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Journal of Clinical Oncology, Vol 25, No 1 (January 1), 2007: pp. 77-84 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.0419 Phase II Study of Neoadjuvant Androgen Deprivation Followed by External-Beam Radiotherapy With 9 Months of Androgen Deprivation for Intermediate- to High-Risk Localized Prostate Cancer
From the Columbia University Medical Center, New York, NY Address reprint requests to Ronald D. Ennis, MD, St Luke's-Roosevelt Hospital Center, 1000 Tenth Avenue, Lower Level, New York, NY 10019; e-mail: rennis{at}chpnet.org
Purpose: To evaluate the toxicity and efficacy of individualized neoadjuvant androgen deprivation (AD) to maximal response followed by external beam radiotherapy (RT) with continued AD for a total of 9 months in a prospective phase II trial. Patients and Methods: One hundred twenty-three patients received a total of 9 months of flutamide and luprolide combined with RT. RT initiation was individualized to begin after maximum response to AD as assessed by monthly digital rectal examination and prostate-specific antigen (PSA). The neoadjuvant phase was restricted to no more than 6 months. Results: Median time to initiation of RT was 4.7 months. Indications to begin RT (and their rates) were undetectable PSA (28%), PSA unchanged from one month to the next (46%), PSA rising from one month to the next (10%), 6 months of AD (14%), and other (2%). Five-year outcomes were biochemical disease-free survival, (DFS) 63% ± 7%; clinical DFS, 75% ± 5%; cancer-specific survival, 99% ± 1%; and overall survival, 89% ± 3%. Patients initiating RT after 6 months of AD had significantly lower biochemical and clinical DFS. Those patients whose testosterone recovered to normal after completion of AD had a significantly superior survival rate. Of those patients potent before treatment, 65% remained so at last follow-up. Conclusion: The combination of 9 months of AD and RT, with initiation of RT individualized on the basis of maximum response to AD, achieves disease control rates comparable with past studies, while preserving potency in many patients. Further studies are warranted to determine the optimal combination of AD and RT in this patient population.
Attempts at decreasing prostate cancer–related morbidity and mortality through the addition of androgen deprivation therapy (AD) to treatment with external beam radiotherapy (RT) have been successful. Emerging data suggest that longer periods of AD are even more beneficial.1-4 The drawback of extended AD is that patients are potentially subject to significant deleterious adverse effects including impotence, loss of libido, and osteoporosis.5-7 In addition to the extent of AD, the timing of RT and AD has varied across studies with strategies ranging from simultaneous initiation to treatment with AD for anywhere from 2 to 8 months before RT initiation.1-4,8 Zietman et al have demonstrated in a mouse androgen-responsive mammary adenocarcinoma model that delivering RT after maximal response to AD is superior to delivering RT on the day AD is given.9,10 In addition, using a rat model, Kaminski et al demonstrated a significant advantage to a longer course of neoadjuvant AD compared with RT administered shortly after beginning AD.11 These models give strong preclinical support to the notion of neoadjuvant AD in combination with RT. Here, they are directly applied and individualized to patients by delivering RT after maximal response of the tumor to AD.
Study Design This is a phase II trial evaluating the toxicity and efficacy of individualized neoadjuvant AD administered to maximal response followed by RT with continued AD for a total of 9 months for clinically localized prostate cancer. Between July 1997 and September 2002, 123 patients were enrolled at the Columbia University Medical Center (CUMC; New York, NY).
Patients
Treatment RT. Patients were treated with either conformal or intensity-modulated (IMRT) radiation therapy. Either a four-field or a six-field technique was used. The four-field technique consisted of 1.8 Gy daily to 45 Gy followed by a three-field technique to 70.2 Gy.The six-field technique utilized this beam arrangement throughout the treatment. The dose per fraction and total dose were the same with either technique. The planning target volume (PTV) was defined as the prostate and seminal vesicles with 1-cm margins. Dose was prescribed to the isodose volume encompassing the PTV. Two patients were treated with a cone-down off the seminal vesicles after 45 Gy. On the basis of preliminary data from Royal Marsden Hospital12 and M.D. Anderson Cancer Center (The University of Texas, Houston, TX),13 beginning in February 2003, the target total dose of radiation per patient was raised to 75.6 Gy. For these high-dose IMRT patients (n = 6), 100% of the prostate and seminal vesicles and at least 95% of the PTV were enclosed by the prescription isodose volume. Analysis revealed that exclusion of these patients did not alter any results (data not shown). Therefore, results are presented for the entire patient population only. One patient did not receive radiation, and one patient discontinued radiation after receiving only 5.4 Gy. The five other noncompliant doses were due to miscellaneous factors such as machine malfunction, extra set-up x-rays, or physician preference. Hormonal therapy. Patients received intramuscular luprolide acetate 7.5 mg/mo injected monthly or once every 3 months and oral flutamide 250 mg tid for a total of 9 months. One patient received goserelin acetate instead of luprolide acetate. Five percent of patients (n = 6) did not receive flutamide at study entry because they did not meet predefined eligibility criteria for taking the medication. Ten percent (n = 13) discontinued flutamide for other than protocol-defined reasons. Determination of time to start RT. Starting at initiation of AD, tumors were monitored monthly by digital rectal examination (DRE) and serum PSA until they reached maximal response by both methods of assessment, at which time patients began RT. A patient was defined as having reached maximal PSA response if his serum PSA became undetectable ("undetectable") or was unchanged ("nadir") or rising ("rising") from one month to the next. A patient was defined as having reached maximal DRE response if his DRE findings stabilized from one month to the next or completely resolved ("complete response"). In order to avoid excessive delay, patients began RT no later than 6 months after initiation of AD ("6 months"), even if the criteria for maximal response were not met.
Efficacy Assessments The primary end point of this study was biochemical disease-free survival (BDFS). Although the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Conference produced guidelines for defining BDFS,14 these guidelines were based on data obtained from clinical studies involving patients treated with radiotherapy alone. BDFS remains difficult to define for patients treated with both radiotherapy and hormonal therapy. Therefore, failure of BDFS was defined according to the definition used by Bolla et al3: serum PSA greater than 1.5 ng/mL and increasing on two consecutive measurements separated by at least 3 months. Death from any cause subsequent to two consecutive measurements demonstrating rising PSA was also considered a failure of BDFS. Clinical disease-free survival (CDFS) was a secondary end point. Failure of local tumor control (defined by prostate biopsy or DRE), failure of metastasis-free survival, and reinitiation of therapy were each defined as a failure of CDFS. Another secondary end point was overall survival, with failure defined as death as a result of any cause. Cause-specific survival, with failure defined as either death during treatment for cancer recurrence or recurrence resulting in death, was additionally considered. Freedom from hormone-refractory prostate cancer (HRPC) was considered as well, because it is a good surrogate end point for survival.15 Failure of HRPC-free survival was defined for patients receiving AD as three consecutive rises in serum PSA, evidence of progressive metastases by imaging, or initiation of new treatment.
Toxicity Assessments
Statistical Analysis
Conduct of Study
Efficacy Patient characteristics at initiation of RT are displayed in Table 2. Measures of disease control and mortality are reported in Table 3.
Predictors of biochemical failure. Patients with baseline serum PSA more than 30 ng/mL were significantly more likely to have a failure of BDFS at 5 years (54% ± 13%) than were those with baseline serum PSA  30 ng/mL (30% ± 7%; P = .045). Similarly, patients who began RT after 6 months were significantly more likely to have a failure of BDFS at 5 years (82% ± 15%) than were patients who began RT with an undetectable (33% ± 12%), nadir (29% ± 8%), or rising (18% ± 11%) serum PSA (pooled comparison P = .002). Pair-wise comparisons of the 6-month group with the undetectable (P = .005) and nadir (P = .001) serum PSA groups were also significant, even after Bonferonni adjustment (required significance of P < .0083). Comparison with the rising serum PSA group was significant by standard criteria (P = .043), but not after Bonferonni adjustment. Clinical stage, GS, risk group, race, age, serum PSA at initiation of RT, and complete response to DRE at initiation of RT failed to predict for biochemical failure. On multivariate analysis, only indication to begin RT independently predicted BDFS (Table 4).
Predictors of clinical failure. Patients with tumors of GS greater than 7 were significantly more likely to have a failure of CDFS at 5 years (40% ± 9%) than were patients with tumors of GS 7 (19% ± 8%) or less than 7 (0%; P = .024). Patients who began RT after 6 months were also significantly more likely to have a failure of CDFS at 5 years (75% ± 15%) than were patients who began RT with an undetectable (27% ± 10%), nadir (15% ± 6%), or rising (0%) serum PSA (pooled comparison P = .001; Fig 1). Pair-wise comparisons of the 6-month group with the nadir (P < .001) and rising (P = .008) serum PSA groups were also significant, even after Bonferonni adjustment. Comparison with the undetectable serum PSA group was significant by standard criteria (P = .043), but not after Bonferonni adjustment. Clinical stage, risk group, race, age, baseline serum PSA, serum PSA at initiation of RT, and complete response to DRE at initiation of RT failed to predict for clinical failure. Multivariate analysis demonstrated that both GS and indication to begin RT independently predicted CDFS (Table 5).
Further analysis of the group beginning RT after 6 months of AD. There were no significant differences in age, race, clinical stage, GS, or risk group between this subgroup at study entry and the other response groups (PSA undetectable, nadir, and rising). There were also no significant differences in serum PSA at study entry, immediately before RT, or at 3 months after initiation of AD. Furthermore, patients who initiated RT after 3 months of AD had elapsed were not more likely to have a failure of any study end point at 5 years compared with those who reached maximal response within 3 months (data not shown).
Testosterone recovery.
Serum testosterone concentration returned to normal ( Patients who recovered serum testosterone to normal levels after completion of AD were not more likely to have a failure of BDFS or CDFS at 5 years compared with those who did not recover serum testosterone to normal levels (BDFS, 40% ± 7% v 26% ± 14%, P = .176; CDFS, 25% ± 6% v 25% ± 12%, P = .840). Interestingly, patients who recovered serum testosterone to normal levels after completion of AD were significantly more likely to survive for 5 years (95% ± 3%) than were those who did not recover serum testosterone to normal levels (70% ± 10%; P < .001; Fig 2). Clinical stage, GS, risk group, race, age, serum PSA at study entry, serum PSA at initiation of RT, reason for initiation of RT, and complete response to DRE at initiation of RT failed to predict for overall mortality. Because of the small numbers of deaths, cause-of-death analysis was limited, but there was no statistically significant difference in cause of death between those who did and did not recover serum testosterone to normal levels.
Toxicity Erectile dysfunction. The majority of patients lost potency during treatment (Table 6). At study entry, 69% (n = 85) of patients had some potency (erectile dysfunction of grades 0, 1, or 2). During treatment, only 16% of patients (n = 25) maintained some potency. Fortunately, many patients recovered potency after treatment (Table 7). Of the 85 patients with some potency at baseline, 65% (n = 55; 45% of total) had some potency at last follow-up. Median time to recovery of potency was 10 months (range, 0 to 57 months). Age, race, and return to normal of serum testosterone concentration failed to predict for return of potency (data not shown).
Other adverse events. Most toxicities were mild, and patients often recovered quickly (Tables 8, 9, and 10). Less than 5% of patients experienced grade 3 toxicity except for anemia and acute urinary frequency/urgency. Ninety percent of patients with grade 3 anemia recovered, and they did so with a median recovery time of less than 1 month. Twenty percent of patients (n = 24) discontinued flutamide due to elevated liver function tests (n = 18) or diarrhea (n = 6), as required by the protocol.
Several randomized clinical trials have indicated improvement in the efficacy of treatment for clinically localized prostate cancer when RT is combined with AD, and some indicate that an extended course of AD may add benefit.1-4 Here, the toxicity and efficacy of a protocol utilizing AD with RT in a novel way have been considered. Tables 11 and 12 put this protocol in the context of previously published prospective AD-with-RT trials.
The suggestion that extending the neoadjuvant phase is advantageous appears to conflict with data from Crook et al,8 who reported no statistically significant differences in 5-year outcomes between patients receiving 3 months and 8 months of neoadjuvant AD. However, in their trial, patients were not monitored during their neoadjuvant phase. Therefore, it is possible that some patients on the 8-month arm were already progressing at initiation of RT. Furthermore, subgroup analysis of the Crook et al trial did show a benefit to 8 months of AD in their high-risk group. The vast majority of patients in the trial reported here were at high risk. To assess different approaches in treating patients with clinically localized prostate cancer, it is useful to compare their treatment toxicities. Such toxicities may be assessed using a patient-reported validated quality-of-life instrument. However, given a multilingual patient population, the robust, clinician-driven CTC toxicity scale, which superbly details all toxicities and their grades, was chosen. Of note in the study presented here is the relatively high rate of preservation of sexual potency after completion of AD. Unfortunately, with the exception of the trial conducted by D'Amico et al in 2004,1 trials that combine AD with RT have not reported impotence rates after treatment. It is certain that patients in those trials that delivered hormone therapy for 2 to 3 years had a longer period of impotence than those treated with our approach. It is not known, however, whether the rates of sexual recovery after completion of AD are as good as those reported in this study. A striking result obtained after analysis of patient outcomes was the high prevalence of biochemical and clinical failure among patients who initiated RT without first reaching maximal response (ie, after 6 months). The mechanism for the recurrence of biochemical and clinical disease in patients who initiate therapy without first reaching maximal response warrants further investigation. These patients might represent a subset of the population requiring more aggressive treatment than administered in this study. Thus, monitoring patient response, as demonstrated here, may be advantageous not only in delivering a more favorable sequence of AD and RT, but also in identifying a high-risk subgroup. The finding of an improved survival in those patients whose testosterone recovered compared with those whose testosterone remained suppressed is surprising. Whether this reflects unseen and unappreciated overall benefits to health of having normal serum testosterone levels or whether lack of testosterone recovery is a marker for overall poor health is uncertain. Of note, those whose testosterone recovered did not have significantly higher rates of biochemical or clinical failure. These findings suggest that testosterone recovery may be beneficial to overall health without having deleterious effects on prostate cancer control, and further support the notion of limiting the length of time AD is administered to the minimum necessary. In summary, the results of this study provide evidence that individualization of neoadjuvant AD to maximal response followed by RT with continued AD for a total of 9 months can safely be used to treat patients with intermediate- to high-risk clinically localized prostate cancer and preserve potency in many patients. Additional studies are needed to determine the optimal combination of AD and RT in this patient population.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Ronald D. Ennis, Integrated Therapeutics Group Inc, TAP Pharmaceuticals Testimony: N/A Other: N/A
Conception and design: Mitchell C. Benson, Kathleen M. O'Toole, Peter B. Schiff, Mahesh M. Mansukhani, Ronald D. Ennis Financial support: Ronald D. Ennis Administrative support: Darleen Vecchio, Peter B. Schiff, Ronald D. Ennis Provision of study materials or patients: Mitchell C. Benson, Kathleen M. O'Toole, Rachel Brody, Darleen Vecchio, Peter B. Schiff, Mahesh M. Mansukhani, Ronald D. Ennis Collection and assembly of data: Jonas J. Heymann, Kathleen M. O'Toole, Bozena Malyszko, Darleen Vecchio, Mahesh M. Mansukhani, Ronald D. Ennis Data analysis and interpretation: Jonas J. Heymann, Ronald D. Ennis Manuscript writing: Jonas J. Heymann, Ronald D. Ennis Final approval of manuscript: Jonas J. Heymann, Mitchell C. Benson, Kathleen M. O'Toole, Bozena Malyszko, Rachel Brody, Darleen Vecchio, Peter B. Schiff, Mahesh M. Mansukhani, Ronald D. Ennis
We thank Jena Giltnane and Jinesh Shah, MD, for their advice, and Clemencia Talero, Ruthie Nunez, Lisa Chin, and Joanne Coates for their support.
Supported by an unrestricted educational grant from Integrated Therapeutics Group Inc, a subsidiary of Schering-Plough, and by TAP Pharmaceuticals. Presented in part at the 43rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, November 4-8, 2001, San Francisco, CA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. D'Amico AV, Manola J, Loffredo M, et al: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial. JAMA 292:821-827, 2004 2. Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 21:3972-3978, 2003 3. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet 360:103-106, 2002[CrossRef][Medline] 4. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243-1252, 2001[CrossRef][Medline] 5. Denis LJ, Carnelro de Moura JL, Bono A, et al: Goserelin acetate and flutamide versus bilateral orchiectomy: A phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center. Urology 42:119-130, 1993[CrossRef][Medline] 6. Crawford ED, Eisenberger MA, McLeod DG, et al: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 321:419-424, 1989[Abstract] 7. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al: Outcomes of external-beam radiation therapy for prostate cancer: A study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas. J Clin Oncol 14:2258-2265, 1996[Abstract] 8. Crook J, Ludgate C, Malone S, et al: Report of a multicenter Canadian phase III randomized trial of 3 months vs 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 60:15-23, 2004[CrossRef][Medline] 9. Zietman AL, Nakfoor BM, Prince EA, et al: The effect of androgen deprivation and radiation therapy on an androgen-sensitive murine tumor: An in vitro and in vivo study. Cancer J Sci Am 3:31-36, 1997[Medline] 10. Zietman AL, Prince EA, Nakfoor BM, et al: Androgen deprivation and radiation therapy: Sequencing studies using the Shionogi in vivo tumor system. Int J Radiat Oncol Biol Phys 38:1067-1070, 1997[CrossRef][Medline] 11. Kaminski JM, Hanlon AL, Joon DL, et al: Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth. Int J Radiat Oncol Biol Phys 57:24-28, 2003[Medline] 12. Dearnaley D, Hall E, Jackson C, et al: Phase III trial of conformal radiotherapy following neoadjuvant hormone treatment in early prostate cancer. Int J Radiat Oncol Biol Phys 54:134-135, 2002 (suppl) 13. Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: Results of the MD Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53:1097-1105, 2002[CrossRef][Medline] 14. Consensus statement: Guidelines for PSA following radiation therapy—American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997[CrossRef][Medline] 15. Zietman AL, Dallow KC, McManus PA, et al: Time to second prostate-specific antigen failure is a surrogate endpoint for prostate cancer death in a prospective trial of therapy for localized disease. Urology 47:236-239, 1996[CrossRef][Medline] 16. Teshima T, Hanks GE, Hanlon AL, et al: Rectal bleeding after conformal 3D treatment of prostate cancer: Time to occurrence, response to treatment and duration of morbidity. Int J Radiat Oncol Biol Phys 39:77-83, 1997[CrossRef][Medline] 17. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995[CrossRef][Medline] Submitted December 20, 2005; accepted September 5, 2006. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
270 ng/dL) in 69% of patients (n = 85). Median time to recovery was 9 months (range, 0 to 54 months). Pretreatment serum testosterone concentrations were determined in 86 patients. Serum testosterone returned to its baseline concentration after completion of AD in 37% (n = 32) of those patients. Median time to recovery was 11 months (range, 0 to 52 months). 
