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Immediate Versus Deferred Hormonal Treatment for Patients With Prostate Cancer Who Are Not Suitable for Curative Local Treatment: Results of the Randomized Trial SAKK 08/88

From the Swiss Group for Clinical Cancer Research (SAKK), and the Department of Urology, University of Bern, Bern, Switzerland

Address reprint requests to Urs E. Studer, MD, Department of Urology, University of Bern, Inselspital, CH-3010 Bern, Switzerland; e-mail: urs.studer{at}insel.ch

	ABSTRACT

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PURPOSE: To determine if immediate hormonal therapy is advantageous compared with deferred treatment in newly diagnosed asymptomatic prostate cancer patients who, for any reason, were not candidates for curative local treatment.

PATIENTS AND METHODS: Between February 1988 and February 1992, 197 patients with a median age of 76 years (range, 56 to 86 years) were randomly assigned to receive either immediate or deferred orchiectomy on symptomatic progression. The two groups did not differ significantly in clinical or laboratory parameters; 67% had T3-4 tumors and 20% had lymph node metastases. Patient accrual was stopped prematurely because of a similar competing trial. Therefore, observation time was prolonged to achieve the desired number of events and statistical power.

RESULTS: Deferred orchiectomy was necessary in 58% of the patients. Median time to disease progression was 2.8 years less than for patients with immediate orchiectomy. However, overall pain-free time from random assignment to symptomatic progression after immediate or deferred orchiectomy, and performance status, were identical in both groups. Cancer-specific survival tended to be longer in the immediate group (P = .09) but there was no difference in overall survival between the two groups (P = .96). The median hemoglobin value decreased significantly after immediate orchiectomy (P < .001).

CONCLUSION: For elderly, asymptomatic patients not undergoing curative local treatment, we were unable to show any major advantage of immediate compared with deferred hormonal treatment regarding quality of life or overall survival in our limited number of patients. Disabling complications were prevented in the deferred-treatment arm by careful follow-up; 42% of these patients never required any tumor-specific treatment.

	INTRODUCTION

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Hormonal therapy for prostate cancer has been used for more than 60 years in patients who are not candidates for definitive treatment with curative intent.^{1 ,2} Although there is general agreement that it delays disease progression and is effective for palliation of symptoms, controversy exists about when it should be initiated and whether it prolongs survival.

Advocates of early hormonal treatment note that delay in progression translates into reduction of symptoms and prolonged survival.^3-5 Proponents of delayed treatment claim that if patients are observed closely, treatment can be initiated before severe symptoms or complications develop, and that they are spared the adverse effects of hormonal therapy for long periods and, indeed, some may never need it. They also cite studies showing no survival advantage with early treatment.^6-10

We evaluated the timing of hormonal therapy with immediate or deferred subcapsular orchiectomy to determine whether there is a significant difference in overall survival, symptom-free survival, or incidence of complications.

	PATIENTS AND METHODS

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Eligibility
Patients with newly diagnosed histologically or cytologically confirmed prostate cancer with or without soft tissue and/or bone metastases who were asymptomatic and without previous treatment entered onto this Swiss multicenter study.

All patients were not suitable or unwilling, for any reason, to undergo radical prostatectomy or radiation therapy. Obstructive voiding symptoms were not a reason for exclusion, given that palliative transurethral resection of the prostate (TUR-P) was possible at any time. Eligibility and exclusion criteria are summarized in Table 1.

Follow-up was equally frequent for both groups to avoid nonrecognized progressive disease that could cause life-threatening complications in patients with deferred treatment and to avoid an observation time bias between the groups (Table 2).

Subcapsular orchiectomy was performed within 1 month after random assignment in the immediate-treatment group, and at the onset of symptoms caused by metastases or when ureteric obstruction or new asymptomatic metastases were likely to cause severe complications (pathologic fractures, spinal palsy, and so on) in the deferred-treatment group. Biochemical progression such as increasing prostate-specific antigen (PSA) or phosphatases, new hot spots, or soft tissue metastases during follow-up did not justify deferred orchiectomy as long as the patient remained asymptomatic and did not have a decrease in performance status of 2 points.

After immediate or deferred subcapsular orchiectomy, patients received no additional treatment until they had pain caused by renewed progressive disease or if radiation therapy was required to prevent pathologic fractures. After the second progression, treatment was left to the discretion of the treating physician. Patients were observed until death.

End Points
The primary end point was overall survival, defined as the interval from the date of random assignment to the date of death as a result of any cause. The main secondary end point was overall post-treatment symptom-free survival; ie, the interval from random assignment to the first symptoms of hormone-refractory prostate cancer after immediate or deferred orchiectomy. Pain, ureteric obstruction, and risk of pathologic fracture were considered symptoms. Other secondary end points were time from random assignment to first pain, ureteric obstruction, and/or documented new metastases. Cancer-specific survival was defined as the time from random assignment to death as a result of prostate cancer, and pain-free interval was defined as the time from random assignment to first occurrence of pain after immediate or deferred treatment. Furthermore, we determined if immediate subcapsular orchiectomy decreased the incidence of complications or symptomatic progression.

Statistical Analysis
The size of the necessary study population was calculated to be 360 patients based on the assumptions of a 5-year survival rate of 50% for those with deferred orchiectomy, an acquisition rate of 100 per year, an observation time of 5 years, significance level of 5%, and power of 90% to detect a 5-year survival rate of 65% with immediate orchiectomy.

The trial was closed in February 1992 because the European Organization for Research and Treatment of Cancer trial 30891 with a similar objective, but including only M0 patients, was opened at that time. To avoid selection bias with predominantly M1 patients in this SAKK 08/88 trial, it was closed prematurely, but the observation time was prolonged until more than 90% of patients had died. This allowed us to acquire the necessary number of events for an adequate statistical power of 88%. The power analysis was based on a sample of 188 patients, the achieved total of 172 events, an accrual duration of 4 years, and a hypothesized difference of 15% in 5-year overall survival.

Time variables were estimated by the Kaplan-Meier method and compared by the log-rank test; the results are presented as hazard ratios (HRs) and corresponding 95% CIs. To account for decreased quality of life during time spent with symptoms, time without symptoms was evaluated as well. The Cox regression model was used for multivariate analysis. A competing risks analysis using Gray's test¹¹ was performed to take into account the mutual exclusion of death as a result of prostate cancer and death as a result of other causes. Hemoglobin trend curves were computed using splines and compared by a bootstrap method as proposed by Tibshirani.¹² Fisher's exact test was used for comparisons for 2 x 2 frequency tables, the exact Wilcoxon test for comparisons in 2 x k tables. The Wilcoxon test was used for comparisons of laboratory measurements. The statistical analysis was done with SAS version 8.2 (SAS Institute Inc, Cary, NC, 2001), Splus version 6 (Insightful Corp, Seattle, WA), and StatXact 5 (Cytel Software Corp, Cambridge, MA). No subgroup analyses were performed.

	RESULTS

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Patients
From February 1988 to February 1992, 197 patients from seven participating centers (two of which contributed 61% of all patients) were randomly assigned to receive immediate or deferred subcapsular orchiectomy. After random assignment, nine patients were ineligible. Two of these patients had consented to participate in the trial but underwent radical prostatectomy elsewhere after a second consultation; two had ureteric obstruction; two had pain; two received antiandrogen treatment before random assignment; and in one review, pathology did not confirm the diagnosis of prostate cancer. Of the 188 assessable patients, 96 were in the immediate-treatment arm and 92 were in the deferred-treatment arm (Fig 1). There were no significant differences between the groups with respect to the baseline characteristics used for stratification or laboratory data (Tables 3 and 4). At random assignment, 46 patients in the immediate-treatment arm and 51 in the deferred-treatment arm had had a TUR-P for obstructive voiding symptoms.

View larger version (35K): [in this window] [in a new window]   Fig 1. CONSORT diagram showing the flow of participants through each stage of the randomized trial.

Initiation of Treatment
Ninety-one of the 96 patients underwent immediate subcapsular orchiectomy within a median of 8 days after random assignment. Three of these patients had immediate treatment more than 3 months after study entry because they either had a myocardial infarction (one patient received treatment after 98 days) or initially refused orchiectomy (one patient agreed after day 238; another agreed on day 927 upon becoming symptomatic from local progressive disease).

Five patients never received immediate treatment because orchiectomy or alternative hormonal treatment was refused. They were analyzed according to intention to treat (ie, with the patients in the immediate-treatment arm).

Of the 92 patients randomly assigned to the deferred-treatment arm, 39 (42%) never required it. Thirty-six of these patients died before becoming symptomatic from prostate cancer as a result of the following causes: cardiovascular (n = 12), pulmonary diseases (n = 5), prostate cancer (n = 1), other cancers (n = 4), renal insufficiency (n = 1), diabetes (n = 1), perforated ulcer (n = 1), trauma (n = 1), and not specified (n = 10). Three patients were alive and asymptomatic at analysis.

In the remaining 53 patients, deferred treatment was started after a median interval of 3.2 years for ureteric obstruction (n = 13), skeletal metastases causing pain or possible complications (n = 24), decrease in performance status (n = 4), progressive disease likely to cause complications (n = 5), infiltration of the rectum (n = 2), and without protocol justification (n = 5; Fig 2) Three patients had medical instead of surgical castration.

View larger version (11K): [in this window] [in a new window]   Fig 2. Median time to orchiectomy for patients in the deferred treatment arm was 3.2 years; nine patients died as a result of non–cancer-related disease before this median time.

View larger version (20K): [in this window] [in a new window]   Fig 3. Time from random assignment to first pain, ureteric obstruction, and/or new metastasis was significantly longer in patients with immediate orchiectomy (i; P < .01); 44 patients in the immediate arm and 27 in the deferred arm (d) died before symptoms occurred.

View larger version (20K): [in this window] [in a new window]   Fig 4. Time from random assignment to pain, ureteric obstruction, or risk of pathological fracture after immediate (i) or deferred (d) orchiectomy was similar. In each treatment arm, 38 patients had symptoms after orchiectomy; 51 patients in the immediate arm died asymptomatic. In the deferred arm, 36 patients died asymptomatic without orchiectomy, and 13 patients died asymptomatic after orchiectomy.

View larger version (18K): [in this window] [in a new window]   Fig 5. Hemoglobin trend estimation with pointwise 95% CIs at years 0 to 4.Hemoglobin decreased by approximately 1 g/dL after immediate orchiectomy. The difference compared with the deferred-orchiectomy group remained evident until a substantial number of patients underwent the deferred orchiectomy. This difference is significant between 0.5 and 2.5 years (P < .02).

View larger version (24K): [in this window] [in a new window]   Fig 6. Cancer-specific survival. The cause of death was attributed to progressive prostate cancer in 24% with immediate orchiectomy (i) v 37% with deferred orchiectomy (d; not significant, P = .09). Sixty-four patients in the immediate arm and 51 in the deferred arm died as a result of causes other than prostate cancer.

View larger version (22K): [in this window] [in a new window]   Fig 7. Overall survival. Overall survival is not significantly different between the groups with immediate (i) or deferred orchiectomy (d; P = .96). Median survival is 5.2 years (95% CI, 4.5 to 6.4 years) for the immediate-orchiectomy group and 4.4 (95% CI, 3.6 to 6.1 years) for the deferred-orchiectomy group.

View larger version (20K): [in this window] [in a new window]   Fig 8. Pain-free interval. Pain-free survival from random assignment until symptomatic progression after orchiectomy was similar in both arms. Pain after orchiectomy was reported by 34 patients in the immediate arm (i) and 33 patients in the deferred arm (d).

Overall survival was significantly lower in patients with metastatic (HR, 1.46, 95% CI, 1.21 to 1.76; P < .001) or node-positive disease (HR, 1.23; 95% CI, 1.02 to 1.49; P = .033), baseline hemoglobin 14 g/dL (HR, 1.22; 95% CI, 1.05 to 1.43; P = .012), PSA 5 ng/mL (HR, 1.37; 95% CI, 1.01 to 1.86; P = .041), and concomitant cardiovascular disease (HR, 1.35; 95% CI, 1.05 to 1.74; P = .019).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Whether immediate or deferred hormonal treatment is best for patients who are not suitable for curative local treatment of prostate cancer has been debated since its introduction.^{1 ,2} Arguments for or against immediate endocrine treatment for minimal or advanced metastatic prostate cancer are evenly distributed.^3-10

The Veterans Administration Research Service Cooperative Urological Research Group were the first to perform a controlled trial on immediate versus deferred hormonal therapy, with patients in the placebo arm receiving deferred hormonal treatment when required. Considering only patients assigned to orchiectomy or placebo, there was no difference in survival between the treatment groups at 9 years. Furthermore, there was no difference in cancer-specific survival in patients with stage III and IV disease.^{13 ,14}

The British Medical Research Council conducted another trial on immediate versus deferred androgen ablation in more than 900 patients with or without metastases. Early results suggested a survival benefit in favor of immediate hormonal treatment for M0 patients; however, there was no significant difference in overall survival after the majority of patients had sufficient follow-up.^{15 ,16}

The Veterans Administration Research Service Cooperative Urological Research Group, as well as the British Medical Research Council trials, have been criticized because the currently employed staging techniques were not available for, or not applied to, every patient. This renders an adequate stratification according to major risk factors impossible and mixes patients with minimal or advanced disease. Furthermore, the intensity and frequency of follow-up was sometimes irregular and left to investigator discretion. In our trial, we used the most accurate clinical staging possible before random assignment and stratified according to known risk factors. This resulted in well-balanced groups (Table 3 and 4). Uncertainties of patient compliance were excluded by performing subcapsular orchiectomy instead of medical castration and by monitoring serum testosterone for treatment efficacy.

The majority of patients eventually developed progressive disease (Fig 3). Patients with immediate orchiectomy showed evidence of pain, ureteric obstruction, or documented new metastases on computed tomography, chest x-ray, or bone scan confirmed by conventional x-ray significantly later than did initially untreated patients under observation. However, the latter still had a chance to respond to antiandrogen treatment when progressive disease was noted. The major finding of this trial is that the time from random assignment to symptomatic hormone-refractory progressive disease after orchiectomy and the overall pain-free survival were no different if orchiectomy was immediate or deferred. With regular follow-up, deferred treatment does not seem to increase the risk of severe complications such as pathologic fractures.

When interpreting our results with equally good overall survival and pain-free survival for immediate and deferred subcapsular orchiectomy, the study population with predominantly locally advanced disease must be considered. Approximately 50% of our patients primarily visited a urologist because of moderate or severe voiding symptoms that required a TUR-P. More than 90% of patients had palpable disease on digital rectal examination. In two thirds of patients, the tumor was staged as growth beyond the prostate capsule and one fourth proved to have metastatic disease. Although the 5-year median survival time of our population is substantially longer than for patients with newly diagnosed metastatic disease,^17-20 it can be argued that most of our patients had locally advanced or systemic disease and that we were comparing late with very late, instead of early with late, hormonal treatment. However, the advantage of our patient population, with most having significant disease, is the increased likelihood that the final outcome would be determined by the prostate cancer. Therefore, it would appear likely that any substantial effect of the timing of hormonal treatment on cancer-specific survival time as well as overall survival time would be detectable.

It is important not to compare our results in this elderly population with advanced disease to a younger population with no voiding symptoms; a nonpalpable, only biopsy-proven prostate cancer; and a normal or only slightly elevated PSA. Our results cannot be used to decide whether early adjuvant hormonal treatment would be beneficial in patients with suspected minimal disease before or after curative local treatment. Indeed, in the smaller Eastern Cooperative Oncology Group study of 98 prostate cancer patients who had positive lymph nodes removed at the time of radical prostatectomy,²⁰ patients with minimal residual disease showed a survival advantage for immediate hormonal treatment. If it is impossible to show a survival difference in our population with advanced disease (even with 42% in the deferred arm never requiring treatment), then other trials, particularly those including patients with a relatively low risk of dying of prostate cancer, must be interpreted carefully when they fail to show a survival difference. Two different forms of immediate treatment may not necessarily be equally good. Perhaps they are equally unnecessary.²¹

Although not statistically significant, a higher number of patients dying as a result of prostate cancer and a decreased cancer-specific survival have been documented for patients in the deferred orchiectomy arm. Whether this difference is real or the result of an interpretation bias by the practitioner issuing the death certificate remains questionable. The true cause of death is often difficult to establish, even with autopsy. It is understandable that a treating physician would be more likely to consider known prostate cancer as the cause of death, particularly if the patient was untreated in the deferred arm and had an increasing, significantly pathologic PSA. In contrast, in a patient with hormone-refractory prostate cancer and only slightly elevated PSA, one might be more likely to attribute the death to unknown causes or cardiovascular disease. It can also be speculated that early death following the diagnosis of prostate cancer, particularly if associated with an increasing PSA, is more likely to be attributed to prostate cancer, whereas sudden death of a patient who has lived with this diagnosis for several years would be more likely attributed to other causes. For these reasons, we are reluctant to overinterpret cancer-specific survival and tend to rely predominantly on overall survival. Cancer-specific survival, as well as overall pain-free survival, does not exhibit any difference between our two treatment groups. Although we were not able to show the hypothesized difference of 15% in 5-year overall survival (retrospective analysis shows a power of 88%, which is close to the planned 90%), smaller differences in survival cannot be excluded with certainty because of the limited number of assessable patients.

If there is no major difference in overall survival time and overall symptom-free survival, then quality of life is of primary importance to the patient. We did not assess this in our patients with validated questionnaires for two reasons. First the questionnaires available in the late 1980s were designed mainly for patients receiving chemotherapy. To ask asymptomatic patients not receiving any treatment about adverse effects seemed inappropriate. Second, the subjective adverse effects of androgen withdrawal, such as hot flushes, negative impact on emotional functioning, decreased activity, gain in body weight, and so on, as well as the objective findings of gynecomastia, osteoporosis, and impaired sexuality, are well known and did not require confirmation. The negative effect of hormonal therapy on quality of life had been well documented.^22-25 The significant decrease in hemoglobin in our patients undergoing immediate orchiectomy is striking and may be another objective negative effect parameter of hormonal treatment. Conversely, significantly more patients in the deferred orchiectomy arm had TUR-P during follow-up. Particularly in view of the current minimally invasive treatment modalities for bladder outlet obstruction, this alone would not justify early androgen blockade.

On the basis of our findings, deferred hormonal treatment in newly diagnosed asymptomatic patients who were not candidates for curative local treatment is a valid option, provided patients are carefully observed and hormonal treatment is started as soon as complications or pain caused by progressive disease occur. A substantial number of patients, particularly in the elderly population, even patients with advanced disease, will never require any treatment. This may significantly affect the quality of life of many patients, as well as health care costs.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Niehans P: Prostata-Krebs wie Paraprostata-Hypertrophie sind Folgen hormonaler Störun-gen, die wir je früher je besser beeinflussen können. Hans Huber, Bern, 1940

2. Huggins C, Hodges CV: Studies on prostatic cancer: Effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1: 293-297, 1941[Free Full Text]

3. Steinberg GD, Bales GT, Brendler CB: An analysis of watchful waiting for clinically localized prostate cancer. J Urol 159: 1431-1436, 1998[CrossRef][Medline]

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5. Schmidt JD: The case for early endocrine treatment of advanced or metastatic prostate cancer. Prostate 28: 201-204, 1996[Medline]

6. Cockburn AG: Carcinoma of the prostate: Delayed endocrine therapy is best. Semin Urol 1: 280-287, 1983[Medline]

7. Grossman HB: Hormonal therapy of prostatic carcinoma: Is there a rationale for delayed treatment? Urology 27: 199-204, 1986[Medline]

8. Parker MC, Cook A, Riddle PR, et al: Is delayed treatment justified in carcinoma of the prostate? Br J Urol 57: 724-728, 1985[Medline]

9. Lepor H, Ross A, Walsh PC: The influence of hormonal therapy on survival of men with advanced prostatic cancer. J Urol 128: 335-340, 1982[Medline]

10. Smith PH: Carcinoma of prostate: Case against immediate hormonal therapy. Prostate 28: 205-208, 1996[Medline]

11. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16: 1141-1154, 1988[CrossRef]

12. Tibshirani R, Knight K: Model search and inference by bootstrap "bumping." Technical report, Department of Statistics, University of Toronto. Presented at the Joint Statistical Meetings, Chicago, IL, August 1996. http://www-stat.stanford.edu/tibs. Splus program: Frank E. Harrell, Division of Biostatistics and Epidemiology, Department of Health Evaluation Sciences, University of Virginia. http://hesweb1.med.virginia.edu/biostat/s/

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16. Kirk D: Immediate vs. deferred hormone treatment for prostate cancer: How safe is androgen deprivation? Br J Urol 86: S220, 2000 (suppl 3)

17. Eisenberger MA, Blumenstein BA, Crawford ED, et al: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339: 1036-1042, 1998[Abstract/Free Full Text]

18. Maximum androgen blockade in advanced prostate cancer: An overview of the randomised trials—Prostate Cancer Trialist's Collaborative Group. Lancet 355: 1491-1498, 2000[CrossRef][Medline]

19. Dalesio O, van Tinteren H, Peto R, et al: Androgen blockade in prostate cancer. Lancet 356: 341-342, 2000[Medline]

20. Collette L, Studer UE, Schröder FH, et al: Why phase III trials of maximal androgen blockade versus castration in M1 prostate cancer rarely show statistically significant differences. Prostate 48: 29-39, 2001[Medline]

21. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341: 1781-1788, 1999[Abstract/Free Full Text]

22. Kurth KH, de Reijke TM, de Haes H: Quality of life assessment in patients with prostatic carcinoma category T1-3 N1-3 MO, who received or did not receive hormonal treatment. J Urol 153: 238, 1995 (abstr 38)[Medline]

23. Moinpour CM, Savage MJ, Troxel A, et al: Quality of life in advanced prostate cancer: Results of a randomized therapeutic trial. J Natl Cancer Inst 90: 1537-1544, 1998[Abstract/Free Full Text]

24. Herr HW, O'Sullivan M: Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urol 163: 1743-1746, 2000[CrossRef][Medline]

25. Schröder FH, Collette L, de Reijke TM, et al: Prostate cancer treated by anti-androgens: Is sexual function preserved? Br J Cancer 82: 283-290, 2000[CrossRef][Medline]

Submitted November 4, 2002; accepted July 26, 2004.

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This Article Abstract Full Text (PDF) Erratum (v23,p936) Erratum (v23,p936) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Studer, U. E. Articles by Dietrich, D. Search for Related Content PubMed PubMed Citation Articles by Studer, U. E. Articles by Dietrich, D.