Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients ...with historically incurable distant metastases.
Twenty five patients with oligometastases, defined as 1-5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1-28) and IGRT 50 Gy (days 8-12 and 15-19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months).
The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests.
Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases.
ClinicalTrials.gov NCT00463060.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To determine factors that influence local control and systemic relapse in patients undergoing permanent prostate brachytherapy (PPB).
A total of 584 patients receiving PPB alone or PPB with external ...beam radiation therapy (19.5%) agreed to undergo prostate biopsy (PB) at 2 years postimplantion and yearly if results were positive or if the prostate-specific antigen (PSA) level increased. Short-term hormone therapy was used with 280 (47.9%) patients. Radiation doses were converted to biologically effective doses (BED) (using alpha/beta = 2). Comparisons were made by chi-square analysis and linear regression. Survival was determined by the Kaplan-Meier method.
The median PSA concentration was 7.1 ng/ml, and the median follow-up period was 7.1 years. PB results were positive for 48/584 (8.2%) patients. Positive biopsy results by BED group were as follows: 22/121 (18.2%) patients received a BED of < or =150 Gy; 15/244 (6.1%) patients received >150 to 200 Gy; and 6/193 (3.1%; p < 0.001) patients received >200 Gy. Significant associations of positive PB results by risk group were low-risk group BED (p = 0.019), intermediate-risk group hormone therapy (p = 0.011) and BED (p = 0.040), and high-risk group BED (p = 0.004). Biochemical freedom from failure rate at 7 years was 82.7%. Biochemical freedom from failure rate by PB result was 84.7% for negative results vs. 59.2% for positive results (p < 0.001). Cox regression analysis revealed significant associations with BED (p = 0.038) and PB results (p = 0.002) in low-risk patients, with BED (p = 0.003) in intermediate-risk patients, and with Gleason score (p = 0.006), PSA level (p < 0.001), and PB result (p = 0.038) in high-risk patients. Fifty-three (9.1%) patients died, of which eight deaths were due to prostate cancer. Cause-specific survival was 99.2% for negative PB results vs. 87.6% for positive PB results (p < 0.001).
Higher radiation doses are required to achieve local control following PPB. A BED of >200 Gy with an alpha/beta ratio of 2 yields 96.9% local control rate. Failure to establish local control impacts survival.
Abstract Purpose Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. ...In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. Materials and methods The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. Results For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. Conclusion This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.
To analyze the effect of biologically effective dose (BED) values on prostate-specific antigen (PSA) failure and posttreatment biopsy.
From 1990 to 2003, 1,377 patients had prostate brachytherapy ...alone (I-125 or Pd-103) (571), hormonal and brachytherapy (371), and trimodality therapy (hormonal, implant, and external beam) (435). Dose was defined as the D90 (dose delivered to 90% of the gland from the dose-volume histogram).
Freedom from PSA failure (FFPF) at 10 years was 87%. The 10-year FFPF for BED<100, >100-120, >120-140, >140-160, <160-180, >180-200, and >200 were 46%, 68%, 81%, 85.5%, 90%, 90%, and 92%, respectively (p<0.0001). BED and Gleason score had the greatest effect, with p values of p<0.0001 in multivariate analysis. Posttreatment positive biopsy rate was 7% (31/446). The positive biopsy rates for BED<or=100, >100-120, >120-140, >140-160, >160-180, >180-200, and >200 were 24% (8/33), 15% (3/20), 6% (2/33), 6% (3/52), 7% (6/82), 1% (1/72), and 3% (4/131), respectively (p<0.0001). BED was the most significant predictor of biopsy outcome in multivariate analysis (p=0.006).
Biologically effective dose equations provide a method of comparing different isotopes and combined therapies in the brachytherapy management of prostate cancer. The effects of BED on FFPF and posttreatment biopsy demonstrate a strong dose-response relationship.
To determine disease-specific survival (DSS) and associated predictive factors after prostate brachytherapy.
A total of 1561 patients underwent brachytherapy for prostate cancer from 1990 to 2004 ...(median follow-up, 3.8 years). Treatment included brachytherapy alone (n = 634), brachytherapy and hormonal therapy (n = 420), and implant and external beam therapy (n = 507).
The DSS and overall survival rates at 10 years were 96% and 74%, respectively. Gleason score significantly impacted DSS, with 10-year rates of 98%, 91%, and 92% for scores of < or = 6, 7, and > or = 8, respectively (p < 0.0001). Multivariate analysis revealed that PSA status after treatment had the most significant effect on DSS. Ten-year DSS rates were 100%, 52%, and 98%, respectively for patients without PSA failure (n = 1430), failure with a doubling time (DT) < or = 10 months (n = 64), and failure with a DT > 10 months (n = 67), respectively (p < 0.0001). In patients with PSA failure, DSS rates were 30%, 67%, and 98%, for those with DT < or = 6 months, > 6-10 months, and > 10 months, respectively (p < 0.0001).
The 10-year DSS rate supports the efficacy of brachytherapy. Patients dying with disease within 10 years after treatment harbor inherently aggressive cancer with high Gleason scores and short DT.
To calculate the actuarial risk of developing a prostate-specific antigen (PSA) bounce after prostate brachytherapy alone, using three definitions of bounce mentioned in the literature, and to ...explore the relationship between disease and treatment variables and the risk of developing a bounce. The impact of PSA bounce on PSA failure was also explored.
A total of 373 patients with T1–T2 prostate cancer underwent radioactive seed implant using
125I (
n = 337) or
103Pd (
n = 36) without hormonal therapy or external beam RT. All patients had a minimum of 1 year (median 4, maximum 11) of follow-up and at least three follow-up PSA values. PSA bounce was defined by a rise of one or two PSA values with a subsequent fall. Three definitions of bounce were used: definition 1, rise ≥0.1 ng/mL; definition 2, rise ≥0.4 ng/mL; and definition 3, rise >35% of previous value.
The actuarial likelihood of experiencing a PSA bounce at 5 years was 31% for definition 1, 17% for definition 2, and 20% for definition 3. The median time to develop a bounce was 19.5 months for definitions 1 and 2 and 20.5 months for definition 3. Gleason score, initial PSA level, and clinical stage did not predict for bounce using any definition. Using definition 1, younger patients (≤65 years) had a bounce rate at 5 years of 38% vs. 24% for older patients (
p = 0.009).
125I patients receiving an implant dose of ≤160 Gy had a bounce rate (definition 1) at 5 years of 24% vs. 38% for those receiving a dose delivered to 90% of the gland on the 1 month postimplant dose–volume histogram (D
90) >160 Gy (
p = 0.04). Using definition 2, prostate volume significantly affected the incidence of bounce. Patients with larger glands (>35 cm
3) were more likely to experience a bounce (23% at 5 years) than those with smaller glands (≤35 cm
3) who had a bounce rate of 11% at 5 years (
p = 0.01). In a multivariate analysis of factors predicting for PSA failure, PSA bounce was not found to be significant.
PSA bounce is a common phenomenon after prostate brachytherapy and occurs at a rate of 17–31%, depending on the definition used. It is more common in younger patients, those receiving higher implant doses, and those with larger glands. PSA bounce does not predict for future PSA failure.
To evaluate retrospectively the biochemical outcomes of young men treated with low-dose-rate brachytherapy for prostate cancer.
From 1990 to 2005, 1,665 men with clinically localized prostate cancer ...were treated with low-dose-rate brachytherapy +/- hormone therapy (HT) +/- external beam radiotherapy and underwent > or = 2 years of follow-up. Patients were stratified on the basis of age: < or = 60 (n = 378) and >60 years (n = 1,287). Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/mL. Univariate and multivariate analyses were used to determine the association of variables with freedom from biochemical failure (FFbF).
Median follow-up was 68 months (range, 24-180) for men < or = 60 years and 66 months (range, 24-200) for men >60. For the entire group, the actuarial 5- and 8-year FFbF rates were 94% and 88%, respectively. Men < or = 60 demonstrated similar 5- and 8-year FFbF (95% and 92%) compared with men >60 (93% and 87%; p = 0.071). A larger percent of young patients presented with low-risk disease; lower clinical stage, Gleason score (GS), and pretreatment PSA values; were treated after 1997; did not receive any HT; and had a high biologic effective dose (BED) of radiation (all ps <0.001). On multivariate analysis, PSA (p = 0.001), GS (p = 0.005), and BED (p < 0.001) were significantly associated with FFbF, but age was not (p = 0.665).
Young men achieve excellent 5- and 8-year biochemical control rates that are comparable to those of older men after prostate brachytherapy. Young age should not be a deterrent when considering brachytherapy as a primary treatment option for clinically localized prostate cancer.
To evaluate the influence of patient- and treatment-related factors on freedom from biochemical failure (FFbF) in patients with intermediate-risk prostate cancer.
From a prospectively collected ...database of 2250 men treated at Mount Sinai Hospital from 1990 to 2004 with low-dose-rate brachytherapy for prostate cancer, 558 men with either one or more intermediate-risk features (prostate-specific antigen PSA level 10-20 ng/mL, Gleason score 7, or Stage T2b) were identified who had a minimum follow-up of 24 months and postimplant CT-based dosimetric analysis. Biologically effective dose (BED) values were calculated to compare doses from different isotopes and treatment regimens. Patients were treated with brachytherapy with or without hormone therapy and/or external-beam radiotherapy. Patient- and treatment-related factors were analyzed with respect to FFbF. The median follow-up was 60 months (range, 24-167 months). Biochemical failure was defined according to the Phoenix definition. Univariate analyses were used to determine whether any variable was predictive of FFbF. A two-sided p value of <0.05 was considered significant.
Overall, the actuarial FFbF at 10 years was 86%. Dose (BED <150 Gy(2) vs. >or=150 Gy(2)) was the only significant predictor of FFbF (p < 0.001). None of the other variables (PSA, external-beam radiotherapy, Gleason score, treatment type, hormones, stage, and number of risk factors) was found to be a statistically significant predictor of 10-year FFbF.
Radiation dose is an important predictor of FFbF in intermediate-risk prostate cancer. Treatment should continue to be individualized according to presenting disease characteristics until results from Radiation Therapy Oncology Group trial 0232 become available.
To analyze the prognosis and outcomes of patients who remain free of biochemical failure during the first 5 years after treatment.
Between 1991 and 2002, 742 patients with prostate cancer were ...treated with brachytherapy alone (n = 306), brachytherapy and hormonal therapy (n = 212), or combined implantation and external beam radiotherapy (with or without hormonal therapy; n = 224). These patients were free of biochemical failure (American Society for Therapeutic Radiology and Oncology ASTRO definition) during the first 5 post-treatment years and had a documented 5-year prostate-specific antigen (PSA) value. The median follow-up was 6.93 years.
The actuarial 10-year freedom from PSA failure rate was 97% using the ASTRO definition and 95% using the Phoenix definition. The median 5-year PSA level was 0.03 ng/mL (range, 0-3.6). The 5-year PSA value was <or=0.01 in 47.7%, >0.01-0.10 in 31.1%, >0.10-0.2 in 10.2%, >0.2-0.5 in 7.82%, and >0.5 in 3.10%. The 5-year PSA value had prognostic significance, with a PSA value of <or=0.2 ng/mL (n = 661) corresponding to a 10-year freedom from PSA failure rate of 99% with the ASTRO definition and 98% with the Phoenix definition vs. 86% (ASTRO definition) and 81% (Phoenix definition) for a PSA value >or=0.2 ng/mL (n = 81; p < .0001). The treatment regimen had no effect on biochemical failure. None of the 742 patients in this study developed metastatic disease or died of prostate cancer.
The results of this study have shown that the prognosis for patients treated with brachytherapy and who remain biochemically free of disease for >or=5 years is excellent and none developed metastatic disease during the first 10 years after treatment. The 5-year PSA value is prognostic, and patients with a PSA value <0.2 ng/mL are unlikely to develop subsequent biochemical relapse.
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