Annals of Oncology Advance Access originally published online on November 15, 2005
Annals of Oncology 2006 17(2):252-258; doi:10.1093/annonc/mdj060
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© 2005 European Society for Medical Oncology
Short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) as second-line therapy in patients with advanced colorectal cancer after failure to irinotecan and 5-fluorouracil
1 Department of Oncology, Odense University Hospital, Odense, Denmark; 2 Department of Oncology, Haukeland University Hospital, Bergen, Norway; 3 Karolinska Pharmacy, Karolinska Hospital and Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; 4 Department of Oncology and Pathology, Karolinska Hospital, Stockholm, Sweden; 5 Department of Oncology, Vejle Hospital, Vejle, Denmark; 6 Department of Oncology, Tromso University Hospital, Tromso, Norway; 7 Department of Oncology, Ullevaal University Hospital, Oslo, Norway; 8 Department of Oncology, Rogaland Central Hospital, Stavanger, Norway; 9 Department of Oncology, Linkoping University Hospital, Linkoping, Sweden; 10 Department of Oncology, Radiology and Clinical Immunology, University Hospital, Uppsala, Sweden
* Correspondence to: Dr P. Pfeiffer, Department of Oncology, Odense University Hospital, Sdr Boulevard 29, DK – 5000 Odense C, Denmark. Tel: +45-65-41-15-90; Fax: +45-65-41-29-57; E-mail: per.pfeiffer{at}ouh.fyns-amt.dk
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Abstract |
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Background: The efficacy of oxaliplatin combined with capecitabine (XELOX) as second-line therapy in patients with advanced colorectal cancer (ACRC) resistant to irinotecan is not well established. Oxaliplatin induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2-h infusion is recommended.
Patients and methods: For practical and economic reasons, but also for patient's convenience, we performed a phase II study to examine XELOX30 (capecitabine 1000 mg/m2 orally twice daily on days 1–14 and oxaliplatin 130 mg/m2 as a 30 min infusion on day 1) in patients with ACRC resistant to irinotecan. In addition the pharmacokinetics of oxaliplatin was studied.
Results: From November 2002 to September 2003, 70 patients with ACRC were treated with XELOX30. Median age was 62 (range 33–74 years) years and median performance status was 1 (range 0–2). The median number of courses was four (range 1–12) and median cumulative dose of oxaliplatin was 530 (range 125–1560 ) mg/m2. The response rate was 17% (95% CI 10–23), median time to progression (TTP) was 5.4 months (95% CI 4.6–6.4) and median survival 9.5 months (95% CI 8.5–11.2). White blood cell count (WBC) and performance status were significantly correlated to TTP. Neurotoxicity was moderate: grade 1 56%, grade 2 17% and grade 3 6%. Other grade 3 toxicities were nausea/vomiting 9%, diarrhoea 14% and PPE 8%. The maximum blood concentration and total body clearance of oxaliplatin was higher than previously reported in studies examining 2-h infusions, but the volume of distribution and terminal half-life was in close agreement with previous results.
Conclusion: XELOX30 is a very convenient second-line regimen in ACRC with an activity and safety profile similar to other oxaliplatin schedules.
Key words: colorectal cancer, short-time infusion, pharmacokinetics, oxaliplatin, capecitabine
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introduction |
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Until the year 2000, 5-fluorouracil (FU) plus folinic acid (FA) was standard therapy in patients with advanced colorectal cancer (ACRC). FU/FA produces tumour regression (complete and partial response) in 20%–25% of patients with ACRC, prolongs survival (from 6 to 12 months) and improves quality of life [1
]. However, most patients develop progressive disease after a median 4–6 months and long-term survival is uncommon. The introduction of two new agents, irinotecan and oxaliplatin, have improved these results. In patients who have progressed while receiving FU-based chemotherapy, irinotecan produced response rates of 15%–20% and increased survival from 6.5 to 9.2 months compared with best supportive care [2]. In addition, irinotecan combined with FU/FA given as first-line treatment for ACRC increased response rates (from 20% to 40%), time to progression (TTP) (from 4–6 months to 6–8 months) and overall survival (from 13–17 months to 15–20 months) compared with FU/FA alone [3–5]. Oxaliplatin produces comparable results when given with FU/FA as first-line treatment [6–8]. As second-line therapy, oxaliplatin has been less well evaluated after failure on FU/FA, but together with FU/FA it produced response rates of 20%–40% and median survival of 11–17 months in phase II trials [9, 10].
Capecitabine is a rationally designed, oral tumour-selective fluoropyrimidine, which is converted to FU preferentially in tumour tissue [11]. Oxaliplatin in combination with FU/FA leads to synergistic antiproliferative activity in vitro as well as in vivo in several tumour models [12, 13]. It has side-effects distinct from other platinum drugs, such as cisplatin or carboplatin, and lacks significant renal toxicity, ototoxicity, alopecia or severe hematotoxicity. The dose-limiting toxicity consists of a cumulative sensory peripheral neuropathy exacerbated by exposure to cold.
Many patients receive a combination of FU/FA and irinotecan as first-line therapy for metastatic disease. Despite progression, several of them are still in an excellent performance without or with only minor symptoms and there is definitely a need for further effective therapy with the capability to induce remissions and prolong life. When this study was planned, no standard therapy was defined in patients resistant to irinotecan and FU/FA.
For practical and economical reasons, but also for the convenience of the patient, cytotoxic therapy is often given as an out-patient regimen. The combination of capecitabine and oxaliplatin (XELOX) is easy to administer and it has efficacy comparable to more complex oxaliplatin regimens [14], although this remains to be proven in ongoing phase III studies. It is recommended that oxaliplatin is given as a 2-h infusion to reduce neurotoxicity. However, when oxaliplatin was given in a pilot study as a 30-min infusion, no extra neuropathy could be observed [15]. Inspired by this favourable experience we have performed a Nordic multicentre phase II study to verify efficacy and toxicity of short-term XELOX as second-line therapy in patients with ACRC after failure to FU/FA and irinotecan. Furthermore, pharmacokinetics of short-time infusion of oxaliplatin was examined.
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patients and methods |
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patient selection
All patients had histologically confirmed adenocarcinoma of the colon or rectum. They had all received irinotecan in combination with either the Nordic FU/FA bolus schedule (FLIRI) [16
, 17] or the de Gramont schedule (FOLFIRI) as first-line treatment for ACRC and progressed during or within 3 months after termination of irinotecan. Most patients had participated in a randomised study (NORDIC VI) comparing FLIRI and FOLFIRI as first-line treatment.
The patients were required to have measurable disease according to RECIST criteria [18]. Target lesions were evaluated with abdominal CT or chest CT/X-ray; abdominal ultrasound was not considered sufficient. Eligibility criteria also included age above 18 years, WHO performance status 0–2, neutrophils more than 1.5 x 109/l, platelets more than 100 x 109/l, bilirubin less than 2 x upper normal limit (UNL), serum creatinine less than 1.5 x UNL and AST or ALT less than 3 x UNL unless in the presence of known liver metastases when no upper limits were set and no signs of clinically significant cardiac disease or myocardial infarction within 12 months. The study was approved by the ethical committees in each country and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent.
treatment protocol
Patients received oxaliplatin 130 mg/m2 on day 1, given as a 30-min infusion in 250 ml of dextrose 5% repeated every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m2 twice daily as an intermittent regimen in 3-week cycles (2 weeks of treatment followed by a 1-week rest period). Capecitabine was given approximately 12 h apart and taken orally with water within 30 min after ingestion of food. Patients received antiemetic prophylaxis with a 5-HT3 antagonist (e.g. granisetrone 1 mg i.v.) and steroids (oral prednisolone 50 mg or i.v. dexametasone 4–8 mg) immediately prior to each dose of oxaliplatin.
XELOX30 was given until progressive disease or unacceptable toxicity. Treatment was delayed if neutrophils were less than 1.5 x 109/l, if platelets were less than 100 x 109/l, or if there was persistent non-haematological toxicity of grade 2 or higher. If treatment was delayed for more than 4 weeks, the patient was withdrawn from the study. The dose of capecitabine and oxaliplatin was reduced by 25% in subsequent cycles for the following toxicities: febrile neutropenia, grade 4 thrombocytopenia or grade 3 or 4 gastrointestinal toxicity. An additional 25% dose reduction was allowed if the above toxicity recurred.
The oxaliplatin dose was also modified in case of neurotoxicity. No dose modifications were made for cold-induced dysesthesias. In case of persisting paresthesias between cycles the next oxaliplatin dose was reduced by 25%. A second 25% dose reduction was possible. If no improvement took place the patient could continue treatment on capecitabine as monotherapy. Oxaliplatin was discontinued if paresthesia was associated with functional impairment.
Subjective symptoms, physical examination, performance status, haematology and adverse reactions were recorded before starting the next treatment cycle. Measurable lesions were reassessed by the imaging method used at baseline after every third cycle until progression was documented. Treatment was continued until disease progression, the occurrence of unacceptable toxicity or the patient's own wish to withdraw.
clinical end points
Toxicity was evaluated according to National Cancer Institute common toxicity criteria, version 2.0, except in the case of neurotoxicity. For neurotoxicity the following commonly used oxaliplatin-specific scale was used: grade 1, paresthesias and/or dysesthesias of short duration with complete resolution before the next cycle; grade 2, paresthesias and/or dysesthesias persisting between two cycles without functional impairment; and grade 3, paresthesias interfering with function.
Response was calculated according to RECIST criteria [18] as assessed by the investigators.
statistical analyses
After cessation of treatment, patients without documented progression were followed every 3 months with clinical and radiological evaluation. Time to progression (TTP) and overall survival (OS) was updated until 1 May 2004. Data were recorded and analysed in a Medlog® database. All analyses were done on an intention to treat population.
OS and TTP were first analysed by univariate analyses using the following covariates [19]: performance status, sex, primary tumour site (colon versus rectum), number of organs involved (one, two or three organs), surgery of primary tumour (yes versus no), WBC count (<10 x 109/l versus 
10 x 109/l), platelets (<400 x 109/l versus 400 x 109/l), haemoglobin (<11 g/dl versus 11 g/dl) and alkaline phosphatase (<300 versus 300 U/l). End points were then subsequently analysed by multivariate analyses using the covariates with P <0.25 from the univariate analyses. The univariate analyses were performed using the Kaplan–Meier method with log-rank (Mantel–Haenszel) tests and the multivariate analysis was performed using the Cox regression. All statistical tests were two-sided using the 5% significance level.
pharmacokinetics
Eight patients treated at the Department of Oncology, Karolinska Hospital were included. Before the start of the infusion (0 min), during (5, 15 and 28 min) and after the infusion (31, 35, 40, 50, 60 and 80 min) of oxaliplatin, blood samples (2 ml) were collected in prechilled Vacutainer® tubes, kept on ice and ultrafiltrated centripetally (Centrisart®) at 4°C. The ultrafiltrates were stored at –80°C and analysed within 3 weeks.
Liquid chromatographic analysis was performed as previously described [20]. Briefly, oxaliplatin was separated on a Hypercarb S column using a mobile phase of methanol/succinic acid buffer pH 7.0 (9/1 v/v). The post-column derivatization was performed by mixing the mobile phase with N,N-diethyldithiocarbamate in methanol. Microwave heating in a Teflon tubing using a Smithcreator instrument was used to carry out the reaction. The quantification was performed by photometric detection at 344 nm. The limit of quantitation was 0.04 µg/ml. Standard curves were prepared by adding oxaliplatin to blood with a hematocrit appropriate to the samples to be analysed. The blood standards (0.04–6.0 µg/ml) were run in parallel with each patient samples.
The pharmacokinetic parameters were evaluated in each patient using WIN NONLIN 1.5 SCI software. The best pharmacokinetic model was evaluated using the F-test [21]. The best fit was obtained with the one-compartment model in three patients and the two-compartment model in five patients.
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patient characteristics
Seventy patients were enrolled onto this study from 19 November 2002 to 15 September 2003. Patient characteristics are listed in Table 1. Six patients stopped therapy early due to toxicity without any clinical benefit and one patient without known heart disease died on his way to the second course of XELOX, probably from a heart attack. For these reasons only 63 patients were evaluable for response; however, response rates were calculated on the intention-to-treat population. All 70 patients were assessable for toxicity.
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response to therapy and survival
The overall response rate was 17% (95% CI 10% to 23%); 12 patients had PR and no patient had CR. Thirty-six patients had stable disease and 22 patients had PD (including the seven patients who only received one or two courses of XELOX due to rapid clinical deterioration or toxicity).
Median survival was 9.5 months (95% CI 8.5–11.2 months) and median TTP was 5.4 months (95% CI 4.6–6.4 months) in the intention-to-treat population (Figure 1). In univariate analyses, PS, WBC and haemoglobin were significantly related to TTP and all co-variates except sex and age were significantly related to OS (Table 2). All covariates except sex and age were included in the multivariate analysis. The only covariates of importance for TTP were WBC and performance status. The covariates performance status, number of organs involved, haemoglobin and WBC were significantly related to OS.
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toxicity
A total of 323 courses of chemotherapy were administered (median four courses; range 1–12 courses). Grade 3 or 4 toxicity is listed in Table 3, both by patient and by cycle. Neuropathy grade 2 was seen in 12 (17%) patients and grade 3 was seen in another four (6%) patients. In patients receiving at least six courses of XELOX, eight (29%) patients had grade 2 neuropathy and four (14%) patients had grade 3 neuropathy. Infusion time was increased in 11 patients (27 cycles) after a median of two courses to a median infusion time of 120 min (60–210 min). In these 11 patients the reason for increased infusion time was laryngo-pharyngo dysesthesia (three patients), pain during infusion (two patients), neurotoxicity (three patients) and no known reasons (three patients). An increased infusion time had no obvious effect but laryngo-pharyngo dysesthesia did not recur.
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The most common non-haematological grade III toxicity was gastrointestinal toxicity (diarrhoea in nine patients, nausea in six patients, hand–foot syndrome in six patients, vomiting in four patients and stomatitis in one patient). A dose reduction of oxaliplatin was necessary in 21 patients whereas dose reduction of capecitabine was necessary in 32 patients. Therapy was delayed in 35 patients (18% of cycles), usually because of neutropenia or thrombocytopenia grade 1 or 2.
Reasons for patient withdrawal from further chemotherapy were PD (n = 34), gastrointestinal toxicity (n = 11), neuropathy (n = 4), fatigue (n = 3), long-standing PR or NC after at least six cycles (n = 8), patient refusal (n = 5), thrombocytopenia (n = 1) and others (n = 4).
pharmacokinetic data
Pharmacokinetic data were established for eight patients receiving 130 mg/m2 oxaliplatin as a 30-min infusion (Table 4). The pharmacokinetic parameters estimated from non-linear regression analysis are given in Table 5. A representative blood concentration-versus-time curve is shown in Figure 2. The short infusion time resulted in steady-state concentrations not being reached. The mean maximum blood concentration was 5.76 µg/ml. There was only small interindividual variation in the pharmacokinetic parameters.
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discussion |
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The objective of this study was to evaluate the safety and efficacy of the XELOX30 combination. In contrast to other XELOX regimens, oxaliplatin was administered as a 30-min infusion. The study showed that XELOX30 is an active second-line regimen, with a median TTP of 5.6 months, a median OS of 9.5 months and a response rate of 17%. The study confirms the promising results of a pilot study in which XELOX30 was given to 34 patients as second-line treatment for ACRC [15
]. In this pilot study, median TTP was 4.7 months, median OS was 7.4 months and the response rate was 26%. The results of the XELOX30 regimen are comparable with the results recorded when FU/FA and oxaliplatin are given according to the de Gramont schedule (FOLFOX4) as second-line treatment in patients with ACRC [22]. In an interim analysis of a large phase III study with 459 patients, FOLFOX4 was significantly superior to single-agent therapy (FU/FA de Gramont schedule or oxaliplatin) thus establishing second-line combination therapy with oxaliplatin as standard therapy after failing an irinotecan bolus FU/FA combination [4]. Patients randomised to FOLFOX4 obtained a response rate of 13%, a TTP of 5.6 months and an OS of 9.8 months, results that are almost identical to the data from our study.
In a French crossover study [8] 226 patients with ACRC were randomised to FOLFIRI followed by FOLFOX6 or the reverse sequence. Median OS (20 and 21 months, respectively) was one of the longest ever seen in a randomised trial but without any difference among the two treatment sequences. Response rate to second-line therapy was 5% (FOLFIRI upon progression to FOLFOX) and 15% (FOLFOX6 upon progression to FOLFIRI), respectively. A recent review reported that median OS for patients with ACRC was significantly correlated with the percentage of patients who received all three drugs. FU/FA, irinotecan and oxaliplatin should, therefore, be available to all patients with ACRC who are candidates for such therapy to increase OS [23].
Infusion FU has several disadvantages, which include inconvenience for the patient and a risk of significant complications such as infections, bleeding, thrombosis and pneumothorax, and therefore capecitabine (or other oral drugs) is a good alternative for combination therapy. Phase II data suggest that XELOX is equivalent to infusion regimens [14]. Definite conclusions must await results from ongoing phase III studies, but at least from a practical perspective XELOX is an attractive schedule for first-line therapy in ACRC. We are not aware of other published data on the efficacy of XELOX as second-line therapy in patients with ACRC resistant to FU/FA in combination with irinotecan.
A number of published phase I, II or III studies using oxaliplatin have reported neurotoxicity grade 3 in 5%–25% and grade 1–2 in 50%–70% [24]. The main dose-limiting toxicity of oxaliplatin is a cumulative neuropathy. The XELOX30 regimen was very well tolerated with few patients experiencing severe toxicity (grade 3 or 4). Neuropathy grade 2 and 3 was seen in only 12 and four patients, respectively (a total of 23% of patients). In patients receiving at least six courses of XELOX30 (median 780 mg/m2 oxaliplatin), eight (29%) and four (14%) patients had grade 2 and 3 neuropathy, respectively. These figures are in the same range as those in an EORTC phase II study [14], where XELOX was given as first-line therapy (median eight courses of XELOX).
It therefore seems that a 30-min infusion does not increase the risk of having severe neurotoxicity if the cumulative dose of oxaliplatin is less than 800 mg/m2. When oxaliplatin is used as adjuvant therapy (the FOLFOX4 regimen) the cumulative dose is approximately 1000 mg/m2. Long-term toxicity cannot be evaluated from the present study in ACRC and before this short-time regimen is recommended as adjuvant, more data on toxicity and especially the degree of reversibility is necessary.
In this study, 6% experienced hand–foot syndrome grade 3, an incidence also found in other XELOX studies, in which hand–foot syndrome grade 3 was seen in less than 10% [12, 14]. In contrast, hand–foot syndrome grade 3 with single-agent capecitabine (with a slightly higher capecitabine dose of 2500 mg/m2/day) was found in almost 20% of patients [24].
Grade 3–4 neutropenia was only reported in four (6.5%) patients, and only one patient exhibited neutropenic fever. Dose reductions or treatment delays were infrequently seen. Few patients also had a grade 3 diarrhoea, vomiting or nausea. The toxicity profile of XELOX30 in the current study is comparable with data from other oxaliplatin studies including the recently published toxicity analysis of more than 5000 patients receiving oxaliplatin according to a compassionate-use study [25].
Kohne et al. [19] have shown that performance status, WBC count, alkaline phosphatase level and the number of metastatic sites predict survival in patients with FU/FA-based treatment for ACRC. The median survival times for the low, intermediate and high-risk groups were 14.7, 10.5 and 6.4 months, respectively. Sorbye et al. found comparable results in patients receiving FLOX (a combination of oxaliplatin and bolus FU/FA Nordic schedule) as first-line therapy [26]. Inspired by these studies, we found roughly the same prognostic factors when XELOX is offered as second-line therapy. In univariate analyses, PS, WBC and anaemia were significantly related to TTP and in addition platelets, number of organs involved, alkaline phosphatase level and resection of primary tumour were significantly correlated to OS. All covariates except sex and age were included in the multivariate analyses, in which the covariates WBC and performance status were significantly related to TTP. Patients with WBC count 10 x 109/l progressed very rapidly with a median TTP of 1.8 months. This subgroup of patients, therefore, did not seem to benefit from second-line therapy with XELOX, but this awaits confirmation from other studies.
The pharmacokinetics of oxaliplatin has previously been studied in patients receiving 85 mg/m2 as a 2-h infusion [27]. The same analytical procedure has been used in the present study allowing the quantification of the intact drug in whole blood. Due to the short infusion time and a higher dose level in this study, the mean maximum blood concentration was considerably higher (5.76 versus 1.44 µg/ml). The volume of distribution and terminal half-life were in close agreement with previous results. However, total body clearance was significantly higher (Mann–Whitney test, P = 0.043; unpaired t-test, P = 0.035) compared with the previous study. A population pharmacokinetic study of oxaliplatin [28] found a decreased plasma ultra-filtrate clearance of platinum with age. The mean age of the patients in this study is, however, close to that in the former one (62 versus 61) ruling out age as a parameter affecting clearance.
Renal clearance of cisplatin has previously been shown to be significantly lower with longer infusion times being attributed to avoidance of saturable renal tubular reabsorption of cisplatin at the lower plasma and urinary levels [29]. The renal fate of oxaliplatin is, as far as we know, unknown. However, more platinum is excreted in urine after oxaliplatin compared with cisplatin infusions as total platinum [30], as well as intact drug [31]. Thus we cannot rule out that similar mechanisms are involved in the renal handling of oxaliplatin.
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conclusions |
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A 30-min infusion of oxaliplatin in combination with capecitabine is an active and very convenient regimen after progression on a combination of irinotecan and FU/FA with an excellent safety profile similar to other oxaliplatin schedules. The ease and convenience of XELOX30 makes it an excellent candidate for standard palliative therapy.
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Acknowledgements |
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We thank the nurses at the Clinical Research Unit at the Department of Oncology and Pathology, Karolinska Hospital, Stockholm for their invaluable assistance in carrying out the study.
Received for publication November 23, 2004. Revision received September 21, 2005. Accepted for publication September 29, 2005.
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