Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen ≥10 ng/ml

: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer.

: We report the biochemical freedom from disease (bNED) rates (BNED) failure in Prostate Specific Antigen (PSA) ≥ 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (<10, 10–19.9, and ≥20 ng/ml). Dose was stated to be at the center of prostate gland.

: There was significant improvement in bNED survuval for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10–19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA ≥ 20 ng/ml (p = 0.003 and 0.02, respectively).

: Increasing dose above 71 or 73 Gy did not result in improved bNED survuval for patient with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in the patients. A significant improvement in bNED survuval was noted for patients with pretreatment PSA ≥ 10 ng/ml treated above 71 of 73 Gy; further dose escalation studies are warranted.     

The impact of race on biochemical disease-free survival in early-stage prostate cancer patients treated with surgery or radiation therapy

Purpose: To assess the impact of race on biochemical freedom from recurrence in patients with early-stage prostate cancer treated either by radical prostatectomy or radiation therapy.

Methods: Between July 1989 and December 1994, 693 patients with early-stage prostate cancer were treated with radiation (302 patients) or by radical prostatectomy (391 patients) at Barbara Ann Karmanos Cancer Institute/Wayne State University. Stage, Gleason score, race, pretreatment PSA, and follow-up PSA values were abstracted. There were 387 Caucasian males (CM) and 306 African-American males (AAM). None of the patients received hormone therapy. Radiation therapy was delivered using photon irradiation (249 patients, median dose 69 Gy) or mixed neutron/photon irradiation (53 patients, median dose 10 NGy + 38 PGy). Median follow-up was 36 months (range 2–70) for CM and 35 months (range 1–70) for AAM.

Results: Thirty-seven percent of patients treated surgically were AAM, compared to 53% in the radiation group (p = 0.0001). AAM had a higher median prostate-specific antigen (PSA) than CM (9.78 ng/ml vs. 8.0 ng/ml, p = 0.01). Thirty-three percent of AAM had a pretreatment PSA greater than 15 ng/ml compared to 20% of CM (p = 0.00001). Disease-free survival (DFS) by race was equivalent at 36 months, 81% for CM and 77% for AAM (p = NS). For patients with PSA ≤ 15, DFS rates were 87% and 85% for CM and AAM, respectively. DFS rates for patients with PSA > 15 were 61% for CM and 64% for AAM (p = NS). Significant prognostic factors on multivariate analysis included pretreatment PSA (p = 0.0001) and Gleason score (p = 0.0001).

Conclusion: Race does not appear to adversely affect biochemical disease-free survival in males treated for early-stage prostate cancer. African-American males with early-stage prostate cancer should expect similar biochemical disease-free survival rates to those seen in Caucasian males.     

Rate of PSA rise predicts metastatic versus local recurrence after definitive radiotherapy

: A rising prostate specific antigen (PSA) following treatment for adenocarcinoma of the prostate indicates eventual clinical failure, but the rate of rise can be quite different from patient to patient, as can the pattern of clinical failure. We sought to determine whether the rate of PSA rise could differentiate future local versus metastatistic failure.

: Two thousand six hundred sixty-seven PSA values from 400 patients treated with radiotherapy for localized adenocarcinoma of the prostate were analyzed with respect to PSA patterns and clinical outcome. Patients had received no hormonal therapy or prostate surgey and had ?4 PSA values post-treatment PSA rate of rise, determined by the slope of the natural log, was classified as gradual (< 0.69 log (ng/ml)/year, or doubling time (DT) > 1 year), moderate (0.69-1.4 log (ng/ml)/year, or DT 6 months-1 year), or rapid [>1.4 log (ng/ml)/year, or DT < 6 months].

: SIxty-one percent of patients had non-rising PSA following treatment; 25% of patients with rising PSA developed clinical failure, and 93% of patients with clinical failure had rising PSA. The rate of rise discerned different clinical failure patterns. Local failure occurred in 23% of patients with moderate rate of rise versus 7% with gradual rise (p = 0.0001). Metastatic disease developed in 46% of those with rapid versus 8% with moderate rise (p < 0.0001). By multivariate analysis, in addition to rate of rise, PSA nadir and rate of decline predicted local failure; those with post-treatment nadir of 1–4 ng/ml were five times more likely to experience local failure than nadir < 1 ng/ml (p = 0.0002). Rapid rate of rise was the most significant independent predictor of metastastic failure.

: The rate of PSA rise following definitive radiotherapy can predict clinical failure patterns, with a rapidly rising PSA indicating metastatic recurrence and moderately rising PSA local recurrence. This information could potentially dirent therapy; if the rise predicts metastatic failure hormonal therapy could be cosidereed, while aggressive salvage therapy may benefit subclinical local recurrence identified by a moderate rate of PSA rise.     

Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial

A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer.

A total of 305 Stage T1–T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis.

There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA ≤10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy.

An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives ≥70 Gy to <25% should be used.     

Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate

To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival.

The study was conducted from 1987 to 1991. Eligible patients were those with bulky tumors (T2–T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II.

As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p = 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p = 0.04), disease-free survival (33% vs. 21%, p = 0.004), biochemical disease-free SURVIVAL = PSA <1.5 (24% vs. 10%, p < 0.0001), and cause-specific mortality (23% vs. 31%, p = 0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score 2–6. In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p = 0.015). In patients with Gleason 7–10 tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival.

In patients with Gleason score 2–6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival.     

Treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy for prostate cancer

Background The indications for and the efficacy of radiation therapy after radical operation for patients with prostate cancer are not clear. We analyzed the treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy. Methods Between September 1997 and November 2004, 57 patients received adjuvant radiotherapy or salvage radiotherapy after radical prostatectomy. Fifteen patients received radiation therapy because of positive margins and/or extracapsular invasion in surgical specimens (adjuvant group). Forty-two patients received radiation therapy because of rising prostate-specific antigen (PSA) during follow-up (salvage group). Radiation therapy was delivered to the fossa of the prostate ± seminal vesicles by a three-dimensional (3-D) conformal technique to a total dose of 60–66 Gy (median, 60 Gy). Biochemical control was defined as the maintenance of a PSA level of less than 0.2 ng/ml. Results The median follow-up period after radiation therapy was 33 months (range, 12–98 months). Three-year biochemical control rates were 87% for the adjuvant group and 61% for the salvage group. For patients in the salvage group treated without hormone therapy, the preradiation PSA value was the most significant factor for the biochemical control rate. The 3-year biochemical control rate was 93% in patients whose preradiation PSA was 0.5 ng/ml or less and 29% in patients whose preradiation PSA was more than 0.5 ng/ml. No severe adverse effects (equal to or more than grade 3) were seen in treated patients. Conclusion Radiation therapy after radical prostatectomy seemed to be effective for adjuvant therapy and for salvage therapy in patients with a preradiation PSA of 0.5 ng/ml or less. Also, radiation to the fossa of the prostate ± seminal vesicles, to a total dose of 60–66 Gy, using a three-dimensional (3-D) conformal technique, seemed to be safe.     

Five-year biochemical outcome after prostate brachytherapy for hormone-naive men ≤ 62 years of age

To evaluate 5-year biochemical disease-free outcome for hormone naïve men 62 years of age or less who underwent transperineal ultrasound-guided permanent prostate brachytherapy.

76 patients underwent transperineal ultrasound guided prostate brachytherapy using either ¹⁰³Pd or ¹²⁵I for clinical T1b–T2b N×M0 (1997 AJCC) adenocarcinoma of the prostate gland from April 1995 to October 1999. No patient was lost to follow-up, and no patient underwent pathologic lymph-node staging. 47 patients were implanted with either ¹⁰³Pd or ¹²⁵I monotherapy, and 29 patients received moderate-dose external-beam radiation therapy followed by a prostate brachytherapy boost. No patient received hormonal manipulation. The median patient age was 58 years (range, 48–62 years). The median follow-up was 37 months (range, 14–70 months). Follow-up was calculated from the day of implantation. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology (ASTRO) consensus definition.

The actuarial 5-year biochemical disease-free survival rate was 98.7%. For patients with low-, intermediate-, and high-risk disease, 97.7%, 100%, and 100%, respectively, were free of biochemical failure. The median posttreatment prostate-specific antigen (PSA) for the entire group was 0.2 ng/mL. When stratified by risk group, the median posttreatment PSA was 0.2, 0.15, and 0.1 for patients with low-, intermediate-, and high-risk disease, respectively.

With a median follow-up of 37 months, hormone naïve patients ≤ 62 years of age have a high probability of 5-year biochemical disease-free survival following permanent prostate brachytherapy with an apparent plateau on the PSA curve.     

Phase I-II study of intraoperative radiation therapy (IORT) after radical prostatectomy for prostate cancer

PURPOSE: Recent studies have suggested an alpha/beta ratio in prostate cancer of 1.5-3 Gy, which is lower than that assumed for late-responsive normal tissues. Therefore the administration of a single, intraoperative dose of irradiation should represent a convenient irradiation modality in prostate cancer. MATERIALS AND METHODS: Between February 2002 and June 2004, 34 patients with localized prostate cancer with only one risk factor (Gleason score > or =7, Clinical Stage [cT] > or =2c, or prostate-specific antigen [PSA] of 11-20 ng/mL) and without clinical evidence of lymph node metastases were treated with radical prostatectomy (RP) and intraoperative radiotherapy on the tumor bed. A dose-finding procedure based on the Fibonacci method was employed. Dose levels of 16, 18, and 20 Gy were selected, which are biologically equivalent to total doses of about 60-80 Gy administered with conventional fractionation, using an alpha/beta ratio value of 3. RESULTS: At a median follow-up of 41 months, 24 (71%) patients were alive with an undetectable PSA value. No patients died from disease, whereas 2 patients died from other malignancies. Locoregional failures were detected in 3 (9%) patients, 2 in the prostate bed and 1 in the common iliac node chain outside the radiation field. A PSA rise without local or distant disease was observed in 7 (21%) cases. The overall 3-year biochemical progression-free survival rate was 77.3%. CONCLUSIONS: Our dose-finding study demonstrated the feasibility of intraoperative radiotherapy in prostate cancer also at the highest administered dose.     

High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients

To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT).

Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6–60 months).

Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of ≥ late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of ≥ late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively.

These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.     

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

: To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer.

: We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74–78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24–102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity.

: At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p <0.0001 for all comparisons), the absolute rectal volume appeared to be a factor only at the higher doses of 70, 75.6, and 78 Gy (p = 0.0514, 0.0016, and 0.0021, respectively). The following variables also correlated with toxicity on the univariate analysis: maximal dose to the clinical target volume, maximal dose to rectum, maximal dose to the rectum as a percentage of the prescribed dose, and maximal dose delivered to 10 cm³ of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p = 0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p <0.05 for all comparisons).

: Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup.     

98例老年前列腺癌根治术后调强技术放疗结果分析

目的 回顾分析老年前列腺癌患者根治术后接受调强技术放疗疗效和不良反应。 方法 2007-2017年收治 98例接受术后放疗的前列腺癌患者,中位年龄 68岁。全组患者中低危 10例、中危 21例、高危 67例。2例患者存在寡转移(均为骨盆骨转移),64例患者联合了内分泌治疗。全组患者中 43例接受辅助放疗,55例接受挽救放疗。放疗均采用了调强技术(55例调强放疗、43例容积调强弧形治疗),前列腺瘤床中位剂量72 Gy。共 29例接受了盆腔淋巴结区域照射,中位放疗剂量50 Gy。 结果 中位随访40个月,全组 5年总生存率、无生化复发生存率、局部控制率分别为90%、76%、100%。辅助放疗和挽救放疗的总生存率、无生化复发生存率、局部控制率均相近[89%和91%(P=0.94)、76%和71%(P=0.79)、100%和100%(P=0.32)]。不良反应方面 1-2级晚期直肠反应发生率为24.1%,1-2级晚期膀胱反应发生率为29.9%,3级为3.4%。 结论 前列腺癌根治术后采用调强技术放疗可以获得很好的疗效,晚期不良反应轻微。     

Temporary PSA rises and repeat prostate biopsies after brachytherapy

The long-standing confusion regarding the clinical relevance of postimplant biopsies is complicated by the common occurrence of temporary PSA rises between 1 and 2 years after brachytherapy. We report here 4 patients with temporary, self-limited PSA rises and postimplant biopsies, for whom radical prostatectomy was strongly advised but for whom surgery would probably have been the wrong choice.

Transperineal I-125 or Pd-103 implants were performed as previously described. After implantation, patients were followed routinely, with repeat PSA and physical examination at approximately every 4 to 6 months. Timing of postimplant PSAs was at the discretion of the patient and his doctors. Postimplant biopsies were performed in all cases out of concern for a persistently elevated serum PSA. Sections of fixed and embedded tissue were stained with standard hematoxylin and eosin.

All 4 patients presented here were advised to have a salvage prostatectomy based primarily on their PSA changes. However, all of the patients have subsequently had a dramatic PSA fall, consistent with long-term cancer control, despite the fact that 3 of the 4 had histologic evidence of persistent cancer on repeat prostate biopsy.

It is crucial that clinicians be aware of the potential for the doubly confusing situation of temporary PSA rises and apparently positive rebiopsies and the pressure it puts on both patients and their physicians to go ahead with inappropriate salvage therapy.     

Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer

Purpose: To report the 5-year prostate-specific antigen (PSA) relapse-free survival outcome and incidence of long-term morbidity for patients with localized prostate cancer treated with CT-planned permanent I-125 prostate implantation using a transperineal technique (TPI).

Methods and Materials: Between 1989–1996, 248 patients with clinically localized prostate cancer were treated with TPI. The median age was 65 years (range: 45–80 years). The clinical stage was T1c in 143 patients (58%), Stage T2a in 102 (41%), and T2b in 3 (1%). Thirty patients (12%) had Gleason scores <6, 158 patients (64%) had Gleason scores of 6, and 60 (24%) had scores ≥7. The median pretreatment PSA was 7 ng/mL (range: 1–58 ng/mL). The median prescribed implant dose was 150 Gy. Patients were characterized as having favorable risk disease if their pretreatment PSA level was ≤10.0 ng/mL and Gleason score ≤6; those with one and two adverse prognostic features (PSA > 10 ng/mL and Gleason score >6) were classified as having intermediate and unfavorable risk disease, respectively. PSA relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was scored according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up was 48 months (range: 12–126 months).

Results: Thirty-eight patients (15%) developed a PSA relapse, and the overall 5-year PSA relapse-free survival (PRFS) rate was 71%. The 5-year PRFS rates for favorable-risk (n = 146), intermediate-risk (n = 85), and unfavorable-risk (n = 17) patients were 88%, 77%, and 38%, respectively (p < 0.0001). The 5-year PRFS rates among patients treated with a 2-month course of neoadjuvant androgen deprivation (NAAD) prior to TPI compared to patients treated with TPI only were 100% and 77%, respectively (p = 0.03). Multivariate analysis identified pretreatment PSA > 10 ng/mL and Gleason score >6 as independent predictors for biochemical relapse after TPI. The 5-year actuarial likelihood of late Grade 2 urinary toxicity was 41%. The 5-year likelihood of urethral stricture development was 10%, and the median time to stricture development was 18 months. One patient (0.4%) in the early phase of this clinical experience developed a Grade 4 urethral complication. The actuarial incidence of late Grade 2 rectal bleeding was 9%. One patient (0.4%) developed a Grade 4 rectal complication.

Conclusions: Especially for favorable risk disease, the 5-year biochemical outcome with this approach was excellent and appears to be comparable to other therapeutic interventions. Grade 2 urinary symptoms were common in these patients but gradually resolved in most. Improved treatment planning approaches that further constrain the urethral dose without compromising the target volume dose will likely decrease the incidence of Grade 2 and 3 urinary symptoms after TPI.     

Effect of a short course of neoadjuvant hormonal therapy on the response to subsequent androgen suppression in prostate cancer patients with relapse after radiotherapy: a secondary analysis of the randomized protocol RTOG 86-10

: To compare, by a secondary analysis, the therapeutic benefits of androgen suppression in protocol prostate cancer patients with relapse after radiotherapy (RT) for locally advanced disease who, in the Phase III trial beginning in 1987, were assigned to receive or not receive a short course of neoadjuvant maximal androgen suppression before definitive RT.

: Between 1987 and 1991, 456 patients were entered in the Radiation Therapy Oncology Group trail 86-10 and randomized to receive (Arm I) or not to receive (Arm II) neoadjuvant hormonal therapy (HT), which was 4 months of goserelin (3.6 mg every 4 weeks) and flutamide (250 mg t.i.d.) before and during RT for bulky T2-T4 tumors. The overall and disease-specific survival after both randomization and salvage HT for patients with relapse was evaluated, as well as the duration of response in those patients undergoing salvage HT. The outcomes in patients who had received neoadjuvant HT vs. those who had not were compared. The median follow-up after randomization for all alive patients was 9.0 years and was 5.5 years for alive patients after beginning salvage HT.

: Fewer patients received salvage HT on Arm I than on Arm II (45% vs. 63%, p <0.001). The outcomes by randomized treatment arm (I vs. II) from the time of beginning salvage HT were similar. At 5 years after salvage HT, the overall survival rates were 41% and 41% and the disease-specific survival rates were 50% and 50%. At 8 years after randomization, the overall survival rates were 47% and 44% and the disease-specific survival rates were 55% and 56%.

: Although a 4-month course of neoadjuvant and concurrent maximum androgen suppression and RT (compared with RT alone) significantly increases the freedom from relapse rate and freedom from receiving salvage HT, it does not compromise the long-term beneficial effect of subsequent salvage HT, if needed for relapse. These findings with long follow-up in patients treated for locally advanced disease diagnosed 9–14 years previously should help allay concerns of the possible development of “resistance” to androgen suppression when 4-month courses of neoadjuvant HT are used before primary treatment.     

Salvage Radiotherapy After Postprostatectomy Biochemical Failure: Does Pretreatment Radioimmunoscintigraphy Help Select Patients with Locally Confined Disease?

PURPOSE: Radioimmunoscintigraphy (RIS) has the potential to demonstrate early recurrences after prostatectomy and might be useful in selecting patients for salvage radiotherapy (RT). METHODS: A total of 82 patients with adenocarcinoma of the prostate were treated with salvage RT between 1988 and 2005, for an elevated prostate-specific antigen (PSA) level after prostatectomy. Of the 82 patients, 32% had Gleason score 6 or less disease, 54% Gleason score 7 disease, 70% had Stage pT3 disease, 55% had positive margins, and 5% had pathologic lymph node involvement. The median pre-RT PSA level was 0.63 ng/mL. Of the 82 patients, 47 (57%) had a pre-RT RIS (ProstaScint) scan, which was used for both patient selection and target delineation. The RT regimen was a median dose of 66 Gy to the prostate bed. Also, 64% received androgen deprivation therapy. Biochemical failure was defined as a PSA level >0.1 ng/mL and increasing. RESULTS: Patients with a pre-RT RIS scan had a lower preoperative PSA level (p = 0.0240) and shorter follow-up (p = 0.0221) than those without RIS. With a median follow-up of 44 months, the biochemical control rate was 56% at 3 years and 48% at 5 years. Margin status was the only factor associated with biochemical control on univariate (p = 0.0055) and multivariate (p = 0.0044) analysis. Patients who had prostate bed-only uptake on RIS (n = 38) did not have improved outcomes, with biochemical control rates of 51% at 3 years and 40% at 5 years. CONCLUSION: Patients treated with salvage RT had modest responses. Patients who were selected for treatment with RIS did not have better biochemical outcomes. Our results indicated that patients with positive margins were most likely to benefit from salvage RT.     

Acute radiation thyroiditis

: Radiation-induced thyroid dysfunction is considered a late effect. We prospectively assessed acute reactions of thyroid to external neck irradiation.

This study included 22 patients in whom the thyroid was incidentally exposed to therapeutic does of radiation. Thyroid function tests included measurements of serum thyroid stimulating hormone (TSH), free and total triiodothyronine (T3) and thyroxine (T4), thyroglobulin, and antithyroid antibodies. These tests were performed before radiotherapy, and 3 and 6 months after the beginning of radiotherapy.

: Mean serum levels of TSH were 1.53, 0.55, 0.78, 2.14, and 7.57 μU/ml before radiotherapy, after 40 Gy irradiation, 2 weeks after the end of radiotherapy, and 3 and 6 months after radiotherapy, respectively. Thus, levels of TSH exhibited two phases: a significant decrease during radiotherapy (thyroxic phase) and an increase after radiotherapy (hypothyroid phase) (baseline vs. 40 Gy: p < 0.0001, baseline vs. 6 months: p = 0.003). Increases of thyroid hormones were subtle during radiotherapy.

: We believe that radiation promotes release of excessive amounts of thyroid hormones during radiotherapy owing to suppression of TSH secretion. In addition to the late damage (hypothyroidism), thyrotoxicosis occurs when the thyroid gland receives a therapeutic doses of external radiation.     

Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy gleason score, and clinical T-stage

Purpose: Ideal candidates for 3D dose escalation conformal radiation or external beam + implant therapy are identified on the basis of the prostate-specific antigen (PSA) level, biopsy Gleason score, and the 1992 American Joint Commission Cancer (AJCC) clinical T-stage.

Methods and Materials: The pathologic findings of 1742 men with clinical stage T1c,2 prostate cancer managed with a radical prostatectomy (RP) between 1990 and 1998 were subjected to a logistic regression multivariable analysis. The endpoints examined included pathologic organ–confined (OC), specimen-confined (SC), and margin (M) or seminal vesicle (SV) positive disease. SC disease was defined as extracapsular extension (ECE) with a negative surgical margin. The clinical factors tested included PSA level, biopsy Gleason score, and the 1992 AJCC clinical T-stage. PSA failure–free (bNED) survival was calculated according to the method of Kaplan and Meier.

Results: Significant negative predictors of pathologic OC–disease or positive predictors of M⁺ or SV⁺ disease included a PSA > 10 ng/ml (p < 0.0001), biopsy Gleason score ≥7 (p ≤ 0.0004), and ≥ T2b disease (p ≤ 0.03). Only biopsy Gleason score 7 (p = 0.0006) and PSA 10–15 ng/ml (p = 0.04) were significant predictors of SC disease. The estimates of 5-year bNED survival were 80%, 62%, and 35% (p < 0.0001) for patients having a low, intermediate, or high likelihood of having M⁺ or SV⁺ disease respectively.

Conclusions: Patients most likely to derive a survival benefit from the improved local control possible using dose escalation techniques were those who had both a low risk of having occult micrometastatic disease (<25% M⁺ or SV⁺) and a reasonable likelihood of remaining disease-free after RP (>50% 5-year bNED). These patients included those having T1c, 2a, PSA > 10–15 ng/ml, and biopsy Gleason ≤6 or T1c, 2a, 2b, PSA ≤ 10 ng/ml, and biopsy Gleason ≤ 7 prostate cancer.     

Postoperative radiotherapy for carcinoma of the prostate: impact on both local control and distant disease-free survival

The role of postoperative irradiation in patients with clinically localized prostate cancer, either as an adjuvant or salvage radiotherapy, remains controversial. In this study, we evaluate the impact of postoperative radiotherapy on patients diagnosed with prostate cancer with respect to biochemical and clinical disease free survival. Between 1987 and 1996, 179 patients with clinically localized prostate cancer were found to have adverse histopathologic findings on radical prostatectomy specimens (positive surgical margins, extracapsular extension, and seminal vesicle invasion). Of these patients, 42 were referred for postoperative adjuvant radiotherapy, whereas 73 were referred for salvage irradiation because of rising serum prostate-specific antigen (PSA) levels postoperatively. The remaining 64 patients underwent prostatectomy only. The 10-year biochemical relapse-free survival (RFS) from date of surgery were 88%, 45%, and 25% for patients treated with postoperative adjuvant radiotherapy, salvage irradiation, and with surgery alone, respectively (p = 0.046). Ten-year distant RFS from date of surgery were 82%, 74%, and 44% for adjuvantly treated patients, those with salvage radiotherapy, and those with surgery alone, respectively (p = 0.0180). Ten-year overall disease RFS from date of surgery was 89%, 76%, and 30% for adjuvantly treated patients, those with salvage radiotherapy, and those with surgery alone, respectively (p = 0.0237). Multivariate analyses revealed that a preoperative PSA greater than 20 ng/ml and pathologic Gleason Score of 8 to 10 were adverse predictors for biochemical relapse, whereas pathologic Gleason Score of 8 to 10, seminal vesicle invasion, and extracapsular extension were adverse predictors of distant metastases. Postoperative radiotherapy, either delivered as adjuvant treatment for adverse histopathologic findings or as salvage therapy for local relapses, appear to confer superior local, distant disease RFS, and overall disease RFS than surgery alone.     

Medication for hearing loss after fractionated stereotactic radiotherapy (SRT) for vestibular schwannoma

To investigate the effectiveness of corticosteroid treatments for patients showing decreases in hearing levels after stereotactic radiotherapy for vestibular schwannoma.

Twenty-one patients experienced a hearing loss in pure-tone average at greater than 20 dB or less than 10 dB within 1 year after irradiation administration of 44 Gy/22 fractions followed by a 4 Gy boost. Eight received oral prednisone at a daily dose of 30 mg, which was gradually decreased (medicated group), and 13 received none (nonmedicated group). The average observation period was 26.7 ± 16.6 (range: 6–69) months.

Hearing recovery was seen after initial onset of the hearing loss in all 8 patients in the medicated group and in 2 of 13 patients in the nonmedicated group (p = 0.001). The hearing recovery, that is, the change in pure-tone average (dB) at the last follow-up from the onset of hearing loss, was 9.8 ± 6.9 dB (recovery) in the medicated group and −9.4 ± 12.8 dB (further loss) in the nonmedicated group (p = 0.0013). The hearing recovery rate, normalizing to the degree of the hearing loss before medication, was also significantly higher in the medicated group than in the nonmedicated group (p = 0.0014).

Corticosteroidal intake is suggested to be effective in improving hearing loss after stereotactic radiotherapy, at least in young patients having a useful pretreatment hearing level, if the treatment for hearing loss is administered immediately after the hearing loss is first detected.     

Salvage radiotherapy in rising PSA after radical prostatectomy]

Salvage radiotherapy after radical prostatectomy can be delivered either in case of biochemical recurrence or in situation of clinical relapse. In this last case, results are poor regarding disease-free survival but quite interesting regarding the local control rate. The best situation for salvage radiotherapy is still the rising PSA case: half of the patients can be in complete remission at 5 years after 65 Gy radiotherapy. The role of hormone therapy combined with salvage radiotherapy is still under investigation.