Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

Oesophageal squamous cell carcinoma (OSCC) accounts for most cases of oesophageal cancer worldwide [1, 2]. Even after complete surgical dissection, the prognosis of patients with OSCC is poor, with 5-year survival rates of 20 to 30%. Factors that contribute to this dismal prognosis include presence of locally advanced disease and undetected metastatic cancer at diagnosis. Because of the high rates of locoregional and distant failure, there is much interest in the combination of systemic chemotherapy and local surgical treatment.

The potential benefits of preoperative chemotherapy include increasing the likelihood of curative resection by downstaging the tumour and rapidly improving tumour-related symptoms. It is also been thought that systemic chemotherapy could contribute to the eradication of micro-metastases and circulating tumour cells. More recently, the importance of systemic disease control has been emphasized by new insights in the metastasizing process of cancer [3]. For decades, the dissemination of cancer has been considered the final stage in a deteriorating process. Now, there is accumulating evidence that dissemination already can occur at an early stage of the disease [4]. In theory, the use of preoperative chemotherapy may therefore have a positive impact on survival of patients with oesophageal cancer. Here, we report the design and long-term results of a randomized controlled trial in patients with resectable OSCC, comparing preoperative chemotherapy with cisplatin and etoposide followed by surgery to surgery alone.

Central randomisation took place at the Erasmus University Medical Center in Rotterdam (by trial coordinator TCK). Random assignment was stratified by age (<50; 51-60; >60), gender (male; female), weight loss (kg) in the past four months (0-5; 6-10; >10) and length of the tumour (cm) as measured by oesophago-gastroscopy (1-3; 4-6; 7-10; >10). Patients assigned to preoperative chemotherapy were treated with two cycles, followed by a clinical response evaluation. Response evaluation was done three to four weeks after the last cycle of chemotherapy. Clinical response after chemotherapy was evaluated by oesophago-gastroscopy and CT of the chest and abdomen. Tumour responses were assessed according to the World Health Organisation (WHO) criteria [5]. Complete absence of any evidence of malignant disease, including negative biopsies from the former tumour area, was defined as complete response (CR). Partial response (PR) was defined as >50% reduction of tumour bulk, without the appearance of new lesions. Stable disease (SD) was defined as <50% reduction of tumour bulk, without the appearance of new lesions. Progressive disease (PD) was defined as >25% progression of tumour bulk or the appearance of new lesions. Patients with complete or partial responses received two additional courses of chemotherapy, whereas non-responding patients (stable disease or progressive disease) were referred for immediate surgery. Patients with progressive disease (T4 or M1 disease) were treated palliative and observed for survival. Patients, who were randomly assigned to undergo surgery alone, underwent the operation as soon as possible. Patients who received chemotherapy were operated 4 to 6 weeks after the last treatment cycle. The study protocol was approved by the ethics committee of all participating institutions and written informed consent was obtained from all patients.

Between January, 1989, and January, 1996, 169 patients from six Dutch University Hospitals (Rotterdam, Amsterdam, Utrecht, Groningen, Nijmegen and Maastricht) were randomly assigned to either chemotherapy followed by surgery (CS group, N = 85) or surgery alone (S group, N = 84; Figure 1). An additional number of nine patients were included to adjust for study drop-outs. The majority of patients (N = 122) were included by the Erasmus Medical Center (EMC), Rotterdam. From all participating centers, the EMC is the only hospital that collected outcome data (prospectively) for all patients with oesophageal cancer referred in time this study was performed. Between January, 1989, and January, 1996, 257 patients with OSCC were referred to the EMC. Of these, 183 patients were deemed eligible for surgical resection, of which 122 (67%) were included in this trial. The reasons why 61 (33%) patients were not randomized for this trial are not well documented.

Table 1 shows that the two groups were similar in terms of age, sex, and performance status. Distribution according to weight loss and size of the tumour was also balanced. One patient, allocated to preoperative chemotherapy, had a tumour located in the cervical part of the oesophagus (the reason why this patient was included and randomized remains unclear, even after retrospective analysis of the patient's record). Preoperative staging by CT of the chest and the upper abdomen was performed in 149 patients (88%); two patients (1%) died before the planned CT scan; six patients (4%) were staged by endoscopic ultrasound, external ultrasonography of the cervical and upper abdominal region and chest radiography. From twelve patients (7%) no additional information on preoperative staging was available.

The long-term results of this randomized controlled trial demonstrated a survival benefit for preoperative chemotherapy followed by surgery in patients with OSCC, when compared with surgery alone. This study has only been reported in abstract form, which hampers interpretation of our findings in context of other randomized trials [9]. Why it took so long to report the design and results of this study is not completely understood. The main reasons are change of personnel (the trial coordinator [TCK] moved to another hospital) and loss of interest in the used chemotherapeutic regime. Nevertheless, we believe that these results contribute to the ongoing debate about the optimal (preoperative) therapy for patients with OSCC.

The results of this study should be interpreted in the timeframe in which this study was performed. This study is one of the three largest randomized controlled trials among patients with OSCC treated with preoperative chemotherapy followed by surgery or surgery alone [10, 11]. All these large randomized controlled trials were performed in the early '90s. The Medical Research Council (MRC) trial included most patients with oesophageal cancer (533 oesophageal adenocarcinoma (OAC) and 247 OSCC patients) and demonstrated a significant survival benefit for the use of preoperative chemotherapy (P = .004) [11, 12]. An other large and well-conducted randomized controlled trial among patients with oesophageal cancer (236 OAC and 204 OSCC patients), by the North American Intergroup (RTOG Trial 8911 or USA Intergroup 113 trial; further called the Intergroup trial), demonstrated no significant difference in survival between patients treated with preoperative chemotherapy and those who received surgery alone [10, 13]. In the light of the results of both trials, we discuss the design and results of the present study.

As most randomized controlled trials performed in the early '90, this study reflects the methods for diagnosis, staging, treatment delivery and outcome measurement that indicate clinical practice during that period. In the present study, the majority of patients (88%) underwent preoperative staging by oesophago-gastroscopy and CT scan of the chest and upper abdomen. The same preoperative staging methods were used in the Intergroup trial. In the MRC trial, however, there was no standardization of preoperative staging. These differences in preoperative staging could, by selection of different populations of OSCC patients, contribute to differences in results between the trials.

In the Intergroup trial as well as in the MRC trial the chemotherapeutic regime consists of cisplatin combined with fluorouracil; in the present study cisplatin was combined with etoposide. The ratio for this combination of chemotherapeutic agents was deducted from trials among patients with non-small-cell lung cancer in which this regime had showed to be safe and effective [14]. Furthermore, a phase II trial in patients with advanced OSCC had shown that the response rate equals that of other cisplatin-based regimes and that the toxicity profile was mild [8]. Patients without clinical response to chemotherapy received a total preoperative dose of 160 mg/m² cisplatin and 1000 mg/m² etoposide. The dose of cisplatin is similar as compared with the MRC trial (160 mg/m²). Patients with clinical response to chemotherapy received total doses up to cisplatin 320 mg/m² and etoposide 2000 mg/m². In this subgroup of patients, the total preoperative dose of cisplatin was slightly higher as compared to the Intergroup trial (300 mg/m²). The compliance to chemotherapy was 88% (patients who received two or more of the planned cycles of chemotherapy). This is similar to 90% of the patients that received both treatment cycles in the MRC trial, but differed from the Intergroup wherein 71% of the patients received all of three planned cycles of chemotherapy. It has been suggested that the higher dose of chemotherapy in the Intergroup trial was detrimental to patients who underwent oesophagectomy. Other factors related to the chemotherapeutic regimes that could contribute to the differences in outcome between the three studies, are the use of chemoradiotherapy in a subset of patients in the MRC trial and the use of postoperative chemotherapy in a subgroup of patients in the Intergroup trial.

In our study the majority of patients underwent a transhiatal oesophagectomy. This type of resection is associated with lower morbidity (and mortality) than a transthoracic resection ([15]). In the other trials, the type of surgical resection that has been performed is not clear (MRC trial) or the exact numbers are not described (Intergroup trial). The postoperative mortality rate (<30 days after surgery) in the current trial was 5% (4/76) in the CS group and 4% (3/82) in the S group and differed not among both groups. These rates are similar as those observed in the Intergroup trial, with 6% postoperative mortality in both treatment arms. In contrast, the MRC trial reported much higher postoperative mortality rate of 10% in the CS group and 11% in the S group.

In the present study surgery was performed in 89% and 98% of patients in the CS group and S group, respectively. Similar rates have been reported by the MRC trial, with surgery rates in the CS group of 92% and in the S group of 97%. In the Intergroup trial fewer patients underwent surgery, 80% of the CS group and 92% of the S group. The rate of microscopically tumour free resection margins (R0) in the CS group was 71%, as compared to 60% and 62% in the CS groups of the MRC and Intergroup trial, respectively. In the S group it was 57%, as compared to 54% and 59% in the S groups of the MRC and Intergroup trial, respectively. The difference in R0 resection rates between the CS group and the S group is likely to contribute to the observed survival benefit for patients treated with preoperative chemotherapy (as showed by the MRC trial; P < 0.001), however, this difference was not statistical significant in the present study (P = 0.086).

The median survival time of the CS group was 16 months, compared to 17 and 15 months in the MRC and Intergroup trial, respectively. The median survival time of the S group was 12 months, compared to 16 and 13 months in the Intergroup and MRC trial, respectively. It appears that the S group in our study had the worst survival outcome, but this may be due to patient selection. Both the MRC as Intergroup trial included more OAC than OSCC patients. Subgroup analysis of the MRC trial, including only OSCC patients, showed a median survival time of 11 months for patients who underwent surgery alone [12]. Remarkably, in the subgroup analysis there is no significant survival benefit for OSCC patients treated with preoperative chemotherapy (P = 0.1).

In line with the results of the MRC and Intergroup trial, there was no significant difference in pattern of failure between both treatment arms in our study. The rate of distant metastases was equal in both treatment groups. These findings provide no evidence for the general hypothesis that preoperative chemotherapy eliminates systemic micro-metastases. The results of this trial and the MRC trial suggest that the biologic effect of preoperative chemotherapy seems to specifically influence the extent of surgery [12]. In the present study, the incidence of incomplete resections was greater in the S group, but sites of first recurrence (local or distant) were similar. Furthermore, at 6 months, the DFS advantage is established for the CS group (Figure 2A) and remains consistent throughout follow-up as the survival curves remain approximately parallel. This suggests that the effect of preoperative chemotherapy is to reduce tumour volume and increase the potential for curative resection.

This study has its limitations. At first, the preoperative staging was hampered by the absence of endoscopic ultrasonography at the beginning of our trial. Therefore, the clinical T- and N-stage were not used as stratification parameters before randomization. Secondly, the missing data on two patients that underwent preoperative chemotherapy and the lack of some clinical characteristics of the patients reflect the difficulty of obtaining all data more than twenty years after the trial was performed. At third, it should be noticed that we selected patients who showed clinical response to chemotherapy based on oesophago-gastroscopy and CT scan of the chest and upper abdomen, for additional cycles of chemotherapy. However, we did not correlate clinical response to pathological response. Therefore, selection of this subgroup could also reflect better prognostic characteristics of patients who respond to chemotherapy, rather than an effect of chemotherapy itself.

In summary, this study reports a significant survival benefit for OSCC patients treated with preoperative chemotherapy. The chemotherapeutic regime used in this trial (etoposide and cisplatin) is not used anymore in treatment of patients with OSCC. Today, in our institution (EMC) the majority of patients with OSCC (and OAC) receive preoperative chemoradiotherapy (a combination of carboplatin and paclitaxel, and concurrent radiotherapy).