Clinical Practice Committee Publication RE SE ARCH I N Accepted: August 14, 2010 Published online: September 22, 2010 PÆDIATRIC S Management of Polycystic Ovary Syndrome in Childhood and Adolescence M. Ojaniemi a P. Tapanainen a L. Morin-Papunen b a Department of Pediatrics and Adolescence, Institute of Clinical Medicine, and b Department of Obstetrics and Gynecolo
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Doi:10.1016/j.ijrobp.2004.08.024Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 5, pp. 1299 –1305, 2005 doi:10.1016/j.ijrobp.2004.08.024
IMPACT OF SHORT COURSE HORMONAL THERAPY ON OVERALL AND
CANCER SPECIFIC SURVIVAL AFTER PERMANENT PROSTATE
DAVID C. BEYER, M.D.,*† TIMOTHY MCKEOUGH,* AND THERESA THOMAS, M.S.† *Arizona Oncology Services and †Foundation for Cancer Research and Education, Scottsdale, AZ Purpose: To review the impact of prior hormonal therapy on 10-year overall and prostate cancer specific survival
after primary brachytherapy.
Methods and Materials: A retrospective review was performed on the Arizona Oncology Services tumor registry
for 2,378 consecutive permanent prostate brachytherapy cases from 1988 through 2001. Hormonal therapy was
administered before the implant in 464 patients for downsizing of the prostate or at the discretion of the referring
physician. All deceased patients with known clinical recurrence were considered to have died of prostate cancer,
irrespective of the immediate cause of death. Risk groups were defined, with 1,135 favorable (prostate-specific
antigen [PSA] < 10, Gleason < 7, Stage T1-T2a), 787 intermediate (single adverse feature), and 456 unfavorable
(two or more adverse features) patients. Kaplan-Meier actuarial survival curves were generated for both overall
and cause-specific survival from the time of treatment. Multivariate analysis was performed to assess the impact
of hormonal intervention in comparison with known risk factors of grade, PSA, and age.
Results: With follow-up ranging up to 12.6 years and a median of 4.1 year, a total of 474 patients died, with 67
recorded as due to prostate cancer. Overall and cause-specific 10-year survival rates are 43% and 88%,
respectively. Overall survival is 44% for the hormone naive patients, compared with 20% for the hormone-
treated cohort (p ؍ 0.02). The cancer-specific survival is 89% vs. 81% for the same groups (p ؍ 0.133).
Multivariate analysis confirms the significance of age > 70 years (p ؍ 0.0013), Gleason score > 7 (p ؍ 0.0005),
and prior hormone use (p ؍ 0.0065) on overall survival.
Conclusions: At 10 years, in prostate cancer patients receiving brachytherapy, overall survival is worse in men
receiving neoadjuvant hormonal therapy, compared with hormone naive patients. This does not appear to be due
to other known risk factors for survival (i.e., stage, grade, PSA, age) on multivariate analysis. The leading causes
of death were cardiovascular, prostate cancer, and other cancers with no obvious discrepancy between the two
groups. This finding is unexpected and requires confirmation from other centers.
2004 Elsevier Inc.
Hormone therapy, Prostate cancer, Survival, Brachytherapy.
increase in the frequency of brachytherapy administration asprimary treatment between 1992 and 2001. In low-risk Men receiving external beam radiation therapy for prostate patients, they report that in 2001 fully 22% were treated cancer are now commonly treated with neoadjuvant andadjuvant hormonal therapy. There have been numerous ret- with brachytherapy, rising to 31% in patients over 75 years rospective single institution reports suggesting benefit to the of age. High response rates have been reported based on combination of androgen ablation and radiation therapy careful prostate-specific antigen (PSA) follow-up of brachy- A number of well-designed prospective multicenter therapy series, and many such patients are considered cured trials have underscored the value of adding hormonal ma- of their disease, with long-term survival data comparable nipulation to standard radiation therapy and have shown improved cancer control rates and a survival benefit Since the introduction of transperineal techniques, andro- gen ablation has been used in selected cases to shrink the Ultrasound-guided brachytherapy for early-stage prostate gland and avoid interference from the pubic arch. More cancer is now a standard treatment option for many patients.
recently neoadjuvant hormonal therapy has been integrated In one survey, Cooperberg et al. report a sevenfold into brachytherapy treatment plans in the hopes that some of Reprint requests to: David C. Beyer, M.D., Arizona Oncology Services, 8994 East Desert Cove, Suite 100, Scottsdale, AZ 85260.
Acknowledgments—The authors thank the members of the Arizona Tel: (602) 274-4484; Fax: (480) 314-3343; E-mail: [email protected] State Tumor Registry for their contribution and assistance.
Received Jan 12, 2004, and in revised form Jul 26, 2004.
Presented at the 45th Annual Meeting of the American Society Accepted for publication Aug 9, 2004.
for Therapeutic Radiology and Oncology, Salt Lake City, UT, I. J. Radiation Oncology ● Biology ● Physics the improved results seen with external beam irradiation can as recorded in the Arizona Department of Vital Records, was also be achieved with brachytherapy. However, to date there obtained from the Arizona State Cancer Registry and confirmed, are no compelling studies supporting this combination ther- when possible, through primary medical records.
apy, and its use remains an extrapolation from the external Patients were stratified retrospectively in risk groups according to commonly accepted criteria. Favorable patients had no adverse beam data. This study was performed to assess the value of risk factors of PSA Ͼ 10, Gleason Grade Ն 7, or Stage Ն T2b.
hormone use in this setting using overall survival and cause- Intermediate risk patients exhibited one of these three risk factors.
Unfavorable patients had two or more of these adverse findings.
For the purposes of analysis, death was considered due to prostate cancer in all patients who were reported to have died of METHODS AND MATERIALS
prostate cancer, or those who died with any treated recurrence, Between December 1988 and December 31, 2001, 2,378 con- even if not recorded as due to the cancer. An untreated rising PSA secutive patients were treated at Arizona Oncology Services with at the time of death was not alone considered as evidence of cancer brachytherapy for clinically localized prostate cancer. All were death. Survival and cause-specific survival were calculated from prospectively entered into an institutional tumor registry. This database and the patients’ records were retrospectively reviewed Stepwise multivariate models were developed using Cox pro- under an Institutional Review Board–approved protocol in 2003.
portional hazards regression. Predictors of cause-specific and over- All patients had biopsy-proven adenocarcinoma of the prostate, all survival in both cases include Gleason Score, PSA value, stage staged T1-T3, N0, M0. Central pathology review was not per- value, and risk group levels. Graphical displays of the survival formed. Treatment consisted of ultrasound-guided transperineal curves for predictor levels were produced using the actuarial permanent brachytherapy with 125I or 103Pd. Details of the tech- method of Kaplan-Meier. Log–rank tests for the equality of sur- nique changed significantly over the span of this review with the vivor functions were made for each predictor with reference to introduction of biplanar ultrasound, computed tomography (CT) based dosimetry and other innovations. The basic approach haspreviously been reported but is briefly as follows. All patients were preplanned with computerized dosimetry optimizedto deliver 160 Gy over the lifetime decay of 125I (145 Gy after the The median patient age was 73 years. Follow-up ranged introduction of TG-43) or 120 Gy over the lifetime of 103Pd (125 from 0 –12.6 years with a median of 4.1 years. At the time Gy after incorporation of NIST-1999) to the prostate with a 3–10 of presentation, the median PSA was 7.3 ng/mL. Details of mm margin. Patients also receiving 45 Gy external beam irradia- the presenting characteristics of the study population are tion were implanted with reduced doses of 120 Gy (110 Gy after shown in for the entire population and stratified for TG-43) or 90 Gy (100 Gy after NIST-1999) for the two isotopes, the 464 men who used neoadjuvant hormones. At the time respectively. Transperineal implantation was carried out as anoutpatient procedure under spinal or general anesthesia with intra- of analysis, 1,297 patients are known to be alive and with no operative ultrasound guidance utilizing afterloaded needles and theMick Applicator (Mick Radio-Nuclear Instruments, Inc., MountVernon, NY).
Neoadjuvant hormone therapy was given to 464 men. An anti- androgen was added to the luteinizing hormone releasing hormone (LHRH) agonist in 226 patients. This was generally given for 3– 6months to reduce the size of the prostate, to avoid pubic arch interference, or at the discretion of the treating physicians. Fre- quently, the reasons for hormonal intervention were not spelled out in the record, particularly when treatment was instituted before the initial referral. The duration of androgen deprivation was 6 months or less in 80%, 6 –9 months in 15%, 9 –12 months in 2%, and more than 12 months in 3%. Hormonal treatment was not continued more than 3 months after implantation.
Before 1996, most patients received implant monotherapy. Sub- sequently, combination therapy with the addition of external beam was offered to 461 patients at the treating physician’s discretion for high-risk features, such as PSA Ͼ 10, Gleason Ն 7 or stage Ն Patients were asked to return 3 months after treatment for PSA and DRE and were then typically seen every 3– 4 months for the first year, every 6 months for the next 2 years, and annually thereafter. In the case of either out-of-state patients or restrictive insurance carriers, follow-up was achieved through referring phy- sician notes or with the patients by phone or letter. Systematic follow-up biopsies were not performed. The Social Security Death Index, a national list of all Social Security recipients who havedied, was accessed to ascertain patient status. The cause of death, Abbreviation: PSA ϭ prostate-specific antigen.
Impact of hormonal therapy on survival after brachytherapy ● D. C. BEYER et al. Fig. 1. Cause-specific survival is shown. At 10 years, cause-specific survival is 97% for the favorable risk group, 83%for the intermediate group, and 77% for unfavorable risk patients. Patients at risk are shown at the start, at 5 years, andat 10 years. All differences between curves are statistically significant (p Ͻ 0.003).
evidence of disease, with another 161 alive with recurrent cancer, the comparable cause-specific survival is 88% at 10 disease. A total of 474 patients are known to have died.
years. The risk of prostate cancer death is highly correlated Sixty-seven died of prostate cancer or after treatment for with the initial risk group of the patient. As can be seen in recurrent prostate cancer and 57 died with untreated recur- patients in the low-risk group had a 10-year cause- rent cancer, as evidenced by only a rising PSA. Addition- specific survival of 97% contrasted with a cause-specific ally, 333 died with no evidence of disease and 17 died of survival of 77% for men with high-risk features (p ϭ Overall actuarial survival at 10 years is 43%. As the vast Cause-specific survival is shown in comparing the majority of deaths were due to causes other than prostate 464 patients who received neoadjuvant hormonal therapy Fig. 2. Cause-specific survival is shown comparing patients who did not receive hormones with patients who weretreated with neoadjuvant hormonal therapy. No significant difference is demonstrated for this endpoint (p ϭ 0.133).
I. J. Radiation Oncology ● Biology ● Physics Fig. 3. Overall survival is compared for the patients not receiving hormones and patients who were treated withhormonal manipulation. At 10 years, survival is significantly better (p ϭ 0.02) for patients not receiving hormones(44%) vs. patients receiving neoadjuvant treatment (20%).
with the 1,884 men who received no hormone treatment. At overall deaths and other cancers accounted for 10% and 10 years, there is no statistically significant difference in 16% of deaths in these two groups. Pulmonary deaths were cause-specific survival, with 89% and 81% for the two reported in 8% and 6%, respectively, while all other re- groups, respectively (p ϭ 0.13). This lack of benefit is seen ported causes of death individually accounted for fewer than in all three risk groups studied-favorable, intermediate, and unfavorable as well (data not shown). However, the overallsurvival is noted to be different for these two patient groups.
The actuarial 10-year survival is 20% for the hormone- DISCUSSION
treated cohort and 44% for the untreated group (p ϭ 0.02)and is shown graphically in Radical surgery, external beam irradiation, and brachy- A stepwise multivariate analysis was performed for over- therapy are all routinely offered to patients as definitive all survival, looking at the independent risk factors thought primary treatment for early-stage prostate cancer. Androgen to most likely confound the outcomes, namely age, Gleason deprivation hormone therapy has been extensively used in score, baseline PSA, and hormone use. Not surprisingly, age the palliative setting for advanced disease, and in selected (Ͼ 70 years) and Gleason score (Ն 7) were most highly early-stage patients who decline potentially curative treat- correlated with survival. Hormone use was also found to be ments. However, there has been growing interest in com- independently significant. However, PSA was not found to bining hormonal intervention along with definitive therapies be an independent predictor of survival as shown in It is not obvious why hormone-treated patients have this Gleave et al. have shown, in animal models, that increased risk. Cardiovascular disease was the single largest hormonal treatment given before definitive cancer therapy, cause of death in both groups, with and without hormones, (neoadjuvant therapy), is superior to hormone treatment representing 24% and 22%, respectively, of the overall after treatment (adjuvant therapy). This finding has been mortality. Prostate cancer caused 17% and 14% of the further examined in cancer patients. In both retrospectiveand randomized trials, neoadjuvant therapy before radicalprostatectomy, caused significant downstaging and reduced Table 2. Multivariate analysis for survival the risk of positive surgical margins However,there was no long-term benefit in cancer control rates. It has been suggested that a longer duration of therapy might be of benefit however, it is presently generally accepted that neoadjuvant treatment has only limited value before A number of well-controlled randomized trials assessing the value of hormonal therapy and external beam irradiation Impact of hormonal therapy on survival after brachytherapy ● D. C. BEYER et al. have been reported over the past 2 decades by the Radiation of these patients have risk factors not commonly found in Oncology Therapy Group (RTOG). Early reports consis- brachytherapy patients. More than 90% of the men in the tently showed improved freedom from recurrence as mea- EORTC report and subsequent updates had palpably sured clinically or by PSA endpoints across bulky cancers (Ն T3) and higher grade cancers. Patients in many subgroups. More recently, and with longer follow-up, RTOG 86 –10 had T3 cancers or PSAs ranging up to 560 improved overall survival has been shown in RTOG 86-10 ng/mL. These are clearly not the subset of patients usually referred for brachytherapy, and are distinctly more ad- Similar results were shown by Bolla et al. In a vanced than patients in the present study. However, Bolla randomized study of 415 patients treated for locally ad- reports benefit to hormone use, even in those 10% who vanced prostate cancer, hormone therapy instituted at the were reported as the “low-risk category.” It should be noted, time of external beam radiotherapy and continued for 3 however, that this low-risk group is not defined the same as years, improved overall survival from 62% to 79% at 5 years. In an update with median follow-up of 66 In a meta-analysis pooling four major RTOG studies months, they document benefit in patients treated with hor- assessing the value of hormones, Roach et al. identified mones for all endpoints studied: local failure (16% vs. 2%), four risk groups and presented recommendations for the disease-free survival 40% vs. 74%), and cause-specific sur- incorporation of hormones in the treatment schema for external beam. All of our prostate brachytherapy population Neoadjuvant hormonal therapy has been used along with is contained within Groups 1 and 2 from that report, for prostate brachytherapy in an effort to shrink the prostate and which benefit from hormone therapy was least convincing.
avoid pubic arch interference. There are several published In fact, even Group 2 may represent a higher risk group of studies confirming the value of hormones in this setting patients, as many T3 and node positive patients could still Others have used hormones with brachytherapy be within this group. Subsequent publication of RTOG with the hope that they might improve outcomes in a man- 94-13 suggests that only patients who receive neoadjuvant ner analogous to patients receiving external beam irradia- hormones plus whole pelvic radiotherapy truly benefit from tion. Looking at biochemical control, Sylvester et al. the additional treatment Thus, it is not entirely sur- suggested some benefit to the use of hormones in a small prising that our study fails to show any benefit on overall series. However, with longer follow-up this conclusion survival and cause-specific survival from the addition of could not be supported A prospective multicenter randomized trial using neoadjuvant hormones for interme- That the use of hormones cut the overall 10-year survival diate and unfavorable brachytherapy patients was attempted in half was unexpected in the present study. Similar results in the 1990s, but was closed owing to poor accrual have not been previously published with LHRH agonists Potters et al. in a retrospective matched pair analysis, and antiandrogens. A review of Group 1 alone in the RTOG compared 132 patients who received neoadjuvant hormones meta-analysis did suggest an adverse effect of hor- and brachytherapy to 131 having brachytherapy alone. No mones, though data on this group alone have never been difference in PSA relapse-free survival was seen with a published It remains entirely possible that some sys- median follow-up of 42 months. In a multivariate analysis, temic effect of these drugs had a detrimental effect on Merrick et al. suggest slight improvement in the PSA overall survival. Such was the case in early studies of DES endpoint only for the high-risk subgroup. In contrast, Stone in prostate caner where despite a therapeutic benefit, overall et al. have found benefit from the use of neoadjuvant survival was diminished owing to excess cardiovascular hormones with brachytherapy. Routine biopsies performed deaths Reviewing the reported cause of death for our 2 years after brachytherapy showed cancer in 14% of 181 patients, however, no single likely explanation can be iden- patients who had no hormones compared with 3.5% of 115 tified for the excess deaths. The relative proportions for the men treated with neoadjuvant hormones. Five-year freedom most common causes appear to be roughly maintained.
from biochemical failure was 54% compared with 79% for Accelerated deaths were also reported in patients receiv- the two groups On multivariate analysis, they found ing 150 mg bicalutamide compared with placebo in the hormone treatment to be the single most important predic- Early Prostate Cancer (EPC) trial program and on that tor, when compared with dose, risk group, PSA, Gleason basis this treatment is no longer recommended for low-risk localized prostate cancer patients. This adverse effect was The exact mechanism of action whereby hormones en- not seen in patients with more advanced local disease. These hance the effect of radiation is not entirely clear. Conse- reports further support the hypothesis that patients suitable quently, it is difficult to predict whether the same survival for permanent brachytherapy do not have sufficiently ad- benefit seen with external beam might be expected with vanced disease to warrant the use of neoadjuvant hormones.
brachytherapy. And with only single-institution studies and We conclude from these published studies that hormonal no prospective research, it is not unexpected that the brachy- therapy improves survival in patients who are most at risk of dying of prostate cancer: men with undifferentiated tumors In conjunction with external beam, survival benefits have (i.e., Gleason 8 –10) or large volume disease (i.e., T3, Nϩ, been primarily seen in men with higher risk features. Many or high PSA). In the majority of patients with early prostate I. J. Radiation Oncology ● Biology ● Physics cancer, the natural history of the disease suggests a rela- formed to properly evaluate the value or risk of neoadjuvant tively lower risk of dying. For these patients, the risks of hormonal intervention in the brachytherapy population. In hormonal intervention may be greater than the small benefit the absence of specific data supporting the addition of hormones to brachytherapy, we urge caution in applying By the very study design, the present data are subject to these combination therapies to patient populations for the limitations inherent with all single-institution retrospec- whom no benefit has been documented. Other than for tive studies. Hormones were administered over a 13-year reduction of the prostate size, there is still no clearly defined period for a variety of uncontrolled reasons. Patients were advantage to combining hormones with any brachytherapy treated for gland size reduction, for downstaging, and in some cases to allow patients to delay definitive treatment.
Additionally, it is clear from the data that hormones were CONCLUSION
more commonly administered to unfavorable patients who Long-term cause-specific and overall survival rates for were also more likely to receive combination therapy with prostate brachytherapy are 88% and 43%, respectively, at external beam irradiation. This suggests a physician bias to 10 years. Cause-specific survival can be estimated from the offer hormonal intervention with the hope that the benefits risk group, using the stage grade and PSA. Favorable, seen in the external beam literature would also accrue to intermediate, and unfavorable patients have cause-specific these brachytherapy patients. We are unable to control for survivals of 97%, 83%, and 77%, respectively. The use of these and other factors, and that may affect our endpoints. It neoadjuvant hormonal therapy for up to 6 months provides is entirely possible that significant selection bias existed in no benefit in cause-specific survival and adversely affected other undefined ways as well. As a result, all such retro- the overall survival, with a reduction from 44% to 20%.
spective studies require confirmation from other centers This finding remains strongly significant on multivariate with access to similar long-term survival data before any analysis. Confirmation is required from other series, and a changes can be recommended in the routine management of prospective evaluation of hormones in the brachytherapy this patient population. Prospective studies should be per- REFERENCES
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Theory-guided Content Analysis in Architectural Research Case: The Colouration of the Home During the Post-War Reconstruction Period: The Everyday and Architecture. Aulikki HERNEOJA Head of Laboratory of Art end Design, Doctor of Science (Technology), Architect University of Oulu, Department of Architecture Postal address: Aulikki Herneoja, University of Oulu, Department of