A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer

N. C. Tebbutt1, A. Norman1, D. Cunningham1,+, T. Iveson2, M. Seymour3, T. Hickish4, P. Harper5, N. Maisey1, K. Mochlinski1, Y. Prior1 and M. Hill1,6

1 Royal Marsden Hospital, London and Surrey; 2 Southampton Hospital, Southampton; 3 Cookridge Hospital, Leeds; 4 Royal Bournemouth and Poole Hospitals, Dorset; 5 Guy’s Hospital, London; 6 Maidstone Hospital, Kent, UK

Received 3 January 2002; revised 3 April 2002; accepted 25 April 2002


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

This randomised study compared protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin C (MMC) in patients with advanced oesophago-gastric cancer.

Patients and methods:

Two hundred and fifty-four patients with adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma involving the oesophagus, oesophago-gastric junction or the stomach were randomised. The major end points were tumour response, survival, toxicity and quality of life.

Results:

The median age of patients treated was 72 years and the two arms were well-balanced for baseline demographic factors. The overall response rate was 16.1% [95% confidence interval (CI) 9.5% to 22.7%] in patients treated with PVI 5-FU alone compared with 19.1% (95% CI 12.0% to 26.0%) for those treated with PVI 5-FU plus MMC (P = 0.555). Median time to treatment failure was 3.9 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P = 0.195). Median survival was 6.3 months for PVI 5-FU and 5.3 months for PVI 5-FU plus MMC (P = 1.0).Toxicity was mild for both treatments. Symptomatic benefit measured by improvement in pain control, weight loss, dysphagia and oesophageal reflux was observed in over 64% of patients in each arm. Quality of life scores were comparable in each arm.

Conclusions:

PVI 5-FU is a safe, effective form of palliation for patients with advanced oesophago-gastric cancer although the addition of MMC adds little extra benefit.

Key words: 5-fluorouracil, mitomycin C, oesophago-gastric cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Randomised studies have shown that chemotherapy achieves palliation of symptoms, improves quality of life and prolongs survival compared with best supportive care in patients with advanced upper gastrointestinal neoplasms [1]. Phase II studies have demonstrated single-agent activity for a variety of chemotherapy drugs including fluorouracil (5-FU), mitomycin C (MMC), anthracyclines and cisplatin [2, 3]. Combination chemotherapy regimens comprising agents with the highest activity have been formulated in an effort to improve the results of treatment of advanced oesophago-gastric cancer. A recent randomised trial has shown that three commonly used combination regimens; 5-FU/Adriamycin/methotrexate (FAMTX), 5-FU/cisplatin (FP) and etoposide/leucovorin/ 5-FU (ELF) are equivalent [4]. In contrast, the regimen of epirubicin/cisplatin/5-FU infusion (ECF) has been demonstrated to be superior to FAMTX in terms of tumour response and survival [5]. Consequently, the ECF regimen is widely, although not universally, regarded as the standard regimen for this disease.

However, many patients with oesophago-gastric cancer are elderly with approximately 60% of patients aged over 70 years [6]. Other co-morbidities, which may affect all age groups, but whose incidence increases with age, may render surgery or chemotherapy difficult for many patients presenting with this disease [7]. Thus, co-existing cardiac, renal or neurological impairment may mean that it is not feasible to treat a proportion of patients using a combination regimen containing an anthracycline drug or cisplatin. Optimal palliative chemotherapy for elderly and medically unfit patients with advanced oesophago-gastric cancer has not been defined.

5-FU as a single agent has demonstrated significant activity with response rates for bolus schedules of 20% in various phase II studies [2]. Its toxicity profile is modest in comparison with epirubicin and cisplatin and it can be tolerated by less-fit patients. The delivery of 5-FU by protracted venous infusion (PVI) results in an altered toxicity profile compared with bolus schedules of 5-FU, with the dose-limiting toxicities being diarrhoea and hand–foot syndrome, but with minimal haematological toxicity [8]. PVI 5-FU has been shown to achieve superior response rates with a small but significant improvement in overall survival in comparison with bolus biochemically modulated 5-FU in advanced colorectal cancer [8]. Similarly, various phase II studies have reported impressive response rates for infusion schedules of 5-FU in advanced oesophago-gastric cancer ranging from 31 to 43.5% [9, 10]. The observation that responses to infused 5-FU may occur despite progression after bolus schedules of 5-FU suggests that the infused schedule of administration may also be superior in oesophago-gastric cancer [11]. MMC as a single agent has achieved response rates of 30% in oesophago-gastric cancer and it is also associated with a mild, predominantly haematological toxicity profile, which is therefore non-overlapping with PVI 5-FU [2]. In human colon cancer cell lines, the combination of 5-FU and MMC was synergistic [12]. It was therefore postulated that PVI 5-FU would be an effective and well-tolerated palliative treatment for patients with advanced oesophago-gastric cancer and that the addition of MMC could improve efficacy without a significant increase in toxicity. It was considered that one of these regimens would provide optimal therapy for elderly or unfit patients who could not be treated using more intensive combination chemotherapy regimens. This study was performed in order to compare the results after treatment using PVI 5-FU or PVI 5-FU plus MMC.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient eligibility
Patients were required to have histologically confirmed adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma of the oesophagus, oesophago-gastric junction or stomach that was inoperable because of locally advanced or metastatic disease or because of concurrent medical disorders. They had to have adequate bone marrow function (platelets >100 x 109/l, white blood count >3 x 109/l, neutrophils >1.5 x 109/l), renal function (serum creatinine <132 µmol/l, urea <10.7 mmol/l) and hepatic function (bilirubin <30 µmol/l). Patients had to be of good performance status (PS) [Eastern Cooperative Oncology Group (ECOG) PS 0–2], life expectancy >3 months and no intercurrent uncontrolled medical illnesses. They were excluded if there were intra-cerebral metastases, history of other malignancy (apart from adequately treated non-melanotic skin cancer or carcinoma in situ of the uterine cervix), uncontrolled angina pectoris or clinically significant cardiac dysrhythmias, pregnancy or any psychological condition precluding informed consent. Before randomisation written informed consent was obtained from all patients. The study was approved by the Local Research and Ethics Committee at each of the five participating centres.

Randomisation
Details of all eligible patients were forwarded to the Data Manager's office based at the Royal Marsden Hospital, Sutton. Eligibility criteria were verified and patients were randomly assigned to treatment with PVI 5-FU or PVI 5-FU plus MMC on a 1:1 basis according to a computer-generated randomisation code. The patients were randomised centrally in blocks of six and stratified by centre. No further stratification was performed.

Pretreatment evaluation, assessment during treatment and follow-up
Baseline evaluation included a complete medical history and physical examination, full blood count, serum biochemistry including electrolytes, liver and renal function tests, ECG and computed tomographic (CT) scans of chest, abdomen and pelvis. Histological samples were reviewed by the local histopathologists.

During the study patients were monitored every 3 weeks with medical history, physical evaluation, full blood count and serum chemistry. In addition, CT scans were performed every 12 weeks.

Intravenous access
On the first day of treatment all patients were admitted to hospital for insertion of a double lumen central venous catheter under local anaesthesia with antibiotic cover. Warfarin (1 mg/day orally) was commenced and administered throughout the treatment to prevent catheter thrombosis. If superficial infection of the indwelling catheter occurred, flucloxacillin was administered pending bacteriology results. Catheters were removed in the following situations: septicaemia due to catheter infection, catheter infection worsening in spite of appropriate antibiotic treatment, catheter thrombosis, intolerable shoulder pain and slippage/incorrect placement of the catheter. The catheter was removed under local anaesthesia at the end of treatment.

Chemotherapy
PVI 5-FU was commenced at a dose of 300 mg/m2/day, via an ambulatory pump. Patients randomised to receive MMC started this treatment on the same day at a dose of 10 mg/m2 intravenous bolus every 6 weeks for four courses. Subsequent to two patients developing haemolytic uraemic syndrome (HUS) in a study of similar design at this institution, the dose of MMC was reduced to a cumulative dose of 28 mg/m2 following Ethics Committee approval (7 mg/m2 per course for four courses). Numbers of patients randomised pre- and post-dose modification were 12 and 117, respectively. Patients in both groups continued on therapy for 12 weeks and were then re-assessed. If there was no progression of disease, therapy continued for a further 12 weeks.

Evaluation of response
Tumour response was assessed by CT scan with response classified according to WHO criteria [13]. ECOG PS and the presence of symptoms of pain, dysphagia, reflux, anorexia, lethargy, diarrhoea, weight loss, nausea, vomiting and dyspnoea were assessed using a checklist before chemotherapy, 6-weekly during chemotherapy and 3-monthly thereafter until death or disease progression. Symptom response was defined as the disappearance of that particular symptom for a minimum of 6 weeks. In the case of weight loss, symptom response was defined as weight stabilisation or weight gain.

Toxicity evaluation and dose modification
Toxicity was evaluated on a weekly basis and graded according to the National Cancer Institute common toxicity criteria [14]. Non-haematological toxicities of grade 1 were treated as follows: diarrhoea—codeine phosphate 30–60 mg p.o. q.d.s., stomatitis—sucralfate mouthwash, and palmar–plantar erythema—pyridoxine 50 mg p.o. t.d.s. If symptoms were grade 2 or greater at onset 5-FU therapy was suspended until the toxicity had resolved and dose alterations were instituted as follows: grade 2 stomatitis, diarrhoea or palmar–plantar syndrome 50 mg/m2 dose reduction; grade 3 stomatitis, diarrhoea or palmar–plantar syndrome, 100 mg/m2 dose reduction; grade 4 stomatitis, diarrhoea or palmar–plantar syndrome, 150 mg/m2 dose reduction.

MMC was delayed for 1 week if white blood count was <3 x 109/l or platelet count <100 x 109/l. Haematological toxicities were managed by reducing MMC doses as follows; grade 3 infection with neutropenia 25% dose reduction; grade 4 infection with neutropenia 50% dose reduction. MMC was stopped if there was evidence of HUS or red blood cell fragmentation on peripheral blood film.

Quality of life
Patients were requested to complete European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaires before randomisation and every 12 weeks thereafter. This 30-item checklist includes five functional scales (physical, role, cognitive, emotional, social), three symptom scales (fatigue, pain, nausea and vomiting), specific items assessing additional symptoms (dyspnoea, appetite loss, sleep disturbance, constipation, diarrhoea), global health and quality of life scales and perceived financial impact of disease and/or treatment. Ratings were made by the patient using standard instructions. The reliability and validity of this measure has been previously reported [15, 16]. Scoring of the questionnaire was performed according to the guidelines specified by the EORTC with conversion of all scores to a 0–100 scale using the recommended algorithm. Scores were interpreted such that increased functional status and decreased symptom status indicates a benefit to patients.

Statistical methods
This study constitutes part of a stratified study designed to investigate the efficacy of PVI 5-FU plus MMC compared with PVI 5-FU alone in advanced gastrointestinal cancer. The original design was stratified based on the site of the primary tumour. Stratification 1 involved patients with oesophago-gastric and colorectal cancer [17] and stratification 2 involved patients with pancreatic cancer [18] and adenocarcinoma of unknown primary. The original design required 340 patients in the oesophago-gastric and colorectal arms in order to detect a difference in response rate of 15% (with 80% power, {alpha} = 5%, two-sided test). After 200 patients had been recruited a preplanned interim analysis was performed. As recruitment of patients with colorectal cancer was occurring more rapidly than those with other tumour types, it was decided to increase the number of patients in each stratification. This was done in order to increase the overall power and also to allow the colorectal and oesophago-gastric arms to be analysed as stand-alone studies. In order to detect the same difference in response rate, 454 randomised patients with oesophago-gastric cancer and colorectal cancer were required (with 90% power, {alpha} = 5%, two-sided test). Two hundred patients were recruited in the colorectal arm and this study has been reported previously [17]. Therefore 254 patients were required in the oesophago-gastric stratification to achieve the required power overall. Within the oesophago-gastric arm, this allowed a detection of a 20% difference in response rate (89% power, {alpha} = 5%, two-sided test).

Statistical analysis was performed using the statistical package SPSS for Windows version 10.1. Categorical data were examined using the chi-square test with Fisher's exact test used where appropriate. Survival and time to events were calculated using the Kaplan–Meier method [19] and were measured from the date of commencement of chemotherapy for all patients. The log-rank test was used to test differences between groups [20]. Analysis of survival and failure-free survival (FFS) was performed using all randomised patients on an intention-to-treat basis. Response was calculated only for eligible patients with measurable disease and then analysed by intention-to-treat. Multivariate Cox regression analysis stratified by treatment centre was used to identify prognostic groups that influenced disease-free survival and overall survival [21]. Multivariate logistic regression was similarly used to determine factors predictive of response. Factors included in these analyses were treatment arm, age, sex, site of tumour, the presence of locally advanced or metastatic disease and PS as well as the biochemical factors serum albumin and alkaline phosphatase. P <0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Two hundred and fifty-four patients were randomised between July 1994 and February 2001. Four patients were ineligible due to inadequate renal, liver or bone marrow function (three patients) and due to non-oesophago-gastric pathology (one colorectal). Five patients withdrew from treatment after randomisation due to patient choice (two patients) or decline in clinical condition (three patients). The two groups were well matched for pretreatment characteristics (Table 1).


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Table 1.  Baseline patient demographics
 
Delivery of chemotherapy
The median duration of chemotherapy was 13 weeks for both arms (P = 0.192). Dose intensity of 5-FU was 45% of the intended total dose over 24 weeks in the 5-FU alone arm compared with 48% in the 5-FU plus MMC arm (P = 0.142). Treatment interruptions occurred in 56% of patients receiving 5-FU alone compared with 54% of patients receiving 5-FU plus MMC (P = 0.946). For cycles actually delivered, average dose intensity of 5-FU was 81% of the initial starting dose in the 5-FU arm and 80% in the 5-FU plus MMC arm.

Tumour response
Eleven patients were not evaluable for response. In the remaining 239 evaluable patients, there were four complete responses and 38 partial responses [overall response rate 17.6%; 95% confidence interval (CI) 12.8% to 22.4%]. Nineteen of 118 (response rate 16.1%; 95% CI 9.5% to 22.7%) patients treated with PVI 5-FU alone responded compared with 23 of 121 patients (response rate 19.1%; 95% CI 12.0% to 26.0%) treated with PVI 5-FU plus MMC (P = 0.555) (Table 2). There was no difference in response rate between the two arms for patients whose tumours were adenocarcinomas (P = 0.462); however, there were too few patients with squamous cell, adeno-squamous or undifferentiated carcinoma to determine meaningful response rates for these histological subtypes.


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Table 2.  Tumour response to chemotherapy
 
Multivariate logistic regression analysis showed that treatment arm did not predict tumour response (P = 0.45). No other factors, including the extent of disease, predicted tumour response.

Survival
At the time of analysis, 230 patients (90.6%) had died, 116 treated with 5-FU alone and 114 treated with 5-FU plus MMC. With a median follow-up of 8.8 months, FFS was not significantly different for patients receiving 5-FU alone (3.9 months) compared with those receiving 5-FU plus MMC (3.8 months; P = 0.195) (Figure 1). One-year FFS was 11.1% (95% CI 6.2% to 17.6%) for 5-FU alone compared with 15.9% (95% CI 9.9% to 23.1%) for 5-FU plus MMC. Multivariate Cox regression analysis showed that the most significant factors predicting FFS were the presence of metastatic disease [hazard ratio (HR) 1.65; 95% CI 1.21–2.26; P = 0.002] and elevated serum alkaline phosphatase (HR 1.001, 95% CI 1.000–1.001; P<0.001). Treatment arm was not significant in univariate Cox regression analysis (P = 0.19), but was significant in multivariate analysis (HR 1.38; 95% CI 1.02–1.87; P = 0.04).



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Figure 1. Failure-free survival following treatment using protracted venous infusion 5-fluorouracil (PVI 5-FU) alone and PVI 5-FU plus mitomycin C (PVI 5-FU + MMC).

 
Treatment with 5-FU plus MMC resulted in no improvement in overall survival. The median overall survival was 6.3 months and 5.3 months with a 1-year survival of 22.2% (95% CI 15.2% to 30.0%) and 18.4% (95% CI 12.0% to 25.9%) for PVI 5-FU and PVI 5-FU plus MMC, respectively (P = 1.0) (Figure 2).



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Figure 2. Overall survival following treatment using protracted venous infusion 5-fluorouracil (PVI 5-FU) alone and PVI 5-FU plus mitomycin C (PVI 5-FU + MMC).

 
Multivariate Cox regression analysis showed that the most significant factors affecting overall survival were the presence of metastatic disease (HR 1.55; 95% CI 1.10–2.18; P = 0.012) and elevated serum alkaline phosphatase (HR 1.001; 95% CI 1.001–1.002; P <0.001). Treatment arm did not predict survival.

Toxicity
The treatment was well-tolerated and toxicity is presented by category in Table 3. Grade 3 or 4 non-haematological toxicities occurred infrequently in both arms. There was significantly more haematological toxicity (all grades) experienced by patients receiving 5-FU plus MMC: leukopenia (P <0.0001), neutropenia (P = 0.01), thrombocytopenia (P = 0.0003). However, there was no significant difference in grade 3 or 4 haematological toxicity. Eight patients developed red blood cell fragmentation, two in the PVI 5-FU arm and six in the 5-FU plus MMC arm but no patients developed HUS.


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Table 3.  Toxicity after chemotherapy
 
Central venous catheter complications
Hickman line complications occurred in 24.8% of patients overall, with a similar proportion of patients affected in each arm. These complications included superficial infection (10%), venous thrombosis (2.8%), slippage (2.0%), pain (8.0%), blockage (1.2%), septicaemia (0.4%) and pneumothorax (0.4%). Five patients (2.0%) required removal and re-insertion of the Hickman line because of complications.

Symptomatic response
Symptomatic improvement was observed in the majority of patients for a variety of tumour-related symptoms with the exception of lethargy (Table 4). Symptomatic benefit measured by improvement in pain control, weight loss, dysphagia and oesophageal reflux was observed in over 64% of patients in each arm, demonstrating significant palliative benefit for both arms. A smaller proportion of patients achieved an improvement in PS after commencement of chemotherapy.


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Table 4.  Number and percentage of patients who achieved a symptomatic response during treatment
 
Quality of life
There were no differences in global quality of life at commencement of chemotherapy, 12 weeks and 24 weeks. Other functional scales and symptom scales were also comparable at commencement of chemotherapy, 12 weeks and 24 weeks with the exception of fatigue and nausea and vomiting, which showed higher scores in the PVI 5-FU plus MMC arm at baseline.

Second-line therapy
Twenty-three patients received second-line chemotherapy after progression, 14 in the PVI 5-FU arm and nine in the PVI 5-FU plus MMC arm. Of the patients initially treated with PVI 5-FU, 10 subsequently received PVI 5-FU plus MMC. Two patients from the PVI 5-FU plus MMC arm subsequently received PVI 5-FU. No responses were observed with either second-line regimen.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This prospective, randomised trial has evaluated the efficacy and toxicity of PVI 5-FU with or without MMC in advanced oesophago-gastric cancer. This trial is the only randomised study to evaluate PVI 5-FU in oesophago-gastric cancer. Superior outcomes using infused schedules compared with bolus schedules of 5-FU have been suggested by various phase II studies, although this has not been the universal experience [9, 10, 22]. On this basis, a number of combination regimens incorporate PVI 5-FU, including ECF [5]. The present study demonstrated that PVI 5-FU as a single agent achieved a response rate of 16.1% with a median overall survival time of 6.3 months. It also achieved excellent palliation of symptoms in the majority of patients and was associated with a modest toxicity profile.

It is important to note that these results were achieved in a cohort of patients with a median age of 72 years. All the centres participating in this study used ECF combination chemotherapy as their standard therapy, and patients were selected for this trial based on assessment of their level of fitness. Comparison of patient demographics in this study with patients selected for treatment using more intensive combination chemotherapy by the same participating centres is shown in Table 5. Patients selected for treatment using more intensive combination chemotherapy were younger and had better PS, but a similar proportion of patients had metastatic disease. Comparison with other phase III studies of combination chemotherapy shows that patients selected for these trials typically had a median age under 60 years [4, 5, 23]. The age range of patients treated in most trials therefore does not reflect the age range of patients in the community with oesophago-gastric cancer, where approximately 60% of patients are aged over 70 years [6]. As a result, it is frequently difficult to apply the results of many clinical trials in oesophago-gastric cancer, involving highly selected younger patients, to actual clinical practice where elderly patients with co-morbid illnesses are frequently encountered. The results of this study, involving older and less-fit patients, are therefore more likely to be applicable to general clinical practice.


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Table 5.  Comparison of patient demographics for patients treated using intensive combination chemotherapy regimens
 
The results achieved using PVI 5-FU alone in this trial are inferior to those achieved in a younger population using ECF, which achieved a response rate of 46% with an overall survival time of 8.7 months [5]. However, they compare favourably with other combination regimens used in younger patients with advanced oesophago-gastric cancer such as FAMTX, FP and ELF, which achieved response rates of 12, 20 and 9% with median survival times of 6.7, 7.2 and 7.2 months, respectively [4].

The impetus for the addition of MMC stemmed from the activity of this drug as a single agent and the low overall and non-overlapping toxicity of this agent when combined with PVI 5-FU. However, this trial demonstrates that the addition of MMC to PVI 5-FU for patients with inoperable oesophago-gastric cancer has no effect on response rates compared with PVI 5-FU alone. In addition, there was no significant effect on overall survival or quality of life, although there was a small benefit for FFS demonstrated using multivariate analysis.

The failure to demonstrate any major additional benefit from the addition of MMC is in contrast to the results seen in advanced colorectal and pancreatic cancer. In advanced colorectal cancer, the addition of MMC to PVI 5-FU improved objective response rates, quality of life and FFS in comparison with PVI 5-FU [17]. Similarly, in pancreatic cancer the addition of MMC led to improved response rates although without any significant impact on FFS, overall survival or quality of life.

However, in advanced oesophago-gastric cancer, two recent randomised trials have studied MMC in combination therapy. A randomised study has demonstrated superior response rates and survival for FAMTX compared with 5-FU/Adriamycin/MMC [23]. In addition, MMC has been compared with epirubicin in a randomised trial comparing MMC, cisplatin and PVI 5-FU (MCF) with ECF. Despite an increased dose intensity of 5-FU in the MCF arm, there were no significant differences in response rates or overall survival between MCF and ECF. However, global quality of life scores as well as physical and emotional functioning at 3 and 6 months were inferior in the MCF arm [24]. These two trials suggest that combination chemotherapy regimens containing epirubicin or high-dose methotrexate are superior to combinations containing MMC in oesophago-gastric cancer. Despite its activity as a single agent in advanced oesophago-gastric cancer, MMC provides little or no additional benefit when combined with 5-FU-based regimens.

New agents which are currently being evaluated in oesophago-gastric cancer include the taxanes and the topoisomerase I inhibitors. However, these agents are associated with significant toxicity such as myelosuppression or diarrhoea and may not be suitable for use in palliative chemotherapy regimens for patients who are not relatively fit. This study demonstrates that PVI 5-FU is a safe and effective form of palliation of symptoms for patients with oesophago-gastric cancer who are elderly and/or have other co-morbidities. This suggests that PVI 5-FU should be considered as a potential reference regimen for palliative treatment of elderly patients who are considered unfit for intensive combination chemotherapy.


    Footnotes
 
+ Correspondence to: Dr D. Cunningham, GI and Lymphoma Units, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton SM2 5PT, UK. Tel: +44-20-8661-3156; Fax: +44-20-8643-9414; E-mail: dcunn{at}icr.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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