Therapy Tolerance in Selected Patients With Androgen-Independent Prostate Cancer Following Strontium-89 Combined With Chemotherapy
http://www.100md.com
《临床肿瘤学》
the Departments of Genitourinary Medical Oncology, Pathology, Nuclear Medicine, Molecular Pathology, and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
ABSTRACT
PURPOSE: Clinicians may have reservations about using strontium-89 for the treatment of bone metastases because of concerns that it may limit future use of chemotherapy. We assessed the rate of bone marrow failure in patients with prostate cancer who had received a dose of strontium-89.
PATIENTS AND METHODS: This subgroup analysis involved 34 patients with androgen-independent prostate cancer who had been given a dose of strontium-89 and six weekly doses of doxorubicin after response to induction chemotherapy. We assessed subsequent hematotoxicity in terms of bone marrow failure and the ability to tolerate additional treatments during a median of 25 months (range, 7 to 76 months) after the strontium-89 was administered.
RESULTS: No patients developed bone marrow failure within 6 months of receiving strontium-89. Five (15%) of 34 patients developed bone marrow failure at a median 23 months (range, 6 to 53 months) after the strontium-89 treatment. Bone marrow biopsy performed in two of these five patients showed complete replacement of the marrow by tumor. Thirty-one patients (91%) received subsequent cytotoxic treatments at a median 11 months (range, 1 to 33 months) after the strontium-89 treatment.
CONCLUSION: This analysis demonstrated that a single dose of strontium-89 combined with chemotherapy did not affect the delivery of subsequent courses of chemotherapy in a select group of patients. However, a majority of these therapies were given off protocol and were administered at a dose schedule that might be considered inappropriate or inadequate. The clinical role and safety profile of radiopharmaceuticals combined with chemotherapy in prostate cancer therapy deserve further exploration.
INTRODUCTION
At least two thirds of the approximately 500,000 individuals in the United States who die of cancer each year have bone metastases.1 Bone is the second most common site of metastasis in human cancer and is often the initial site of androgen-independent progression in prostate cancer. Treatment of bone metastases by surgery, radiation, chemotherapy, and use of bone-targeted agents such as bisphosphonates and radiopharmaceuticals can provide palliative benefit. However, many clinicians have reservations about the use of radiopharmaceuticals because of the concerns that they may cause severe bone marrow toxicity, which would compromise the use of subsequent palliative chemotherapy.
Bone-seeking radiopharmaceuticals have been used to alleviate pain from osseous metastases. These agents target bone metastases by preferential deposition at sites of increased osteoblastic activity and bone matrix synthesis.2 Their unique physical properties allow them to irradiate multiple sites of skeletal metastases simultaneously. Therefore, these agents are ideally suited for the treatment of patients with advanced prostate cancer who develop multifocal osteoblastic metastases, especially those patients for whom bone is the predominant or only site of metastasis.
Although radiopharmaceuticals are an important treatment option for bone metastases, their long-term safety profile, particularly with regard to hematologic toxicity, remains to be elucidated. Use of strontium-89 (Sr-89) is of special concern because of its prolonged half-life (50.6 days) and its potential to cause serious or permanent damage to the bone marrow.3,4 Additional information about the long-term adverse effects of radiopharmaceuticals is imperative if these agents are to be used more extensively for the treatment of skeletal metastases in the future.
One reason few data are available on the long-term effects of radiopharmaceuticals is that until recently most patients who have been given radiopharmaceuticals have had a short life expectancy owing to their disease and thus are not usually monitored for any chronic adverse effects or complications, nor are they subjected to intensive or invasive tests. Therefore, when bone marrow failure occurs in a patient given radiopharmaceuticals, one often does not know whether it is caused by tumor infiltration or whether it is a treatment effect.5
In our previous study,6 we found that consolidation therapy that included Sr-89 might prolong overall survival time in patients with androgen-independent prostate cancer and bone metastases that had responded to induction chemotherapy. The clinical follow-up information available from that trial provides an opportunity to assess the long-term effects of Sr-89. In this article, we assessed the long-term hematologic effects of Sr-89 by determining the incidence of bone marrow failure among patients given a single dose of Sr-89 and assessed whether that treatment adversely affected the ability of the patients to undergo subsequent therapies such as cytotoxic chemotherapy, investigational drugs, external-beam irradiation, or repeated use of radiopharmaceutical agents.
PATIENTS AND METHODS
The study population was a subset of patients from a previous trial that studied induction chemotherapy with or without Sr-89 for progressive androgen-independent prostate carcinoma involving bone.6 Progressive disease was defined as a worsening of cancer-related symptoms or an increase in prostate-specific antigen (PSA) values on two occasions that were at least 2 weeks apart. For those patients without symptoms, the PSA value had to be higher than 40 ng/dL. All patients had shown disease progression after antiandrogen withdrawal and had castrate-level serum testosterone concentrations of less than 50 ng/dL. Continuation of primary testicular androgen suppression was required during treatment. Patients had to have had a life expectancy of 12 weeks or longer and a performance status (Zubrod scale) of 3 or lower. Patients must not have had more than one previous treatment with chemotherapy and should not have previously received doxorubicin, vinblastine, or Sr-89. Prior external-beam irradiation for metastatic disease was allowed only if the treatment had been confined to a single focus of bony metastasis. Patients with predominantly visceral metastases or with tumors containing small-cell carcinoma were excluded, as were those patients with serious intercurrent illnesses or major organ dysfunction. Specifically, patients must have had a left ventricular ejection fraction of at least 50%, a platelet count greater than 100,000/μL, a neutrophil count of at least 1,500/μL, a bilirubin level less than 1.5 mg/dL, a serum ALT level less than four times the upper limit of normal, and a serum creatinine level less than 2.0 mg/dL (or a predicted creatinine clearance of at least 40 mL/min) at baseline before induction chemotherapy. All patients had given written informed consent to participate in the study, which was approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center (Houston, TX).
The induction regimen was "KAVE,"7 which consisted of doxorubicin (20 mg/m2, usually as a 24-hour intravenous infusion on the first day of each week) in combination with ketoconazole (400 mg orally three times each day for 7 days) during weeks 1, 3, and 5. This treatment was alternated with vinblastine (4 mg/m2 intravenously on the first day of each week) in combination with estramustine (140 mg orally three times each day for 7 days) during weeks 2, 4, and 6. After completion of two or three courses of KAVE, patients with stable or responding disease were randomly assigned to receive consolidation therapy8 consisting of six additional weekly doses of doxorubicin with or without a single dose of Sr-89 (55 μCi/kg) within the first week after the first dose of doxorubicin. The 34 patients who had received Sr-89 treatment were the subjects of this analysis.
The patients' clinical histories, laboratory results, and treatment responses were obtained from their medical records and from M.D. Anderson Cancer Center's computer data management system (NETPASS or ClinicStation; MDACC, Houston, TX). Bone marrow failure was defined as having at least one of the following features: a blood platelet count 20,000/μL, a blood absolute neutrophil count 500/μL, or a hypoplastic marrow depleted of hematopoietic cells with less than 25% normal cellularity or less than 50% normal cellularity in which less than 30% of the cells were hematopoietic. Overall survival data were obtained from the clinical records or from the Social Security Death Index Interactive Search Web Site (MyFamily.com Inc, Provo, UT; http://ssdi.genealogy.rootsweb.com). Time-to-event analysis was performed and overall survival curves were generated by using the methods of Kaplan and Meier.9 Time to subsequent treatments was measured from the time of Sr-89 administration until the time those subsequent treatments were initiated. Overall survival was calculated from the time of Sr-89 treatment until death from any cause or last follow-up visit.
RESULTS
A total of 34 patients received one dose of Sr-89 between October 22, 1996, and September 19, 1999, (two patients from the original study did not receive Sr-89 because their primary oncologists decided not to administer the treatment when their bone metastases or bone pains resolved after induction chemotherapy). Baseline characteristics of these patients are listed in Table 1. The median age of the patients was 67 years (range, 46 to 84 years). Median baseline (before induction chemotherapy) serum PSA level was 89 ng/dL (range, 7.3 to 2,366 ng/dL); alkaline phosphatase level was 155 U/L (range, 78 to 3,174 U/L); and hemoglobin level was 13.0 g/dL (range, 9.8 to 14.7 g/dL). Twenty-seven patients (79%) had more than six lesions on bone scans and 28 patients (82%) had bone pain at study entry. Twenty-eight (93%) of 30 patients who had prior bone scans available for review showed evidence of disease progression, with new lesions mostly developing within 6 months before registration. Three patients (9%) had superscans taken, and two patients (6%) had symptoms of impending cord compression, base-of-skull syndrome, or nerve root entrapment before therapy.
After the consolidation therapy, five (15%) of the 34 patients developed bone marrow failure according to the criteria defined in Patients and Methods and another five patients developed myelosuppression, with platelet counts 50,000/μL (Table 2). None of the patients' bone marrow failures occurred within 6 months of Sr-89 treatment (Table 3). Anemia could be contributed to various other factors (including gastrointestinal or genitourinary bleeds, poor nutrition, renal insufficiency, castration effect, thyroid dysfunction) besides bone marrow failure. Therefore, anemia was not used as a criterion to determine bone marrow failure. Eleven patients developed anemia with a hemoglobin level of less than 10 g/dL. Anemia was recorded at a median 15 months (range, 6 to 53 months) after the Sr-89 treatment and 2 months (range, 1 to 11 months) before patients' demise. Eight patients received packed RBC transfusions. The median interval from the time of Sr-89 treatment to that of documented bone marrow failure for the five patients was 23 months (range, 6 to 53 months). In comparison, the median overall survival time after the initial Sr-89 treatment for all 34 patients was 25 months (range, 7 to 76 months; Fig 1). Biopsy findings from the two patients who had bone marrow biopsies showed complete replacement of the marrow by tumor at the time of bone marrow failure. Three of the five patients with bone marrow failure had clinical evidence of disseminated intravascular coagulopathy, and two patients had impending spinal cord compression requiring irradiation therapy or surgery to the affected sites. No patient developed myelodysplastic syndrome or hematologic malignancies. One patient developed cardiomyopathy that was probably related to doxorubicin.
As an indirect indicator of hematologic toxicity, we also evaluated whether patients who had received Sr-89 were able to tolerate additional treatments. All but three of the 34 patients received at least one other chemotherapy regimen (or investigational drug) after receiving Sr-89 treatment. All five patients who developed bone marrow failure, as well as the four patients who had bone marrow suppression, had been able to receive at least one chemotherapy regimen after the Sr-89 treatment (Table 2). The number of chemotherapy regimens given after Sr-89 did not include the six weekly doses of doxorubicin, which were administered concurrently with the Sr-89 treatment. A total of 66 treatments (up to eight per patient) were administered (Table 4), with a median number of 10 treatments (range, one to eight) and a median time of 11 months (range, 1 to 33 months) from the Sr-89 treatment to the first administration of the second-line treatment (Table 5). The chemotherapy agents administered were docetaxel, mitoxantrone, cyclophosphamide, paclitaxel, etoposide, carboplatin, vincristine, gemcitabine, mitomycin C, cisplatin, fluorouracil, capecitabine, and ifosfamide. Investigational or noncytotoxic agents given were TNP-470 (an angiogenesis inhibitor), ABT-627 (an endothelin antagonist), GBC-590 (a pectin), bortezomib, gamma interferon, imatinib mesylate, ketoconazole, estramustine, dexamethasone, diethylstilbestrol, and thalidomide.
Eleven patients received external-beam irradiation to a symptomatic site of bone metastasis after the Sr-89 treatment, with a median time of 12 months (range, 2 to 76 months) from Sr-89 treatment to the first external irradiation treatment (Table 5). Six patients received at least one additional dose of either Sr-89 or samarium-153 lexidronam (Sm-153). Three of these six patients developed bone marrow failure or suppression at 1, 9, and 38 months after the second Sr-89 treatment (Table 2). Patient 5, who experienced bone marrow failure at 9 months after his second Sr-89 treatment, had evidence on biopsy of marrow replacement by tumor. The longest surviving individual ( 93 months) of the 34 patients has had four radiopharmaceutical treatments as of September 2005: the initial Sr-89 dose in December 1997, Sm-153 in August 1999, and repeated Sr-89 treatments in August 2000 and April 2004. At the time of his last blood counts check on March 15, 2005, he has not developed any evidence of bone marrow failure or experienced other chronic adverse events.
DISCUSSION
this subset analysis of 34 patients with androgen-independent prostate cancer and bone metastases who had responded to induction chemotherapy, we concluded that a dose of Sr-89 administered with cytotoxic chemotherapy did not lead to serious or permanent damage to the bone marrow. First, no patients developed bone marrow failure within 6 months of the Sr-89 treatment (Table 3). Second, bone marrow failure occurred in only five (15%) of 34 patients and was likely to have been caused by tumor infiltration in these cases (Table 2). Third, the median interval between Sr-89 treatment and development of bone marrow failure in those five patients (23 months) coincided with the overall survival time for all 34 patients (25 months) following Sr-89 treatment (Table 5). Fourth, almost all patients were able to tolerate additional treatments, such as chemotherapy, investigational drugs, radiation therapy, and radiopharmaceutical agents, subsequent to the Sr-89 treatment (Table 4).
Use of Sr-89 for palliation of pain from skeletal metastases was approved by the US Food and Drug Administration in 1993. Since that time, no clinical studies have reported the long-term adverse effects of Sr-89 treatment. Information on the safety profile of Sr-89 is particularly important if Sr-89 is to be used more often and administered earlier during disease progression. Findings from our randomized phase II clinical trial6 showed that Sr-89 in combination with chemotherapy could prolong the overall survival of patients with advanced prostate cancer and bone metastases. Our findings from the subgroup analysis reported in this article suggest that the few cases of marrow failure resulted from tumor infiltration (a speculation supported by the presence of disseminated intravascular coagulopathy and spinal cord compression), that use of this radiopharmaceutical did not lead to myelodysplastic syndrome or hematologic malignancy,10 and that any hematologic adverse effects experienced were sufficiently mild as to not prevent patients from undergoing subsequent potentially hematotoxic treatments.
Results from the current study suggested that additional chemotherapy could be delivered in sufficient doses and delivered for sufficient durations in selected patients after they responded to induction chemotherapy and a dose of Sr-89 treatment. Twenty-eight (42%) of 66 cytotoxic treatments (cyclophosphamide/vincristine/dexamethasone [CVD], estramustine/paclitaxel/etoposide [TEE], estramustine/paclitaxel/carboplatin [TEC], docetaxel/imatinib, estramustine/paclitaxel/thalidomide, paclitaxel/doxorubicin, and paclitaxel/TNP-470) were given according to a clinical protocol and the dose schedules were considered appropriate and adequate.11-14 The chemotherapy treatments were given at a median 15 months (range, 1 to 46 months) after the Sr-89 treatment, and the median duration of treatment was 2 months (range, 1 to 14 months). There was no evidence of any unexpected toxic effects. Most patients were taken off treatment because of disease progression rather than adverse events. Nineteen (29%) of 66 cytotoxic treatments were docetaxel-based regimens (combined with estramustine, thalidomide, diethylstilbestrol, vincristine, carboplatin, mitoxantrone, gemcitabine, capecitabine, or etoposide) given off protocol. These chemotherapy treatments were given at a median 23 months (range, 4 to 57 months) after the Sr-89 treatment. The median duration of treatment was 3 months (range, 1 to 8 months). Again, most patients were taken off treatment because of disease progression rather than adverse events. The docetaxel dose was dependent on the type of combination treatment and varied from 25 to 40 mg/m2 on the weekly schedule and from 60 to 70 mg/m2 on the once every 3 weeks schedule. The rest of the chemotherapy treatments (29%) comprised of modified versions of the above regimens or any treatments used at the discretion of the primary oncologists (mitoxandrone, doxorubicin, or cyclophosphamide combined with one dose of Sr-89 or Sm-153, mitoxantrone combined with ketoconazole, vincristine added to TEE, paclitaxel-based combinations, etoposide substituting for vincristine in CVD, ketoconazole and doxorubicin alternating with gemcitabine and cyclophosphamide, etoposide combined with cisplatin and cyclophosphamide, fluorouracil/gemcitabine, gemcitabine/ifosphamide, mitomycin C/vinblastine, and single-agent treatments using gemcitabine or cyclophosphamide) given off protocol because the patients did not meet eligibility criteria (eg, had received > two prior chemotherapy regimens) or no clinical trials were available at the time.
Radiopharmaceuticals have been shown in randomized studies to improve pain control and reduce use of analgesics among patients with bone metastases.15-18 Overall, such treatment provides substantial pain relief in approximately two thirds of cases, with complete responses reported by nearly one third of the patients treated. In addition to palliation of bone pain, Sr-89 can delay the occurrence of new bone metastases in prostate cancer.15,19 However, a single dose of a radiopharmaceutical alone does not provide any advantage for overall survival.15,19,20 Recent studies suggested that combining Sr-89 with other treatment modalities6 or using repeated doses of radiopharmaceuticals21 might improve overall survival. Information on the chronic toxic effects of radiopharmaceuticals may help to justify or facilitate therapeutic strategies using these agents in the future.
In this subgroup analysis, Sr-89 was given in the context of consolidation therapy with doxorubicin after response to induction chemotherapy. Had Sr-89 been given alone for the palliation of bone pain later during disease progression, as is common practice today, the toxicity profile might not have been the same as that reported in this article. We speculate that the safety profile of Sr-89 was improved when the tumor burden in the bone marrow was reduced by the cytotoxic chemotherapy. Although results from our analysis suggested that Sr-89 could be safely combined with cytotoxic chemotherapy and given earlier during the course of disease, this therapeutic approach should not be considered the standard of care as yet. Indeed, many patients with androgen-independent prostate cancer and bone metastases have compromised marrow reserve and cannot be given chemotherapy. The value and safety of giving Sr-89 in the context of consolidation bone-targeted therapy after response to induction chemotherapy needs to be further validated in clinical trials.
A potential advantage of radiopharmaceuticals is that they can be used repeatedly for palliation of bone pain. However, repeated administration may potentially cause severe or permanent damage to the bone marrow. One way to minimize this risk is to ensure that the intervals between repeated Sr-89 treatments are sufficiently long to allow the bone marrow to recover from the toxic effects of treatment. Unfortunately, a rapidly progressive tumor may not permit many opportunities for repeated treatments over extended intervals. Results from our analysis suggest that consolidation bone-targeted therapy can prolong progression-free survival and provide opportunities to give multiple radiopharmaceutical treatments over extended intervals. The value and safety of this approach, giving repeated radiopharmaceuticals in a consolidation setting, needs further validation in clinical trials.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Christine Wogans for editorial assistance.
NOTES
Supported in part by Grants No. SPORE P50 CA 90270 (to C.J.L.), NIH CA 86342, and the Association for the Cure of Cancer of the Prostate (CaPCURE) (to S.-H.L.), and a grant from Nycomed Amersham, which also provided the strontium-89 free of charge.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001 [Erratum: CA Cancer J Clin 51:144, 2001]
Ben-Josef E, Lucas DR, Vasan S, et al: Selective accumulation of strontium-89 in metastatic deposits in bone: Radio-histological correlation. Nucl Med Commun 16:457-463, 1995
Robinson RG, Spicer JA, Blake GM, et al: Strontium-89: Treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone. Radiographics 9:271-281, 1989
Nightengale B, Brune M, Blizzard SP, et al: Strontium chloride Sr89 for treating pain from metastatic bone disease. Am J Health Syst Pharm 52:2189-2195, 1995
Powsner RA, Zietman AL, Foss FM: Bone marrow suppression after strontium-89 therapy and local radiation therapy in patients with diffuse marrow involvement. Clin Nucl Med 22:147-150, 1997
Tu SM, Millikan RE, Mengistu B, et al: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomized phase II trial. Lancet 357:336-341, 2001
Ellerhorst JA, Tu SM, Amato RJ, et al: Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer. Clin Cancer Res 3:2371-2376, 1997
Tu SM, Delpassand ES, Jones D, et al: Strontium-89 combined with doxorubicin in the treatment of patients with androgen-independent prostate cancer. Urol Oncol 2:191-197, 1996
Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457-461, 1958
Kossman S, Weiss M: Acute myelogenous leukemia after exposure to strontium-89 for adenocarcinoma of the prostate. Cancer 88:620-624, 2000
Daliani DD, Assikis V, Tu SM, et al: Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma. Cancer 97:561-567, 2003
Mathew P, Thall PF, Jones D, et al: Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: A modular phase I trial in androgen-independent prostate cancer. J Clin Oncol 22:3323-3329, 2004
Herbst RS, Madden TL, Tran HT, et al: Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: Evidence for activity in non-small-cell lung cancer. J Clin Oncol 20:4440-4447, 2002
Thall PF, Millikan RE, Sung HG: Evaluating multiple treatment courses in clinical trials. Stat Med 19:1011-1028, 2000
Porter AT, McEwan AJB, Powe JE, et al: Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25:805-813, 1993
Serafini AN, Houston SJ, Resche I, et al: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: A double-blind placebo-controlled clinical trial. J Clin Oncol 16:1574-1581, 1998
Sartor O, Reid RH, Hoskins PJ, et al: Samarium-153 lexidronam complex for treatment of painful bone metastases in hormone refractory prostate cancer. Urology 63:940-945, 2004
Han SH, de Klerk JMH, Tan S, et al: The placorhen study: A double-blind, placebo-controlled, randomized radionuclide study with 186-Re-etidronate in hormone-resistant prostate cancer patients with painful metastases. J Nucl Med 43:1150-1156, 2002
Quilty PM, Kirk D, Bolger JJ, et al: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31:33-40, 1994
Sciuto R, Festa A, Rea S, et al: Effects of low-dose cisplatin on Sr-89 therapy for painful bone metastases from prostate cancer: A randomized clinical trial. J Nucl Med 43:79-86, 2002
lmedo H, Manka-Waluch A, Albers P, et al: Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: Randomized phase II trial with the new, high-energy radiopharmaceutical Rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol 21:2869-2875, 2003(Shi-Ming Tu, Jeri Kim, La)
ABSTRACT
PURPOSE: Clinicians may have reservations about using strontium-89 for the treatment of bone metastases because of concerns that it may limit future use of chemotherapy. We assessed the rate of bone marrow failure in patients with prostate cancer who had received a dose of strontium-89.
PATIENTS AND METHODS: This subgroup analysis involved 34 patients with androgen-independent prostate cancer who had been given a dose of strontium-89 and six weekly doses of doxorubicin after response to induction chemotherapy. We assessed subsequent hematotoxicity in terms of bone marrow failure and the ability to tolerate additional treatments during a median of 25 months (range, 7 to 76 months) after the strontium-89 was administered.
RESULTS: No patients developed bone marrow failure within 6 months of receiving strontium-89. Five (15%) of 34 patients developed bone marrow failure at a median 23 months (range, 6 to 53 months) after the strontium-89 treatment. Bone marrow biopsy performed in two of these five patients showed complete replacement of the marrow by tumor. Thirty-one patients (91%) received subsequent cytotoxic treatments at a median 11 months (range, 1 to 33 months) after the strontium-89 treatment.
CONCLUSION: This analysis demonstrated that a single dose of strontium-89 combined with chemotherapy did not affect the delivery of subsequent courses of chemotherapy in a select group of patients. However, a majority of these therapies were given off protocol and were administered at a dose schedule that might be considered inappropriate or inadequate. The clinical role and safety profile of radiopharmaceuticals combined with chemotherapy in prostate cancer therapy deserve further exploration.
INTRODUCTION
At least two thirds of the approximately 500,000 individuals in the United States who die of cancer each year have bone metastases.1 Bone is the second most common site of metastasis in human cancer and is often the initial site of androgen-independent progression in prostate cancer. Treatment of bone metastases by surgery, radiation, chemotherapy, and use of bone-targeted agents such as bisphosphonates and radiopharmaceuticals can provide palliative benefit. However, many clinicians have reservations about the use of radiopharmaceuticals because of the concerns that they may cause severe bone marrow toxicity, which would compromise the use of subsequent palliative chemotherapy.
Bone-seeking radiopharmaceuticals have been used to alleviate pain from osseous metastases. These agents target bone metastases by preferential deposition at sites of increased osteoblastic activity and bone matrix synthesis.2 Their unique physical properties allow them to irradiate multiple sites of skeletal metastases simultaneously. Therefore, these agents are ideally suited for the treatment of patients with advanced prostate cancer who develop multifocal osteoblastic metastases, especially those patients for whom bone is the predominant or only site of metastasis.
Although radiopharmaceuticals are an important treatment option for bone metastases, their long-term safety profile, particularly with regard to hematologic toxicity, remains to be elucidated. Use of strontium-89 (Sr-89) is of special concern because of its prolonged half-life (50.6 days) and its potential to cause serious or permanent damage to the bone marrow.3,4 Additional information about the long-term adverse effects of radiopharmaceuticals is imperative if these agents are to be used more extensively for the treatment of skeletal metastases in the future.
One reason few data are available on the long-term effects of radiopharmaceuticals is that until recently most patients who have been given radiopharmaceuticals have had a short life expectancy owing to their disease and thus are not usually monitored for any chronic adverse effects or complications, nor are they subjected to intensive or invasive tests. Therefore, when bone marrow failure occurs in a patient given radiopharmaceuticals, one often does not know whether it is caused by tumor infiltration or whether it is a treatment effect.5
In our previous study,6 we found that consolidation therapy that included Sr-89 might prolong overall survival time in patients with androgen-independent prostate cancer and bone metastases that had responded to induction chemotherapy. The clinical follow-up information available from that trial provides an opportunity to assess the long-term effects of Sr-89. In this article, we assessed the long-term hematologic effects of Sr-89 by determining the incidence of bone marrow failure among patients given a single dose of Sr-89 and assessed whether that treatment adversely affected the ability of the patients to undergo subsequent therapies such as cytotoxic chemotherapy, investigational drugs, external-beam irradiation, or repeated use of radiopharmaceutical agents.
PATIENTS AND METHODS
The study population was a subset of patients from a previous trial that studied induction chemotherapy with or without Sr-89 for progressive androgen-independent prostate carcinoma involving bone.6 Progressive disease was defined as a worsening of cancer-related symptoms or an increase in prostate-specific antigen (PSA) values on two occasions that were at least 2 weeks apart. For those patients without symptoms, the PSA value had to be higher than 40 ng/dL. All patients had shown disease progression after antiandrogen withdrawal and had castrate-level serum testosterone concentrations of less than 50 ng/dL. Continuation of primary testicular androgen suppression was required during treatment. Patients had to have had a life expectancy of 12 weeks or longer and a performance status (Zubrod scale) of 3 or lower. Patients must not have had more than one previous treatment with chemotherapy and should not have previously received doxorubicin, vinblastine, or Sr-89. Prior external-beam irradiation for metastatic disease was allowed only if the treatment had been confined to a single focus of bony metastasis. Patients with predominantly visceral metastases or with tumors containing small-cell carcinoma were excluded, as were those patients with serious intercurrent illnesses or major organ dysfunction. Specifically, patients must have had a left ventricular ejection fraction of at least 50%, a platelet count greater than 100,000/μL, a neutrophil count of at least 1,500/μL, a bilirubin level less than 1.5 mg/dL, a serum ALT level less than four times the upper limit of normal, and a serum creatinine level less than 2.0 mg/dL (or a predicted creatinine clearance of at least 40 mL/min) at baseline before induction chemotherapy. All patients had given written informed consent to participate in the study, which was approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center (Houston, TX).
The induction regimen was "KAVE,"7 which consisted of doxorubicin (20 mg/m2, usually as a 24-hour intravenous infusion on the first day of each week) in combination with ketoconazole (400 mg orally three times each day for 7 days) during weeks 1, 3, and 5. This treatment was alternated with vinblastine (4 mg/m2 intravenously on the first day of each week) in combination with estramustine (140 mg orally three times each day for 7 days) during weeks 2, 4, and 6. After completion of two or three courses of KAVE, patients with stable or responding disease were randomly assigned to receive consolidation therapy8 consisting of six additional weekly doses of doxorubicin with or without a single dose of Sr-89 (55 μCi/kg) within the first week after the first dose of doxorubicin. The 34 patients who had received Sr-89 treatment were the subjects of this analysis.
The patients' clinical histories, laboratory results, and treatment responses were obtained from their medical records and from M.D. Anderson Cancer Center's computer data management system (NETPASS or ClinicStation; MDACC, Houston, TX). Bone marrow failure was defined as having at least one of the following features: a blood platelet count 20,000/μL, a blood absolute neutrophil count 500/μL, or a hypoplastic marrow depleted of hematopoietic cells with less than 25% normal cellularity or less than 50% normal cellularity in which less than 30% of the cells were hematopoietic. Overall survival data were obtained from the clinical records or from the Social Security Death Index Interactive Search Web Site (MyFamily.com Inc, Provo, UT; http://ssdi.genealogy.rootsweb.com). Time-to-event analysis was performed and overall survival curves were generated by using the methods of Kaplan and Meier.9 Time to subsequent treatments was measured from the time of Sr-89 administration until the time those subsequent treatments were initiated. Overall survival was calculated from the time of Sr-89 treatment until death from any cause or last follow-up visit.
RESULTS
A total of 34 patients received one dose of Sr-89 between October 22, 1996, and September 19, 1999, (two patients from the original study did not receive Sr-89 because their primary oncologists decided not to administer the treatment when their bone metastases or bone pains resolved after induction chemotherapy). Baseline characteristics of these patients are listed in Table 1. The median age of the patients was 67 years (range, 46 to 84 years). Median baseline (before induction chemotherapy) serum PSA level was 89 ng/dL (range, 7.3 to 2,366 ng/dL); alkaline phosphatase level was 155 U/L (range, 78 to 3,174 U/L); and hemoglobin level was 13.0 g/dL (range, 9.8 to 14.7 g/dL). Twenty-seven patients (79%) had more than six lesions on bone scans and 28 patients (82%) had bone pain at study entry. Twenty-eight (93%) of 30 patients who had prior bone scans available for review showed evidence of disease progression, with new lesions mostly developing within 6 months before registration. Three patients (9%) had superscans taken, and two patients (6%) had symptoms of impending cord compression, base-of-skull syndrome, or nerve root entrapment before therapy.
After the consolidation therapy, five (15%) of the 34 patients developed bone marrow failure according to the criteria defined in Patients and Methods and another five patients developed myelosuppression, with platelet counts 50,000/μL (Table 2). None of the patients' bone marrow failures occurred within 6 months of Sr-89 treatment (Table 3). Anemia could be contributed to various other factors (including gastrointestinal or genitourinary bleeds, poor nutrition, renal insufficiency, castration effect, thyroid dysfunction) besides bone marrow failure. Therefore, anemia was not used as a criterion to determine bone marrow failure. Eleven patients developed anemia with a hemoglobin level of less than 10 g/dL. Anemia was recorded at a median 15 months (range, 6 to 53 months) after the Sr-89 treatment and 2 months (range, 1 to 11 months) before patients' demise. Eight patients received packed RBC transfusions. The median interval from the time of Sr-89 treatment to that of documented bone marrow failure for the five patients was 23 months (range, 6 to 53 months). In comparison, the median overall survival time after the initial Sr-89 treatment for all 34 patients was 25 months (range, 7 to 76 months; Fig 1). Biopsy findings from the two patients who had bone marrow biopsies showed complete replacement of the marrow by tumor at the time of bone marrow failure. Three of the five patients with bone marrow failure had clinical evidence of disseminated intravascular coagulopathy, and two patients had impending spinal cord compression requiring irradiation therapy or surgery to the affected sites. No patient developed myelodysplastic syndrome or hematologic malignancies. One patient developed cardiomyopathy that was probably related to doxorubicin.
As an indirect indicator of hematologic toxicity, we also evaluated whether patients who had received Sr-89 were able to tolerate additional treatments. All but three of the 34 patients received at least one other chemotherapy regimen (or investigational drug) after receiving Sr-89 treatment. All five patients who developed bone marrow failure, as well as the four patients who had bone marrow suppression, had been able to receive at least one chemotherapy regimen after the Sr-89 treatment (Table 2). The number of chemotherapy regimens given after Sr-89 did not include the six weekly doses of doxorubicin, which were administered concurrently with the Sr-89 treatment. A total of 66 treatments (up to eight per patient) were administered (Table 4), with a median number of 10 treatments (range, one to eight) and a median time of 11 months (range, 1 to 33 months) from the Sr-89 treatment to the first administration of the second-line treatment (Table 5). The chemotherapy agents administered were docetaxel, mitoxantrone, cyclophosphamide, paclitaxel, etoposide, carboplatin, vincristine, gemcitabine, mitomycin C, cisplatin, fluorouracil, capecitabine, and ifosfamide. Investigational or noncytotoxic agents given were TNP-470 (an angiogenesis inhibitor), ABT-627 (an endothelin antagonist), GBC-590 (a pectin), bortezomib, gamma interferon, imatinib mesylate, ketoconazole, estramustine, dexamethasone, diethylstilbestrol, and thalidomide.
Eleven patients received external-beam irradiation to a symptomatic site of bone metastasis after the Sr-89 treatment, with a median time of 12 months (range, 2 to 76 months) from Sr-89 treatment to the first external irradiation treatment (Table 5). Six patients received at least one additional dose of either Sr-89 or samarium-153 lexidronam (Sm-153). Three of these six patients developed bone marrow failure or suppression at 1, 9, and 38 months after the second Sr-89 treatment (Table 2). Patient 5, who experienced bone marrow failure at 9 months after his second Sr-89 treatment, had evidence on biopsy of marrow replacement by tumor. The longest surviving individual ( 93 months) of the 34 patients has had four radiopharmaceutical treatments as of September 2005: the initial Sr-89 dose in December 1997, Sm-153 in August 1999, and repeated Sr-89 treatments in August 2000 and April 2004. At the time of his last blood counts check on March 15, 2005, he has not developed any evidence of bone marrow failure or experienced other chronic adverse events.
DISCUSSION
this subset analysis of 34 patients with androgen-independent prostate cancer and bone metastases who had responded to induction chemotherapy, we concluded that a dose of Sr-89 administered with cytotoxic chemotherapy did not lead to serious or permanent damage to the bone marrow. First, no patients developed bone marrow failure within 6 months of the Sr-89 treatment (Table 3). Second, bone marrow failure occurred in only five (15%) of 34 patients and was likely to have been caused by tumor infiltration in these cases (Table 2). Third, the median interval between Sr-89 treatment and development of bone marrow failure in those five patients (23 months) coincided with the overall survival time for all 34 patients (25 months) following Sr-89 treatment (Table 5). Fourth, almost all patients were able to tolerate additional treatments, such as chemotherapy, investigational drugs, radiation therapy, and radiopharmaceutical agents, subsequent to the Sr-89 treatment (Table 4).
Use of Sr-89 for palliation of pain from skeletal metastases was approved by the US Food and Drug Administration in 1993. Since that time, no clinical studies have reported the long-term adverse effects of Sr-89 treatment. Information on the safety profile of Sr-89 is particularly important if Sr-89 is to be used more often and administered earlier during disease progression. Findings from our randomized phase II clinical trial6 showed that Sr-89 in combination with chemotherapy could prolong the overall survival of patients with advanced prostate cancer and bone metastases. Our findings from the subgroup analysis reported in this article suggest that the few cases of marrow failure resulted from tumor infiltration (a speculation supported by the presence of disseminated intravascular coagulopathy and spinal cord compression), that use of this radiopharmaceutical did not lead to myelodysplastic syndrome or hematologic malignancy,10 and that any hematologic adverse effects experienced were sufficiently mild as to not prevent patients from undergoing subsequent potentially hematotoxic treatments.
Results from the current study suggested that additional chemotherapy could be delivered in sufficient doses and delivered for sufficient durations in selected patients after they responded to induction chemotherapy and a dose of Sr-89 treatment. Twenty-eight (42%) of 66 cytotoxic treatments (cyclophosphamide/vincristine/dexamethasone [CVD], estramustine/paclitaxel/etoposide [TEE], estramustine/paclitaxel/carboplatin [TEC], docetaxel/imatinib, estramustine/paclitaxel/thalidomide, paclitaxel/doxorubicin, and paclitaxel/TNP-470) were given according to a clinical protocol and the dose schedules were considered appropriate and adequate.11-14 The chemotherapy treatments were given at a median 15 months (range, 1 to 46 months) after the Sr-89 treatment, and the median duration of treatment was 2 months (range, 1 to 14 months). There was no evidence of any unexpected toxic effects. Most patients were taken off treatment because of disease progression rather than adverse events. Nineteen (29%) of 66 cytotoxic treatments were docetaxel-based regimens (combined with estramustine, thalidomide, diethylstilbestrol, vincristine, carboplatin, mitoxantrone, gemcitabine, capecitabine, or etoposide) given off protocol. These chemotherapy treatments were given at a median 23 months (range, 4 to 57 months) after the Sr-89 treatment. The median duration of treatment was 3 months (range, 1 to 8 months). Again, most patients were taken off treatment because of disease progression rather than adverse events. The docetaxel dose was dependent on the type of combination treatment and varied from 25 to 40 mg/m2 on the weekly schedule and from 60 to 70 mg/m2 on the once every 3 weeks schedule. The rest of the chemotherapy treatments (29%) comprised of modified versions of the above regimens or any treatments used at the discretion of the primary oncologists (mitoxandrone, doxorubicin, or cyclophosphamide combined with one dose of Sr-89 or Sm-153, mitoxantrone combined with ketoconazole, vincristine added to TEE, paclitaxel-based combinations, etoposide substituting for vincristine in CVD, ketoconazole and doxorubicin alternating with gemcitabine and cyclophosphamide, etoposide combined with cisplatin and cyclophosphamide, fluorouracil/gemcitabine, gemcitabine/ifosphamide, mitomycin C/vinblastine, and single-agent treatments using gemcitabine or cyclophosphamide) given off protocol because the patients did not meet eligibility criteria (eg, had received > two prior chemotherapy regimens) or no clinical trials were available at the time.
Radiopharmaceuticals have been shown in randomized studies to improve pain control and reduce use of analgesics among patients with bone metastases.15-18 Overall, such treatment provides substantial pain relief in approximately two thirds of cases, with complete responses reported by nearly one third of the patients treated. In addition to palliation of bone pain, Sr-89 can delay the occurrence of new bone metastases in prostate cancer.15,19 However, a single dose of a radiopharmaceutical alone does not provide any advantage for overall survival.15,19,20 Recent studies suggested that combining Sr-89 with other treatment modalities6 or using repeated doses of radiopharmaceuticals21 might improve overall survival. Information on the chronic toxic effects of radiopharmaceuticals may help to justify or facilitate therapeutic strategies using these agents in the future.
In this subgroup analysis, Sr-89 was given in the context of consolidation therapy with doxorubicin after response to induction chemotherapy. Had Sr-89 been given alone for the palliation of bone pain later during disease progression, as is common practice today, the toxicity profile might not have been the same as that reported in this article. We speculate that the safety profile of Sr-89 was improved when the tumor burden in the bone marrow was reduced by the cytotoxic chemotherapy. Although results from our analysis suggested that Sr-89 could be safely combined with cytotoxic chemotherapy and given earlier during the course of disease, this therapeutic approach should not be considered the standard of care as yet. Indeed, many patients with androgen-independent prostate cancer and bone metastases have compromised marrow reserve and cannot be given chemotherapy. The value and safety of giving Sr-89 in the context of consolidation bone-targeted therapy after response to induction chemotherapy needs to be further validated in clinical trials.
A potential advantage of radiopharmaceuticals is that they can be used repeatedly for palliation of bone pain. However, repeated administration may potentially cause severe or permanent damage to the bone marrow. One way to minimize this risk is to ensure that the intervals between repeated Sr-89 treatments are sufficiently long to allow the bone marrow to recover from the toxic effects of treatment. Unfortunately, a rapidly progressive tumor may not permit many opportunities for repeated treatments over extended intervals. Results from our analysis suggest that consolidation bone-targeted therapy can prolong progression-free survival and provide opportunities to give multiple radiopharmaceutical treatments over extended intervals. The value and safety of this approach, giving repeated radiopharmaceuticals in a consolidation setting, needs further validation in clinical trials.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Christine Wogans for editorial assistance.
NOTES
Supported in part by Grants No. SPORE P50 CA 90270 (to C.J.L.), NIH CA 86342, and the Association for the Cure of Cancer of the Prostate (CaPCURE) (to S.-H.L.), and a grant from Nycomed Amersham, which also provided the strontium-89 free of charge.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001 [Erratum: CA Cancer J Clin 51:144, 2001]
Ben-Josef E, Lucas DR, Vasan S, et al: Selective accumulation of strontium-89 in metastatic deposits in bone: Radio-histological correlation. Nucl Med Commun 16:457-463, 1995
Robinson RG, Spicer JA, Blake GM, et al: Strontium-89: Treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone. Radiographics 9:271-281, 1989
Nightengale B, Brune M, Blizzard SP, et al: Strontium chloride Sr89 for treating pain from metastatic bone disease. Am J Health Syst Pharm 52:2189-2195, 1995
Powsner RA, Zietman AL, Foss FM: Bone marrow suppression after strontium-89 therapy and local radiation therapy in patients with diffuse marrow involvement. Clin Nucl Med 22:147-150, 1997
Tu SM, Millikan RE, Mengistu B, et al: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomized phase II trial. Lancet 357:336-341, 2001
Ellerhorst JA, Tu SM, Amato RJ, et al: Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer. Clin Cancer Res 3:2371-2376, 1997
Tu SM, Delpassand ES, Jones D, et al: Strontium-89 combined with doxorubicin in the treatment of patients with androgen-independent prostate cancer. Urol Oncol 2:191-197, 1996
Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457-461, 1958
Kossman S, Weiss M: Acute myelogenous leukemia after exposure to strontium-89 for adenocarcinoma of the prostate. Cancer 88:620-624, 2000
Daliani DD, Assikis V, Tu SM, et al: Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma. Cancer 97:561-567, 2003
Mathew P, Thall PF, Jones D, et al: Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: A modular phase I trial in androgen-independent prostate cancer. J Clin Oncol 22:3323-3329, 2004
Herbst RS, Madden TL, Tran HT, et al: Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: Evidence for activity in non-small-cell lung cancer. J Clin Oncol 20:4440-4447, 2002
Thall PF, Millikan RE, Sung HG: Evaluating multiple treatment courses in clinical trials. Stat Med 19:1011-1028, 2000
Porter AT, McEwan AJB, Powe JE, et al: Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25:805-813, 1993
Serafini AN, Houston SJ, Resche I, et al: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: A double-blind placebo-controlled clinical trial. J Clin Oncol 16:1574-1581, 1998
Sartor O, Reid RH, Hoskins PJ, et al: Samarium-153 lexidronam complex for treatment of painful bone metastases in hormone refractory prostate cancer. Urology 63:940-945, 2004
Han SH, de Klerk JMH, Tan S, et al: The placorhen study: A double-blind, placebo-controlled, randomized radionuclide study with 186-Re-etidronate in hormone-resistant prostate cancer patients with painful metastases. J Nucl Med 43:1150-1156, 2002
Quilty PM, Kirk D, Bolger JJ, et al: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31:33-40, 1994
Sciuto R, Festa A, Rea S, et al: Effects of low-dose cisplatin on Sr-89 therapy for painful bone metastases from prostate cancer: A randomized clinical trial. J Nucl Med 43:79-86, 2002
lmedo H, Manka-Waluch A, Albers P, et al: Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: Randomized phase II trial with the new, high-energy radiopharmaceutical Rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol 21:2869-2875, 2003(Shi-Ming Tu, Jeri Kim, La)