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 Georges Hospital, London, UK
Received 17 November 2001; revised 17 April 2002; accepted 13 May 2002
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Abstract |
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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
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Introduction |
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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.
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Patients and methods |
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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 investigators 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 1015 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 1020 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 35 cm inferior and superior margin, to allow for microscopic tumour extension and the adjacent lymph nodes. A three-dimensional margin of 1520 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, anteriorposterior and posterioranterior 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 beams 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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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 radiologists 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 ORourke 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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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. KaplanMeier estimates were used to calculate overall and progression-free survival and differences between variables were examined using the log-rank test.
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Results |
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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 ORourke grading system was 3 (range 15), whereas after chemotherapy treatment the median dysphagia score was 2 (range 15). 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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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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Discussion |
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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 T13N01M01A 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.
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Acknowledgements |
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Footnotes |
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