Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy.

The aim of this study was to investigate the role of 70 Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48 months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA >0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p<0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8-10 in the prostatectomy specimens 17/40 (43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA >1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT) <10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3-4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in >50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.

Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5-10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.

Hypofractionation for radiotherapy of prostate cancer using a low alfa/beta ratio--possible reasons for concerns? An example of five dimensional radiotherapy.

UNLABELLED: It is very attractive, due to the assumed low alfa/beta ratio of prostate cancer (PC), to construct new treatment schedules for prostate cancer using only a few large fractions of radiation (hypofractionation). This will widen the therapeutic window since the ratio for PC might be lower than that of the organs at risk (OAR). PC is an extremely variable disease and often contains both highly and poorly differentiated cells. It is reasonable to assume that different cells have different patterns of radiosensitivity, i.e. alfa/beta ratios and proliferation. In this study we will simulate the effect on the outcome of the treatment with different fractionations and different ratios. MATERIAL AND METHODS: In this simulation we use an extension of the Linear Quadratic (LQ)/Biological Effective Dose (BED) formula called the dose volume inhomogeneity corrected BED (DVIC-BED). In the formula the tumour volume is divided in 50 subvolumes (step of 2%) and it is possible to calculate the relative effect of the treatment with different ratios (1.5, 4 and 6.5) in different subvolumes. RESULTS: The simulations demonstrate that only a small portion (5-10%) of cells with a higher ratio will dramatically change the effect of the treatment. Increasing the total dose can compensate this, but this will on the other hand increase the dose to the OAR and also the risk for severe side effects. CONCLUSION: These simulations highlight possible reasons for concerns about the use of hypofractionation for pathologically heterogeneous tumours, such as prostate cancer, and also demonstrate the need for testing new treatment schedules using both high and low ratios.

Four and five dimensional radiotherapy with reference to prostate cancer--definitions, state of the art and further directions--an overview.

Radiotherapy (RT) always requires a compromise between tumor control and normal tissue side-effects. Technical innovation in radiation therapy (RT), such as three dimensional RT, is now established. Concerning prostate cancer (PC), it is reasonable to assume that RT of PC will increase in the future. The combination of small margins, a movable target (prostate), few fractions and high doses will probably demand dynamically positioning systems and in real time. This is called four dimensional radiotherapy (4DRT). Moreover, biological factors must be included in new treatments such as hypofractionation schedules. This new era is called five dimensional radiotherapy, 5DRT. In this paper we discuss new concepts in RT in respect to PC.

Use of the Charlson combined comorbidity index to predict postradiotherapy quality of life for prostate cancer patients.

PURPOSE: To determine the impact of pretreatment comorbidity on late health-related quality of life (HRQoL) scores after patients have undergone combined radiotherapy for prostate cancer, including high-dose rate brachytherapy boost and hormonal deprivation therapy. METHODS AND MATERIALS: Results from the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire survey of 158 patients 5 years or more after completion of therapy were used from consecutively accrued subjects treated with curative radiotherapy at our institution, with no signs of disease at the time of questionnaire completion. HRQoL scores were compared with the Charlson combined comorbidity index (CCI), using analysis of covariance and multivariate regression models together with pretreatment factors including tumor stage, tumor grade, pretreatment prostate-specific antigen level, neoadjuvant hormonal treatment, diabetes status, cardiovascular status, and age and Charlson score as separate variables or the composite CCI. RESULTS: An inverse correlation between the two HRQoL domains, long-term global health (QL) and physical function (PF) scores, and the CCI score was observed, indicating an impact of comorbidity in these function areas. Selected pretreatment factors poorly explained the variation in functional HRQoL in the multivariate models; however, a statistically significant impact was found for the CCI (with QL and PF scores) and the presence of diabetes (with QL and emotional function). Cognitive function and social function were not statistically significantly predicted by any of the pretreatment factors. CONCLUSIONS: The CCI proved to be valid in this context, but it seems useful mainly in predicting long-term QL and PF scores. Of the other variables investigated, diabetes had more impact than cardiovascular morbidity on HRQoL outcomes in prostate cancer.

Undetectable late hepatic sequelae after hypofractionated stereotactic radiotherapy for liver tumors.

Hypofractionated liver stereotactic radiotherapy has produced long-term survival, but the hepatobiliary system is radiosensitive and may be severely damaged by the treatment. We have evaluated long-term radiation effects on hepatobiliary functions in the first long-term survivors reported after radiotherapy to the hepatobiliary system for liver tumors. Eleven patients were followed for up to 13 years after treatment of tumors≤9 cm in size. Conventional blood chemistry, clearance of indocyanine green and segmental uptake and excretion of radiolabeled mebrofenin were assayed. Slightly abnormal routine blood chemistry was found during the first 2 years in some patients with pre-existing liver damage. Other parameters were seemingly unaffected, and liver segments which received differing mean doses did not differ measurably with regard to parenchymal or ductal function. Late liver functions were therefore not demonstrably affected by the radiotherapy in most patients even in the presence of mild cirrhosis, after previous exposure to liver toxic agents, or after resection. However, slight to moderate late dysfunction occurred in one patient after three courses of irradiation, and in a cirrhotic patient after two major liver resections following radiotherapy. Our previous doses for irradiation of liver tumors gave no measurable chronic side effects and may be increased in order to control tumors more effectively. In selected patients, irradiation is possible even in the presence of liver dysfunction, and previous irradiation or resection does not absolutely contraindicate salvage treatment by re-irradiation or resection.

Curative stereotactic body radiotherapy for liver malignancy.

Nine patients with 11 primary or secondary liver non-neuroendocrine malignancies with mean and maximum diameters of 4.0 and 7.7 cm became long-term survivors after precision irradiation in a stereotactic body frame. Doses varied from 20 to 45 Gy split at 2-4 occasions a few days apart, with higher doses in the target centers. Occasional chemotherapy was stopped well before irradiation. No hospitalizations were needed because side effects, regional pain and nausea, were mild. All patients have now survived 5-14 years without recurrences. Two verified and one suspected secondary cancers occurred in organs close to the irradiated targets, and two of them could be resected for cure. Precision irradiation can thus cure selected liver malignancies. It is the first non-invasive method to achieve this, and the present patients are its first long-term survivors. A prolonged follow-up period is, however, necessary, because we have in other patients seen local tumor regrowth as late as four years after irradiation. The approach may cure some tumors, which are technically unsuited for other treatment modalities, and can be used for patients at high surgical risk. The success rate for local control seems good, but has to be defined by formal studies after optimization of radiation doses.

Is the use of a surrogate urethra an option in prostate high-dose-rate brachytherapy?

PURPOSE: To investigate the accuracy and the dosimetric consequences of substituting a surrogate urethra assumed to be at the geometric center of the prostate, in place of the true urethra when using high-dose-rate (HDR) brachytherapy for the treatment of prostate cancer. METHODS AND MATERIALS: One hundred prostate cancer patients treated with HDR brachytherapy constituted the study group. A pre-plan was made with the urethra visualized. The true urethra was defined, and a surrogate urethra was placed at the geometric center of the prostate. The distance between the two urethras was measured. The deviation was evaluated at the base, middle, and apex. To evaluate the dosimetric consequences for the true urethra when using a surrogate urethra, two different dose plans were made: one based on the true urethra and one based on the surrogate urethra. The dose-volume histograms for the true urethra were analyzed. RESULTS: The deviation between the true urethra and the surrogate urethra was greatest at the base of the prostate. A statistically significant difference was seen between the dosimetric parameters for the true and the surrogate urethra when the dose plan was made using the surrogate urethra. In this situation the dose to the true urethra was increased above our defined maximum tolerance limit. CONCLUSIONS: When using dose plans made according to a surrogate urethra the dose to the true urethra might be too high to be acceptable. If the true urethra is not visualized, severe damage could easily develop in a significant number of patients.

Clinical outcome in patients with prostate cancer treated with external beam radiotherapy and high dose-rate iridium 192 brachytherapy boost: a 6-year follow-up.

To report the long-term results for treatment of localized carcinoma of the prostate using high dose rate (HDR) brachytherapy, conformal external beam radiotherapy (3D EBRT) and neo-adjuvant hormonal therapy (TAB). From 1998 through 1999, 154 patients with localized prostate cancer were entered in the trial. Biologically no evidence of disease (bNED) was defined at PSA levels < 2 microg/l. In order to compare the results of this treatment with other treatment modalities, the patient's pre-treatment data were used to calculate the estimated 5-year PSA relapse free survival using Kattan's nomograms for radical prostatectomy (RP) and 3D EBRT. After 6 years of follow-up, 129 patients remain alive. The actual 5-year relapse-free survival is 84%. None of the patients demonstrated clinical signs of local recurrence. The median PSA at follow-up among the relapse-free patients was 0.05 microg/l. Among the 80 patients who presented with clinical stage T3 tumours, 55 (68%) were relapse-free. The expected 5-year relapse-free survival using nomograms for RP and 3D EBRT was 54% and 70%, respectively. Late rectal toxicity RTOG grade 3 occurred in 1% of the patients. Late urinary tract toxicity RTOG grade 3 developed in 4% of the patients. Combined treatment, utilizing HDR, 3D EBRT and TAB, produces good clinical results. Rectal toxicity is acceptable. Urinary tract toxicity, most likely can be explained by the fact that during the first years of this treatment, no effort was made to localize the urethra, which was assumed to be in the middle of the prostate.

The 20-Yr outcome in patients with well- or moderately differentiated clinically localized prostate cancer diagnosed in the pre-PSA era: the prognostic value of tumour ploidy and comorbidity.

OBJECTIVE: This observational cohort study describes the long-term outcome of patients with clinically localized prostate cancer managed with watchful waiting, the prognostic value of tumour ploidy, and the impact of comorbidity. METHODS: A total of 119 patients with clinically localized (T1-2) prostate cancer consecutively diagnosed from 1978 to 1982 were prospectively managed by watchful waiting, with treatment given if progression occurred. RESULTS: Median age was 68 yr. Median observation time was 24 yr+/-6.25 (SD). Of the 112 patients who died, 42 died of prostate cancer. Disease-specific survival rates were 85% (95% CI: 77-93%), 58% (46-70%), and 32% (19-46%) at 10, 15, and 20 yr, respectively. Treatment-free survival rate was 43% (95% CI: 33-54%) at 10 yr. Patients aged 70 yr and over had a statistically significant increased risk of dying from any cause. There was a statistically significant increased risk of dying from prostate cancer for patients with nondiploid tumours. CONCLUSION: In the present series from the pre-PSA era, watchful waiting yielded a relatively high long-term disease-specific survival rate in patients with well- or moderately differentiated clinically localized prostate cancer, and almost half were not treated 10 yr after diagnosis. Watchful waiting may be an option at least for such patients with a 10- to 15-yr life expectancy. Age of 70 yr or more predicted an increased overall mortality. High comorbidity increased the risk (although not statistically significant) for death from any cause and for death from prostate cancer. Patients with nondiploid tumours were at an increased risk to die from prostate cancer.

Dosimetry of anal radiation in high-dose-rate brachytherapy for prostate cancer.

PURPOSE: The objective of this study is to determine the radiation dose to the anus during brachytherapy using high-dose-rate Ir-192 sources. METHODS AND MATERIALS: Thermoluminescence dosimeters were used for measuring the dose to the distal part of the anus in 10 patients, and in a prostate phantom to measure the radiation dose during the transport of the radiation source. RESULTS: The measured dose to the anus in vivo was on average 0.85 Gy (range, 0.48-1.37 Gy) per treatment. The transport dose using 15 and 19 needles in the prostate phantom was 0.07 and 0.08 Gy, respectively. CONCLUSIONS: The dose delivered to the anus using high-dose-rate brachytherapy with Ir-192 sources is quite low. There is a contribution to the anal radiation dose during the transport of the Ir-192 source into the needles. However, in clinical practice when using 15-20 needles, the dose from transporting the Ir-192 source can be ignored.

Prostate displacement kit: reducing the radiation dose to the rectum.

During high dose-rate brachytherapy boost in 20 patients the use of a prostate-water-rectal-displacement-kit contributed to an increase in the distance between the prostate and the rectum, however, the prostate was not totally immobilized by the needles, implying the necessity for an very careful on-line dose-planning dosimetry.

Prostate volume determination: differential volume measurements comparing CT and TRUS.

PURPOSE: To compare the differences in prostate volume assessed by computerized tomography (CT), step-section transrectal ultrasound (TRUS-step), and TRUS with ellipsoid-formula volume calculation (TRUS-ellipsoid). METHODS AND MATERIALS: Thirty-one patients with localized prostate cancer treated with combined external conformal radiotherapy and high dose rate brachytherapy, who had prostate volumes evaluated using CT, TRUS-step and TRUS-ellipsoid according to our clinical routine for dose planning. The measurements were collected retrospectively based on actual dose-plans. RESULTS: The prostate volume was on average 34 cc (range 18-60 cc) according to CT, 28 cc (range 12-57 cc) and 24 cc (range 13-44 cc) according to TRUS-step and TRUS-ellipsoid, respectively. The differences between the lengths measured were most pronounced with a mean length of 4.5 cm (range 3.0-6.0 cm) defined by CT as compared to 3.6 cm (range 3.0-5.0 cm) and 3.6 cm (range 2.8-5.0 cm) when defined by TRUS-step and TRUS-ellipsoid, respectively. CONCLUSION: CT defined volumes are 30% larger than volumes defined with TRUS-step. This is probably due to uncertainty in defining the apex of the prostate and thereby the length of the prostate using CT. When defining target in radiotherapy, it is important to be aware of the differences in volumes depending on the technique used.

Evidence-based medicine: its effect on treatment recommendations as illustrated by the changing role of postmastectomy irradiation to treat breast cancer.

PURPOSE: To illustrate the effect that the quality of evidence has on clinical practice, we examined how the role of radiotherapy in treating breast cancer has changed over the years as the quality of evidence evolved from anecdotal evidence based on expert opinion to randomized clinical trials and meta-analyses. METHODS: We searched the medical literature for key randomized studies and meta-analyses that have influenced the clinical use of postmastectomy irradiation since the first randomized trials in breast cancer in the 1950s. We discuss how clinical practice changed based on the outcomes of these trials, and then discuss the quality of those trials based on the criteria currently used to assess evidence from randomized trials (CONSORT) and meta-analysis (QUORUM). RESULTS: Evidence published from the early trials and meta-analyses on the role of postmastectomy irradiation had a strong effect on clinical practice. Examination of these studies, however, continues to show significant flaws in trial design that, by today's evidence-based standards, would not meet standards of quality. CONCLUSION: The quality of evidence has a strong effect on shaping clinical practice and needs to be continually assessed. Current guidelines developed to critique both individual randomized trials and meta-analyses are helping to establish high standards for trial design and interpretation. Evidence from older trials that were not guided by well-developed guidelines need to be reviewed, particularly when results from those trials are continually updated and used to generate evidence on which to base current clinical practice.