Cancer Therapy Vol 3, 401-406, 2005
Progress in prostate cancer research: a focus on bone health
Susan Doyle-Lindrud1,* and Robert S. DiPaola1,2
1Department
of Medicine, University of Medicine and Dentistry- Robert Wood Johnson Medical
School, New Brunswick New Jersey, USA.
2The Dean and Betty Gallo Prostate Cancer Center at The Cancer
Institute of New Jersey, New Brunswick New Jersey, USA
__________________________________________________________________________________
*Correspondence: Susan Doyle-Lindrud, MS, NPC, The Dean and Betty Gallo Prostate
Cancer Center, The Cancer Institute of New Jersey, 195 Little Albany Street,
New Brunswick, New Jersey 08901; Phone: (732) 235-6988; Fax: (732) 235-8095;
E-mail: Lindrusm@umdnj.edu
Key words: prostate cancer, Clinical studies of
bisphosphonates, Potential recommendations,
Abbreviations: androgen deprivation therapy, (ADT); bone mineral density, (BMD);
bone progression free survival, (BPFS); confidence interval, (CI); dual energy
x-ray absorptiometry, (DEXA); hazard ratio, (HR); hormone refractory prostate
cancer, (HRPC); quantitative computed tomography, (QCT);
World Health Organization, (WHO)
Summary
One in six
men will be diagnosed with prostate cancer in their lifetime; in this year,
approximately 200,000 will be diagnosed with, and 30,000 will die of prostate
cancer (Hemminki et
al; Jemal et al, 2004). Recent
advances reported this past year in the therapy of prostate cancer include data
demonstrating the survival benefit of chemotherapy in metastatic hormone
refractory prostate cancer (HRPC) (Gulley and
Dahut, 2004). Despite
these successes, many questions about the management of prostate cancer need to
be answered. For example, further studies are needed to determine the value of
chemotherapy earlier in the progression of disease, the value of
chemopreventive approaches, and efforts to decrease morbidity of the disease
and current therapies. This review will focus on recent and ongoing studies
with bisphosphonates in prostate cancer.
Recent data supports a potential role of bisphosphonates to
decrease bone complications of androgen ablation therapy in patients with
non-metastatic prostate cancer and to decrease skeletal problems in patients
with metastatic prostate cancer. The primary treatment for metastatic prostate
cancer and locally advanced non-metastatic prostate cancer is androgen
deprivation therapy (ADT). This is usually obtained through an orchiectomy or
by treatment with a gonadotropin-releasing hormone agonist. Studies reveal that
adjuvant androgen deprivation therapy improves survival for men with locally
advanced prostate cancer treated with radiation therapy and for men with lymph
node positive prostate cancer treated with radical prostatectomy and pelvic
lymphadenectomy (Bolla et al, 2002; Messing et al,
2002). An unfortunate complication of
such therapy is a decrease in bone mineral density. A recent study by
Shahinian, et al in The NEJM demonstrated that androgen-deprivation therapy for
prostate cancer may increase the risk of fracture (Shahinian et al, 2005).
Recent data also demonstrates that treatment with bisphosphonates may improve
bone density in men without metastatic disease and decrease skeletal related
events in men with hormone refractory bone metastasis (Saad, 2002; Smith et al, 2003). Despite possible benefits of
bisphosphonates, specific guidelines on the use of bisphosphonates in patients
with non-metastatic disease, to decrease bone loss, or metastatic disease, to
decrease skeletal events are unclear.
Multiple studies have
demonstrated that androgen ablation therapy represents an important risk factor
for osteoporosis in men (Barrass et al, 2004). This effect to decrease bone density in men on androgen
ablation therapy has occurred within 6 months (Daniell et al, 2000). The significance of bone loss in patients on androgen
ablation therapy, without metastasis, has also been documented. Increased
skeletal fractures have been associated with the use of androgen ablation
therapy and decreased bone mineral density (BMD) (Melton et al, 2003; Diamond
et al, 2004; Krupski et al, 2004).
Shahinian, et al reviewed
the records of 50,613 men who were linked in the database of the Surveillance,
Epidemiology, and End Results program and Medicare as having received a
diagnosis of prostate cancer between 1992 through 1997 and being at least 66
years of age. Comparisons were limited to men who received at least one dose of
a gonadotropin-releasing hormone agonist or underwent an orchiectomy within 6
months after receiving the diagnosis with those with prostate cancer who
received neither type of treatment at any time after diagnosis. The primary
outcomes were the occurrence of any fracture and the occurrence of a fracture
resulting in hospitalization. The review demonstrated that 19.4 percent of those
who received androgen deprivation therapy (ADT) had a fracture, as compared
with 12.6 percent of those not receiving ADT (P<0.001) (Shahinian et al, 2005).
Multiple studies have now
demonstrated improved bone mineral density with bisphosphonate therapy. For
example, a study by Diamond et al. (1998) looked at markers of bone turnover and bone mineral density
in men with disseminated prostate cancer treated with combined androgen
blockade prior to and after 6 months of intermittent cyclic etidronate and
calcium supplementation. The results of this study show that after treatment
with etidronate, a significant increase in BMD was observed in the femoral neck
and lumbar spine, concluding that adjuvant therapy with intermittent cyclic
etidronate may prevent the high bone turnover and decrease the risk of spinal
fractures. A second study involving patients with locally advanced,
lymph node positive or recurrent prostate cancer and no bone metastases were
randomly assigned to treatment with either a 22.5mg IM depot leuprolide
injection and 60mg i.v. pamidronate every 12 weeks versus 22.5mg IM depot leuprolide
injection alone (Smith et al, 2001). The results revealed that the men receiving the depot
leuprolide injection alone had a decrease in bone mineral density in the lumbar
spine and hip. In contrast, the bone mineral density did not change
significantly in the men treated with depot leuprolide and i.v. pamidronate.
A recent study looked at
a third generation bisphosphonate, zoledronic acid in the prostate cancer
population (Smith et al, 2003). This study involved a randomized controlled trial of
zoledronic acid to prevent bone loss in men receiving androgen deprivation for
nonmetastatic prostate cancer. Zoledronic acid at a dose of 4mg i.v. was given
every 3 months for one year. Results demonstrated that men receiving zoledronic
acid had an increase in mean bone mineral density in the lumbar spine by 5.6%
as compared to a decrease by 2.2% in those given placebo. Mean bone mineral
density of the femoral neck, trochanter and total hip also increased in the
zoledronic acid group and decreased in the placebo group. In summary, these
data suggest that bisphosphonates may reduce the bone loss associated with ADT in
men without metastasis, but the effect of bisphosphonates to decrease rates of
fracture is unclear and needs further study.
III. Clinical studies of
bisphosphonates in metastatic prostate cancer
Clinical studies have
also assessed the role of bisphosphonates in men with metastatic prostate
cancer to bone; randomized phase III studies have included the assessment of
clodronate, pamidronate and zoledronic acid. For example, a double blind,
placebo controlled, randomized trial was completed (Dearnaley et al, 2003) to determine whether the first generation bisphosphonate
sodium clodronate improved bone progression-free survival times among men with
bone metastases from prostate cancer. Between 1994 and 1998, 311 men who were
started or responding to first line hormone therapy for bone metastases were
randomly assigned to receive oral sodium clodronate or placebo for a maximum of
three years. The primary endpoint was symptomatic bone progression free
survival (BPFS). Secondary endpoints included overall survival, treatment
toxicity and change in World Health Organization (WHO) performance status.
After a median follow up of 59 months, the sodium clodronate group was reported
to have a better symptomatic BPFS, but this was not statistically significant
(hazard ratio (HR) =0.79, 95% confidence interval (CI)=0.61 to 1.02; P=.066).
Patients in the clodronate group were less likely to have worsened WHO
performance status (HR+ 0.71, 96% CI= 0.56 to 0.92; P=.008). The clodronate
group did experience more gastrointestinal problems and increased LDH levels
and required more frequent modification of the trial drug dose. Results of subgroup analyses suggested that
clodronate might be more effective if started earlier after diagnosis of
metastatic bone disease. These results suggest that further studies are needed
to determine a benefit of bisphosphonates on BPFS in men with metastatic
prostate cancer that are responding to ADT.
In contrast to studies on
this group of patients with metastasis responding to ADT, studies of patients
with metastatic disease and progression on ADT have more definitive
conclusions. For example, a study randomly assigned patients with HRPC and
metastasis to treatment with i.v. zoledronic acid at 4mg, zoledronic acid at
8mg (subsequently reduced to 4mg) or placebo every 3 weeks for 15 months.
Skeletal related events, time to first SRE, skeletal morbidity rate, pain and
analgesic scores, disease progression and safety were assessed. SRE was defined
as pathologic bone fracture (vertebral or nonvertebral), spinal cord
compression, surgery to bone, radiation to bone (including radioisotopes) or a
change of antineoplastic therapy to treat
bone. The study demonstrated that a greater proportion of patients who
received placebo had an SRE than those who received zoledronic acid at 4mg
(44.2 % versus 33.2%) (Saad, 2002; Saad et al, 2002). These data, therefore, demonstrated a benefit to
zoledronic acid in patients with metastatic prostate cancer, with hormone
refractory disease. This study however does not assess the bone density status
of the men and therefore does not clearly differentiate between malignant or
osteoporotic fractures. This leaves the question as to whether the decreased
risk of fracture was related to osteoporosis or metastatic disease.
IV. Bisphosphonates and pain
palliation
Eastham. et al (2005) looked at the effect of zoledronic acid on bone pain and skeletal morbidity in patients with advanced prostate cancer. 422 patients were enrolled. Zoledronic acid 4mg or placebo was given intravenously every three weeks. Bone pain was assessed using the Brief Pain Inventory (BPI) at 6 week intervals. Of the 371 evaluable patients, 73% reported a baseline BPI score of 2.8 (range 0-10) in both groups. Among the patients receiving zoledronic acid, mean baseline pain scores of -10%, -4% and –1% at months 3, 6 and 9 respectively were reported compared with increases of 6%, 9% and 13% from baseline in the placebo group (P=.021 at month 3).
After month 12, both groups had
increases in pain scores, although the zoledronic acid treated patients had
smaller increases (range of 1% to 6%) compared to placebo (15% to 25%) (Eastham
et al, 2005).
Studies not revealing
benefit include an analysis of two multicenter, double-blind, randomized,
placebo-controlled trials involving patients with bone pain due to metastatic
prostate cancer, with disease progression after first-line hormonal therapy.
Intravenous pamidronate disodium (90 mg) or placebo was administered every 3
weeks for 27 weeks. Efficacy was measured via self-reported pain score (Brief
Pain Inventory), and analgesic use. The results of the two trials were pooled.
There were no sustained significant differences between the pamidronate and
placebo groups in self-reported pain measurements and analgesic use. The
conclusion of this analysis, with inherent limitations of a pooled analysis,
was that Pamidronate disodium failed to demonstrate a significant overall
treatment benefit compared with placebo in palliation of bone pain (Wong,
2004).
An open-label study
conducted in community centers assessed the safety of zoledronic
acid 4 mg intravenously over 15 minutes every 3–4 weeks for a
planned six infusions as treatment of bone metastases in patients with
multiple myeloma, breast cancer, or prostate cancer with and without
previous bisphosphonate exposure. Adverse events (AEs), pain, and
quality-of-life (QOL) scores were recorded. Of 638 patients, 415 patients (65%)
had received prior bisphosphonate therapy. 102 prostate
cancer patients were enrolled. The change from baseline pain score
was analyzed using paired t-tests.
Kaplan-Meier estimates were used to assess time to development of pain for patients who reported no pain upon study entry. Pain assessments were conducted at baseline, before each infusion, and at the final study visit using a 100-mm visual analog scale(VAS). Patients with prostate cancer experienced a reduction in pain scores from baseline at visit 2 only, although there was never any increase in pain noted on the pain score assessment (Vogel et al, 2004)
A clinical phase III, double blind study assessing the
development of bone metastases from prostate cancer (Mason, ASCO 2004) looked
at patients with stage T2-T4 prostate cancer with no evidence of metastatic
bone disease. The primary endpoint was time to the development of symptomatic
bone metastases or death from prostate cancer. 508 patients were randomized and
followed over 3.5 years. Patients were either given oral clodronate or placebo.
Results revealed no difference in time to symptomatic bone metastases, death
from prostate cancer or overall survival (Mason, 2004).
Although there is not enough information at the
present time to give definitive guidelines for the use of bisphosphonates in
all of the stages of prostate cancer, there are ongoing clinical trials. One
ongoing study is a CALGB protocol 90202 for metastatic prostate cancer
patients, initiating androgen ablation within 3 months of study. It is a
randomized, double blind phase III study comparing zoledronic acid 4 mg i.v.
every 4 weeks, versus placebo i.v. every 4 weeks. The objectives of this study
are to determine whether treatment with zoledronic acid, at the time of
initiating androgen ablation therapy for metastatic prostate cancer will delay
time to first skeletal related event, and to determine whether treatment with
zoledronic acid will decrease the proportion of men with one or more vertebral
fractures at two years compared to placebo in men receiving androgen ablation
therapy for metastatic prostate cancer.
A second study, involving the same population,
metastatic prostate cancer to bone, commencing androgen ablation is being
conducted by the Hoosier Oncology Group. It is a Phase III, Randomized, Double
Blind, Placebo Controlled Trial evaluating the ability of risedronate to
prevent skeletal related events. Patients were randomized to either daily oral
risedronate combined with androgen deprivation or daily oral placebo combined
with androgen deprivation. The primary objective of this study was to evaluate
a daily oral dose of 30mg risedronate as compared to placebo to prevent
skeletal complications in patients undergoing androgen deprivation for
metastatic prostate cancer by measuring the time to a skeletal related event.
The MRC trial entitled, Systemic Therapy in Advancing or Metastatic Prostate
Cancer Evaluation of Drug Efficacy (STAMPEDE) trial is a multicentre
international, randomized study, that will assess the safety and efficacy of
three drugs, Zoledronic Acid, docetaxel and a cox 2 inhibitor in combination
and alone along with ADT and a control arm of ADT.
Further studies will also
be needed to better define toxicities associated with short or long term use of
therapy. For example, a poorly understood complication which may be associated
with the use of the intravenously administered bisphosphonates pamidronate and
zoledronate is osteonecrosis of the jaw (Greenberg, 2004). In 2003, Marx described 36 cases of necrotic jaw bone seen
in patients receiving intravenous bisphosphonates as part of their cancer
therapy. 78% of the cases occurred after dental extractions and 22% were
spontaneous. These patients were also receiving chemotherapy drugs and
corticosteroids which put into question whether these factors were the cause of
the osteonecrosis (Marx, 2003). In June 2004, Ruggiero, et al performed a retrospective chart review of patients who presented for Oral
Surgery service between February 2001 and November 2003 with the diagnosis of
refractory osteomyelitis and a history of chronic bisphosphonate therapy. This
review revealed 63 cases of osteonecrosis of the jaw; 56% had received
an intravenous bisphosphonate for at least 6 months as part of cancer therapy
and six were receiving long term oral bisphosphonate therapy for osteoporosis.
Most occurred after dental extractions, but some were spontaneous (Ruggiero et al, 2004). Clearly, these retrospective associations need further
study.
VII. Conclusions
Skeletal complications in men with prostate cancer are
an under-recognized problem. Men undergoing treatment with androgen ablation
for their prostate cancer, even without metastasis, are at increased risk of
bone loss, and men with bone metastasis are at risk for adverse skeletal
related events. Recent studies have demonstrated a benefit of bisphosphonates
to improve bone density in men without bone metastasis receiving ADT, and to
decrease skeletal related events in men with hormone refractory metastatic
prostate cancer. The benefit of bisphosphonates in other stages of progression
of prostate cancer are less clear at this point and further studies are needed.
Likewise, further studies are needed to better understand other potential short
term or long term toxicities. Accrual to clinical trials will be critical, and
should be encouraged, to better define the use of bisphosphonate therapy in
prostate cancer.
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