Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS: We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS: Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380). CONCLUSION: The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Select men benefit from androgen deprivation therapy delivered with salvage radiation therapy after prostatectomy.

BACKGROUND: Which men benefit most from adding androgen deprivation therapy (ADT) to salvage radiation therapy (SRT) after prostatectomy has not clearly been defined; therefore, we evaluated the impact of ADT to SRT on failure-free survival (FFS) in men with a rising or persistent PSA after prostatectomy. METHODS: We identified 332 men who received SRT after prostatectomy from 1987 to 2010. Recursive partitioning analysis (RPA) identified favorable, intermediate and unfavorable groups based on the risk of failure after SRT alone. Kaplan-Meier and log-rank tests compared FFS with and without ADT. RESULTS: Forty-three percent received SRT alone and 57% received SRT with ADT (median 6.6 months (interquartile range (IQR) 5.8-18.1) ADT). Median SRT dose was 70 Gy (IQR 70-70), and median follow-up after SRT was 6.7 years (IQR 4.5-10.8). On Cox's proportional hazard regression, ADT improved FFS (adjusted hazard ratio 0.60, 95% confidence interval: 0.42-0.86; P=0.006). RPA classified unfavorable disease as negative surgical margins (SMs) and preradiation PSA of ⩾0.5 ng ml-1. Favorable disease had neither adverse factor, and intermediate disease had one adverse factor. The addition of ADT to SRT improved 5-year FFS for men with unfavorable disease (70.3% vs 23.4%; P<0.001) and intermediate disease (69.8% vs 48.0%; P=0.003), but not for men with favorable disease (81.2% vs 78.0%; P=0.971). CONCLUSIONS: The addition of ADT to SRT appears to improve FFS for men with a preradiation PSA of ⩾0.5 ng ml-1 or with negative SM at prostatectomy. Men with involved surgical margins and PSA <0.5 ng ml-1 appear to be at a lower risk of failure after SRT alone and may not derive as much benefit from the administration of ADT with SRT. These results are hypothesis-generating only, and further prospective data are required to see if ADT can safely be omitted in this select group of men.

PSA for outcome prediction and posttreatment evaluation following radiation for prostate cancer: do we know how to use it?

Pretreatment prostate-specific antigen (PSA) has been shown to be a powerful predictor of expected outcome after radiation for prostate cancer. Additional measures such as recursive partitioning analysis and PSA Cancer Volume calculations are further refining this useful tool to provide the greatest degree of prognostic information. The post-treatment PSA level is also being used as a means to assess therapeutic efficacy rapidly and objectively. Although no single PSA value has been shown to equate to long-term clinical tumor control consistently, consensus has been reached regarding the value of a rising PSA level as an early surrogate for tumor recurrence. Since the first introduction of PSA as a tumor marker, we have become much more comfortable with what it means, the ways it can help us, and how to use it.

The effect of TURP on prognosis in prostatic carcinoma.

Of 553 patients definitively irradiated for biopsy proven prostatic adenocarcinoma from January 1976 to March 1986, 287 patients with a minimum follow-up of 4 years were studied. One hundred sixty-two patients had transurethral prostatic resection (TURP); one hundred twenty-five patients did not. When subdivided by stage and histologic grade, those patients with poorly differentiated tumors who underwent TURP had a noticeably higher, but not statistically different, incidence of bony metastasis as compared to those who did not have TURP. Survival at 5 years also appeared to be better in patients with poorly differentiated and stage C disease without TURP. However, local tumor recurrence in poorly differentiated tumor with TURP was 42% as compared to 20% in the NO TURP group, p = .04. Moreover, when the incidence of osseous metastasis was assessed by local tumor status, 20% of the TURP patients with local tumor control developed metastases as compared to 66% of those with local failure. Similarly, within the NO TURP group, the incidence of bony metastasis was 16% for those with local control and 50% for those with local recurrence, p = .005 in both cases. Survival was likewise affected by local tumor control, regardless of whether or not TURP was performed. In patients with local tumor control, survival was 80% at 5 years with TURP and 86% without TURP (p greater than 0.1). In contrast, only 14% of patients with local recurrence and TURP were alive at 5 years which was not statistically different from the 32% survival in those with local recurrence but NO TURP. It seems, therefore, that comparing prognosis by TURP alone overlooks the inherent characteristics of the tumor and the extent of the disease.

The significance of post-irradiation prostate biopsy with long-term follow-up.

Ninety-four patients, Stage A2-C, definitively irradiated for adenocarcinoma of the prostate from 1975 to 1981 underwent digitally directed transperineal needle biopsy of a clinically negative prostate gland at least 18 months post-therapy. Ten of 55 patients (18%) treated with Iodine-125 implantation and 7 of 39 patients (18%) externally irradiated were found to have positive biopsy specimens. Overall, clinical local failure occurred in 53% of patients with positive biopsy results but in only 18% with negative specimens, p = .006. The false negative biopsy rate in patients treated with I-125 was nearly three times that for external beam, 24% versus 9%, perhaps because of the greater possibility of inhomogeneous dose distribution with I-125, allowing for a higher degree of sampling error. Actuarial local failure at 5 years was 44% versus 8% with positive and negative biopsies, respectively, and 75% versus 24% at 10 years (p = .0001). The distant metastatic rate was twice as high in biopsy-positive as compared to biopsy-negative patients, 71% versus 35%, p = .015. Actuarially, only 19% of patients with a positive biopsy are NED at 10 years as compared to 62% of those with a negative biopsy (p = .0001). PSA values are supportive in those patients thought to be disease-free. The incidence of positive biopsy and associated local recurrence are in keeping with clinical treatment failure rates as reported in multiple studies to date.

Prostate-specific antigen for pretreatment prediction and posttreatment evaluation of outcome after definitive irradiation for prostate cancer.

PURPOSE: This study was undertaken to assess the predictive value of pretreatment prostate-specific antigen (PSA) and the difference between clinical and PSA disease-free status in patients with long-term follow-up after irradiation for prostatic carcinoma. Comparison of the distribution of prognostic factors between surgical and radiation series was also made. METHODS AND MATERIALS: From 1975-1989, 652 patients with clinical Stage A2-C prostatic adenocarcinoma were definitively irradiated using external beam therapy. One hundred and fifty patients with banked serum and up to 14 years follow-up have pretreatment PSA levels and 355 patients with up to 17 years follow-up have posttreatment values. Treatment failure was analyzed by tumor stage, grade, and four pretreatment PSA categories. Disease-progression was evaluated by clinical and biochemical (PSA) endpoints. Prognostic factors were compared to two surgical series. RESULTS: A significant difference was seen in clinical and PSA disease-free (PSA < or = 4.0 ng/ml) status based on tumor grade, stage, and pretreatment PSA category. Although the expected clinical outcome has been well-documented previously, results based on posttreatment PSA levels show 5-year disease-free survivals reduced by 10-16% and 10-year survivals lessened by 15-39% depending upon the particular tumor grade and stage. The earlier stage, lower grade tumors showed the largest difference between clinical and biochemical recurrence rates at the longest interval from treatment. Even more notable were the differences in the clinical and PSA disease-free rates based on the pretreatment PSA level. Comparing the irradiated patients to two surgical series showed that the former had a larger percentage of more advanced stage tumors with more unfavorable PSA levels as compared to prostatectomy patients. CONCLUSION: With long-term follow-up, the pretreatment PSA level continues to be a powerful predictor of clinical and biochemical outcome in patients irradiated for apparently localized prostate cancer. Differences between clinical and PSA outcome can be considerable, but oftentimes clinically insignificant. The distribution of prognostic factors between radiation and prostatectomy series seems to favor the latter.

Nuclear roundness factor and local failure from definitive radiation therapy for prostatic carcinoma.

Of 375 patients with prostatic carcinoma treated definitively with radiation therapy at this institution with at least a 5 year follow-up, 23 patients failed locally only, 72 failed with distant metastasis only, 60 had both local and distant failure, while 220 showed no evidence of disease. In search for a possible marker for local failure following radiation therapy, we examined several nuclear morphometric parameters which have been shown to correlate with the biologic aggressiveness of this disease. The 23 locally failed only patients were matched with 23 no evidence of disease patients for stage, grade, treatment modality, prior surgery, age at diagnosis and race. Archival hematoxylin and eosin slides were obtained for 22 of the 23 matched pairs, and morphometric features, including nuclear roundness factor and nuclear area, as well as numbers of nucleoli were assessed using computer-assisted image analysis in both tumor cells and normal prostatic epithelium. Tumor nuclei from the locally failed only patients had significantly higher nuclear roundness factor values (p = 0.0089) compared with tumor cells from no evidence of disease patients. Analysis of these data by clinical stage demonstrated no significant differences between the locally failed only and no evidence of disease patients. Likewise, there were no significant differences in nuclear roundness factor values of locally failed only and no evidence of disease patients with poorly or moderately well-differentiated tumors. However, there was a highly significant difference (p = 0.0012) in the nuclear roundness factor values of locally failed only and no evidence of disease patients with well-differentiated tumors. Thus, there appears to be a subset of patients with well-differentiated adenocarcinoma of the prostate who have significantly more irregular tumor nuclei and who fail locally only following definitive radiation therapy.

Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer.

PURPOSE: The optimal role of radiotherapy (RT) to the prostate bed after radical prostatectomy (RP) is the subject of much debate. In this study, the results of adjuvant RT (ART) and salvage RT (SRT) were compared. METHODS AND MATERIALS: A total of 146 lymph node-negative patients were treated postoperatively after RP with RT to the prostate bed between 1987 and 1998. Of these, 75 patients had an undetectable prostate-specific antigen (PSA) level and were treated with ART for adverse pathologic features only to a median dose of 60 Gy (range 51-70). A positive margin was identified in 96%, and two of the three with negative margins had seminal vesicle involvement (SVI). SRT was administered for either a persistently detectable PSA level after RP (n = 27) or for a delayed rise in PSA (n = 44) to a median dose of 70 Gy (range 60-78). Adjuvant androgen ablation was given to 37 patients; 2 who had received ART and 35 had who received SRT. The median duration of androgen ablation was 24 months. The primary end point was freedom from biochemical failure (bNED), which was considered to be an undetectable PSA level. The median follow-up was 53 months for all patients: 68 months for the ART patients and 35 months for the SRT patients. RESULTS: For the ART group, 8 patients subsequently developed a rising PSA level. The 5-year bNED rate was 88%. SVI was the strongest predictor of outcome, with a 5-year bNED rate of 94% for those without SVI and 65% for those with SVI (p = 0.0002). SVI was the only significant factor in Cox proportional hazards regression analysis in the ART cohort. For the SRT group, 20 patients developed a rising PSA level after RT. The 5-year bNED rate was 66% for all SRT patients, and 43% and 78% in those with a persistently detectable PSA and those with a delayed rise in PSA, respectively. In the Cox proportional hazards regression analysis, this subdivision of SRT was statistically significant. Moreover, when the Cox model included all patients and variables, the timing of RT (ART vs. SRT) was an independent correlate of bNED, as was androgen ablation. CONCLUSION: For RP patients with high-risk pathologic features, the timing of postoperative RT and the PSA status after RP were strong determinants of outcome. Because of the potential confounding factors, direct comparisons of ART and SRT are problematic; however, ART is extremely effective and offers the surest approach for maintaining biochemical control.

Overexpression of p53 in prostate carcinoma is associated with improved overall survival but not predictive of response to radiotherapy.

p53 gene mutations are among the most common specific genetic alterations in human cancer. Inactivation of p53 and subsequent protein accumulation has been implicated in a variety of human malignancies and associated with prostate cancer progression. In this study, we assessed p53 protein overexpression and gene mutations in prostate carcinoma and investigated associations between p53 alterations and clinicopathological parameters, survival, and response to radiotherapy. We evaluated 58 archival formalin-fixed, paraffin-embedded prostate carcinomas to detect abnormal p53 nuclear protein accumulation using immunohistochemistry. p53 mutational status of tumor DNA was evaluated using polymerase chain reaction-single-strand conformation polymorphism analysis of exons 5-9 and confirmed by direct DNA sequencing. Univariate and multivariate statistical analysis was used to determine the association of p53 status with clinical characteristics and response to radiotherapy. Overexpression of p53 was detected in 42 (72%) of 58 primary prostate carcinomas, but was undetectable in 7 samples of benign prostatic hyperplasias or 5 samples of normal prostate tissue. p53 exon 5-9 mutations were detected in 8 (14%) of 58 patient specimens. p53 mutational status, but not overexpression, was associated with higher Gleason scores (p=0.0145). Neither p53 overexpression nor mutation was associated with clinical stage, biochemical disease-free probability, or predictive of response to radiotherapy. p53 protein accumulation was inversely associated with improved overall survival (p=0.0108). Our studies demonstrate that p53 protein accumulation is a frequent alteration in prostate cancer. The disparity between p53 protein overexpression and p53 exon 5-9 mutations suggests the possibility of mutations outside this region or stabilization of wild-type p53 by alternative mechanisms. In our patient population, p53 protein overexpression or mutational status was not predictive of outcome in patients treated with radiation therapy. Additional studies are needed to further evaluate the association between p53 protein overexpression and improved overall survival.

Effect of local tumor control on distant metastasis and survival in prostatic adenocarcinoma.

Of 495 patients definitively irradiated for prostatic carcinoma, 286 with a minimum follow-up of thirty-six months were studied. While tumor histology appeared to predict prognosis, the poorly differentiated tumors showing the highest incidence of distant metastasis and the lowest survival, local tumor control was an important factor within the poorly differentiated group. Of those with local recurrence, distant metastases developed in 68 per cent compared with 37 per cent of those with no local disease (p = 0.025). Survival was similarly affected with 86 per cent of those with locally controlled tumor who were alive at five years (not significantly different from the more well-differentiated tumors) versus a 56 per cent actuarial survival in those with locally recurrent disease (p less than 0.05).

Mortality in prostatic carcinoma.

One hundred forty-seven patients definitively irradiated for biopsy-proved adenocarcinoma of the prostate from December, 1975, to March, 1979, have either died after a median survival of forty-five months or have been followed up for a minimum of seven years. Seventy-six patients (52%) are currently alive, 62 of them with no evidence of disease. Seventy-one patients (48%) have died, 28 without disease. In addition, 12 patients died with prostatic carcinoma but of other causes. In assessing the characteristics of those patients who remain disease-free following treatment, a significant difference in disease control was seen based on tumor stage, histologic differentiation, pelvic lymph node status, and whether or not tumor was present microscopically at rebiopsy. Of those deceased patients with recurrent prostate cancer, more than one-half had distant metastasis only. In all, 61 percent of patients had no further evidence of prostatic carcinoma after definitive irradiation, 20 percent had distant metastasis alone, and only 18 percent had locally recurrent disease along with distant disease spread.

Characteristics of spinal cord compression in adenocarcinoma of prostate.

Of 611 patients with biopsy-proved adenocarcinoma of the prostate, spinal cord compression developed in 41 (6.7%) at a median interval of twenty-four months after primary diagnosis. Spinal cord involvement most often occurred in the thoracic area, with 95 per cent of patients showing radiographic evidence of osseous vertebral metastasis at the level of cord compression. All lesions but one were located extradurally, and patients with Stage D2 disease, by virtue of bony metastases, were therefore at greatest risk for development of neurologically compressive disease. There was also a significant increase in the incidence of spinal cord involvement among the more poorly differentiated tumors, although tumor histology did not appear to influence the median interval between vertebral metastasis and cord compromise. Survival following spinal cord involvement was relatively poor and unrelated to tumor differentiation. Forty-six per cent of patients survived less than six months and 20 per cent less than two months. The two most noteworthy survivors are alive at thirty and ninety-seven months, the latter after combined treatment for an intradural lesion.

Brain metastases from transitional cell carcinoma of urinary bladder.

Of 293 patients with transitional cell carcinoma of the bladder seen at our institution between April 1977 and December 1987, 9 patients were found to have brain metastasis. Seven of 9 patients were found to have a solitary brain lesion, and in 4 of these, no other site of metastatic disease was identified. Five patients received palliative whole brain irradiation, 3,000 cGy in 10 fractions, due to the presence of multiple lesions of the central nervous system (CNS) or metastases to other sites. The average survival for this group was seven weeks. One patient with a solitary brain metastasis and no other documented metastatic site was hospitalized at another institution, and was managed expectantly receiving only parenteral steroid therapy and survived four weeks. Three patients with solitary lesions and no evidence of other metastatic sites were treated with a combined surgical and radiotherapeutic approach receiving 4,000-5,000 cGy to the lesion site postoperatively. The average survival of that group was twenty-nine months, with one five-year survivor and 1 patient with no evidence of disease fourteen months after treatment. It appears that survival is longer in those patients with solitary lesions, perhaps due, at least in part, to a more aggressive therapeutic approach.

Hemibody irradiation in advanced prostatic carcinoma.

In summary, hemibody irradiation has developed as a safe, efficient technique for palliating multiple sites of symptomatic osseous metastases, which occur so often in advanced prostatic carcinoma. The rapidity, frequency, and duration of pain relief, as well as the convenience to the patient of a solitary treatment to multiple symptomatic areas simultaneously, make this type of treatment especially appealing. By following premedication and radiation dose guidelines, both acute and delayed side effects can be kept tolerable or at a minimal incidence. Although sequential hemibody radiation has also been explored as "systemic" therapy, the results in prostatic carcinoma have not proved dramatic, and complications have been considerable. Hormonal therapy would certainly seem to be less life-threatening and equally beneficial according to present data. As a palliative treatment, however, hemibody irradiation is a pragmatic option for relieving prostatic cancer pain.

Local failure after definitive radiation or surgical therapy for carcinoma of the prostate and options for prevention and therapy.

The incidence of local failure and its relation to distant failure following definitive therapy of carcinoma of the prostate is discussed. Local failure may arise from incomplete resection, tumor spillage, clones of radioresistant cells, development of new tumors in an organ left in situ, or inadequate treatment portals. The authors review the various measures used as prophylaxis or treatment of local failure in relation to clinical and pathologic stage.

Prostate-specific antigen after radiation therapy. Prognosis by pretreatment level and post-treatment nadir.

After external beam radiation therapy, pretreatment prostate-specific antigen (PSA) is the most powerful predictor of outcome as measured PSA (biochemical) failure. The post-treatment nadir levels of PSA that predict best for subsequent freedom from PSA failure are debatable, and many nadir levels have been proposed as targets. Although lower nadirs generally are associated with superior outcomes, the identification of a single absolute nadir level was not selected at a recent ASTRO consensus conference. Rather, three consecutive PSA rises above the nadir, with date of failure at the midpoint between the nadir and first rise, were selected as a more useful end point for treatment failure.

Dual radiobiological interpretations of retrospective clinical data: the time factor.

Dual interpretations are different radiobiological mechanisms that explain theoretically the same observed results. Radiobiological interpretations of the time factor are most frequently based on changes in total dose that produce a given effect. If this dose is increased by different mechanisms (e.g. increasing overall time and decreasing dose per fraction) at the same time, proposals for altered fractionation schemes based on the choice of one or the other mechanism, in principle, can lead to erroneous predictions of outcome. This is especially the case when the analyses are based on retrospective clinical data, where the influence of patient selection is unknown. Examples of dual interpretations taken from the literature on head and neck, melanoma and prostate cancer are discussed.

Prognostic significance of post-irradiation prostate biopsies.

Over the last 2 decades, the prognostic significance of post-irradiation prostate biopsy has been debated. Studies with long-term follow-up have shown a predictive effect with regard to local tumor failure and disease-free survival. More recently collected data involve the use of prostate ultrasound and prostate-specific antigen; the latter appears to be a good prognostic indicator on its own. Currently, the practical usefulness of post-treatment biopsy for clinically undetectable disease remains undefined, since definitive therapy for positive findings cannot be widely applied, carries significant morbidity, and, as yet, is of questionable benefit. Further study is certainly necessary, and it is perhaps under these conditions that this post-therapy procedure should be used.

The treatment of choice for localized poorly differentiated adenocarcinoma of the prostate.

Of 286 evaluable patients definitively irradiated for adenocarcinoma of the prostate, 71 with Stage B2 and C poorly differentiated lesions were studied. Forty-six patients were treated with external beam therapy and 25 with 125I implantation and pelvic lymph node dissection. Within both the external beam and the 125I treatment groups, the local recurrence rate was noticeably higher in the Stage C than in the Stage B2 tumors. Moreover, the incidence of local failure was significantly increased in those patients treated with 125I implantation, 56% vs. 24% (p = 0.008), suggesting that external beam irradiation may be the treatment of choice for localized, poorly differentiated prostatic tumors.

High dose rate vaginal brachytherapy in early stage endometrial carcinoma: preliminary analysis.

From 1987 to 1993, 69 women diagnosed with FIGO stages I and II carcinoma of the endometrium underwent postoperative adjuvant irradiation (RT) under protocol with high dose rate (HDR) afterloading vaginal apex brachytherapy. All patients initially underwent total abdominal hysterectomy and bilateral salpingo-oopherectomy. Forty-four women received HDR brachytherapy alone and 25 received external beam RT as well as HDR brachytherapy. The median follow-up was 45 months. The 5-year disease-free survival was 92% and the overall survival rate was 79%. Multivariate Cox regression analysis revealed that grade, age, and stage were significant predictors of survival. The overall acute and late side effects were minimal. It appears that HDR vaginal brachytherapy is prevention of vaginal recurrence in endometrial carcinoma and should be considered an effective treatment option.