Intermittent weekly high-dose capecitabine in combination with oxaliplatin: a phase I/II study in first-line treatment of patients with advanced colorectal cancer

W. Scheithauer1,+, G. V. Kornek1, M. Raderer1, B. Schüll1, K. Schmid1, F. Längle2 and H. Huber1

1 Department of Internal Medicine I, Division of Oncology and 2 Department of Surgery, Vienna University Medical School, Vienna, Austria

Received 23 April 2002; accepted 8 May 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The aim of this phase I study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of an intermittent weekly capecitabine regimen in combination with oxaliplatin. Furthermore, we intended to explore its safety at the recommended dose, and to assess its principal antitumor activity in patients with advanced colorectal cancer.

Patients and methods:

Thirty patients with measurable metastatic colorectal cancer who previously were unexposed to palliative chemotherapy were enrolled on to this disease-oriented phase I trial. They were treated with a fixed dose of oxaliplatin (85 mg/m2 administered as a 2-h intravenous infusion on day 1) plus escalating doses of capecitabine (given at two divided daily doses from days 1 to 7), repeated every 2 weeks. The dose of oral fluoropyrimidine was escalated in consecutive cohorts of three to six patients from 2500 to 4000 mg/m2/day. After having defined the toxic dose, nine additional patients were entered at the MTD/recommended dose to confirm its safety profile, and assure suitability for future phase II/III studies.

Results:

In the phase I part of the study, 21 patients were enrolled, and a total of 222 courses were administered through four dose levels of capecitabine combined with oxaliplatin 85 mg/m2. Gastrointestinal toxicities, predominantly diarrhea, were the principal DLTs. Other severe adverse events included grade 3 asthenia, acute neurological symptoms and skin toxicity. The combination was not myelosuppressive, eliciting only sporadically grade 3/4 neutropenia and/or thrombocytopenia. There was no alopecia, and only a few patients experienced mild symptoms of hand-foot syndrome. Externally reviewed objective responses were noted in 15 of all 30 evaluable patients (overall response rate, 50%; 95% confidence interval 31% to 69%) including three complete remissions and median progression-free survival was 8.8 months (range 7–14+ months).

Conclusions:

Overall results of this study indicate that the administration of clinically relevant single-agent doses of both capecitabine and oxaliplatin is feasible and seems to result in promising therapeutic activity in patients with advanced colorectal cancer. On the basis of the toxicological profile of the combination regimen shown in the present study, oxaliplatin 85 mg/m2 as a 2-h intravenous infusion every 2 weeks administered in combination with capecitabine 3500 mg/m2/day x7 in two divided doses is recommended for further evaluations.

Key words: advanced colorectal cancer, capecitabine, oral fluoropyrimidines, oxaliplatin, palliative chemotherapy, phase I study


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Until a few years ago, treatment options in patients with advanced colorectal cancer (ACC) were limited to 5-fluorouracil (5-FU) with or without biochemical modulators such as leucovorin (LV) or methotrexate, resulting in modest median overall survival times of ~1 year [1]. Recent insights into the biology of this cancer have spurred the development of several promising new anticancer drugs, which according to different mechanisms of action, synergistic activity with 5-FU and/or reduced toxicity seem to have considerably strengthened our therapeutic armamentarium [2, 3]. Notable among this new agents are the oral 5-FU prodrugs, specifically capecitabine, which is characterized by a high and predictable oral bioavailability, as well as a preferential conversion to 5-FU in neoplastic tissues [4, 5]. In two recently published randomized trials, each comprising ~600 patients, a superior therapeutic index was reported compared with bolus 5-FU/LV [6, 7]. Another promising agent is the third-generation 1,2-diaminocyclohexane-platinum derivate oxaliplatin, which is still not yet commercially available in the US. This drug, which acts by inhibiting DNA synthesis primarily by causing inter- and intrastrand cross-links in DNA, has shown activity in chemotherapy-naïve and 5-FU/LV-pretreated patients [8]. Moreover, it seems to have a synergistic effect when used in combination with fluoropyrimidines. In randomized controlled trials of continuous infusional 5-FU/LV plus or minus oxaliplatin, a significantly higher objective response rate and progression-free survival have been confirmed for the three-drug combination compared with 5-FU/LV [9, 10].

Among several different possible experimental combination regimens of the novel agents that have become available for the treatment of ACC, the combination of oxaliplatin with capecitabine seems to be particularly attractive. This seems to be true not only because of the experimentally and clinically confirmed supraadditive effect of the platinum derivate with a thymidilate synthase inhibitor, but also because of the simplicity of concomitant administration without the need of indwelling vascular devices or pumps, and the different and relatively mild toxicity profile of each drug. Preliminary results of a number of clinical phase I/II trials evaluating this combination in chemotherapeutically pretreated and previously untreated patients with ACC have demonstrated feasibility and encouraging antitumor activity [1114]. Preclinical studies in human tumor xenografts indicate that inhibition of tumor growth depends on the total dose of capecitabine but not on its administration schedule [15]. Since intermittent rather than continuous administration of this drug may allow an increase in the dose intensity (and thus enhance antitumor efficacy) in addition to a reduction in toxicity (by incorporation of drug-free intervals) [11, 15], we have decided to investigate a weekly administration schedule in combination with a fixed-dose biweekly oxaliplatin schedule. We present here the results of a noncomparative dose-escalation study of capecitabine plus oxaliplatin in patients with previously untreated ACC. This study was designed to determine the maximum tolerated dose (MTD) and the clinical toxicities of this combination regimen and to elicit a recommended dose for further clinical investigation.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Eligible patients had histologically-confirmed, nonresectable metastatic or locally recurrent colorectal cancer and bidimensionally measurable disease (defined as presence of at least one index lesion capable of two-dimensional measurement by computed tomographic (CT) scan outside any irradiated zone and >2 cm in diameter). Other eligibility criteria included age between 19 and 75 years, a World Health Organization (WHO) performance status of 0 or 1, a life expectancy of at least 3 months, adequate bone marrow reserve [absolute neutrophil count (ANC) > 1500/µl, platelet count >100 000/µl), adequate renal (serum creatinine concentration <132 µmol) and hepatic function (serum bilirubin level <34 µmol/l and serum transaminase level <2 x upper limit of normal). Patients may have received adjuvant fluoropyrimidine-based chemotherapy and/or radiation therapy, which must have been completed at least 6 months before study entry. Similarly, palliative radiotherapy was allowed, provided that less than 20% of the bone marrow was involved, presence of a target lesion outside the radiation port and full resolution of toxicities. Exclusion criteria included the presence of CNS metastases, serious or uncontrolled concurrent medical illness, peripheral neuropathy and a history of other malignancies, with the exception of excised cervical or basal skin/squamous cell carcinoma. Informed consent according to institutional regulations was obtained from all patients prior to study entry.

Treatment protocol
Patients were treated with a fixed dose of oxaliplatin 85 mg/m2 on day 1, diluted in 250 ml of 5% glucose and administered as a 2-h intravenous (i.v.) infusion plus escalating doses of capecitabine, given orally in equally divided two daily doses approximately 12 h apart, from days 1 to 7. The latter drug was supplied as film-coated tablets in two dose strengths: 150 mg and 500 mg, which were not to be split and taken orally with water within 30 min after the ingestion of food. Compliance with the oral medication regimen was assessed by tablet counts at each clinical visit. Treatment courses were repeated every 2 weeks for a total of 12 courses (6 months) unless evidence of progressive disease was found. The starting dose of capecitabine was 2500 mg/m2 and dose levels were escalated in consecutive cohorts of three to six patients to 3000, 3500 and 4000 mg/m2, utilizing an escalating-dose phase I trial design. For determination of the MTD, the first two treatment cycles were evaluated (according to the National Cancer Institute-Common Toxicity Criteria) [16]. The MTD was defined as the dose level below that producing dose-limiting toxicity (DLT, i.e. any grade 4 hematological toxicity and/or grade >=3 nonhematologic toxicity except alopecia) in >=50% of patients. No intra-patient dose escalation was allowed. In the event of grade 4 hematological or any other severe organ toxicity in individual patients, the dose of oxaliplatin and capecitabine was reduced by 25% for subsequent cycles. Oxaliplatin was discontinued if paresthesia associated with pain or functional impairment persisted between treatment cycles, or if a patient had experienced any other severe neurotoxicity. Treatment could be delayed for up to 2 weeks if symptomatic toxicity persisted and/or the absolute neutrophil count (ANC) was <1000/µl and/or the platelet count <75 000/µl. Administration of granulocyte colony-stimulating factor (G-CSF) was recommended in the former group of patients. Any patient who required more than 2 weeks for recovery of adverse reactions was taken off the study. Concomitant medications routinely administered before oxaliplatin administration included ondansetron 8 mg plus dexamethasone 8 mg both given intravenously.

Pretreatment and follow-up evaluation
Prior to initiating chemotherapy, all patients were assessed by physical examination, routine hematological and biochemical analyses, chest X-ray and CT scans of assessable target lesions. Complete blood cell counts with platelet and differential counts were obtained weekly during chemotherapy and serum chemistries were repeated at least once every course. Subjective symptoms, body-weight, physical examination, performance status and all adverse reactions were recorded before each treatment cycle. Measurable lesions were reassessed every 8 weeks by CT scan, X-ray or any other technique that allows retrospective and independent evaluation.

Study endpoints and assessment of response
The primary study endpoint was the definition of the MTD and DLTs of the described capecitabine plus oxaliplatin combination regimen. The MTD and thus ‘recommended dose’ was further examined in additional patients to confirm its toxicity/safety profile and assure its suitability for future phase II trials. Additional end points of this study were to determine the following: (i) objective response rate according to standard WHO criteria with an independent review of all tumor measurements by an external panel of oncologists and radiologists; (ii) progression-free survival (calculated from the start of treatment to time of progression or relapse); and (iii) overall survival. For response rates, 95% confidence intervals (CI) were calculated as previously described [17]. The distribution of time to death from date of study entry was estimated using the Kaplan–Meier product-limit method [18].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients characteristics
Between July 2000 and February 2001, a total of 30 patients entered this trial, all of whom were considered evaluable for response and toxicity assessment. In the phase I stage of the study, 21 patients were treated in sequential cohorts of three to six patients per dose level. After having defined the MTD, nine additional patients were enrolled to confirm the suitability of this recommended dose for further phase II/III investigations. The demographic data, sites of metastatic tumor and prior adjuvant therapies are listed in Table 1. There were 11 female and 19 male patients, and their median age was 65 years. Despite the presence of multiple metastases involving two or more organ systems in 60% of patients, all patients had a WHO performance status of 0 or 1. The predominant sites of metastases were as follows: liver, 21; lung, eight; abdominopelvic mass, 16 and soft-tissue or other sites, nine. Seven patients had received adjuvant therapy with bolus 5-FU/LV plus or minus postoperative radiotherapy and one patient with rectal cancer had undergone preoperative hyper-fractionated radiotherapy.


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Table 1. Patient characteristics (n = 30)
 
Determination of MTD
In the phase I part of the study, 21 patients were enrolled, and a total of 222 courses were administered through four dose levels of capecitabine combined with oxaliplatin 85 mg/m2. The various dose levels, number of patients and DLTs which were observed during the first two courses in determination of MTD are summarized in Table 2. At the starting dose level of capecitabine (2500 mg/m2/day), no grade 3 or 4 toxicity was observed in the three patients treated. At dose level 1, only one of six patients experienced grade 3 nausea/emesis. At level 2, two of the first six patients had grade 3 diarrhea or acute neurologic symptoms in the form of transient ataxia and aphasia. Dose level 3 (4000 mg/m2/day) constituted the toxic dose with four of six patients experiencing DLTs including diarrhea plus or minus neutropenia grade 4, grade 3 asthenia and grade 3 skin toxicity. After having thus defined the MTD, nine additional patients were entered at this dose level, which was considered the recommended dose for further phase II/III investigations. A total of 84 treatment courses were administered to these patients. In agreement with our findings in the phase I stage, only two of them had severe adverse events, i.e. grade 3 diarrhea, which in one case was complicated by an intercurrent (non-neutropenic) bronchopneumonia.


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Table 2. Dose-limiting toxicities in determination of the maximum tolerated dose (MTD)
 
Cumulative acute toxicities
The worst-ever toxicities associated with the treatment regimen by dose level are summarized in Table 3. A total of 306 courses were administered with a median number of 12 (range 3–12) cycles per patient. Hematological side effects were infrequent and generally mild. Neutropenia was recorded in 13 patients (43%) with only one grade 4 episode in a patient who was treated at the highest dose. Anemia and thrombocytopenia were noted in 14 and 13 cases, respectively, with only two patients each presenting with grade 3 toxicity at the MTD and toxic dose level, respectively. The most frequently encountered nonhematological adverse reaction was nausea/emesis (63%), though symptoms could be generally alleviated or fully reversed by intensification and/or maintenance of antiemetic treatment during the entire duration of chemotherapeutic drug intake. Other, less common nonmyelosuppressive toxicities included diarrhea (33%), which was rated severe in 3/15 and 2/6 patients treated at the MTD- and toxic dose-level, respectively, asthenia (43%), generally mild or moderate peripheral sensory neuropathy (60%) and transient clinically insignificant elevations in liver functional parameters (57%). Other treatment-associated symptoms were infrequent or negligible and it seems noteworthy that only six patients experienced a mild form of hand-foot syndrome.


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Table 3. Worst-ever toxicity of the treatment regimen by dose level
 
Dose intensity
Twelve patients (40%) had at least one treatment delay of 1 week at some time during therapy and the total number of delayed courses was 26 (8.5%). The reasons for delayed courses were hematological in five patients (thrombocytopenia in four and combined thrombocytopenia and neutropenia in one), nonhematological in five patients (diarrhea and infection in two patients each, requirement for surgical intervention because of dislocation/perforation of an intestinal stent in one case) and both hematological and nonhematological in two patients (diarrhea associated with thrombocytopenia or neutropenia).

In the phase I stage, six patients had a 25% dose reduction of both cytotoxic drugs according to the study protocol because of severe adverse reactions, as indicated in Table 2; the patient, who repeatedly experienced transient acute oxaliplatin-related neurological symptoms (slurred speech and ataxic abesia) had treatment discontinued after three courses. Among the nine patients who were subsequently treated to reconfirm the recommended dose, a 25% dose attenuation was effected in two cases for grade 3 diarrhea. At dose levels 1 and 2 there was one patient each who warranted early discontinuation for personal reasons.

Response to therapy
Antitumor responses for all 30 patients who were enrolled in this study are summarized in Table 4. The overall response rate was 50% (95% CI 31.3% to 68.7%), including three complete remissions (CR; 10%) and 12 partial remissions (PR; 40%). Eleven additional patients (36.7%) showed stabilization of disease lasting for a median duration of 8.8 months (range 4–9.5+ months) and in only four patients (13.3%) the disease progression was not influenced by chemotherapy. The median time to response was 2.8 months (range 1.5–4.5) and its estimated median duration was 7.2 months (range 3.0+ to 10.0+). Objective responses occurred invariable of prior adjuvant 5-FU/LV exposure: PRs were noted in four of seven pretreated patients. The sites of tumor involvement in the three patients who experienced CR (with one patient each being treated at the initial, MTD and toxic dose level, respectively) were lung (n = 1) and liver plus or minus abdominopelvic disease recurrence. Secondary surgery to remove (liver) metastases could be performed in four patients (13%), none of which have experienced recurrent disease by August 2002.


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Table 4. Objective tumor response after external review (n = 30)
 
The median progression-free survival in all 30 patients was 8.8 months, with a range of 2.5–14.0+ months. With a median follow-up duration of 9.0 months (range 7–14 months) as of September 2001, six of 30 patients (20%) entered on the study have died due to progressive disease. With 24 patients still alive at the time of this report, median survival duration has not been reached yet.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
With the recent availability of a number of new active anticancer agents with different cellular targets, some of which exert synergistic activity with 5-FU, current treatment options for patients with ACC seem to have improved considerably [19, 20]. Despite our better therapeutic armamentarium, however, additional investigational efforts will be necessary for further improvements not only in terms of antitumor activity but also with regard to treatment tolerance and ease of administration.

Based on the documented activity of capecitabine and oxaliplatin in ACC, their different/potentially-synergistic mechanism of action and non-overlapping toxicity profile, the present phase I/II study was initiated. For the oral 5-FU prodrug, we have selected a weekly intermittent administration schedule to increase dose intensity and reduce toxicity by incorporating drug-free intervals [15]. The combination partner oxaliplatin was given intravenously at a clinically well established fixed dose of 85 mg/m2 once every 2 weeks [21].

For this particular combination regimen, we have defined an MTD of 3500 mg/m2/day for capecitabine. DLTs included gastrointestinal symptoms i.e. mainly diarrhea, and nausea/vomiting, skin toxicity, asthenia and acute neurotoxicity. Apart from one patient with grade 4 neutropenia, who was treated at the highest dose level, myelosuppression was minimal with only two additional grade 3 events among the remaining 29 patients. Similarly, only two patients each experienced grade 3 thrombocytopenia or anemia at the MTD and the toxic dose level, respectively. Other abnormalities in laboratory parameters were generally minor, transient and clinically insignificant elevations in liver functional parameters. It should be noted that there were no severe cases of (capecitabine-related) hand-foot syndrome and only two instances of (oxaliplatin-associated) grade 3 sensory neuropathy in our patients. The former finding is likely to be related to the short, dose-intense, intermittent administration schedule of the oral 5-FU prodrug, whereas the latter observation might be ex-plained by the limited duration of treatment according to our study protocol and thus avoiding high cumulative doses of the third-generation platinum analog.

The encouraging response activity (50% confirmed re-sponses, including three CR) and median progression-free survival (8.8 months) observed in this phase I/II investigation must be seen in the light of a single institution study involving a rather small patient population with favourable prognostic features; all of them had a WHO performance score of 0 or 1 and 23 of 30 patients enrolled had never received any chemotherapy. An additional contributing factor, however, may be the high-dose intensity of capecitabine with this regimen when compared with other single agent or combination studies with this drug. With an MTD/recommended dose of capecitabine 3500 mg/m2/day given every other week, which was be realized in 11/15 patients treated at this dose level, the projected cumulative dose is as high as 12 250 mg/week; this dose corresponds to 105% of the standard intermittent single-agent capecitabine schedule (2500 mg/m2/day x 14 every 3 weeks) and to 105–131.25% of that currently being investigated by other study groups in combination with oxaliplatin [1114]. The hypothesis that a higher dose of the oral 5-FU prodrug might have contributed to the favourable therapeutic outcome is supported by the experimental data, indicating that inhibition of tumor growth in human xenograft models depends on total dose but not on the dosing schedule [15].

Finally, another potential advantage of the weekly dose-intense capecitabine administration schedule used in this combination study with oxaliplatin, is related to the longer duration of non-exposure to cytotoxic medication (‘drug holidays’). With the conventional intermittent schedule, within a 3 months period, patients are only 4 weeks off drug as compared with 6 weeks with the weekly regimen.

The overall results of this study indicate that the administration of clinically relevant single-agent doses of both capecitabine and oxaliplatin is feasible and seem to result in promising therapeutic activity in patients with ACC. On the basis of the toxicological profile of the capecitabine/oxaliplatin regimen shown in the present study, oxaliplatin 85 mg/m2 as a 2-h i.v. infusion every 2 weeks administered in combination with capecitabine 3500 mg/m2/day x 7 in two divided doses is recommended for further evaluations. In view of the observed major response activity, acceptable toxicity profile and convenient administration schedule, a randomized phase II study has been initiated to further elucidate the potential advantage of a dose-intense weekly (versus standard intermittent 2-weekly) administration schedule of the oral 5-FU prodrug in combination with oxaliplatin.


    Acknowledgements
 
This study was supported in part by the Gesellschaft zur Erforschung der Biologie und Behandlung von Tumorkrankheiten.


    Footnotes
 
+ Correspondence to: Prof. W. Scheithauer, Department of Internal Medicine I, Division of Oncology, Vienna University Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel: +43-1-40400; Fax: +43-1-45462; E-mail: werner.scheithauer{at}akh-wien.ac.at Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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