Annals of Oncology Advance Access published online on May 16, 2008
Annals of Oncology, doi:10.1093/annonc/mdn288
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Survival and PSA response of patients in the TAX 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa
1 Division of Medical Oncology and Hematology
2 Department of Biostatistics, Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada
3 Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands
4 Department of Oncology, Sydney Kimmel Comprehensive Cancer Centre, Johns Hopkins University, Baltimore, MD, USA
* Correspondence to: Dr I. F. Tannock, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Tel: +1-416-946-2245; Fax: +1-416-946-4563; E-mail: ian.tannock{at}uhn.on.ca
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Abstract |
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Background: The TAX 327 study compared 3-weekly docetaxel, weekly docetaxel or 3-weekly mitoxantrone, each with prednisone, for 1006 patients with metastatic hormone-refractory prostate cancer. Survival and symptom control were superior following 3-weekly docetaxel as compared with mitoxantrone. At progression, many patients were treated with the other drug. Here, we provide a retrospective report of survival and prostate-specific antigen (PSA) response after second-line therapy.
Methods: The TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values.
Results: We identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (
50% reduction) occurred in 15% of 71 men receiving mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after mitoxantrone. Median PSA progression-free survival was 3.4 months for mitoxantrone after docetaxel and 5.9 months for docetaxel after mitoxantrone.
Conclusions: One quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after mitoxantrone was higher than that for mitoxantrone after docetaxel.
docetaxel, hormone-refractory prostate cancer, mitoxantrone, second-line chemotherapy
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introduction |
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If prostate cancer is detected at an early stage, local treatments such as radical prostatectomy, radical external beam radiotherapy or brachytherapy are frequently offered. If prostate cancer recurs after local treatment or is diagnosed at an advanced stage, hormonal therapy is usually successful in controlling symptoms, reducing prostate-specific antigen (PSA) and shrinking the disease. However, androgen ablation therapy usually loses its ability to control tumor growth after an average of
2 years due to a multitude of molecular mechanisms that allows tumor growth in the face of a minimal concentration of androgens. Some men will benefit from further hormonal manipulation, but ultimately the disease becomes hormone refractory. Patients with hormone-refractory prostate cancer (HRPC) are candidates for chemotherapy, with the goals of prolonging survival and/or relieving, preventing or delaying symptoms due to the disease. In the mid-1990s, mitoxantrone (given with low-dose prednisone or hydrocortisone) gained a role in the management of HRPC as a result of randomized trials that demonstrated that this well-tolerated drug led to palliative benefit in a subset of patients as compared with steroids alone [1, 2]. Mitoxantrone was registered by the United States Food and Drug Administration (FDA) for the treatment of HRPC in 1996.
In 2004, the results of two randomized studies involving docetaxel, TAX 327 and Southwest Oncology Group 99-16 were published [3, 4]. Both studies showed a significant survival advantage for men treated with docetaxel compared with mitoxantrone.
In the TAX 327 study, 1006 patients were randomized to one of three treatment arms: docetaxel (75 mg/m2) every 3 weeks, docetaxel (30 mg/m2) weekly for 5 weeks out of 6 or mitoxantrone (12 mg/m2) every 3 weeks, each with prednisone or prednisolone 5 mg twice daily. The main results of this study showed significant improvement in overall survival for men treated with 3-weekly docetaxel: the median duration of survival obtained from a recent updated analysis [5] was 19.2 versus 16.3 months in the mitoxantrone group. Patients in the docetaxel group had a higher PSA response rate as well as a higher probability of reduction in pain and of improvement in quality of life (QoL) [3]. Adverse effects were also more common in the docetaxel arm. Docetaxel is now established as the first-line treatment of choice for most patients with HRPC who are considered suitable for chemotherapy.
The widespread use of PSA monitoring has resulted in earlier detection of metastatic prostate cancer, often in men without symptoms other than anxiety due to a rising serum PSA. As a result, many patients undergo chemotherapy earlier in the course of their disease. This stage migration has led to an increase in median duration of survival in recent clinical trials of first-line chemotherapy for men with HRPC [6], and many men are now fit enough for further treatments after progression of disease after first-line chemotherapy. There is no standard second-line treatment in men with HRPC, although mitoxantrone is often given after progression on docetaxel and vice versa: the probability of response to second-line chemotherapy is not well established, although small series indicate that it is relatively low, especially for mitoxantrone given after docetaxel [7–9]. Here, we contacted investigators who managed patients in the TAX 327 study in an attempt to determine the PSA response rate among participating patients who were treated with the alternative drug following their initially assigned treatment.
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methods |
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The TAX 327 study was a randomized phase III trial that involved >100 centers in 24 countries. Details have been published elsewhere [3] but, in brief, patients were required to have progressive adenocarcinoma of the prostate and evidence of metastatic disease by imaging or clinical examination. All patients were required to maintain their androgen ablation status by prior castration or administration of Gonadotropin Releasing Hormone agonist and at least 4 weeks had to elapse since the last hormonal modification. If progression was on the basis of a rising serum PSA, patients were required to have at least three successive rising PSA values. The Karnofsky performance status (PS) was required to be at least 60%, and patients were not allowed to have prior treatment with chemotherapy except for estramustine. Participants were required to have no peripheral neuropathy of grade II or greater, normal cardiac function and a blood count with at least 1500 neutrophils/l, a platelet count of at least 100 x 109/l and hemoglobin of at least 10 g/dl. Patients underwent physical exam as well as imaging and determination of serum PSA at baseline; they were required to complete a pain questionnaire and to document their analgesic consumption and QoL using the Functioned Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire [10]. Levels of serum PSA, pain, analgesic use and QoL were documented at 3-weekly intervals while on study. All patients provided written informed consent and the study was approved by local ethics review boards.
Information about therapy used after the initially assigned treatment was stopped, including use of mitoxantrone after docetaxel (Taxotere) or vice versa, and was available from the TAX 327 database. We then contacted investigators who had managed patients who were known to have crossed over from one drug to the other and inquired retrospectively about the date of crossover, reason for crossover and the dose and schedule of the drug received after crossover. We asked investigators to provide the number of courses received, the serial levels of serum PSA during and after crossover and the date of the last treatment. The date of death (or date last seen alive) of patients was available from the TAX 327 database, which our group has updated recently [5]. Descriptive statistics were used to summarize patient characteristics by treatment group. The Kaplan–Meier method was used to estimate survival outcomes. Since patients were not randomly selected for crossover, no statistical testing was carried out to compare results between treatment groups.
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results |
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We identified 232 men who crossed over from one treatment to receive the other. Demographics and patient characteristics at time of randomization in the TAX 327 study are summarized in Table 1. Eighty-nine men received 3-weekly docetaxel followed by mitoxantrone, 76 men received mitoxantrone after weekly docetaxel and 67 men received docetaxel after mitoxantrone (14 received weekly docetaxel 30–36 mg/m2, 24 received 3-weekly docetaxel 60–100 mg/m2; the dose and schedule for the remaining 29 men were not specified). The patients who crossed over were a subset of the initially randomized groups; those allocated originally to the docetaxel arms had at that time somewhat greater disease burden as indicated by lower Karnosfky PS, higher values of serum PSA, alkaline phosphatase levels and more pain or analgesic intake than those crossing over from mitoxantrone to docetaxel arms (Table 1).
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Table 2 specifies the duration of first-line treatment while enrolled in the TAX 327 study and the response to that treatment: patients who crossed over from the docetaxel arms had been on their initially assigned treatment longer than patients treated with mitoxantrone (median 21 versus 10 weeks). Concordant with the overall results from the TAX 327 study, patients crossing over from the 3-weekly docetaxel arm had experienced higher pain, PSA and QoL response rates than those assigned to receive mitoxantrone.
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The median follow-up after crossover was 11 months and the majority of patients had died at the time of this analysis (Table 3). The median survival from the date of crossover was 10 months for those crossing over in either direction. The Kaplan–Meier survival curves after crossover are shown in Figure 1.
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We received PSA data after crossover for 96 patients. The median baseline levels of serum PSA at start of second-line treatment were 183, 194 and 123 ng/ml for those assigned initially to 3-weekly docetaxel, weekly docetaxel and mitoxantrone, respectively. The percentage of patients who experienced at least 50% reduction in serum PSA was 9.8% in the D3
M group, 22.2% in the D1M group and 28% in the MD group with confirmed PSA responses observed in 7%, 14.8% and 20% of patients, respectively. A total of 34%, 37% and 72% of patients experienced some degree of reduction in serum PSA, respectively. The median PSA progression-free survival (PFS) was short at 3.2, 3.7 and 5.9 months, respectively. Response to first-line chemotherapy did not predict response to second-line chemotherapy, although the sample size may be too small to reveal such a relationship.
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discussion |
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Both mitoxantrone and docetaxel have shown activity in the treatment of hormone-resistant prostate cancer. The TAX 327 study has shown better results for initial use of docetaxel when compared with mitoxantrone and is therefore considered by most physicians to be the preferred first-line chemotherapy. Among the 1006 patients included in the TAX 327 study, 237 (23%) received the other drug as second-line therapy off study. This number is substantial considering that the efficacy of second-line treatment is not well established and that this patient population is frequently elderly and frail; it reflects the increasing use of second-line therapy in clinical practice.
In our retrospective study, the PSA response rate was higher for docetaxel after mitoxantrone (28%) than for mitoxantrone after docetaxel (15%). These results are in line with results from other investigators, which we have summarized in Table 4. The median time to PSA progression was in the order of 3.5 months for those receiving mitoxantrone after docetaxel and 5.9 months for those receiving docetaxel after mitoxantrone. The median number of cycles was also somewhat higher in those crossing over to receive docetaxel.
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The present analysis has intrinsic limitations. The sample is relatively small (although larger than in other studies summarized in Table 4) and our ability to obtain more complete PSA data was limited by the response from investigators and, in some centers, by regulatory issues that prevented release of information due to expiry of ethics approval. The cohort was not equally distributed; patients receiving docetaxel after mitoxantrone had a lower level of serum PSA at time of initiation of second-line treatment compared with the patients receiving mitoxantrone after docetaxel. Fewer patients crossed over from mitoxantrone to docetaxel, which was probably due to the limited availability of docetaxel at the time of the study in some countries. Considering the retrospective nature and the geographical distribution of our patients, toxicity could not be accessed. We would expect toxicity to second-line treatment to be somewhat higher than to first-line treatment in line with the results of other small series (Table 4). The potential for increased toxicity and the short duration of second-line responses makes it less likely that palliative benefit will be achieved compared with treatment in the first-line setting.
The present data indicate that some patients with HRPC may experience a response to second-line treatment and that the rate of response to docetaxel after mitoxantrone is higher than the reverse. Most patients now receive docetaxel first line, and given the relatively low response rate to mitoxantrone as second-line treatment, patients who are fit for further chemotherapy should be referred for inclusion in clinical trials evaluating new approaches to second-line treatment when such trials are available. Second-line treatment is appropriate for patients with better PS, while those with poorer PS should be referred to palliative care [13].
There is uncertainty about the optimal choice of a control arm in randomized trials of second-line chemotherapy for men with HRPC. A recent trial evaluated second-line satraplatin plus prednisone as compared with a control arm of prednisone alone (SPARC trial) [14]. A total of 950 patients was accrued and about half of the patients had received prior docetaxel. The results show significant longer PFS (11.1 versus 9.7 weeks), PSA response (25% versus 12%), tumor response and pain response for satraplatin and prednisone. The FDA and other agencies are currently awaiting survival data before considering approval of satraplatin as second-line treatment in HRPC. Considering the low response to mitoxantrone, the second-line control arm might reasonably be prednisone alone as in the SPARC trial, while other investigators might prefer to use mitoxantrone and prednisone in the control arm, as in the randomized phase II trial of ixabepilone versus mitoxantrone, each with prednisone [13].
In conclusion, second-line treatment for men with HRPC is not well established and fit patients should be enrolled in clinical trials where available. Second-line treatment with mitoxantrone after first-line docetaxel has modest activity and should be reserved for fit patients in the absence of clinical trials.
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Supported by a reserch grant from Sanofi-Aventis.
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We thank many patients who volunteered to participate in the TAX 327 study and the investigators who recruited them and managed their care: Drs Campos and Orlando (Argentina); Drs Gurney, Rosenthal and Stockler (Australia); Drs Horninger, Rauchenwald, Schmeller and Studler (Austria); Drs Gil, Humblet and van Oosterom (Belgium); Drs Herchenhorn and Vinholes (Brazil); Drs Chi, Dube, Ernst, Lacombe, Moore, Reyno, Soulieres, Saad, Venner and Winquist (Canada); Dr Urban (Czech Republic); Dr Kellokumpu-Lehtinen (Finland); Drs Chevreau, Deplanque, Duclos, Gravis, Krakowski, Mignot, Muracciole, Oudard, Rixe and Theodore (France); Drs Ackermann, Breul, Jakse and Paul (Germany); Drs Bodrogi and Horti (Hungary); Dr Tonato (Italy); Dr Chahine (Lebanon); Drs Bruins and Witjes (The Netherlands); Dr Iversen (Norway); Drs Bar, Demkow and Pluzanska (Poland); Drs Kariakine and Matveev (Russia); Dr Andrasina (Slovak Republic); Drs Abratt and Vorobiof (South Africa); Drs Bellmunt, Cortes and Germa (Spain); Drs Turesson and Widmark (Sweden); Drs Fennelly, Horwich, James, Roberts and Wylie (UK); Drs Baez, Berry, Dugan, Garewal and Tirumali (USA).
Received for publication December 30, 2007. Revision received April 2, 2008. Accepted for publication April 14, 2008.
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References |
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1. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol (1996) 14:1756.
2. Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol (1999) 17:2506.
3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med (2004) 351:1502.
4. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med (2004) 351:1513.
5. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol (2008) 26:242–245.
6. Ryan CJ, Eisenberger M. Chemotherapy for hormone-refractory prostate cancer: now it's a question of "when?" J Clin Oncol (2005) 23:8242.
7. Joshua AM, Nordman I, Venkataswaran R, et al. Weekly docetaxel as second line treatment after mitozantrone for androgen-independent prostate cancer. Intern Med J (2005) 35:468.[CrossRef][Web of Science][Medline]
8. Michels J, Montemurro T, Murray N, et al. First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer: does sequence matter? Cancer (2006) 106:1041.[CrossRef][Medline]
9. Oh WK, Manola J, Babcic V, et al. Response to second-line chemotherapy in patients with hormone refractory prostate cancer receiving two sequences of mitoxantrone and taxanes. Urology (2006) 67:1235.[CrossRef][Web of Science][Medline]
10. Esper P, Mo F, Chodak G, et al. Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. Urology (1997) 50:920.[CrossRef][Web of Science][Medline]
11. Saad F, Routher D, Ernst S, et al. Canadian Urologic Oncology Group (CUOG) phase II multi-center study using docetaxel/predrisone in the second line setting for metastatic hormone-refractory prostate cancer in patients progressing after first line mitoxantrone/prednisone. J Clin Oncol (2005) 23. (Abst 4612).
12. Rosenberg JE, Weinberg VK, Kelly WK, et al. Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients: randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer (2007) 110:556.[CrossRef][Medline]
13. Berthold DR, Sternberg CN, Tannock IF. Management of advanced prostate cancer after first-line chemotherapy. J Clin Oncol (2005) 23:8247.
14. Sternberg CN, Petrylak DP, Witjes F, et al. Satraplatin demonstrates significant clinical benefits for the treatment of patients with HRPC: results of a randomized phase III trial. ASCO Proceedings. J Clin Oncol (2007) (Abstr 5019).
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