Combination of irinotecan (CPT-11) plus oxaliplatin (L-OHP) as first-line treatment in locally advanced or metastatic gastric cancer: a multicentre phase II trial

J. Souglakos1, K. Syrigos2, A. Potamianou3, A. Polyzos4, I. Boukovinas5, N. Androulakis1, Ch. Kouroussis1, N. Vardakis1, Ch. Christophilakis6, A. Kotsakis1 and V. Georgoulias1,*

1 Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete; 2 Medical Oncology Unit, 3rd Department of Internal Medicine and 4 Medical Oncology Unit, Propedeutic Department, University of Athens, Athens; 3 First Department of Medical Oncology, ‘Metaxa’ Hospital of Athens, Athens; 5 2nd Department of Medical Oncology, ‘Theagenion’ Anticancer Hospital of Thessaloniki, Thessaloniki; 6 Medical Oncology Unit, Department of Medical Oncology, 401 Military Hospital of Athens, Athens, Greece

* Correspondence to: Dr Vassilis Georgoulias, MD, PhD, Department of Medical Oncology, University General Hospital of Heraklion, P.O. Box 1352, Heraklion 71110, Crete, Greece. Tel: +30-2810392747; Fax: +30-2810392802; Email: georgsec{at}med.uoc.gr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The purpose of this study was to evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) as first-line treatment in patients with locally advanced or metastatic gastric cancer (AGC).

Patients and methods: Thirty-two patients with AGC who had not received previous therapy for metastatic disease were enrolled. The median age was 62.5 years and the World Health Organization performance status was 0–1 in 29 patients; 13 (40.6%) patients had previous surgery and three (9.4%) had adjuvant chemotherapy. L-OHP (85 mg/m2 as a 2-h i.v. infusion) followed by CPT-11 (200 mg/m2 as a 30-min i.v. infusion) was given on day 1, in cycles of 21 days.

Results: All patients were evaluable for toxicity and 31 were evaluable for response. Complete response was achieved in one (3.1%) patient and a partial response was achieved in 15 (46.9%) [overall response rate = 50% (95% confidence interval 38.7–72.4%)]. Eight (25%) patients had stable disease, and eight (25%) had progressive disease. The median duration of response was 5 months and the median time to disease progression was 5.5 months. After a median follow-up period of 16 months, the median survival time was 8.5 months. Grade 3–4 neutropenia occurred in six (18.6%) patients, febrile neutropenia in two (6.2%) and grade 3 anaemia in one (3.1%). Grade 3 diarrhoea was observed in two (6.2%) patients, grade 1 neurotoxicity in five (15.6%) and grade 3 asthenia in two (6.2%). There was no treatment-related death.

Conclusions: The combination of CPT-11/L-OHP is an active regimen as front-line treatment in AGC with a favourable toxicity profile and deserves further evaluation in randomised studies.

Key words: gastric cancer, irinotecan, oxaliplatin


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Gastric cancer is one of the leading causes of death from cancer worldwide. It is more frequent in the elderly (median age at diagnosis >70 years) and in males (twice as common as in females). The majority of cases are diagnosed in the advanced stages and the 5-year relative survival is 23% [1Go]. Surgical resection is the only potentially curative treatment for localised disease. Chemotherapy is used for the treatment of advanced or metastatic disease, with a palliative effect [2Go].

Several randomised trials have demonstrated that 5-fluorouracil (5-FU)-based chemotherapy may improve overall survival and quality of life when compared with best supportive care [3Go]. Many combinations have been used, such as FAM (5-FU, doxorubicin and mitomycin), FAMTX (5-FU, doxorubicin and high-dose methotrexate), EAP (etoposide, doxorubicin and cisplatin), ELF (etoposide, leucovorin and 5-FU), ECF (epirubicin, cisplatin and 5-FU continuous infusion) and PELF (cisplatin, epirubicin, leucovorin and 5-FU), and several regimens of cisplatin and 5-FU (FP regimens). In randomised studies, FAMTX, cisplatin/5-FU and PELF have been demonstrated to be more effective than FAM [4Go–6Go], FAMTX is more effective than EAP [7Go], FAMTX is more effective than cisplatin/5-FU or ELF [8Go], and ECF is more effective than FAMTX [9Go]. Although high response rates (up to 51%) have been documented in these trials, median survival has been consistently reported as <10 months. In addition, the toxicity profile of these regimens is often severe, with leukopenia and alopecia representing serious problems in anthracycline- and/or etoposide-based regimens.

Irinotecan (CPT-11) is a hemi-synthetic, water soluble derivative of the plant alkaloid camptothecin. After conversion to its active metabolite, SN-38, CPT-11 acts by inhibiting the eukaryotic enzyme DNA-topoisomerase I [10Go]. This unique mechanism of action of CPT-11 provides an opportunity for combination with other non-cross-resistant chemotherapeutic agents. Phase II studies have shown that CPT-11 is an active drug against gastric cancer in both chemo-naïve [response rate (RR)=18%, median survival = 7.5 months] [11Go] and pre-treated (RR = 11.4%–23.3%) patients [12Go]. The combination of CPT-11 with cisplatin achieved an impressive 59% objective response rate [13Go] in a Japanese trial, and a lower one of 25% in a European trial [14Go].

Oxaliplatin (L-OHP), a new diaminocyclohexane-platinum analogue, has shown significant activity in advanced colorectal cancer [15Go]. The main mechanism of action of L-OHP is similar to that of cisplatin since it induces the formation of DNA adducts leading to inhibition of DNA synthesis [16Go], but has some important differences compared with cisplatin, such as: (i) the DNA adducts of L-OHP are bulkier and more hydrophobic than those of cisplatin and, thus, the inhibitory effect on DNA synthesis is more pronounced [17Go]; and (ii) unlike cisplatin, the DNA adducts of L-OHP are not recognised by the DNA mismatch repair enzymes [18Go].

Synergistic effects were observed when topoisomerase I inhibitors were combined with cisplatin or L-OHP in several tumour cell lines, and schedule-dependent interactions have been demonstrated for CPT-11 and L-OHP in vitro [19Go–21Go]. Based on the hypothesis of Goldie and Coldman, the development of drug-resistant clones could be minimised by early tumour exposure to as many active agents as possible [22Go]. Therefore the early administration of active agents may be a way of avoiding the emergence of chemo-resistant clones. A previous phase I study of CPT-11 and LOHP in combination in patients with gastrointestinal solid tumours demonstrated that the regimen is feasible with an acceptable toxicity [23Go].

Based on these data, a multicentre phase II study was conducted by the Colorectal Working Group of the Hellenic Oncology Research Group (HORG) in order to assess the efficacy and safety of CPT-11 plus L-OHP administered every 3 weeks as first-line treatment in patients with advanced or metastatic gastric cancer.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility criteria
Patients with unresectable locally advanced or metastatic histologically proven gastric adenocarcinoma were enrolled into the study. Previous chemotherapy for advanced or metastatic disease was not allowed. Patients who had received previous adjuvant chemotherapy were eligible if they had remained free of disease for at least 6 months after the completion of adjuvant therapy. Other eligibility criteria were: age ≥18 years, World Health Organization (WHO) performance status (PS) 0–2; at least one bidimensionally measurable lesion of ≥2 cm; a life expectancy of at least 3 months; adequate haematologic parameters (absolute neutrophil count ≥1.5 x 109/l and platelets ≥100 x 109/l); creatinine and total bilirubin ≤1.25 times the upper limit of normal; aspartate and alanine aminotransferase ≤3.0 times the upper limit of normal; absence of active infection or malnutrition (loss of >20% of body weight); and absence of a second primary tumour other than non-melanoma skin cancer or in situ cervical carcinoma. Patients treated with palliative radiotherapy had to have measurable metastatic disease outside the irradiation fields. Patients with severe cardiac dysfunction, liver metastases involving >50% of the liver parenchyma, chronic diarrhoea, peripheral neuropathy grade >1 or previous irradiation affecting >30% of the active bone marrow were excluded. The study was approved by the ethics and scientific committees of participating centres. All patients gave written informed consent before participation in the study.

Treatment plan
L-OHP (Eloxatin; Sanofi-Synthelabo; Bedford, OH, USA) 85 mg/m2 was administered as a 2-h i.v. infusion on day 1, followed on the same day by the administration of CPT-11 (Campto; Aventis Pharma, Bridgewater, NJ, USA) 200 mg/m2 as a 30-min i.v. infusion. CPT-11 was administered according to guidelines for CPT-11 monotherapy, including recommendations for using atropine and loperamide. Routine anti-emetic prophylaxis with a 5-hydroxytryptamine-3-receptor antagonist was used on days 1–3. Treatment was administered every 3 weeks until disease progression or unacceptable toxicity, or until the patient declined further treatment. No prophylactic growth factor support was allowed.

Dose modifications
Patients were assessed for toxicity before each cycle using the National Cancer Institute Common Toxicity Criteria [24Go]. Peripheral sensitive neuropathy was graded according to the L-OHP-specific scale, modified from Caussanel et al. [25Go]: grade 1, paresthesias/dysethesias of short duration with complete recovery before the next cycle; grade 2, paresthesias/dysethesias persisting between two cycles without functional impairment; grade 3, paresthesias/dysethesias with functional impairment. Chemotherapy was delayed until neutrophils were recovered (≥1.5 x 109/l) or platelets reached ≥100 x 109/l, or until resolution of any significant non-haematologic toxicity. Doses of all drugs were reduced by 15% in subsequent cycles in case of grade 4 neutropenia or grade 3–4 thrombocytopenia lasting for >3 days, or in case of febrile neutropenia, which was treated with granulocyte-colony stimulating factor (G-CSF) (Granocyte; Aventis Pharma) 150 µg/m2/day s.c. and i.v. broad-spectrum antibiotics. Doses of CPT-11 were reduced by 15% in subsequent cycles in case of grade 3–4 diarrhoea. The doses of both drugs were reduced by 15% in subsequent cycles in case of grade 3–4 mucositis. L-OHP dose was reduced by 15% in cases of temporary (7–14 days), painful paresthesia. In cases of persistent (≥14 days) painful paresthesia or functional impairment, L-OHP was omitted in subsequent cycles until recovery.

Patient evaluation
Pre-treatment evaluation included a detailed medical history and physical examination, complete blood cell count (CBC) with differential and platelet count, blood chemistry, serum levels of carcinoembryonic antigen, and computed tomography (CT) scans of the chest and abdomen. Pre-treatment evaluation had to be performed within 2 weeks before study entry. During treatment, a CBC with differential and platelet count was performed weekly, and in cases of grade 3–4 neutropenia or thrombocytopenia or febrile neutropenia it was performed daily until haematologic recovery. In addition, patients were clinically assessed and blood chemistry was performed before each treatment cycle. Response to treatment was evaluated every three chemotherapy cycles, or sooner if clinically indicated.

WHO criteria were used to assess tumour response [26Go]. Complete response was defined as the complete disappearance of all clinically assessable disease for at least 4 weeks, and partial response (PR) was defined as a decrease of at least 50% of the sum of the products of the diameters of measurable lesions for at least 4 weeks. CT scans were repeated 4 weeks later to confirm the response. An external panel of radiologists reviewed all CT scans. Stable disease (SD) was defined as a decrease of <50% or an increase of <25% in measurable lesions, and progressive disease (PD) was defined as an increase of at least 25% in measurable lesions or the appearance of new malignant lesion(s).

Patients' quality of life was assessed at baseline and every 9 weeks, at the same time as response assessment during the study using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 self-administered questionnaire. The Global Health Status/QoL scale was selected as the primary end point [27Go]. Tumour-related symptoms were assessed at baseline and before each cycle.

Statistical considerations
The primary end point of the study was tumoural response rate. The study followed the optimal Simon two-step design. If a minimum objective response rate >40% was observed in the first 15 patients, an additional 15 patients should be enrolled, and if >12 responses were observed in 30 patients (40%), the regimen was considered sufficiently active to be submitted for further evaluation. The duration of response was measured from the first documentation of response to disease progression. Time to tumour progression (TTP) was determined as the interval between the initiation of treatment and the date when disease progression was first documented or date of death from any cause. Overall survival (OS) was measured from the date of treatment initiation to the date of death. Follow-up time was measured from the day of first treatment administration to the study's cut-off date (for living patients). TTP and OS were estimated by the Kaplan–Meier method [28Go], and the confidence intervals for response rates were calculated using methods for exact binomial confidence intervals [29Go].


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
From February 2000 to November 2002, 32 patients with locally advanced or metastatic gastric cancer, fulfilling the inclusion criteria, from six participating centres were enrolled. Median age was 62.5 years (range 38–82). Twenty-nine (80.6%) patients had PS 0–1, and the median number of involved sites was two per patient (Table 1). Thirteen patients (40.6%) had initially undergone a curative operation. Three patients (9.4%) had received previous 5-FU-based adjuvant chemotherapy. None of the patients had previously been treated with either CPT-11 or L-OHP. None of the patients had received adjuvant radiotherapy and only one was treated with palliative radiotherapy for a bone metastasis before study entry. The median time elapsed between first diagnosis of metastasis and study entry was 1 month (range 0–3), while the median time between initial disease diagnosis and the first metastasis was 12.5 months (range 0–21). All patients were evaluable for toxicity and 31 were evaluable for response. One patient was not evaluable for response due to the absence of a bidimensionally measurable lesion, and in the intention-to-treat analysis he was considered a progressor.


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Table 1. Patient characteristics [no. of patients (%), except where otherwise stated]

 
Treatment efficacy
In an intention-to-treat analysis, a documented complete response was observed in one (3.1%) patient and PR in 15 (46.9%) patients, for an overall response rate of 50% [95% confidence interval (CI) 38.7–72.4%]. In addition, eight (25%) patients had SD and eight (25%) had PD. The site-specific response rates were 57% for lymph nodes, 65% for liver metastases, 75% for lung metastases and 40% for local disease. No difference in the RR was recorded according to tumour location [cardia: four of nine (46.5%) patients; gastric: 12 of 23 (52%) patients] or tumour status [locally advanced: four of six (66%); metastatic: 12 of 26 (46%)]. None of the patients with locally advanced disease was secondarily operated. The median time to initial documentation of response was 3 months. The median duration of response was 5 months (95% CI 2.7–7.3 months; range 2–12.5) and the median TTP was 5.5 months (95% CI 2.9–7.6 months; range 2–28). After a median follow-up period of 16 months (range 2–29.5), 23 patients had died; the overall median survival time was 8.5 months (95% CI 5.7–11.1 months; range 2–30) (Figure 1).



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Figure 1. Kaplan–Meier survival curve for the 32 patients receiving the CPT-11/L-OHP combination.

 
Treatment toxicity
Diarrhoea and neutropenia were the most common adverse events of the CPT-11/L-OHP combination (Table 2). Grade 3 and 4 neutropenia were observed in five (15.6%) and one (3.1%) patients, respectively; two (6.3%) developed febrile neutropenia requiring hospitalisation and treatment with intravenous antibiotics and G-CSF support. Both patients recovered uneventfully. Grade 3 anaemia occurred in one (3.1%) patient. Thrombocytopenia did not exceed grade 1. Grade 3 diarrhoea developed in two (6.2%) patients, with grade 3 fatigue developing in two (6.2%). Grade 2 nausea/vomiting was observed in seven (21.9%) patients and reached grade 3 in three (9.4%). Neurosensory toxicity was observed in five (15.6%) patients and did not exceed grade 1. Three (9.4%) patients developed infection without concomitant neutropenia, but only one (3%) of them required hospitalisation and treatment with intravenous antibiotics. Grade 1 and 2 acute cholinergic syndrome was reported in three (9.4%) patients each. Grade 2 alopecia presented in only three (9.4%) patients. Other grade 3 or 4 toxicities were infrequent. Three treatment-related admissions to the hospital were reported. There were no treatment-related deaths.


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Table 2. Worst toxicity grade by patient during all cycles of treatment with the CPT-11/L-OHP combination

 
Compliance with the treatment
At the time of this analysis, 30 (93.8%) patients had discontinued treatment because of progressive disease [n=27 (88.4%)] and patient withdrawal [n=3 (10.6%)]. One hundred and sixty-two courses of chemotherapy had been administered (median of five courses per patient; range 2–14). Thirty (18.5%) courses were delayed for a median of 4 days (range 1–6) because of haematologic [n=4 (2.5%)] or non-haematologic [n=1 (0.6%)] toxicity; 25 (15.4%) courses were delayed because of reasons unrelated to disease or treatment (i.e. pending imaging studies for response evaluation or patients' request). The median interval between cycles was 21 days (range 21–27). Dose reduction was required in five (3.1%) cycles because of haematologic [n=2 (1.2%)] and non-haematologic toxicity [n=3 (1.9%)]. G-CSF was administered in eight (4.9%) cycles for the treatment of severe or febrile neutropenia. The delivered relative dose intensity was 92.5% and 95% of the protocol planned doses for L-OHP and CPT-11, respectively.

Quality of life and relief of symptoms
One hundred and thirty-one questionnaires were completed by 32 patients. The rate of form return was 88%. The Global Health Status/QoL mean scale score remained unchanged, with a slight improvement during the treatment (Figure 2). Twenty-eight (52%) patients had at least one disease-related symptom at baseline (Table 3). Twenty patients complained of abdominal pain. Pain relief (as assessed by the use of decreasing doses or discontinuation of analgesics) was observed in 16 (85%) patients; a PR was achieved in 11 and SD in five of these patients. In one patient with gastrointestinal bleeding and in five with fever, complete resolution of their symptoms was observed after two or three cycles of chemotherapy; a PR was documented in all patients.



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Figure 2. Variation of the Global Health Status mean scale score during treatment with the CPT-11/L-OHP combination.

 

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Table 3. Symptom relief during treatment

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
At the time of diagnosis, the majority of patients with gastric cancer have inoperable locally advanced or metastatic disease, and therefore an effective treatment is needed for this poor prognosis population. In this multicentre phase II trial we report an overall response rate of 50%, which is in the same range as those reported in phase II trials using FAMTX, ELF, EAP or ECF, and recently in studies using taxane–irinotecan or oxaliplatin-based regimens [30Go–36Go]. In addition, the observed TTP and OS of 5.5 and 8.5 months, respectively, are comparable to those reported in the aforementioned trials. Moreover, a clear clinical benefit could be observed during treatment with CPT-11/L-OHP, as expressed by the relief of tumour-related symptoms in the majority of the patients. It is noteworthy that these results were obtained with minimal toxicity, which supports the use of this regimen as a palliative treatment in patients with locally advanced or metastatic gastric cancer. The observed grade 3 or 4 neutropenia was found in 15.6% and 3.1% of cases, respectively, with only two (6.2%) cases of febrile neutropenia; moreover, severe diarrhoea nausea/vomiting and fatigue were reported in <10% of patients, while other toxicities were infrequent. The absence of toxic deaths in this study due to haematologic toxicity reflects the low incidence of febrile neutropenia, which is a common cause of morbidity and mortality in anthracycline-containing regimens. In addition, the incidence of grade 3 or 4 thrombocytopenia, diarrhoea and stomatitis was less frequent than that observed with other regimens. Severe nausea/vomiting occurred as frequently (9.4% of patients) as with other platinum-based regimens (ECF and FUP). Finally, grade 2 alopecia (9.4%) was less frequent than as observed with other anthracycline- or etoposide-based regimens (ECF, FAMTX and ELF).

Treatment compliance was excellent, with median relative dose intensities of 92.5% and 95% for L-OHP and CPT-11, respectively. This is further supported by the observation that: (i) only five out of 162 chemotherapy cycles were delayed because of haematological and non-haematological toxicity; (ii) dose reductions were required in only 3.1% of the chemotherapy cycles; and (iii) a median of five (range 2–14) chemotherapy cycles could be delivered without problem in our patients.

In conclusion, this phase II study demonstrates that the combination of CPT-11/L-OHP is an active regimen, in terms of response rate, with a favourable toxicity profile. This combination is attractive as a front-line treatment in patients with advanced or metastatic gastric cancer, and merits further investigation in comparative trials.


    Acknowledgements
 
This work was supported in part by a grant from the Cretan Association for Biomedical Research (CABR). J.S. and N.V. were recipients of a CABR clinical fellowship.

Received for publication December 22, 2003. Revision received March 31, 2004. Accepted for publication April 6, 2004.


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 Patients and methods
 Results
 Discussion
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