A multicentre phase II trial of primary chemotherapy with cisplatin and protracted venous infusion 5-fluorouracil followed by chemoradiation in patients with carcinoma of the oesophagus

J. S. Waters1, D. Tait1, D. Cunningham1,+, A. R. Padhani1, M. E. Hill1, S. Falk2, F. Lofts3, A. Norman1, J. Oates1 and A. Hill1

1 Cancer Research Campaign Section of Medicine and Gastrointestinal Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton; 2 Bristol Oncology Centre, Bristol; 3 Department of Medical Oncology, St George’s Hospital, London, UK

Received 17 November 2001; revised 17 April 2002; accepted 13 May 2002


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

We undertook a multicentre phase II trial to evaluate the safety and efficacy of primary chemotherapy followed by chemoradiation for localised adenocarcinoma or squamous carcinoma of the oesophagus.

Patients and methods:

Chemotherapy comprised five 3-weekly cycles of cisplatin and protracted continuous infusion 5-fluorouracil, with conformally planned radiotherapy commencing at the start of the fifth cycle.

Results:

The planned treatment programme was completed by 39 of 72 patients (54%), and a further 13% completed chemotherapy and proceeded to surgical oesophagectomy. Response rates to chemotherapy and to the entire treatment programme were 47% [95% confidence interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved in 54% of patients. The median survival duration was 14.6 months with 1- and 2-year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy-related toxicity occurred in 38% of patients, and there were no treatment-related deaths.

Conclusions:

This is a feasible and active treatment regimen providing palliative benefits for patients with poor-prognosis localised oesophageal cancer.

Key words: chemotherapy, cisplatin, 5-fluorouracil, oesophagus, radiotherapy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Survival rates for patients with localised carcinoma of the oesophagus are currently poor. Outcome following surgical resection is dependent on depth of tumour invasion and nodal status, with 5-year survival rates <5% for patients with either node-positive disease or tumour invading the oesophageal adventitia. Unfortunately, the majority of patients diagnosed with oesophageal carcinoma in the UK fall into these categories. In addition, patients are often elderly, and consequently the mortality rates following surgical oesophagectomy are not insignificant. In a large UK series, the 5-year survival rate for all surgically treated patients with squamous cell carcinoma of the oesophagus was only 4%, and the operative mortality rate was 29% [1]. Figures from the USA for a comparable period are only slightly better, with a 5-year survival rate of 9.6% and a surgical mortality rate of 22% [2]. Recent data suggest better outcomes from surgery, but 3-year survival rates reach only 26%, and case selection may account for at least some of the apparent improvement [3, 4]. A similar 5-year survival rate of 21% has been demonstrated for radical radiotherapy in a group of patients unwilling to undergo surgery or unable to do so because of co-morbid medical conditions [5]. This study highlighted the value of computed tomography (CT)-assisted radiotherapy planning in improving outcome.

Two randomised studies have been conducted to compare chemoradiation with radiotherapy alone for patients with localised oesophageal cancer, both of which demonstrated a survival benefit for the use of chemoradiation. The Radiation Therapy Oncology Group (RTOG) trial included 121 patients with adenocarcinoma or squamous cell carcinoma who were felt to be unsuitable for surgical resection. Radiotherapy (64 Gy) was compared with chemoradiation comprising cisplatin and a 4-day continuous infusion of 5-fluorouracil (5-FU) given in weeks 1 and 5 of radiotherapy (50 Gy), and a further two cycles of chemotherapy after completion of radiotherapy [68]. Median survival was 8.9 months in the radiotherapy arm and 12.5 months in the combined therapy arm (P <0.001). The Eastern Cooperative Oncology Group (ECOG) trial enrolled 135 patients with localised squamous carcinoma [9, 10]. Randomisation was between radiotherapy alone or radiotherapy plus chemotherapy with mitomycin C and a 4-day continuous infusion of 5-FU during the first week of radiotherapy. Patients were assessed for operability after a dose of 40 Gy had been administered. For those patients not proceeding to surgery, a further 20 Gy radiotherapy was delivered, and for the patients in the chemoradiation arm this was accompanied by a second 4-day infusion of 5-FU. Survival was significantly improved in the chemoradiation group (14.8 months versus 9.4 months; P = 0.04) The utility of chemoradiation for this disease has been further suggested by two randomised trials comparing preoperative chemoradiation with surgery alone [11, 12]. However, other trials testing this hypothesis have been negative, perhaps because of suboptimal chemotherapy and radiotherapy regimens [1315]. The optimal chemoradiation regimen is not known.

We devised a regimen combining 3-weekly cisplatin and protracted venous infusion 5-FU on the basis of the established activity of these agents in adenocarcinoma and squamous cell carcinoma of the oesophagus. Infused delivery of 5-FU allows a high dose intensity, with an improved therapeutic ratio over 5-FU bolus [16]. Twelve weeks of chemotherapy were planned before chemoradiotherapy to allow tumour downstaging and eradication of micrometastatic disease outside the radiation field. It was anticipated that primary chemotherapy may provide early palliation of tumour-related symptoms, in particular dysphagia, that may be exacerbated by chemoradiation. Radiotherapy was delivered concurrently with the final dose of cisplatin and the 5-FU infusion was continued throughout the radiotherapy, as there is experimental evidence to suggest that 5-FU-based radiosensitisation is more effective when the exposure to 5-FU exceeds the cell-cycle duration [17]. Radiotherapy was conformally planned to minimise normal tissue toxicity in this chemoradiation schedule. The primary aim of this study was to establish the feasibility and efficacy of this regimen.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Protocol population
Patients were recruited at six UK institutions, all of which are referral centres for oesophageal cancer. Patients were eligible for this trial if they had a diagnosis of invasive adenocarcinoma or squamous cell carcinoma of the oesophagus; assessable disease as evaluated by CT scanning and/or endoscopy; unsuitable for immediate surgical resection due to either disease extent, co-morbid medical conditions or patient choice; disease encompassable within a radical radiotherapy field; no prior chemotherapy, radiotherapy or surgical therapy for this disease; no prior history of malignancy other than adequately treated non-melanotic skin cancer or in situ cervical carcinoma; no concurrent uncontrolled medical condition; ECOG performance status 0–2; glomerular filtration rate >=60 ml/min measured by EDTA clearance or 24-h creatinine clearance; life expectancy >3 months. Pregnant or lactating women were excluded. All patients were required to give written informed consent to participate before entering the study, which was approved by the individual institute’s Scientific and Research Ethics Committee, and by the United Kingdom Multicentre Research Ethics Committee (MREC/99/2/44).

Staging
Tumour staging was based on CT scan findings and classified according to the International Union Against Cancer TNM staging system [18]. T stage was defined according to previously published guidelines [19]. Endoscopic ultrasound was not routinely available at the participating institutions during the period of this study, and was not a requisite part of the staging evaluation.

Treatment
Chemotherapy was administered through a central venous catheter sited in the subclavian vein. Warfarin (1 mg/day, orally) was administered at the investigator’s discretion to prevent catheter-related thrombosis. There have been several case reports of potentiation of the anticoagulant effect of warfarin in patients treated with 5-FU [20, 21]. However, our experience is that low-dose warfarin can be given safely to patients receiving infused 5-FU, provided there are no other contraindications to its use [22]. Prolongation of the prothrombin time is exceptional in these circumstances, but in the light of these reports we now recommend a single evaluation of the prothrombin time 10–15 days after commencing the combination of these drugs. The treatment schedule is shown in Figure 1. 5-FU was given as a protracted venous infusion at a dose of 300 mg/m2/day using a portable pump for 12 weeks, and continued at a reduced dose of 200 mg/m2/day for a further 6 weeks during radiotherapy. Cisplatin was administered at a dose of 60 mg/m2/day as an intravenous infusion with standard hydration [23], once every 3 weeks for five cycles. Consideration of surgical resection was allowed for patients achieving a good response to chemotherapy at week 11 or upon completion of chemoradiation. Radiotherapy was commenced at the beginning of week 13, to coincide with the fifth dose of cisplatin. Patients were CT scanned in a supine position with images taken at 10–20 mm intervals throughout the entire thorax, including the whole lung volume, to allow for dose volume histogram calculation. The clinical target volume (CTV), spinal cord and lung parenchyma were outlined on each image. The CTV included the oesophageal tumour, with a 3–5 cm inferior and superior margin, to allow for microscopic tumour extension and the adjacent lymph nodes. A three-dimensional margin of 15–20 mm was added to the CTV to account for movement and uncertainty in target definition, creating the planned target volume (PTV). Three-dimensional conformal plans were created using a two-phase technique, employing the same target volume for each phase. The first phase consisted of parallel-opposed, anterior–posterior and posterior–anterior fields. The second phase comprised an anterior and two posterior oblique fields at gantry angles of approximately 110° and 250°. Beam angles were manually adjusted to avoid the spinal cord and the beam weights were selected in order to maximise PTV dose homogeneity. Wedges were used on the posterior oblique fields when indicated. All fields were conformally shaped using the beam’s eye view of the PTV. A margin of 6 mm was allowed between the PTV and the field edge to allow for the beam penumbra. Conformal shaping was achieved with either conformal blocks or multi-leaf collimation. The dose given in the two phases was adjusted so that the total dose was 54 Gy in 1.8 Gy daily fractions.



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Figure 1. Planned treatment schedule. RT, radiotherapy; 5-FU, 5-fluorouracil.

 
Toxicity assessment and dose modification
Chemotherapy toxicity was graded according to the National Cancer Institute of Canada Clinical Trials Group Expanded Common Toxicity Criteria [24]. Dose modifications to 5-FU and cisplatin were made according to previously published guidelines [25]. Acute radiotherapy toxicity was graded using the RTOG Acute Radiation Morbidity Criteria, and was assessed weekly during treatment and at 2, 4 and 6 weeks after completion of radiotherapy. No adjustments to radiotherapy dose as a result of toxicity were planned.

Response assessment
Assessment of response was performed at 11 weeks and 30 weeks by CT scanning and when appropriate also by endoscopy. Biopsy was encouraged but not required. Response in bi-dimensionally measurable lesions was defined according to WHO criteria [26]. Responding mediastinal lymph nodes measuring less than 1 cm in maximum diameter were considered to represent a complete response at that site. Measurement of response for primary oesophageal lesions was based on the maximum oesophageal wall thickness. A partial response was defined as a reduction of >=50%, progressive disease as an increase of >=25%, and stable disease as an increase of <25% and a reduction in this uni-dimensional measurement of <50%. For patients in whom the primary oesophageal tumour was the only site of disease, normalisation of endoscopic appearances were considered to represent a partial response in the presence of residual thickening on CT scan. A complete response in the primary tumour was defined as a normal appearance on CT scan with a maximum oesophageal wall thickness of 3 mm at all sites, together with a normal endoscopy. CT scans were reviewed by a single radiologist (A.R.P.) to verify responses. CT scans from eight patients were unavailable at the time of review, and response data were based on the original radiologist’s report in these cases. For lesions visible only on endoscopy, a response was defined as resolution of all mucosal abnormality. A pathologically complete response was defined as the resolution of malignant appearances on biopsy specimens taken from the site of the original abnormality, or in the surgical specimen in cases where oesophagectomy was performed. The degree of dysphagia was recorded using the modified O’Rourke grading system (Table 1) [27]. A response in the degree of dysphagia was defined as an improvement by at least 1 point in this grading system.


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Table 1. The modified O’Rourke swallowing-status staging system
 
Patterns of failure
Patterns of failure were defined as the first site of failure. Local failure included the primary tumour and local/regional lymph nodes. Distant failure included any other site of disease recurrence. Follow-up CT scanning was not mandated by the trial protocol beyond 30 weeks, and investigation of disease relapse was at the discretion of the individual clinician.

Statistical analysis
The primary end point of interest was response rate. Secondary end points were overall survival, progression-free survival, patterns of failure, toxicity and symptom response. Kaplan–Meier estimates were used to calculate overall and progression-free survival and differences between variables were examined using the log-rank test.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between April 1995 and January 2000, 72 patients from six institutions in the UK were enrolled in the study. Their characteristics are summarised in Table 2. Of note, the majority of patients enrolled had poor-prognosis disease. Forty-one patients had technically operable disease (i.e. not T4 or M1–1B). However, of this group nine patients were medically unfit for surgery, and of the remaining 32 patients, only eight had tumours <5 cm in length. Of the 12 patients with apparently good prognosis disease on staging criteria (T1–2N0M0), six were medically unfit for surgery, and two of the remaining six patients had tumours measuring between 5 and 10 cm in length. Furthermore this is an elderly population, with a median age of 65 years and 24 patients aged 70 years or over.


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Table 2. Baseline patient characteristics
 
Treatment delivered
Of the 72 patients enrolled in the study, 70 were eligible and two (3%) were ineligible. Reasons for ineligibility were no oesophageal primary (one) and hepatic metastatic disease (one). At least four courses of induction chemotherapy were completed by 80% of eligible patients. One patient failed to commence chemotherapy due to complications during Hickman line insertion. Sixteen patients commenced chemotherapy but did not receive radical chemoradiotherapy due to disease progression (three), deteriorating performance status (five), toxicity (one), early death (two), and unsuitability for radical radiotherapy due to disease extent (four) or poor respiratory function (one). Three patients proceeded to radiotherapy alone after two, three and four cycles of chemotherapy, respectively, and received a dose (60 Gy) modified to reflect the absence of concomitant chemotherapy. This was the result of patient choice, toxicity and progressive dysphagia, respectively, in the three cases. One patient proceeded to radical chemoradiation after only one cycle of chemotherapy due to symptoms related to bone invasion by tumour that did not respond to chemotherapy alone and one patient proceeded to radical chemoradiation after three cycles of chemotherapy because of poor tolerance of the chemotherapy regimen. Nine patients (13%) proceeded to surgery after their initial period of chemotherapy. Thirty-nine patients (54%) received per-protocol treatment comprising chemotherapy followed by radical chemoradiotherapy, of whom five underwent surgery after completion of this therapy.

Response
Response assessment by CT scan and endoscopy following the chemotherapy component of treatment alone is shown in Table 3. The response rate to initial chemotherapy was 43% [95% confidence interval (CI) 31% to 55%]. Four patients had a complete response and a further three had normal endoscopic biopsies with responding nodal disease. One patient had a complete response at the primary site, with normal endoscopic biopsies, but developed nodal enlargement in the subcarinal and precarinal areas. These nodes subsequently resolved following radiotherapy, raising the possibility that the enlargement was reactive rather than malignant. However, this patient was classified as having progressive disease at this response assessment. Response assessment on completion of the entire treatment programme is shown in Table 3. The overall response rate was 50% (95% CI 38% to 62%). Ten patients achieved a complete remission including three who had a pathologically complete response in the surgical specimen after oesophagectomy and one patient who had residual squamous cell carcinoma in only one lymph node in the pathological specimen. A further six patients had normal endoscopic biopsies at the end of treatment with residual thickening of the oesophageal wall on CT scan, four of whom had no other sites of disease. By univariate analysis, the only factor found to be predictive of overall response was tumour histology. The response rate for patients with squamous cell carcinoma was 61% (95% CI 45% to 76%), while for those with adenocarcinoma it was 33% (95% CI 17% to 54%) (P = 0.026). At the end of induction chemotherapy, we observed a non-significant trend for improved response rate in patients with squamous cell carcinoma compared with those with adenocarcinoma (51% versus 30%; P = 0.078). Factors found not to predict for response were sex, age, performance status, tumour site, tumour stage and tumour length. However, patient numbers were small in many of these categories. Of sixty-one patients for whom data were available, 54 reported dysphagia on trial entry. Median baseline score according to the modified O’Rourke grading system was 3 (range 1–5), whereas after chemotherapy treatment the median dysphagia score was 2 (range 1–5). Thirty-three patients (54%) had an improvement in their dysphagia by at least 1 grade while eight patients (13%) suffered worsening dysphagia during chemotherapy. Two of these eight had objective tumour responses suggesting that treatment-related oesophageal fibrosis may have caused their worsening dysphagia. Of those patients experiencing improvements in dysphagia, this had occurred after the first cycle of chemotherapy in 60% and by the end of the second cycle of chemotherapy in 75% of cases.


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Table 3. Response rates to chemotherapy and complete treatment programme
 
Surgery
Nine patients had an attempted surgical resection following their initial period of chemotherapy. In eight cases this was planned electively, and in the final case it was performed as an emergency procedure following oesophageal perforation at assessment endoscopy. This patient died in the postoperative period as a result of sepsis. There were no other postoperative deaths. Six of these nine patients had a complete surgical resection with clear resection margins; two patients had a macroscopic clearance of tumour but were found to have involved resection margins on histological assessment. The histology is unavailable in the final case. There were no pathologically complete responses in this group. Five patients underwent elective surgical oesophagectomy after completing the full chemoradiation programme. Of these, four patients had a complete surgical resection with clear resection margins. Three of these patients had a pathologically complete remission and the fourth had residual microscopic disease in one of the 24 resected lymph nodes only, with a normal oesophagus. The fifth patient had a macroscopically incomplete resection due to tumour adherent to the aorta. There were no postoperatives deaths in this group.

Survival and patterns of failure
The median duration of follow-up is 14.2 months and 40 of the 72 patients have died. The median survival duration is 14.6 months and 1- and 2-year survival rates are 58.7% and 44.1%, respectively (Figure 2). There were no statistically significant predictive factors for survival on univariate analysis. Furthermore there was no statistically significant survival difference between patients treated radically with chemoradiation (median survival 35.8 months) and those treated with surgery after chemotherapy or chemoradiation (median survival 43.4 months; P = 0.67). Twenty-three patients remain alive with no documented evidence of disease progression. Disease relapse has been documented in 23 patients. In two cases this was an isolated local recurrence; in 10 cases relapse was at a distant site without evidence of local recurrence; in 11 cases relapse was detected both locally and at a distant site. The most frequent sites of disease progression were lung (10 patients), local lymph nodes (nine patients), non-local lymph nodes (five patients), oesophagus (four patients), liver (four patients) and bone (four patients). A further 21 patients have died with clinically suspected progressive disease without documentation of the site(s) of relapse, and one patient developed a second malignancy. The median progression-free survival is 9.8 months and 1- and 2-year progression-free survival rates are 41.8% and 33.8%, respectively (Figure 2).



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Figure 2. Overall and progression-free survival for all patients.

 
Toxicity
Toxicity data are available for 69 patients with respect to non-haematological toxicity and for 57 patients with respect to haematological toxicity of the chemotherapy component of treatment. Overall, worst grade toxicity per patient was grade I in 8%, grade II in 55%, grade III in 33% and grade IV in 5%. The most frequently encountered toxic effects were mucositis (11% grade III/IV), lethargy (7% grade III/IV), diarrhoea (6% grade III/IV) and neutropenia (5% grade III/IV) (Table 4). Delays in chemotherapy delivery due to toxicity were required in 37 patients, with an average total length of delay per patient of 11.7 days (range 0–148 days). Reductions in the dose of cisplatin and 5-FU were required in 42 and 49 patients, respectively. An average of 76% of the intended dose of cisplatin and 74% of the intended dose of 5-FU were delivered. Chemoradiation-associated toxicity was also relatively infrequent. Oesophagitis of any grade occurred in 72% of patients while severe oesophagitis occurred in 17%. Other toxic effects of treatment are shown in Table 5. Non-haematological toxicity data are available for all 42 patients who underwent any chemoradiation treatment and haematological toxicity data are available for 30 patients. Of the patients planned to receive radical chemoradiation, the average radiotherapy dose was 52.8 Gy (range 30–60 Gy).


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Table 4. Toxicity of the chemotherapy component of treatment. Rates of toxicity are calculated as highest grade per patient occurring at any time during single modality chemotherapy treatment
 

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Table 5. Toxicity of chemoradiation. Rates of toxicity are calculated as highest grade per patient occurring at any time during combined modality chemoradiotherapy treatment
 
Five patients died before the first assessment point. One patient died while receiving chemotherapy due to aspiration pneumonia. Two patients were taken off chemotherapy due to declining performance status and died within the next 2 months. One patient developed a pneumothorax during insertion of the Hickman line and elected not to proceed with chemotherapy or radiotherapy treatment and died 3 weeks later. Finally, one patient died postoperatively after an emergency oesophagectomy.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We have demonstrated the feasibility of this regimen of induction chemotherapy followed by radical chemoradiation for patients with localised adenocarcinoma and squamous cell carcinoma of the oesophagus. The planned induction treatment was delivered to 80% of the eligible patients enrolled in the trial and radical local treatment was achieved in 69% according to protocol. Reasons for protocol violation included early disease progression, early death or poor tolerance of chemotherapy in 20% of patients. Of these, two patients had upper thoracic tumours measuring 8 and 11 cm, respectively, with involvement of supraclavicular fossa lymph nodes (M1A), and two patients had tumours that were in excess of 10 cm in length. On review these patients are unlikely to have been candidates for radical chemoradiotherapy. A further five patients who completed chemotherapy with stable disease were found to be unsuitable for radical chemoradiotherapy due to disease extent following review of the staging CT scans or because of impaired pulmonary function. Thus if we consider only the patients in whom radical chemoradiotherapy could have been contemplated, 79% were able to complete the protocol.

It is possible that the relatively long period of induction chemotherapy may have reduced the number of patients able to achieve a radical treatment approach, due to either early disease progression or toxicity. However, all four patients with early disease progression developed metastatic disease outside the potential radiotherapy field, indicating failure of the systemic component of treatment. Toxicity, poor tolerance of chemotherapy or death resulted in early discontinuation of treatment in 10 cases. A similar trial reported by the RTOG/ECOG Intergroup found a 31% rate of non-completion of induction chemotherapy overall, with toxicity or early death accounting for treatment discontinuation in 16% (7 of 45) of the patients enrolled [28]. This trial led the RTOG/ECOG Intergroup to abandon the induction chemotherapy approach in favour of immediate chemoradiation as used in the RTOG study [6]. Important differences in the chemotherapy regimens used in our trial and the Intergroup trial may account for the better tolerance we observed. In particular, we used a schedule of cisplatin in which a lower dose was given at more frequent intervals together with a protracted venous infusion of low-dose 5-FU. We have previously demonstrated the tolerability of this chemotherapy regimen for patients with advanced upper gastrointestinal tract cancers [25]. A similar regimen was found to be well-tolerated and to produce a median survival of 23 months among 14 patients with unresectable localised squamous carcinoma of the oesophagus [29].

Is there evidence of additional benefit to patients as a result of the induction phase of chemotherapy? The majority of responses to treatment were apparent at the 11-week assessment point, indicating that a response to chemotherapy is a good predictor of overall response. Improvements in dysphagia score were also observed early in the course of treatment, often within one cycle of chemotherapy, suggesting that palliative benefits are not postponed by this approach. The median survival of patients in our study was longer than that reported for the patients treated with chemoradiation in the RTOG study, and similar to that reported for patients treated with 5-FU- and mitomycin C-based chemoradiation in the ECOG study. It should be noted that the latter study only enrolled patients with stage T1–3N0–1M0–1A squamous cell carcinoma, and surgery was performed in 37% of patients, indicating a more favourable prognosis than expected for the group of patients enrolled in our trial. However, systemic relapse remained a common site of failure in our study, indicating the need for more active regimens to control micrometastatic disease.

Simple prolongation of the chemotherapy exposure appears insufficient to greatly improve the long-term outcome of patients with this disease. Newer drug regimens including the taxanes and irinotecan have been evaluated as a component of multi-modality treatment for carcinoma of the oesophagus. However, despite encouraging response rates, survival does not appear to be convincingly prolonged over conventional regimens, and toxicity is increased when these drugs are added to cisplatin and 5-FU [30, 31]. At present, the optimal management of localised oesophageal cancer remains controversial. The large Medical Research Council (MRC) trial of preoperative cisplatin and 5-FU, showing a 10% improvement in survival compared with surgery alone, suggests a clear role for neoadjuvant chemotherapy in those patients planned for oesophagectomy [4]. The 2-year survival rate of 44% seen in a relatively poor prognosis group of patients in our trial is identical to that seen in the chemotherapy plus surgery arm of the MRC trial. This regimen of induction chemotherapy followed by radical chemoradiotherapy may allow a group of patients with this disease to avoid oesophagectomy, but further improvements in systemic treatment are required.


    Acknowledgements
 
We would like to express our thanks to Dr Adrian Crellin, Cookridge Hospital, Leeds and to Dr Francis Daniel, Plymouth Oncology Centre, Derriford Hospital, Plymouth for their valuable contribution to this study.


    Footnotes
 
+ Correspondence to: Dr D. Cunningham, Head of GI and Lymphoma Units, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey, 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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