Annals of Oncology Advance Access published online on February 14, 2008
Annals of Oncology, doi:10.1093/annonc/mdn002
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Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil
1 Department of Oncology, Odense University Hospital
2 Institute of Clinical Research, University of Southern Denmark, Odense
3 Department of Oncology, Aalborg University Hospital, Aalborg, Denmark
4 Department of Oncology, Rogaland Central Hospital, Stavanger, Norway
5 Department of Oncology, Radiology and Clinical Immunology University Hospital, Uppsala University Hospital, Uppsala, Sweden
6 Department of Oncology, Tromso University Hospital, Tromso, Norway
7 Department of Oncology, Vejle Hospital, Vejle, Denmark
8 Department of Oncology and Pathology, Karolinska Hospital, Stockholm
9 Department of Oncology, Linkoping University Hospital, Linkoping, Sweden
10 Department of Oncology, Haukeland University Hospital, Bergen
11 Department of Oncology, Ullevål University Hospital, Oslo, Norway
* Correspondence to: Dr C. Qvortrup, Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C 5000, Denmark. Tel: +45 65413147; Fax: +45 66135477; E-mail: camilla.qvortrup{at}ouh.regionsyddanmark.dk
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Abstract |
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Background: Oxaliplatin in combination with capecitabine prolongs survival in patients with metastatic colorectal cancer (mCRC). Chronomodulation might reduce toxicity and improve efficacy.
Patients and methods: A phase II study examining chronomodulated XELOX30 (XELOX30chron): oxaliplatin: 130 mg/m2 on day 1, as a 30-min infusion between 1 and 3 p.m. Capecitabine: total daily dose of 2000 mg/m2, 20% of the dose between 7 and 9 a.m. and 80% of the dose between 6 and 8 p.m. in patients with mCRC resistant to irinotecan. Seventy-one patients were enrolled. Response rate was 18%; median progression-free survival 5.1 months and median overall survival (OS) 10.2 months. Platelet count and performance status were significantly correlated to OS in multivariate analyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2% of patients, respectively, other grade 3 toxic effects were as follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experienced grade 4) and palmoplantart erytem 9%.
Conclusion: XELOX30chron is a convenient second-line regimen with efficacy and safety profile similar to other oxaliplatin schedules. To further investigate chronomodulated XELOX, we have started a Nordic randomised phase II study comparing XELOX30 and XELOX30chron as first-line therapy in patients with mCRC.
capecitabine, chronotherapy, metastatic colorectal cancer, oxaliplatin, short-time infusion, XELOX
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background |
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TopAbstractbackgroundpatients and methodsresultsdiscussionconclusionsfundingReferences |
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Approximately 50% of patients diagnosed with colorectal cancer (CRC) will develop metastatic disease (mCRC). For decades, 5-fluorouracil (FU) modulated by folinic acid (FA) has been the mainstay in the treatment of CRC [1]. The introduction of irinotecan and oxaliplatin most often given in combination with FU/FA has increased the expected survival >18 months [2–6]. It has been shown that it is important that all patients are exposed to all three drugs [7].
Capecitabine is a rationally designed, oral tumour-selective fluoropyrimidine, which is converted to FU preferentially in tumour tissue [8, 9]. Capecitabine as monotherapy is as efficient as i.v. FU/FA [10] and in combination with oxaliplatin (XELOX) as effective as FOLFOX with balanced safety profiles both as first-line therapy [11] and as second-line therapy [12].
Oxaliplatin induces both acute and cumulative neurotoxicity. The incidence is claimed to be infusion rate dependent and therefore a 2-h infusion is recommended. However, in a pilotstudy, oxaliplatin was given as 30-min infusion without increased toxicity [13]. In our XELOX-I study, we evaluated XELOX30–capecitabine 1000 mg/m2 orally twice daily on days 1–14 and short-time oxaliplatin 130 mg/m2 as 30-min infusion on day 1, each 3 weeks and demonstrated a safety profile and efficacy similar to other oxaliplatin schedules [14].
Several enzymatic activities, cellular detoxification and pharmacokinetics vary according to a 24-h scale—the circadian rhythm. The adaptation of chemotherapy delivery to this rhythm—chronomodulation—has been investigated over years [15]. Infusion of oxaliplatin and FU/FA can be delivered at a constant rate or chronomodulated using programmable ambulatory pumps. Clinical studies have shown that chronomodulation (oxaliplatin delivery peak rate at 1 to 3 p.m. and FU delivery peak rate at 4 a.m.) significantly reduces toxicity and perhaps improves antitumour activity as compared with flat rate [16].
To improve the therapeutic index of the XELOX regimen, we designed a XELOX regimen that mimicked a chronomodulated regimen. If 20% of the daily dose of capecitabine dose is given in the morning and 80% in the evening and oxaliplatin administered as an i.v. infusion between 1 and 3 p.m. then this XELOX regimen might mimic a chronomodulated regimen. We tested this regimen in a phase II study in patients with mCRC with progressive disease after therapy with irinotecan and FU/FA.
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patients and methods |
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All patients had histologically confirmed adenocarcinoma of the colon or rectum and metastatic measurable disease according to the RECIST criteria. All patients had received irinotecan in combination with either the Nordic FU/FA bolus schedule (FLIRI) [17] or the de Gramont schedule (FOLFIRI) [4] and had progressed during or within 3 months after termination of irinotecan.
Other inclusion criteria were age >18 years, World Health Organisation performance status 0–2, neutrophils >1.5 x 109/l, platelets >100 x 109/l, bilirubin <1.5 x upper normal limit (UNL) and aspartate transaminase or alanine transaminase <3 x UNL (unless in presence of known liver metastases where no upper limit were set), creatinine clearance >30 ml/min and no sign of 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% between 1 and 3 p.m. capecitabine was administered orally at a total daily dose of 2000 mg/m2, 20% of the dose (400 mg/m2) was given between 7 and 9 a.m. and 80% of the dose (1600 mg/m2) between 6 and 8 p.m. The first dose in each cycle was administered in the evening day 1 and the last dose in the morning day 15. Capecitabine was taken orally with water within 30 min after ingestion of food. Cycles were repeated every 3 weeks.
At least six cycles of XELOX30chron were recommended unless progressive disease or unacceptable toxicity occurred.
Treatment was postponed if neutrophils were <1.5 x 109/l, if platelets were <100 x 109/l or if there was persistent nonhaematological toxicity of grade 2 or higher. If treatment was postponed >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 toxic effects: 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 dysethesias. In case of persisting paresthesias between cycles, the next oxaliplatin dose was reduced by 25%. A second 25% dose reduction was possible.
Subjective symptoms, physical examination, performance status, haematology and adverse reactions were recorded before starting the next treatment cycle. Tumour lesions were evaluated every third cycle and response was assessed by investigators according to RECIST criteria. After completion of treatment, computed tomography scan was carried out every third month until progression was documented.
clinical end points
The primary end point of the study was response rate (RR). Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS).
Toxicity was evaluated according to National Cancer Institute common toxicity criteria, version 2.0, except in case of neurotoxicity. For neurotoxicity, the following commonly used oxaliplatin-specific scale was used: grade 1, paresthesias and/or dysethesias of short duration with complete resolution before the next cycle; grade 2, paresthesias and/or dysethesias persisting between two cycles without functional impairment and grade 3, paresthesias interfering with function.
PFS was defined as the time from inclusion to progressive disease occurred (according to the RECIST criteria) or death of any cause. OS was defined as the time from inclusion to death of any cause. PFS and OS were updated until 1 April 2007.
statistical analyses
Data were recorded and analysed in a Medlog® database. All analyses were done on the intention-to-treat population.
In the trial planning phase, a two-stage design to calculate the sample size was used. If the RR was <5%, the combination was considered not to have sufficient activity. If not at least two responders were observed among the first 21 assessable patients, the study would be terminated. If the numbers of responders were met, 20 additional assessable patients would be enrolled, until at least 41 patients were assessable for response. To ensure 41 assessable patients, we planned to include at least 50 patients in this phase II study. This design had a 90% power to reject a RR of 5% at a 5% significance level. However, as the actual sample size exceeded the planned number, the rejection thresholds were adjusted before analysis.
Survival analyses were carried out using the Kaplan–Meier method with log-rank (Mantel–Haenszel) test, and the multivariate analysis was carried out using the Cox regression. All statistical tests were two sided using the 5% significance level.
End points were then subsequently analysed by univariate analyses and the multivariate analyses; in univariate analyses, the following covariates were used [18, 19]: performance status, sex, primary tumour site (colon versus rectum), number of organs involved (one versus two or more), resection of primary tumour (yes versus no), white blood count (WBC) count (<10 x 109/l versus 
10 x 109/l), platelets (<400 x 109/l versus 400 x 109/l), hemoglobin (<11 g/dl versus 11 g/dl) and alkaline phosphatase (<300 versus 300 U/l). The covariates found to be significant in univariate analyses were included in the multivariate analyses.
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results |
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patient characteristics
Seventy-one patients were enrolled onto this study from November 2002 to September 2003. Patient characteristics are listed in Table 1.
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Five patients stopped therapy before the first efficacy assessment were made and therefore they were not assessable for response; however, the efficacy results were calculated in the intention-to-treat population.
Sixty-nine patients were assessable for toxicity.
All patients in the study have died during the follow-up period.
response to therapy and survival
The overall RR was 18% in the intention-to-treat population: 1 patient had complete response, 12 patients had partial response and 34 patients had no change. Nineteen patients had progressive disease at their first evaluation. In addition, five patients who stopped therapy before first evaluation were classified as non-assessable (one patient due to rapid clinical deterioration, two patients due to toxicity and two patients due to their wish).
Median PFS was 5.1 months (Figure 1) [95% confidence interval (CI) 4.4–6.3 months] and median OS (Figure 2) was 10.2 months (95% CI 9.1–10.9 months) in the intention-to-treat population.
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In univariate analyses performance status (PS), WBC, platelets, hemoglobin, alkaline phosphatase and sex were significantly related to OS (Table 2). The two covariates PS and platelets were significantly related to OS in mulitvariate analyses. In univariate analyses, only platelet count was significantly related to PFS (Table 2).
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safety
A total of 358 cycles of chemotherapy were administered (median 6 cycles, range 1–10 cycles). Grade 3 and 4 toxicity is listed in Table 3. Neuropathy grade 2 was seen in 17 patients (25%) and grade 3 in 1 patient. In 38 patients receiving at least six courses of therapy, 11 patients (29%) had grade 2 neuropathy and only one patient experienced grade 3 neurotoxicity.
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Diarrhoea was the most common severe nonhaematological toxicity with 12% grade 3 and 3% grade 4. Other grade 3 gastrointestinal toxicity was nausea (6%) and vomiting (3%). Palmoplantart erytem grade 3 was seen in 9% of patients.
Fourteen patients stopped therapy before the recommended six cycles for reasons other than progression [eight due to toxicity, two due to patient’s wish, one due to surgery for mCRC (radical resection), one due to allergic reaction to oxaliplatin and two patients due to a rapid deterioration in performance status].
Infusion time was increased (defined as infusion time >45 min) in eight patients. Most often infusion time was increased to 60 min. In these patients, the reasons for increased infusion time were arm pain during infusion (four patients), patient's wish (one patient) and laryngopharyngodysesthesia (one patient). In two patients, the reasons for increased infusion time were not specified.
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discussion |
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It has previously been shown that chronomodulated infusion of oxaliplatin and FU/FA reduces toxicity compared with flat infusion of oxaliplatin and FU/FA in patients with mCRC [16].
In the present study, we evaluated an orally regimen (XELOX30chron) that mimics a chronomodulated regimen. We found that XELOX30chron is an active second-line regimen in patients with mCRC producing a RR of 18%, a median PFS of 5.1 months and a median OS of 10.2 months.
The results of our study are comparable with results from other studies evaluating oxaliplatin-based regimens as second-line (after failure to irinotecan-based chemotherapy) therapy in patients with mCRC. In a study comparing FOLFOX4 (FU/FA infusion according to the de Gramont schedule) and single-agent therapy (either FU/FA de Gramont schedule or oxaliplatin) as second-line treatment a RR of 13%, a median PFS of 5.6 months and a median OS of 9.8 months in the FOLFOX4 arm were obtained [5].
In a recently presented phase III study, comparing standard XELOX regimen to the FOLFOX4 regimen as second-line treatment including 627 patients with mCRC a RR of 20%, median PFS of 4.7 months and a median OS of 11.9 months were found [12].
Santini et al. [20] have tested chronomodulated XELOX as second-line therapy in 36 patients with mCRC. Patients received continuous infusion of oxaliplatin for 12 h on days 1 and 8 and capecitabine 1750 mg/m2/day given three times daily with 50% of the dose in the evening days 1–14 every 21 days. They found a RR as high as 31%, median PFS of 6.7 months and a median OS of 11.3 months.
In our own XELOX-I study [14] (with short-time infusion of oxaliplatin but otherwise standard administration schedule), as second-line treatment we found a RR of 17%, a median thymidine triphosphate of 5.6 months and a median survival of 9.5 months.
The principle of chronotherapy is to deliver agents at an optimal time according to the circadian rhythm so that toxic effects are reduced and efficacy is improved [15]. We found that the XELOX30chron regimen was a convenient regimen with an acceptable toxicity profile comparable to other XELOX regimens [11, 12].
Santini et al. [20] have examined their chronomodulated XELOX regimen both in first and second-line settings [21] and found toxicity profiles comparable to ours, apart from neurotoxicity which was higher in the first-line setting (second-line: grades 2 and 3 in 14% and 8% of patients and in first-line treatment grades 2 and 3 in 39% and 2% of patients, respectively). Patients received a higher median number cycles of treatment (four and six cycles) as expected in the first-line setting than in the second-line setting.
Giachetti et al. found different but balanced toxic effects profiles in patients receiving chronomodulated FU/FA and oxaliplatin compared with patients receiving FOLFOX2. Significant more neutropenia was found in the FOLFOX2 arm but significantly more diarrhoea in the chronomodulated arm [22].
The main dose-limiting toxicity of oxaliplatin is neuropathy, which worsens with increasing cumulative dose of oxaliplatin. We found an incidence of grade 2 and 3 neurotoxicity of 25% and 3%, respectively. In the MOSAIC trial [23], patients treated with FOLFOX (oxaliplatin dose 85 mg/m2 every second week) received median 12 cycles of chemotherapy with a median oxaliplatin dose of 34.2 mg/m2/week (total 820 mg/m2). They reported an incidence of grade 2 and 3 neuropathy of 32% and 12%, respectively. In the OPTIMOX-1 study [24], patients receiving FOLFOX4 (oxaliplatin dose 85 mg/m2) 12% experienced grade 3 neuropathy after 12 cycles.
In our XELOX-I study [14], we found 29% and 14% grade 2 and 3 neuropathy in patients receiving at least six courses of XELOX compared with 29% and 3% receiving at least six cycles of chronomodulated XELOX.
Kohne et al. [18] have shown that four baseline parameters (performance status, WBC, alkaline phosphatase level and number of metastatic sites) predict survival in patients with mCRC treated with FU-based chemotherapy. Sorbye et al. [19] confirmed that increased alkaline phosphatase, platelets and unresected primary tumour were poor parameters for survival in patients with mCRC treated with FLOX (combination of Nordic bolus FU/FA and oxaliplatin) as first-line therapy. Futhermore, it is shown that poor PS or a high alkaline phosphatase level at start of first-line chemotherapy predicts whether second-line chemotherapy will initiate or not [25]. In our own XELOX-I study [14], we found in multivariate analysis that PS, number of organs involved, hemoglobin and WBC were correlated to OS.
Recently, Sorbye et al. [26] assessed the use of potential prognostic factors in 143 publications in mCRC. In their extensive overview, they found that clinical characteristics were very often reported but in contrast laboratory values were rarely stated. Sorbye et al. [26] indicated a number of baseline characteristics (clinical and laboratory) which must be reported in future studies but also some which should be reported. Information on these factors will definitely enhance the opportunity to compare results across studies.
Inspired by the above-mentioned studies, we examined a range of these parameters with the same cut-off points as used in the other studies. We found that increased platelet count (>400 x 109/l) and PS 1–2 were negative prognostics factors. In patients with high platelet count, OS was only 4.4 months compared with 10.7 months in patients with normal values. Increased platelet count has also been found to be a negative prognostic factor in others studies as well [26] but presently the reason for this is not known.
Giachetti et al. [22] found the chronomodulated FU and oxaliplatin produced a survival advantage over FOLFOX in men. In contrast, we found in univariate analysis that women had a survival advantage compared with men (median OS 11.7 and 9.1 months, respectively, P = 0.027).
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conclusions |
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We found a satisfactory RR of 18% comparable to the RR found in other studies evaluating second-line treatments. The study was not designed to evaluate differences in toxicity between XELOX30 and XELOX30chron but patients receiving more than six courses of chronomodulated XELOX tended to develop less severe neuropathy compared with historical controls in our XELOX-I study. In order to confirm a reduction in toxicity, we have conducted a Nordic multicentre randomised study comparing XELOX30 and XELOX30chron, as first-line therapy in patients with advanced CRC with the primary objective of reducing toxicity.
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Roche, Sanofi-Aventis.
Received for publication October 24, 2007. Revision received December 28, 2007. Accepted for publication December 31, 2007.
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References |
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