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First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer
Does sequence matter?
Article first published online: 2 FEB 2006
Copyright © 2006 American Cancer Society
Volume 106, Issue 5, pages 1041–1046, 1 March 2006
How to Cite
Michels, J., Montemurro, T., Murray, N., Kollmannsberger, C. and Nguyen Chi, K. (2006), First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer. Cancer, 106: 1041–1046. doi: 10.1002/cncr.21695
- Issue published online: 17 FEB 2006
- Article first published online: 2 FEB 2006
- Manuscript Accepted: 30 SEP 2005
- Manuscript Revised: 9 AUG 2005
- Manuscript Received: 27 APR 2005
- Abbott Laboratories
- prostate cancer;
Docetaxel and mitoxantrone are considered first-line chemotherapeutic options in patients with hormone-refractory prostate cancer (HRPC), but their clinical effectiveness in a second-line setting is unknown. Therefore, the authors conducted a population-based retrospective study to establish activity and tolerability of second-line docetaxel or mitoxantrone in HRPC.
The study included 68 patients who had failed androgen ablation therapy and who received docetaxel and mitoxantrone in either sequence. Clinical efficacy in terms of median overall survival (OS), progression-free survival (PFS), posttreatment prostate-specific antigen (PSA) decline of ≥ 50% and treatment-related toxicity were evaluated.
Of 68 patients, 35 received docetaxel followed by mitoxantrone, and 33 received mitoxantrone followed by docetaxel. Both groups were comparable for recognized pretreatment prognostic factors. Patients who received docetaxel first-line had a trend toward longer median OS compared with patients treated with second-line docetaxel after mitoxantrone failure (22 mos, 95% confidence interval [CI], 17.2–26.8 mos vs. 15 mos, 95% CI, 10.4–19.6 mos). Median number of second-line chemotherapy cycles was 3 and median PFS survival was 2–3 months in both groups. Second-line docetaxel produced a higher PSA response compared with mitoxantrone (38% vs. 12%, P = 0.012), but this did not translate to a survival benefit. Both second-line docetaxel and mitoxantrone were associated with a high frequency of treatment-related adverse events that resulted in dose reduction, delay, or discontinuation (64% and 46% of patients, respectively).
Study results favored docetaxel given up-front for patients with HRPC considered suitable for further chemotherapy. Second-line docetaxel or mitoxantrone had limited efficacy and tolerability. Patients who are candidates for second-line chemotherapy, should be enrolled into clinical trials. Cancer 2006. © 2006 American Cancer Society.
Prostate cancer is the most common cancer diagnosed and the second most common cause of cancer death in men in North America.1 Approximately 221,000 patients with newly diagnosed prostate cancer and 29,000 prostate cancer deaths are estimated to have occurred in 2004 in the USA. Patients with locally advanced and metastatic disease have a poor prognosis, and although hormonal therapy in the form of medical or surgical castration can induce significant long-term remissions, development of androgen-independent disease, also termed hormone-refractory prostate cancer (HRPC), is inevitable.2 Once patients reach this stage, therapeutic options are limited, and prognosis is poor, with a median survival of less than 12 months for symptomatic patients.3–5
Previously, cytotoxic chemotherapy was considered to be of limited use in patients with HRPC because of the absence of any demonstration of survival improvement. Mitoxantrone in combination with prednisone has been shown to produce an improved palliative response rate and a longer duration of response but no improvement in overall survival (OS) compared with prednisone alone.3, 4 Docetaxel has recently been considered the new standard cytotoxic agent in patients with HRPC based on results of 2 randomized trials that reported a statistically significant median survival benefit of 2–3 months compared with mitoxantrone.6, 7 In addition, improved palliative responses and quality of life (QOL) parameters were associated with docetaxel therapy. However, these potential benefits come at the expense of increased toxicity during treatment. Interestingly, median survival in the control arms of these trials was longer than in previously reported randomized studies, reflecting stage migration that has occurred in patients now being diagnosed with HRPC. Frequent prostate-specific antigen (PSA) monitoring has led to earlier identification of progression after androgen ablation, and, therefore, diagnosis of HRPC. Many patients with HRPC are, thus, receiving first-line chemotherapy earlier during the natural course of progression and, therefore, are potential candidates for second-line chemotherapy. Currently, there are no proven effective second-line systemic treatments available for these patients.
Efforts are now being directed at identifying novel agents with activity in taxane-resistant populations and with less toxicity than the current combination regimens.8–11 However, until more active or better tolerated regimens become available, docetaxel and mitoxantrone remain the preferred chemotherapeutic options for patients with HRPC. It is not currently known whether mitoxantrone in patients who have failed first-line docetaxel still remains a well tolerated and a useful option for palliation. Conversely, the 2–3 months median survival gain with first-line docetaxel-based treatment is modest in patients with HRPC, and patients experienced significantly more toxic side effects with docetaxel compared with mitoxantrone. Therefore, it is of interest to determine whether the efficacy of docetaxel as a second-line treatment is preserved in patients after failure of a less toxic mitoxantrone regimen. We conducted this retrospective analysis in patients with HRPC who received both docetaxel and mitoxantrone in either sequence to evaluate clinical effectiveness and the toxicity profile of the sequence of drug administration.
MATERIALS AND METHODS
All patients who received mitoxantrone- and docetaxel-based chemotherapy in either sequence for HRPC were identified from the British Columbia Cancer Agency pharmacy formulary database that has kept record of all patients receiving chemotherapy in the province of British Columbia since 1995. Cancer care in the province of British Columbia is uniformly organized by the British Columbia Cancer Agency, which both delivers and funds cancer care for the entire province. Patients are all registered centrally and cared for throughout the province according to provincial guidelines. Patients with a histologic diagnosis of adenocarcinoma of the prostate were eligible if they had failed androgen ablation therapy. In total, 83 patients with the diagnosis of HRPC were identified who were treated with first- or second-line docetaxel-based chemotherapy since January 2000. Of these, 68 patients had their records available for review in this population-based analysis.
Starting doses for docetaxel were either 75mg/m2 intravenously (i.v.) repeated every 3 weeks or 30mg/m2 weekly for 5 of 6 weeks. Mitoxantrone was given at a starting dose of 12mg/m2 i.v. every 3 weeks. First-line chemotherapy in 18 patients consisted of docetaxel in combination with an experimental agent (Bcl-2 antisense, clusterin antisense, calcitriol, ZD0473), and 8 patients received mitoxantrone in combination with an experimental agent (Bcl-2 antisense, clodronate) as part of our clinical trials program. All patients received prednisone orally at 5mg twice a day for the duration of chemotherapy treatment. Patient records were reviewed to determine base-line characteristics of patients and clinical efficacy and tolerability of docetaxel and mitoxantrone and to establish prognostic and predictive markers for outcome after second-line chemotherapy. The study was approved by the University of British Columbia BC Cancer Agency Research Ethics Board.
Descriptive statistics were used to describe the sample. Base-line characteristics of patients who received docetaxel followed by mitoxantrone were compared with patients who received mitoxantrone followed by docetaxel, and these characteristics were tested for differences using the Mann–Whitney U test for continuous variables and the chi-square or Fisher exact test for categorical variables.
The total Gleason score (GS) at initial diagnosis was assigned to a low (GS ≤ 5), intermediate (GS 6–7), or high score group (GS 8–10). The time interval from the development of HRPC to first-line chemotherapy was defined as the time period between failure of first-line androgen deprivation treatment despite castrate levels of testosterone (documented by rising PSA and/or occurrence or progression of measurable or evaluable disease) and the date of starting first-line chemotherapy. Outcome and tolerability data were evaluated according to the intention to treat. A treatment-related adverse event was defined as any event that required hospitalization during chemotherapy treatment or modification of the standard regimen by delay, dose reduction, or cessation of treatment as chemotherapy-related side effects were not consistently documented according to the National Cancer Institute (USA) criteria. PSA response was defined as a 50% decline from the base-line PSA level immediately before treatment, confirmed by a second PSA level at least 3 weeks later. Median overall survival (OS) time was calculated from the start of treatment (first- or second line chemotherapy) to either death of the patient from any cause or date of last follow-up. Median progression free survival (PFS) was calculated from the start of treatment to the first sign of disease progression documented by either PSA progression (PSA rise on 2 consecutive measurements taken at least 3 weeks apart of at least 50% or 25% from the nadir for patients achieving ≥ 50% or < 50% PSA reduction, respectively12), objective progression on imaging or clinical progression as judged by the treating physician. The median PFS and OS were calculated using the Kaplan–Meier method and compared by the log-rank test. Prognostic and predictive markers were compared by univariate analysis. A P value of ≤ 0.05 (two-sided) was considered statistically significant for all comparisons. The statistical software SPSS® for Windows (version 11; SPSS, Chicago, IL) was used for analysis.
Sixty-eight patients with HRPC received docetaxel and mitoxantrone as first- and second-line treatment. Of those, 35 patients received docetaxel first (30 patients received docetaxel on an every 3-week schedule and 5 patients on a weekly schedule) followed by mitoxantrone. Thirty-three of the 68 patients were treated with mitoxantrone before docetaxel-based chemotherapy (27 patients received docetaxel on an every 3-week schedule and 6 patients on a weekly schedule). The median treatment start time for patients receiving first-line docetaxel was in 2002 (range, 2000–2004), and it was in 2001 (range, 1999–2004) for patients who received first-line mitoxantrone. The median follow-up time in all patients was 21 months (95% CI, 15.9– 26.1mos).
Patient characteristics at baseline before starting first-line chemotherapy are outlined in Table 1. Both patient groups were comparable for pretreatment base-line characteristics and prognostic factors. There was no statistically significant difference in distribution of patients when considering Gleason score, Eastern Cooperative Oncology Group performance status, level of hemoglobin, alkaline phosphatase, lactate dehydrogenase, PSA doubling before starting first-line chemotherapy, and extent of disease. The median number of chemotherapy cycles was 6 for docetaxel and 5 for mitoxantrone. A significantly higher proportion of patients receiving docetaxel achieved a PSA response compared with those treated with mitoxantrone (65% vs. 31%, respectively; P = 0.008). The median PFS in both treatment groups was similar (docetaxel: 6 mos, 95% CI, 5.3–6.7 vs. mitoxantrone: 5 mos, 95% CI, 2.2–7.8 mos). Patients who received up-front docetaxel had a trend toward longer median OS (22 mos, 95% CI, 17.2–26.8 mos) compared with patients treated with mitoxantrone initially (15 mos, 95% CI, 10.4–19.6 mos, P = 0.12), (Fig. 1). Patients who received docetaxel were more likely to experience an adverse event requiring a dose reduction, delay, or cessation of chemotherapy, or hospitalization during treatment compared with patients treated with mitoxantrone (54% vs. 31%, respectively, P = 0.09). The incidence and frequency of treatment-related adverse events were similar to those previously reported for first-line docetaxel or mitoxantrone (results not shown).6, 7
|Age, median in yrs||68.3||68.3|
|Gleason score at dx||n = 30||n = 29|
|< 6||2 (6%)||1 (3%)|
|6–7||14 (47%)||10 (35%)|
|8–10||14 (47%)||18 (62%)||0.42|
|PSA at dx (ng/mL)||n = 30||n = 30|
|Median (range)||38.7 (4–1273)||33 (2.7–1230)|
|< 10||5 (17%)||8 (27%)|
|10–20||5 (17%)||4 (13%)|
|> 20||20 (66%)||18 (60%)||0.68|
|Time interval (mos)||77||71||0.26|
|Dx to start ChT, range||14–208||11–147|
|Time interval (mos)||12||12||0.93|
|HRPC to ChT, range||0.5–64||0.5–56|
|ECOG performance status||n = 35||n = 33|
|0–1||30 (91%)||28 (85%)|
|> 1||5 (9%)||5 (15%)||0.92|
|Hb (g/L)||n = 34||n = 33|
|> 120||23 (68%)||18 (55%)|
|⩽ 120||11 (32%)||15 (45%)||0.32|
|ALP||n = 34||n = 28|
|Normal||18 (53%)||11 (39%)|
|Elevated||16 (47%)||17 (61%)||0.32|
|LDH||n = 18||n = 16|
|Normal||10 (56%)||7 (44%)|
|Elevated||8 (44%)||9 (56%)||0.73|
|PSA (ng/mL)||n = 32||n = 32|
|Median (range)||140 (16–1000)||142 (1.8–3489)||0.82|
|PSA doubling time||n = 32||n = 32|
|⩽ 3 mos||25 (78%)||26 (81%)|
|> 3 mos||7 (22%)||6 (19%)||0.76|
|Extent of disease||n = 35||n = 33|
|Bone/LN/local||32 (91%)||29 (88%)|
|Visceral||3 (9%)||4 (12%)||0.71|
Pretreatment patient characteristics are outlined in Table 2. Patients who received docetaxel had a trend toward better performance status, and more patients had a lower hemoglobin level and higher lactate dehydrogenase (LDH) level before their treatment compared with patients who received mitoxantrone. The median number of second-line chemotherapy cycles administered was 3 in both groups. There was a higher PSA response in patients who received second-line docetaxel compared with mitoxantrone (38% and 12%, respectively, P = 0.012) but the PFS was short (2–3 mos) in both treatment groups. The median OS after second-line therapy in all patients was 9 months (95% CI, 6.1–11.9 mos) with no difference in OS according to the second-line agent given (docetaxel: 7 mos, 95%CI, 3.7–10.3 vs. mitoxantrone: 12 mos, 95% CI, 7.8–16.2, P = 0.27). Second-line chemotherapy was poorly tolerated in both treatment groups: 46% of patients who received mitoxantrone and 64% of patients treated with docetaxel experienced an adverse event requiring a dose reduction, delay, or cessation of chemotherapy, or hospitalization during treatment. The incidences of second-line chemotherapy-related adverse events are illustrated in Table 3. The most common events associated with mitoxantrone were fatigue (14%), neutropenia (12%), nausea (11%), and neutropenic fever (9%), and for docetaxel, they were fatigue (36%), neutropenia (12%), neutropenic fever (12%), thrombocytopenia (12%), and diarrhea (12%).
|Median time 1st–2nd ChT||10||8||0.38|
|(Mos) 95% CI||8.6–11.4||6.3–9.7|
|ECOG performance status||n = 35||n = 33|
|0–1||20 (57%)||26 (79%)|
|> 1||15 (43%)||7 (21%)||0.10|
|PSA (ng/mL)||n = 33||n = 32|
|Median (range)||240 (19–2200)||268 (3–3600)||0.82|
|PSA doubling time||n = 31||n = 32|
|≤ 3 mos||19 (61%)||19 (59%)|
|> 3 mos||12 (39%)||13 (41%)||1.0|
|Hb (g/L)||n = 34||n = 33|
|> 120||15 (44%)||8 (24%)|
|≤ 120||19 (56%)||25 (76%)||0.12|
|ALP||n = 25||n = 28|
|Normal||12 (48%)||11 (39%)|
|Elevated||13 (52%)||17 (61%)||0.42|
|LDH||n = 23||n = 24|
|Normal||12 (52%)||6 (25%)|
|Elevated||11 (48%)||18 (75%)||0.075|
|Docetaxel 33 patients, no. (%)||Mitoxantrone 35 patients, no. (%)|
|Neutropenia||4 (12)||4 (11)|
|Neutropenic fever||4 (12)||3 (9)|
|Thrombocytopenia||4 (12)||1 (3)|
|Fatigue||12 (36)||5 (14)|
|Nausea||2 (6)||4 (11)|
|Myalgia/fluid retention||3 (9)||0|
|Death||2 (6)||2 (6)|
|Miscellaneous||Pneumonia 1, TEE 1, abnormal LFTs 1||Pneumonia 1, summary of moderate side effects 1|
There was no difference in palliative efficacy of second-line chemotherapy between the treatment groups as evaluated by the incidence in patients requiring palliative radiotherapy (RT) after the start of their chemotherapy treatment. Approximately 60% of patients with documented skeletal metastases in both treatment groups required palliative RT (17 of 30 patients and 18 of 31 patients who received second-line mitoxantrone or docetaxel, respectively, P = 0.43), and the median time from starting second-line chemotherapy to the first palliative RT to symptomatic bony sites was 2 months in both treatment groups.
There was no apparent predictive marker for PSA response after second-line chemotherapy in our patient cohort when considering the pretreatment characteristics of performance status, levels of hemoglobin, LDH or alkaline phosphatase (ALP), or PSA response to first-line treatment. An elevated pretreatment LDH level (OS = 4 mos, 95% CI, 2.4–4.6 mos vs. 13 mos, 95% CI, 9.2–16.8 mos, P = 0.0016) was the only prognostic marker that was significantly associated for poor outcome on univariate analysis. Patients with a pretreatment hemoglobin level > 120 g/L had a trend toward better OS after second-line chemotherapy (10 mos, 95% CI, 7.7–12.3 mos vs. 4 mos, 95% CI, 1.9–6.1 mos, P = 0.089).
Docetaxel-based chemotherapy has recently been shown to be superior to mitoxantrone in terms of clinical effectiveness and is now considered to be the standard first-line chemotherapeutic treatment in patients with HRPC.6, 7 Similar to these studies, patients treated with docetaxel first-line in our cohorts had a trend toward better OS (22 mos vs. 15 mos). The inferior OS in patients initially treated with mitoxantrone first-line compared with docetaxel was not rescued by using docetaxel as a second-line treatment after mitoxantrone failure. Compared with mitoxantrone, second-line docetaxel produced a higher rate of PSA response, but this did not translate to an obvious clinical benefit. Patients in both treatment groups had an overall short median PFS of 2–3 months, and no difference in OS from second-line treatment was detected.
There was also no apparent difference in terms of palliative effect of second-line chemotherapy. We used the proportion of patients with documented bony metastasis who required palliative RT after the date of starting second-line chemotherapy as a measure to assess the palliative effect in an attempt to objectify these results in a retrospective setting. These results indicated that second-line docetaxel did not produce an improved palliative effect compared with mitoxantrone. Pain and QOL scores of patients were not prospectively collected, and this represents a limitation of our study.
Second-line chemotherapy was poorly tolerated with a high risk of adverse events in both treatment groups, and the median numbers of cycles given were few. A similar proportion of patients who received first-line chemotherapy experienced treatment-related adverse events compared with the landmark trials in HRPC, which may validate our approach assessing adverse events related to treatment in a retrospective setting.6, 7 Compared with first-line chemotherapy, there was an increased incidence of adverse events associated with second-line treatment. Nearly one-half of the patients who received mitoxantrone and about two-thirds of the patients treated with docetaxel second-line experienced treatment-related adverse events, and there was a 6% treatment-related mortality rate in both groups. The high likelihood of adverse events from second-line treatment in these patients is at least partly explained by the nature of their disease and the general poorer performance status of patients before treatment.
In an attempt to identify patients most suitable for second-line treatment, we investigated recognized predictive and prognostic factors for outcome in HRPC.13–16 At least in our cohort, only elevated LDH level was related to clinical outcome, but patient numbers were small. Further studies, therefore, are urgently needed to identify relevant outcome variables for patients who are candidates for second-line chemotherapy.
Despite improvement in median OS of 47% for patients receiving docetaxel followed by mitoxantrone compared with the cohort of patients treated in reverse sequence, the OS number did not reach statistical significance and highlights the small sample size as a limitation of our study. To detect such a survival difference with a power of 80% and a two-sided P-value of 0.05, approximately 393 patients would have been required. More realistically, sequence may be expected to improve survival on the order of 20%, but 1594 patients would be required to demonstrate this difference, and prospectively controlled trials are unlikely to be carried out to address the question of sequence. Another limitation of retrospective studies such as this is selection bias; however, the treatment groups in this study were comparable in terms of recognized pretreatment prognostic factors,13, 14 and patients started first-line docetaxel or mitoxantrone treatment at very similar times.
Overall, within the limitations of a retrospective analysis, our findings indicated that docetaxel is the preferred up-front treatment option compared with mitoxantrone in HRPC patients considered suitable for further chemotherapy. Because of limited efficacy and poor tolerability of second-line treatment with mitoxantrone and docetaxel, chemotherapy in these patients should be considered experimental, and patients should be enrolled into clinical trials whenever possible.
The authors thank Dr. J. Spinelli, Senior Scientist, Cancer Control Research, Vancouver, Canada, for his statistical advice.