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13-cis Retinoic Acid and Complete Androgen Blockade in Advanced Hormone-Naive Prostate Cancer Patients: Report of a Phase II Randomized Study

From the Division of Medical Oncology and Departments of Urology, Radiation Oncology, and Biomathematics, Mount Sinai School of Medicine, New York; and Division of Oncology, Veterans Administration Medical Center, Bronx, NY.

Address reprint requests to Anna C. Ferrari, MD, Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1129, New York, NY 10029; email: anna.ferrari{at}mssm.edu

	ABSTRACT

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PURPOSE: 13 cis Retinoic acid (isotretinoin) is a retinoid with preclinical evidence of anti–prostate cancer activity. This phase II, cross-over, randomized study of advanced, predominantly androgen-dependent prostate cancer patients was designed to assess primarily the effect on prostate-specific antigen (PSA) decline and toxicity of adding isotretinoin to hormonal therapy and, secondarily, the potential antitumor activity of the combination.

PATIENTS AND METHODS: Thirty-seven D0 to D2 patients were randomized soon after initiating luteinizing hormone–releasing hormone agonist with antiandrogen treatment to add (arm 1) or not (arm 2) isotretinoin from weeks 1 to 12. After cross-over on week 13, patients in arm 1 discontinued while patients in arm 2 added isotretinoin from weeks 14 to 25. Observation on hormonal therapy alone continued until week 49.

RESULTS: Baseline and randomization median PSA for 30 assessable patients were, respectively, 34 and 18.2 ng/mL for arm 1 and 31 and 13.4 ng/mL for arm 2. Median PSA at week 13 was 0.5 ng/mL (range, < 0.05 to 136 ng/mL) for arm 1 and 0.7 ng/mL (range, < 0.05 to 4.4 ng/mL) for arm 2; at week 25, 0.1 ng/mL (range, < 0.05 to 121 ng/mL) and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL), respectively. At week 49, arm 1 had median PSA of 0.1 ng/mL (range, < 0.05 to 345 ng/mL) and arm 2, 0.3 ng/mL (range, < 0.05 to 8.8 ng/mL); seven of 15 and three of 15 patients, respectively, had undetectable PSA levels (P = .12). Frequent isotretinoin-related toxicity included grade 1 cheilitis (76%), skin dryness (43%), and elevated triglycerides (50%).

CONCLUSION: Isotretinoin does not impair PSA decline or add significant toxicity to hormonal therapy. An adequately powered, randomized study would be required to determine whether the combination is superior to standard hormonal treatment.

	INTRODUCTION

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ALTHOUGH THE vast majority of patients with advanced prostate cancer will initially respond to androgen ablation due to apoptosis of androgen-dependent tumor cells,^1-6 they invariably experience disease progression. A recurrent androgen-independent tumor arises from the remaining pool of prostatic stem cells after castration by a process of selection of preexisting androgen-independent clones⁷ or by adaptation of surviving androgen-dependent clones.⁴ A strategy to improve outcome of these patients may include delaying or preventing this process.

Epidemiologic⁸ and experimental^9-13 evidence support that retinoids are compounds with influence on prostate cancer cells in vitro and in vivo.¹⁴ The mechanism of antitumor activity seems to be multifactorial. They can directly induce differentiation with prostate-specific antigen (PSA) expression^15,16 or apoptosis of androgen-dependent and androgen-independent prostate epithelial cells.¹⁷ Their activity can block proliferation in response to growth factors or testosterone by reducing 5-alpha reductase activity.^18,19 Retinoids can also reduce invasiveness of prostate cancer cells and angiogenesis in primary tumors.^20,21 In the limited experience with retinoids in prostate cancer patients, all-trans retinoic acid alone was unable to elicit significant clinical responses in patients with hormone-refractory disease.²²

These observations lend support to the hypotheses that 13-cis retinoic acid (isotretinoin) might potentially enhance the initial androgen ablation response to hormonal therapy and/or inhibit the adaptation or selection process of the residual tumor stem cells that lead to progression.^23,24

To test these hypotheses, a number of variables were considered. We postulated that hormone-naive patients with advanced but predominantly androgen-dependent disease would be the most responsive to isotretinoin and that the activity of isotretinoin could change as the phenotype of the tumor cell population shifted from the early to the later phases of response to androgen ablation, possibly disturbing the characteristic biphasic pattern of PSA decline. It is well recognized that 80% to 90% of the hormone-naive patients experience a steep PSA decline, reaching levels less than 4 ng/mL during the initial 10 to 12 weeks of hormonal therapy. During the slower, plateau phase of decline, PSA reaches a nadir that can be sustained for prolonged periods.^1,2 Because the PSA nadir and the duration of the nadir in response to hormonal therapy have been correlated with prognostic significance,² it was important to first determine whether the value of PSA as a marker of response to hormonal treatment could be impaired by isotretinoin. We speculated that if induction of differentiation was the prevailing effect of isotretinoin, a net increase or slowing in the rate of PSA decline with a higher nadir could occur. In this setting, separating a paradoxical PSA increase from true tumor progression would be critical to assess response. In contrast, if apoptosis was markedly enhanced by isotretinoin, the rate of PSA decline and the nadir might be lower compared with that achieved with hormonal therapy alone. Moreover, if the activity of isotretinoin was less pronounced than anticipated and required some time to become clinically apparent, a period of observation after discontinuation of isotretinoin would be necessary to assess more subtle PSA changes.

Therefore, to test the activity of isotretinoin in the context of androgen ablation and the consequences on PSA as a marker, we sought primarily to investigate the effect of two different schedules of isotretinoin on PSA levels and the additional toxicity it might entail. A secondary goal was to assess efficacy by the end of 1 year.

	PATIENTS AND METHODS

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Eligible patients had histologically confirmed diagnosis of adenocarcinoma of the prostate with evidence of stage D1 or D2 metastatic disease documented on bone scan or computed tomography or evidence of disease progression defined only by an increasing PSA (D0) on two consecutive determinations at least 2 weeks apart after definitive radiation therapy or prostatectomy. Prior hormonal therapy was not acceptable except in the neoadjuvant setting for a period up to 6 months before radiation and provided it had been discontinued at least 12 months before study entry and the PSA became undetectable during that interval. The required PSA level before initiation of hormonal therapy was 10 ng/mL. Performance status (PS) requirement was 0 to 2 by Eastern Cooperative Oncology Group (ECOG) criteria. Required laboratory parameters for all patients also included granulocytes more than 1,500/mL, hemoglobin 8.0 g/dL, platelets more than 100,000 cells/mL, serum creatinine 2 mg/dL, bilirubin 1.5 times the upper limit of normal, and AST less than 1.5 times the upper limit of normal. Exclusion criteria included a history of acute spinal cord compression or brain metastasis; treatment with orchiectomy, chemotherapy, biologic response modifiers, or sustained hormonal therapy; and a history of sensitivity to parabens or skin disorders adversely affected by isotretinoin. All patients were required to sign informed consent in accordance with institutional, state, and federal guidelines.

Pretreatment evaluation for eligible patients included a complete history and physical examination, including potency status, serum testosterone, prostate acid phosphatase, lactate dehydrogenase, alkaline phosphatase, and cholesterol and triglycerides within 7 days of registration. A bone scan, computed tomography scan of the abdomen and pelvis, chest x-ray, transrectal ultrasound of the prostate, and ultrasound of the kidney for suspected hydronephrosis were required within 60 days of enrollment.

Eligible patients received an antiandrogen (flutamide 250 mg orally three times per day or bicalutamide 50 mg daily) followed 10 days later by monthly injections of a luteinizing hormone–releasing hormone agonist (leuprolide acetate 7.5 mg by intramuscular injection or goserelin 3.6 mg by subcutaneous injection). Hormonal therapy was maintained for at least 12 months and thereafter was managed by the treating physician. Isotretinoin was administered orally at 1 mg/kg daily in two divided doses with meals and provided at no cost to patients by the Cancer Treatment Evaluation Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD. Patients were advised to discontinue vitamin supplements containing vitamin A and to avoid foods rich in vitamin A such as liver, animal organs, carrots, squash, pumpkin, and sweet potatoes.

Patients were evaluated by clinical and laboratory parameters every 4 weeks until week 25 and on weeks 37 and 49. A history and physical examination were obtained with emphasis on anticipated toxicity associated with vitamin A (cheilitis, pruritus, epistaxis, nocturnal vision, headaches, dizziness, arthritic pain, and so on) and with hormonal treatment (hot flushes and loss of libido and potency). Laboratory parameters included PSA, complete blood cell counts, bilirubin, AST, ALT, blood-urea nitrogen, creatinine, alkaline phosphatase, prostatic acid phosphatase, lactate dehydrogenase, and cholesterol and triglyceride levels. Scans were repeated on weeks 25 and 49 or at any time progression was considered. Toxicity was graded and recorded according to the National Cancer Institute common toxicity criteria. Persistent grade 2 or greater elevation of bilirubin, ALT, or AST required discontinuation of flutamide and isotretinoin. Elevation of triglyceride levels 800 mg/dL, unresponsive to lipid lowering agents, and any grade 3 or 4 visual abnormality or pseudotumor cerebri required stopping isotretinoin.

End Points, Study Design, and Statistical Methods
The main end points of this study were to assess changes in PSA levels induced by isotretinoin during the steep or plateau phase of decline of PSA in response to hormonal therapy and the toxicity of the combination. A secondary objective was to evaluate whether the schedule of isotretinoin influenced the efficacy after 1 year of initiating treatment.

To accomplish these goals we used a phase II, randomized, cross-over design that included three periods (Fig 1): (1) a lead-in period of hormonal therapy alone to identify among the pool of hormone-naive patients registered in the study those with predominantly androgen-dependent disease and to exclude those with predominantly androgen-independent disease; (2) an isotretinoin treatment period after randomization to study the PSA curve in response to the addition of isotretinoin to hormonal therapy from weeks 1 to 12 or 14 to 25 while preserving a control group on hormonal therapy alone; and (3) an observation period of hormonal therapy alone from weeks 25 to 49 to evaluate the significance of possible PSA changes induced by isotretinoin and whether a subtle, long-term antitumor effect could be detected.

View larger version (20K): [in this window] [in a new window]   Fig 1. Study schema. Patients initiating hormonal therapy were randomized after a brief lead-in period to add (arm 1) or not (arm 2) isotretinoin on weeks 1 to 12, to cross-over on week 13, to discontinue or add isotretinoin, respectively, on weeks 14 to 25, and observation on hormones through week 49. Abbreviation: Q, every.

For the purpose of addressing the main hypothesis of the effect of isotretinoin on androgen-dependent prostate cancer, the statistical analysis of PSA response in the postrandomization periods was restricted to patients free of biochemical or clinical evidence of progression during that interval. This measure was adopted to avoid interpreting PSA increases caused by androgen-independent tumor growth from those possibly related to tumor differentiation induced by isotretinoin. PSA progression was defined by three consecutive PSA increases above the nadir at least 2 weeks apart or a 50% increase above the randomization level for patients receiving isotretinoin. The latter required discontinuation of isotretinoin. Evaluation of nonmeasurable but assessable and measurable disease was performed in all cases with clinical or biochemical evidence of progression. Complete biochemical response was defined as a PSA level less than 0.1 ng/mL without clinical evidence of progression.

The required sample size was determined in order to detect a moderately large effect of isotretinoin on serum PSA levels. Because the distribution of PSA measurements is highly skewed, serum PSA data were logarithmically transformed to the base 2, as in Miller et al.¹ Sixteen patients in each group (arm 1 and arm 2) would allow detection of a difference of one SD (in the log₂ scale) between the mean PSA levels of the two groups with power of 0.80 for a two-sided test at the .05 significance level. We estimated, from our data, that the SD of PSA levels, 25 weeks after the start of combined androgen suppression therapy, is approximately 2.5 in the log₂ scale. A difference of 2.5 in the log₂ scale corresponds to a six-fold increase in PSA level. Hence, the sample size of 16 patients in each arm was adequate for detecting a six-fold difference in PSA levels between the two groups with power of 0.80.

PSA levels were compared between arm 1 and arm 2 at each time point by the Wilcoxon rank sum test. The proportion of patients achieving a PSA less than 0.1 ng/mL were compared for arm 1 and 2 by the ² test. Survival and progression-free survival were estimated by the Kaplan-Meier method.

	RESULTS

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Patient Characteristics
Thirty-seven patients from the Mount Sinai Medical Center in New York and the Bronx Veterans Administration Hospital were registered to the study from 1995 to 1999. Three patients were removed from study during the lead-in period because they did not meet protocol criteria for randomization (two because of noncompliance with hormonal treatment and one because of complications from local-regional progression). Thirty-four patients were randomized, 18 to arm 1 and 16 to arm 2. As described in Table 1, the distribution according to patient characteristics was balanced between arms 1 and 2, respectively: median age, 68 and 67 years; Gleason score of the primary tumor 6, four and six patients, 7, 14 and 10 patients; treatment of the primary tumor, eight and 12 patients had eperienced treatment failure with radiation therapy and two and one patients had experienced treatment failure with radical prostatectomy; six patients in each arm had received neoadjuvant hormonal therapy before radiation and, except for one patient in arm 2 who discontinued hormonal therapy for 10 months, the remaining patients in both arms had discontinued hormonal treatment for at least 12 months before study entry. Based on clinical staging criteria, arms 1 and 2, respectively, had five and four patients with stage D0, three and three patients with stage D1, and 10 and nine patients with stage D2 disease. The latter included 19 patients with a positive bone scan, eight with fewer than six lesions, nine with six to 20 lesions, and two with more than 20 lesions. Fifteen and 14 patients in arms 1 and 2, respectively, had ECOG PS of 0, two and one patients had PS of 1, and one patient in each arm had PS of 2. The median PSA levels at baseline and randomization were similar, 34 ng/mL (range, 10 to 1,383 ng/mL) and 18.2 ng/mL (range, 4.7 to 553 ng/mL), respectively, for arm 1; 31 ng/mL (range, 12 to 582 ng/mL) and 13.6 ng/mL (range, 5.9 to 81.3 ng/mL), respectively, for arm 2. The median time from initiation of hormonal therapy to the date of randomization was also similar between the arms, 12 days (range, 3 to 39 days) for arm 1 and 10 days (range, 4 to 57 days) for arm 2.

Table 2 describes the median and range of PSA levels observed at established time points for patients randomized to arm 1 and 2. Week 1 median PSA levels were those described at randomization. Patients in arm 1 reached a median PSA of 0.5 ng/mL (range, < 0.05 to 136 ng/mL) at week 13 after adding isotretinoin from weeks 1 to 12; patients in arm 2 reached a median PSA of 0.7 ng/mL (range, < 0.05 to 4.4 ng/mL) while on hormonal therapy alone for the same period. After week 13, patients in arm 1 discontinued isotretinoin and, vice versa, patients in arm 2 added isotretinoin from weeks 14 to 25. The median PSA levels by week 25 were 0.1 ng/mL (range, < 0.05 to 121 ng/mL) and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL), respectively, for patients randomized to arms 1 and 2. By weeks 37 and 49, the median PSA levels were, respectively, 0.1 ng/mL (range, < 0.05 to 2035 ng/mL) and 0.1 ng/mL (range, < 0.05 to 345 ng/mL) for arm 1, and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL) and 0.3 ng/mL (range, < 0.05 to 8.8 ng/mL) for arm 2 patients. None of the differences in median PSA were significant at any time point (week 25, P = .64; week 37, P = .45; week 49, P = .21).

	DISCUSSION

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More relevant to the proposed hypothesis, the results indicated that the coadministration of retinoids, whether during the first or second 12 weeks after the beginning of androgen ablation therapy, did not impair the initial steep nor the secondary plateau phase of PSA decline.^1,2 In fact, by week 13, we could not detect (Table 2) significant differences in median PSA for patients randomized to arm 1, who received isotretinoin from weeks 1 to 12, and patients randomized to arm 2, who received only hormonal therapy in that interval (0.5 ng/mL and 0.7 ng/m, respectively; P = .64). Neither could we find a significant difference in median PSA achieved by week 25 for patients randomized to arm 2, who received isotretinoin from weeks 14 to 25, and patients randomized to arm 1, who received hormonal therapy for that period (0.4 ng/mL and 0.1 ng/mL, respectively; P = .45).

These observations indicate that any differentiation effect of isotretinoin on the hormone-sensitive prostate cancer cells associated with increased PSA production was offset by the massive apoptosis of this cell population that occurs in the early phases of response to androgen deprivation.^3-6 The lack of an increase or slowing in PSA decline observed in the plateau phase also suggests that isotretinoin did not induce differentiation of the smaller pool of remaining tumor cells. These results indicate that PSA remains a reliable surrogate end point to assess response to hormonal therapy in combination with a differentiation inducer.

As predicted from previous experience,²² isotretinoin was not active in patients with predominantly androgen-independent disease, as illustrated by the 24% failures observed in the postrandomization period. This rate is within the range of failure expected for hormone-naive patients treated with androgen-ablative hormonal therapy alone.²

In terms of assessing our secondary objective, whether the timing of isotretinoin affected the long-term activity of the combination, we found that by the end of 1 year, the differences between arms 1 and 2, measured as either median PSA (0.1 and 0.3 ng/mL, respectively) or number of complete biochemical responders (seven of 15 and three of 15, respectively), were not significant (P = .21 and P = .12, respectively). Thus this study provides no support for the possibility that isotretinoin might affect the response to androgen-ablative hormonal therapy in patients with advanced, predominantly androgen-dependent disease.

Nevertheless, recognizing the limitations of this study, we suggest that the possibility should be considered, that the differences in PSA noted between the early and late addition of isotretinoin could reflect a real potentiating effect of isotretinoin during the initial phase of androgen ablation. It is intriguing that although at baseline and randomization (Table 1) the median PSA values were higher for patients receiving early (arm 1) rather than late isotretinoin (arm 2), arm 1 experienced a slightly more pronounced PSA decline and a lower nadir at all time points (Table 2). In light of previously published data, this might explain why by the end of the study this group had seven rather than three of 15 patients with complete PSA response (Table 3).^2,25

There is ample precedent for retinoids inducing cell apoptosis rather than differentiation in a variety of cell types under certain conditions.^26,27 Thus it is conceivable that isotretinoin facilitated the recruitment of prostate cancer cells to the apoptosis cascade triggered soon after androgen ablation but that the patient sample size was inadequate to evaluate a relatively small additional benefit on PSA decline over the background of steep reductions that follow massive cell death.

Finally, with regard to evaluating whether the combination had any potential benefit on outcome, we note that this study was not designed to answer this question, but the evidence suggests that there was no deleterious activity of isotretinoin on the long-term outcome in response to hormonal therapy. At 48 months of follow-up, the disease-free survival of the protocol cases was 59%, which compares favorably with the 40% to 20% rates previously reported for hormone-naive patients with a similar spectrum of advanced disease (D0 to D2) treated with combined androgen suppression alone.^28-31 A larger randomized study of patients with predominantly androgen-dependent, low tumor burden disease would be needed to determine whether the combination with isotretinoin is of additional benefit over standard hormonal therapy.

	ACKNOWLEDGMENTS

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Sponsored by the Cancer Treatment Evaluation Program, National Cancer Institute, and supported by grants from the T.J. Martell Foundation for Leukemia, AIDS and Cancer Research and the Cancer Research Institute, New York, NY.

We thank Richard Kaplan, MD, and Henry C. Stevenson-Perez, MD, from the Cancer Therapy Evaluation Program, National Cancer Institute, for critical assessment and discussion of the protocol design.

	REFERENCES

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Submitted April 6, 2001; accepted August 27, 2001.

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This Article Abstract Full Text (PDF) 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ferrari, A. C. Articles by Mandeli, J. Search for Related Content PubMed PubMed Citation Articles by Ferrari, A. C. Articles by Mandeli, J.