1 Leon Berard, Lyon; 2 Centre Hospitalier Universitaire (CHU) La Timone, Marseille; 3 CHU G. Doumergue, Nimes; 4 CHU Bicêtre, Le Kremlin Bicêtre; 5 Clinique Hartman, Neuilly; 6 Clinique Pasteur, Evreux; 7 Centre Régionale de Lutte Contre le Cancer Val dAurelle, Montpellier; 8 CHU Bichat, Paris; 9 CHU Paul Brousse, Villejuif; 10 Cvitkovic et Associés Consultants, Le Kremlin-Bicêtre, France
Received 20 September 2002; revised 4 April 2003; accepted 15 April 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A randomized, multicenter phase II study evaluating oxaliplatin alone (OXA) and oxaliplatin5-fluorouracil combination (OXFU) in advanced hormone-refractory prostate cancer (HRPC) patients.
Patients and methods:
Metastatic, pathologically proven prostate carcinoma patients, progressing despite anti-androgen therapy, received intravenous OXA (130 mg/m2 over 2 h), alone or with 5-FU (1000 mg/m2/day, continuous intravenous infusion, days 14), every 3 weeks. OXA patients could receive OXFU after treatment failure.
Results:
Fifty-four patients (26 OXA, 28 OXFU) from nine centers received 269 treatment cycles (106 OXA, 163 OXFU; median 3.5 OXA or 5 OXFU cycles per patient; range 110 or 114, respectively). Patient characteristics were similar in both arms. Three partial responses (PR) occurred in 21 evaluable OXA patients [14%; 95% confidence interval (CI) 1% to 30%], and in five of 26 evaluable OXFU patients (19%; 95% CI 7% to 39%). Clinical benefit response (pain, performance status and weight changes) was assessed in 20 OXA and 22 OXFU symptomatic patients, with more responders in the OXFU arm (39% compared with 12%). Median time to progression in the OXA and OXFU arms was 2.6 and 3.4 months, and median overall survival was 9.4 and 11.4 months, respectively. Hematotoxicity was common, but mostly mild to moderate. Neutropenia was more common in OXFU than OXA patients. After oxaliplatin failure, 12 patients received 46 cycles of OXFU and one of 11 evaluable patients had a PR.
Conclusion:
The objective response rate, palliation benefit, survival and manageable toxicity obtained in this heavily pretreated HRPC population with OXFU merit further study.
Key words: DACH-platinum, 5-fluorouracil, HRPC, oxaliplatin
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The recent development of new agents and combinations, and the definition of appropriate study end points, has resulted in some improvement in patient prognosis. The mitoxantroneprednisone combination is the standard treatment for hormone-refractory prostate cancer (HRPC) patients, with prednisone proving superior in terms of response and symptom palliation in phase III trials; however, this treatment is suboptimal [47]. Treatment employing more recent chemotherapy regimens, such as the estramustine phosphatedocetaxel combination, has so far only been evaluated in phase II trials, which have shown that over half of all patients benefit from chemotherapy as evidenced by sustained prostate-specific antigen (PSA) decline, measurable sustained disease regression or palliation of symptoms [812]. Although high response rates have been observed, complete responses are a rarity and the median survival of HRPC patients has remained unchanged, rarely exceeding 1 year [13]. Furthermore the toxicity of these combinations is not negligible, especially in this patient population which is usually both fragile and elderly.
Oxaliplatin, a new DACH-platinum agent recently approved in Europe for use in colorectal cancer patients, has a different spectrum of preclinical activity linked to genetic and epigenetic mismatch repair deficiencies. In addition, oxaliplatin is not nephrotoxic and has a good safety profile limited only by a mild hematotoxicity and cumulative neurosensory toxicity, which is usually reversible upon treatment discontinuation [14]. It has also been shown to be synergistic with many anti-cancer agents, especially 5-FU, as demonstrated in vitro, in vivo and clinically [15]. Single-agent infusional 5-FU has demonstrated some efficacy in HRPC and response rates up to 27% have been reported [1619]. The prevalence of DNA mismatch repair defects in human prostate cancer [20] and the lack of an effective treatment for HRPC along with the above-mentioned facts, provided the basis of the rationale for this randomized phase II trial aimed at exploring the safety and efficacy profile of oxaliplatin in HRPC patients, both as a single agent and in association with 5-FU.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients were excluded from the study if they had: (i) concomitant second malignancy, with the exception of treated basal cell carcinoma of the skin; (ii) known or suspected brain metastases; (iii) risk of impending cord compression; (iv) symptomatic peripheral neuropathy, higher than grade 1 according to National Cancer Institute Common Toxicity Criteria (NCI-CTC); (v) concurrent treatment with other experimental drugs or anti-cancer therapy including hormone therapy (except LH-RH agonists) and corticosteroids; (vi) another serious illness or medical condition; (vii) cardiac disease requiring treatment; (viii) active uncontrolled infection; (ix) uncontrolled severe hypercalcemia; or (x) history of significant neurological or psychiatric disorders.
Study design
The protocol was approved by the CCPPRB (ethics committee) of Bicêtre University Hospital. Eligible patients were stratified by center and randomly assigned to receive either (i) single-agent oxaliplatin 130 mg/m2 2-h i.v. infusion (OXA), every 3 weeks; or (ii) oxaliplatin 130 mg/m2 2-h i.v. infusion plus 5-FU 1000 mg/m2/day continuous i.v. infusion from days 1 to 4 (OXFU), also every 3 weeks. The addition of 5-FU for OXA patients failing treatment was performed whenever feasible. Patients received 5-HT3 antagonists and methylprednisolone on day 1 of each treatment cycle. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent.
Pretreatment evaluation included a complete medical history and physical examination, complete blood cell count (CBC), biochemical profile, testosterone and PSA levels, electrocardiogram, bone scintigraphy, and assessment of all measurable/evaluable lesions by chest X-ray, and abdominal and pelvic computed tomography (CT) scan. Before each treatment cycle, patients had a physical examination, CBC (performed weekly), biochemical profile and PSA evaluation. Toxicity was evaluated according to the NCI-CTC criteria (version 1). Neurological toxicity was evaluated using an oxaliplatin-specific scale (grade 1: paresthesia/dysesthesia of short duration, with complete recovery before next cycle; grade 2: paresthesia/dysesthesia persisting between two cycles without functional impairment; grade 3: permanent paresthesia/dysesthesia resulting in functional impairment) [21].
To be evaluable for response, patients had to receive at least three treatment cycles (over 9 weeks) and have had at least one follow-up tumor assessment, unless early disease progression occurred. For patients with measurable disease, overall best response was determined according to both antitumor activity (WHO criteria), assessed by imaging in all measurable/evaluable target lesions, and by PSA levels if available (Table 1). Patients with non-measurable disease were assessed by PSA levels alone (Table 1). Measurable disease was assessed every three cycles and PSA levels every cycle; responses were confirmed 34 weeks after initial observation. Patients were assessed monthly after the last treatment infusion up to the date of relapse or progression. Patients were classified for PSA response as follows, in accordance with the recommendations of the Prostate-Specific Antigen Working Group [22]: complete response (CR) if confirmed normalization occurred (PSA <4 ng/ml); partial response (PR) if a confirmed decrease of 50% from baseline occurred; stable disease (SD) if the best response was a confirmed decrease of <50% from baseline or an increase of <25%; progressive disease if an increase of
25% occurred. Results are also presented employing a definition of PSA progression as an increase of
50% over baseline, as defined in the protocol. Time to progression (TTP) was calculated from the first treatment infusion to the first objective evidence of tumor progression, last contact or start of further antitumor therapy. Overall survival (OS) was measured from initial treatment to death. TTP and OS were analyzed using the KaplanMeier method.
|
When NCI-CTC grade 34 neutropenia or leukopenia occurred, oxaliplatin and 5-FU were reduced by 25%. In the event of insufficient platelet or neutrophil recovery at day 21 or 35, treatment was delayed by 1 week or discontinued, respectively. When grade 3 or 4 gastrointestinal toxicity occurred, oxaliplatin was reduced by 25% or 40%, respectively, and 5-FU was reduced by 20% or 35%, respectively. For grade 2 or 3 handfoot syndrome, 5-FU was reduced by 20% or 35%, respectively, and was discontinued for grade 4. In the event of paresthesia or dysesthesia lasting permanently between cycles, oxaliplatin was reduced by 25%. For paresthesia or dysesthesia associated with pain, or functional impairment lasting >7 days or permanently between cycles, oxaliplatin was reduced by 25% then 40% or discontinued.
Statistical methods
The expected number of patients was calculated following a Simon Minimax two-stage design for a parallel separate analysis of the two arms. Fifteen evaluable patients per arm were needed for the first stage, using a type I error of 0.05 to conclude an uninteresting regimen (response rate <10%) and a type II error of 0.20 implying the rejection of an active regimen (response rate 30%). If more than one response was observed during the first stage, 10 additional patients per arm were recruited. If more than five responses were observed in the 25 patients of an arm by the end of the second stage, the regimen was submitted to further evaluation. An interim analysis was conducted on the 30 evaluable patients included in the first stage of the study.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patient characteristics
Patient characteristics are shown in Table 2 and were well balanced between the two arms. The median patient age was 68 years (range 4477), and 70% of patients had a PS of 01. The median Gleason score in the primary tumor was >7. Median time from diagnosis to first metastases was 32.5 months (range 0.4120) and the median time between first metastases and start of study treatment was 14 months (range 0.791). Patients had a median of two involved disease sites (range 15) and disease occurred in sites other than bone in 59% of cases. Median PSA levels were higher in the OXFU arm (254 ng/ml; range 182763) than in the OXA arm (85 ng/ml; range 11651). All patients with PSA <10 ng/ml had measurable disease.
|
|
Significantly more cycle delays occurred in the OXFU arm (75% of patients, 32% of cycles) than in the OXA arm (15% of patients, 7% of cycles; P <104) and 21% of patients in the OXFU arm experienced at least three cycle delays compared with none in the OXA arm. This difference was due to moderate myelosuppression, which was moderately prevalent with the OXFU combination. Approximately half the delays were no longer than 7 days, and were mostly due to toxicity. Oxaliplatin dose reductions were marginally more frequent in the OXFU arm (21% of patients) than in the OXA arm (8% of patients). All dose reductions were due to toxicity, mostly neutropenia and/or neurosensory toxicity.
Efficacy
Of the eligible patients, five were not evaluable for response: one had a 10-week treatment delay after the first cycle due to experiencing acute urine retention, one withdrew after one cycle due to severe asthenia (not study treatment related), two died from unknown causes after one and two cycles, respectively, and PSA levels were not measured consistently in one patient. Thus, there were 47 evaluable and eligible patients (21 OXA, 26 OXFU).
In the overall response assessment (Table 4), three PRs were observed in the 21 evaluable OXA patients [14%; 95% confidence interval (CI) 1% to 30%] and five PRs in the 26 evaluable OXFU patients (19%; 95% CI 7% to 39%). No complete responses were observed. Only 13 patients had measurable disease, eight in the OXA arm and five in the OXFU arm. Of them, three OXA patients had a PR (38%; 95% CI 9% to 76%), and two OXFU patients experienced PR (40%; 95% CI 5% to 85%). PSA response was assessable in 45 of the evaluable patients. Of these, two out of the 19 evaluable OXA patients (11%; 95% CI 1% to 33%) and five out of 26 evaluable OXFU patients (19%; 95% CI 7% to 39%) had a PSA partial response.
|
|
Toxicity
All 54 treated patients were assessed for safety (Table 5). The most prevalent toxicity was hematological, which was more common in the OXFU arm. Although 85% of OXA patients and 96% of OXFU patients reported anemia during treatment, mild anemia was common at baseline and the rate of severe anemia was higher in such patients. Grade 34 neutropenia was rare in the OXA arm, being present in only 4% of patients and 1% of cycles, and was more prevalent in the OXFU arm, being reported in 29% of patients and 14% of cycles. The ineligible immunosuppressed patient with a renal allograft in the OXFU arm died of septic shock during an episode of febrile neutropenia. Severe thrombocytopenia (but without bleeding) was observed in 14% of OXFU patients.
|
Grade 1 and 2 neurotoxicity (assessed using the oxaliplatin-specific scale [21]; Table 6) was seen, respectively, in 73% and 8% of OXA patients and in 50% and 25% of OXFU patients. Four patients experienced grade 3 neurotoxicity, two of whom withdrew [one OXA patient after 10 cycles (cumulative oxaliplatin dose 1165 mg/m2), and one OXFU patient after seven cycles (cumulative oxaliplatin dose 880 mg/m2)]. Another OXA patient withdrew after nine treatment cycles due to grade 2 neurotoxicity (cumulative oxaliplatin dose 1170 mg/m2). Other reported events were all consistent with tumor-related symptoms, including a high rate of lower limb edema.
|
A total of 46 cycles were administered after 5-FU addition, with patients receiving a median of 3.5 additional cycles (range 26). Toxicity was comparable to that observed in the OXFU arm (Table 5). The median dose intensities of oxaliplatin (43.3 mg/m2/week) and 5-FU (1333.3 mg/m2/week) were similar to those with first-line therapy. The median cumulative oxaliplatin dose intensity (455 mg/m2) was the same as that administered in this arm before 5-FU addition. Fourteen cycles were delayed in four patients (33%), mostly due to hematological toxicity and/or neurotoxicity. Three patients underwent dose reductions for toxicity (neurosensory, neutropenia).
Out of the 11 evaluable patients, one experienced a PR (9%; 95% CI 0.25% to 44.5%) having progressed without response after four cycles of oxaliplatin alone. Median OS in eligible patients from the start of 5-FU addition was 11.3 months (95% CI 5.417.2 months).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The anti-androgen withdrawal effect [25] was assessed with a washout period of at least 4 weeks before study entry in all but two patients who continued anti-androgen treatment to avoid a potential withdrawal effect. Two of the eight responding patients (PR; OXFU arm) may have had a withdrawal effect; however, the quality and duration (8 and >4 months at the data cut-off date) of their responses suggest that this was unlikely.
The tumor response rate, TTP and survival of both the first- and second-line combination therapies compare favorably with results of mitoxantroneprednisone, the current standard in the USA for HRPC patients [4]. It is important to note that the 33% PSA response rate observed with the mitoxantronesteroid combination was in patients who had not received prior chemotherapy. In contrast, in the present study, with a 19% PSA response rate in the OXFU arm, 58% of these patients had received at least one prior chemotherapy regimen. Furthermore, OS was 11 months in both studies. A higher rate of clinical benefit responders was achieved with the OXFU combination therapy (39% compared with 12%), indicating the high capacity of symptom palliation and clinical benefit of the OXFU combination in HRPC patients. This is similar to the results observed for mitoxantroneprednisone, with 38% pain palliation with mitoxantronesteroids compared with 21% with prednisone alone.
The safety in both arms was acceptable. As expected, when compared with the single-agent arm, more patients in the combination arm experienced grade 3 or 4 neutropenia, thrombocytopenia, stomatitis and asthenia, with little or no morbidity. Neurotoxicity is similar to that observed in other oxaliplatin studies. The level of severe neutropenia observed in our study combination arm compares favorably with that observed in the mitoxantrone study (14% compared with 45% of cycles, respectively) [4, 6, 7], and with docetaxel-induced hematotoxicity and neurotoxicity in estramustine studies [26, 27].
It is of note that while the OXFU regimen objective activity may be lower than taxane and estramustine phosphate combinations, which have reported response rates higher than 50%, the time-related parameters for disease progression are similar [8, 11, 12]. Furthermore, with the taxane and estramustine combinations, heavily prophylactic steroid and anticoagulant therapy is required as well as granulocyte colony-stimulating factor (G-CSF) support because of the severe morbidity potential of both agents. Whilst myelosuppression is prevalent and cumulative neurotoxicity may be dose-limiting with the OXFU combination, this regimen has manageable toxicity and multiple cycles can be administered safely, especially in this elderly patient population. The choice of infusional 5-FU in the present study was based on its known superiority to bolus 5-FU, in addition to the established activity of 5-FU in combination with other active drugs in HRPC [28]. Given that capecitabine, an oral 5-FU prodrug, has not yet been explored in HRPC, the combination of oxaliplatin and capecitabine is of interest and needs to be assessed in this respect.
In conclusion, the OXFU combination is active and well tolerated. The objective response rate and the clinical benefit rate observed with the OXFU combination are interesting in light of the fact that our population was heavily pretreated, and this combination merits further investigation in this patient population.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Scott R, Mutchnic D, Lajkowski T. Cancer of the prostate in elderly men; incidence, growth characteristics and clinical significance. J Urol Oncol 1969; 101: 602607.
3. Small E, Vogelzang NJ. Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 1997; 15: 382388.[Abstract]
4. Tannock IF, Osoba D, Stockler M et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian trial with palliative end point. J Clin Oncol 1996; 14: 17561764.[Abstract]
5. Berry W, Dakhil S, Modiano M et al. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol 2002; 168: 24392443.[ISI][Medline]
6. Dowling AJ, Tannock IF. Systemic treatment for prostate cancer. Cancer Treat Rev 1998; 24: 283301.[CrossRef][ISI][Medline]
7. Osoba D, Tannock IF, Ernst DS et al. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol 1999; 17: 16541663.
8. Pienta K, Redman B, Hussain M et al. Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 1994; 12: 20052012.[Abstract]
9. Sitka CM, Ledakis P, Lynch J et al. Weekly docetaxel and estramustine in patients with hormone-refractory prostate cancer. Semin Oncol 2001; 28: 1621.[CrossRef][ISI][Medline]
10. Sinibaldi V, Carducci M, Moore-Cooper S et al. Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma. Cancer 2002; 94: 14571465.[CrossRef][ISI][Medline]
11. Hudes G, Nathan F, Khater C et al. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 1997; 17: 958967.
12. Petrylak D, Macarthur R, OConnor J. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999; 17: 958967.
13. Eisenberger M, Simon R, ODwyer P. A re-evaluation of non-hormonal cytotoxic chemotherapy for prostate carcinoma. J Clin Oncol 1985; 3: 827841.[Abstract]
14. Extra JM, Espie M, Calvo F et al. Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 1990; 25: 299303.[ISI][Medline]
15. Raymond E, Buquet-Fagot C, Djelloul S et al. Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anti-Cancer Drugs 1997; 8: 876885.[ISI][Medline]
16. Kuzel T, Tallman M, Shevrin D et al. A phase II study of continuous infusion 5-fluorouracil in advanced hormone refractory prostate cancer. An Illinois Cancer Center study. Cancer 1993; 72: 19651968.[ISI][Medline]
17. Heim W, Ahlgren JD, Lokich J et al. Long term continuous infusion (CI) of 5-fluorouracil (5-FU) in treatment of metastatic prostate cancer: a phase II Mid-Atlantic Oncology Group (MAOP) study. Proc Am Soc Clin Oncol 1991; 10: 179 (Abstr).
18. Atkins J, Muss HB, Case D et al. High-dose 24 hour infusion of 5-fluorouracil in metastatic prostate cancer: a phase II trial of the Piedmont Oncology Association. J Clin Oncol 1996; 14: 526529.
19. Huan S, Aitken S, Stewart DJ. 5-Fluorouracil and high dose folinic acid in hormone-refractory metastatic prostate cancer: a phase II study. Ann Oncol 1994; 5: 644645.[Abstract]
20. Chen Y, Wang J, Fraig MM et al. Defects of DNA mismatch repair in human prostate cancer. Cancer Res 2001; 61: 41124121.
21. Caussanel JP, Lévi F, Brienza S et al. Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm modulated rate compared with constant rate. J Natl Cancer Inst 1990; 82: 10461050.[Abstract]
22. Bubley G, Carducci M, Dahut W et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17: 34613467.
23. Burris H, Moore M, Andersen J et al. Improvement in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 24032413.[Abstract]
24. Rougier P, Ducreux M, Ould Kaci M et al. Randomized Phase II study of oxaliplatin alone (OXA), 5-fluorouracil (5-FU) alone, and the two drugs combined (OXA-FU) in advanced or metastatic pancreatic adenocarcinoma (APC). Proc Am Soc Clin Oncol 2000; 19: 262a (Abstr).
25. Scher H, Kelly W. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol 1993; 11: 15661572.[Abstract]
26. Beer TM, Pierce WC, Lowe BA et al. Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol 2001; 12: 12731279.[Abstract]
27. Savarese DM, Halabi S, Hars V et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001; 19: 25092516.
28. Lin CC, Hsu C-H, Chen J et al. A pilot study of AFL-T (doxorubicin, 5-fluorouracil, leucovorin, and tamoxifen) combination chemotherapy for hormone-refractory prostate cancer. Anticancer Res 2001; 21: 13851390.[ISI][Medline]