Phase II study of oxaliplatin versus oxaliplatin combined with infusional 5-fluorouracil in hormone refractory metastatic prostate cancer patients

J. P. Droz1, X. Muracciole2, N. Mottet3, M. Ould Kaci4, J. M. Vannetzel5, N. Albin6, S. Culine7, J.-M. Rodier8, J.-L. Misset9, S. Mackenzie10,+, E. Cvitkovic10 and G. Benoit4

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 d’Aurelle, 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
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

A randomized, multicenter phase II study evaluating oxaliplatin alone (OXA) and oxaliplatin–5-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 1–4), 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 1–10 or 1–14, 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
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Carcinoma of the prostate is the second highest cause of cancer-related deaths in men, with an estimated 179  300 new cases diagnosed each year and 37 000 deaths in 1999 in the USA. Worldwide, the incidence of microscopic prostate malignancy increases from 30% in men over 50 years of age, to well over 50% in men in their eighties [1, 2]. Approximately 25%–30% of men with prostate cancer have distant metastases at the time of diagnosis. Castration with or without anti-androgens is the first therapy to show efficacy in reducing tumor growth. Among symptomatic patients, 70%–80% experience subjective symptomatic relief, and approximately 40%–60% of patients achieve objective remission, the duration of response averaging only 12–18 months. Second-line hormonal therapy procures modest clinical improvement, has a duration of <6 months and its impact on survival remains unknown, indicating that a large number of patients become hormone refractory after first-line treatment [3].

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 mitoxantrone–prednisone 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 phosphate–docetaxel 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
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient population
All eligible patients fulfilled the following criteria for inclusion in the study they had: (i) pathologically proven prostate carcinoma; (ii) metastatic disease; (iii) failure of an effective anti-androgen therapy by orchidectomy or luteinizing hormone-releasing hormone (LH-RH) analogs (chemical castration had to be continued), with castrate testosterone serum levels <30 ng/ml; (iv) discontinued prior treatment by at least 4 weeks for chemotherapy, 8 weeks for anti-androgen therapy and 6 weeks for strontium89 or equivalent radioactive isotope before inclusion; (v) not previously received chemotherapy with either study drug; (vi) either measurable disease (regardless of PSA level) or ‘bone-only’ disease with rising PSA levels >10 ng/ml; (vii) progressive disease under the last therapy (appearance of a new measurable/evaluable lesion or an increase in size of >=25% of an existing measurable/evaluable lesion, or by a doubling of the nadir PSA value during the last treatment with a baseline level of at least 10 ng/ml, documented by two successive determinations not less than 4 weeks apart by the same laboratory for non-measurable/evaluable disease or bone metastasis); (viii) age <80 years; (ix) life expectancy >=3 months; (x) World Health Organization (WHO) performance status (PS) <2; (xii) adequate bone marrow reserve, renal and liver functions; and (xiii) signed informed consent.

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 3–4 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 Kaplan–Meier method.


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Table 1. Overall response criteria
 
Clinical benefit response was assessed (in symptomatic patients only) as a surrogate end point. Assessment was made using a combination of pain (pain intensity, analgesic consumption) and PS measurements, evaluated weekly by patient questionnaire. In the event of stability of these parameters, weight changes were considered. Responders were defined using a slightly modified algorithm from Burris et al. [23] (‘response’ being defined as improvement in one parameter and at least stable assessment in the others). The presence of symptoms at screening was not required. Patient eligibility, evaluability, overall responses and time-related parameters were assessed by a clinical expert panel (an independent oncologist and a sponsor representative). CT scans for measurable disease were reviewed by an expert panel (an independent radiological expert and a sponsor representative).

When NCI-CTC grade 3–4 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 hand–foot 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
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Fifty-four patients were enrolled (26 and 28 in the OXA and OXFU arms, respectively) and treated in nine French centers between February 1998 and August 1999. Two of those patients included were considered ineligible after review by the clinical expert panel: one in the OXA arm due to liver metastases, strongly suspected to be of digestive origin after biopsy (probably pancreatic carcinoma), and another in the combination arm due to a previous renal allograft with concomitant immunosuppressive therapy and poor baseline PS.

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 44–77), and 70% of patients had a PS of 0–1. The median Gleason score in the primary tumor was >7. Median time from diagnosis to first metastases was 32.5 months (range 0.4–120) and the median time between first metastases and start of study treatment was 14 months (range 0.7–91). Patients had a median of two involved disease sites (range 1–5) 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 18–2763) than in the OXA arm (85 ng/ml; range 1–1651). All patients with PSA <10 ng/ml had measurable disease.


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Table 2. Patient characteristics, all treated patients
 
Previous therapy in this patient population is described in Table 3. Thirty percent had received primary radiotherapy. Chemical castration with LH-RH agonists had been carried out in 69% of patients, the remaining 31% having undergone a bilateral orchidectomy. Patients had received a median of two previous hormone therapy regimens. Fifty-eight percent of patients in the OXA arm and 46% in the OXFU arm had undergone previous chemotherapy (estramustine, etoposide, mitoxantrone–prednisone, cyclophosphamide, adriamycin, cisplatin, vinblastine, ifosfamide).


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Table 3. Prior therapy, all treated patients
 
Treatment
In the OXA and OXFU arms, respectively, 106 and 163 cycles of study treatment were administered. The median number of cycles administered was higher in the OXFU arm (5; range 1–14) than in the OXA arm (3.5; range 1–10). Oxaliplatin dose-intensity was similar in the two arms (OXA 43 mg/m2/week; OXFU 40 mg/m2/week). Median relative oxaliplatin dose intensity in the OXA arm was 100% compared with 91% in the OXFU arm. The median cumulative oxaliplatin dose was lower in the OXA arm (455 mg/m2; range 130–1170) than in the OXFU arm (650 mg/m2; range 130–1690).

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 <10–4) 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.


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Table 4. Best overall response and PSA evaluation in eligible patients
 
Response durations of the three patients with PR in the OXA arm were 4.1, >6.4 and 11.8 months, and of the five PR patients in the OXFU arm they were >5, 5.9, >7.3, 8.4 and 9 months. As of 31 July 1999, with a median follow-up of 7.9 months, 23 of the 25 eligible OXA patients had progressed and 13 had died, while 22 of 27 eligible OXFU patients had progressed and 11 had died. Median TTP in eligible patients was 2.6 months (95% CI 1.8–3.3 months) in the OXA arm and 3.4 months (95% CI 2.5–4.3 months) in the OXFU arm (Figure 1). In the OXA arm only, one patient out of 25 had not progressed at 8 months (patient censored at 6.4 months), while in the OXFU arm five patients out of 27 had not progressed (three patients censored at 5, 6.8 and 7.3 months, respectively). Median OS in eligible patients was 9.4 months (95% CI 3.8–15.1 months) and 11.4 months (95% CI 4.3–18.5 months) in the OXA and OXFU arms, respectively. Clinical benefit response could be assessed in 20 (77%) and 22 (79%) patients in the OXA and OXFU arms, respectively, showing a higher rate of clinical benefit responders with the combination therapy (39% compared with 12% in all eligible patients, 50% compared with 15% in patients assessable for clinical benefit). Median duration of clinical benefit was four cycles (range 3–10 cycles) and eight cycles (range 3–10 cycles) in the OXFU and OXA arms, respectively, and benefit was ongoing in four and two patients, respectively, at the end of treatment.



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Figure 1. TTP in eligible patients..

 
In one patient, the presence of liver metastases of digestive adenocarcinoma origin, elevated CA 19.9 levels and the heterogeneous aspect of the head of the pancreas (CT scan) led to the conclusion that this patient probably had a simultaneous pancreatic carcinoma. This patient had a PSA PR (a decrease from 21.3 to 9.7 ng/ml) after one cycle with oxaliplatin alone. This was followed by seven cycles of combination therapy, after which confirmed partial responses were seen in PSA (a decrease from 21.3 to 2.6 ng/ml), as well as in liver lesions (CT scan) and CA 19.9 levels. This double response confirms results from the randomized OXFU phase II study in advanced pancreatic adenocarcinoma [24].

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 3–4 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.


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Table 5. Toxicity per patient, in all treated patients (National Cancer Institute-Common Toxicity Criteria)
 
Non-hematological toxicity was present at similar levels in both arms, with the exception of nausea, which was more common in the OXA arm, and stomatitis which was more common in the OXFU arm. Gastrointestinal toxicity was mostly mild, with one cycle of grade 3–4 vomiting and two cycles of grade 3–4 anorexia (in one patient) in the OXFU arm. Stomatitis was severe in four patients (one cycle each) in the OXFU arm. Severe asthenia occurred in 15% of OXA patients and 25% of OXFU patients. No nephrotoxicity was reported, even in the nine patients with abnormally elevated baseline serum creatinine.

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.


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Table 6. Maximal grade of neurotoxicity, by patient and cycle
 
5-FU addition after failure of oxaliplatin treatment
Twelve patients in the OXA arm (46%) went on to receive combination treatment, 10 of whom were progressing. Most patients who did not receive second-line therapy had rapidly progressing disease and deterioration of general status. 5-FU addition occurred after a median of three cycles (range 1–6) of single-agent oxaliplatin. Patient characteristics of this cohort were similar to those of the overall study cohort, with a median patient age of 66 years (range 59–77) and with 75% of patients having a PS of 0–1.

A total of 46 cycles were administered after 5-FU addition, with patients receiving a median of 3.5 additional cycles (range 2–6). 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 5.4–17.2 months).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Management of HRPC remains controversial and no optimal standard treatment exists. Furthermore, in this elderly patient population who may have reduced bone marrow reserve and poor renal function, it is important to define well tolerated and active chemotherapy regimens. The aim of this study was to assess the activity of oxaliplatin, a new platinum compound without nephrotoxicity, as a single agent and in combination with 5-FU, using several end points including post-therapy PSA decline, assessment of measurable disease when applicable, symptom palliation and survival. Although the study design did not allow for formal statistical comparison between the two arms, the antitumor activity appears higher in the oxaliplatin–5-FU combination (19%) than with single-agent oxaliplatin (14%), as is the median TTP (3.4 compared with 2.6 months, respectively). The ratio of non-progressing patients at 8 months (4%:19%) is noteworthy. The prevalence of mismatch repair defects in advanced prostrate cancer is also of note in this regard. Two patients in each group achieved PR in both measurable disease and PSA. Only two discrepancies were seen between PSA and measurable disease responses, confirming the clinical relevance of the >=50% PSA decrease benchmark in HRPC [6].

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 mitoxantrone–prednisone, the current standard in the USA for HRPC patients [4]. It is important to note that the 33% PSA response rate observed with the mitoxantrone–steroid 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 mitoxantrone–prednisone, with 38% pain palliation with mitoxantrone–steroids 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
 
We thank Moshe Istzhaki for the statistical analysis and Dr Youssef Yataghene (Sanofi-Synthélabo) for comments. This work was supported by a grant from Sanofi-Synthélabo, France.


    Footnotes
 
+ Correspondence to: Dr S. Mackenzie, Cvitkovic et Associés Consultants, 18–20 rue Pasteur, 94278 Kremlin-Bicêtre, France. Tel: +33-1-45-15-40-52; Fax: +33-1-45-15-40-41; E-mail: s.mackenzie{at}caconcology.com Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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