1 Royal Marsden Hospital, London and Sutton, Surrey; 2 MidKent Oncology Centre, Maidstone, Kent, UK
Received 28 July 2003; revised 4 August 2003; accepted 13 August 2003
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ABSTRACT |
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The purpose of this study was to assess the efficacy and toxicity of irinotecan and 5-fluorouracil (5-FU) in primary refractory or relapsed locally advanced or metastatic oesophagogastric (O-G) carcinoma.
Patients and methods:
Patients with documented progression on or within 3 months of chemotherapy were recruited between July 2000 and May 2002. Irinotecan (180 mg/m2) was given with 5-FU (400 mg/m2 bolus) and leucovorin (folinic acid) (125 mg/m2) followed by 5-FU (1200 mg/m2 infusion over 48 h) every 2 weeks. Response confirmed by computed tomography was assessed at 12 and 24 weeks.
Results:
Thirty-eight of 40 registered patients (95%) were assessable. Median follow-up was 9.3 months and median age was 59.0 years. Thirty-three patients (86.8%) had metastatic disease and 37 patients (97.4%) had previously received platinum-based chemotherapy. Overall response rate was 29% (95% confidence interval 15.4% to 45.9%) while an additional 34% had stable disease. Improvement in tumour-related symptoms included dysphagia 78.6%, reflux 60.0%, pain 54.5%, anorexia 64.3% and weight loss 72.7%. Grade 3/4 toxicities were anaemia 13.2%, neutropenia 26.4%, febrile neutropenia 5.2%, stomatitis 2.6%, nausea and vomiting 13.2% and diarrhoea 7.9%. Median failure-free survival was 3.7 months and median overall survival was 6.4 months.
Conclusion:
5-FU/irinotecan is a valuable regimen for second-line treatment in 5-FU/platinum-resistant O-G carcinoma.
Key words: advanced, cancer, gastric, irinotecan, oesophageal, second-line
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Introduction |
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Randomised trials have demonstrated improved survival and quality of life with chemotherapy over best supportive care in patients with advanced O-G carcinoma [24]. In phase III studies exploring different first-line treatments in advanced gastric or O-G cancer, response rates (RRs) have ranged from 12% to 50% with overall survivals (OSs) of 610 months for the 5-fluorouracil (5-FU)/doxorubicin/methotrexate regimen [3, 58] and RRs of 4045% and OS of approximately 9 months with the epirubicin/cisplatin/5-FU regimen [8, 9]. At present there is no standard first-line treatment for advanced O-G carcinoma, although throughout Europe and North America, a 5-FU- and platinum-based regimen is usually employed [1].
Although a large proportion of patients with locally advanced or metastatic O-G carcinoma respond initially to chemotherapy, they ultimately relapse. In addition, a significant proportion of patients have primary refractory disease. For these patients, there are no currently established palliative treatment options. There is, therefore, a need for development of alternative, active drug combinations.
Irinotecan, a novel topoisomerase I inhibitor, has recently been shown to have significant activity in refractory adenocarcinoma arising from the lower gastrointestinal tract [10, 11]. The role of this drug in the management of relapsed colorectal cancer is now established with 1725% of patients achieving objective responses and a further significant proportion of patients achieving disease stabilisation [11]. Irinotecan has also been shown to be active in gastric, oesophageal and other upper gastrointestinal tumours, with objective responses in up to 18% of patients with gastric cancer when the drug is used as a single agent [12, 13].
5-FU is one of the central drugs used in the treatment of gastrointestinal tumours and can be effectively and safely combined with irinotecan [1419]. In patients with metastatic colorectal cancer, the combination of irinotecan and 5-FU was superior to either drug used alone, with an objective RR of 30% in chemotherapy-naive patients for the combination, compared with 19% for irinotecan alone [14]. Based on this finding it is likely that the addition of 5-FU to irinotecan may result in higher activity for tumours arising from the upper gastrointestinal tract. A bolus/infusion (DeGramont) schedule of 5-FU can be safely combined with irinotecan at a dose of 180 mg/m2 given every 2 weeks in patients with colorectal cancer [1517].
This phase II study evaluated the efficacy and safety of 5-FU and irinotecan in patients with advanced O-G cancer who had either progressed on or within 3 months of chemotherapy.
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Patients and methods |
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Patients had to have received at least one previous chemotherapy regimen given at least 4 weeks before inclusion in the study, although no previous exposure to irinotecan was permitted. Patients were required to have adequate bone marrow (platelets >100 x 109/l, white blood cells >3 x 109/l, neutrophils >1.5 x 109/l), renal (serum creatinine <135 µmol/l), and hepatic [in the absence of liver metastases, bilirubin <1.25 upper limit of normal range (ULN), hepatic transaminases <2.5 ULN and prothrombin time <1.25 ULN; in the presence of hepatic metastases, bilirubin <1.5 ULN, hepatic transaminases <5 ULN and prothrombin time <1.5 ULN] function. Patients were Eastern Cooperative Oncology Group performance status of 02, had to have life expectancy of >3 months, to have had no previous malignant disease except for non-melanotic skin cancer or in situ carcinoma of the uterine cervix and to have no concurrent uncontrolled medical illness. Patients were advised to take adequate precautions to prevent pregnancy. Participants gave written informed consent before entering the study, which was approved by Scientific and Research Ethics Committees of the participating institutions.
Baseline investigations included classification of histology as well, moderate or poorly differentiated adenocarcinoma or squamous cell carcinoma, full blood count, clotting screen, urea and electrolytes, creatinine clearance, liver function tests and tumour markers carcinoembryonic antigen and CA19.9. An ECG was carried out along with baseline CT scan of thorax, abdomen and pelvis with bidimensional evaluation of measurable disease.
Chemotherapy
Chemotherapy was administered through a central venous catheter placed in the subclavian vein. Warfarin (1 mg/day orally) was administered, at the investigators discretion, to prevent catheter thrombosis. Irinotecan was administered at 180 mg/m2 over 30 min (followed by a 30-min break) followed by leucovorin (folinic acid) 125 mg/m2 over 15 min and then 5-FU 400 mg/m2 over 34 min intravenously. Then 5-FU 1200 mg/m2 per day was given by continuous intravenous infusion over 2 days. Irinotecan administration was preceded with atropine 0.25 mg subcutaneously to prevent cholinergic syndrome associated with irinotecan. Dexamethasione and a 5-hydroxytryptamine type 3 receptor antagonist were given as antiemetic prophylaxis before commencement of chemotherapy. Loperamide and ciprofloxacin was provided for every patient and they were advised to commence loperamide with the onset of diarrhoea (4 mg after first loose stool then 2 mg every 2 h for at least 12 h, or for 12 h after the last liquid stool). They were advised to commence prophylactic oral ciprofloxacin if the diarrhoea persisted for more than 24 h despite appropriate loperamide therapy. If diarrhoea was accompanied by fever or vomiting or persisted for longer than 48 h, patients were admitted to hospital. Chemotherapy was repeated every 2 weeks up to a maximum of 12 cycles, or 24 weeks.
Evaluation of toxicity and dose adjustments
Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (CTC) [20]. Patients developing CTC grade 3/4 mucositis or grade 3/4 palmarplantar erythema stopped treatment until resolution of toxicity and resumed with a 20% dose reduction of bolus and infused 5-FU. This dose modification was made if grade 2 mucositis recurred with repeated cycles of chemotherapy. The irinotecan dose remained the same. Patients developing CTC grade 3/4 diarrhoea or lethargy, grade 3/4 febrile neutropenia and grade 4 neutropenia or thrombocytopenia stopped treatment until resolution of toxicity and resumed treatment with a dose reduction of irinotecan from 180 to 150 mg/m2 and a 20% dose reduction of bolus and infusional 5-FU. This dose modification was also made if grade 2 toxicities recurred with repeated cycles of chemotherapy. If severe toxicities recurred despite dose modifications then irinotecan was reduced from 150 to 130 mg/m2 with 5-FU remaining the same.
Treatment with a further chemotherapy cycle at day 14 occurred if the absolute neutrophil count was >1.5 x 109/l, platelets >100 x 109/l and diarrhoea had resolved. Otherwise treatment was delayed for 7 or 14 days until haematological and enteric recovery had taken place. If any treatment course was delayed for more than 21 days the patient was withdrawn from the study.
Evaluation of response
Tumour response was measured by CT scan according to the revised World Health Organisation criteria, Response Evaluation Criteria in Solid Tumors, developed by response evaluation criteria in solid tumour groups after six and 12 cycles of chemotherapy [21]. Target lesions were documented at baseline and included all measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs. Target lesions were selected based on their size (those with the longest diameter) and their suitability for accurate repeated measurements. Complete response (CR) was resolution of all measurable/evaluable disease, partial response (PR) at least a 30% decrease in the sum of the longest diameter of target lesions and PD at least a 20% increase in the sum of the longest diameter of target lesions or the appearance of one or more new lesions. Stable disease (SD) was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. All other lesions or sites of disease were identified as non-target lesions and were recorded at baseline but measurements of these lesions was not required. The presence or absence of each lesion was noted throughout follow-up. The unequivocal progression of existing non-target lesions qualified as a definition of PD. CT scans were reviewed by a single experienced radiologist.
Symptom response was recorded before each cycle of chemotherapy and a symptomatic response was defined as the resolution of that particular symptom for a minimum of 3 weeks. Response of body weight was defined as maintenance or an increase in the pretreatment weight.
Statistical methods
This phase II trial was carried out as two parallel trials with patients entered according to site of disease (O-G or pancreas). We report here the results of patients with O-G cancer. It was conducted according to a standard Gehan design, aiming to detect a 20% RR with 95% power in each disease group. The sample size was calculated using a two-stage design. Fourteen patients from each disease site were initially entered into the study as a first step; following this an interim analysis was carried out. As there were more than three responding patients, an additional 11 patients were enrolled. After a total of 25 patients, Ethics Committee approval was sought for an additional 15 patients to a total of 40 patients.
Primary end point was RR. Secondary end points were OS, failure-free survival (FFS), symptom response and toxicity. Intention-to-treat analyses were carried out on eligible patients. Survival analysis from the date of starting chemotherapy to death from any cause and FFS (time to progression or death) were carried out using the KaplanMeier method. Differences between groups were examined using the log-rank test.
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Results |
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Patient demographics are shown in Table 1. Median age was 59.0 years (range 3773 years) and the majority of patients were male (89.5%). The majority of patients had oesophageal or OGJ carcinomas (63%) and the histology was predominantly adenocarcinoma (92%); 87% of patients had metastatic disease at study entry. Twenty patients (52.6%) had primary refractory disease while 17 patients (44.7%) had progressed within 3 months of completing their previous chemotherapy, before study entry (Table 2). One patient was enrolled on the study before the protocol amendment in August 2000; he had progressed 7 months after receiving chemotherapy for positive resection margins. Thirty-seven patients (97.4%) had previously received a platinum agent.
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Of the 11 patients who demonstrated an objective response, five (45.5%) had had primary refractory disease. One patient had progressed on raltitrexed on entry to the study, having received epirubicin/carboplatin/5-FU before raltitrexed, while four patients had received platinum-based chemotherapy just before study entry.
Survival
All 38 patients were included in the survival data, which were analysed on an intention-to-treat basis. Median FFS and OS for patients with primary refractory disease compared with those who had progressed within 3 months of treatment were not significantly different (2.8 versus 5.1 months, P = 0.795 and 4.0 versus 6.8 months, P = 0.694). For all patients, median FFS was 3.7 months (95% CI 2.35.1 months) and median OS was 6.4 months (95% CI 3.29.6 months). One-year FFS was 8.2% (95% CI 1.8% to 1.1%) and OS was 16.3% (95% CI 5.7% to 31.6%).
Symptom response
Symptom RRs were high with an improvement seen in patients with dysphagia (78.6%), reflux (60.0%), pain (54.5%), anorexia (64.3%), nausea (66.6%) and vomiting (100%); 73% of symptomatic patients stabilised or gained weight. Lethargy, however, was improved in only 23.3% of patients.
Dose intensity and toxicity
The median number of courses of treatment received was 5.5 (range 119). Two patients received 18 and 19 courses as a result of a continuing response, associated with improvement in symptoms. Percentage of intended dose administered was 88.4% of 5-FU, 95.3% of folinic acid and 89.2% of irinotecan.
Treatment was well-tolerated with no toxic deaths (Table 3). Six patients (15.8%) had grade 3 lethargy while five patients (13.2%) had grade 3 nausea. Two patients (5.2%) had grade 3 and 4 febrile neutropenia and six patients (15.8%) had grade 3/4 fever or infection. Grade 3/4 haematological toxicities were anaemia [n = 5 (13.2%)] and neutropenia [n = 10 (26.4%)]. Grade 4 toxicities seen were febrile neutropenia [n = 1 (2.6%)] and neutropenia [n = 4 (10.5%)]. The 10 patients (26.4%) who had grade 1/2 peripheral neuropathy documented had received cisplatin or oxaliplatin before study entry.
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Discussion |
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Phase II studies evaluating irinotecan with 5-FU/leucovorin in chemotherapy-naive patients in upper O-G malignancy have demonstrated RRs of 2242% with OSs of approximately 6 months [2224]. Grade 3/4 neutropenia was 2536%, although one study employing a weekly schedule of irinotecan and 5-FU observed three (7.7%) toxic deaths [22]. Other phase II studies have employed the combination of irinotecan and cisplatin; RRs have ranged from 28% to 59% in chemotherapy-naive patients with corresponding OSs of 6.314.6 months [2427]. Grade 3/4 neutropenia was seen in 2780% of patients with the incidence of febrile neutropenia being 711%, although one group did not observe any febrile neutropenia, probably as a result of administering granulocyte colony-stimulating factor [25].
Newer agents, such as the taxanes, have been investigated as first-line treatment in advanced O-G carcinoma within the context of phase II studies. Phase II studies with paclitaxel or docetaxel in combination with cisplatin with or without 5-FU have demonstrated RRs of 3751% and OSs of 914 months in chemotherapy-naive patients [2830]. Grade 3 and 4 neutropenia ranged from 15% to 70% in these studies, although no febrile neutropenia was observed.
This phase II study indicates that patients derive benefit from second-line treatment in O-G cancer, with symptom benefit in the majority of patients. In addition, it indicates that 5-FU and irinotecan may be an important regimen in this setting; it is active in platinum-resistant disease, is well-tolerated and demonstrates encouraging RR, FFS and OS. Although a 20% RR was not ruled out, the threshold usually employed for chemotherapy-naive patients, an RR of <15% was excluded. Furthermore, an alternative to bolus/infusional 5-FU may be a continuous oral fluoropyrimidine, such as capecitabine, in combination with irinotecan.
We have demonstrated that second-line chemotherapy with irinotecan and 5-FU in primary refractory and resistant O-G carcinoma is a worthwhile approach and warrants further investigation, possibly within the context of a phase III trial against best supportive care to assess potential improvement in quality of life, FFS and OS.
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Acknowledgements |
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FOOTNOTES |
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