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Clinical Trials |
-Hydroxyvitamin D2 in the Treatment of Advanced Androgen-independent Prostate Cancer1
University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-OH-D2, in patients with advanced hormone-refractory prostate cancer.
Experimental Design: The patients initially received 1-OH-D2 at 12.5 µg p.o. every day, which was dose adjusted for hypercalcemia. Given the cytostatic nature of the drug, the primary study end point was progression-free survival for a minimum of 6 months. The secondary end point was further characterization of drug toxicity.
Results: A total of 26 patients was enrolled. Using the intent-to-treat population, stable disease was seen for an average of 19.2 weeks (median 12 weeks, range 3–108 weeks). Twenty patients were evaluable for response. The one patient that achieved disease stabilization for >2 years elected to come off-study because of patient preference. His last disease evaluation showed no evidence of progression. No objective responses were seen. Previous and ongoing clinical observations strongly imply that PSA could be a misleading surrogate marker for clinical effect with this type of drug. Therefore, prostate-specific antigen was not used as a marker for disease response. Toxicity was as expected with mild hypercalcemia and associated symptoms like constipation and prerenal azotemia seen in some patients. Six (30%) evaluable patients experienced stable disease for >6 months, suggesting possible cytostatic activity.
Conclusion: The results of this and other trials suggest further clinical investigation in this disease with vitamin D analogues alone or in combination with other agents, such as chemotherapy, should be pursued.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In 1990, it was hypothesized that vitamin D deficiency could be a risk factor for prostate cancer as age, African-American race, and residence in a northern latitudes were not only associated with an increased incidence of prostate cancer but also a relative decrease in the levels of the vitamin (3) . It was thought that vitamin D could maintain the differentiated phenotype of prostatic cells, and in the presence of low levels of vitamin D, subclinical prostate cancer may progress to clinical disease. This hypothesis was supported by two separate retrospective analyses measuring vitamin D levels from stored sera and showing that mean calcitriol levels were lower in patients who later developed prostate cancer compared with age-matched controls (4 , 5) .
Because vitamin D has well-defined roles in calcium and phosphate homeostasis, it is of no surprise that VDRs have been found in the bone, intestine, kidney, and parathyroid gland. We now know that VDRs are found in a wide variety of other cells and that this seco-steroid hormone can regulate the growth and maturation of these various tissues. In vitro cultures of prostate cancer cell lines with physiological levels of calcitriol inhibited proliferation of LNCaP and PC3 but not DU145. Calcitriol also caused a dose-dependent stimulation of PSA production in LNCaP cells, suggesting that vitamin D was both antiproliferating and differentiating in prostate cancer cells (6) .
Early clinical trials using oral calcitriol in prostate (7)
and hematological malignancies (8)
were conducted but yielded negative results. Presumably, inadequate doses of calcitriol were able to be administered secondary to complications from hypercalcemia. Later, a small pilot study in patients with biochemical failure after radical prostatectomy or radiation therapy did show evidence in prolongation of the PSA doubling time using calcitriol in the select patients studied (9)
. Because the chemotherapeutic benefit of calcitriol was difficult to exploit because of hypercalcemic side effects, less hypercalcemic vitamin D analogues have been developed for clinical testing. Some biological effects have already been observed in colon (10
, 11)
, bone (12)
, and breast cancer cell lines (13)
. Many of these have also shown similar or increased activity compared with calcitriol in prohibiting prostate cancer growth in vitro, with markedly decreased effects with regards to hypercalcemia development. These studies confirmed that the inhibitory growth properties of vitamin D can be enhanced with analogues, as long as the binding affinity for the VDR is retained (14, 15, 16)
. One such analogue of interest is 1-OH-D2.
We have completed previously and published a Phase I study using 1-OH-D2 in patients with HRPC (17)
. This p.o. drug was administered with doses ranging from 5 to 15 µg every day. Main toxicities were hypercalcemia with associated secondary serum creatinine increases. A total of 21 evaluable patients was treated. Two patients achieved a PR, whereas 5 others maintained SD for >6 months. Given the promising results, this Phase II trial using 1-OH-D2 was conducted in advanced HRPC starting at the recommended dose of 12.5 µg/day given continuously.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2 weeks apart and 50% increased over the baseline values obtained during hormonal interventions. PSA abnormalities alone were not considered evaluable, and those patients were excluded from this trial. Patients were eligible if they had an Eastern Cooperative Oncology Group performance status of 0–2; adequate bone marrow function with absolute neutrophil count 1200/µl, hemoglobin 8 grams/dl, and platelets 100,000/µl; stable renal function with creatinine 
1.8 mg/dl, adequate hepatic reserve with normal bilirubin, and asparatase aminotransferase 2.5 times the upper limit of normal. A corrected serum calcium 10.2 mg/dl was required at study entry. Patients were excluded if they had received more than two previous cytotoxic chemotherapy regimens (or chemotherapy within 4 weeks of beginning study), had received strontium in the past, or had any history of brain metastasis. Any history of idiopathic urinary calcium stone disease, chronic hypercalcemia, or gastrointestinal malabsorptive conditions was also prohibited. Lastly, any use of digitalis, thiazide diuretics, or calcium supplementation was not allowed. Patients who did not have an orchiectomy were continued on their luteinizing hormone-releasing hormone during the study, although the antiandrogen was discontinued. Uncontrolled infections or other serious intercurrent medical illnesses were not allowed. All patients gave written informed consent in compliance with state, federal, and institutional guidelines.
Study Plan.
At study entry, all patients underwent a complete history and physical exam, including a complete blood count, serum chemistries, and disease assessment (bone scan, CT imaging, and PSA). Baseline vitamin D metabolites, 24-h urine calcium levels, as well as other investigational laboratories were obtained as well. Eligible patients were given 12.5 µg of 1-OH-D2 (five each of 2.5 µg capsules) continuous once a day p.o. before their a.m. meals. This dose is based on the recommended Phase II dose from the completed Phase I trial. 1-OH-D2 was provided by Bone Care International (Madison, WI) in soft, gelatinized capsules in units of 2.5 µg/capsule. Inactive ingredients in order of decreasing weight included: fractionated coconut oil, gelatin, glycerin, titanium dioxide, D&C yellow no. 10, ethanol, and butylated hydroxyanisole.
Weekly toxicity assessments, vital signs, calcium, phosphorus, and albumin levels were obtained during the first 4 weeks of drug administration. Thereafter, physical examinations, complete blood counts, serum chemistries, vitamin D metabolite levels, 24-h urine calcium, and PSA levels were evaluated every 4 weeks while the patient was on study. Radiographic disease assessments were repeated every 12 weeks or sooner if clinically indicated.
Toxicity and Dose Modifications.
Patients with any grade 1–2 toxicity (defined by the National Cancer Institute common toxicity criteria) were allowed to continue on treatment without dose modification. However, any grade 3 toxicity (excluding anemia and alopecia) felt related to drug required holding drug until the toxicity resolved to 2. The drug was then resumed at a dose one capsule (2.5 µg) lower. If the toxicity did not improve to grade 2 within 14 days of stopping the drug, that patient was removed from the study. Patients with grade 1 hypercalcemia (corrected for serum albumin) or grade 2 creatinine elevation had their drug held, then resumed at one capsule (2.5 µg) lower once toxicity resolved.
Response Criteria.
Because of the presumed slow onset of any potential benefit, we elected to only use patients who completed 8 weeks of therapy in the determination of potential usefulness of this cytostatic agent. Therefore, only patients completing 8 weeks of therapy were considered evaluable for response. Evidence of progression after 8 weeks was considered a treatment failure. Changes in performance status, PSA, and weight were noted but not used as response criteria. For this study, a complete response was defined as disappearance of all known disease during two observations at least 4 weeks apart, during which no new lesions develop. For patients with bone only disease, normalization of the bone scan was required. A PR was defined as >50% decrease in the sum of the products of the perpendicular tumor diameters of all measurable disease documented for 4 weeks. No new lesions or increased size of any existing lesion was allowed. For patients with bone only disease, a PR required a 50% decrease in the number of bone scan lesions. Progressive disease included any unequivocal increase 25% in the size of any existing lesion or the appearance of any new lesion. SD was any other condition not met by the criteria outlined in complete response, PR, or progression.
Correlative Studies.
Blood samples were collected at baseline and throughout the treatment period and stored at -70°C in the University of Wisconsin Analytical Laboratory. Serum levels of osteocalcin, bone-specific alkaline phosphatase, and N-telopeptide were assayed by Pacific Biometrics, Inc. (Seattle, WA). Additional samples were collected in 7-ml EDTA tubes using 19 or 21 gauge needles to minimize hemolysis. These samples were immediately stored at 4°C until centrifugation when the top 1 ml of plasma was isolated and frozen at 70°C in NUNC tubes. These samples were later analyzed for TGFß1 using a 96-well plate quantitative sandwich immunoassay (Quantikine human TGFß1; R&D System, Minneapolis, MN). The buffy coat was also collected and frozen for future analysis of T-cell receptor-associated 
chain expression.
Statistical Analysis.
This study was planned using a two-stage design. At the time of the protocol development, the published median survival for patients with advanced HRPC was 
12 months. Therefore, most patients should develop evidence of radiographic disease progression well before that median survival is reached. Given the cytostatic nature of the 1-OH-D2, we chose to use PFS at 6 months as the primary outcome measure. We assumed that if 30% of the patients maintained freedom from progression for 6 months, this therapy would be of clinical interest. Initially, 20 evaluable patients would be enrolled in the first phase of the trial. These patients would then be followed for 6 months with the assumption that if <5 of the first 20 patients maintained PFS for 6 months, the trial would be terminated and declared negative. Otherwise, an additional 20 patients (40 patients maximum) would be enrolled in a second phase of the trial. Time to progression was computed from the first day of drug.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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for patient characteristics.
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8 weeks of therapy and were therefore not evaluable for response. One of those patients had visceral as well as bony metastasis and progressed by week 7 with a worsening perirectal mass. Another had liver and bony metastasis and was removed from the study at week 5 for clinical progression (worsening pain), despite stable bone scan. Two patients progressed clinically with new lesions on their bone scan, one at week 5 and the other by week 6. Another patient was removed at week 4 after developing pneumonia. He was then found to have a secondary malignancy with a stage IIIA squamous cell lung cancer. The last patient had to be removed from study at week 3 for development of drug toxicity (see Toxicity). Of the remaining 20 (evaluable) patients, no objective responses were seen despite 8 patients having measurable disease. One of those patients had biopsy confirmed pulmonary metastases and mediastinal lymphadenopathy at enrollment and has had maintained SD since July 2000 (>2 years). He recently chose to discontinue drug after 108 weeks of therapy given that he now resides out of state and when last seen had a second episode of a grade 1 hypercalcemia despite remaining at the lowest dose of 1-OH-D2 allowed. His CT, bone scans, and PSA remain stable. All but two patients had radiographic evidence for disease progression. Those two patients had clinical deterioration with increased bony pain. In total, 6 evaluable patients did achieve SD for >6 months meeting our initial criteria for drug activity.
PSA Response.
PSA response was not considered a surrogate marker in this study given in vitro data, indicating stimulation of PSA production with vitamin D analogues. We observed all but 2 patients with a continual rise in PSA while on therapy (figure not shown). Of interest, one of the patients with a PSA decline had a baseline PSA of 44.7 ng/ml, and this dropped from the start to a nadir of 29.6 ng/ml at week 12. He had evaluable lymphadenopathy as well as bone scan positivity from the beginning and eventually progressed by bone scan only at week 44 with an associated PSA of 74.7 ng/ml. The other patient started with a PSA of 23.4 ng/ml, and his PSA reached nadir at week 8 to a PSA of 6.7 ng/ml. Although his PSA never did rise again above baseline, he was removed from the study at week 28 secondary to clinical progression with increased bony pain. His PSA at that time was only 20 ng/ml.
Toxicity.
A total of >448 weeks of drug was administered during this study. Of the 26 total patients, all but 6 completed 8 weeks of therapy. As expected, common toxicities included hypercalcemia (grade 1) with occasional resultant effects like a transient elevated creatinine level (Table 2)
or constipation. Few patients had nausea, abdominal discomfort and bloating, fatigue, or anorexia. Individual patients complained of hot flashes, diarrhea, or weakness. Two patients developed grade 1 asparatase aminotransferase elevation at the time of their disease progression. This was felt possible related to the study drug but more likely attributable to progressive bony metastasis. One patient at the 12.5 µg/day dose did develop grade 3 hypophosphatemia (phosphate 2 mg/dl) with a concurrent grade 1 corrected calcium (Ca2+ 10.32 mg/dl) at day 29 of therapy. His drug was held with normalization of both his calcium and phosphorus level within 1 week, and he was restarted on drug at the next lower dose level. See Table 3
for frequent adverse events. Only one patient was withdrawn for an adverse drug effect (grade 3 hypercalcemia, grade 2 creatinine, and grade 2 dehydration). This patient was receiving 12.5 µg of 1-OH-D2 and developed hypercalcemia only after 1 week of drug. He was removed from the study with concerns of rapidly progressive cancer and persistent grade 1 hypercalcemia and grade 2 dehydration after 2 weeks of holding drug. Of the 26 patients, only 8 patients received 8 weeks of therapy at 12.5 µg/day. Dose reductions were eventually performed on 16 of the 26 patients with final doses ranging from 5 to 12.5 µg/day, median 10 µg/day (five patients were reduced to 10 µg/day, nine patients to 7.5 µg/day, and two patients to 5 µg/day). No patients died while on this study.
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. Various markers of bone turnover (osteocalcin, N-telopeptide, and bone-specific alkaline phosphatase) were analyzed using the same time points. As reported previously (17)
, the large inter and intrapatient variability made interpretation of the measured values difficult, and no specific trends relative to baseline values [bone-specific alkaline phosphatase: mean 76.9 units/liter, range 15.3–274.5 units/liter; osteocalcin: mean 39.3 ng/ml, range 10.6–90.8 ng/ml; N-telopeptide: mean 21 nmol bone collagen equivalent, range 6.4–38.1 nmol bone collagen equivalent] could be made when looking at mean values. To normalize for the interpatient variability, measured values were adjusted relative to the baseline values and plotted against time. Again, no significant trend could be established when looking at N-telopeptide and bone-specific alkaline phosphatase levels. There was a slight increase in osteocalcin levels as shown in Fig. 2
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As of August 21, 2002, 16 patients had expired. Using an intent-to-treat analysis, the median survival as computed by the Kaplan-Meier method was 487 days with a 95% CI of (381, infinity). Considering only evaluable patients (those receiving at least 8 weeks of drug), we chose to calculate the baseline survival starting at 8 weeks beyond treatment onset to minimize the bias of selecting patients on the basis of their future outcome. Using this method, the actuarial median post-first-course survival was 630 days with a 95% CI of (381, infinity). These survival curves are shown in Figs. 3
and 4
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Vitamin D is a secosteroid that has shown extensive laboratory and clinical evidence that it may be useful in the treatment or prevention of prostate cancer. Because early trials with calcitriol resulted in dose-limiting hypercalcemia, we have focused instead on vitamin D analogues to maximize dose intensity. Despite more current data suggesting safety of pulse-dose calcitriol, we have continued to pursue these analogues with the assumption that more chronic administration of these cytostatic agents are necessary to optimally maintain the antiproliferative and differentiating effects of this class of drug. During Phase I evaluation of 1-OH-D2, two patients at dose levels of 5 and 7.5 µg/day had radiographically confirmed PRs, indicating drug activity in patients with prostate cancer. Toxicity was limited to hypercalcemia and secondary reversible increases in serum creatinine with a recommended Phase II dose of 12.5 µg/day (17)
. This Phase II trial was conducted to better define the drug toxicity and activity in patients with advanced hormone-refractory prostate cancer.
Overall, we did not observe any unexpected drug toxicity. Mild, clinically insignificant hypercalcemia was frequently seen and easily controlled with either dose modifications or brief cessation of therapy. Because of the toxicity (one grade 2 and one grade 3 serum creatinine increase) observed in our Phase I trial, we proceeded cautiously and had a low threshold for dose reductions. One may argue that we were too conservative given that the majority of the hypercalcemia seen in this trial was only grade one, but our previous experience showed that a few of these patients could develop more clinically significant hypercalcemia with continued therapy. In any event, dose intensity was likely not fully maximized (50% of evaluable patients eventually dose reduced), and many patients were probably dose reduced for clinically insignificant hypercalcemia. The dose modification schema made assessment of drug activity difficult to generalize as each patient eventually received various doses of 1-OH-D2.
We did meet our first study end point during this study as 6 of 20 evaluable patients did achieve PFS for >6 months on therapy. As mentioned previously, the statistical basis for this decision was the assumption that the median survival in patients with advanced hormone-refractory prostate cancer was 12 months. As we neared the closure of the first stage in this trial, other trials began reporting more recent median survival data approaching 18 and 20 months (22) . Thus, we decided not to proceed to the second phase of the protocol (enrollment of an additional 20 patients) because the more recent survival data implied that our initial statistical parameter was too low and that investing more patients was not going to allow us to develop any clinically relevant response information. In any event, we were encouraged that six patients did achieve disease stabilization for >6 months. This included one patient who remains stable for over 2 years and counting. What is interesting is that our survival data are similar to those reported in these recent trials with median survival of 16 months in the intent to treat population. We questioned whether our median survival was inflated given the fact that our patients were carefully selected to exclude those requiring urgent chemotherapy and thus not good candidates for this cytostatic agent. Because individual trials use different exclusion criteria or contain various levels of patient acuity, generalizing survival results has to be made with much reservation. To allow some inter-trial comparison, we used the nomogram developed by Kattan et al. (Memorial Sloan-Kettering) that predicts median survival of patients with progressive prostate cancer after castration using baseline screening laboratories and clinical parameters (23) . Using the nomogram, our predicted median survival would be 16.3 months for the intent-to-treat population. This is very similar to our observed median survival of 16 months. Using the nomogram for the evaluable patients, our predicted median survival would be 17.7 months (compared with the observed median survival of 21 months). We have questioned whether a more pronounced response could have been observed had we been more aggressive in maintaining dose intensity. Dose intensity could have been maintained either by allowing grade 1 hypercalcemia and/or not dose reducing after resolution of grade 1 or 2 hypercalcemia.
TGFßs are multifunctional growth factors that have been associated with both protumorigenic as well as tumor-inhibitory properties (24) . Interestingly, vitamin D and TGFß may share identical actions on the cell’s growth and differentiation because TGFß has been observed to inhibit proliferation of epithelial cells. It has been demonstrated that the inhibitory effect of calcitriol on cell growth could in fact be related to an induction of TGFß synthesis in a paracrine/autocrine loop (25) . We did observe increasing mean TGFß levels over baseline during this trial. Whether this increase is secondary to disease progression or evidence of drug activity is unknown. Theoretically, because TGFß has downstream effects on cell growth, it is conceivable that its level may rise early because of the inducing effect of the vitamin D analogue, before later decreasing because of tumor regression. Because no objective tumor responses were seen in this trial, no additional inferences could be made.
As reported previously, it is difficult to correlate drug activity using the markers for bone turnover in this patient population (19) . Presumably, the presence and amount of osteoblastic metastasis will influence the levels of osteocalcin, N-telopeptide, and/or bone-specific alkaline phosphatase measured. Data confirming doxercalciferol absorption (reflected by measured metabolite levels) and pharmacodynamics were described previously in our Phase I trial (17) and do confirm the physiological presence of active drug in all patients.
Lastly, the observed increase in PSA can raise some questions to whether the increase is simply attributable to disease progression versus the differentiating effects of the treatment. Understandably, the increase in PSA while on therapy can be difficult to ignore, not only for the patient, but also for the treating physician. Although the use of PSA as a marker for disease response has been validated by the Prostate-Specific Antigen Working Group as a reasonable method to evaluate outcomes in Phase II clinical trials (26) , they do acknowledge that some newer, noncytotoxic agents may modulate PSA expression independent of their effects on cell growth, and therefore, the use of PSA as a surrogate marker in these cases has not yet been validated. Although rising PSA is of concern, given the preclinical data and early clinical data showing rising PSA despite tumor response, this trial relied on other accepted "surrogate markers" like CT scans and bone scans to assess disease progression.
In conclusion, from our Phase I and II trials of 1-OH-D2 in patients with advanced HRPC, we have shown evidence of drug activity that warrants further investigation. Although the Phase II trial did not have any objective responses, we did observe disease stability >6 months in 30% of the patients. For a cytostatic drug, this is encouraging, especially because the treatment involves a fairly nontoxic, p.o. medication. We are also encouraged by the observed median survival of 630 days (21 months) in the evaluable patients, which is higher than the 17.7 months predicted by the survival nomogram for that patient group. Admittedly, we did not have a control arm for this Phase II trial so any implication on improvement in overall survival cannot be made.
We are currently looking at the effects of 1-OH-D2 on both normal prostate cells and prostate carcinoma cells by matching prostate biopsies with subsequent 1-OH-D2-treated prostatectomy specimens. Hopefully, the mechanism and effect of vitamin D can be further elucidated. In addition, there is presumably synergistic activity with vitamin D and chemotherapy (27)
because of different mechanisms of action, and we are currently examining this issue clinically. Lastly, the use of these vitamin D analogues can be combined with bisphosphonates to maximize dose intensity and further exploit different mechanisms of action, especially in a disease prone to bony metastasis like prostate cancer. What is clear is that additional trials involving vitamin D and its analogues are needed.
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FOOTNOTES |
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1 Supported by funding from the Department of Defense (DAMD 17-98-1-8503), CaPCure, and Bone Care International, Inc. 
2 To whom requests for reprints should be addressed, at Department of Medicine, Medical Oncology Section, 600 Highland Avenue, Madison, WI 53792. Phone: (608) 265-8131; Fax: (608) 265-8133.
3 The abbreviations used are: VDR, vitamin D receptor; 1-OH-D2, 1-Hydroxyvitamin D2; PR, partial response; SD, stable disease; TGF, transforming growth factor; PFS, progression-free survival; CT, computed tomography; PSA, prostate-specific antigen; CI, confidence interval; HRPC, hormone refractory prostate cancer.
Received 3/14/03; accepted 4/ 8/03.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 25-dihydroxyvitamin D3 analogs: structure-function relationships. J. Pharmacol. Exp. Ther., 275: 1254-1260, 1995., 25-dihydro-16-ene-23-yne-26, 27-hexafluorocholecalciferol (Ro 24–5531) modulation of insulin-like growth factor-binding protein-3 and induction of differentiation and growth arrest in a human osteosarcoma cell line. J. Clin. Endocrinol. Metab., 81: 93-99, 1996.[Abstract]
-hydroxyvitamin D2 in patients with hormone refractory prostate cancer. Clin. Cancer Res., 9: 2820-2827, 2002.
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