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Clinical Trials |
Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine [W. K. K., I. O., H. I. S.], and Departments of Pathology [V. E. R.], Nursing [T. C.], and Urology [W. D. W. H.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Division of Hematology and Medical Oncology, Department of Medicine [D. M. N.], and Department of Medicine [W. K. K., H. I. S.], Joan and Sanford Weill Medical College of Cornell University, New York, New York 10021
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTScRA\/IFN in Patients with...DISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTScRA\/IFN in Patients with...DISCUSSIONREFERENCES |
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Previously, we proposed a methodology for evaluation of new agents in prostate cancer using posttherapy changes in PSA (6) . This was required because the patterns of spread of the disease preclude the use of more traditional end points of efficacy. This method restricted entry to patients that had progressive disease, despite castrate levels of testosterone and tumor progression after the withdrawal of the antiandrogens and steroid hormones (6 , 7) . Outcomes are reported on the basis of changes in PSA, changes in bone, and changes in soft tissue independently (6) . For differentiating agents in particular, it was recognized that a unique end point would be required because these compounds may initially increase PSA levels, which might be misinterpreted as "treatment failure." As such, a pathological end point using accessible tumor tissue was used in these studies. Posttherapy PSA changes, increases or decreases, were not used to determine response or to continue treatment in the absence of other parameters.
ATRA was the first agent studied. The results showed that the compound induced its own degradation within 48–72 h, which may have contributed to the lack of clinical activity seen (8 , 9) . In the second trial, cRA was combined with IFN, based on an improved pharmacokinetic profile (10) , the antiproliferative effects in vitro, and the additive effects of IFN. (11) Patients with both AI and AD tumors were studied, and the disease was evaluated by pre- and posttherapy biopsy for histology, proliferative index, and apoptotic changes. To assess for differentiation effect, PSMA expression was also assessed.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTScRA\/IFN in Patients with...DISCUSSIONREFERENCES |
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Patients must have been at least 3 weeks from major surgery and at least 4 weeks from any prior radiation. Individuals were excluded if they had New York Heart Association class III or IV heart disease, history of bleeding disorders, peripheral neuropathy, central nervous system disease, active infection, or the presence of brain metastases. Patients who had not undergone a surgical orchiectomy were continued on medical therapies. These protocols were approved by the Institutional Review Board and written informed consent was required in all patients.
The pretreatment evaluation included a complete history and physical examination with a baseline KPS. Laboratory studies included an automated blood and platelet count, serum electrolytes, 12-channel screening profile (alkaline phosphatase, lactate dehydrogenase, aspartate transglutaminase, blood urea nitrogen, creatinine, calcium, phosphorus, uric acid, total protein, albumin, and total bilirubin), cholesterol, triglycerides, serum acid phosphatase (ACP), and PSA. Imaging studies included an abdominal and pelvic CT scan, bone scan, and chest radiograph or magnetic resonance imaging when clinically indicated.
In posttreatment, the automated blood and platelet count was performed weekly for the first 4 weeks and then every 2 weeks. A screening profile, electrolytes, creatinine, cholesterol, triglycerides, ACP, and PSA were repeated biweekly for the first 8 weeks and at a minimum of monthly thereafter. Measurable disease was evaluated at 8-week intervals, whereas radionuclide bone scans were generally repeated at 12-week intervals in the absence of other criteria of disease progression. All drug-related toxicities were recorded and graded according to the NCI Common Toxicity Criteria (version 1).
Assessment of Tumor Biopsies.
All patients on the ATRA study and patients with assessable tumors in
the cRA\/IFN study had pre- and posttherapy tumor
biopsies obtained. Biopsies were obtained within 4 weeks of starting
the therapy and were repeated after 4 weeks of therapy. The same
lesions were biopsied when possible. Pre- and posttherapy tumor
biopsies were evaluated for histological changes on H&E stains, for
apoptosis using a modified terminal deoxynucleotidyl
transferase-mediated nick end labeling method as described by Gavrieli
et al. (12)
, and for proliferation index using
anti-Ki67 monoclonal antibody MIBI (Immunototech; 1:50 dilution). Ki67
proliferative index was considered high when 
20% of tumor cells
displayed a positive MIBI nuclear immunoreactivity pattern.
Two different antibodies against the intracellular domain of PSMA, PM2 (Hybritech), and 7E11(Cytogen Corp., Princeton, NJ) were used to detect expression of this antigen. MIgS-KpI, a mouse monoclonal antibody of the same subclass as the primary antibodies listed above, was used as negative control at similar working dilutions. Sections were subsequently immersed in boiling 0.01% citric acid (pH 6.0) for 15 min to enhance antigen retrieval, allowed to cool, and incubated with primary antibodies overnight at 4°C. Biotinylated horse antimouse IgG antibodies were applied for 1 h (Vector Laboratories, Burlingame, CA; 1:500 dilution), followed by streptavidin peroxidase complexes for 1 h (Vector Laboratories; 1:500 dilution). Diaminobenzidine was used as the nuclear counterstain. For each case, the percentage of invasive tumor cells expressing cytoplasmic immunoreactivity was estimated in a continuum from 1 to 100%. Intensity was recorded using a scale of 0–3 (0, undetectable staining; 3, highest staining).
All pathological specimens were reviewed by one pathologist (V. R.), who was blinded as to the pre- and posttherapy status of the specimen and clinical outcomes. All pathological slides were prepared at the same time to avoid intraexperimental variation of the results and so that both positive and negative controls were examined simultaneously.
Treatment Plan.
For the administration of ATRA, the drug was supplied by the NCI and
consisted of soft gelatin-filled capsules, each containing 10 mg of
ATRA. Other ingredients included butylated hydroxyanisole, disodium
edate, refined soybean oil, and a wax mixture consisting of purified
beeswax, hydrogenated soybean oil flakes, and hydrogenated vegetable
oil. Patients were started on 50 mg/m2 ATRA p.o.
every 8 h and instructed to take it with food. The dose was
rounded to the nearest 10 mg.
The dose of ATRA was escalated by 25% if the patient did not experience a greater than grade 2 toxicity after 4 weeks of therapy. If a patient developed a grade 3 or 4 toxicity, the therapy was held until the adverse event resolved. Therapy was continued until progression of disease or dose-limiting toxicity.
Pharmacology of ATRA.
On day 1 of therapy, 10 ml of heparinized blood were drawn at 0.5, 1,
2, 3, 4, 6, 8, 12, and 24 h. Urine was also collected in three
aliquots from 0 to 6, 6 to 12, and 12 to 24 h. These
pharmacokinetic tests were repeated after 4 weeks of treatment to
assess changes over time. After the initial pharmacokinetic parameters
were evaluated for the first five patients, there was a marked drop in
ATRA in the serum at day 28, and subsequently patients had pharmacology
studies performed on day 3 (heparinized blood was drawn at 0.5, 1, 2,
and 3 h). We have reported previously the pharmacokinetics of
ATRA, and these results will not be discussed further (8)
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Administration of cRA\/IFN.
Recombinant human IFN (Roferon-A) and cRA (Accutane) were obtained from
Hoffmann-LaRoche, Inc. (Nutley, NJ) through the Division of Cancer
Treatment, NCI. IFN was provided in 3-million unit and 18-million unit
vials, which were mixed with sterile water. cRA was available in 10-
and 40-mg tablets. Patients were administered IFN starting at 3 million
units s.c. daily, and the dose was escalated to 6 million units the
second week and 9 million units the third week if patients did not
experience a grade 2 or greater drug toxicity. Patients were
premedicated with 650 mg of acetaminophen p.o. prior to the
administration of IFN. The dose was held for grade 3 or 4 NCI toxicity,
except for a hematological toxicity manifested by low hemoglobin. In
case of a severe adverse reaction, the IFN was held until the toxicity
returned to grade 0 or 1. Patients with a persistent grade 3 or 4
toxicity for greater than 4 weeks were removed from the study. Patients
received 1 mg/kg of cRA in two divided doses daily. This was taken with
food for maximal absorption. The treatment of cRA was interrupted in
patients who experienced any grade 3 or 4 toxicity and reinitiated at a
dose of 0.5 mg/kg p.o. in two daily doses once patients’ toxicity
resolved (grade 0 or 1). If grade 3 or 4 toxicity persisted on the
attenuated dose of cRA, the treatment was discontinued.
Once the safety of this regimen was established, the protocol was amended to include patients with a rising PSA after surgery or radiation therapy that had not undergone castration. The same dose and schedule was used. After 16 weeks of therapy, if the patient did not have a partial response (>80% posttherapy decline in PSA), they were withdrawn from the study and offered androgen ablation or observation.
Posttherapy Assessment.
Patients were followed in the outpatient department at weekly intervals
for the first 4 weeks and then biweekly afterward. At each visit, the
history and physical were repeated, and adverse events were recorded
using the NCI Common Toxicity Scale (version 1.0). Patients were
considered evaluable for response if they had completed a minimum of 4
weeks of treatment. Outcomes were assessed independently using
radionuclide bone scan for osseous lesions, CT scan or magnetic
resonance imaging for measurable lesions, and posttherapy changes in
PSA (Tandem-E; Hybritech; upper limit of normal range, 4.0 ng/ml).
Posttherapy PSA changes were assessed as described previously (6
, 13)
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTScRA\/IFN in Patients with...DISCUSSIONREFERENCES |
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Patient characteristics and baseline biochemical parameters are
detailed in Tables 1
and 2
. The median performance status was
80%; 12 of 30 (40%) had more than one prior hormonal manipulation,
and the majority had measurable disease. Other baseline parameters are
consistent with patients with advanced prostate cancer.
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Adverse Events Associated with Treatment
A dry scaling skin rash and cheilitis were the most common adverse
events (Table 3)
. Both were treated with skin emoluments and did
not require a change in systemic therapy. Significant weight loss and
anorexia was seen in <10% of the patients; however, one patient
discontinued treatment because of persistent fatigue and anorexia.
Hematological toxicities were most common in patients treated with
cRA\/IFN with mild leukopenia; anemia and
thrombocytopenia were the most common abnormalities.
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Mild elevation of hepatic transaminases was common, along with elevation of serum triglycerides. Most triglycerides were <200 mg/dl (normal range, 50–160 mg/dl); however, one patient had an extreme elevation of the triglycerides to 3280 mg/dl. Minor sensory, motor, visual, and mood changes occurred during treatment with cRA\/IFN, but headaches were the most common neurological abnormality reported with ATRA. Only one patient treated with cRA\/IFN reported a similar headache. One patient treated with ATRA had a nonfatal pulmonary embolism, which was treated with anticoagulants without further complications.
Clinical Outcomes
Response in Bone.
Twenty-five patients had metastatic disease to the bone prior to
therapy. No improvement or progression in the bone scan was documented
in all cases after treatment. One patient treated with
cRA\/IFN with measurable disease and no osseous disease
at the beginning of treatment developed bone metastasis after 9 months
of therapy.
Response in Measurable Disease.
One of 24 patients (4%; 95% confidence interval, 3.8–11.8%) with
measurable disease treated with cRA/IFN showed a <50% decrease in a
pelvic nodal mass, which was confirmed as necrotic on posttherapy tumor
biopsy.
Changes in Posttherapy PSA.
All 30 had a rising PSA at the initiation of the study. No patients
normalized their PSA or had an 80% reduction (partial response) in the
PSA from the baseline. No patients with ATRA had a significant PSA
decline. One of 13 (8%; 95% confidence interval, 0.5–15.5%)
patients treated with cRA\/IFN had a >50% reduction
in the PSA from baseline for a 4-month duration. Fig. 1
shows one patient treated with
cRA\/IFN that had a steady rise in the PSA with no
evidence of progression in his retroperitoneal and osseous disease.
After 4 months of continuous therapy, the PSA declined below his
pretherapy baseline value. The patient continued
cRA\/IFN for 9 months and then had evidence of
measurable disease progression associated with a 50% rise in the PSA
from his nadir value. After the discontinuation of
cRA\/IFN, a >50% decline in PSA was documented, which
was maintained for 4 months. There were no other concurrent
interventions.
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No difference in histology, Ki67 index, or apoptosis were observed after ATRA. Of the seven biopsy sites evaluated after cRA\/IFN, one patient had pelvic lymph node biopsy and transurethral resection of the prostate pre- and posttherapy, four had prostate biopsy, one had retroperitoneal lymph nodes, and one had bone marrow biopsy. The two patients with biopsies of the lymph nodes showed tumor necrosis on the posttherapy specimen, with only one of two of the patients showing a parallel regression on CT scan. No other specimens demonstrated other gross histopathological changes. Only one case showed a decrease in the proliferation index in a posttherapy biopsy of the prostate when compared with the pretherapy sample. No evidence of induction of apoptosis was seen in the posttherapy specimens.
Nine of 21 of the paired samples (in 12 cases, the tissue blocks were
exhausted) had additional pathological material available to assess
PSMA expression based on the percentage of cells stained and intensity
(Table 4)
. In posttherapy, there was an increased expression of PSMA,
defined as both an increase in percentage of positive tumor cells as
well as an increased intensity in immunoreactivity. This was seen in
seven of nine cases (77.7%) using the PM2 antibody and in two of nine
(22.2%) using the 7E11 antibody. Fig. 2
demonstrates the changes in PSMA expression using the PM2 antibody in
cases 7 and 9. We observed increased intensity, and the percentage of
cells that showed expression for PSMA was greater with the PM2 antibody
than the 7E11 antibody in all cases. There was a concordance of
increased expression using the two antibodies in the two cases (nos. 2
and 9).
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cRA\/IFN in Patients with AD Disease |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTScRA\/IFN in Patients with...DISCUSSIONREFERENCES |
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and 2
. Adverse events were similar to the AI patients
(Table 3)
.
After 16 weeks of therapy, none of the patients had progression in the
bone, but one of the four patients had interval development of pelvic
lymphadenopathy, suggesting metastatic disease. All of the patients had
a rising PSA prior to therapy, and the PSA stabilized in all cases
(Fig. 3)
. A 50% decline in posttherapy
PSA for 2 months was documented in one case. Pre- and posttherapy
levels of testosterone were evaluated, which demonstrated normal
physiological levels of serum testosterone in all patients. Because
none of the patients achieved >80% decline in PSA or normalized the
PSA (partial response or complete response), they were withdrawn from
the study as per protocol at the end of 4 months. Three patients
elected to be treated with androgen ablation. One patient was observed
without treatment and has maintained a stable PSA for >1 year (Fig. 3D)
without other evidence of disease progression.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTScRA\/IFN in Patients with...DISCUSSIONREFERENCES |
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Because retinoic acid may confound the interpretation of posttherapy
changes in PSA and early biological effects from the retinoic acid
therapy may not be detected using standard radiographic and
pathological techniques, we also assessed changes in tumor cell antigen
expression during therapy. Posttherapy tumor specimens did show an
increased expression of PSMA after therapy in seven of nine cases using
the PSM2 antibody and a parallel observation in two of nine cases using
the 7E11 antibody. This increased expression of PSMA was seen with ATRA
and cRA\/IFN. Two different antibodies were used
because PM2 and 7E11 bind to different intracellular PSMA domains with
different affinities (14)
. As seen in other studies, the
PM2 antibody consistently had a greater expression in intensity and
percentage of cells stained than the 7E11 antibody (14)
.
PSMA is a type II membrane glycoprotein of
Mr 
100,000 and is expressed
in benign prostate secretory-acinar epithelium, prostatic
intraepithelial neoplasia, and prostatic adenocarcinoma
(15)
. The PSMA functions as a neurocarboxypeptidase and
folate hydrolase and may be involved in neuroendocrine regulation of
prostate growth and differentiation (15
, 16)
. Increased
PSMA expression is reported in high-grade localized tumors (16
, 17)
; however, PSMA expression is decreased in metastatic disease
(18)
. In this study, an increased expression of PSMA
posttreatment suggests a biological effect from the therapy and may
indicate a favorable differentiation effect on the tumor. This finding
needs to be further confirmed in larger prospective trials.
Prior to the studies, it was a concern that retinoids might increase
PSA secretion independent of cell growth. This was not generally
observed; however, in one case, a 50% posttherapy decline in PSA was
documented (Fig. 1)
but only after 4 months of treatment and a
transient rise in the PSA. The 4-week biopsy in this patient also
showed no tumor necrosis but an increased expression of PSMA from the
baseline (patient 8 in Table 4
). After 9
months of treatment, this patient discontinued cRA\/IFN
secondary to objective disease progression. Without further therapeutic
intervention, the patient’s objective disease stabilized, and a
decline in PSA >50% was observed. This is similar to what has been
described in the "steroid withdraw syndrome" (7
, 19)
.
Preclinical studies and our initial results suggested that patients
might require prolonged exposure to the retinoids to see a clinical
benefit. Often in patients with advanced PC, symptomatic progression
occurs rapidly, not allowing adequate drug exposure. This was the case
in our study with the majority of patients with advanced AI prostate
cancer progressing in 2–3 months. This would indicate that patients
with minimal tumor volume might be better candidates for this treatment
approach. To test this hypothesis, hormone-naive patients that had a
rising PSA after radical prostatectomy or radiation therapy were
treated with cRA\/IFN. The PSA declined or stabilized
in all cases (Fig. 3)
, but the treatment was associated with cumulative
fatigue. Serum testosterone levels were not altered by
cRA\/IFN treatment in our patients, but retinoic acid
may inhibit 5
-reductase, decreasing the conversion of testosterone
to dihydrotestosterone (20)
. This could effect PSA
secretion, although the inhibition of PSA should reverse once the drugs
are discontinued. One patient was observed without androgen ablation
after cRA\/IFN therapy and has remained clinically
stable without biochemical progression for >1 year (Fig. 3D)
. Although the natural history of his cancer is unknown,
this patient appears to have had a clinical benefit from the combined
therapy, which cannot be contributed to the suppression of DHT.
Similar studies in AD patients by Dipaola et al.
(5)
showed that 5 of 21 patients treated with cRA and
lower doses of IFN had a decline in posttherapy PSA. Plasma TGF-ß
levels increased with the cRA\/IFN and correlated with
a decrease in the PSA (5)
. This also suggested an indirect
biological effect from the therapy. The results of
cRA\/IFN in patients with minimal disease are
encouraging, but the cumulative fatigue from the therapy is a concern
in this asymptomatic population and often deters patients from
continuing therapy.
The clinical observation made from this series of investigations with retinoic acid has provided strategies for developing other differentiation therapies. The increased expression of PSMA on posttherapy biopsies suggested that there was a biological impact from the therapy that was not apparent while using conventional measures of outcome. In the future, the modulating effect of retinoic acid may be exploited to enhance PSMA expression on prostate cancer cells to increase the targeting of specific antibodies to the PSMA.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by ACS-CRTG-97-118-01-CCE, CA-05826,
CCPP, the PepsiCo Foundation, and NIH DK/CA 47650. 
2 To whom requests for reprints should be
addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue,
New York, NY 10021. Phone: (212) 639-7992; Fax: (212) 794-5813.
3 The abbreviations used are: ATRA,
all-trans-retinoic acid; cRA,
13-cis-retinoic acid; PSA, prostate-specific antigen;
IFN, IFN-2a; AI, androgen independent; AD, androgen dependent; PSMA,
prostate-specific membrane antigen; KPS, Karnofsky Performance Status;
CT, computed tomography; NCI, National Cancer Institute.
Received 10/25/99; revised 12/23/99; accepted 12/27/99.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTScRA\/IFN in Patients with...DISCUSSIONREFERENCES |
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interferon on transforming growth factor B1 in patients with a rising prostate specific antigen. Clin. Cancer Res., 3: 1999-2004, 1997.[Abstract]
-2a in the therapy of solid tumors. Leukemia (Baltimore), 8: 38-41, 1994.
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