFFS. The 5-year BFFS rates for patients in the positive biopsy core rate <50% and ≥50% groups were 89.3% and 78.2%, respectively (p = 0.03). The 5-year BFFS rate for patients with the any single high-risk factor was 86.1%, compared with 73.6% for those with any 2 or all 3 high-risk factors (p = 0.03). Neoadjuvant ADT did not impact the 5-year BFFS.
At a median follow-up of 60 months, high-risk prostate cancer patients undergoing combined I-125 brachytherapy and EBRT without adjuvant ADT have a high probability of achieving 5-year BFFS.
PMCID: PMC3904455  PMID: 24401540
Prostate cancer; Brachytherapy; High risk; Androgen deprivation therapy
10.  High-risk surgical stage 1 endometrial cancer: analysis of treatment outcome 
To report the relapse and survival rates associated to treatment for patients with stage IC, grade 2 or grade 3 and IB grade 3 diseases considered high risk patients group for relapse.
Materials and methods
From January 1993 to December 2003, 106 patients with endometrial cancer stage I were managed surgically in our institution. Based on data from the medical records, 106 patients with epithelial endometrial cancer met the following inclusion criteria: stage IC grade 2 or 3 and IB grade 3 with or without lymphovascular invasion. Staging was defined according to the FIGO surgical staging system. Postoperative adjuvant radiotherapy consisted of external beam pelvic radiation, vaginal brachytherapy alone or both. The median age was 65 years (range, 32–83 years), lymph node dissection was performed in 45 patients (42.5%) and 14 patients (13.2%) received vaginal brachytherapy only, and 92 (86.8%) received combined vaginal brachytherapy and external beam radiotherapy. The median dose of external beam radiotherapy administered to the pelvis was 4500 cGy (range 4000 – 5040). The median dose to vaginal surface was 2400 cGy (range 2000 – 3000). Predominant pathological stage and histological grade were IC (73.6%) and grade 3 (51.9%). The lymphovascular invasion was present in 33 patients (31.1%) and pathological stage IC grade 2 was most common (48. 1%) combination of risk factors in this group.
With a follow up median of 58.3 months (range 12.8 – 154), five year overall survival and event free survival were 78.5% and 72.4%, respectively. Locoregional control in five year was 92.4%. Prognostic factors related with survival in univariate analyses were: lymphadenectomy (p = 0.045), lymphovascular invasion (p = 0.047) and initial failure site (p < 0.0001). In multivariate analyses the initial failure in distant sites (p < 0.0001) was the only factor associated with poor survival. Acute and chronic gastrointestinal and genitourinary toxicity grades 3 were not observed.
In conclusion, our results showed that the stage IC, grade 2, 3 and IB grade 3 endometrial cancer was associated with significantly increased risk of distant relapse and endometrial carcinoma-related death independently of salvage treatment modality.
PMCID: PMC1555589  PMID: 16887018
11.  Prostate Cancer–Specific Survival Following Salvage Radiotherapy vs Observation in Men With Biochemical Recurrence After Radical Prostatectomy 
Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival, and if so, the subgroup of men most likely to benefit.
To quantify the relative improvement in prostate cancer–specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial.
Design, Setting, and Patients
Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982–2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n=397), salvage radiotherapy alone (n=160), or salvage radiotherapy combined with hormonal therapy (n=78).
Main Outcome Measure
Prostate cancer–specific survival defined from time of recurrence until death from disease.
With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer–specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19–0.54]; P<.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer–specific survival (HR, 0.34 [95% CI, 0.17–0.69]; P=.003). The increase in prostate cancer–specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer–specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer–specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival.
Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer–specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.
PMCID: PMC3076799  PMID: 18560003
12.  Management of Biochemical Recurrence after Primary Localized Therapy for Prostate Cancer 
Clinically localized prostate cancer is typically managed by well established therapies like radical prostatectomy, brachytherapy, and external beam radiation therapy. While many patients can be cured with definitive local therapy, some will have biochemical recurrence (BCR) of disease detected by a rising serum prostate-specific antigen (PSA). Management of these patients is nuanced and controversial. The natural history indicates that a majority of patients with BCR will not die from prostate cancer but from other causes. Despite this, a vast majority of patients with BCR are empirically treated with non-curable systemic androgen deprivation therapy (ADT), with its myriad of real and potential side effects. In this review article, we examined the very definition of BCR after definitive local therapy, the current status of imaging studies in its evaluation, the need for additional therapies, and the factors involved in the decision making in the choice of additional therapies. This review aims to help clinicians with the management of patients with BCR. The assessment of prognostic factors including absolute PSA level, time to recurrence, PSA kinetics, multivariable nomograms, imaging, and biopsy of the prostatic bed may help stratify the patients into localized or systemic recurrence. Patients with low-risk of systemic disease may be cured by a salvage local therapy, while those with higher risk of systemic disease may be offered the option of ADT or a clinical trial. An algorithm incorporating these factors is presented.
PMCID: PMC3358653  PMID: 22655274
prostate cancer; radical prostatectomy; radiation therapy; biochemical recurrence; PSA recurrence; salvage
13.  Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial 
BMC Cancer  2012;12:110.
Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required.
This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 (125I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with 125I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during 125I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.
The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events.
To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa.
Trial registration
PMCID: PMC3350387  PMID: 22439742
Prostate cancer; Trimodality; Radiation therapy; Brachytherapy; External beam radiation therapy; Hormone therapy; Randomized controlled trial; Biochemical progression-free survival
14.  Clinical significance and treatment of biochemical recurrence after definitive therapy for localized prostate cancer 
Surgical oncology  2009;18(3):268-274.
Radical prostatectomy and external beam radiation therapy are the established and definitive interventions for clinically localized prostate cancer. These treatment modalities are yet subject to failure observed first by biochemical recurrence, defined by increases in the serum PSA level. We investigated the significance of biochemical recurrence after definitive therapy and the available salvage therapy options for cancer recurrence.
A literature search was performed in PubMed, and applicable studies addressing biochemical recurrence and salvage options after radical prostatectomy or external beam radiation therapy were reviewed.
After radical prostatectomy, a detectable serum PSA level indicates biochemical recurrence. Whether to administer salvage therapy locally or systemically depends largely on prognostic factors including PSA doubling time, Gleason’s score, pathologic stage, and the time interval between radical prostatectomy and biochemical recurrence. Early initiation of salvage therapy has been shown to significantly impact on cancer outcomes.
After external beam radiation therapy, no single PSA level can define biochemical recurrence. Instead, it has been defined by increases in the PSA level above the nadir. Following radiation therapy, PSA doubling time and Gleason score play important roles in determining the need for local versus systemic salvage therapy.
After the diagnosis of biochemical recurrence, it is critical to perform a timely clinical assessment using the prognostic factors mentioned above. Prompt initiation of salvage therapy may prevent subsequent clinical progression and prostate cancer-specific mortality.
PMCID: PMC3501211  PMID: 19394814
Prostate cancer; Radical prostatectomy; Radiation therapy; Biochemical recurrence; PSA recurrence; Salvage
15.  Primary treatments for clinically localized prostate cancer: a comprehensive lifetime cost-utility analysis 
BJU international  2012;111(3):437-450.
To characterize the costs and outcomes associated with radical prostatectomy (open, laparoscopic, or robot-assisted) and radiation therapy (dose-escalated 3-dimensional conformal radiation, intensity-modulated radiation, brachytherapy, or combination), using a comprehensive, lifetime decision analytic model.
Patients and Methods
A Markov model was constructed to follow hypothetical men with low-, intermediate-, and high-risk prostate cancer over their lifetimes following primary treatment; probabilities of outcomes were based on an exhaustive literature search yielding 232 unique publications.
Patients could experience remission, recurrence, salvage treatment, metastasis, death from prostate cancer, and death from other causes.
Utilities for each health state were determined, and disutilities were applied for complications and toxicities of treatment.
Costs were determined from the U.S. payer perspective, with incorporation of patient costs in a sensitivity analysis.
Differences in quality-adjusted life years across modalities were modest, ranging from 10.3 to 11.3 for low-risk patients, 9.6 to 10.5 for intermediate-risk patients, and 7.8 to 9.3 for high-risk patients.
There were no statistically significant differences among surgical modalities, which tended to be more effective than radiation modalities, with the exception of combination external beam + brachytherapy for high-risk disease.
Radiation modalities were consistently more expensive than surgical modalities; costs ranged from $19,901 (robot-assisted prostatectomy for low-risk disease) to $50,276 (combination radiation for high-risk disease).
These findings were robust to an extensive set of sensitivity analyses.
Our analysis found small differences in outcomes and substantial differences in payer and patient costs across treatment alternatives.
These findings may inform future policy discussions regarding strategies to improve efficiency of treatment selection for localized prostate cancer.
PMCID: PMC3587031  PMID: 23279038
prostate neoplasms; decision analysis; comparative effectiveness; surgery; radiation
16.  Oral cancer: Current role of radiotherapy and chemotherapy 
The term oral cavity cancer (OSCC) constitutes cancers of the mucosal surfaces of the lips, floor of mouth, oral tongue, buccal mucosa, lower and upper gingiva, hard palate and retromolar trigone. Treatment approaches for OSCC include single management with surgery, radiotherapy [external beam radiotherapy (EBRT) and/or brachytherapy], as well as adjuvant systemic therapy (chemotherapy and/or target agents); various combinations of these modalities may also be used depending on the disease presentation and pathological findings. The selection of sole or combined modality is based on various considerations that include disease control probability, the anticipated functional and cosmetic outcomes, tumor resectability, patient general condition, and availability of resources and expertise. For resectable OSCC, the mainstay of treatment is surgery, though same practitioners may advocate for the use of radiotherapy alone in selected “early” disease presentations or combined with chemotherapy in more locally advanced stage disease. In general, the latter is more commonly reserved for cases where surgery may be problematic. Thus, primary radiotherapy ± chemotherapy is usually reserved for patients unable to tolerate or who are otherwise unsuited for surgery. On the other hand, brachytherapy may be considered as a sole modality for early small primary tumor. It also has a role as an adjuvant to surgery in the setting of inadequate pathologically assessed resection margins, as does postoperative external beam radiotherapy ± chemotherapy, which is usually reserved for those with unfavorable pathological features. Brachytherapy can also be especially useful in the re-irradiation setting for persistent or recurrent disease or for a second primary arising within a previous radiation field. Biological agents targeting the epithelial growth factor receptor (EGFR) have emerged as a potential moda-lity in combination with radiotherapy or chemoradiotherpy and are currently under evaluation in clinical trials.
Key words:Radiotherapy, chemoradiotherapy, oral cavity cancer, treatment.
PMCID: PMC3613874  PMID: 23385513
17.  Optimizing the Management of High-Risk, Localized Prostate Cancer 
Korean Journal of Urology  2012;53(12):815-820.
Prostate cancer has a high prevalence and a rising incidence in many parts of the world. Although many screen-detected prostate cancers may be indolent, prostate cancer remains a major contributor to mortality in men. Therefore, the appropriate diagnosis and treatment of localized prostate cancer with lethal potential are of great importance. High-risk, localized prostate cancer has multiple definitions. Treatment options that should be individualized to each patient include observation, radical prostatectomy, external beam radiotherapy, brachytherapy, androgen deprivation, and combined modality treatment. Specific outcomes of radical prostatectomy and combined modality treatment for high-risk prostate cancer are reviewed. The rationale for extended pelvic lymphadenectomy at the time of surgery is discussed, as is the role for surgery in the setting of node-positive, high-risk disease. There is not yet a biomarker that accurately identifies lethal prostate cancer, but rigorous clinical studies have identified methods of optimizing oncologic outcomes in high-risk men.
PMCID: PMC3531632  PMID: 23301123
Prostate-specific antigen; Prostatectomy; Prostatic neoplasms; Radiotherapy
18.  Dosimetric analysis and comparison of IMRT and HDR brachytherapy in treatment of localized prostate cancer 
Radical radiotherapy is one of the options for the management of prostate cancer. In external beam therapy, 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) are the options for delivery of increased radiation dose, as vital organs are very close to the prostate and a higher dose to these structures leads to an increased toxicity. In brachytherapy, low dose rate brachytherapy with permanent implant of radioactive seeds and high dose rate brachytherapy (HDR) with remote after loaders are available. A dosimetric analysis has been made on IMRT and HDR brachytherapy plans. Ten cases from each IMRT and HDR brachytherapy have been taken for the study. The analysis includes comparison of conformity and homogeneity indices, D100, D95, D90, D80, D50, D10 and D5 of the target. For the organs at risk (OAR), namely rectum and bladder, V100, V90 and V50 are compared. In HDR brachytherapy, the doses to 1 cc and 0.1 cc of urethra have also been studied. Since a very high dose surrounds the source, the 300% dose volumes in the target and within the catheters are also studied in two plans, to estimate the actual volume of target receiving dose over 300%. This study shows that the prescribed dose covers 93 and 92% of the target volume in IMRT and HDR brachytherapy respectively. HDR brachytherapy delivers a much lesser dose to OAR, compared to the IMRT. For rectum, the V50 in IMRT is 34.0cc whilst it is 7.5cc in HDR brachytherapy. With the graphic optimization tool in HDR brachytherapy planning, the dose to urethra could be kept within 120% of the target dose. Hence it is concluded that HDR brachytherapy may be the choice of treatment for cancer of prostate in the early stage.
PMCID: PMC2884303  PMID: 20589121
Brachytherapy; conformity; intensity modulated radiotherapy; prostate
19.  Proposed salvage treatment strategy for biochemical failure after radical prostatectomy in patients with prostate cancer: a retrospective study 
Treatment options for patients with recurrent disease after radical prostatectomy include salvage radiotherapy of the prostatic bed and/or androgen deprivation therapy. To establish an effective treatment strategy for recurrent disease after radical prostatectomy, we retrospectively analyzed the outcome of salvage radiation monotherapy in such cases.
Data from 61 men who had undergone salvage radiation monotherapy for biochemical recurrent disease after radical prostatectomy were retrospectively reviewed. In all patients, salvage radiotherapy consisted of iraradiation to the prostatic bed (70 Gy) using three-dimensional conformal radiotherapy techniques. Treatment outcome was analyzed to identify predictive factors of salvage radiotherapy.
The biochemical recurrence-free survival after salvage radiation monotherapy at 2 and 5 years was 55% and 38%, respectively. Cox proportional regression models revealed that the independent predictive factors for biochemical recurrence were Gleason Score ≥ 8, negative surgical margin, and PSA velocity ≥ 0.38 ng/mL/year. Negative surgical margin and PSA velocity ≥ 0.8 ng/mL/year were significantly associated with poor response in the serum PSA levels after salvage radiotherapy.
Based on our findings, we propose a treatment strategy for biochemical recurrent disease after radical prostatectomy. Patients with Gleason score ≤ 7, positive surgical margin, and PSA velocity < 0.38 ng/mL/year are categorized the most favorable group, so that eradication by salvage radiation monotherapy could be expected. Other patients could be divided to two groups depending on surgical margin status and PSA velocity: 1) patients who might require combination of SRT and short-term androgen deprivation therapy and 2) patients who should be treated by androgen deprivation monotherapy.
PMCID: PMC4283125  PMID: 25331298
Prostate cancer; Biochemical failure; Salvage radiotherapy; Prostate-specific antigen; PSA doubling time; PSA velocity
20.  Outcomes and predictors of localized or locally-advanced prostate cancer treated by radiotherapy in Indonesia 
Prostate International  2013;1(1):16-22.
Presently there is no published data on the outcomes of localized or locally-advanced prostate cancer (PCa) treated by external-beam radiotherapy (RT) in Indonesia.
This study retrospectively analyzed 96 patients with localized or locally-advanced PCa treated by RT from year 1995 to 2009, at the national referral hospital and the national cancer hospital of Indonesia. Cumulative prostate and pelvic radiation dose/type was <70 Gy conventional RT in 84.4% patients, and ≥70 Gy Three dimensional-conformal or intensity modulated RT in 15.6% patients. Overall survival (OS) and biochemical progression-free survival (BFS) were estimated by Kaplan-Meier. Predictors of OS and biochemical recurrence were analyzed by multivariate Cox regressions.
The median follow-up was 61 months (range, 24 to 169 months). There were 3.1% low-risk, 26% intermediate-risk, and 70.8% high-risk cases. More than half of the patients (52.1%) had pretreatment prostate-specific antigen (PSA) >20 ng/mL. The 5-year survival outcome of low-risk, intermediate-risk, and high-risk patients were: OS, 100%, 94.7%, and 67.9% (P=0.297); and BFS, 100%, 94.1%, and 57.1% (P=0.016), respectively. In the high-risk group, the 5-year OS was 88.3% in patients who received adjuvant hormonal androgen deprivation therapy (HT), compared to 53% in RT only, P=0.08. Significant predictors of OS include high-risk group (hazard Ratio [HR], 9.35; 95% confidence interval [CI], 1.52 to 57.6; P=0.016), adjuvant therapy (HR, 0.175; 95% CI, 0.05 to 0.58; P=0.005), detection by transurethral resection of the prostate (TUR-P) (HR, 6.81; 95% CI, 2.28 to 20.33; P=0.001), and pretreatment PSA (HR, 1.003; 95% CI, 1.00 to 1.005; P=0.039). The sole predictor of biochemical failure was pretreatment PSA (P=0.04), with odds ratio of 4.52 (95% CI, 1.61 to 12.65) for PSA >20 ng/mL.
RT is an effective treatment modality for localized or locally-advanced PCa in Indonesian patients, with outcomes and predictors consistent to that reported elsewhere. Predictors of poorer outcomes include high-risk group, higher pretreatment PSA, incidental detection by TUR-P, and lack of adjuvant HT. Adjuvant hormonal therapy significantly improve the survival of high risk patients.
PMCID: PMC3821522  PMID: 24223397
Prostatic neoplasms; Radiotherapy; Survival
21.  Up-to-date results of carbon-ion radiotherapy for prostate cancer 
Journal of Radiation Research  2014;55(Suppl 1):i28-i29.
Carbon ion radiotherapy (C-ion RT) for prostate cancer was started in 1995 using the Heavy-Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS), Japan. After preceding phase I/II dose-escalation studies of 20 fractions over 5 weeks, a phase II study was initiated in April 2000 using the treatment techniques and the recommended dose fractionations established by the phase I/II studies. This study was also successfully completed in October 2003 when the C-ion RT for solid tumors, including the prostate cancer, was approved as ‘Advanced Medicine’ by the Ministry of Health, Labor, and Welfare. Since then, more than 1400 patients have been treated with C-ion RT as of February 2012, and advancement of hypofractionation has also been achieved. In this paper, the treatment outcomes in 1144 patients who underwent the established C-ion RT between April 2000 and July 2012 were analyzed.
Out of 1144 patients, 585 patients were categorized as high-risk group, which includes patients having at least one of the following conditions: T3 clinical stage, Gleason's score of 8 or higher and PSA of 20 or higher. One hundred and ninety-seven patients who met the conditions such as clinical stage of T2a or lower, Gleason's score of 6 or lower and PSA of <20 were categorized as low-risk group. Three hundred and sixty-two patients who were not included in either high- or low-risk group were categorized as intermediate-risk group. All patients were pathologically proven to have adenocarcinoma of the prostate, and Gleason's score was determined by the chief pathologist of our study group. Written consent was obtained from all patients included in the clinical study. Patients with the following conditions were not registered in the clinical trial: having distant metastases, having synchronous primary malignancy, not histologically proven cancer, without informed consent, post-operative/post-irradiation recurrence.
All patients were treated with three field irradiations (vertical one field and horizontal opposing two fields). The prostate and proximal part of the seminal vesicle were contoured as clinical target volume (CTV), and planning target volume (PTV) was set with 5–10 mm margins around the CTV. On the way of radiotherapy, a part of irradiation field of the posterior side was cut to reduce the rectal dose. The 197 patients in the low-risk group did not undergo androgen deprivation therapy (ADT), whereas the 947 patients of intermediate- and high-risk groups underwent ADT. The patients of intermediate-risk group underwent about 6 months of neoadjuvant ADT, and the patients of high-risk group also underwent about 6 months of neoadjuvant ADT and sequential adjuvant ADT for more than 18 months. The median age of all patients was 68 years, and the median follow-up time was 48.7 months (range: 3.6–151.1 months).
The 5-year overall survival rate and biochemical relapse-free rate of the entire groups was 95.7% and 91.0%, respectively. T-stage and Gleason's score were significant prognostic factors for both the biochemical control and patient survival and initial PSA was also a predictive factor for survival. Regarding the late radiation toxicity, the incidence of rectal toxicity of grade 2 or worse was 1.1% and that of genitourinary toxicity was 6.5%. These outcomes seemed to be better than those of the past publications [ 1– 4]. In addition, the incidence of toxicity in patients treated with more hypofractionated C-ion RT of 16 fractions over 4 weeks was lower than those of 20 fraction treatment. These favorable outcomes can be thought as apparent evidence of physical and biological advantages of the hypofractionated C-ion RT.
PMCID: PMC3941550
carbon-ion radiation therapy; prostate cancer; hypofractionation
22.  Low rate of lymphedema after extended pelvic lymphadenectomy followed by pelvic irradiation of node-positive prostate cancer 
The aim of the present study was to evaluate the prevalence and severity of lower limb lymphedema after pelvic lymphadenectomy and radiotherapy to the pelvic lymph nodes in patients with prostate cancer.
Twenty-six patients underwent combined treatment for high-risk node-positive prostate cancer at Skåne University Hospital between April 2008 and March 2011. The treatment consisted of extended pelvic lymphadenectomy followed by androgen deprivation therapy and radiotherapy. The pelvic lymphnodes, prostate and seminal vesicles were treated with external beam radiotherapy (EBRT) to an absorbed dose of 50 Gy followed by a brachytherapy (BT) boost of 2x10 Gy to the prostate only. Twenty-two patients accepted an invitation to a clinical examination with focus on lower limb swelling. The median time between the end of radiotherapy and examination was 2.2 years (range 1.2–4.1).
Six patients (27%) experienced grade 1 lymphedema and two patients (9%) grade 2 while none had grade 3 or 4 according to the CTC Common Toxicity Criteria scale 4.0. Three patients required treatment with compression stockings.
Brachytherapy and pelvic EBRT have a low incidence of lymphedema (at median 2.2 y after treatment) in patients with high-risk node-positive prostate cancer that have undergone pelvic lymph node dissection.
PMCID: PMC3842657  PMID: 24252686
Prostate cancer; Lymphadenectomy; Pelvic irradiation; Node-positive; Lymphedema
23.  Analysis of prognostic factors in localized high-risk prostate cancer patients treated with HDR brachytherapy, hypofractionated 3D-CRT and neoadjuvant/adjuvant androgen deprivation therapy (trimodality therapy) 
Journal of Radiation Research  2013;55(3):527-532.
Trimodality therapy consisting of high dose rate (HDR) brachytherapy combined with external beam radiation therapy (EBRT), neoadjuvant hormonal therapy (NHT) and adjuvant hormonal therapy (AHT) has been used to treat localized high-risk prostate cancer. In this study, an analysis of patients receiving the trimodality therapy was performed to identify prognostic factors of biochemical relapse-free survival (bRFS). Between May 2005 and November 2008, 123 high-risk prostate cancer patients (D'Amico classification) were treated with NHT prior to HDR brachytherapy combined with hypofractionated EBRT. Among these patients, 121 had completed AHT. The patients were assigned by time to be treated with a low-dose or high-dose arm of HDR brachytherapy with subsequent hypofractionated 3D conformal radiation therapy (3D-CRT). Multivariate analysis was used to determine prognostic factors for bRFS. With a median follow-up of 60 months, the 5-year bRFS for all patients was 84.3% (high-dose arm, 92.9%; low-dose arm, 72.4%, P = 0.047). bRFS in the pre-HDR PSA ≤ 0.1 ng/ml subgroup was significantly improved compared with that in the pre-HDR PSA > 0.1 ng/ml subgroup (88.3% vs 68.2%, P = 0.034). On multivariate analysis, dose of HDR (P = 0.045, HR = 0.25, 95% CI = 0.038–0.97) and pre-HDR PSA level (P = 0.02 HR = 3.2, 95% CI = 1.18–10.16) were significant prognostic factors predicting bRFS. In high-risk prostate cancer patients treated with the trimodality therapy, the dose of HDR and pre-HDR PSA were significant prognostic factors. The pre-HDR PSA ≤ 0.1 subgroup had significantly improved bRFS. Further studies are needed to confirm the relevance of pre-HDR PSA in trimodality therapy.
PMCID: PMC4014157  PMID: 24351458
high-risk prostate cancer; HDR; trimodality therapy; PSA response
24.  Type and dose of radiotherapy used for initial treatment of non-metastatic prostate cancer 
We sought to describe patterns of initial radiotherapy among non-metastatic prostate cancer (PC) patients by recurrence risk groups.
Medical records were abstracted for a sample of 9017 PC cases diagnosed in 2004 as a part of the Center for Disease Control and Prevention’s Prostate and Breast Patterns of Care Study in seven states. Non-metastatic PC cases are categorized as low-risk (LR), intermediate-risk (IR) or high-risk (HR) groups based on pretreatment PSA, tumor stage, and Gleason score per 2002 NCCN guidelines. Univariate and multivariate analyses were employed to determine factors associated with the type and dose of radiotherapy by the risk groups.
Of the 9,017 patients, 3153 who received definitive radiotherapy either alone or in combination with hormone therapy (HT) were selected for in-depth analysis. Multivariate models showed that LR patients were more likely to receive seed implant brachytherapy (BT) than those in higher risk groups. Those in the IR group were most likely to receive external beam radiotherapy (EBRT) combined with BT or high-dose radiotherapy. Use of HT in combination with radiotherapy was more common in the IR and HR groups than for LR patients. Intensity modulated radiation treatment (IMRT) was used to treat 32.6% of PC patients treated with EBRT, with the majority (60.6%) treated with high-dose radiotherapy.
Radiotherapy types and dosage utilization varied by PC risk groups. Patients in IR were more likely than those in LR or HR to receive high-dose radiotherapy. IMRT was used in about one third of patients to deliver high-dose radiotherapy.
PMCID: PMC3940027  PMID: 24499610
Prostate cancer; Radiotherapy; Patterns of care study
25.  Esophageal cancer management controversies: Radiation oncology point of view 
Esophageal cancer treatment has evolved from single modality to trimodality therapy. There are some controversies of the role, target volumes and dose of radiotherapy (RT) in the literature over decades. The present review focuses primarily on RT as part of the treatment modalities, and highlight on the RT volume and its dose in the management of esophageal cancer. The randomized adjuvant chemoradiation (CRT) trial, intergroup trial (INT 0116) enrolled 559 patients with resected adenocarcinoma of the stomach or gastroesophageal junction. They were randomly assigned to surgery plus postoperative CRT or surgery alone. Analyses show robust treatment benefit of adjuvant CRT in most subsets for postoperative CRT. The Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) used a lower RT dose of 41.4 Gray in 23 fractions with newer chemotherapeutic agents carboplatin and paclitaxel to achieve an excellent result. Target volume of external beam radiation therapy and its coverage have been in debate for years among radiation oncologists. Pre-operative and post-operative target volumes are designed to optimize for disease control. Esophageal brachytherapy is effective in the palliation of dysphagia, but should not be given concomitantly with chemotherapy or external beam RT. The role of brachytherapy in multimodality management requires further investigation. On-going studies of multidisciplinary treatment in locally advanced cancer include: ZTOG1201 trial (a phase II trial of neoadjuvant and adjuvant CRT) and QUINTETT (a phase III trial of neoadjuvant vs adjuvant therapy with quality of life analysis). These trials hopefully will shed more light on the future management of esophageal cancer.
PMCID: PMC4133794  PMID: 25132924
Radiotherapy; Chemotherapy; Esophagus; Cancer; Treatment

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