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
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Abstract |
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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 01 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 38.772.4%)]. 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 34 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
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Introduction |
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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 [3]. 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 [4
6
], FAMTX is more effective than EAP [7
], FAMTX is more effective than cisplatin/5-FU or ELF [8
], and ECF is more effective than FAMTX [9
]. 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 [10]. 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] [11
] and pre-treated (RR = 11.4%23.3%) patients [12
]. The combination of CPT-11 with cisplatin achieved an impressive 59% objective response rate [13
] in a Japanese trial, and a lower one of 25% in a European trial [14
].
Oxaliplatin (L-OHP), a new diaminocyclohexane-platinum analogue, has shown significant activity in advanced colorectal cancer [15]. 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 [16
], 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 [17
]; and (ii) unlike cisplatin, the DNA adducts of L-OHP are not recognised by the DNA mismatch repair enzymes [18
].
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 [1921
]. 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 [22
]. 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 [23
].
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.
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Patients and methods |
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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 13. 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 [24]. Peripheral sensitive neuropathy was graded according to the L-OHP-specific scale, modified from Caussanel et al. [25
]: 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 34 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 34 diarrhoea. The doses of both drugs were reduced by 15% in subsequent cycles in case of grade 34 mucositis. L-OHP dose was reduced by 15% in cases of temporary (714 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 34 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 [26]. 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 [27]. 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 KaplanMeier method [28], and the confidence intervals for response rates were calculated using methods for exact binomial confidence intervals [29
].
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Results |
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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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Discussion |
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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 214) 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.
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Acknowledgements |
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Received for publication December 22, 2003. Revision received March 31, 2004. Accepted for publication April 6, 2004.
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