© 2004 Foundation for Promotion of Cancer Research
A Modified Low-dose Regimen of Mitoxantrone and Prednisolone in Patients with Androgen-independent Prostate Cancer
Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Background: We conducted this retrospective study to analyze a modified dose schedule of mitoxantrone and prednisolone (MP) in patients with androgen-independent prostate cancer.
Methods: From June 1997 to April 2002, 28 patients were enrolled. Their median age was 69 years (range, 58–79 years). The median duration of hormonal therapy was 30 months (range, 6–84 months). The median performance status was 2. Sixteen of the patients had bone disease only. The chemotherapy consisted of 8 mg/m2 mitoxantrone by intravenous infusion every 3 weeks and 10 mg prednisolone orally twice per day. WHO response criteria, prostatic-specific antigen (PSA), pain and performance status were used to assess the response.
Results: The median number of treatment cycles was six (range, 2–20). Nine (32.1%) and 15 patients (53.8%) had 
80% and 50% reduction in serum PSA level, respectively. Of 16 patients using narcotics, five (31.3%) had a 50% reduction in narcotics consumption compared with the baseline. Nine patients (32.1%) showed improved performance. For 12 patients with measurable disease, only two (16.7%) showed a partial response. Grade 3–4 toxicities included neutropenia (three patients), anemia (three patients) and vomiting (one patient). The median survival was 12 months and the median time to PSA progression was 4 months.
Conclusions: This modified regimen is feasible for palliative intent. The toxicity of this regimen is manageable. Exploring further combinations of this regimen with novel agents against androgen-independent prostate cancer is warranted.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Prostate cancer is an emerging problem in Taiwanese males owing to its rapidly increasing incidence over the past 5 years. In 1999, it was the eighth leading cause of cancer death (1). Because there is no mass screening program in Taiwan, most patients do not find out that they have prostate cancer until metastatic disease has developed. Although androgen ablation is a very useful strategy for patients with metastatic prostate cancer, almost every patient eventually develops androgen-independent prostate cancer (AIPCa) over a certain period of time (2,3).
Treatment of AIPCa is an art in which physicians need to balance the costs and benefits of administering toxic agents to a group of patients of advanced age and relatively poor performance status. In general, second-line hormone therapy has limited effects and the duration of the response is short (4–6). Ketoconazole is another alternative, but the adverse effects of adrenal suppression and hepatotoxicity are difficult to manage in a proportion of patients (7). Chemotherapy is increasingly being used; however, some controversial issues remain regarding the use of chemotherapy in patients with AIPCa (8–10).
Mitoxantrone was found to be active in patients with prostate cancer in 1983 (11), but it was not until the late 1990s that mitoxantrone was approved by the US Food and Drug Administration after several extensive studies conducted on AIPCa by the Canadian National Cancer Center (12) and the Cancer and Leukemia Group B (CALGB) (13). The two randomized trials confirmed that the combination of mitoxantrone and a steroid produced clinical advantages by improving the response rate, cancer-related symptoms and quality of life over steroid use alone. Since then, mitoxantrone with a steroid has commonly been used for AIPCa and as a reference regimen for randomized trials (14,15).
In 1997, we began to use mitoxantrone and prednisolone to treat selected patients with AIPCa. We have been concerned that 12–14 mg/m2 mitoxantrone might be too high for our patient population. Therefore, we used 10 mg/m2 mitoxantrone to initiate our protocol. However, we had to reduce this to 8 mg/m2 after the first two patients who had received 10 mg/m2 mitoxantrone developed grade IV febrile neutropenia. The present retrospective study describes our clinical observations of 28 consecutive patients with AIPCa treated with mitoxantrone and prednisolone. In addition, we adopted the prostatic-specific antigen (PSA) response, World Health Organization (WHO) response criteria and clinical benefit assessment for evaluating the outcomes.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients were prospectively collected to participate in this study. All patients had to have histologically confirmed prostate adenocarcinoma and have disease progression from an orchiectomy or medical castration with a castrated testosterone level of <0.4 ng/ml. The disease progression was defined as having three consecutive rising serum PSA levels at least 3 weeks apart or a >25% increase in size of the measurable site during hormonal therapy. Consent for chemotherapy was obtained from each patient.
Patients had either evaluable disease or measurable disease. If no evaluable disease existed, such as bone metastasis only, a pretreatment serum PSA level of 40 ng/ml was essential for assessing the PSA response. Patients were required to have adequate hepatic, renal and bone marrow function (WBC >3000/mm3, platelets >100 000/mm3, creatinine <2 mg/dl, bilirubin <3 mg/dl and ALT and AST <3 times the upper limit) and a relatively good performance status (ECOG 
2) before chemotherapy. Before treatment, all patients had baseline studies consisting of a chest X-ray, abdominal CT scan, bone scan and serum PSA. The performance status was assessed at each clinical visit. The dosage of narcotics (morphine, morphine sulfate continus and codeine) was calculated as a morphine-equivalent dose over a weekly average basis. All of the above medical information was retrieved from the medical charts.
All patients received 8 mg/m2 mitoxantrone in 0.9% saline by way of a 200 ml intravenous infusion over 1 h every 3 weeks plus 10 mg prednisolone orally twice per day. Chemotherapy continued until unacceptable toxicity, patient refusal or disease progression occurred. The dose was not escalated or diminished for any patient during the treatment. However, prednisolone was omitted if prednisolone-related toxicity developed.
The tumor response for measurable diseases was evaluated every 3–4 cycles using the WHO response criteria. During each mitoxantrone treatment session, the serum PSA level, a complete and differential blood count, narcotics use, performance status and toxicity were evaluated. The definition of the PSA response included a 50% reduction response, i.e. a reduction of 50% in the serum PSA level from the baseline which lasted for at least three consecutive examinations in at least a 3 week interval, and an 80% reduction response, i.e. a reduction of 80% in the serum PSA level from the baseline which lasted for at least three consecutive examinations in at least a 3 week interval. The PSA response was not assessed in patients whose baseline PSA level was <40 ng/ml. Clinical benefit was evaluated by narcotics consumption and performance status (PS). The narcotics response was defined as a reduction of at least 50% of the baseline narcotics consumption for at least 4 weeks. If a patient’s narcotic consumption increased, then that patient was considered to be experiencing disease progression. The performance status response was defined as having at least a one-point increase in the ECOG scale for at least 4 weeks. A patient showing a decline in the PS was considered to be experiencing disease progression. The time to progression was defined as from the date of beginning mitoxantrone to the date of clinical progression (according to symptoms or imaging studies) or PSA progression. The time to PSA progression was defined as from the date of beginning mitoxantrone to the date of the third consecutive rise in PSA in at least a 3 week interval. Survival was calculated using Kaplan–Meier methods. Toxicity was assessed according to the National Cancer Institute, National Institutes of Health common toxicity criteria (NCICTC) version 2.0.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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From June 1997 to September 2000, 28 consecutive patients with AIPCa were enrolled. Their median age was 69 years (range, 58–79 years). The median duration of hormonal therapy was 30 months (range, 13–61 months). All patients had received either orchiectomy, depot leuprolide or daily oral 3 mg diethylstilbestrol and with a castrated level of testosterone. In addition, all patients had received at least one of the second-line hormonal therapy including flutamide, bicalutamide and/or cyproterone sequentially. The lengthened duration of hormonal manipulation was a result of delayed chemotherapy because these patients had received various sequential salvage hormonal therapies. The majority of patients were moderately healthy prior to treatment. Half of the patients had a PS of 0 or 1. Sixteen (57.1%) of the patients had bone disease only. Other soft tissue involvement was mostly limited to locoregional lymph nodes. Patients with non-osseous distant metastases accounted for only 15% of the population. Patient demographics and tumor characteristics are summarized in Table 1.
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In total, 180 cycles of chemotherapy were delivered to these patients, with a median of 6 cycles (range, 2–20). No reduction in the dose of mitoxantrone was required in any of these patients. One patient discontinued prednisolone after duodenal ulcer bleeding and a hyperglycemic event.
Patients with measurable disease were evaluated by the WHO response criteria, but only 12 patients who had two-dimensional measurable lesions were evaluable. Two (16.7%) patients showed a partial response (PR), seven (58.3%) had stable disease (SD) and three (25%) experienced progression of disease (PD). In summary, the disease-control rate (PR + SD) was 75%. According to sites of disease, one of six patients with lymph nodes and one of the two with liver metastases achieved response. None of the patients with local tumor or lung metastasis responded to chemotherapy.
PSA Response
Two patients developed rapid disease progression after the first two cycles of treatment and we were unable to obtain their follow-up serum PSA levels. However, they were considered to have progressive disease since their clinical course deteriorated rapidly. Among the 28 patients, 15 had a 50% reduction and nine had an 80% reduction in the baseline PSA, i.e. 53.8% [95% confidence interval (CI): 33.9–73.3%] with a 50% reduction and 32.1% (95% CI: 13.7–50.6%) with an 80% reduction in PSA. Other patients were considered to have a non-PSA response.
Pain Assessment
Of the 16 patients who required narcotics, five (31.3%) reduced their narcotics consumption by >50% from the baseline, five (31.3%) remained unchanged and six (37.5%) increased their dose of narcotics. All patients who decreased their narcotics consumption >50% were patients who had >80% serum PSA reduction.
Performance Status Changes
One patient with no symptoms (PS = 0) was excluded from the analysis. Nine patients (33.3%) showed improvements in their performance status, 14 (51.6%) remained unchanged and five (18.5%) worsened. Six of the nine patients who showed improved performance status had >80% decrease of their baseline PSA.
Survival
The median follow-up period was 12 months. The median time to PSA progression was 4 months and the overall median survival was 12 months.
Toxicity
The most severe individual toxicities according to NCICTC are summarized in Table 2. In general, the toxicity was mild, but grade 4 neutropenia occurred in three (11%) patients. One patient died of febrile neutropenia and sepsis 3 days after the 10th cycle of chemotherapy, at which time his disease remained in response. Prior to the 10th chemotherapy, his performance status was 1 with only mild bone pain and his hematological data were in the normal range. His death was classified as being treatment-related, although it was unclear whether the cause of the neutropenia was directly related to the chemotherapy. One patient who had abdominal nodes, mediastinal nodes and superior vena cava obstruction and with a performance status of 2 experienced febrile neutropenia after the first cycle of chemotherapy; he subsequently discontinued treatment owing to toxicity and rapid disease progression. The third patient was fairly well, but after first cycle of chemotherapy he developed neutropenic fever. He recovered very soon and continued to receive chemotherapy for a total of six cycles and febrile neutropenia did nor recur. One patient with no history of diabetes mellitus had an episode of hyperosmolar non-ketotic hyperglycemia and duodenal ulcer bleeding; he subsequently became diabetic and required an oral hypoglycemic agent. This was attributed to the use of prednisolone. He continued with the mitoxantrone, but prednisolone was terminated without further complications.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We determined that even with a relatively low dose of mitoxantrone, the mitoxantrone and prednisolone (MP) regimen was effective for our patients with AIPCa in terms of PSA response and improvements in narcotics consumption and the performance status. However, in patients with measurable disease, there was only a 16.7% response rate. Although there was one treatment-related death, the toxicity of mitoxantrone was generally manageable and mild. Therefore, we suggest that MP is suitable for AIPCa patients in a palliative setting.
There have been two large randomized trials on MP regimens for AIPCa. The Canadian group started from a phase II trial using 12 mg/m2 mitoxantrone and 10 mg/day prednisolone and found a 36% response rate based on palliative parameters (pain score and quality of life) (16). Subsequently, they completed a phase III randomized trial comparing mitoxantrone–prednisolone with prednisolone alone. The palliative effect (pain relief) was 29 versus 12% (P = 0.01). The 50% PSA reduction rate was 33 versus 22%. There was no difference in overall survival. The treatment was well tolerated. They concluded that chemotherapy with mitoxantrone and prednisolone provided palliation for some patients with symptomatic AIPCa. Their sub-studies on the quality of life and medical economics further highlighted additional benefits other than medical issues (12). The CALGB phase III trial was similar to that of the Canadian study except that they increased the dose of mitoxantrone (M) to 14 mg/m2 and substituted 40 mg/day hydrocortisone (H) for prednisolone, which is equivalent to 10 mg/day prednisolone. This combination generated more frequent responses (50% reduction in PSA with M + H vs H was 38 vs 22%, respectively; P = 0.008) and exhibited a possible benefit for pain control (quality of life assessment of pain, how often, P = 0.06 and how severe, P = 0.03), but no survival difference was observed (12.3 months for M + H vs 12.6 months for H alone) (13). Based on these large trials, it was concluded that the role of MP in AIPCa was important in a palliative setting, rather than for improving survival. Our observations are in general agreement with those results, although we used a lower dosage of mitoxantrone.
Evaluating metastatic prostate cancer has been troublesome, since the majority of patients may have only bone disease. It is difficult to evaluate the disease based solely on anatomically oriented criteria, such as the WHO response criteria. Thus, serum PSA has been a surrogate endpoint for evaluating the chemotherapeutic response (17). Recent studies, including studies from both Canada and the CALGB, found that the PSA response correlated well with survival after chemotherapy. However, many controversies exist and some investigators still question its role for assessing disease response. For example, the amplitude of the PSA reduction is also a contentious issue. Therefore, we decided to calculate the PSA reduction on two different scales. Although the PSA response of our patient population was higher than those in the randomized trials, our sample size was small and the response rate still fell within the 95% confidence intervals of the other two studies. In addition, we found that an 80% reduction in PSA was more closely relevant to the symptom-related response. This is an interesting issue worthy of further exploration.
A symptom-based assessment is increasingly recognized as being important. For example, a ‘clinical benefit’ concept was initially proposed by Cullinan et al. using a symptom-related evaluation, based on improvements in performance, cancer-related symptoms and weight for reporting on randomized trials of patients with gastric or pancreatic cancers (18). Burrus et al. used the ‘clinical benefit criteria’ for a phase II trial of gemcitabine in patients with advanced pancreatic cancer (19). They found that the rigorous assessment of cancer-related symptoms was more ‘objective’ in evaluating the response, despite the WHO response rate being low (19). In our previous work on gastric cancer, we found that this criterion was suitable for patients with gastric cancer (20). The clinical symptoms of advanced prostatic cancer are similar to those of pancreatic cancer. Therefore, the clinical benefit criteria may also be suitable for prostate cancer patients. However, the retrospective nature of the present study precluded the possibility of applying this sophisticated method to validate the clinical tools for assessing the treatment response. We modified the methods and looked only at the use of narcotics and the performance status, both of which were easily retrieved from medical records. We found that in terms of improvements in cancer-related symptoms, the MP regimen did produce clinical benefit in patients with AIPCa. The present data were also in accordance with those of the Canadian (12) and CALGB trials (13).
The other difference in this regimen with the randomized trials was the dosage of steroids. We attempted to double the dosage of prednisolone in order to compensate for the reduction in mitoxantrone, since prednisolone remains an active palliative regimen for AIPCa (9). Our results show that the palliative effect of the low-dose MP regimen was equal to those in the randomized trials. Whether the dosage of prednisolone plays a critical role remains elusive. However, it should be noted that we had a patient who developed diabetes mellitus and duodenal ulcer bleeding. Therefore, we recommend that patients with diabetes or a history of peptic ulcers should be treated with caution when increasing the dosage of prednisolone.
After mitoxantrone use, chemotherapy for AIPCa produced dramatic changes. New chemicals, such as taxanes (21–27), vinorelbine (28,29) and other agents, have been extensively studied in many phase II trials. Their promising activity has attracted more clinical trials in this area. Adding new agents to the standard MP regimen has also been studied. However, it is worth noting that most of these new agents are myelosuppressive and therefore the toxicity of novel combinations might be difficult to handle. Therefore, a reduced dosage of mitoxantrone may provide a good alternative for such combinations.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our results show that a modified low-dose MP regimen was effective in reducing serum PSA levels and pain and increasing the performance status of patients with AIPCa. Even with a reduced dosage of mitoxantrone, there were still 11% of patients with grade 4 neutropenia and one treatment-related death. Further escalation of the mitoxantrone might not be feasible for Oriental patients. The survival was acceptable for late-stage AIPCa patients. Patients with diabetes should be treated with caution when using prednisolone. The low toxicity profile of this modified MP regimen allows the potential for combination with novel chemotherapeutic agents in further trials.
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FOOTNOTES |
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+ For reprints and all correspondence: Yung-Chang Lin, Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei 105, Taiwan. E-mail: yclinof{at}adm.cgmh.org.tw
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Received January 6, 2004; accepted March 22, 2004
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